A Prospective,Single Site, Single-Arm Pilot Study of CPX-351 (VYXEOS) in Individuals < 22 Years With Secondary Myeloid Neoplasms
Phase: PHASE2
Conditions: Myeloid Neoplasm
Sponsor: St. Jude Children's Research Hospital

 
 
Official Study Title: Study of CPX-351 (VYXEOS) in Individuals < 22 Years With Secondary 
Myeloid Neoplasms 
CTG Number: NCT05656248 
Document Date: 06/03/2025 

C P X S M N
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
Pr ot oc ol S u m m ar y
C P X S M N, A P R O S P E C TI V E, SI N G L E SI T E, SI N G L E- A R M PI L O T S T U D Y O F C P X- 3 5 1 
( V Y X E O S) I N I N DI VI D U A L S < 2 2 Y E A R S WI T H S E C O N D A R Y M Y E L OI D N E O P L A S M S 
Pri nci p al I n vesti g at or: Ra ul C. Ri beir o, M D
I nstit uti o n/ S p o ns or-I N D h ol der: St. J u de C hil dre n’s Researc h H os pital. I N D # 1 6 4 3 8 3
Brief o ve r vie w: Sec o n dar y m yel oi d ne o plas ms ( S M N) e nc o m pass t hera p y-relate d A M L a n d M D S, a n d 
t h ose wit h a ntece de nt he mat ol o gical dis or ders. T hese mali g na ncies ha ve a l o w i nci de nce i n t he first t w o 
deca de s of life, ha ve a p o or pr o g n osis a n d lac k u nifie d treat me nt a p pr oac hes. T here are n o s pecific 
treatme nt g ui deli nes f or t his s u b gr o u p of m yel oi d ne o plas ms i n c hil dre n, e xce pt t hat m ost patie nts are 
ca n di dates f or he mat o p oietic ste m cell tra ns pla ntati o n ( H S C T). C P X- 3 5 1 was F D A a p pr o ve d i n t he U S 
f or t hera p y-relate d A M L a n d A M L wit h m yel o d ys plasia relate d c ha n ges s y n dr o me i n a d ults i n 2 0 1 7, a n d 
t he a p pr o val e xte n de d t o patie nts ol der t ha n 1 year of a ge i n 2 0 2 1. T he F D A a p pr o val f or y o u n ger a ge 
gr o u p was base d o n t he use of C P X- 3 5 1 i n a P hase II st u d y i n c hil dre n wit h rela pse d A M L, a n d 
p har mac o ki netic data s h o wi n g si milar distri b uti o n para meters i n c hil dre n a n d a d ults. S pecific cli nical 
efficac y a n d t o xicit y of C P X- 3 5 1 data i n c hil dre n a n d a d olesce nts wit h S M N are n ot a vaila ble.  
I nter ve nti o n: I nter ve nti o nal, pri mar y t hera pe utic
Dr u g: C P X- 3 5 1 ( V y xe os)
Brief o utli ne of tre at me nt pl a n:  We pr o p ose t o use t he sa me d ose a n d sc he d ule a p pr o ve d f or a d ults 
wit h sec o n dar y A M L a n d rece ntl y e x pa n de d t o i ncl u de c hil dre n. T he C P X- 3 5 1 d ose f or t he first 
i n d ucti o n c ycle is 1 0 0 u nits/ m2 (c orres p o n ds t o 4 4 m g/ m2 da u n or u bici n a n d 1 0 0 m g/ m2 c ytara bi ne) o n 
Da ys 1, 3 a n d 5. A sec o n d i n d ucti o n c ycle at t he sa me C P X- 3 5 1 d ose is a d mi nistere d o n Da ys 1 a n d 3 f or 
patie nts wit h C R/ C Ri b ut p ositi ve resi d ual disease ( M R D ≥0. 1 %)  b y fl o w c yt o metr y. Patie nts attai ni n g 
c o m plete re missi o n a n d M R D < 0. 1 % c o ul d pr ocee d t o he mat o p oietic ste m cell tra ns pla ntati o n ( H S C T). 
If H S C T ca n n ot be perf or me d wit hi n f o ur wee ks fr o m t he e val uati o n date ( Da y 2 2 of t he first c ycle), 
patie nts will recei ve a sec o n d c o urse wit h l o wer d oses of da u n or u bici n ( 2 9 m g/ m 2) a n d c ytara bi ne ( 6 5 
m g/ m 2).
St u d y desi g n:  Pr os pecti ve, si n gle site, si n gle-ar m pil ot st u d y.
S a m ple size a n d d ur ati o n:  2 5 patie nts accr ue d o ver 2- 3 years.
D at a m a n a ge me nt:  Data ma na ge me nt a n d statistical a nal ysis will be pr o vi de d b y t he C o m pre he nsi ve 
Ca ncer Ce nter He mat ol o gical Mali g na ncies Pr o gra m a n d t he Bi ostatistics De part me nt at St. J u de 
C hil dre n’s Researc h H os pital.
H u m a n s u bjects:  T he mai n ris k t o researc h partici pa nts will be t he p ote ntial t o xicities ass ociate d wit h 
t he use of i n vesti gati o nal a ge nt, C P X- 3 5 1. T he researc h partici pa nts will be i nf or me d of t he t o xicities 
t hat ha ve bee n ass ociate d wit h t he st u d y dr u gs a n d p ote ntial si de effects of pr oce d ures rec o m me n de d i n 
t his st u d y. A d verse e ve nts will be m o nit ore d, treate d, a n d re p orte d f oll o wi n g i nstit uti o nal a n d fe deral 
g ui deli nes a n d re g ulati o ns.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
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Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
T A B L E O F C O N T E N T S
1. 0  
O BJ E C TI V E S...................................................................................................................... 1
1. 1 
Pri mar y O bjecti ve................................................................................................................ 1
1. 2 
Sec o n dar y O bjecti ves .......................................................................................................... 1
1. 3 
E x pl orat or y O bjecti ves........................................................................................................ 1
2. 0 
B A C K G R O U N D A N D R A TI O N A L E................................................................................ 1
2. 1 
Bac k gr o u n d.......................................................................................................................... 1
2. 2 
Rati o nale f or t his St u d y....................................................................................................... 3
2. 3 
Rati o nale f or C orrelati ve St u dies......................................................................................... 4
3. 0 
E LI GI BI LI T Y C RI T E RI A A N D S T U D Y E N R O L L M E N T.............................................. 5
3. 1 
I ncl usi o n Criteria................................................................................................................. 5
3. 2 
E xcl usi o n Criteria................................................................................................................ 8
3. 3 
Researc h Partici pa nt Recr uit me nt a n d Scree ni n g.............................................................. 1 0
3. 4 
E nr oll me nt o n St u d y at St. J u de ........................................................................................ 1 0
4. 0 
T R E A T M E N T P L A N........................................................................................................ 1 0
4. 1  
Desi g n a n d St u d y O ver vie w ( Fi g ure 1)............................................................................. 1 0
4. 2  
D osi n g a n d Sc he d ule ......................................................................................................... 1 2
4. 3 
S u p p orti ve Care................................................................................................................. 1 4
4. 4  
D ose M o dificati o ns f or T o xicities..................................................................................... 1 5
5. 0  
D R U G I N F O R M A TI O N................................................................................................... 1 7
5. 1 
C P X- 3 5 1............................................................................................................................ 1 7
6. 0 
E V A L U A TI O N S, T E S T S, O B S E R V A TI O N S................................................................. 2 0
6. 1 
Pre- Treat me nt Cli nical E val uati o ns................................................................................... 2 0
6. 2 
E val uati o ns Bef ore a n d D uri n g T hera p y........................................................................... 2 1
6. 3 
Researc h St u dies................................................................................................................ 2 2
6. 4 
E val uati o ns after C o m pleti o n of T hera p y.......................................................................... 2 2
7. 0 
E V A L U A TI O N C RI T E RI A.............................................................................................. 2 2
7. 1 
Res p o nse E val uati o n d uri n g t he First C o urse of C P X- 3 5 1............................................... 2 2
7. 2 
Res p o nse E val uati o n d uri n g t he Sec o n d C o urse of C P X- 3 5 1........................................... 2 3
7. 3 
T o xicit y E val uati o n Criteria.............................................................................................. 2 3
8. 0  
O F F- T R E A T M E N T A N D O F F- S T U D Y C RI T E RI A ...................................................... 2 3
8. 1  
Off- Treat me nt Criteria....................................................................................................... 2 3
8. 2  
Off- St u d y Criteria.............................................................................................................. 2 4
9. 0 
S A F E T Y A N D A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S.......................... 2 4
9. 1  
A d verse E ve nts ( A E)......................................................................................................... 2 4
9. 2  
Defi niti o ns ......................................................................................................................... 2 4
9. 3  
Ha n dli n g of A d verse E ve nts ( A Es) a n d Deat hs ................................................................ 2 5
9. 4 
Re p orti n g t o Dr u g Ma n ufact urer (Jazz P har mace uticals) ................................................. 2 6
1 0. 0  
D A T A C O L L E C TI O N, M O NI T O RI N G A N D C O N FI D E N TI A LI T Y............................ 2 6
1 0. 1  
Data C ollecti o n.................................................................................................................. 2 6
1 0. 2 
St u d y M o nit ori n g............................................................................................................... 2 7
1 0. 3 
C o nfi de ntialit y................................................................................................................... 2 7
1 1. 0 
S T A TI S TI C A L C O N SI D E R A TI O N S .............................................................................. 2 7
1 1. 1 
Si m o n’s T w o- Sta ge Desi g n f or Pri mar y E n d p oi nt ( C R/ C Ri) ........................................... 2 7
1 1. 2 
T hree- Sta ge Desi g n f or T olera bilit y M o nit ori n g............................................................... 2 8
1 1. 3 
Statistical A nal ysis Pla n f or Sec o n dar y O bjecti ves........................................................... 2 9
1 1. 4 
Statistical A nal ysis Pla n f or E x pl orat or y O bjecti ves......................................................... 2 9
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
1 2. 0  
O B T AI NI N G I N F O R M E D C O N S E N T............................................................................ 3 0
1 2. 1 
C o nse nt Pri or t o Researc h I nter ve nti o ns ........................................................................... 3 0
1 2. 2 
C o nse nt at A ge of Maj orit y ............................................................................................... 3 0
1 2. 3 
C o nse nt W he n E n glis h is N ot t he Pri mar y La n g ua ge....................................................... 3 0
1 3. 0 
R E F E R E N C E S.................................................................................................................. 3 1
A P P E N DI C E S
A p pe n di x I:
Perf or ma nce Stat us Criteria
A p pe n di x II:
Me dicati o ns, F o o d, a n d S u p ple me nts t hat Ma y I nteract wit h Da u n or u bici n a n d 
C ytara bi ne
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 1 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
1. 0  
O B J E C TI V E S
H y p ot hesis: C P X- 3 5 1 is acti ve a n d well-t olerate d i n i n di vi d uals < 2 2 years wit h sec o n dar y 
m yel oi d ne o plas ms ( S M N).
1. 1 
Pri m ar y O bjecti ve
1. 1. 1
Deter mi ne t he c o m p osite c o m plete re missi o n ( C R) a n d c o m plete re missi o n wit h 
i nc o m plete peri p heral bl o o d rec o ver y ( C Ri) rates, safet y, a n d t olera bilit y i n patie nts 
u n der 2 2 years of a ge wit h S M N treate d wit h o ne or t w o c o urses of C P X- 3 5 1 bef ore 
H S C T.
1. 2 
Sec o n d ar y O bjecti ves
1. 2. 1
Descri be t he t o xicit y pr ofile of patie nts wit h S M N treate d wit h o ne or t w o c o urses 
of C P X- 3 5 1.
1. 2. 2
Descri be t he bi ol o gic c orrelates of res p o nse i n patie nts wit h S M N after o ne or t w o 
c o urses of C P X- 3 5 1.
1. 2. 3
Esti mate t he 3- year o verall s ur vi val of patie nts w h o recei ve d o ne or t w o c o urses of 
C P X- 3 5 1 f oll o we d b y H S C T.
1. 3 
E x pl or at or y O bjecti ves
1. 3. 1
Descri be t he cli nical c orrelates of t he c ytara bi ne ( Ara- C) p har mac o ge n o mic 
res p o nse sc ore ( A C S), t he le u ke mia ste m cell sc ore ( p L C S 6) a n d dr u g resista nce 
sc ore ( A D E- R S 5) i n patie nts recei vi n g C P X- 3 5 1.
1. 3. 2
I n vesti gate h o w ge netic lesi o ns i n le u ke mic cells c ha n ge after C P X- 3 5 1treat me nt.
1. 3. 3
E x pl ore t he feasi bilit y of si n gle-cell D N A se q ue nci n g (sc D N Ase q) f or 
c haracterizati o n a n d trac ki n g of cl o nal re pert oires.
2. 0 
B A C K G R O U N D A N D R A TI O N A L E
2. 1 
B ac k gr o u n d
Sec o n dar y m yel oi d ne o plas ms i n c hil dre n a n d a d olesce nts are rare a n d ha ve a p o or 
pr o g n osis. 1 T his disti nct s u b gr o u p of m yel oi d ne o plas ms is heter o ge ne o us a n d i ncl u des 
patie nts pre vi o usl y treate d f or mali g na ncies or sec o n dar y t o a ntece de nt he mat ol o gic 
dis or ders, i ncl u di n g ac q uire d a n d i n herite d b o ne marr o w fail ure, a n d ger mli ne ca ncer 
pre dis p ositi o n s y n dr o mes. De pe n di n g o n t he blast c o u nt at t he dia g n osis, t he disease 
c o nti n u u m s pa ns fr o m sec o n dar y m yel o d ys plastic s y n dr o me (s M D S) ( < 2 0 % marr o w 
blasts) t o sec o n dar y ac ute m yel oi d le u ke mia (s A M L) ( ≥2 0 % marr o w blasts), h o we ver, 
al m ost all patie nts s h o w i ncrease blast c o u nts o ver ti me. 
Resista nt le u ke mia a n d treat me nt-relate d m ortalit y acc o u nt f or m ost of t he fail ures a m o n g 
c hil dre n a n d a d olesce nts wit h S M N. A S E E R p o p ulati o n- base d st u d y s h o we d t hat t he 5-
year s ur vi val of s A M L was ar o u n d 2 3 %. 2 A n a bstract prese nte d at t he A S H meeti n g i n 
2 0 1 9 b y t he A M L- B F M st u d y gr o u p re p orte d t hat t he o verall s ur vi val f or 1 4 5 patie nts wit h 
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 2 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
s A M L treate d bet wee n 1 9 9 3- 2 0 1 8 was 2 8 % ( me dia n a ge, 1 0. 6 years; ra n ge, 1. 4- 2 6. 6 
years). F or patie nts treate d bet wee n 2 0 1 2 a n d 2 0 1 8, t he s ur vi val was 4 5 %, alt h o u g h t he 
f oll o w- u p was s h ort.3 I n ge neral, t he patie nts w h o were e nr olle d bet wee n 1 9 9 3- 2 0 0 3 o n 
B F M A M L pr ot oc ols recei ve d t w o i nte nsi ve i n d ucti o n re missi o n c o urses f oll o we d b y t w o 
c o ns oli dati o n c o urses bef ore pr ocee di n g t o he mat o p oietic cell tra ns pla ntati o n ( H C T). T he 
rate of earl y deat hs was hi g h a m o n g t hese patie nts ( 1 4 %). After 2 0 1 4, patie nts recei ve d 
o nl y t w o c ycles of i nte nsi ve c he m ot hera p y bef ore tra ns pla ntati o n. T he 5 yrs ‐ o verall  
s ur vi val ( O S) rate i ncrease d fr o m 1 9 ± 5 % ( n = 7 0 1 9 9 3 ‐ 2 0 0 3)  t o 3 4 ± 7 % ( n = 4 1, 
2 0 0 4 ‐ 2 0 1 1)  a n d 4 5 ± 9 % ( n = 3 4, 2 0 1 2 ‐ 2 0 1 8;  p l o g ra n k < 0. 0 3) s u g gesti n g t hat pr of o u n d 
m yel os u p pressi o n mi g ht n ot be necessar y f or i m pr o ve d o utc o mes. T he p o or t olera nce t o 
c o n ve nti o nal i nte nsi ve A M L t hera p y is partiall y e x plai ne d b y pre vi o us e x p os ure t o 
c he m ot hera p y or pre vi o us b o ne marr o w da ma ge ass ociate d wit h i m m u n ol o gic, 
e n vir o n me ntal, or c o nstit uti o nal ge netic c haracteristics. 4- 1 0 Sec o n dar y M D S a p pears t o ha ve 
si milar o utc o me t o t he A M L c o u nter part. A re p ort fr o m t he E ur o pea n W or ki n g Gr o u p of 
M D S i n c hil d h o o d, s h o we d t hat t he o verall s ur vi val ( O S) at 5 years was 4 4 % f or 8 0 
patie nts wit h treat me nt-relate d M D S. I n t his st u d y c yt o ge netic c haracteristics were 
ass ociate d wit h o utc o me. Cases wit h str uct ural c o m ple x kar y ot y pes ha d O S < 1 0 %. 1 1 
Bi ol o gicall y, S M N har b or c o m ple x kar y ot y pic a n d m olec ular c ha n ges t y picall y ass ociate d 
wit h p o or pr o g n osis i n de n ov o  A M L.
T he F D A gra nte d a brea kt hr o u g h t hera p y desi g nati o n f or C P X- 3 5 1 i n 2 0 1 6 base d o n pre-
cli nical a n d P hase I a n d II st u dies. 1 2- 2 0 I n a P hase III ra n d o mize d trial, C P X- 3 5 1 was 
c o m pare d t o sta n dar d 7 pl us 3 c he m ot hera p y. C P X- 3 5 1 le d t o a si g nifica ntl y hi g her 
re missi o n rate ( 4 8 % vs. 3 3 %) a n d relati vel y l o w 6 0- da y m ortalit y ( 1 3. 7 %).2 1 At 1 2 m o nt hs, 
4 2 % of patie nts e nr olle d i n t he C P X- 3 5 1 ar m re mai ne d ali ve c o m pare d wit h 2 8 % i n t he 
c o ntr ol ar m. 2 1 A 5- year f oll o w- u p of t his st u d y has rece ntl y bee n re p orte d.2 2 Des pite t hese 
e xcelle nt res ults, C P X- 3 5 1 has n ot bee n i n vesti gate d i n c hil dre n a n d a d olesce nts wit h S M N. 
T he o n g oi n g C hil dre n's O nc ol o g y Gr o u p fr o ntli ne A M L trial ( A A M L 1 8 3 1) c o m pares C P X-
3 5 1 + M yl otar g t o sta n dar d c he m ot hera p y + M yl otar g i n i n d ucti o n re missi o n f or i n di vi d uals 
less t ha n 2 2 years wit h de n ov o  A M L.2 3 I n t his trial, patie nts wit h S M N or wit h a ger mli ne 
pre dis p ositi o n t o le u ke mia are n ot eli gi ble. T heref ore, c urre ntl y t here is n o a vaila ble 
pr ot oc ol f or patie nts wit h S M N i n t his a ge gr o u p i n t he U S. T here is a n u n met nee d t o 
i n vesti gate a u nif or m treat me nt f or pe diatric patie nts wit h S M N pri or t o H S C T.
Si nce 2 0 1 7, we ha ve treate d se ve n patie nts wit h C P X- 3 5 1 f or s A M L/ M D S. F o ur patie nts 
ha d a hist or y of c he m ot hera p y a n d ra di ot hera p y f or s oli d t u m ors, o ne c he m ot hera p y f or T-
cell ac ute l y m p h o blastic le u ke mia, a n d t w o ha d A M L wit h p o or ge netic feat ures t hat 
ra pi dl y pr o gresse d fr o m M D S. T he a ge at dia g n osis of t hese patie nts ra n ge d fr o m 1 3 t o 2 3 
years, me dia n 1 7 years. T he n u m ber of c o urses of C P X- 3 5 1 ra n ge d fr o m 1 t o 3. All se ve n 
patie nts ha d C R or C Ri. Si x of t he se ve n patie nts recei ve d all o graft i n c o m plete 
m or p h ol o gic re missi o n; s o me wit h mi ni mal resi d ual disease le vel < 1 %. O ne patie nt was 
n ot tra ns pla nte d beca use of l o gistic diffic ulties, a n d le u ke mia pr o gresse d bef ore H S C T 
c o ul d be arra n ge d. C P X- 3 5 1 was well t olerate d i n all se ve n patie nts, a n d e xce pt f or s ki n 
ras hes, n o se vere c o m plicati o ns attri b ute d t o C P X- 3 5 1 were n ote d. M ortalit y wit hi n t he 
first 6 0 da ys was zer o. Si x patie nts u n der we nt tra ns pla ntati o n. H S C T was well-t olerate d, 
le d t o f ull e n graft me nt, a n d n o ne of t he patie nts e x perie nce d se vere t o xicit y. All si x 
patie nts w h o u n der we nt H S C T are ali ve f or peri o ds ra n gi n g fr o m 1 t o 3 years after 
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 3 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
dia g n osis. Base d o n t his li mite d series, we s u g gest t hat C P X- 3 5 1 mi g ht be as effecti ve i n 
c hil dre n a n d a d olesce nts as i n a d ults wit h treat me nt-relate d A M L or M D S-relate d A M L. 
I deall y, H S C T s h o ul d be perf or me d as s o o n as p ossi ble after re missi o n is attai ne d. If H S C T 
will n ot be a vaila ble i n a ti mel y fas hi o n, t hera p y a da pte d t o t he le u ke mia ge n ot y pe c o ul d be 
c o nsi dere d t o bri d ge t o H S C T. 
2. 1. 1
A nt hrac ycli ne car di ot o xicit y
Alt h o u g h car di ot o xicit y is a c o ncer n wit h t he use of a nt hrac ycli ne dr u gs, a n d s o me patie nts 
ma y reac h a c u m ulati ve d o x or u bici n e q ui vale nt d ose of 5 3 0 m g/ m 2 i n o ur st u d y, a vaila ble 
data s h o we d t hat C P X- 3 5 1 is n ot partic ularl y car di ot o xic. I n t he P hase I/II C O G st u d y of 
C P X- 3 5 1 1 8, m yel os u p pressi o n was t he li miti n g t o xicit y. Car diac t o xicit y was n ot see n i n 
d oses u p t o 1 0 0 u/ m 2. O ne patie nt ha d tra nsie nt car di ot o xicit y at a hi g her d ose ( 1 3 5 u/ m2). 
Eli gi bilit y criteri o n was 4 5 0 m g/ m 2 ( da u n o m yci n/ d o x or u bici n e q ui vale nce) f or e ntr y i n t he 
C O G st u d y. M ore o ver, o ne t hir d of t he patie nts ha d rela pse d after he mat o p oietic ste m cell 
tra ns pla ntati o n. T he li p os o mal  C P X- 3 5 1 e nca ps ulati o n is li kel y t he mai n reas o n 
car di ot o xicit y is less c o m m o n. I nte nsificati o n of c he m ot hera p y wit h a n ot her li p os o mal 
e nca ps ulate d da u n or u bici n, Da u n o X o me ®  ( D N X), has pr o ve n effecti ve a n d t olera ble i n t he 
c o nte xt of pe diatric A M L st u dies c o n d ucte d b y t he I nter nati o nal Berli n- Fra n kf urt- M ü nster 
St u d y Gr o u p. I n t he rela pse setti n g, D N X pl us fl u dara bi ne a n d c ytara bi ne ( F L A G- D N X) 
de m o nstrate d e n ha nce d le u ke mic efficac y a n d si milar car di ot o xicit y c o m pare d t o F L A G 
al o ne ( n o a nt hrac ycli ne). 2 4 Alt h o u g h, data o n car di o pr otecti o n of C P X- 3 5 1 are still s parce, 
t he e nca ps ulati o n of t he c o m p o u n ds i n li pi d particles a p pears t o li mit t he release of t he 
dr u gs i n n o n- he mat o p oietic or ga ns. Pre-cli nical st u dies i nf or me d t hat t he free dr u g 
distri b uti o n is mai nl y i n t he b o ne, marr o w, s plee n, a n d li ver. C P X- 3 5 1 ( wit h o ut 
de xraz o xa ne) is c urre ntl y bei n g st u die d i n ne wl y dia g n ose d pe diatric A M L b y C O G i n 
P hase III ra n d o mize d st u d y ( N C T 0 4 2 9 3 5 6 2). Fi nall y, c urre ntl y, m ost c hil dre n a n d 
a d olesce nts w h o recei ve a nt hrac ycli ne f or treati n g t heir pri mar y ca ncer als o recei ve 
de xraz o xa ne. De xraz o xa ne si g nifica ntl y re d uce d s h ort-ter m car diac d ysf u ncti o n, alt h o u g h 
it is n ot k n o w n w het her t he be neficial effect of de xraz o xa ne e xte n ds t o l o n g-ter m car diac 
c o m plicati o ns. T heref ore is pla usi ble t hat t he lifeti me e x p os ure rec o m me n de d f or 
d o x or u bici n e q ui vale nts mi g ht c ha n ge. I n s u m mar y, t he li pi dic f or m ulati o n of da u n or u bici n 
i n C P X- 3 5 1, t he relati vel y l o w d o x or u bici n e q ui vale nt d ose ( 6 5 m g/ m2 per c o urse) i n o ur 
st u d y, t he pre-cli nical a n d cli nical data s u g gesti n g less car di ot o xicit y of a nt hrac ycli ne i n 
li pi d f or m ulati o n, C P X- 3 5 1 efficac y i n t his p ote ntiall y fatal dis or der, a n d pri or a p pr o val b y 
F D A f or t his i n dicati o n, s u p p ort f urt her st u dies of C P X- 3 5 1.
2. 2  
R ati o n ale f or t his St u d y
T he res ults of P hase I a n d P hase II trials of C P X- 3 5 1 i n i n di vi d uals y o u n ger t ha n 2 2 years 
wit h rela pse d A M L c o n d ucte d b y C hil dre n’s O nc ol o g y Gr o u p ( C O G) re veale d a res p o nse 
rate of 6 8. 3 % ( C R + C R wit h o ut platelet rec o ver y) a n d n o t o xic deat hs d uri n g i n d ucti o n or 
after H S C T ( 1 8, 1 9). T he st u d y c o h ort c o m prise d patie nts wit h p o or pr o g n osis i ncl u di n g 
t w o-t hir ds of w h o m ha d rela pse d wit hi n t he first year fr o m t he dia g n osis, a n d 1 0 of 3 8 
patie nts rela pse d after H S C T. T he res p o nse rates (efficac y) i n t his trial c o m pare d fa v ora bl y 
t o t h ose re p orte d b y t he sa me gr o u p treati n g c hil dre n a n d a d olesce nts wit h rela pse d A M L 
usi n g sta n dar d re gi me ns. 2 5, 2 6 H o we ver, cases of S M N were n ot e nr olle d o n t his trial. T o o ur 
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 4 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
k n o wle d ge, n o ot her st u dies are c urre ntl y acti ve or u n der de vel o p me nt t o i ncl u de c hil dre n 
a n d a d olesce nts wit h S M N. O ur st u d y will pr o vi de u na vaila ble data f or t his patie nt 
p o p ulati o n o n t he res p o nse t o u pfr o nt treat me nt wit h C P X- 3 5 1.
Beca use t he b o ne marr o w a n d ot her or ga ns of ma n y patie nts wit h S M N ha ve bee n e x p ose d 
t o pri or hi g h d oses of c he m ot hera p y a n d/ or ra di ot hera p y or har b or i ntri nsic ge netic 
a b n or malities of t he he mat o p oietic s yste m, t he y are pr o ne t o de vel o p se vere t o xicit y after 
i nte nsi ve sal va ge c o n ve nti o nal i n d ucti o n t hera p y. A d va nta ges of li p os o mal pre parati o ns 
i ncl u de pr ol o n ge d ti me i n circ ulati o n d ue t o pr otecti o n of t he dr u g fr o m e nz y matic 
i nacti vati o n, circ u m ve nti o n of dr u g effl u x tra ns p orters res p o nsi ble f or dr u g resista nce a n d 
altere d bi o- distri b uti o n of t he li p os o me f or m ulati o n fa v ori n g acc u m ulati o n of t he dr u g i n 
t he b o ne marr o w a n d s plee n w hile s pari n g of n or mal tiss ue.2 7 Relate d t o a nt hrac ycli ne-
i n d uce d t o xicit y, w hic h is p ote ntiall y de vastati n g f or c hil dre n treate d wit h c o n ve nti o nal 
A M L i n d ucti o n t hera p y, a nt hrac ycli ne li p os o mal deli ver y s yste ms ha ve t he p ote ntial t o 
decrease car di ot o xicit y, 2 8, 2 9 alt h o u g h this be nefit is n ot yet well st u die d f or C P X- 3 5 1. 2 0, 3 0, 3 1
I n s u m mar y, efficac y, a n d t o xicit y data of C P X- 3 5 1 i n c hil dre n wit h S M N, ca n pr o vi de 
critical i nf or mati o n f or i m pr o vi n g t he o utc o me of t his rare s u b gr o u p of m yel oi d ne o plas ms.
2. 3  
R ati o n ale f or C orrel ati ve St u dies
2. 3. 1
P har mac o ge n o mics
C o nsi deri n g t hat C P X- 3 5 1  nee ds t o be acti vate d t o t he acti ve meta b olite ara- C T P f or its 
a ntile u ke mic effect, we a ntici pate t hat ge netic pr ofili n g of patie nts base d o n A C S S sc ore 
will be hel pf ul i n pre dicti n g res p o nse a n d de vel o pi n g strate gies t o a da pt c ytara bi ne d osi n g 
i n f ut ure st u dies.3 2 O ur tra nscri pt o mic base d pe diatric si x- ge ne le u ke mic ste m cell sc ore 
( p L S C 6) is pre dicti ve of o verall o utc o me a n d H S C T relate d o utc o me.3 3 We ha ve als o 
rece ntl y de vel o pe d a dr u g resista nce sc ore t hat is c o m p ose d of 5 ge nes of rele va nce t o 
c ytara bi ne a n d da u n or u bici n t hat is pre dicti ve of o utc o me. 3 4 Base d o n t hese res ults we 
pr o p ose t o e val uate t hese tra nscri pt o mic varia bles i n res p o nse t o C P X- 3 5 1 as well as 
res p o nse t o H S C T.
2. 3. 2
Ge n o mic c haracteristics of pe diatric S M N
Sec o n dar y m yel oi d ne o plas ms i n c hil dre n ha ve disti nct ge netic lesi o ns, as defi ne d 
pre vi o usl y. 1 1, 3 5 It is n ot k n o w n h o w C P X- 3 5 1 alters t he arc hitect ure of a berra nt 
he mat o p oietic cl o nes. T his st u d y offers t he o p p ort u nit y t o deter mi ne h o w ge netic lesi o ns i n 
le u ke mic cells c ha n ge after C P X- 3 5 1 o n cl o nal hierarc h y a n d size. T his ca n be ac hie ve d 
usi n g sta n dar d ge n o mic met h o d ol o gies esta blis he d at o ur i nstit uti o n. Sta n dar d ge n o mic 
met h o ds ( w h ole e x o me / ge n o me / tra nscri pt o me se q ue nci n g) will be use d t o i de ntif y 
ge netic alterati o ns at dia g n osis. H o we ver, t he tec h nical li mitati o n of t hese a p pr oac hes is t he 
i na bilit y t o call s o matic m utati o ns wit h l o w allelic b ur de n, t h us p ote ntiall y missi n g s mall, 
m utate d cl o nes t hat decrease i n size after C P X- 3 5 1. T his pr o vi des a rati o nale t o a p pl y 
tar gete d ultra- dee p se q ue nci n g pa nels wit h a se nsiti vit y of at least 0. 1 %, or ot her 
a p pr oac hes s uc h as P C R or cell free D N A se q ue nci n g. A n ot her p ossi bilit y is t o e x pl ore t he 
feasi bilit y of si n gle-cell se q ue nci n g (sc D N Ase q) f or c haracterizati o n a n d trac ki n g of cl o nal 
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 5 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
re pert oires i n res p o nse t o C P X- 3 5 1 treat me nt. I n a d diti o n, t his met h o d ca n res ol ve t he 
q uesti o n if disti nct m utati o ns are f o u n d i n t he sa me or se parate cells, a n d w hic h is t he 
d o mi na nt o ne t hat is C P X- 3 5 1 res p o nsi ve.
O verall, we belie ve t hat t he res ults fr o m t hese i n vesti gati o ns will o pe n u p o p p ort u nities f or 
t he cli nical utilit y of ge n o mic, p har mac o ge n o mic a n d tra nscri pt o mic data i n pe diatric S M N.
3. 0 
E LI GI BI LI T Y C RI T E RI A A N D S T U D Y E N R O L L M E N T
3. 1 
I ncl usi o n Criteri a
Acc or di n g t o i nstit uti o nal a n d NI H p olic y, t he st u d y will e nr oll researc h partici pa nts 
re gar dless of ge n der a n d et h nic bac k gr o u n d. I nstit uti o nal e x perie nce c o nfir ms br oa d 
re prese ntati o n i n t his re gar d.
3. 1. 1
Patie nts m ust be > 1 year a n d < 2 2 years of a ge at t he ti me of e nr oll me nt.
3. 1. 2
Patie nt m ust ha ve o ne of t he f oll o wi n g dia g n oses:
Treat me nt-relate d M D S/ A M L: Patie nts wit h s oli d or ga n or he mat o p oietic 
ne o plas ms pre vi o usl y treate d wit h al k ylati n g a ge nts, i o nizi n g ra diati o n, 
t o p ois o merase i n hi bit ors, a nti meta b olites, t hi o p uri nes, m yc o p he n olate m ofetil, 
fl u dara bi ne, a n d a nti-t u b uli n a ge nts ( vi ncristi ne, vi n blasti ne, vi n desi ne, paclita xel, 
a n d d oceta xel us uall y i n c o m bi nati o n), w h o de vel o p M D S, or A M L are ca n di dates 
f or t he C P X S M N pr ot oc ol. If t he b o ne marr o w has bet wee n 5 % a n d 2 0 % blasts 
( hi g her-ris k M D S), patie nts are disc usse d wit h t he he mat o p oietic ste m cell 
tra ns pla ntati o n ( H S C T) tea m f or c o nsi derati o n t o recei ve c he m ot hera p y bef ore 
H S C T. If t he c o nse ns us is t hat c yt ore d ucti o n bef ore H S C T is necessar y, a n d t he 
c u m ulati ve d ose of d o x or u bici n e q ui vale nt is < 5 0 0 m g/ m 2 (i n cases of car di o 
pr otecti o n) or ≤ 4 0 0 m g/ m2 (cases wit h o ut car di o pr otecti o n), patie nts are eli gi ble 
f or t he C P X S M N pr ot oc ol.
O R
Sec o n dar y M D S/ A M L: Patie nts wit h pri mar y M D S i n tra nsf or mati o n t o A M L 
(refract or y c yt o pe nia wit h a n e xcess of blasts), ac q uire d a plastic a ne mia e v ol vi n g t o 
A M L, m yel oi d ne o plas ms arisi n g fr o m i n herite d b o ne marr o w fail ure s y n dr o mes 
(i ncl u di n g se vere c o n ge nital ne utr o pe nia, Sc h wac h ma n- Dia m o n d s y n dr o me, 
M E C O M s y n dr o me) or M D S/ A M L pre dis p ositi o n s y n dr o mes (i ncl u di n g ger mli ne 
pre dis p ositi o n i n G A T A 2 , R U N X 1 , S A M D 9/ S A M D 9 L , E R C C 6 L 2 , N F 1 , E T V 6 , 
A N K R D 2 6 , E R C C 6 L 2, T P 5 3  or C E B P A  ge nes) are eli gi ble f or t he C P X S M N trial. 
If t he b o ne marr o w has bet wee n 5 % a n d 2 0 % blasts ( hi g her-ris k M D S), patie nts are 
disc usse d wit h t he H S C T tea m f or c o nsi derati o n t o recei ve c he m ot hera p y bef ore 
H S C T. If t he c o nse ns us is t hat c yt ore d ucti o n bef ore H S C T is necessar y, t he patie nts 
are eli gi ble f or t he C P X S M N pr ot oc ol.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 6 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
3. 1. 3
Patie nts m ust ha ve a perf or ma nce stat us c orres p o n di n g t o a n Easter n C o o perati ve 
O nc ol o g y Gr o u p ( E C O G) sc ore of 0, 1 or 2. Use Kar n ofs k y f or patie nts > 1 6 years 
of a ge a n d La ns k y f or patie nts < 1 6 years of a ge.  See A p pe n di x I f or perf or ma nce 
stat us c orrelati o ns.
N ote: Patie nts w h o are u na ble t o wal k beca use of paral ysis, b ut w h o are u p i n a 
w heelc hair, will be c o nsi dere d a m b ulat or y f or t he p ur p ose of assessi n g t he 
perf or ma nce sc ore.
3. 1. 4
C o nc o mita nt me dicati o ns restricti o ns
See Secti o n 4. 2. 5 or A p pe n di x II f or c o nc o mita nt t hera p y restricti o ns f or patie nts 
d uri n g treat me nt.
3. 1. 5
Or ga n f u ncti o n re q uire me nts
3. 1. 5. 1 A de q uate re nal f u ncti o n defi ne d as:

Creati ni ne cleara nce or ra di ois ot o pe G F R > 7 0 m L/ mi n/ 1. 7 3 m 2, or

A ser u m creati ni ne base d o n a ge/ ge n der as f oll o ws:
Ma xi m u m Ser u m Creati ni ne
A ge
Male
Fe male
1 t o < 2 years
0. 6
0. 6
2 t o < 6 years
0. 8
0. 8
6 t o < 1 0 years
1
1
1 0 t o < 1 3 years
1. 2
1. 2
1 3 t o < 1 6 years
1. 5
1. 5
> 1 6 years
1. 7
1. 4
T he t hres h ol d cre ati ni ne v al ues i n t his t a ble were derive d fr o m t he Sc h w artz f or m ul a f or 
esti m ati n g G F R ( R E F) utilizi n g c hil d le n gt h a n d st at ure d at a p u blis he d by t he C D C.
3. 1. 5. 2 A de q uate li ver f u ncti o n defi ne d as ( u nless it is relate d t o le u ke mic 
i n v ol ve me nt):

Direct bilir u bi n < 1. 5 x u p per li mit of n or mal ( U L N) f or a ge a n d i nstit uti o n. 
At i nstit uti o ns t hat d o n ot o btai n a direct bilir u bi n i n patie nts wit h a n or mal 
t otal bilir u bi n, a n or mal t otal bilir u bi n ma y be use d as e vi de nce t hat t he direct 
bilir u bi n is n ot > 1. 5 x t he U L N.

S G P T ( A L T) < 3. 0 x U L N f or a ge a n d i nstit uti o n
3. 1. 5. 3 A de q uate car diac f u ncti o n defi ne d as:

S h orte ni n g fracti o n of > 2 7 % b y ec h ocar di o gra m, or

Ejecti o n fracti o n of > 5 0 % b y ra di o n ucli de a n gi o gra m or ec h ocar di o gra m, 
a n d
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 7 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5

C orrecte d Q T ( Q Tc B) i nter val < 5 0 0 msecs
3. 1. 5. 4 Ce ntral ner v o us s yste m f u ncti o n defi ne d as:

Patie nts wit h seiz ure dis or der ma y be e nr olle d if o n a ntic o n v ulsa nts a n d if 
seiz ures are well c o ntr olle d

C N S t o xicit y < Gra de 2
3. 1. 6
Pri or t hera p y
Patie nts m ust ha ve rec o vere d fr o m t he ac ute t o xic effects of all pri or c he m ot hera p y, 
i m m u n ot hera p y, H S C T or ra di ot hera p y pri or t o e nteri n g t his st u d y. All pri or 
treat me nt-relate d t o xicities m ust ha ve res ol ve d t o < Gra de 2 pri or t o e nr oll me nt.
a.
M yel os u p pressi ve c he m ot hera p y: M ust n ot ha ve recei ve d m yel os u p pressi ve 
c he m ot hera p y wit hi n 3 wee ks of e ntr y o nt o t his st u d y (e xcl u di n g h y dr o x y urea). 
C yt o-re d ucti o n wit h h y dr o x y urea ca n be i nitiate d a n d c o nti n ue d f or u p t o 2 4 
h o urs pri or t o t he start of C P X- 3 5 1.
b.
Bi ol o gic (a nti- ne o plastic a ge nt): At least 7 da ys si nce t he c o m pleti o n of t hera p y 
wit h ster oi ds, reti n oi ds or h y p o met h ylati n g a ge nts. N ote: F or a ge nts t hat ha ve 
k n o w n a d verse e ve nts occ urri n g be y o n d 7 da ys after a d mi nistrati o n (i.e. 
m o n ocl o nal a nti b o dies), t his peri o d m ust be e xte n de d be y o n d t he ti me d uri n g 
w hic h ac ute a d verse e ve nts are k n o w n t o occ ur.
c.
Ra diati o n t hera p y ( R T): > 2 wee ks f or l ocal palliati ve R T (s mall p ort); > 6 
m o nt hs m ust ha ve ela pse d if pri or cra ni os pi nal R T or if > 5 0 % ra diati o n of 
pel vis; > 6 wee ks m ust ha ve ela pse d if ot her s u bsta ntial B M ra diati o n. 
N ote: Patie nts m ust ha ve recei ve d ≤ t ha n 1 3. 6 G y pri or ra diati o n t o 
me diasti n u m. Patie nts wit h pri or c u m ulati ve d o x or u bici n e q ui vale nt > 4 0 0 
m g/ m 2 a n d pri or ra diati o n (a n y d ose) t o t he me diasti n u m are n ot eli gi ble f or t he 
pr ot oc ol. 
d.
He mat o p oietic ste m cell tra ns pla ntati o n: N o e vi de nce of acti ve graft vs. h ost 
disease f or at least 4 wee ks. F or all o ge neic H S C T patie nts, > 3 m o nt hs m ust 
ha ve ela pse d si nce H S C T.

M ust ha ve recei ve d n o m ore t ha n 1 pri or a ut ol o g o us or all o ge neic ste m 
cell tra ns pla nt.

Patie nts m ust be off all s yste mic i m m u n os u p pressi ve t hera p y f or at least 
2 wee ks, e xcl u di n g h y dr oc ortis o ne f or p h ysi ol o gic c ortis ol re place me nt.
e.
I ntrat hecal c yt ot o xic t hera p y:

N o waiti n g peri o d is re q uire d f or patie nts ha vi n g recei ve d i ntrat hecal 
c ytara bi ne, met h otre xate, a n d/ or h y dr oc ortis o ne.

At least 1 4 da ys m ust ha ve ela pse d si nce recei vi n g li p os o mal c ytara bi ne 
( De p o C yte ) b y i ntrat hecal i njecti o n.
f.
Gr o wt h fact ors:

Patie nts m ust n ot ha ve recei ve d he mat o p oietic gr o wt h fact ors f or 7 da ys 
pri or t o C P X- 3 5 1.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 8 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5

Patie nts m ust n ot ha ve recei ve d pe gfil grasti m f or 1 4 da ys pri or t o C P X-
3 5 1.
3. 1. 7
HI V disease
Patie nts wit h a k n o w n hist or y of HI V are eli gi ble, if t he y meet all of t he f oll o wi n g 
c o n diti o ns:

N o hist or y of HI V c o m plicati o ns wit h t he e xce pti o n of C D 4 c o u nt < 2 0 0 
cells/ m m 3

N o a ntiretr o viral t hera p y wit h o verla p pi n g t o xicit y s uc h as 
m yel os u p pressi o n

C D 4 c o u nt > 5 0 0 cells/ m m 3 pri or t o t he dia g n osis of rela pse d A M L

HI V viral l oa ds bel o w t he li mit of detecti o n

N o hist or y of hi g hl y acti ve a ntiretr o viral t hera p y ( H A A R T)-resista nt HI V
3. 1. 8
Resi d ual or rela pse d s oli d mali g na nc y
Patie nts wit h resi d ual or rela pse d s oli d mali g na nc y (f or e xa m ple oste osarc o ma) at 
t he ti me of t he dia g n osis of S M N are n ot e xcl u de d fr o m t his trial a n d t he treat me nt 
i n di vi d ualize d t o i nte grate t he ma na ge me nt of t he t w o mali g na ncies.
3. 1. 9
All patie nts a n d/ or t heir pare nts or le gal g uar dia ns m ust si g n a writte n i nf or me d 
c o nse nt.
3. 2 
E xcl usi o n Criteri a
3. 2. 1
Patie nts wit h de n ov o  A M L (i.e., patie nts eli gi ble f or St. J u de or C O G 
fr o ntli ne A M L trials).
3. 2. 2
Patie nts wit h a n y of t he f oll o wi n g:

C o nstit uti o nal tris o m y 2 1 or wit h c o nstit uti o nal m osaicis m of 
c hr o m os o me tris o m y 2 1 

Patie nts wit h Fa nc o ni A ne mia ( F A)
N ote: Ver y rarel y patie nts wit h F A ma y n ot dis pla y a n y of t he classic 
c o nstit uti o nal si g ns a n d s y m pt o ms ass ociate d wit h t he disease. 
M yel o d ys plastic s y n dr o mes ( M D S) or ac ute m yel oi d le u ke mia ( A M L) 
c o ul d be t he first ma nifestati o n of a patie nt wit h F A. 3 6 F or patie nts 
prese nti n g wit h M D S/ A M L wit h o ut a clear eti ol o g y —s uc h as hist or y of 
c he m ot hera p y or ra diati o n (i n dicati ve of treat me nt-relate d A M L), or a n y 
well- defi ne d ge netic ori gi ns (e. g., m utati o ns i n G A T A 2, S D A M 9, 
S D A M 9/ L, R U N X 1 , or E T V 6 ) — ge netic testi n g f or F A s h o ul d be 
c o nsi dere d, es peciall y if t he disease pr o gressi o n is n ot ac utel y ra pi d. I n 
cases w here A M L is a d va nci n g ra pi dl y, c o nsi derati o n f or e nr olli n g t he 
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 9 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
patie nt s h o ul d f oll o w a t h or o u g h disc ussi o n wit h t he pri nci pal 
i n vesti gat or of t he pr ot oc ol.

D N A re pair s y n dr o mes

D ys kerat osis c o n ge nita (tel o mer o pat h y)

Wils o n disease or ot her c o p per-relate d meta b olic dis or ders 

Mi xe d p he n ot y pe ac ute le u ke mia

P hila del p hia c hr o m os o me- p ositi ve m yel oi d ne o plas ms ( A M L or C M L)

Ac ute pr o m yel oc ytic le u ke mia ( A P L), or

J u ve nile m yel o m o n oc ytic le u ke mia (J M M L) a n d relate d R A S o pat h y 
dis or ders i n c hr o nic p hase. 
3. 2. 3
Patie nts w h o ha ve recei ve d greater a m o u nt of d o x or u bici n e q ui vale nts as 
state d i n Secti o n 3. 1. 2  para meters are n ot eli gi ble. F or t he p ur p oses of 
deter mi ni n g eli gi bilit y f or t his pr ot oc ol, t he f oll o wi n g car di ot o xicit y 
m ulti pliers will be use d t o deter mi ne d o x or u bici n e q ui vale nts. 3 7- 3 9

D o x or u bici n (refere nce): 1

Da u n o m yci n: 0. 5

E pir u bici n: 0. 5

I dar u bici n: 5

Mit o xa ntr o ne: 1 0
3. 2. 4
Patie nts w h o are c urre ntl y recei vi n g a n ot her i n vesti gati o nal dr u g.
3. 2. 5
Patie nts recei vi n g me dicati o ns f or treat me nt of left ve ntric ular s yst olic 
d ysf u ncti o n.
3. 2. 6
Patie nts wit h d oc u me nte d acti ve, u nc o ntr olle d i nfecti o n at t he ti me of st u d y 
e ntr y.
3. 2. 7
Patie nts wit h k n o w n acti ve H B V a n d H C V i nfecti o ns.
3. 2. 8
Patie nts wit h pri or aller g y t o da u n or u bici n a n d/ or c ytara bi ne.
3. 2. 9
Pre g na nc y a n d breast fee di n g

Fe male patie nts w h o are pre g na nt are i neli gi ble d ue t o ris ks of fetal a n d 
terat o ge nic a d verse e ve nts as see n i n a ni mal/ h u ma n st u dies.

Lactati n g fe males w h o are breastfee di n g a n i nfa nt/c hil d

Fe male patie nts of c hil d beari n g p ote ntial are n ot eli gi ble u nless a 
ne gati ve pre g na nc y test res ult has bee n o btai ne d.

Se x uall y acti ve patie nts of re pr o d ucti ve p ote ntial are n ot eli gi ble u nless 
t he y ha ve a gree d t o use a n effecti ve c o ntrace pti ve met h o d f or t he 
d urati o n of t heir st u d y partici pati o n a n d f or at least 6 m o nt hs after t he 
last d ose of pr ot oc ol t hera p y.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 1 0 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
3. 3  
Rese arc h P artici p a nt Recr uit me nt a n d Scree ni n g
T his is a si n gle site st u d y t o be c o n d ucte d at St. J u de C hil dre n’s Researc h H os pital.
3. 4 
E nr oll me nt o n St u d y at St. J u de
A me m ber of t he st u d y tea m will c o nfir m p ote ntial partici pa nt eli gi bilit y a n d c o m plete t he 
‘ Partici pa nt Eli gi bilit y C hec klist’ i n O n C ore. A researc h partici pa nt-s pecific c o nse nt f or m 
will be ge nerate d. T he e ntire si g ne d c o nse nt/asse nt f or m m ust be sca n ne d i nt o t he 
Electr o nic Healt h Rec or d b y t he st u d y tea m desi g nee.
4. 0 
T R E A T M E N T P L A N
4. 1  
Desi g n a n d St u d y O ver vie w ( Fi g ure 1)
T his is a pr os pecti ve, si n gle site, si n gle-ar m pil ot st u d y t o assess t he safet y a n d efficac y of 
C P X- 3 5 1 (li p os o mal da u n or u bici n a n d c ytara bi ne) f or t he treat me nt of pe diatric sec o n dar y 
m yel oi d ne o plas ms.
Patie nts will recei ve u p t o 2 c ycles of C P X- 3 5 1 f or re missi o n i n d ucti o n, a n d t he n will 
pr ocee d t o all o ge neic H S C T or ot her t hera pies as per i nstit uti o nal practice. T he sec o n d 
C P X- 3 5 1 c ycle is n ot gi ve n bef ore 2 9 da ys fr o m t he first c ycle. If a patie nt attai ns 
re missi o n a n d has ne gati ve M R D after t he first c o urse of C P X- 3 5 1, a n d H S C T ca n occ ur 
wit hi n 3 t o 4 wee ks fr o m t he e val uati o n date of t he first c o urse, t he patie nt ca n pr ocee d t o 
H S C T wit h o ut recei vi n g t he sec o n d c o urse of C P X- 3 5 1.
I n cases i n w hic h H S C T ca n n ot be perf or me d wit hi n 3 t o 4 wee ks fr o m t he e val uati o n date 
of t he sec o n d c o urse of C P X- 3 5 1, i nteri m c he m ot hera p y c o ul d be use d. F or e xa m ple, 
a n ot her c o urse (t hir d c o urse) of C P X- 3 5 1 (c ytara bi ne 6 5 m g/ m 2, da u n or u bici n 2 9 m g/ m2) 
Da ys 1 a n d 3 f or patie nts wit h c u m ulati ve d o x or u bici n e q ui vale nts of < 4 0 0 ( wit h o ut 
car di o pr otecti o n) or < 5 0 0 m g/ m 2 ( wit h car di o pr otecti o n), F L T 3 -I T D i n hi bit ors, or 
ve net ocla x al o ne or i n c o m bi nati o n. I n t hese i nsta nces, partici pa nts will be e val uate d f or 
t he pri mar y st u d y o bjecti ves (res p o nse a n d t o xicit y t o t he t w o c ycles of C P X- 3 5 1). T he y 
will c o nti n ue i n t he st u d y f or f oll o w- u p t o assess t he sec o n dar y a n d e x pl orat or y o bjecti ves). 
Acc or di n g t o St. J u de g ui deli nes, i nf or me d c o nse nt is re q uire d f or t he i nteri m 
c he m ot hera p y a n d H S C T ( n o n- pr ot oc ol treat me nt pla n or ot her st u d y pr ot oc ol.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 1 1 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
Fi g ure 1 – M a n a ge me nt Acc or di n g t o M or p h ol o gic Res p o nse a n d Resi d u al Dise ase b y Fl o w C yt o metr y
* P atie nts wit h a c u m ul ative d ox or u bici n-e q uiv ale nt d ose excee di n g > 4 0 0 m g/ m 2 ( wit h o ut c ar di o pr otecti o n) or > 5 0 0 
m g/ m² ( wit h c ar di o pr otecti o n) after t he Cycle 1, will n ot receive a sec o n d c o urse of C P X- 3 5 1. I nste a d, t he s u bse q ue nt 
tre at me nt o pti o ns will be deli ber ate d wit h t he pr ot oc ol Pri nci p al I nvesti g at or.
¥Cycle 2 st arts o n or after D ay 2 9 of t he first cycle wit h t w o d oses ( d a u n or u bici n 4 4 m g/ m 2 a n d cyt ar a bi ne 1 0 0 m g/ m2).
λCycle 2 st arts bet wee n D ays 2 9- 3 6 of t he first cycle wit h t w o d oses ( d a u n or u bici n 2 9 m g/ m 2 a n d cyt ar a bi ne 6 5 m g/ m2).
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 1 2 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
4. 2  
D osi n g a n d Sc he d ule
Ti mi n g of pr ot oc ol t hera p y a d mi nistrati o n, res p o nse assess me nt st u dies, a n d s ur gical 
i nter ve nti o ns are base d o n sc he d ules deri ve d fr o m t he e x peri me ntal desi g n or o n 
esta blis he d sta n dar ds of care. Mi n or u na v oi da ble de part ures ( u p t o 7 2 h o urs) fr o m pr ot oc ol 
directe d t hera p y a n d/ or disease e val uati o ns f or vali d cli nical, patie nt a n d fa mil y l o gistical, 
or facilit y, pr oce d ure a n d/ or a nest hesia sc he d uli n g iss ues are acce pta ble (e xce pt w here 
e x plicitl y pr o hi bite d wit hi n t he pr ot oc ol).
4. 2. 1
C ycle 1 T hera p y
A ge nt
D ose ( D a u n o)
D ose 
(c yt ar a bi ne)
R o ute
N u m ber 
of d oses
Sc he d ule
N otes
C P X- 3 5 1
4 4 m g/ m 2/ d ose, 
or
1. 5 m g/ k g if 
patie nt is < 1 0 k g
1 0 0 m g/ m 2
or
3. 3 m g/ k g if 
patie nt is < 1 0 k g
I V o ver 9 0 
mi n utes
3
Da ys 1, 3 
a n d 5
Calc ulate 
d ose base d o n 
t he 
Da u n or u bici n 
c o m p o ne nt. 
See Secti o ns 
4. 2. 3 a n d 
4. 2. 5 f or 
a d diti o nal 
a d mi nistrati o n 
details.
I ntrat hecal 
T hera p y
See Secti o n 4. 2. 4
I T
1
Da y 1
4. 2. 2
C ycle 2 T hera p y *
A ge nt
D ose ( D a u n o)
D ose 
(c yt ar a bi ne)
R o ute
N u m ber 
of d oses
Sc he d ule
N otes
C P X- 3 5 1
4 4 m g/ m 2/ d ose, 
or
1. 5 m g/ k g if 
patie nt is < 1 0 k g
1 0 0 m g/ m 2
or
3. 3 m g/ k g if 
patie nt is < 1 0 k g
I V o ver 9 0 
mi n utes
2
Da ys 1  
a n d 3 
Calc ulate 
d ose base d o n 
t he 
Da u n or u bici n 
c o m p o ne nt. 
See Secti o ns 
4. 2. 3 a n d 
4. 2. 5 f or 
a d diti o nal 
a d mi nistrati o n 
details.
I ntrat hecal 
T hera p y
See Secti o n 4. 2. 4
I T
1
Da y 1
* P atie nts i n C R, C R p or C Ri a n d M R D < 0. 1 % a n d i m p ossi bility of u n der g oi n g b o ne m arr o w tr a ns pl a nt ati o n i n 3 t o 4 
weeks fr o m t he res p o nse ev al u ati o n will receive a Cycle 2 at l o wer d ose ( d a u n or u bici n 2 9 m g/ m 2 a n d cyt ar a bi ne 6 5 
m g/ m 2), D ays 1 a n d 3.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 1 3 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
4. 2. 3
Treat me nt details
C P X- 3 5 1 ( D a u n or u bici n 4 4 m g/ m 2 a n d C yt ar a bi ne 1 0 0 m g/ m2) i n C ycle 1
C P X- 3 5 1 ( D a u n or u bici n 4 4 m g/ m 2 a n d C yt ar a bi ne 1 0 0 m g/ m2) i n C ycle 2, f or p atie nts 
wit h P R or C R/ C Ri wit h M R D ≥ 0. 1 %.
C P X- 3 5 1 ( D a u n or u bici n 2 9 m g/ m 2 a n d C yt ar a bi ne 6 5 m g/ m2) i n C ycle 2, f or p atie nts 
wit h C R/ C Ri wit h M R D < 0. 1 %.
I V a d mi nistr ati o n o ver 9 0 mi n utes, a n d h os pit al i n p atie nt. 
C ycle 1, Da ys 1, 3, a n d 5
C ycle 2, Da ys 1 a n d 3 
1 0 0 u nits/ m 2 of C P X- 3 5 1 c orres p o n ds t o 4 4 m g/ m2 of da u n or u bici n a n d 1 0 0 m g/ m2 of 
c ytara bi ne.
Patie nts will be a d mitte d t o t he h os pital t o recei ve C P X- 3 5 1. It s h o ul d be a d mi nistere d b y 
ce ntral ve n o us or peri p herall y i nserte d ce ntral ( PI C C) cat heter. D o n ot use a n i n-li ne filter. 
Fl us h t he li ne wit h N S or D 5 W after i nf usi o n. D o n ot mi x wit h or a d mi nister wit h a n y 
ot her me dicati o ns. If i nf usi o n-relate d reacti o ns occ ur, pre me dicati o n wit h a nti hista mi nes 
a n d/ or c ortic oster oi ds ma y be necessar y (see Secti o n 4. 4. 1).
C P X- 3 5 1 will be pr o vi de d b y Jazz P har mace uticals. D o n ot use c o m merci al s u p pl y.
4. 2. 4
I ntrat hecal c he m ot hera p y
L u m bar p u nct ure a n d i ntrat hecal (I T) c he m ot hera p y will be gi ve n o n Da y 1 of eac h c ycle, 
f or all patie nts, b ut ma y be dela ye d or a ntici pate d if cli nicall y i n dicate d. T he patie nts 
wit h o ut e vi de nce of C N S le u ke mia will n ot recei ve f urt her I T t hera p y d uri n g C ycle 1. 
Patie nts wit h C N S disease ( defi ne d as t he prese nce of a n y blasts i n t he cere br os pi nal fl ui d) 
will u n der g o wee kl y I T M H A starti n g o n Da y 8 u ntil t he cere br os pi nal fl ui d is le u ke mia-
free. Le uc o v ori n resc ue ( 5 m g/ m2/ d ose, ma x 5 m g, P O or I V) ma y be gi ve n at 2 4 a n d 3 0 
h o urs after eac h tri ple i ntrat hecal treat me nt.
I ntr at hec al t her a p y d osi n g
P atie nt A ge
Met h otre x ate
H y dr oc ortis o ne
C yt ar a bi ne
V ol u me *
< 1 year
6 m g
1 2 m g
1 8 m g
6 ml
> 1 t o < 2 years
8 m g
1 6 m g
2 4 m g
8 ml
> 2 t o < 3 years
1 0 m g
2 0 m g
3 0 m g
1 0 ml
> 3 years
1 2 m g
2 4 m g
3 6 m g
1 2 ml
*I nstit uti o n al st a n d ar d v ol u mes c a n be use d
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 1 4 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
4. 2. 5
C o nc o mita nt t hera p y restricti o n
See A p pe n di x II f or dr u gs, f o o d a n d s u p ple me nts t hat ma y i nteract wit h da u n or u bici n a n d 
c ytara bi ne.
4. 2. 5. 1
M yel oi d gr o wt h fact or s u p p ort
M yel oi d gr o wt h fact ors s h o ul d n ot be use d as pr o p h yla xis. T he y ca n be a d mi nistere d t o 
patie nts i n t he f oll o wi n g cli nical sce nari os: ( 1) pr ol o n ge d ne utr o pe nia t hat is cli nicall y 
si g nifica nt; ( 2) cli nical or c ult ure pr o ve n bactere mia d uri n g ne utr o pe nia, or wit h i n vasi ve 
f u n gal i nfecti o n. F or i nitiati o n of gr o wt h fact or o utsi de of sce nari os ( 1) or ( 2) a b o ve, n otif y 
t he Pri nci pal I n vesti gat or.
4. 2. 5. 2 C ortic oster oi d t hera p y
C ortic oster oi ds s h o ul d n ot be use d as a nti-e metic t hera p y. C ortic oster oi d t hera p y is n ot 
per missi ble e xce pt f or t he f oll o wi n g i n dicati o ns: ( 1) as treat me nt or pr o p h yla xis f or 
a na p h ylactic reacti o ns; ( 2) As a treat me nt or pr o p h yla xis f or s y m pt o ms of Ara- C s y n dr o me 
i ncl u di n g fe ver, ras h, or c o nj u ncti vitis (see Secti o n 4. 3. 2); ( 3) As treat me nt f or ras h 
p ossi bl y relate d t o C P X- 3 5 1 (see Secti o n 4. 4. 5); ( 4) cases wit h h y peri nfla m mat or y 
prese ntati o n of sec o n dar y m yel oi d ne o plas m a n d ( 5) s us pecte d or c o nfir me d a dre nal 
i ns ufficie nc y.
4. 2. 5. 3 He pat ot o xic me dicati o ns
C o nc o mita nt use wit h he pat ot o xic a ge nts ma y i m pair li ver f u ncti o n a n d i ncrease t he 
t o xicit y of C P X- 3 5 1. M o nit or he patic f u ncti o n m ore fre q ue ntl y if c o-a d mi nistrati o n wit h 
he pat ot o xic me dicati o ns is necessar y.
4. 2. 5. 4 D urati o n of t hera p y
T he C P X S M N tri al i ncl u des o ne or t w o c ycles f or re missi o n i n d ucti o n.  Patie nts i n 
re missi o n f oll o wi n g C ycle 1 or C ycle 2 s h o ul d pr ocee d t o H S C T. I n sit uati o ns w here f or 
a n y reas o n t he H S C T is e x pecte d t o be dela ye d f or m ore t ha n 3 t o 4 wee ks, t he patie nt 
s h o ul d be disc usse d wit h pr ot oc ol PI f or t he c o nsi derati o n of alter nati ves as a t o bri d ge t o 
H S C T, i ncl u di n g o ne c o urse of a b bre viate d C P X- 3 5 1 ( da u n or u bici n 2 9 m g/ m 2 a n d 
c ytara bi ne 6 5 m g/ m 2; Da ys 1 a n d 3).
4. 3 
S u p p orti ve C are
4. 3. 1
Ce ntral ve n o us access 
It is rec o m me n de d t hat all patie nts ha ve at least a si n gle l u me n ce ntral ve n o us access li ne 
or a PI C C cat heter place d pri or t o t he be gi n ni n g of t hera p y.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 1 5 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
4. 3. 2
C o nj u ncti vitis pr o p h yla xis
A d mi nister artificial tears (e. g., h y dr o x y met h ylcell ul ose, h y pr o mell ose, p ol y vi n yl alc o h ol), 
2 dr o ps i n eac h e ye e ver y 4 h o urs w hile a wa ke, be gi n ni n g i m me diatel y bef ore t he first d ose 
of C P X- 3 5 1 a n d c o nti n ui n g u ntil 2 4 h o urs after t he last d ose. Ma y als o c o nsi der 
a d mi nisteri n g ster oi d e ye dr o ps s uc h as 0. 1 % de xa met has o ne or 1 % pre d nis ol o ne 
o p ht hal mic s ol uti o n, 2 dr o ps i n eac h e ye e ver y 6 h o urs.
4. 3. 3
Pr o p h yla xis f or P ne u m ocystis jir oveci  p ne u m o nia
All partici pa nts s h o ul d recei ve pr o p h yla xis f or P ne u m ocystis jir oveci  p ne u m o nia acc or di n g 
t o i nstit uti o nal g ui deli nes.
4. 3. 4
Pr o p h yla xis f or f u n gal i nfecti o ns
Beca use patie nts wit h le u ke mia are at hi g h ris k f or f u n gal i nfecti o ns, all partici pa nts s h o ul d 
recei ve a ntif u n gal pr o p h yla xis acc or di n g t o i nstit uti o nal g ui deli nes.
4. 3. 5
Pr o p h yla xis f or bacterial i nfecti o ns
Beca use patie nts u n der g oi n g treat me nt f or le u ke mia are at hi g h ris k f or bacterial i nfecti o ns, 
all partici pa nts s h o ul d recei ve a nti bi otic pr o p h yla xis acc or di n g t o i nstit uti o nal g ui deli nes. 
We rec o m me n d starti n g pr o p h ylactic a nti bi otics w he n t he A N C ≤ 5 0 0 a n d falli n g or 
pre dicte d t o fall a n d c o nti n ue d u ntil t he A N C ≥ 1 0 0 o n t hree c o nsec uti ve da ys a n d risi n g.
4. 3. 6
Ma na ge me nt of fe brile ne utr o pe nia
All patie nts wit h fe ver ≥ 3 8. 3° C o n a si n gle occasi o n or ≥ 3 8. 0° C t hat persists f or o ne h o ur 
s h o ul d be h os pitalize d a n d treate d i m me diatel y wit h br oa d s pectr u m a nti bi otics acc or di n g t o 
i nstit uti o nal g ui deli nes.
Ot her s u p p orti ve care s h o ul d be d o ne as per i nstit uti o nal sta n dar d.
4. 4  
D ose M o dific ati o ns f or T o xicities
4. 4. 1
Aller g y t o C P X- 3 5 1
F or h y perse nsiti vit y reacti o ns, i nterr u pt t he i nf usi o n i m me diatel y. F or mil d s y m pt o ms, 
i nitiate t he i nf usi o n at half t he pri or rate of t he i nf usi o n o nce s y m pt o ms res ol ve. F or 
m o derate s y m pt o ms, d o n ot restart t he i nf usi o n. F or s u bse q ue nt d oses pre me dicate wit h 
a nti- hista mi nes a n d/ or c ortic oster oi ds pri or t o i nitiati n g i nf usi o n at sa me rate. Per ma ne ntl y 
disc o nti n ue C P X- 3 5 1 f or se vere or life-t hreate ni n g s y m pt o ms.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 1 6 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
4. 4. 2
Car diac t o xicit y
If ejecti o n fracti o n falls < 5 0 % ( or if E F is u ne val ua ble, S F < 2 4 %), h ol d C ycle 2 a n d re peat 
E C H O i n 1- 2 wee ks. If E F re mai ns < 5 0 % ( or if E F is u ne val ua ble, S F < 2 4 %), t he patie nt 
will n ot recei ve C ycle 2.
4. 4. 3
Tra nsa mi nases 
If t he A L T or A S T are > 1 0 x U L N, atte m pts s h o ul d be ma de t o i de ntif y t he ca use a n d 
n otif y t he PI. I n m ost cases, t he t hera p y will pr ocee d wit h o ut m o dificati o n.
4. 4. 4
H y per bilir u bi ne mia
I n se vere li ver d ysf u ncti o n, t he half-life of da u n or u bici n is pr ol o n ge d a n d t he A U C ma y be 
m ore t ha n 3-f ol d t hat of patie nts wit h n or mal he patic f u ncti o n. H o we ver, t here are n o 
a vaila ble d ose a dj ust me nt g ui deli nes i n t he literat ure. T heref ore, t he d ose re d ucti o ns 
i m ple me nte d f or da u n or u bici n will be utilize d as o utli ne d i n t he ta ble bel o w.
Direct Bilir u bi n
C P X- 3 5 1
> 2 a n d < 3
5 0 % of t he calc ulate d d ose
> 3 a n d < 5
2 5 % of t he calc ulate d d ose
> 5 m g/ d L
H ol d d ose a n d n otif y PI
F ull d ose of C P X- 3 5 1 ma y res u me w he n t he direct bilir u bi n has falle n t o < 1. 2 m g/ d L.
4. 4. 5
Ras h wit h C P X- 3 5 1 
A mac ul o pa p ular ras h occ urri n g wit hi n o ne wee k of treat me nt i nitiati o n occ urs i n t he 
maj orit y of patie nts treate d wit h C P X- 3 5 1. Gra de 3 ras hes occ urre d i n 3 9. 6 % of c hil dre n 
partici pati n g i n t he C O G A A M L 1 4 2 1 st u d y after recei vi n g C P X- 3 5 1. T he ras h t y picall y 
res p o n de d t o t o pical or s yste mic c ortic oster oi ds. S u bjects e x perie nci n g a ras h fr o m C P X-
3 5 1 s h o ul d first recei ve t o pical c ortic oster oi ds.
Pr urit us ma y be treate d wit h a nti hista mi nic ( di p he n h y dra mi ne). If e xte nsi ve or refract or y t o 
t o pical t hera p y, a 3 - 5 da y c o urse of s yste mic pre d nis o ne or met h yl pre d nis ol o ne ma y be 
use d. Ras h is n ot a n i n dicati o n t o d ose-re d uce or disc o nti n ue C P X- 3 5 1.
4. 4. 6
Ha n d-f o ot s y n dr o me
Ha n d-f o ot s y n dr o me has bee n re p orte d i n patie nts treate d wit h ot her li p os o mal 
c he m ot hera p y pr o d ucts a n d hi g h- d ose c ytara bi ne re gi me ns. Patie nts w h o de vel o p ha n d-f o ot 
s y n dr o me ma y recei ve t o pical e m ollie nts (s uc h as A q ua p h or) as well as t o pical or s yste mic 
ster oi ds or a nti hista mi nes if a p pr o priate. Oral a d mi nistrati o n of vita mi n B 6 ( p yri d o xi ne) ca n 
als o be use d f or t hese patie nts - B S A < 0. 5 m 2: 5 0 m g per da y; B S A 0. 5 - 1. 0 m2: 1 0 0 m g 
per da y; B S A 1. 1 - 1. 5 m 2: 2 0 0 m g per da y, a n d B S A > 1. 5 m2: 3 0 0 m g per da y.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 1 7 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
5. 0  
D R U G I N F O R M A TI O N
5. 1  
C P X- 3 5 1
S o urce a n d p har mac ol o g y: C ytara bi ne is meta b olize d i ntracell ularl y b y de o x yc yti di ne 
ki nase t o its acti ve f or m c yt osi ne ara bi n osi de tri p h os p hate. T he acti ve meta b olite da ma ges 
D N A d uri n g t he S- p hase b y i n hi biti n g al p ha- D N A p ol y merase, i n hi biti n g D N A re pair 
t hr o u g h a n effect o n beta- D N A p ol y merase, a n d b y i nc or p orati o n i nt o D N A i n place of 
c yt osi ne. Da u n or u bici n is a n a nt hrac ycli ne a nti bi otic t hat da ma ges D N A b y i ntercalati n g 
D N A stra n ds res ulti n g i n u nc oili n g of t he heli x. Da u n or u bici n als o i n hi bits p ol y merase 
acti vit y w hic h affects ge ne e x pressi o n re g ulati o n a n d t he f or mati o n of o x y ge n free ra dicals.
C ytara bi ne: da u n or u bici n li p os o me ( C P X- 3 5 1) is a 5: 1 fi xe d m olar rati o of t he t w o dr u gs 
wit hi n a li p os o me. T his rati o has s h o w n s y ner g y a n d i m pr o ve d acti vit y i n vitr o i n 
c o m paris o n t o t he a ge nts gi ve n se paratel y. T he li p os o me is c o m p ose d of 
distear yl p h os p hati d ylc h oli ne ( D S P C), distear yl p h os p hati d yl gl ycer ol ( D S P G), a n d 
c h olester ol i n a 7: 2: 1 m olar rati o. Da u n or u bici n is c o m ple xe d wit h c o p per gl uc o nate ( 0. 9 
m g/ m L) t o sta bl y e nca ps ulate it a n d t he n s us pe n de d i n s ucr ose. C ytara bi ne: da u n or u bici n 
li p os o mes acc u m ulate i n t he b o ne marr o w. T he dr u g is prefere ntiall y ta ke n u p wit hi n t he 
c yt o plas m of le u ke mic cells t he n release d ca usi n g efficie nt a n d ra pi d le u ke mic cell deat h.
P h ar m ac oki netics: C ytara bi ne is c o n verte d t o t he i nacti ve meta b olite uracil ara bi n osi de b y 
a p yri mi di ne n ucle osi de dea mi nase. Da u n or u bici n h y dr oc hl ori de is e xte nsi vel y a n d ra pi dl y 
meta b olize d i n t he li ver a n d ot her tiss ues, pr o d uci n g t he acti ve meta b olite da u n or u bici n ol. 
F urt her meta b olis m via re d ucti o n clea va ge of t he gl yc osi dic b o n d, 4- O de met h ylati o n, a n d 
c o nj u gati o n wit h b ot h s ulfate a n d gl uc ur o ni de als o occ ur. F oll o wi n g a si n gle da u n or u bici n 
h y dr oc hl ori de d ose, 2 5 % is eli mi nate d i n a n acti ve f or m b y uri nar y e xcreti o n a n d a n 
esti mate d 4 0 % is eli mi nate d b y biliar y e xcreti o n.
Li p os o mal e ncase me nt mar ke dl y decreases cleara nce a n d res ults i n pr ol o n ge d half-life. T he 
ter mi nal half-life f or c ytara bi ne is ge nerall y 1- 3 h o urs b ut is pr ol o n ge d t o 3 7- 4 2 h o urs f or 
t he li p os o mal pr o d uct. T he ter mi nal half-life of da u n or u bici n is 4 5 mi n utes i n t he i nitial 
p hase a n d 1 8. 5 h o urs i n t he ter mi nal p hase b ut is pr ol o n ge d t o 2 2- 2 5 h o urs f or t he 
li p os o mal pr o d uct.
He p atic I m p air me nt: N o cli nical trials ha ve bee n c o n d ucte d t o e val uate t he effect of 
he patic i m pair me nt o n t he p har mac o ki netics of c ytara bi ne: da u n or u bici n li p os o me.
Re n al I m p air me nt: N o cli nical trials ha ve bee n c o n d ucte d t o e val uate t he effect of re nal 
i m pair me nt of c ytara bi ne: da u n or u bici n li p os o me.
Dr u g I nter acti o ns: Please refer t o la belli n g of c ytara bi ne a n d da u n or u bici n as t he ris k of 
dr u g i nteracti o ns are e x pecte d t o be s u bsta ntiall y si milar f or C P X- 3 5 1. N o f or mal dr u g-
dr u g i nteracti o n trials ha ve bee n c o n d ucte d wit h C P X- 3 5 1.
C o nc o mita nt use of car di ot o xic a ge nts ma y i ncrease t he ris k of car di ot o xicit y.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 1 8 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
C o nc o mita nt use wit h he pat ot o xic a ge nts ma y i m pair li ver f u ncti o n a n d i ncrease t he 
t o xicit y of C P X- 3 5 1.
F or m ulati o n a n d sta bilit y: C P X- 3 5 1 is a p ur ple l y o p hilize d f or m ulati o n. O ne u nit c o ntai ns 
1 m g c ytara bi ne a n d 0. 4 4 m g da u n or u bici n. Eac h 5 0 m L vial c o ntai ns 1 0 0 u nits, 
c orres p o n di n g t o 1 0 0 m g c ytara bi ne a n d 4 4 m g da u n or u bici n. St ore vials refri gerate d at 
5° C ( ± 3° C) i n a n u pri g ht p ositi o n.
C o m p o ne nts of C P X- 3 5 1 (c ytara bi ne: da u n or u bici n) Li p os o me I njecti o n
C o m p o ne nt
M w
A m o u nt 
per vi al
A m o u nt 
per u nit
C ytara bi ne, U S P/ P h E ur
2 4 3
1 0 0 m g
1 m g
Da u n or u bici n H Cl U S P/ P h E ur (re p orte d as t he free base)
5 2 8
4 4 m g
0. 4 4 m g
Distear o yl p h o p hati d ylc h oli ne
7 9 0
4 5 4 m g
4. 5 m g
Distear o yl p h os p hati d yl gl ycer ol
8 0 1
1 3 2 m g
1. 3 m g
C h olester ol, H P
3 8 7
3 2 m g
0. 3 m g
C o p per gl uc o nate, U S P
4 5 4
9 2 m g
0. 9 m g
Triet ha n ola mi ne, N F, P h E ur
1 4 9
7 m g
0. 0 7 m g
S ucr ose, N F, P h E ur
3 4 2
2 0 5 4 m g
2 0. 5 4 m g
C P X- 3 5 1 s h o ul d be rec o nstit ute d wit h 1 9 m L sterile water f or i njecti o n t o a fi nal 
c o nce ntrati o n of 5 u nits/ m L. D o n ot heat C P X- 3 5 1 f or i njecti o n. Caref ull y s wirl c o nte nts of 
t he vial f or 5 mi n utes w hile ge ntl y i n verti n g e ver y 3 0 sec o n ds. After rec o nstit uti o n, let rest 
f or 1 5 mi n utes. Re peat vial i n versi o n 5 ti mes pri or t o wit h dra wi n g dr u g f or dil uti o n. T he 
dr u g s h o ul d be f urt her dil ute d wit h 0. 9 % S o di u m C hl ori de or D 5 W a n d dis pe nse d i n n o n-
D E H P p ol y pr o p yle ne or p ol y olefi n ba gs or n o n- D E H P s yri n ges. See s u g geste d fi nal 
dil uti o n v ol u mes bel o w. C P X- 3 5 1 is sta ble f or 4 h o urs refri gerate d at 2 ‐ C  t o 8 ‐ C  ( 3 6 ‐ F 
t o 4 6 ‐ F)  after t he fi nal dil uti o n if n ot use d i m me diatel y. If st ore d refri gerate d f or 4 h o urs, 
m ust use i m me diatel y. U n use d dr u g s h o ul d be discar de d.
S u g geste d fi nal dil uti o n v ol u mes f or pre parati o n:
C P X- 3 5 1
D ose ( D a u n o)
D 5 W or 0. 9 % N a C L fi n al v ol u me ( m L)
4. 4 t o < 4 4
1 0 0 m L
> 4 4 t o < 1 1 0
2 5 0 m L
> 1 1 0 t o > 1 7 6
5 0 0 m L
S u p plier: Dr u g will be s u p plie d b y Jazz P har mace uticals.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 1 9 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
T o xicit y: See ta ble bel o w
I nci de nce
T o xicities
C o m m o n
( > 2 0 % of patie nts)

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

Na usea, v o miti n g, diarr hea/c olitis, 
c o nsti pati o n

Decrease d a p petite

A b d o mi nal pai n

E de ma

Ras h

Fati g ue

Hea dac he

C o u g h, d ys p nea

Fe ver, c hills

He m orr ha ge

I ns o m nia

H y p ote nsi o n

I nfecti o n

M usc ul os keletal pai n
Occ asi o n al
( 4- 2 0 % of patie nts)

Dizzi ness

D ys pe psia

A n xiet y, deliri u m

Pr urit us

H y p o xia

Ple ural eff usi o n

M uc ositis

H y perte nsi o n

Tac h ycar dia, atrial fi brillati o n

H y p o kale mia

H y per hi dr osis

Re nal fail ure

Res pirat or y fail ure

Car di ot o xicit y

C hest pai n

Vis ual i m pair me nt

Ni g ht s weats
R are
( < 3 % of patie nts)

Al o pecia

Pal mar- pla ntar er yt hr o d ysest hesia

H y perse nsiti vit y reacti o n

T u m or l ysis s y n dr o me

I ncrease d bl o o d c o p per le vels
Pre g n a nc y & 
L act ati o n
Base d o n a ni mal data C P X- 3 5 1 ca n ca use fetal har m w he n a d mi nistere d 
t o a pre g na nt w o ma n. T here are n o a de q uate a n d well-c o ntr olle d st u dies 
of C P X- 3 5 1 i n pre g na nt w o me n. C ytara bi ne a n d da u n or u bici n are 
re pr o d ucti ve a n d de vel o p me ntal t o xica nts i n m ulti ple s pecies ( mice, rats, 
a n d/ or d o gs). Patie nts s h o ul d be a d vise d t o a v oi d bec o mi n g pre g na nt 
w hile recei vi n g C P X- 3 5 1. If t his dr u g is use d d uri n g pre g na nc y, or if t he 
patie nt bec o mes pre g na nt w hile ta ki n g t his dr u g, a p prise t he patie nt of t he 
p ote ntial har m t o a fet us. A d vise w o me n a n d me n of re pr o d ucti ve 
p ote ntial t o use effecti ve c o ntrace pti o n d uri n g treat me nt a n d f or 6 m o nt hs 
f oll o wi n g t he last d ose of C P X- 3 5 1.
It is u n k n o w n w het her C P X- 3 5 1 is e xcrete d i n h u ma n mil k. C P X- 3 5 1 is 
n ot rec o m me n de d f or n ursi n g m ot hers. Beca use of p ossi ble dr u g 
e xcreti o n i n h u ma n mil k a n d beca use of t he p ote ntial f or seri o us a d verse 
reacti o ns i n n ursi n g i nfa nts, lactati n g w o me n n ot t o breastfee d d uri n g 
treat me nt wit h C P X- 3 5 1 a n d f or at least 2 wee ks after t he last d ose.
* D ue t o t he l o n g pl as m a h alf-life of C P X- 3 5 1, ti me t o rec overy of ne utr o p hils a n d pl atelets m ay be 
pr ol o n ge d.
* * Vis u al i m p air me nt i ncl u des p h ot o p h o bi a, p h ot o psi a, p h ot ose nsitivity re acti o n, reti n al te ar, uveitis, bl urre d 
visi o n, re d uce d vis u al ac uity, a n d vitre o us fl o aters.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 2 0 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
D osa ge a n d r o ute of a d mi nistrati o n: See Treat me nt a n d D ose M o dificati o ns secti o ns of t he 
pr ot oc ol. T he dr u g s h o ul d be i nf use d o ver 9 0 mi n utes via n o n- D E H P t u bi n g. D o N O T 
a d mi nister t hr o u g h a n i nli ne filter.
Acc o u nta bilit y: Beca use t his st u d y is bei n g c o n d ucte d u n der a n I N D, partici pati n g 
p har macies will be re q uire d t o s u b mit Dr u g Acc o u nta bilit y L o gs at t he ti me of m o nit ori n g 
d oc u me nti n g recei pt a n d s hi p me nt of dr u g s u p pl y, dis pe nsi n g/ or deri n g of s u p pl y, a n d 
destr ucti o n of u n use d st u d y me dicati o n a n d/ or da ma ge d or e x pire d dr u g.
6. 0 
E V A L U A TI O N S, T E S T S, O B S E R V A TI O N S
6. 1 
Pre- Tre at me nt Cli nic al E v al u ati o ns

P h ysical e xa m wit h vital si g ns, hei g ht, wei g ht, a n d B S A

C o m plete bl o o d c o u nt wit h differe ntial

C he mistr y pr ofile: gl uc ose, electr ol ytes, B U N, creati ni ne, L D H, uric aci d, bilir u bi n, 
S G O T, S G P T, calci u m, p h os p h or o us, ma g nesi u m, t otal pr otei n, a n d al b u mi n

E K G, ec h ocar di o gra m or M U G A

B o ne marr o w e val uati o n f or m or p h ol o g y, i m m u n o p he n ot y pi n g t o c o nfir m dia g n osis 
a n d t o esta blis h a le u ke mia-ass ociate d p he n ot y pe f or s u bse q ue nt M R D st u dies, 
ge n o mics, a n d pr ote o mics. F or St. J u de cases, left o ver b o ne marr o w a n d peri p heral 
bl o o d se nt t o bi ore p osit or y.

F or patie nts wit h ele vate d le u k oc yte c o u nts a n d hi g h blast perce nta ges, or patie nts 
t o o ill t o u n der g o b o ne marr o w as pirate, all dia g n ostic st u dies ma y be perf or me d o n 
bl o o d rat her t ha n b o ne marr o w.

L u m bar p u nct ure wit h C S F cell c o u nt a n d differe ntial a n d i ntra-t hecal 
c he m ot hera p y (si n gle- pr oce d ure c o nse nt).

Pre g na nc y test f or fe males of c hil d beari n g p ote ntial

H L A t y pi n g of t he patie nt, si bli n gs, a n d pare nts if n ot pre vi o usl y d o ne.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 2 1 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
6. 2 
E v al u ati o ns Bef ore a n d D uri n g T her a p y
Re q uire d st u dies
B aseli ne/ Pre-
Tre at me nt
( wit hi n 7 d a ys)
C ycle 1
C ycle 2
E n d of T her a p y
E v al u ati o ns wit hi n + 7 d a ys
Cli nic al
P h ysical e xa m, vital si g ns
X
Da y 1
Da y 1
Da y 2 2, Da y 2 9 or at t he ti me of 
he mat ol o gic rec o ver y
C B C, wit h differe ntial
X
Da y 1 a n d t wice a wee k 
f or t he first wee k a n d 
t he n wee kl y
Da y 1 a n d t wice a wee k 
f or t he first wee k a n d 
t he n wee kl y
Da y 2 2, Da y 2 9 or at t he ti me 
he mat ol o gic rec o ver y
T u m or l ysis pa nel ( p otassi u m, 
calci u m, p h os p h or us, uric aci d, 
B U N, creati ni ne, a n d L D H)
X
T wice a wee k f or t he first 
wee k a n d t he n wee kl y
T wice a wee k f or t he first 
wee k a n d t he n wee kl y
N A
E C G
X
Pri or t o C ycle 2
Da y 2 2, Da y 2 9 or at t he ti me 
he mat ol o gic rec o ver y
Ec h ocar di o gra m or M U G A
X
Pri or t o C ycle 2
Da y 2 2, Da y 2 9 or at t he ti me of 
he mat ol o gic rec o ver y
B o ne marr o w bi o ps y a n d 
as pirate λ
X
Da y 2 2
Da y 2 2, Da y 2 9 or at t he ti me 
he mat ol o gic rec o ver y
L u m bar p u nct ure, C S F cell 
c o u nt a n d c yt ol o g y
See Secti o n 4. 2. 4
C ycle 1 – See Secti o n 4. 2. 4
C ycle 2 – Da y 1
N/ A
L a b or at or y Rese arc h ¥
P har mac o ge n o mics
--
--
--
P B a n d B M Da y 2 2, Da y 2 9 or at t he ti me 
he mat ol o gic rec o ver y
Ge n o mic st u dies
X
P B a n d B M e n d of C ycle 
P B a n d B M e n d of c ycle
P B a n d B M Da y 2 2, Da y 2 9 or at t he ti me 
he mat ol o gic rec o ver y
A b bre viati o ns: B M, b o ne marr o w; P B, peri p heral bl o o d; N A, n ot a p plica ble.
λM R D st u dies will be perf or me d l oc ally or ce ntr ally. B o ne m arr o w as pir ate a n d bi o psy ce ntr ally revie we d ( at di a g n osis, pri or t he sec o n d c o urse a n d e n d of t her a py)
¥Rese arc h: s peci me ns will be c ollecte d o nly d uri n g r o uti ne cli nic al testi n g ( b o ne m arr o w a n d peri p her al bl o o d). O n e ac h occ asi o n, t he a m o u nt of peri p her al bl o o d m ay n ot 
excee d t he lesser of 5 0  ml or 3 ml per k g i n a n 8- week peri o d a n d c ollecti o n m ay n ot occ ur m ore fre q ue ntly t h a n 2 ti mes per week. B o ne m arr o w f or rese arc h: E ac h as pir ate 
will c o nsist of a p pr oxi m ately 2 m L of m arr o w. A si n gle extr a as pir ate ( ~ 2 m L) will be o bt ai ne d fr o m c hil dre n u n der t he a ge of 8 ye ars, t w o a d diti o n al as pir ates ( u p t o ~ 4 m L) 
will be o bt ai ne d fr o m t h ose bet wee n t he a ges of 9 a n d 1 3, a n d u p t o t hree as pir ates ( u p t o ~ 6 m L) will be o bt ai ne d fr o m p atie nts w h o are 1 4 ye ars a n d ol der. F oll o w u p 
rese arc h st u dies c a n be c ollecte d at t he discreti o n of t he i nvesti g at or d uri n g r o uti ne cli nic al testi n g.
Pre-cycle tests o bt ai ne d wit hi n 7 d ays of st arti n g t he c he m ot her a py.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 2 2 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
6. 3  
Rese arc h St u dies
6. 3. 1
P har mac o ge n o mics
Ge n o mic D N A ( peri p heral bl o o d) will be o btai ne d fr o m patie nts bef ore H S C T f or 
ge n ot y pi n g of 1 0 S N Ps t hat are part of t he A C S 1 0 sc ore. Ge n ot y pe sc ore will be de vel o pe d 
f or eac h patie nt f oll o we d b y ge nerati o n of p ol y ge nic sc ores t o classif y patie nts i nt o l o w or 
hi g h sc ore gr o u ps. T he sc ore will be e val uate d f or ass ociati o n wit h t he cli nical o utc o me 
e n d p oi nts. Si milar ass ociati o n will be perf or me d f or tra nscri pt o mic base d p L S C 6 a n d dr u g 
resista nce sc ores. We re q uest R N A/s peci me n pri or t o H S C T f or testi n g ge ne e x pressi o n 
le vels of 1 1 ge nes t hat are part of t he t w o sc ores. We ha ve all t he necessar y e q ui p me nt, 
pr ot oc ols, a n d res o urces t o test b ot h D N A base d p har mac o ge n o mics a n d R N A base d 
tra nscri pt o mic sc ore al o n g wit h f u n ds t o s u p p ort t his.
6. 3. 2
Ge n o mic c haracterizati o n of S M N
Sta n dar d hi g h t hr o u g h p ut ge n o mic met h o ds ( w h ole e x o me/ ge n o me se q ue nci n g, R N A 
se q ue nci n g) will be use d t o i de ntif y t he m utati o ns a n d ot her ge n o mic lesi o ns i n b o ne 
marr o w a n d peri p heral bl o o d sa m ple at dia g n osis. T o i de ntif y s o matic m utati o ns wit h l o w 
allelic b ur de n, we will a p pl y tar gete d dee p-se q ue nci n g or alter nati ve a p pr oac hes s uc h as 
d d P C R or cell free a m plificati o n. F or c haracterizati o n a n d trac ki n g of cl o nal re pert oires, 
sc D N Ase q will be perf or me d i n b o ne marr o w or bl o o d s peci me ns at dia g n osis a n d after 
C P X- 3 5 1 treat me nt. T hese met h o ds re q uire d e q ui p me nt a n d f u n ds are a vaila ble t o us.
6. 4 
E v al u ati o ns after C o m pleti o n of T her a p y
W he n a partici pa nt disc o nti n ues t he st u d y treat me nt, a fi nal visit will be c o n d ucte d. 
F oll o wi n g disc o nti n uati o n of t he st u d y treat me nt, t he partici pa nt will be treate d acc or di n g 
t o t he i n vesti gat or’s discreti o n. Partici pa nts will be m o nit ore d f or a d verse e ve nts f or 3 0 
da ys p ost pr ot oc ol treat me nt, or u ntil a d diti o nal a nti- S M N t hera p y is recei ve d ( w hic he ver 
occ urs first).
If a partici pa nt disc o nti n ues fr o m t he st u d y d ue t o a n a d verse e ve nt c o nsi dere d relate d t o 
st u d y treat me nt, a f oll o w- u p visit s h o ul d be c o n d ucte d n o later t ha n 3 0 da ys after t he last 
d ose of pr ot oc ol t hera p y. Safet y assess me nts are rec o m me n de d at least e ver y 3 0 da ys, u ntil 
all t o xicities res ol ve, ret ur n t o baseli ne, or bec o me cli nicall y satisfact or y, sta ble, or are 
c o nsi dere d irre versi ble, or u ntil patie nt recei ves ot her a nti- S M N t hera p y.
7. 0 
E V A L U A TI O N C RI T E RI A
7. 1  
Res p o nse E v al u ati o n d uri n g t he First C o urse of C P X- 3 5 1
A b o ne marr o w as pirate a n d bi o ps y will be o btai ne d o n Da y 2 2 of C ycle 1. C o m plete 
m or p h ol o gic re missi o n res p o nse ( C R) is defi ne d as less t ha n 5 % blasts wit h o ut A uer r o ds 
b y m or p h ol o gical e val uati o n of t he b o ne marr o w ( M 1 marr o w). Patie nts i n m or p h ol o gic 
C R wit h o ut he mat ol o gical rec o ver y ( w hite cell bl o o d c o u nt ≥ 1. 0 x 1 09/ L, u ns u p p orte d 
platelet c o u nt ≥ 3 0. 0 x 1 09/ L a n d a bs ol ute ne utr o p hil c o u nt ≥ 0. 3 x 1 09/ L) are classifie d as 
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 2 3 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
m or p h ol o gical C R a n d  i nc o m plete rec o ver y ( C Ri) of a bs ol ute ne utr o p hil, w hite bl o o d cell, 
a n d/ or platelet c o u nts. Patie nts i n C R or C Ri a n d M R D < 0. 1 % after t he first c ycle are 
ca n di dates f or he mat o p oietic ste m cell tra ns pla ntati o n. T hese patie nts will recei ve t he 
sec o n d c o urse of C P X- 3 5 1( da u n or u bici n 2 9 m g/ m 2 a n d c ytara bi ne 6 5 m g/ m2) w he n t he y 
meet t he criteria f or he mat ol o gical rec o ver y a n d a he mat o p oietic ste m cell tra ns pla nt will 
n ot be a vaila ble wit hi n 3 t o 4 wee ks fr o m t he e val uati o n date. If he mat ol o gical rec o ver y is 
n ot o bser ve d b y Da y 4 2 a n ot her b o ne marr o w e val uati o n will be o btai ne d. Partial res p o nse 
( P R) is defi ne d as 5 % t o 2 5 % blasts. Patie nts i n P R, C R,  or C Ri, b ut wit h M R D ≥ 0. 1 % 
blasts wit h a le u ke mia-ass ociate d p he n ot y pe b y fl o w c yt o metr y will pr ocee d t o t he sec o n d 
c o urse (t w o d oses) of C P X- 3 5 1 ( da u n or u bici n 4 4 m g/ m 2 a n d c ytara bi ne 1 0 0 m g/ m2, o n 
Da y 2 9 of C ycle 1. F or treat me nt decisi o ns, i n case of discre pa nc y bet wee n t he n u m ber of 
blasts b y m or p h ol o gical a n d b y fl o w c yt o metric a nal ysis, t he n u m ber of blasts b y fl o w 
c yt o metr y will be use d. Lac k of res p o nse is defi ne d as a n a bs ol ute i ncrease of 2 0 % of 
marr o w blasts fr o m t he baseli ne val ue, 2 5 % or m ore blasts, circ ulati n g le u ke mia blasts or 
de vel o p me nt of e xtra me d ullar y disease. T hese patie nts are c o nsi dere d t o ha ve treat me nt 
fail ure a n d ta ke n off st u d y. 
7. 2  
Res p o nse E v al u ati o n d uri n g t he Sec o n d C o urse of C P X- 3 5 1 
A b o ne marr o w as pirate a n d bi o ps y will be o btai ne d bet wee n Da ys 2 2- 2 8 of C ycle 2. F or 
patie nts wit h M 1 marr o w a n d ne gati ve M R D after C ycle 1, b o ne marr o w e val uati o n after 
C ycle 2 ma y be perf or me d o n Da y 2 8, w hereas b o ne marr o w e val uati o n will be d o ne o n 
Da y 2 2 f or t he re mai ni n g patie nts. T he sa me criteria f or res p o nse e val uati o n f or C ycle 1 is 
use d f or C ycle 2. 
7. 3 
T o xicit y E v al u ati o n Criteri a
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts v 5 ( C T C A E): T his st u d y will utilize t he 
C T C A E of t he Nati o nal Ca ncer I nstit ute ( N CI) f or t o xicit y a n d perf or ma nce re p orti n g. A 
c o p y of t he c urre nt versi o n of t he C T C A E ca n be d o w nl oa de d fr o m t he Ca ncer T hera p y 
E val uati o n Pr o gra m h o me pa ge ( htt p://cte p.i nf o. ni h. g o v). A d diti o nall y, t o xicities will be 
re p orte d o n t he a p pr o priate data c ollecti o n scree ns.
8. 0  
O F F- T R E A T M E N T A N D O F F- S T U D Y C RI T E RI A
8. 1  
Off- Tre at me nt Criteri a

N o res p o nse t o t hera p y

Rela pse

S u bse q ue nt mali g na nc y

De vel o p me nt of u nacce pta ble t o xicit y d uri n g treat me nt

Ref usal of f urt her pr ot oc ol t hera p y b y partici pa nt, pare nt, or g uar dia n

C o m pleti o n of pr ot oc ol t hera p y a n d 3 0 da ys e val uati o n peri o d or partici pa nt 
recei ves ot her a nti- S M N t hera p y, at t he discreti o n of t he PI
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 2 4 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
8. 2  
Off- St u d y Criteri a

Deat h

L ost t o f oll o w u p

Wit h dra wal of c o nse nt
9. 0 
S A F E T Y A N D A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S
9. 1  
A d verse E ve nts ( A E) 
A d verse e ve nts will be m o nit ore d fr o m t he ti me of first st u d y i nter ve nti o n or treat me nt a n d 
will be c ollecte d t hr o u g h o ut t he st u d y.
9. 2  
Defi niti o ns
A d verse E ve nt ( A E):  A n y u nt o war d me dical occ urre nce ass ociate d i n a st u d y partici pa nt 
after t he first treat me nt or i nter ve nti o n o n st u d y. A d verse E ve nts will be gra de d b y t he N CI 
C T C A E versi o n 5. 0 
Seri o us A d verse E ve nt ( S A E): A n y a d verse e ve nt te m p orall y ass ociate d wit h t he 
s u bject’s partici pati o n i n researc h t hat meets a n y of t he f oll o wi n g criteria:

res ults i n deat h;

is life-t hreate ni n g ( places t he s u bject at i m me diate ris k of deat h fr o m t he e ve nt as it 
occ urre d);

re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n;

res ults i n a persiste nt or si g nifica nt disa bilit y/i nca pacit y;

res ults i n a c o n ge nital a n o mal y/ birt h defect; or

a n y ot her a d verse e ve nt t hat, base d u p o n a p pr o priate me dical j u d g me nt, ma y 
je o par dize t he s u bject’s healt h, a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt o ne of t he ot her o utc o mes liste d i n t his defi niti o n.
U n a ntici p ate d pr o ble m ( U P): A n e ve nt w hic h was n ot e x pecte d t o occ ur, a n d w hic h 
i ncreases t he de gree of ris k p ose d t o researc h partici pa nts.  S uc h e ve nts, i n ge neral, meet all 
of t he f oll o wi n g criteria:

u ne x pecte d

relate d or p ossi bl y relate d t o partici pati o n i n t he researc h, a n d

s u g gests t hat t he researc h places s u bjects or ot hers at a greater ris k of har m (i ncl u di n g 
p h ysical, ps yc h ol o gical, ec o n o mic, or s ocial har m) t ha n was pre vi o usl y k n o w n or 
rec o g nize d.  A n u na ntici pate d pr o ble m i n v ol vi n g ris k t o s u bjects or ot hers ma y e xist 
e ve n w he n act ual har m d oes n ot occ ur t o a n y partici pa nt.
T he f oll o wi n g e ve nts are e x pecte d a n d will n ot be c o nsi dere d seri o us a d verse e ve nts or 
u na ntici pate d pr o ble ms a n d will n ot re p orte d i n a n e x pe dite d ma n ner, u nless a n a g gre gate 
a nal ysis i n dicates t hat s uc h e ve nts are occ urri n g m ore fre q ue ntl y t ha n e x pecte d. T his will 
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 2 5 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
be m o nit ore d cl osel y b y t he PI a n d st u d y tea m. T hese e ve nts will be re p orte d wit h A n n ual 
Re p ort:

H os pitalizati o n f or k n o w n c o nse q ue nces of t he u n derl yi n g disease. 

Gra de 3 or 4 i nfecti o n or fe ver ≤ 7 da ys i n d urati o n.

Gra de 3 na usea, v o miti n g or diarr hea t hat is a de q uatel y ma na ge d wit h s u p p orti ve 
care (i.e., d oes n ot re q uire t u be fee di n g, t otal pare nteral n utriti o n, or pr ol o n ge d 
h os pitalizati o n) or t hat res ol ves t o < Gra de 3 wit hi n 7 2 h o urs.

Gra de 3 or 4 electr ol yte or la b orat or y a b n or malities c orrecta ble wit h s u p p orti ve 
t hera p y or t hat res ol ve t o < Gra de 3 wit hi n 7 2 h o urs.

Gra de 3 or 4 t u m or l ysis s y n dr o me m ust res ol ve i n ≤ 7 da ys wit h o ut e vi de nce of 
e n d- or ga n da ma ge. 
9. 3  
H a n dli n g of A d verse E ve nts ( A Es) a n d De at hs
9. 3. 1
Re p orti n g of A Es a n d Deat hs
A Es will be e val uate d a n d d oc u me nte d b y t he cli nical staff a n d i n vesti gat ors t hr o u g h o ut 
i n patie nt h os pitalizati o ns a n d eac h o ut patie nt visit. T he st u d y tea m is res p o nsi ble f or 
re vie wi n g d oc u me ntati o n relate d t o A Es a n d e nteri n g directl y i nt o t he pr ot oc ol-s pecific 
data base f or all n o n- he mat ol o gic a d verse e ve nts Gra de 2 or hi g her. T he data t o be rec or de d 
are:
1) t he e ve nt descri pti o n
2) t he N CI C T C A E v 5. 0 c o de a n d gra de 
3) t he o nset date a n d t he res ol uti o n date ( or o n g oi n g if it has n ot res ol ve d at ti me of off 
st u d y)
4)
acti o n ta ke n f or e ve nt 
5)
patie nt o utc o me
6)
attri b uti o n of A E t o pr ot oc ol treat me nt/i nter ve nti o ns, 
7) if A E was e x pecte d or u ne x pecte d 
A Es t hat are classifie d as seri o us, u ne x pecte d, a n d at least p ossi bl y relate d will be n otate d 
as s uc h i n t he data base as u na ntici pate d pr o ble ms ( U Ps). T hese e ve nts will be re p orte d 
e x pe diti o usl y t o t he St. J u de I R B wit hi n t he ti mefra mes as descri be d a b o ve. All seri o us 
a d verse e ve nts will be n otate d as S A Es i n t he data base.
Attri b uti o n is t he relati o ns hi p bet wee n a n a d verse e ve nt or seri o us a d verse e ve nt a n d t he 
st u d y treat me nt. Attri b uti o n will be assi g ne d as f oll o ws: 

Defi nite – T he a d verse e ve nt is clearl y relate d t o t he st u d y treat me nt. 

Pr o ba ble – T he a d verse e ve nt is li kel y relate d t o t he st u d y treat me nt. 

P ossi ble – T he a d verse e ve nt ma y be relate d t o t he st u d y treat me nt. 

U nli kel y – T he a d verse e ve nt is d o u btf ull y relate d t o t he st u d y treat me nt. 

U nrelate d – T he a d verse e ve nt is clearl y N O T relate d t o t he st u d y treat me nt. 
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 2 6 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
C u m ulati ve s u m mar y of Gra de 2- 5 n o n- he mat ol o gic e ve nts will be re p orte d as part of t he 
pr o gress re p orts t o I R B at t he ti me of c o nti n ui n g re vie w. S pecific data e ntr y i nstr ucti o ns f or 
A Es a n d ot her pr ot oc ol-relate d data will be d oc u me nte d i n pr ot oc ol-s pecific data e ntr y 
g ui deli nes, w hic h will be de vel o pe d a n d mai ntai ne d b y st u d y tea m a n d cli nical researc h 
i nf or matics. T he st u d y tea m will meet re g ularl y t o disc uss A Es. T he PI will re vie w A E 
re p orts ge nerate d fr o m t he researc h data base, a n d c orrecti o ns will be ma de if a p plica ble. 
O nce t he i nf or mati o n is fi nal t he PI will si g n a n d date re p orts, t o ac k n o wle d ge his re vie w 
a n d a p pr o val of t he A E as e ntere d i n t he researc h data base.
9. 3. 2
Re p orti n g A Es a n d S A Es
T he St. J u de PI, u p o n a ware ness of a n e ve nt, will deter mi ne t he seri o us ness of A Es a n d 
e ns ure t hat (all S A Es a n d U Ps are e ntere d i nt o t he I R B electr o nic s u b missi o n s yste m wit hi n 
1 0 da ys.  All Gra de 2- 5 A Es, seri o us or n ot, will be rec or de d i n t he Trial Master data base 
a n d re p orte d t o t he St. J u de I R B at t he ti me of c o nti n ui n g re vie w.  
9. 3. 3
Re p orti n g of U na ntici pate d Pr o ble ms
T he St. J u de PI will refer t o St. J u de H u ma n Researc h Pr otecti o n Pr o gra m ( H R P P) P olic y 
0 1. 7 2 0 f or s pecifics o n t he re p orti n g of u na ntici pate d pr o ble ms t o t he St. J u de I R B. 
T he St. J u de Re g ulat or y Affairs Office, u p o n recei pt, re p orts U Ps o n st u d y t o t he F D A 
wit hi n ma n date d re g ulat or y ti meli nes per 2 1 C R F 3 1 2 or 8 1 2. 
9. 4  
Re p orti n g t o Dr u g M a n uf act urer ( J azz P h ar m ace utic als)
Seri o us a d verse e ve nts a n d u na ntici pate d pr o ble ms as defi ne d a b o ve will be re p orte d b y 
e mail n o later t ha n o ne ( 1) cale n dar da y of k n o wle d ge of t he e ve nt f or fatal a n d life-
t hreate ni n g e ve nts t o Jazz at:

1 0. 0  
D A T A C O L L E C TI O N, M O NI T O RI N G A N D C O N FI D E N TI A LI T Y
1 0. 1  
D at a C ollecti o n 
Electr o nic case-re p ort f or ms (e- C R Fs) will be c o m plete d b y t he St. J u de Cli nical Researc h 
Ass ociates or t he site St u d y C o or di nat or. Data fr o m t he partici pa nt’s rec or d will be e ntere d 
directl y i nt o a sec ure st u d y-s pecific data base.  I nstr ucti o ns f or data e ntr y are o utli ne d i n t he 
data base.
Data ma na ge me nt will be s u per vise d b y PI a n d t he He mat ol o gical Mali g na ncies Ma na ger 
of Cli nical Trials O perati o ns. Pr ot oc ol-s pecific data. All pr ot oc ol-s pecific data a n d all n o n-
he mat ol o gic Gra de 2- 5 a d verse e ve nts will be rec or de d b y t he cli nical researc h ass ociates 
i nt o a pr ot oc ol-s pecific data base, A Es s h o ul d be e ntere d wee kl y, es peciall y d uri n g t he 
t olera bilit y p hase. All q uesti o ns will be directe d t o t he Pri nci pal I n vesti gat or ( PI) or 
desi g nee a n d will be re vie we d at re g ularl y sc he d ule d w or ki n g meeti n gs.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 2 7 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
Re g ular s u m maries of t o xicit y a n d pr ot oc ol e ve nts will be ge nerate d f or t he PI a n d t he 
De part me nt of Bi ostatistics t o re vie w.
1 0. 2 
St u d y M o nit ori n g
T his st u d y will be m o nit ore d acc or di n g t o a st u d y s pecific cli nical trial m o nit ori n g pla n 
( C T M P). T he C T M P is base d o n t he c urre nt St. J u de C hil dre n’s Researc h H os pital 
I nstit uti o nal Pla n f or Data a n d Safet y M o nit ori n g of Cli nical Trials ( D S M P) w hic h o utli nes 
t he m o nit ori n g strate g y base d o n t he ris k of t he st u d y wit h a n e m p hasis o n partici pa nt 
safet y, data q ualit y, a n d h u ma n s u bjects pr otecti o ns. A d diti o nall y, t he C T M P is a 
s u p ple me nt t o t he pr ot oc ol, Cli nical Trial O perati o ns S O Ps a n d st u d y s pecific materials 
w hic h will ai d i n t he m o nit ori n g of t his st u d y.
T he I n vesti gat or will per mit st u d y-relate d m o nit ori n g b y pr o vi di n g direct access t o s o urce 
data a n d t o t he partici pa nts’ me dical hist ories. T he I n vesti gat or will als o mai ntai n a n 
I n vesti gat or Site File wit h esse ntial d oc u me nts acc or di n g t o I C H a n d all a p plica ble 
re g ulat or y g ui deli nes a n d ma ke t he file accessi ble f or m o nit ori n g visits as nee de d.
T he M o nit or will visit t he st u d y site at re g ular i nter vals d uri n g t he st u d y. Visits ma y be 
perf or me d o nsite, re m otel y, or i n a h y bri d fas hi o n ( b ot h o nsite a n d re m ote) as nee de d f or 
t he s p o ns or ( SJ C R H) t o f ulfill t heir o bli gati o ns. Site m o nit ori n g is c o n d ucte d acc or di n g t o 
a p plica ble I C H a n d G C P g ui deli nes t o e ns ure t he pr otecti o n of partici pa nts’ ri g hts a n d 
well- bei n g, pr ot oc ol a d here nce, q ualit y of data (acc urate, c o m plete, a n d verifia ble), st u d y 
treat me nt acc o u nta bilit y, c o m plia nce wit h re g ulat or y re q uire me nts, a n d c o nti n ue d 
a de q uac y of t he i n vesti gati o nal site a n d its facilities.
1 0. 3  
C o nfi de nti alit y
St u d y n u m bers will be use d i n place of a n i de ntifier s uc h as a me dical rec or d n u m ber. N o 
researc h partici pa nt na mes will be rec or de d o n t he data c ollecti o n f or ms. T he list 
c o ntai ni n g t he st u d y n u m ber a n d t he me dical rec or d n u m ber will be mai ntai ne d i n a l oc ke d 
file a n d will be destr o ye d after all data ha ve bee n a nal yze d. T he me dical rec or ds of st u d y 
partici pa nts ma y be re vie we d b y t he St. J u de I R B, F D A, Jazz P har mace uticals, a n d cli nical 
researc h m o nit ors.
1 1. 0 
S T A TI S TI C A L C O N SI D E R A TI O N S
1 1. 1 
Si m o n’s T w o- St a ge Desi g n f or Pri m ar y E n d p oi nt ( C R/ C Ri)
Pri mar y O bjecti ve: Deter mi ne t he c o m p osite c o m plete re missi o n ( C R) a n d c o m plete 
re missi o n wit h i nc o m plete peri p her al bl o o d rec overy ( C Ri) r ates, s afety, a n d t oler a bility i n 
p atie nts u n der 2 2 ye ars of a ge wit h S M N tre ate d wit h o ne or t w o c o urses of C P X- 3 5 1 
bef ore H S C T.
T he Si m o n’s t w o-sta ge mi ni ma x desi g n wit h a ma xi m u m e nr oll me nt of 2 5 patie nts will be 
use d t o e val uate t his e n d p oi nt ( Ta ble 1). T he desi g n has a 4. 2 9 % le vel f or t he n ull 
h y p ot hesis t hat t he p o p ulati o n rate of ac hie vi n g C R or C Ri ( C R + C Ri) bef ore t he e n d of t he 
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 2 8 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
sec o n d c o urse of t hera p y is less t ha n or e q ual 4 5 % a n d 8 0. 4 2 % p o wer f or t he alter nati ve 
t hat t he p o p ulati o n C R + C Ri rate is greater t ha n or e q ual 7 0 %. It will st o p earl y a n d declare 
pr ot oc ol t hera p y t o ha ve a n u n desira ble C R + C Ri rate if 5 or less of t he first 1 2 patie nts 
ac hie ve C R + C Ri. If 6 or m ore of t he first 1 2 patie nts ac hie ve C R + C Ri, t he n u p t o 1 3 
a d diti o nal patie nts will be e nr olle d t o ha ve a t otal of 2 5 patie nts. If 1 5 or fe wer of t he 2 5 
patie nts ac hie ve C R + C Ri, t he n t he t hera p y will be declare d u n desira ble. Ot her wise, if 1 6 or 
m ore of t he 2 5 patie nts ac hie ve C R + C Ri, t he t hera p y will be declare d pr o misi n g a n d 
w ort h y of f urt her e val uati o n i n a f ut ure trial.
T a ble 1: Si m o n’s T w o- St a ge Desi g n f or C R + C Ri
O utc o me Pr o ba bilities
O utc o me
C R + C Ri Rate = 4 5 %
C R + C Ri Rate = 7 0 %
St o p f or ≤ 5/ 1 2 C R + C Ri
0. 5 2 6 9
0. 0 3 8 6
St o p f or ≤ 1 5/ 2 5 C R + C Ri
0. 4 3 0 1
0. 1 5 7 2
O btai n ≥ 1 6/ 2 5 C R + C Ri
0. 0 4 2 9
0. 8 0 4 2
T he desi g n para meters of a n u nacce pta ble C R + C Ri rate of 4 5 % a n d a pr o misi n g C R + C Ri 
rate of 7 0 % were c h ose n base d o n t he p u blis he d e x perie nce3 ( htt p:// d oi. or g/ 1 0. 1 1 8 2/ bl o o d-
2 0 1 9- 1 3 1 9 1 1) wit h 1 4 5 t hera p y relate d A M L patie nts. Of t hese patie nts, 4 7 % ac hie ve d C R 
a n d 3 9 % ha d n o e vi de nce of le u ke mia.
We pla n t o pa use e nr oll me nt at a n y ti me t he o utc o me of t he m ost rece nt e nr ollee ma y 
satisf y t he st o p pi n g criteria of t his t w o-sta ge desi g n f or C R + C Ri. We will c hec k t he data at 
t he ti me of eac h ne w patie nt e nr oll me nt t o deter mi ne w het her t he st u d y is i n s uc h a 
sit uati o n.
1 1. 2 
T hree- St a ge Desi g n f or T oler a bilit y M o nit ori n g
It is als o critical t o m o nit or t he t olera bilit y of t he t hera p y of t his pr ot oc ol. F or t his p ur p ose, 
we defi ne a t oler a bility s uccess as a patie nt c o m pleti n g t w o c o urses of t hera p y wit h o ut 
e x perie nci n g a gra de 4 or 5 n o n- he mat ol o gic t o xicit y. We c o nsi der a t oler a bility s uccess 
r ate ( T S R) less t ha n 7 0 % t o be u nacce pta ble. We will m o nit or t olera bilit y wit h t he e xact 
t hree-sta ge bi n o mial desi g n s h o w n i n Ta ble 2 bel o w. We will st o p e nr oll me nt a n d declare 
t he t hera p y t o be i nt olera ble if n o ne of t he first 5 patie nts, 5 or fe wer of t he first 1 2, or 1 4 or 
fe wer of 2 5 patie nts s uccessf ull y t olerate t he first t w o c o urses of pr ot oc ol t hera p y. If n o ne 
of t hese criteria are met a n d 1 5 or m ore of 2 5 patie nts s uccessf ull y t olerate t he first t w o 
c o urses, t he n t he t hera p y will be declare d t olera ble. T his m o nit ori n g r ule has a 2 0 % 
pr o ba bilit y of declari n g t he t hera p y t olera ble if t he p o p ulati o n T S R is 5 0 % a n d a n 8 8. 8 % 
pr o ba bilit y of declari n g t he t hera p y t olera bilit y if t he p o p ulati o n T S R is 7 0 %.
We pla n t o pa use e nr oll me nt at a n y ti me t he o utc o me of t he m ost rece nt e nr ollee ma y 
satisf y t he t olera bilit y m o nit ori n g st o p pi n g r ule. We will c hec k t he data at t he ti me of eac h 
ne w patie nt e nr oll me nt t o deter mi ne w het her t he st u d y is i n s uc h a sit uati o n.
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 2 9 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
1 1. 3 
St atistic al A n al ysis Pl a n f or Sec o n d ar y O bjecti ves
O bjecti ve 1. 2. 1: Descri be t he t oxicity pr ofile of p atie nts wit h S M N tre ate d wit h o ne or t w o 
c o urses of C P X- 3 5 1.
We will defi ne cate g ories f or t he t o xicit y e ve nts (res pirat or y, car diac, etc.) a n d f or eac h 
cate g or y we will deter mi ne t he hi g hest gra de e x perie nce d b y eac h patie nt. We will t he n 
re p ort t he n u m ber of patie nts wit h eac h gra de i n eac h cate g or y.
O bjecti ve 1. 2. 2: Descri be t he bi ol o gic c orrel ates of res p o nse i n p atie nts wit h S M N after 
o ne or t w o c o urses of C P X- 3 5 1.
We will use l o gistic re gressi o n m o deli n g e x pl ore bi ol o gic c orrelates ( ge n o mic, 
tra nscri pt o mic, met h yl o mic, p har mac ol o gic, c yt o ge netics, etc.) as pre dict ors of res p o nse. 
F or ge n o mic ass ociati o ns, we will use false disc o ver y rate met h o ds t o a d dress m ulti ple 
testi n g.
O bjecti ve 1. 2. 3: Esti m ate t he 3-ye ar over all a n d eve nt-free s urviv al of p atie nts w h o 
receive d o ne or t w o c o urses of C P X- 3 5 1 f oll o we d by H S C T.
We will use t he Ka pla n- Meier met h o d t o esti mate o verall s ur vi val a n d e ve nt-free s ur vi val 
of all patie nts. We defi ne O S as t he ti me ela pse d fr o m pr ot oc ol e nr oll me nt t o deat h a n d 
ce ns or ti mes of li vi n g patie nts at last f oll o w- u p. We defi ne E F S as t he ti me ela pse d fr o m 
pr ot oc ol e nr oll me nt t o deat h, rela pse, disc o nti n uati o n of t hera p y d ue t o e xcessi ve t o xicit y 
or resista nt disease, or de vel o p me nt of a n a d diti o nal mali g na nc y a n d ce ns or ti mes f or 
patie nts free of t hese e ve nts at last f oll o w- u p. T o e x pl ore t he i m pact of tra ns pla nt, we will 
fit C o x m o dels wit h tra ns pla nt as a ti me- de pe n de nt c o variate ( wit h val ue 0 pri or t o 
tra ns pla nt a n d 1 after tra ns pla nt).
1 1. 4 
St atistic al A n al ysis Pl a n f or E x pl or at or y O bjecti ves
E x pl orat or y O bjecti ve 1. 3. 1: Descri be t he cli nic al c orrel ates of t he cyt ar a bi ne ( Ar a- C) 
p h ar m ac o ge n o mic res p o nse sc ore ( A C S), t he le uke mi a ste m cell sc ore ( p L C S 6) a n d dr u g 
resist a nce sc ore ( A D E- R S 5) i n p atie nts receivi n g C P X- 3 5 1.
We will use t he ra n k-s u m test t o c o m pare eac h of t hese sc ores bet wee n res p o n ders a n d 
n o n-res p o n ders. Als o, we will use C o x re gressi o n m o dels t o ass ociate eac h of t hese sc ores 
wit h E F S a n d O S.
T a ble 2. T hree St a ge Desi g n f or T oler a bilit y M o nit ori n g
O utc o me Pr o ba bilities as a F u ncti o n of T S R
O utc o me
T S R = 5 0 %
T S R = 6 0 %
T S R = 7 0 %
T S R = 8 0 %
St o p f or ≤ 0/ 5 s uccesses
0. 0 3 1 2
0. 0 1 0 2
0. 0 0 2 4
0. 0 0 0 3
St o p f or ≤ 5/ 1 2 s uccesses
0. 3 5 7 9
0. 1 4 9 6
0. 0 3 7 0
0. 0 0 3 8
St o p f or ≤ 1 4/ 2 5 s uccesses
0. 4 0 9 3
0. 2 7 4 6
0. 0 7 2 9
0. 0 0 4 4
O btai n ≥ 1 5/ 2 5 s uccesses
0. 2 0 1 5
0. 5 6 5 5
0. 8 8 7 7
0. 9 9 1 5
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 3 0 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
E x pl orat or y O bjecti ve 1. 3. 2: I nvesti g ate h o w ge netic lesi o ns i n le uke mic cells c h a n ge after 
C P X- 3 5 1tre at me nt.
T his will be a descri pti ve a nal ysis.
E x pl orat or y O bjecti ve 1. 3. 3: Ex pl ore t he fe asi bility of si n gle-cell D N A se q ue nci n g 
(sc D N Ase q) f or c h ar acteriz ati o n a n d tr acki n g of cl o n al re pert oires.
T his will be a descri pti ve a nal ysis.
1 2. 0  
O B T AI NI N G I N F O R M E D C O N S E N T
1 2. 1  
C o nse nt Pri or t o Rese arc h I nter ve nti o ns
I nitiall y, i nf or me d c o nse nt will be s o u g ht f or t he i nstit uti o nal ba n ki n g pr ot oc ol ( T B A N K) 
a n d f or ot her pr oce d ures as necessar y. D uri n g t he scree ni n g pr ocess f or eli gi bilit y, i nf or me d 
c o nse nt is re q uire d bef ore a n y researc h tests are perf or me d.
T he pr ocess of i nf or me d c o nse nt a n d asse nt f or C P X S M N will f oll o w i nstit uti o nal p olic y. 
T he i nf or me d c o nse nt pr ocess is a n o n g oi n g o ne t hat be gi ns at t he ti me of dia g n osis a n d 
e n ds after t he c o m pleti o n of t hera p y. I nf or me d c o nse nt s h o ul d be o btai ne d b y t he atte n di n g 
p h ysicia n or his/ her desi g nee, i n t he prese nce of at least o ne n o n- p h ysicia n wit ness. 
T hr o u g h o ut t he e ntire treat me nt peri o d, partici pa nts a n d t heir pare nts recei ve c o nsta nt 
e d ucati o n fr o m healt h pr ofessi o nals at St. J u de a n d are e nc o ura ge d t o as k q uesti o ns 
re gar di n g alter nati ves a n d t hera p y. All fa milies ha ve rea d y access t o c ha plai ns, 
ps yc h ol o gists, s ocial w or kers, a n d c hil d life s pecialists, i n a d diti o n t o t hat pr o vi de d b y t he 
pri mar y cli nicia ns i n v ol ve d i n t heir care.
1 2. 2  
C o nse nt at A ge of M aj orit y
T he a ge of maj orit y i n t he state of Te n nessee is 1 8 years ol d. Researc h partici pa nts m ust be 
c o nse nte d at t he ne xt cli nic visit after t heir 1 8 t h birt h da y. If a n affiliate is l ocate d i n a 
c o u ntr y or state w here a differe nt a ge of maj orit y a p plies, t hat l ocati o n m ust c o nse nt t he 
partici pa nts acc or di n g t o t heir l ocal la ws.
1 2. 3  
C o nse nt W he n E n glis h is N ot t he Pri m ar y L a n g u a ge
W he n E n glis h is n ot t he patie nt, pare nt, or le gall y a ut h orize d re prese ntati ve’s pri mar y 
la n g ua ge, t he S ocial W or k de part me nt will deter mi ne t he nee d f or a n i nter preter. T his 
i nf or mati o n d oc u me nte d i n t he partici pa nt’s me dical rec or d. Eit her a certifie d i nter preter or 
t he tele p h o ne i nter preter’s ser vice will be use d t o tra nslate t he c o nse nt i nf or mati o n. T he 
pr ocess f or o btai ni n g a n i nter preter a n d f or t he a p pr o priate use of a n i nter preter is o utli ne d 
o n t he I nter preter Ser vices, O H S P, a n d C T O we bsites. 
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 3 1 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
1 3. 0  
R E F E R E N C E S
1.
A d va ni P G, Sc h o nfel d SJ, C urtis R E, et al: Ris k of t hera p y-relate d m yel o d ys plastic 
s y n dr o me/ac ute m yel oi d le u ke mia after c hil d h o o d ca ncer: a p o p ulati o n- base d st u d y. Le u ke mia 
3 3: 2 9 4 7- 2 9 7 8, 2 0 1 9
2.
Hiji ya N, Ness K K, Ri beir o R C, et al: Ac ute le u ke mia as a sec o n dar y mali g na nc y i n c hil dre n 
a n d a d olesce nts: c urre nt fi n di n gs a n d iss ues. Ca ncer 1 1 5: 2 3- 3 5, 2 0 0 9
3.
Waac k K, et al: Treat me nt-relate d ac ute m yel oi d le u ke mia. Bl o o d, 2 0 1 9
4.
Mc Ner ne y M E, G o dle y L A, Le Bea u M M: T hera p y-relate d m yel oi d ne o plas ms: w he n ge netics 
a n d e n vir o n me nt c olli de. Nat Re v Ca ncer 1 7: 5 1 3- 5 2 7, 2 0 1 7
5.
B hatia S: T hera p y-relate d m yel o d ys plasia a n d ac ute m yel oi d le u ke mia. Se mi n O nc ol 4 0: 6 6 6-
7 5, 2 0 1 3
6.
Wi nic k NJ, Mc Ke n na R W, S h uster JJ, et al: Sec o n dar y ac ute m yel oi d le u ke mia i n c hil dre n 
wit h ac ute l y m p h o blastic le u ke mia treate d wit h et o p osi de. J Cli n O nc ol 1 1: 2 0 9- 1 7, 1 9 9 3
7.
Glasser C L, Lee A, Esli n D, et al: E pi ge netic C o m bi nati o n T hera p y f or C hil dre n Wit h 
Sec o n dar y M yel o d ys plastic S y n dr o me ( M D S)/ Ac ute M yel oi d Le u ke mia ( A M L) a n d 
C o nc urre nt S oli d T u m or Rela pse. J Pe diatr He mat ol O nc ol 3 9: 5 6 0- 5 6 4, 2 0 1 7
8.
B hatia S, Krail o M D, C he n Z, et al: T hera p y-relate d m yel o d ys plasia a n d ac ute m yel oi d 
le u ke mia after E wi n g sarc o ma a n d pri miti ve ne ur oect o der mal t u m or of b o ne: A re p ort fr o m t he 
C hil dre n's O nc ol o g y Gr o u p. Bl o o d 1 0 9: 4 6- 5 1, 2 0 0 7
9.
Ma her O M, Sil va J G, W u J, et al: O utc o mes of c hil dre n, a d olesce nts, a n d y o u n g a d ults 
f oll o wi n g all o ge neic ste m cell tra ns pla ntati o n f or sec o n dar y ac ute m yel oi d le u ke mia a n d 
m yel o d ys plastic s y n dr o mes- T he M D A n ders o n Ca ncer Ce nter e x perie nce. Pe diatr Tra ns pla nt 
2 1, 2 0 1 7
1 0. K o b os R, Stei n herz P G, Ker na n N A, et al: All o ge neic he mat o p oietic ste m cell tra ns pla ntati o n 
f or pe diatric patie nts wit h treat me nt-relate d m yel o d ys plastic s y n dr o me or ac ute m yel o ge n o us 
le u ke mia. Bi ol Bl o o d Marr o w Tra ns pla nt 1 8: 4 7 3- 8 0, 2 0 1 2
1 1. Stra h m B, Wl o dars ki, M., Past or, V., et al: I m pact of s o matic m utati o ns o n t he o utc o me of 
c hil dre n a n d a d olesce nts wit h t hera p y-relate d m yel o d ys plastic s y n dr o me, Bl o o d, 2 0 1 6, p p 
3 1 6 2
1 2. Tar di P, J o h nst o ne S, Haras y m N, et al: I n vi v o mai nte na nce of s y ner gistic 
c ytara bi ne: da u n or u bici n rati os greatl y e n ha nces t hera pe utic efficac y. Le u k Res 3 3: 1 2 9- 3 9, 
2 0 0 9
1 3. Ki m H P, Ger har d B, Haras y m T O, et al: Li p os o mal e nca ps ulati o n of a s y ner gistic m olar rati o 
of c ytara bi ne a n d da u n or u bici n e n ha nces selecti ve t o xicit y f or ac ute m yel oi d le u ke mia 
pr o ge nit ors as c o m pare d t o a nal o g o us n or mal he mat o p oietic cells. E x p He mat ol 3 9: 7 4 1- 5 0, 
2 0 1 1
1 4. Fel d ma n EJ, La ncet J E, K olitz J E, et al: First-i n- ma n st u d y of C P X- 3 5 1: a li p os o mal carrier 
c o ntai ni n g c ytara bi ne a n d da u n or u bici n i n a fi xe d 5: 1 m olar rati o f or t he treat me nt of rela pse d 
a n d refract or y ac ute m yel oi d le u ke mia. J Cli n O nc ol 2 9: 9 7 9- 8 5, 2 0 1 1
1 5. La ncet J E, C ortes J E, H o g ge D E, et al: P hase 2 trial of C P X- 3 5 1, a fi xe d 5: 1 m olar rati o of 
c ytara bi ne/ da u n or u bici n, vs c ytara bi ne/ da u n or u bici n i n ol der a d ults wit h u ntreate d A M L. 
Bl o o d 1 2 3: 3 2 3 9- 4 6, 2 0 1 4
1 6. C ortes J E, G ol d ber g S L, Fel d ma n EJ, et al: P hase II, m ultice nter, ra n d o mize d trial of C P X- 3 5 1 
(c ytara bi ne: da u n or u bici n) li p os o me i njecti o n vers us i nte nsi ve sal va ge t hera p y i n a d ults wit h 
first rela pse A M L. Ca ncer 1 2 1: 2 3 4- 4 2, 2 0 1 5
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 3 2 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
1 7. A bsal o n MJ: A p hase I/ pil ot st u d y of C P X- 3 5 1 [ da u n or u bici n a n d c ytara bi ne li p os o me f or 
i njecti o n ( V y xe os ®)] f or c hil dre n, a d olesce nts a n d y o u n g a d ults wit h rec urre nt or refract or y 
ac ute le u ke mia. 1 3 2:, 2 0 1 8
1 8. C o o per T M, A bsal o n MJ, Al o nz o T A, et al: P hase I/II St u d y of C P X- 3 5 1 F oll o we d b y 
Fl u dara bi ne, C ytara bi ne, a n d Gra n ul oc yte- C ol o n y Sti m ulati n g Fact or f or C hil dre n Wit h 
Rela pse d Ac ute M yel oi d Le u ke mia: A Re p ort Fr o m t he C hil dre n's O nc ol o g y Gr o u p. J Cli n 
O nc ol 3 8: 2 1 7 0- 2 1 7 7, 2 0 2 0
1 9. Li m W S, Tar di P G, D os Sa nt os N, et al: Le u ke mia-selecti ve u pta ke a n d c yt ot o xicit y of C P X-
3 5 1, a s y ner gistic fi xe d-rati o c ytara bi ne: da u n or u bici n f or m ulati o n, i n b o ne marr o w xe n o grafts. 
Le u k Res 3 4: 1 2 1 4- 2 3, 2 0 1 0
2 0.
Wa n g Q, G osseli n, N., A bsal o n M.J., et. al: C P X- 3 5 1 e x p os ure-res p o nse a nal yses f or efficac y 
a n d safet y i n pe diatric patie nts wit h rela pse d or refract or y ac ute m yel oi d le u ke mia ( A M L). 
Prese nte d at t he Bl o o d, 2 0 2 0
2 1. La ncet J E, U y, G., C ortes, J., et al: Fi nal res ults of a p hase III ra n d o mize d trial of C P X- 3 5 1 
vers us 7 + 3 i n ol der patie nts wit h ne wl y dia g n ose d hi g h ris k (sec o n dar y) A M L. J Cli n O nc ol 
3 4: 7 0 0 0, 2 0 1 6
2 2. La ncet J E, U y G L, Ne well L F, et al: C P X- 3 5 1 vers us 7 + 3 c ytara bi ne a n d da u n or u bici n 
c he m ot hera p y i n ol der a d ults wit h ne wl y dia g n ose d hi g h-ris k or sec o n dar y ac ute m yel oi d 
le u kae mia: 5- year res ults of a ra n d o mise d, o pe n-la bel, m ultice ntre, p hase 3 trial. La ncet 
Hae mat ol 8:e 4 8 1-e 4 9 1, 2 0 2 1
2 3. A A M L 1 8 3 1: A p hase 3 ra n d o mize d trial f or patie nts wit h de n o v o A M L c o m pari n g sta n dar d 
t hera p y i ncl u di n g ge mt uz u ma b oz o ga mici n G O t o C P X- 3 5 1 wit h G O, a n d t he a d diti o n of t he 
F L T 3 i n hi bit or gilteriti ni b f or patie nts wit h F L T 3 m utati o ns., 
2 4. Kas pers GJ, Zi m mer ma n n M, Rei n har dt D, et al: I m pr o ve d o utc o me i n pe diatric rela pse d ac ute 
m yel oi d le u ke mia: res ults of a ra n d o mize d trial o n li p os o mal da u n or u bici n b y t he I nter nati o nal 
B F M St u d y Gr o u p. J Cli n O nc ol 3 1: 5 9 9- 6 0 7, 2 0 1 3
2 5. H ort o n T M, Pere ntesis J P, Ga mis A S, et al: A P hase 2 st u d y of b ortez o mi b c o m bi ne d wit h 
eit her i dar u bici n/c ytara bi ne or c ytara bi ne/et o p osi de i n c hil dre n wit h rela pse d, refract or y or 
sec o n dar y ac ute m yel oi d le u ke mia: a re p ort fr o m t he C hil dre n's O nc ol o g y Gr o u p. Pe diatr 
Bl o o d Ca ncer 6 1: 1 7 5 4- 6 0, 2 0 1 4
2 6. C o o per T M, Al o nz o T A, Ger bi n g R B, et al: A A M L 0 5 2 3: a re p ort fr o m t he C hil dre n's 
O nc ol o g y Gr o u p o n t he efficac y of cl ofara bi ne i n c o m bi nati o n wit h c ytara bi ne i n pe diatric 
patie nts wit h rec urre nt ac ute m yel oi d le u ke mia. Ca ncer 1 2 0: 2 4 8 2- 9, 2 0 1 4
2 7.
Wa n g Q, Tar di P, Sa d o ws ki N, et al: P har mac o ki netics, dr u g meta b olis m, a n d tiss ue 
distri b uti o n of C P X- 3 5 1 i n a ni mals. Na n o me dici ne 3 0: 1 0 2 2 7 5, 2 0 2 0
2 8. Rafi yat h S M, Ras ul M, Lee B, et al: C o m paris o n of safet y a n d t o xicit y of li p os o mal 
d o x or u bici n vs. c o n ve nti o nal a nt hrac ycli nes: a meta-a nal ysis. E x p He mat ol O nc ol 1: 1 0, 2 0 1 2
2 9. Batist G, Ra ma kris h na n G, Ra o C S, et al: Re d uce d car di ot o xicit y a n d preser ve d a ntit u m or 
efficac y of li p os o me-e nca ps ulate d d o x or u bici n a n d c ycl o p h os p ha mi de c o m pare d wit h 
c o n ve nti o nal d o x or u bici n a n d c ycl o p h os p ha mi de i n a ra n d o mize d, m ultice nter trial of 
metastatic breast ca ncer. J Cli n O nc ol 1 9: 1 4 4 4- 5 4, 2 0 0 1
3 0. Li n T L, Ne well L F, St uart R K, et al: A p hase 2 st u d y t o assess t he p har mac o ki netics a n d 
p har mac o d y na mics of C P X- 3 5 1 a n d its effects o n car diac re p olarizati o n i n patie nts wit h ac ute 
le u ke mias. Ca ncer C he m ot her P har mac ol 8 4: 1 6 3- 1 7 3, 2 0 1 9
3 1. Le ger KJ, A bsal o n, M.J., De missel, B. G., et al: C ha n ge i n car diac f u ncti o n wit h C P X- 3 5 1 i n 
rela pse d pe diatric A M L: a C hil dre n's O nc ol o g y Gr o u p ( C O G) re p ort fr o m A A M L 1 4 2 1. J Cli n 
O nc ol 3 8: 1 0 5 3 2, 2 0 2 0
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

C P X S M N
Pa ge 3 3 of 3 3
Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
3 2. Elsa ye d A H, Ca o X, Cre ws K R, et al: C o m pre he nsi ve Ara- C S N P sc ore pre dicts le u ke mic cell 
i ntracell ular ara- C T P le vels i n pe diatric ac ute m yel oi d le u ke mia patie nts. P har mac o ge n o mics 
1 9: 1 1 0 1- 1 1 1 0, 2 0 1 8
3 3. Elsa ye d A H, Rafiee R, Ca o X, et al: A si x- ge ne le u ke mic ste m cell sc ore i de ntifies hi g h ris k 
pe diatric ac ute m yel oi d le u ke mia. Le u ke mia 3 4: 7 3 5- 7 4 5, 2 0 2 0
3 4. A b delra h ma n Hea: a 5- ge ne Ara- C, da u n or u bici n a n d et o p osi de ( A D E) dr u g res p o nse sc ore as 
a pr o g n ostic t o ol t o pre dict A M L treat me nt o utc o me. Bl o o d 1 3 4: 1 4 2 9, 2 0 1 9
3 5. Sc h wartz J R, Ma J, Ka me ns J, et al: T he ac q uisiti o n of m olec ular dri vers i n pe diatric t hera p y-
relate d m yel oi d ne o plas ms. Nat C o m m u n 1 2: 9 8 5, 2 0 2 1
3 6. Nic oletti E, Ra o G, B uere n J A, et al: M osaicis m i n Fa nc o ni a ne mia: c o ncise re vie w a n d 
e val uati o n of p u blis he d cases wit h f oc us o n cli nical c o urse of bl o o d c o u nt n or malizati o n. A n n 
He mat ol 9 9: 9 1 3- 9 2 4, 2 0 2 0
3 7. Feije n E A, Leise nri n g W M, Stratt o n K L, et al: E q ui vale nce Rati o f or Da u n or u bici n t o 
D o x or u bici n i n Relati o n t o Late Heart Fail ure i n S ur vi v ors of C hil d h o o d Ca ncer. J Cli n O nc ol 
3 3: 3 7 7 4- 8 0, 2 0 1 5
3 8. Feije n E A M, Leise nri n g W M, Stratt o n K L, et al: Deri vati o n of A nt hrac ycli ne a n d 
A nt hra q ui n o ne E q ui vale nce Rati os t o D o x or u bici n f or Late- O nset Car di ot o xicit y. J A M A 
O nc ol 5: 8 6 4- 8 7 1, 2 0 1 9
3 9. Nara ya n H K, Getz K D, Le ger KJ: Mi ni mizi n g car diac t o xicit y i n c hil dre n wit h ac ute m yel oi d 
le u ke mia. He mat ol o g y A m S oc He mat ol E d uc Pr o gra m 2 0 2 1: 3 6 8- 3 7 5, 2 0 2 1
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
A P P E N DI X I: P E R F O R M A N C E S T A T U S C RI T E RI A
P E R F O R M A N C E S T A T U S C RI T E RI A
K ar n ofsky a n d L a nsky perf or m a nce sc ores are i nte n de d t o be m ulti ples of 1 0
E C O G ( Z u br o d)
K ar n ofs k y
L a ns k y
Sc ore
Descri pti o n
Sc ore
Descri pti o n
Sc ore
Descri pti o n
1 0 0
N or mal, n o c o m plai nts, 
n o e vi de nce of disease
1 0 0
F ull y acti ve, n or mal
0
F ull y acti ve, a ble t o 
carr y o n all pre- disease 
perf or ma nce wit h o ut 
restricti o n
9 0
A ble t o carr y o n n or mal 
acti vit y, mi n or si g ns or 
s y m pt o ms of disease
9 0
Mi n or restricti o ns i n 
p h ysicall y stre n u o us 
acti vit y
8 0
N or mal acti vit y wit h 
eff ort; s o me si g ns or 
s y m pt o ms of disease
8 0
Acti ve, b ut tires m ore 
q uic kl y
1
Restricte d i n p h ysicall y 
stre n u o us acti vit y b y 
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
7 0
Cares f or self; u na ble t o 
carr y o n n or mal acti vit y 
or d o acti ve w or k
7 0
B ot h greater 
restricti o n of a n d less 
ti me s pe nt i n pla y 
acti vit y
6 0
Re q uires occasi o nal 
assista nce, b ut is a ble t o 
care f or m ost of his/ her 
nee ds
6 0
U p a n d ar o u n d, b ut 
mi ni mal acti ve pla y; 
kee ps b us y wit h 
q uieter acti vities
2
A m b ulat or y a n d 
ca pa ble of 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
5 0
Re q uires c o nsi dera ble 
assista nce a n d fre q ue nt 
me dical care
5 0
Gets dresse d, b ut lies 
ar o u n d m uc h of t he 
da y; n o acti ve pla y, 
a ble t o partici pate i n 
all q uiet pla y a n d 
acti vities
4 0
Disa ble d, re q uires s pecial 
care a n d assista nce
4 0
M ostl y i n be d; 
partici pates i n q uiet 
acti vities
3
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
3 0
Se verel y disa ble d, 
h os pitalizati o n i n dicate d; 
deat h n ot i m mi ne nt
3 0
I n be d; nee ds 
assista nce e ve n f or 
q uiet pla y
2 0
Ver y sic k, h os pitalizati o n 
i n dicate d.  Deat h n ot 
i m mi ne nt
2 0
Ofte n slee pi n g; pla y 
e ntirel y li mite d t o 
ver y passi ve acti vities
4
C o m pletel y disa ble d; 
ca n n ot carr y o n a n y 
self-care; t otall y 
c o nfi ne d t o be d or 
c hair
1 0
M ori b u n d, fatal pr ocesses 
pr o gressi n g ra pi dl y
1 0
N o pla y; d oes n ot get 
o ut of be d
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5

Re visi o n 2. 1, date d: 0 3- 3 1- 2 0 2 5
Pr ot oc ol d oc u me nt date: 0 3- 3 1- 2 0 2 5
A P P E N DI X II: D R U G S, F O O D A N D S U P P L E M E N T S I N T E R A C TI O N S
Dr u gs t hat ma y i nteract wit h da u n or u bici n:

S o me a nti bi otics a n d a ntif u n gals (clarit hr o m yci n, er yt hr o m yci n, itrac o naz ole, 
ket oc o naz ole, rifa m pi n)

S o me a ntie pile ptics (car ba maze pi ne, p he n o bar bital, p he n yt oi n, f os p he n yt oi n)

S o me a ntiretr o virals (la pati ni b, l o pi na vir; nelfi na vir, rit o na vir, sa q ui na vir, tela pre vir, 
ti pra na vir)

S o me heart me dicati o ns (a mi o dar o ne, car ve dil ol, di g o xi n, dr o ne dar o ne, q ui ni di ne, 
pr o pafe n o ne, vera pa mil)

Ot her a ge nts, s uc h as at or vastati n, cl oza pi ne, c ycl os p ori ne, de xa met has o ne, i vacaft or, 
lefl u n o mi de, l u macaft or, nataliz u ma b, nefaz o d o ne, pr o gester o ne, ra n olazi ne, rifa m pi n, 
tacr oli m us, t ofaciti ni b, a n d traz o d o ne 
F o o d a n d s u p ple me nts t hat ma y i nteract wit h da u n or u bici n:

Ec hi nacea

Gra pefr uit, gra pefr uit j uice, Se ville ora n ges, star fr uit

St. J o h n’s W ort

Dri n ks, f o o d, s u p ple me nts, or vita mi ns c o ntai ni n g “fla v o n oi ds” or ot her “a nti o xi da nts”
Dr u gs t hat ma y i nteract wit h c ytara bi ne ( b y vei n):

Cl oza pi ne, fl uc yt osi ne, lefl u n o mi de, nataliz u ma b
F o o d a n d s u p ple me nts t hat ma y i nteract wit h c ytara bi ne:

Ec hi nacea
St. J u d e C hil dr e n's R es e ar c h H os pit al
I R B N U M B E R: 2 2- 1 0 2 1
I R B A P P R O V A L D A T E: 0 6 / 0 3 / 2 0 2 5