Phase I/II Trial of CPX-351 + Palbociclib in Patients With Acute Myeloid Leukemia
Phase: PHASE1
Conditions: Acute Myeloid Leukemia, AML
Sponsor: Sudipto Mukherjee, MD, PhD, MPH



  
  
  
 
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Versi o n date:  1/ 2 5/ 2 0 2 2 
 
S U M M A R Y O F C H A N G E S  
Pr ot oc ol 
D ate  
Secti o n  
C h a n ge 
3/ 8 / 2 0 1 9 
Title  
Pr ot oc ol title c ha n ge d t o reflect P hase I/II u p dat e a n d f urt her clarif y 
i ncl u de d diseases 
3/ 8/ 2 0 1 9  
2. 0  
2. 1. 1 a n d 2. 1. 2 - P hase IIa a n d P hase II b w ere c h a n ge d t o P hase I 
a n d P hase II res pecti vel y  
3/ 8 / 2 0 1 9 
3. 0 
F urt her c ha n ges as a res ult of P hase IIa a n d II b bei n g c ha n ge d t o 
P hase I a n d P hase II  
3/ 8 / 2 0 1 9 
3. 1  
 
Secti o n  3. 1  “ N u m b er  of  S u bjects”  c ha n g e d  t o  “ St u d y  Desi g n  
i ncl u di n g d ose escalati o n/c o h orts” 
 
A d de d D L T ta ble a n d u p date d starti n g d ose of Pal b o t o 7 5 m g.  
 
A d de d details a b o ut t he P hase I desi g n. P hase II will be gi n after 
ma xi m u m t olerate d d ose is defi ne d. P hase II will ha ve pal b oci cli b 
a d mi nistere d at t he rec o m me n de d p hase II d ose c h ose n fr o m t he 3 
d ose le vels e val u ate d i n P hase I.  
 
A d de d secti o n a b o ut usi n g h y drea at p h ysicia n discreti o n f or pts 
wit h > 2 5, 0 0 0 W B C ; pati e nts ca n n ot b e treate d wit h pal b ocicli b a n d 
C P X -3 5 1 u ntil W B C is less t ha n or e q ual t o 2 5, 0 0 0 t o pre v e nt o vert 
t u m or l ysis s y n dr o me 
3/ 8 / 2 0 1 9 
3. 2 
Si m plifie d te xt f or n u m ber of s u bj ects t o j ust a t otal t o be e nr olle d 
bet wee n P has e I a n d P hase II  
3/ 8 / 2 0 1 9 
3. 3 
A d de d s pecifi cati o n o n h o w/if s u bjects will be re place d  
3/ 8 / 2 0 1 9 
3. 4 
A d de d: “ Patie nts will be ta ke n off t he st u d y after t h e y c o m plete t h eir 
i n d ucti o n a n d c o ns oli dati o n c he m ot hera p y will be at t he discreti o n 
of t he treati n g p h ysicia n. ”  
3/ 8 / 2 0 1 9 
4. 1 
I n cl usi o n Criteria s plit i nt o P hase I a n d P hase II p orti o ns 
3/ 8 / 2 0 1 9 
4. 1 
I n cl usi o n Criteria a ge f or P hase 1 is n o w ≥1 8 years of a ge  i nstea d 
of ≥1 8- 6 5 
 
F urt her cl arifie d t he t y pes of ac ute m yel oi d le u ke mia all o we d o n 
trial 
 
A d de d a n I n cl usi o n Criteria secti o n f or t h e P hase II p orti o n  
3/ 8 / 2 0 1 9 
6. 1 
C ha n ge d details of d osi n g sc he ma t o reflect c ha n g es ma de earlier i n 
t he pr ot oc ol; a d de d o pti o n f or F L T 3-I T D patie nts t o c h o ose b et wee n 
sta yi n g  o n  trial  or  s witc hi n g  t o  mi d osta uri n;  H y drea  discreti o n  
a d de d here t o o 
 
U p date d st u d y s c he ma gra p hic t o reflect t h e p al b ocicli b starti n g 
d ose c ha n ge  

  
  
  
 
Pa ge 4    
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
Pr ot oc ol 
D ate  
Secti o n  
C h a n ge 
3/ 8 / 2 0 1 9 
6. 1. 2 
Clarifie d C P X - 3 5 1 d osi n g 
3/ 8 / 2 0 1 9 
6. 2 
F urt her clarifi e d D L T a n d a d de d H y’s L a w  
3/ 8 / 2 0 1 9 
6. 3 
Misse d d oses of pal b ocicli b will n ot be ma de u p 
3/ 8 / 2 0 1 9 
7. 0  
U p date d d ose d ela y/ m o dificati o n g ui deli nes u p dat e d  
3/ 8 / 2 0 1 9 
8. 0- 8. 2 
A d de d a d diti o nal ris ks a n d si de effects  
3/ 8 / 2 0 1 9 
1 4. 2  
F urt her d efi ne d pri mar y e n d p oi nt f or P hase II safet y m o nit ori n g  
3/ 8 / 2 0 1 9 
1 4. 0 – 1 4. 3 
U p dates t o statistical a nal ysis pla n a n d safet y/efficac y m o nit ori n g  
3/ 8 / 2 0 1 9 
A p pe n di x III  
D u plicate A p pe n di x III re gar di n g Pal b ocicli b 1 2 5 m g d ose sc he d ule 
was delete d  
3/ 8 / 2 0 1 9 
T hr o u g h o ut 
U p date d C P X -3 5 1 d ose u nits fr o m u/ m 2 t o s pecif y h o w m uc h of 
da u n or u bici n a n d c yt ara bi ne is bei n g use d 
 
Mi n or a d mi nistrati ve a n d f or matti n g c ha n ges  
3/ 8 / 2 0 1 9 
1 3. 2 
U p date d secti o n t o reflect t he use of m ulti ple data bases  
7/ 1 8/ 2 0 1 9  
T hr o u g h o ut 
A d mi nistrati ve, f or matti n g, a n d c o nsiste nc y u p dat es were ma de 
t hr o u g h o ut t he pr ot oc ol 
7/ 1 8/ 2 0 1 9  
T hr o u g h o ut 
C T C A E versi o n was c orrecte d fr o m versi o n 4. 0 versi o n 5. 0 
7/ 1 8/ 2 0 1 9  
3. 1; 3. 4; 6. 1  
Da y 2 8 ( ± 5 da ys) bi o ps y was c ha n g e d t o Da y 3 5 ( ± 7 da ys)  
7/ 1 8/ 2 0 1 9  
3. 1; 6. 2 
Clarificati o n was a d d e d t o D L T ti mi n g a n d defi niti o n  
7/ 1 8/ 2 0 1 9  
4. 1  
P hase II eli gi bilit y clarifi cati o n of a ge ra n g e  
7/ 1 8/ 2 0 1 9  
6. 1; 6. 2; 7. 0 
D ose m o dificati o n g ui deli nes were re vise d t o i nstr uct t o s ki p 
pal b ocicli b d osi n g if Q Tc B is a b o ve 4 8 0 ms  
7/ 1 8/ 2 0 1 9  
6. 1 
St u d y sc he ma was re vise d t o be c o nsiste nt wit h t he te xt  a n d t o 
ill ustrate t he treat me nt sc he d ule f or re-i n d ucti o n 
7/ 1 8/ 2 0 1 9  
6. 4 
Earl y re m o val criteria was clarifie d t o be s e parate t ha n E n d Of 
Treat me nt criteria  
7/ 1 8/ 2 0 1 9  
6. 5 
D urati o n of f oll o w u p w as re vise d t o m ore cl osel y ali g n wit h 
i nstit uti o nal sta n dar d of care 
7/ 1 8/ 2 0 1 9  
9. 1. 1 
Pal b ocicli b dis pe nsi n g i nstr ucti o ns were re vise d t o m ore 
acc uratel y reflect i nstit uti o nal g ui deli nes a n d pr oce d ures.  
7/ 1 8/ 2 0 1 9  
1 0. 0 
C o ntact i nf or mati o n was u p date d f or c ollecti n g a n d se n di n g 
c orrel ati ve sa m ples  
7/ 1 8/ 2 0 1 9  
1 1. 1. 3; 1 1. 3  
A d diti o n of i nstr ucti o ns f or re-i n d ucti o n 
7/ 1 8/ 2 0 1 9  
1 1. 1. 4 
A d diti o n of i nstr ucti o ns f or E n d of Treat me nt ti mi n g a n d 
pr oce d ures  
7/ 1 8/ 2 0 1 9  
1 1. 2 
A d de d a n E C H O or M U G A t o be d o ne at s cree ni n g t o test f or 
L V E F  
7/ 1 8/ 2 0 1 9  
1 1. 3 
A d de d se parate cale n d ar f or re-i n d ucti o n f or cl arit y 
7/ 1 8/ 2 0 1 9  
1 3. 1 
A d de d re vise d l a n g ua ge f or data b ase t o i ncl u de F orte E D C 

  
  
  
 
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Versi o n date:  1/ 2 5/ 2 0 2 2 
 
Pr ot oc ol 
D ate  
Secti o n  
C h a n ge 
1 0/ 2 4 / 1 9 
A p pe n di x I V  
C yt o ge netics were m a de t o n ot be re q uire d o n t he Da y 1 4 b o ne 
marr o w bi o ps y  
1 0/ 2 4/ 1 9  
t hr o u g h o ut 
Mi n or f or matti n g a n d c o nsiste nc y u p dates were ma de t hr o u g h o ut 
t he pr ot oc ol 
3/ 9 / 2 0 2 0 
3. 1; 1 4. 0 
M o difie d t he re q uire me nts t o all o w 3 (i nstea d of 6) patie nts i n 
p hase 1 t o be e nr olle d at t he rec o m me n d e d p hase II d ose  
3/ 9/ 2 0 2 0  
3. 2 
C ha n ge d t he o verall  e nr oll me nt g oal fr o m 3 6 t o 3 5 
3/ 9/ 2 0 2 0  
8. 1; 8. 2 
Re vise d t he ris k ta bles t o matc h t he c o nse nt 
3/ 9/ 2 0 2 0  
1 1. 2 
Re m o ve d t he Da y 1 4 E C G fr o m t he st u d y cale n d ar 
3/ 9/ 2 0 2 0  
1 4. 0; 1 4. 1; 
1 4. 2  
Re vise d t he P hase II effi cac y a n d safet y m o nit ori n g statistical pla n  
4/ 2 2/ 2 0 2 0  
C o ver Pa ge 
A d di n g U H as a site t o t h e st u d y 
4/ 2 2/ 2 0 2 0  
1 0. 0  
U p date d w or kfl o w f or c orrelati ve bl o o d dra w at scree ni n g  
1/ 1 5/ 2 0 2 1  
T hr o u g h o ut 
A d mi nistrati ve, f or matti n g, a n d c o nsiste nc y u p dat es were ma de 
t hr o u g h o ut t he pr ot oc ol t o reflect tra nsiti o n fr o m Dr. Naz ha t o Dr. 
M u k herjee  
1/ 1 5/ 2 0 2 1  
9. 1. 1 
A d de d i n c ha n g es t o refl ect t he use of eit her ca ps ules or ta blets f or 
Pal b ocicli b.  
1/ 1 5/ 2 0 2 1  
9. 1. 1 
I nf or mati o n a d de d t o s h o w t he differe nt c haracteristics of t he 
Pal b o cicli b ta blets 
1/ 1 5/ 2 0 2 1  
9. 1. 1 
Re m o ve d d osi n g le vels of 7 5 m g a n d 1 0 0 m g of Pal b ocicli b si nce 
st u d y has m o ve d past t he d ose escal ati o n p hase a n d o nl y usi n g 
1 2 5 m g n o w.  
1/ 2 5/ 2 0 2 2  
T hr o u g h o ut 
Re m o ve d U H as t he y are n o l o n ger partici pati n g 
 
 
 

  
  
  
 
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A B B R E VI A TI O N S  
C C C C  
Case C o m pre he nsi ve Ca ncer Ce nter  
C R F  
Case Re p ort F or m  
D S T C  
Data Safet y a n d T o xicit y C o m mittee  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
I C F 
I nf or me d C o nse nt F or m 
I R B 
I nstit uti o nal Re vie w B oar d 
P R M C  
Pr ot oc ol Re vie w a n d M o nit ori n g C o m mittee  
S O C  
Sta n dar d of Car e  
C C F  
Cle vela n d Cli nic F o u n dati o n  
M D S  
M yel o d ys plastic S y n dr o mes  
C M M L  
C hr o nic M yel o m o n oc ytic Le u ke mia  
M P N  
M yel o pr olif erati ve Ne o plas m 
A M L  
Ac ute M yel oi d Le u k e mia  
D N A  
De o x yri b o n ucleic aci d  
F D A  
T he F o o d a n d Dr u g A d mi nistrati o n  
H M As  
H y p o met h ylati n g A ge nts  
O R R  
O verall Res p o nse Rate  
S C  
S u bc uta ne o us  
N CI  
Nati o nal Ca ncer I nstit ute  
P O  
Orall y  
S p  
S pecificit y pr otei n  
E O T  
E n d of Treat me nt  
C R  
C o m plete Re missi o n  
P R  
Partial Re missi o n  
HI  
He mat ol o gic I m pr o ve m e nt 
I W G 
I nter nati o nal W or ki n g Gr o u p 
W H O  
W orl d Healt h Or ga nizati o n  
A P L  
Ac ute pr o m yel oc ytic l e u ke mia  
W B C  
W hite Bl o o d Cell  
C S F  
C ol o n y -Sti m ulati n g Fact or  
C T C A E  C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts  
A E  
A d verse E v e nt  
S A E  
Seri o us A d verse E v e nt  
D S M P  
Data a n d Saf et y M o nit ori n g Pla n  
P R B C  
Pac ke d Re d Bl o o d Cell  
A L T  
Ala ni ne tra nsa mi nas e  
A S T  
As partate a mi n otra nsferase  
E C O G  
Easter n C o o per ati ve O nc ol o g y Gr o u p  
R B C  
Re d Bl o o d Cells  
C Ri  
C o m plete Res p o nse ( C R) wit h  
i nc o m plete he mat ol o gic rec o ver y 
C R p  
C o m plete Res p o nse ( C R) wit h  
i nc o m plete platelets 

  
  
  
 
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I E C 
I n d e pe n de nt Et hics C o m mittee 
G C P  
G o o d Cli nical Practice  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
HI P A A  
Healt h I ns ura nce P orta bilit y a n d  
Acc o u nta bilit y Act of 1 9 9 6  
E O S  
E n d of St u d y  
B U N  
Bl o o d Urea Nitr o ge n  
M C V  
Mea n C or p usc ular V ol u me  
M C H C  
Mea n Cell He m o gl o bi n C o nce ntrati o n  

  
  
  
 
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T A B L E O F C O N T E N T S  
 
1. 0  
I N T R O D U C TI O N   
 
1. 1  
Bac k gr o u n d of St u d y Disease  
1. 2   
Na me/ descri pti o n of C P X - 3 5 1 
1. 3   
Na me/ descri pti o n of Pal b ocicli b  
1. 4  
Rati o nale    
 
2. 0 
O B J E C TI V E S  
2. 1 
Pri mar y O bjecti ve  
 
2. 2  
Sec o n dar y O bj ecti ve(s)  
 
3. 0 
S T U D Y D E SI G N  
3. 1  
St u d y desi g n i ncl u di n g d ose escal ati o n / c o h orts 
3. 2  
N u m ber of S u bjects 
3. 3 
Re place me nt of S u bjects  
3. 4 
E x pecte d D urati o n of Tr eat me nt a n d S u bject Partici pati o n   
 
 
4. 0  
S U B J E C T S E L E C TI O N  
4. 1 
I n cl usi o n Criteria 
4. 2  
E xcl usi o n Criteria  
4. 3  
I n cl usi o n of W o me n a n d Mi n orities 
 
5. 0 
R E GI S T R A TI O N  

  
  
  
 
Pa ge 9    
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
  
 
6. 0  
T R E A T M E N T P L A N  
6. 1 
Treat me nt Re gi me n O v er vie w  
6. 2 
Defi niti o n of D ose Li miti n g T o xicit y  
6. 3  
Ge ner al C o nc o mita nt Me dicati o ns a n d S u p p orti ve Care G ui deli nes 
6. 4 
Criteria f or Re m o val fr o m St u d y  
6. 5  
D urati o n of F oll o w- U p  
 
7. 0 
D O S E D E L A Y S / D O S E M O DI FI C A TI O N S  
 
8. 0 
A D V E R S E E V E N T S A N D P O T E N TI A L RI S K S  
8. 1  
Pal b ocicli b  
8. 2 
C P X - 3 5 1 
8. 3 
Defi niti o ns  
8. 4  
S A E Re p ort F or m 
8. 5  
Re p orti n g Pr oce d ures f or Seri o us A d verse E v e nts  
8. 6  
Seri o us A d verse E v e nts a n d O n C ore T M     
8. 7 
Data Safet y T o xi cit y C o m mittee  
8. 8  
Data a n d Saf et y M o nit ori n g Pla n 
 
9. 0 
P H A R M A C E U TI C A L I N F O R M A TI O N  
9. 1  
I n v esti gati o nal A ge nt(s)  
 
9. 2  
I n v esti gati o nal A ge nt(s) 
 

  
  
  
 
Pa ge 1 0     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
1 0. 0 
E X P L O R A T O R Y/ C O R R E L A TI V E  
 
1 1. 0 
S T U D Y P A R A M E T E R S A N D C A L E N D A R  
1 1. 1 
St u d y Para meters  
1 1. 2 
Cale n dar  
 
1 2. 0 
M E A S U R E M E N T O F E F F E C T   
 
1 3. 0 
R E C O R D S T O B E K E P T/ R E G U L A T O R Y C O N SI D E R A TI O N S  
1 3. 1 
Data Re p orti n g  
1 3. 2  
Re g ulat or y C o nsi derati o ns  
  
 
1 4. 0 
S T A TI S TI C A L C O N SI D E R A TI O N S  
1 4. 1  
P hase II Efficac y M o nit ori n g 
1 4. 2  
P hase II Saf et y M o nit ori n g 
1 4. 3 
A nal ysis Pla n  
R E F E R E N C E S  
 
A P P E N DI C E S  
 
A P P E N DI X I: E C O G / Kar n ofs k y Perf or ma n ce Stat us Criteria    
A P P E N DI X  II: Earl y Re m o val Criteria   
A P P E N DI X  III: Res p o ns e Criteria  
A P P E N DI X  I V: Cli nical La b orat or y Para meters 
A P P E N DI X  V:  W H O Cl assificati o n  

  
  
  
 
Pa ge 1 1     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
1. 0 
I ntr o d ucti o n  
1. 1  
B ac k gr o u n d of St u d y Dise ase  
A p pr o xi matel y 2 0, 0 0 0 patie nts were di a g n ose d wit h ac ute m yel oi d le u ke mia ( A M L) wit h 
greater t ha n 1 0, 0 0 0 A M L patie nt deat hs i n t he U nite d States i n 2 0 1 7( 1 ). W hile t he 
res p o nse r ate t o c urre nt i n d ucti o n sta n dar d c h e m ot hera p y ( 7 + 3) is a p pr o xi matel y 7 0-
7 5 %, o nl y 2 0- 3 0 % of A M L patie nts will s ur vi ve be y o n d 5 years a n d t he maj orit y will 
rela pse wit hi n t he first year of treat me nt (1 ). F urt h er, a p pr o xi mat el y 2 0- 3 0 % of ne wl y 
dia g n ose d patie nts is refr act or y t o i n d ucti o n c he m ot hera p y a n d h a ve ver y p o or o utc o me 
wit h a me dia n o ver all s ur vi val of 3 m o nt hs ( 2 ). I n d ucti o n c he m ot hera p y wit h 7 + 3 has 
bee n t he sta n dar d of car e treat me nt f or n e wl y dia g n ose d A M L f or t he l ast 4 deca d es. 
N o vel a p pr oac hes t o e n h a nce t he effi cac y of treat me nt a n d decreas e rela ps e is des perat el y 
nee de d.  
 
1. 2   
N a m e a n d Descri pti o n of I n vesti g ati o n al A ge nt C P X - 3 5 1 
1. 2. 1  Precli nical Data  
C P X - 3 5 1 is a li p os o mal f or m ulati o n of a fi xe d c o m bi nati o n of t he a nti ne o plastic dr u gs 
c ytara bi ne a n d da u n or u bici n. T he t w o dr u gs are prese nt i nsi de t he li p os o me i n a 5: 1 
m olar rati o. T he li p os o me me m bra ne is c o m p ose d of distear o yl p h os p hati d ylc h oli ne, 
distear o yl p h os p hati d yl gl ycer ol a n d c h olester ol i n a 7: 2: 1 m olar rati o ( 3 ). T hese 
li p os o mes ha ve a n o mi nal dia meter of a p pr o xi matel y 1 0 0 n m a n d are s us p e n de d i n 
s ucr ose. Sterilizati o n is ac hie ve d b y filtrati o n t hr o u g h a 0. 2 2 μ m filter. C P X - 3 5 1 is 
pr o vi de d as a sterile, p yr o ge n-fr ee l y o p hilize d f or m ulati o n i n 5 0 m L glass,si n gle- use 
vials. Eac h vial c o ntai ns 1 0 0 u nits of C P X- 3 5 1 w here eac h u nit c o ntai ns 1. 0 m g 
c ytara bi ne a n d 0. 4 4 m g d a u n or u bici n base i n li p os o mes. T he l y o p hilize d ca ke is 
rec o nstit ute d wit h sterile water f or i njecti o n t o o btai n a h o m o ge ne o us dis persi o n at 5 
u nits/ m L  (3 ). T he pre- cli nical p har mac ol o g y a n d t o xic ol o g y are s u m marize d i n t he 
I n v esti gat or’s Br oc h ure f or C P X- 3 5 1. 
 

  
  
  
 
Pa ge 1 2     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
1. 2. 2 
Cli nical Data  
P h ase I st u dy of C P X- 3 5 1 
I n a p hase 1 d os e-es calati o n trial, C P X - 3 5 1 i n d ucti o n was a d mi nistere d o n d a ys 1, 3, a n d 
5 b y 9 0- mi n ute i nf usi o n t o 4 8 rela pse d or refract or y patie nts wit h ac ute m yel oi d le u ke mia 
( A M L) or hi g h-ris k m yel o d ys plasia (4 ). D oses starte d at 3 u nits/ m 2 wit h d ose d o u bli n gs 
i n si n gle- patie nt c o h orts u ntil a p har mac o d y na mic effect (treat me nt-rel ate d a d verse 
e ve nts or re d u cti o n i n b o ne marr o w cell ularit y or blast c o u nt) was o bser ve d, f oll o we d b y 
3 3 % escal ati o ns i n t hree patie nt c o h orts u ntil d ose-li miti n g t o xicit y ( D L T) occ urre d. T he 
ma xi m u m -t olerate d d ose was 1 0 1 u nits/ m 2 (4 ). D L Ts c o nsiste d of h y perte nsi ve crisis, 
c o n gesti ve heart fail ur e, a n d pr ol o n ge d c yt o pe ni as ( 4 ). A d vers e e v e nts were c o nsiste nt 
wit h c ytara bi ne a n d da u n or u bici n treat me nt. Res p o nse occ urre d at d os es as l o w as 3 2 
u nits/ m 2. Of 4 3 patie nts wit h A M L, ni ne ha d c o m plete res p o nse ( C R) a n d o ne ha d C R 
wit h i nc o m plete platelet rec o ver y; of patie nts wit h ac ute  l y m p h o blastic le u ke mia, o ne of 
t hree ha d C R. Ei g ht C Rs were ac hie v e d a m o n g t he 3 1 patie nts wit h pri or c ytara bi ne a n d 
da u n or u bici n treat me nt. C R i n A M L occ urre d i n fi ve of 2 6 patie nts a ge >/ = 6 0 years a n d 
i n fi ve of 1 7 patie nts y o u n ger t ha n a g e 6 0 years. Me dia n half-life was 3 1. 1 h o urs 
(c ytar a bi ne) a n d 2 1. 9 h o urs ( da u n or u bici n), wit h b ot h dr u gs a n d t heir meta b olites 
detecta ble > 7 da ys after t he last d ose. T he tar g ete d 5: 1 m olar rati o was mai ntai ne d at all 
d ose le vels f or u p t o 2 4 h o urs ( 4 ). 
 
P h ase II st u d ies of C P X - 3 5 1 
A ra n d o mize d, m ultice nt er, o pe n- l a bel, p hase 2 trial was c o n d uct e d t o e val uate t he 
efficac y a n d s afet y of C P X - 3 5 1 wit h i n vesti gat ors’ c h oice of first sal va g e treat me nt i n 
a d ult patie nts wit h first rela pse A M L  (5 ). T he pri mar y e n d p oi nt of t he st u d y was 1-year 
o verall s ur vi val ( O S), a n d Ka pla n- Mei er a n al ysis di d n ot s h o w a si g nifica nt differe n ce 
bet wee n t he t w o tr eat me nt gr o u ps ( H R, 0. 7 5; P = 0. 3 3). S ur vi val at 1- year was 3 6 % a n d 
2 7 % ( P = 0. 3 3) f or C P X - 3 5 1 a n d sal va ge treat me nt ar ms, res pecti vel y  (5 ). Patie nts were 
stratifie d at baseli ne acc or di n g t o t he E ur o pea n Pr o g n ostic I n d e x ( E PI), a n d res ults 
s h o we d t hat C P X - 3 5 1 treate d patie nts wit h t he E PI- defi ne d p o or-ris k strata de m o nstrate d 
hi g her res p o nse rates ( 3 9. 3 % C P X - 3 5 1 vers us 2 7. 6 % sal va ge ar m) a n d i m pr o ve me nts i n 

  
  
  
 
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e ve nt-free s ur vi v al ( E F S) ( H R, 0. 6 3; P = 0 8) a n d O S ( H R, 0. 5 5; P = 0. 0 2). T he o verall 
rates of gr a de 5 A Es wer e si milar bet wee n t h e C P X- 3 5 1 ( 2 3. 5 %) a n d sal va ge treat me nt 
ar ms ( 2 0. 5 %) ( 5 ). 
A sec o n d p has e 2, ra n d o mize d, m ultice nter, parallel-ar m, o pe n-l a bel st u d y e val uate d t he 
efficac y a n d s afet y of C P X - 3 5 1 c o m pare d wit h c o n ve nti o nal 7 + 3 re gi me n i n ne wl y 
dia g n ose d el derl y p atie nts wit h A M L ( 6 ). T he pri mar y effi cac y e n d p oi nt was res p o nse 
rate, defi ne d as c o m plet e res p o nse ( C R) + c o m plete res p o nse wit h i nc o m pl ete bl o o d 
c o u nt rec o v er y ( C Ri). T h e st u d y was p o were d t o d etect a 2 3 % i n crease i n res p o nse rate 
wit h at least 8 5 % p o wer a n d a o ne- si d e d si gnifica nce le vel of 0. 1. C P X- 3 5 1 pr o d uce d 
hi g her res p o nse rates ( 6 6. 7 % vs 5 1. 2 %, P = 0. 0 7), meeti n g pre defi ne d criteria f or s uccess 
(P < 0. 1) ( 6 ). T he c o m m o n A Es were si milar bet wee n t he t w o treat me nt gr o u ps, h o we ver, 
me dia n ti me t o A N C a n d platelet rec o v er y ti mes were l o n ger i n t he C P X - 3 5 1 gr o u p 
c o m pare d wit h 7 + 3 gr o u p ( 6 ). 
 
P h ase III st u dy of C P X- 3 5 1 
T he  p hase 3, r a n d o mize d, m ultice nter, o pe n-la b el st u d y e val uate d t he efficac y a n d safet y 
of C P X - 3 5 1 c o m pare d wit h c o n ve nti o nal 7 + 3 (c ytara bi ne f or 7 da ys pl us da u n or u bici n 
f or 3 da ys) re gi me n i n a d ult patie nts ( 6 0 t o 7 5 years) wit h ne wl y- dia g n os e d t A M L or 
A M L -M R C  (7 ). T he pri mar y effi cac y e n d p oi nt was o verall s ur vi val ( O S). T he res ults 
s h o we d O S was si g nifica ntl y greater i n t he C P X - 3 5 1 gr o u p c o m pare d wit h t he 7 + 3 
gr o u p ( 7 ). T he m e dia n O S was 9. 5 6 m o nt hs wit h C P X - 3 5 1a n d 5. 9 5 m o nt hs wit h 7 + 3 
( Hazar d Rati o [ H R] 0. 6 9; P = 0. 0 0 5). Gra de 3- 5 n o n- he mat ol o gic a d verse e ve nts ( A Es) 
occ urri n g ≥ 5 % wer e si milar bet wee n t h e t w o gr o u ps, e xce pt p ne u m o nia ( 2 0 % vs 1 5 %) 
a n d bactere mia ( 1 0 % vs 2 %) were n u meri call y hi g her i n t he C P X - 3 5 1c o m pare d wit h 7 + 
3 gr o u ps, res pecti vel y. Als o, me dia n ti me t o rec o v er y of a bs ol ute n e utr o p hil c o u nt ( A N C) 
≥ 5 0 0/ μ L a n d platelets ≥ 5 0, 0 0 0/ μ L were l o n ger i n t he C P X - 3 5 1 gr o u p t ha n 7 + 3 
gr o u p. 2- 4 ( 7 ).   
 
 

  
  
  
 
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1. 3  
N a m e a n d Descri pti o n of P al b ocicli b  
1. 3. 1  Precli nical Data  
Treat me nt  of  c ult ure d  t u m or  cells  wit h  Pal b ocicli b  ca uses  gr o wt h  arrest  t hat  is  
acc o m pa ni e d b y t he i n hi biti o n of s pecific R b p h os p h or ylati o n b y C D K 4 or C D K 6 o n 
resi d ues seri ne - 7 8 0 a n d -7 9 5 of R b. T he I C 5 0 v al ues f or re d ucti o n of R b p h os p h or ylati o n 
at serine - 7 8 0 a n d -7 9 5 i n M D A -M B -4 3 5 breast carci n o ma cells were 0. 0 6 6 a n d 0. 0 6 3 μ M, 
res pecti vel y. T h e I C 5 0 val ues f or re d ucti o n of R b p h os p h or ylati o n are si milar t o t he I C 5 0 
val ues of i n hi biti o n of t h y mi di ne i nc or p orati o n acr oss a ra n ge of c ult ure d t u m or a n d n o r m al 
cells. 
Pal b ocicli b was teste d i n vitr o o n m olec ularl y c haracterize d h u ma n breast ca ncer 
cell li nes. Res ults fr o m t hese e x peri me nts i n dicat e t hat t h ose cell li nes t hat are m ore 
se nsiti ve t o Pal b ocicli b (I C 5 0 < 1 5 0 n M) ha ve l o w le vels of C D K N 2 A ( p 1 6) a n d hi g h 
le vels of R b 1, w hile resista nt cell li nes s h o w t he o p p osite c haracteristics. Se nsiti ve cell 
li nes i n t his pa nel re prese nt m ostl y t he l u mi nal E R + s u bt y pe.  
Pal b ocicli b  has  bee n  e val uate d  i n  safet y  p har mac ol o g y,  ge netic  t o xicit y,  
re pr o d ucti ve a n d de v el o p me nt (fertilit y a n d earl y e m br y o nic de vel o p me nt, e m br y ofetal 
de vel o p me nt), a n d re peat -d ose t o xicit y st u dies of u p t o 1 5 -wee ks d urati o n i n t he rat a n d 
d o g. Base d o n t he n o ncli nical  safet y st u dies c o n d ucte d wit h Pal b ocicli b, t he pri mar y  
Pal b ocicli b -relate d  s yste mic  t o xicities  were  o bs er ve d  i n  he mat ol y m p h o p oietic  tiss ues  
( decr ease d cell ularit y, i ncrease d ir o n pi g me nt, decreases i n p eri p heral le u k o c ytes a n d R B C 
para meters)  a n d  male  re pr o d ucti ve  or ga ns  ( d e ge nerati o n  of  s e mi nifer o us  t u b ules,  
sec o n dar y e pi di d y mal h y p os per mia a n d i ncrease d i ntrat u b ular cell ular de bris). Partial t o 
c o m plete re versi bilit y of t o xicities was de m o nstrate d f oll o wi n g a 4 wee k rec o ver y peri o d, 
w it h t he e xce pti o n of t h e male r e pr o d u cti ve or g a n fi n di n gs i n t he d o g. T hese t o xicities 
occ urr e d i n b ot h rats a n d d o gs, a n d are c o nsiste nt wit h t he i nte n de d p har mac ol o gic effect 
of Pal b ocicli b (i.e., cell c ycle i n hi biti o n) ( Fi n k et al, 2 0 0 1; Ar g uell o et al,  1 9 9 8; Bart k o va 
et al, 2 0 0 3). Pal b ocicli b was als o i de ntifie d wit h t he p ote ntial t o ca use Q T pr ol o n gati o n, 
de vel o p me ntal  effects,  a n d  a ne u ge nicit y.  D e vel o p me ntal  effects  t hat  w ere  c o nsi dere d  
a d verse i ncl u d e d a decr ease i n fetal b o d y wei g hts i n rats a n d a l o w i nci de nce of s mall 
p hala n ges o n t he f ore p a ws i n r a b bits. A n o effect le vel f or a n e u ge nicit y was o bser ve d at 

  
  
  
 
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a p pr o xi matel y 7 -f ol d hi g her t ha n u n b o u n d s yste mic A U C 2 4 e x p os ures ass ociate d wit h t he 
h u ma n cli nical d ose of 1 2 5 m g Q D. 
 
1. 3. 2  Cli nic al D at a  
Pal b ocicli b has bee n test e d i n a P hase 1 d ose escalati o n St u d y ( A 5 4 8 1 0 0 1) i n 7 4 patie nts 
wit h a d va nce d ca n cer. T w o d osi n g sc he d ules were e val uat e d: Sc he d ule 3/ 1 ( 3 wee ks o n 
treat me nt/ 1 wee k off tr eat me nt) a n d Sc he d ule 2/ 1 ( 2 wee ks o n treat me nt/ 1 wee k off 
treat me nt). All D L Ts o bs er ve d i n t his st u d y were relate d t o m yel os u p pressi o n a n d mai nl y 
c o nsiste d of Gra d e 3 ne utr o pe nia lasti n g m ore t ha n 7 da ys after t h e e n d of t h e treat me nt 
c ycle. H o w e ver, n e utr o p e nia was r e versi ble a n d n o n -c u m ulati ve. Ot her m ost c o m m o n 
a d verse e ve nts i ncl u de d f ati g ue,  a ne mia, diarr hea, c o nsti pati o n, v o miti n g a n d d ys p nea, all 
wit h mil d t o m o derate se verit y. At t he M T D, a greater pr o p orti o n of patie nts o n t he 2 0 0 
m g Q D, 2/ 1 sc he d ule ha d treat me nt-relate d T E A Es d uri n g a n d after C ycle 1 t ha n patie nts 
o n t he 1 2 5 m g Q D, 3/ 1 sc he d ule alt h o u g h t he pr o p orti o n of patie nts wit h treat me nt-
relate d ne utr o pe nia w as si milar wit h res pect t o t he 2 d osi n g sc he d ules, b ot h d uri n g a n d 
after C ycle 1. O ne partial res p o nse w as re p ort e d i n a patie nt wit h testic ular ca ncer. A 
t otal of 1 3/ 3 7 patients treate d wit h Sc he d ule 3/ 1 e val ua ble f or effi cac y e x p erie nce d sta ble 
disease ( S D), i ncl u di n g 6 patie nts wit h S D lasti n g 4 0 wee ks or l o n ger. Base d o n t he 
precli nical e vi d e nce t h at Pal b ocicli b is hi g hl y acti ve i n E R( +) cell li nes a n d t he 
e nc o ura gi n g s afet y a n d P K pr ofiles o bser v e d i n t he i nitial cli nical st u dies, a ra n d o mize d, 
m ultice nter acti ve - c o ntr olle d P hase 1/ 2 St u d y ( A 5 4 8 1 0 0 3) was desi g ne d t o assess t he 
efficac y, safet y a n d p h ar mac o ki netics of letr o z ole 2. 5 m g Q D (c o nti n u o usl y) i n 
c o m bi nati o n wit h Pal b ocicli b 1 2 5 m g Q D (sc he d ule 3/ 1) vers us si n gle a ge nt letr oz ole 2. 5 
m g Q D (c o nti n u o usl y) f or t he first- li ne treat me nt of E R( +), H E R 2 (-) a d v a nce d breast 
ca ncer i n p ost me n o pa usal w o me n. Letr oz ole was selecte d as t h e acti ve c o ntr ol base d o n 
its w orl d wi de a ppr o val a n d use as sta n dar d of care f or t he first- li ne h or m o nal treat me nt of 
p ost me n o pa usal w o me n wit h E R( +) a d va n ce d breast ca ncer. St u d y A 5 4 8 1 0 0 3 was 
c o m prise d of a li mite d P hase 1 p orti o n, ai me d at c o nfir mi n g t he safet y a n d t olera bilit y of 
t he c o m bi nati on a n d e xcl u di n g a P K i nteracti o n wit h t he c o m bi nati o n, a n d a ra n d o mize d 
P hase 2 p orti o n ai me d at e val uati n g t he efficac y a n d safet y of letr o z ole i n c o m bi nati o n 

  
  
  
 
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wit h Pal b ocicli b w he n c o m pare d t o letr oz ol e al o ne i n t he first- li ne treat me nt of 
p ost me n o pa usal patie nts wit h E R( +), H E R 2(- ) a d v a nce d breast ca ncer. T he P hase 2 
p orti o n c o nsiste d of 2 parts. I n Part 1, p atie nt selecti o n was base d o nl y o n E R/ H E R 2 
stat us. I n Part 2, p atie nts were pr os pecti vel y sel ect e d als o ta ki n g i nt o acc o u nt t u m or 
C C N D 1 a m plificati o n a n d/ or p 1 6 l oss. I n Ma y 2 0 1 2, 1 7 7 patie nts ha ve bee n e nr olle d i n 
t his st u d y a n d e nr oll me nt is cl ose d. T wel ve ( 1 2) w ere e nr olle d i n t he P hase 1 p orti o n a n d 
1 6 5 ( 6 6 a n d 9 9 i n Part 1 a n d 2, res pecti vel y) were e nr olle d i n t he P hase 2 p orti o n. Res ults 
fr o m t he P hase 1 p orti o n, 8 3 i n dicate d n o P K i nteracti o n bet wee n Pal b ocicli b a n d 
letr oz ole wit h mea n A U C ( 0 - 2 4) of 2 0 0 2 a n d 2 0 4 3 n g hr/ m L ( n = 1 1) f or Pal b ocicli b i n t he 
a bse nce a n d pr ese nce of l etr oz ole, res pecti vel y, a n d 1 9 9 0 a n d 1 7 3 0 n g• hr/ m L ( n = 1 0) f or 
letr oz ole i n t he a bs e nce a n d prese nce of Pal b ocicli b, res pecti vel y. T h e R P 2 D was 
deter mi ne d G B G 7 8 - P E N E L O P E B St u d y Pr ot oc ol E ( Versi o n 1 0 – 1 2 A pril 2 0 1 6) – 
C o nfi de ntial 5 5 t o be 1 2 5 m g Q D o n Sc he d ule 3/ 1 ( 3 wee ks c o nti n u o us treat me nt 
f oll o we d b y 1 wee k off tr eat me nt) i n c o m bi nati o n wit h letr oz ole 2. 5 m g Q D 
c o nti n u o usl y. Partial res p o nses were re p orte d f or 3 ( 3 3 %) o ut of 9 patie nts wit h 
meas ura ble disease ( 3 h a d b o ne- o nl y disease). A n ot her 5 patie nts ( 4 2 %) h a d sta ble 
disease f or ≥ 6 m o nt hs a n d t he cli nical be nefit rat e ( P R + S D ≥ 6 m o nt hs) was 6 7 %. Ei g ht 
( 8) patie nts disc o nti n ue d fr o m t he st u d y d ue t o disease pr o gressi o n, i ncl u di n g 2 patie nts 
wit h cli nical pr o gressi o n, 1 patie nt wit h dre w c o ns e nt a n d 3 patie nts are still o n g oi n g. 
T w o ( 2) i nteri m a n al yses f or t he P hase 2 p orti o n of t he st u d y ha ve bee n c o n d ucte d. T he 
res ults of t he i nteri m a nal yses s h o we d c o nsiste nt tre n d of cli nicall y mea ni n gf ul 
i m pr o ve me nts i n pr o gressi o n-free s ur vi val ( P F S; pri mar y e n d p oi nt). I n t he first i nteri m 
a nal ysis ( Part 1; N = 6 6), t he me dia n P F S f or t he P D 0 3 3 2 9 9 1 pl us letr oz ole ar m was 1 8. 2 
m o nt hs vers us 5. 7 m o nt hs f or t he letr oz ol e al o ne ar m ( H R = 0. 3 5; 9 5 % CI: 0. 1 7, 0. 7 2; 
p = 0. 0 0 6). T he s ec o n d i nteri m a nal ysis ( N = 1 6 5) c o nti n ue d t o de m o nstrate a statisticall y 
si g nifica nt i m pr o ve me nt i n P F S ( 2 6. 1 vs. 7. 5 m o nt hs, res pecti vel y; H R = 0. 3 7; 9 5 % CI: 
0. 2 1, 0. 6 3; p < 0. 0 0 1).  
T he c o m bi nati o n of Pal b ocicli b pl us letr oz ole was ge nerall y w ell t olerate d wit h 
safet y pr ofile si milar t o P al b ocicli b as a si n gle a g e nt. T he m ost fre q ue ntl y re p orte d 
treat me nt-r elate d a d v erse e ve nts i ncl u de d ne utr o p e nia, le u k o pe nia, a ne mia, a n d fati g ue. 
T h ere w ere fe brile n e utr o pe nia re p orte d t o date i n t his st u d y. O verall, 8 patie nts i n t he 

  
  
  
 
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c o m bi nati o n ar m wer e disc o nti n ue d fr o m t he st u d y treat me nt d ue t o a n a d v erse e v e nt, of 
w hic h 5 wer e c o nsi dere d treat me nt -relate d ( gra de 3 ne utr o pe nia [ n = 4] a n d isc he mic 
c olitis) a n d 1 patie nt fr o m t he letr oz ole al o ne ar m.  
T hese res ults i n dicate t h at t he c o m bi nati o n of Pal b ocicli b wit h letr oz ole is well 
t olerate d wit h A Es si milar t o t h ose see n wit h eit her Pal b ocicli b or letr oz ole w he n 
a d mi nistere d al o ne.  
 
1. 3. 3 
Cli nic al P h ar m ac oki netics   
As of 1 0 Dece m ber 2 0 1 4, t we nt y- o ne cli nical st u dies ha ve e v al uate d t he P K of 
Pal b ocicli b. F o ur of t hes e trials were c o n d uct e d i n patie nts wit h a d va nce d mali g na nt 
disease.  
P hase 1 cli nical p har m ac ol o g y a n d bi o p har mace utic st u dies of Pal b ocicli b were 
c o n d ucte d i n healt h y s u bjects. Te n of t hes e 1 7 cli nical trials were cli nical p har mac ol o g y 
st u dies c o n d ucte d t o i n vesti gate t he a bs or pti o n, distri b uti o n, meta b olis m, a n d e xcreti o n of 
Pal b ocicli b as well as e x a mi ne t he p ote ntial f or D DI wit h Pal b ocicli b. T he re mai ni n g 7 of 
t he 1 7 cli nical trials wer e bi o p har mace utic st u dies c o n d ucte d t o e x a mi ne t he 
bi oa vaila bilit y, bi oe q ui vale nce, a n d f o o d effect of t he pal b ocicli b f or m ulati o ns. 
P har mac o ki netic para met ers are a vaila bl e fr o m all 7 4 patie nts e nr olle d i n St u d y 
A 5 4 8 1 0 0 1 (a first- i n- h u ma n d ose-escalati o n st u d y i n patie nts wit h a d va nce d ca n cer) 
f oll o wi n g m ulti ple- d ose a d mi nistrati o n ( Da y 8 of C ycle 1) at dail y d oses ra n gi n g fr o m 2 5 
t o 2 2 5 m g of Pal b ocicli b. I n a d diti o n, P K para met ers are als o a v aila ble f or ni ne patie nts 
o n Da y 1 4 of C ycle 1 (fr o m patie nts o n Sc he d ule 2/ 1, i.e., 2 wee ks o n treat me nt f oll o we d 
b y 1 wee k off treat me nt) a n d 4 patie nts o n Da y 2 1 of C ycle 1 (fr o m patie nts o n Sc he d ule 
3/ 1, i.e., 3 wee ks o n treat me nt f oll o we d b y 1 wee k off treat me nt). T he e x p os ure ( A U C( 0-
1 0) a n d C ma x) i ncr ease d i n a d ose pr o p orti o nal m a n ner (i. e. d ose li nearit y) o ver t he d ose 
ra n ge of 2 5 t o 2 2 5 m g Q D f oll o wi n g Pal b ocicli b a d mi nistrati o n o n Da ys 1 a n d 8 of C ycle 
1, alt h o u g h s o me varia bilit y (l o w t o m o derate) ar o u n d t hese d oses was o bs er ve d 
partic ularl y at t he 1 5 0 m g Q D d ose le vel. F oll o wi n g re peat e d dail y d osi n g t o Da y 1 4 a n d 
Da y 2 1 Pal b ocicli b was a bs or be d wit h a me dia n T ma x of ~ 4 h o urs w he n fasti n g 2 h o urs 

  
  
  
 
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bef ore a n d aft er Pal b ocicli b a d mi nistrati o n. T he mea n Pal b ocicli b Vz/ F was 3 1 0 3 L, 
w hic h is si g nifica ntl y greater t ha n t otal b o d y wat er ( 4 2 L), i n dicati n g t hat Pal b ocicli b 
e xte nsi vel y pe netr ates i nt o peri p heral tiss ues. T he a bilit y f or Pal b ocicli b t o cr oss t he 
bl o o d brai n barrier i n h u ma ns is u n k n o w n. I n rats, Pal b ocicli b dis pla ye d mi ni mal a bilit y 
t o cr oss t he i ntact bl o o d brai n barri er. Pal b ocicli b was eli mi nate d sl o wl y; t he mea n t ½ 
was 2 6. 5 h o urs (r a n ge d 1 5. 8 t o 3 6. 2 h o urs) a n d t h e mea n C L/ F w as 8 6. 1 L/ h o ur. 
Pal b ocicli b acc u m ulate d f oll o wi n g re peat e d d osi n g wit h a me dia n Rac of 2. 4, w hic h is 
c o nsiste nt wit h a half -life of ~ 2 7 h o urs. 
T he s ol u bilit y of t he Pal b ocicli b free b ase is p H de pe n de nt — Pal b ocicli b is water 
s ol u ble at l o w p H ( 2. 1-4. 5), w hile t he s ol u bilit y dra maticall y decreas es as p H rises a b o ve 
4. 5. C o nc o mita nt a d mi nistrati o n of a ge nts w hic h i n creas e gastric p H ca n alter t he s o l u bilit y 
a n d a bs or pti o n of Pal b ocicli b free b ase f or m ulati o ns. 
Pal b ocicli b is meta b olize d t o m ulti ple meta b olites i n a q ualitati vel y si milar ma n ner 
i n rat, d o g a n d h u ma n li ver micr os o mes. I n vitr o, Pal b ocicli b is pri maril y meta b olize d b y 
C Y P 3 A 4 e nz y mes. A n e x pl orat or y e val uati o n of t h e circ ulati n g meta b olites f or Pal b ocicli b 
was c o n d ucte d i n plas ma sa m ples o btai ne d fr o m p atie nts treate d wit h Pal b ocicli b 2 0 0 m g 
Q D ( Sc he d ul e 2/ 1) i n St u d y A 5 4 8 1 0 0 1. Assess me nt of t he p o ole d plas ma s a m ples o n Da y 
1 4 of C ycle 1 i n dicate d t hat t he gl uc ur o ni de c o nj u gate of Pal b ocicli b a n d t he  lacta m of 
Pal b ocicli b ( P F -0 5 0 8 9 3 2 6) wer e t he mai n meta b olites prese nt i n plas ma. Gl uc ur o ni de 
c o nj u gate of Pal b ocicli b is u nli kel y t o be acti ve vs t he i nte n de d tar get ( C D K 4/ 6). Alt h o u g h 
P F -0 5 0 8 9 3 2 6 s h o w e d si milar i n vitr o acti vit y vs C D K 4/ 6 as wit h Pal b o cicli b, t he u n b o u n d 
e x p os ure  of  t his  meta b olite  is  c o nsi dera bl y  l o wer  t ha n  t he  pare nt  dr u g.  T heref or e,  
c o ntri b uti o n of t his meta b olite t o t he p har mac ol o gic acti vit y i n h u ma ns is a ntici pate d t o be 
l o w.  Ot her  met a b olites  o bser ve d  were  t he  gl uc ur o ni de  c o nj u gates  of  h y dr o x ylate d  
Pal b ocicli b a n d t he gl uc ur o ni de c o nj u gate of re d u ce d Pal b ocicli b. P F -0 5 0 8 9 3 2 6 was als o 
o bser ve d  i n  t he  circ ul ati o n  of  rats  f oll o wi n g  re peat e d  dail y  oral  a d mi nistrati o n  of  
Pal b ocicli b. Plas ma pr otei n bi n di n g of Pal b ocicli b a n d P F - 0 5 0 8 9 3 2 6 is ~ 8 5 % a n d 9 5 %, 
res pecti vel y. 
I n vitr o ( h E R G) a n d i n vi v o ( d o g tele metr y) st u dies re veal e d a p ote ntial f or Q T 
pr ol o n gati o n at u n b o u n d c o nce ntr ati o ns ≥1 4 -f ol d t he u n b o u n d stea d y-state C ma x 

  
  
  
 
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ass ociate d wit h t he cli nical d ose of 1 2 5 m g Q D (refer t o t he Pal b ocicli b i n v esti gat or's 
br oc h ure f or a d diti o nal d etails).  
A preli mi nar y p har m ac o ki netic/ p har mac o d y n a mic a nal ysis has bee n c o n d ucte d t o 
e x pl ore t he Q T/ Q T c a n d plas ma P D - 0 3 2 9 9 1 c o nce ntrati o n relati o ns hi p f or St u d y 
A 5 4 8 1 0 0 1 ( FI H st u d y) b y usi n g gra p hical met h o ds a n d mi xe d effects li near m o deli n g 
( N O N M E M). D ata fr o m 7 3 patie nts were us e d f or t he a nal ysis, a n d a n a nal ysis of t he 
Q Tc F a n d Q Tc B d ata de m o nstrate d t hat Q Tc F was t he m ore a p pr o priate c orrecti o n 
met h o d base d o n pl ots of t he Q Tc vers us R R i nter val. N o patie nt ha d a m a xi m u m o n 
treat me nt Q Tc F val u e of ≥ 5 0 0 msec. T he Q T c F c ha n ges fr o m t he b aseli ne at t he mea n 
C ma x calc ulate d f or 2 0 0 m g d ose were si m ulate d f or 1 0 0 0 0 patie nts. T he mea n a n d 
u p per 9 5 % 
 
1. 4  
R ati o n ale  
T he lac k of res p o nse or resista nce t o c urre nt t hera pies i n patie nts wit h A M L is mai nl y 
relate d t o r esista nce t o c ytara bi ne or a nt hrac ycli n es (t he m ost effecti ve dr u gs i n A M L). 
O verc o mi n g c ytara bi n e r esista nce ca n pr o vi de a n attracti ve treat me nt strat e g y c o m pare d 
t o c urr e nt pr actice of a d di n g m ore c yt ot o xic a ge nts or tar g ete d t h era pies s uc h as F L T 3 
i n hi bit ors or I D H 1/ 2 i n hi bit ors t hat ca n o nl y be gi ve n t o a s mall fracti o n of patie nts. 
C ytara bi ne is a p yri mi di ne n ucle osi de a nal o g t hat ca n i n hi bit D N A s y nt hesis. Its 
acti o n is s pecific t o t he S p hase of t he cell c y cle  (8 ). It has bee n de m o nstrate d t hat le u ke mia 
cells are at differ e nt sta ges i n t heir cell c ycle wit h s o me cells at G 0 / G 1 p has e w hile ot hers 
are at differ e nt p hases li ke S a n d M p hase (9 ). T hese cells re mai n q uies ce nt a n d resist 
treat me nt wit h S p hase d e pe n de nt c he m ot hera p y s uc h as c yt ara bi ne. Treat me nt wit h cell 
c ycle i n hi bit ors ca n p ote ntiall y s y nc hr o nize t hese cells t o e nter t he S p hase a n d i ncrease its 
res p o nse t o c ytara bi ne. It ca n als o i n d uce a p o pt osis i n t he cells t hat re mai n i n G 0/ G 1 p h ase 
t h us pr o vi di n g a n attracti ve strate g y t o o verc o me c ytara bi ne resista nce.  
C ycli n -de pe n de nt ki nas e ( C D Ks) are fre q ue ntl y o vere x presse d or h y peracti vate d 
i n h u ma n ca ncers a n d re prese nt a ke y t hera p e utic tar get (1 0 ). Pal b ocicli b, a cell per mea bl e 
p yri d o p yri mi di ne  wit h  oral  bi oa vaila bilit y,  is  a n  e xce pti o nall y  selecti ve  a n d  p ote nt  

  
  
  
 
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i n hi bit or of C D K 4 a n d C D K 6 (I C 5 0 ~ 1 0 n M f or rec o m bi na nt pr otei ns) (1 0 ). I n vitr o a n d i n 
vi v o  st u dies  ha ve  s h o w n  t hat  Pal b ocicli b  ca n  effecti vel y  i n d uce  earl y  G 1  arrest  b y  
i n hi biti n g C D K 4/ 6 i n A M L cell li nes a n d x e n o grafts s u g gesti ve of u ni q ue o p p ort u nit y t o 
tar get s pecific p h ases of t he cell c ycle i n A M L (1 0 ). Treat me nt of H L-6 0 A M L cell li nes 
wit h Pal b ocicli b ca n i n d uce G 1 arrest f oll o we d b y s y nc hr o n o us pr o gressi o n of s ur vi v i n g 
A M L cells i nt o S p hase after wit h dra wi n g t he d ru g, t here b y creati n g a ti me wi n d o w t o 
i nc or p orate  c ytar a bi ne  a n d  e n ha n ce  its  acti vit y  (1 0 ).  Se q u e ntial  a d mi nistrati o n  of  
pal b ocicli b a n d c he m ot hera p y res ulte d i n dra matic i ncrease i n t he c yt ot o xic killi n g of 
c ytara bi ne i n vi v o   (1 0 ). M ore i m p orta ntl y, it tri g ge d a p o pt osis of A M L cells t hr o u g h 
i n hi biti o n of t he h o me o b ox ( H O X) A 9 o n c o ge ne e x pressi o n b y re d uci n g t he tra nscri pti o n of 
its tar get PI M 1 . Re d uce d PI M 1 s y nt hesis atte n uates PI M 1-me diate d p h os p h or ylati o n of t he 
pr o -a p o pt otic B A D a n d acti vates B A D-de p e n de nt a p o pt osis.  
 
 
 
T hese o bser v ati o ns c o u ple d wit h t he a bilit y of Pal b ocicli b  t o i n d uce a p o pt osis i n 
le u ke mic cells t hat ar e at G 0/ G 1 p hase s u g gest t hat C D K 4/ 6 i n hi bit ors ca n be partic ularl y 
effecti ve w he n a d mi nistere d pri or t o c h e m ot hera p y a n d t he n se q ue ntiall y d uri n g 
c he m ot hera p y e ver y 4 8 h o urs t o all o w f or A M L cell c ycle reset a n d S p has e e ntr y ( b ase d 

  
  
  
 
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o n t he dr u g half-lif e). We ha ve als o s h o w n t hat pri or a d mi nistrati o n of Pal b ocicli b  f or 4 8 
h o urs ca n arrest 9 1 % of t he cells i n G 0/ G 1 p hase a n d t hese cells will pr ocee d t o S p hase 
after t he cessati o n of Pal b ocicli b  hi g hli g hti n g t he i m p orta nce of a d mi nistrati n g 
Pal b ocicli b  f or 4 8 h o urs pri or t o starti n g c he m ot h era p y.  
Herei n, w e pr o p ose t o start Pal b ocicli b  pri or t o C P X- 3 5 1 a n d t he n e ver y 4 8 h o urs 
d uri n g t hera p y (si nce t he half- life of Pal b o cicli b  is 2 4- 2 7 h o urs) t o e n ha n ce C P X- 3 5 1 
c ytot o xic acti vit y b y s y nc hr o nizi n g A M L cell e ntr y t o S p hase a n d als o i n d uce a p o pt osis 
i n t he cells t hat re mai n i n G 0/ G 1 p hase. 
 
2. 0  
O bjecti ves  
2. 1  
Pri m ar y O bjecti ve s  
2. 1. 1 P h ase I  
E val uate t he safet y a n d t olera bilit y of Pal b ocicli b  i n c o m bi nati o n wit h C P X - 3 5 1 
2. 1. 2 P h ase II  
E val uate t he efficac y of Pal b ocicli b  i n c o m bi nati o n wit h c he m ot hera p y as 
meas ure d b y o v erall r es p o nse rate ( O R R), i.e. c o m plete res p o nse ( C R) a n d C R 
wit h i nc o m plete bl o o d c o u nt rec o ver y ( C Ri) b y I W G criteria ( 1 1 ). 
2. 2 
Sec o n d ar y O bjecti ve(s)  
1.  Ti me t o res p o nse ( T T R)  
2.  E val uate d ur ati o n of res p o nse ( D O R) 
3.  E val uate t he e v e nt -fr ee s ur vi val ( E F S)  
4.  E val uate O verall S ur vi val ( O S) pr o ba bilit y  
3. 0 
St u d y Desi g n  
3. 1  
St u d y desi g n i ncl u di n g d ose esc al ati o n / c o h orts 
T his is a si n gle ar m, o pe n la bel st u d y of t he c o m bi nati o n of Pal b ocicli b wit h C P X -3 5 1 i n 
a d ults wit h A M L. T he tri al c o nsists of t w o c o m p o ne nts: p hase I t o e val uat e t he safet y wit h 
d ose escalati o n of Pal b o cicli b i n c o m bi nati o n wit h C P X -3 5 1 a n d p hase II t o e val uate t he 

  
  
  
 
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o verall res p o ns e rat e of t he c o m bi nati o n i n t he tar gete d patie nt p o p ulati o n. A c ycle is 3 5 
da ys.  
T he  p hase I p orti o n of t he st u d y will be 3 + 3 desi g n.  Pal b ocicli b will be gi ve n at 
d ose le vel 1 ( 7 5 m g p o) ( Please see sc h e ma i n secti o n 6 f or d ose le vels) o n da y - 1 a n d - 2, 
da y 0 will be rest a n d t he n 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) 
will be starte d o n da y 1, 3, a n d 5 al o n g wit h Pal b ocicli b o n da y 2, 4, a n d 6 f oll o we d b y 
rest/ m o nit ori n g peri o d ( da ys 7- 3 5). 
D ose escalati o n will pr ocee d wit hi n eac h c o h ort acc or di n g t o t he f oll o wi n g 
sc he me. Bef ore es calati n g t o t he ne xt d ose le vel, t he fi nal s u bject i n t he pre vi o us d ose 
le vel m ust ha ve reac he d  t he Da y 3 5 bi o ps y i n or der t o all o w s ufficie nt ti me t o o bser ve f or 
d ose- li miti n g t o xicities (D L T ). D L T s are d efi ne d i n secti o n 6. 2.  
 
N u m ber of S u bjects wit h D L T 
at a Gi ve n D ose Le vel 
Esc al ati o n Decisi o n R ule 
0 o ut of 3  
E nter 3 s u bjects at t he n e xt d ose le vel.  
1 o ut of 3  
E nter 3 m ore s u bjects at t his d ose le vel.  
•  If 0 of t hese 3 s u bj ects e x perie nce D L T, 
pr ocee d t o t he n e xt d ose le vel. 
•  If 1 or m ore of t his gr o u p s uffer D L T, t he n 
d ose escal ati o n is st o p pe d, a n d t his d ose is 
declare d t he ma xi mall y a d mi nistere d d ose. 
T hree ( 3) a d diti o nal s u bjects will be e ntere d 
at t he ne xt l o west d ose le vel if o nl y 3 
s u bjects were treat e d pre vi o usl y at t hat d ose. 
> 2  
D ose escalati o n will be st o p pe d. T his d ose le vel 
will be declare d t he ma xi mall y a d mi nistere d 
d ose ( hi g hest d ose a d mi nistere d). T hree ( 3) 
a d diti o nal s u bjects will be e ntere d at t he ne xt 
l o west d ose le vel if o nl y 3 s u bjects were treat e d 
pre vi o usl y at t hat d o se. 

  
  
  
 
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< 1 o ut of 6 or 0 o ut of 3 at 
hi g hest d ose le vel bel o w t he 
ma xi mall y a d mi nistere d d ose  
T his is ge nerall y t he rec o m me n de d ma xi mall y 
t olerate d d ose. 
 
 
After t he p h ase I is c o m plete d a n d t he ma xi m u m t olerate d d ose ( M T D) is d efi ne d, t he 
st u d y will pr ocee d wit h p hase II wit h Pal b ocicli b a d mi nistere d at t he rec o m me n de d p hase 
2 d ose ( R P 2 D). R P 2 D of Pal b ocicli b f or t he c o m bi nati o n t hera p y will be sel ecte d a m o n g 
t he 3 d ose le vels e v al uate d i n p hase I f oll o wi n g e v al uati o n of safet y d ata ac q uire d fr o m 
all p hase patie nts c o m pleti n g at least 1 c ycle of t h era p y . T h e p hase II part of t he st u d y is 
Si m o n t w o sta ge desi g n wit h o bjecti ve t o assess t he effi cac y of t he c o m bi n ati o n i n t he 
tar gete d patie nt p o p ulati o n.  
Patie nts will recei ve 1 - 2 i n d ucti o n c o urses of t he c o m bi nati o n of Pal b ocicli b a n d 
C P X - 3 5 1.  
H y drea wit h a d ose at t h e discreti o n of treati n g p h ysicia n is all o we d f or p atie nts 
wit h W B C  > 2 5, 0 0 0 a n d treat me nt wit h Pal b oci cli b a n d C P X -3 5 1 ca n n ot be starte d u ntil 
W B C is less < 2 5, 0 0 0 t o pre ve nt o v ert t u m or l ysis s y n dr o me. Pr o p h yla xis f or t u m or l ysis 
is re q uire d d uri n g t his peri o d. Pr o p h ylactic a nti bi otics are all o we d at t he discreti o n of t he 
treati n g p h ysicia n a n d i n acc or d a nce wit h t he i nstit uti o nal g ui deli nes.  
3. 2  
N u m ber of S u bjects  
A t otal o f 3 5 patie nts will be e nr olle d o n p has e I/II.  
3. 3 
Re pl ace m e nt of S u bjects  
S u bjects t hat fail t he s cree ni n g pr ocess will be re place d. N o s u bject will be re place d after 
recei vi n g tr eat me nt. 
3. 4  E x pecte d D ur ati o n of Tre at me nt a n d S u bject P artici p ati o n  
T he i nte nt of t he st u d y desi g n is f or all patie nts t o recei v e u p t o 2 i n d ucti o n c ycles wit h 
t he c o m bi nati o n of Pal b ocicli b a n d C P X- 3 5 1. Treat me nt will be c o nti n ue d d uri n g t he 
d urati o n of t he st u d y u nless patie nts meet a n y or all of t he earl y wit h dra w al  criteria stat e d 
i n a p pe n di x II.  T he e x pecte d d urati o n of t he treat me nt peri o d f or s u bjects is 

  
  
  
 
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a p pr o xi matel y 3 5 da ys, wit h a 2 year f oll o w u p peri o d. S u bse q ue nt c o ns oli dati o n 
c he m ot hera p y will be gi ve n at t he discreti o n of t he treati n g p h ysicia n off st u d y . 
 
4. 0 S u bject Selecti o n  
Eac h of t he criteria i n t he secti o ns t hat f oll o w m ust be met i n or d er f or a s u bject t o b e 
c o nsi dere d  eli gi ble  f or  t his  st u d y.  Use  t he  eli gi bilit y  criteria  t o  c o nfir m  a  s u bject’s  
eli gi bilit y.  
 
4. 1  I ncl usi o n Criteri a 
F or P h ase I o nl y 
S u bjects m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or e nr oll me nt:  
1.  S u bjects m ust be > 1 8 
2.  Pri mar y refract or y (t o 1 or 2 i n d ucti o n c y cles  of c he m ot hera p y ) or rel a pse d A M L 
acc or di n g t o 2 0 1 6 W H O criteria  
3.  Hi g her- ris k ne wl y dia g n ose d  A M L ( dia g n ose d acc or di n g t o 2 0 1 6 W H O criteria). 
Hi g her-ris k defi ne d as hi g her- ris k per E L N 2 0 1 7 criteria. 
4.  Easter n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce Stat us < 2 
5.  S u bjects m ust ha ve n or mal or ga n f u n cti o n as defi n e d bel o w:   
•  T otal bilir u bi n < 2 ti m es u p per li mit of n or mal ( ≤ 3 x U L N if c o nsi dere d t o be 
d ue t o le u ke mic i n v ol ve me nt or Gil bert’s s y n dr o me) or if hi g her t ha n 2 ti mes 
u p per li mit of n or mal wit h a p pr o val fr o m t he PI 
•  Ser u m Creati ni ne < 2 x U L N or  if hi g her t ha n 2 ti mes u p per li mit of n or mal 
wit h a p pr o val fr o m t he PI 
•  Left ve ntric ular ejecti o n fracti o n of ≥ 4 5 %  
6.  W o me n of c hil d beari n g p ote ntial 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 
a n d me n s h o ul d be a d vis e d t o n ot fat her a c hil d w hile recei vi n g treat me nt. All me n 

  
  
  
 
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a n d w o me n of c hil d beari n g p ote ntial m ust use acce pta ble met h o ds of birt h c o ntr ol 
t hr o u g h o ut t he st u d y. 
7.  S u bjects m ust ha ve t he a bilit y t o u n dersta n d a n d t he willi n g ness t o si g n a writte n 
i nf or me d c o nse nt d oc u m e nt. 
F or P h ase II p art:  
S u bjects m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or e nr oll me nt:  
1.  S u bjects m ust be 1 8- 6 5 years of a ge 
2.  Ne wl y  dia g n ose d  ac ut e  m yel oi d  le u ke mia  acc or di n g  t o  2 0 1 6  W H O  criteria  
(e xcl u di n g A P L [ A M L-M 3])  
3.  Easter n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce Stat us < 2 
4.  S u bjects m ust ha ve n or mal or ga n f u n cti o n as defi n e d bel o w:   
•  T otal bilir u bi n < 2 ti mes u p per li mit of n or mal (( ≤ 3 x U L N if c o nsi dere d t o be 
d ue t o le u ke mic i n v ol ve me nt or Gil bert’s s y n dr o me)  or if hi g her t ha n 2 ti mes 
u p per li mit of n or mal wit h a p pr o val fr o m t he PI 
•  Ser u m Creati ni ne < 2 x U L N  or i f hi g her t ha n 2 ti mes u p per li mit of n or mal 
wit h a p pr o val fr o m t he PI 
•  Left ve ntric ular ejecti o n fracti o n of ≥ 4 5 % 
5.  Pa tie nts  wit h  sec o n dar y  A M L  arisi n g  o ut  of  M D S  (all  s u bt y pes  u n der  W H O  
classificati o n), c hr o nic m yel o m o n oc ytic le u ke mia ( C M M L) a n d t hera p y-relate d 
A M L are eli gi ble.  
6.  W o me n of c hil d beari n g p ote ntial 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 
a n d me n s h o ul d be a d vis e d t o n ot fat her a c hil d w hile recei vi n g treat me nt. All me n 
a n d w o me n of c hil d beari n g p ote ntial m ust use acce pta ble met h o ds of birt h c o ntr ol 
t hr o u g h o ut t he st u d y. 
7.  S u bjects m ust ha ve t he a bilit y t o u n dersta n d a n d t he willi n g ness t o si g n a writte n 
i nf or me d c o nse nt d oc u m e nt. 
 

  
  
  
 
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4. 2 
E xcl usi o n Criteri a  
T he prese n ce of a n y of t h e f oll o wi n g will e xcl u de a s u bject fr o m st u d y e nr oll me nt: 
1.  Pri or treat me nt wit h C P X - 3 5 1, Pal b ocicli b or ot h er cell c y cle i n hi bit ors. 
2.  A n y seri o us me dical c o n diti o n, la b orat or y a b n or malit y, or ps yc hiatric ill ness t hat, 
i n t he vie w of t he tr eati n g p h ysicia n, w o ul d place t he partici pa nt at a n u nacce pta ble 
ris k if he or s he wer e t o partici pate i n t he st u d y or w o ul d pre ve nt t hat pers o n fr o m 
gi vi n g i nf or me d c o nse nt.  
3.  A n y  acti ve  m ali g na nc y  ( u nrelat e d,  n o n -he m at ol o gical  mali g na nc y)  di a g n ose d  
wit hi n t he past 6 m o nt hs of starti n g t he st u d y dr u g ( ot her t ha n c urati vel y treate d 
carci n o ma -i n-sit u of t he cer vi x or n o n-m ela n o ma s ki n ca ncer).  
4.  Hist or y  of  aller gic  reacti o ns  attri b ute d  t o  c o m p o u n ds  of  si milar  c he mical  or  
bi ol o gic c o m p ositi o n t o C P X - 3 5 1, Pal b ocicli b or ot her cell c y cle i n hi bit ors. 
5.  S u bjects wit h u nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o o n g oi n g 
or acti ve i nf ecti o n, s y m pt o matic c o n gesti ve heart fail ure, u nsta ble a n gi na pect oris, 
u nc o ntr olle d car diac arr h yt h mia, or ps yc hiatric ill ness/s ocial sit uati o ns t hat w o ul d 
li mit c o m plia nce wit h st u d y re q uire me nts. 
6.  K n o w n hist or y of HI V or acti ve he p atitis B or C. 
7.  N o maj or s ur ger y wit hi n 2 wee ks pri or t o st u d y e nr oll me nt. 
8.  Pre g na nc y or breast fee di n g  
9.  Male a n d fe male p atie nts w h o are fertile w h o d o n ot a gree t o use a n effecti ve barrier 
met h o ds of birt h c o ntr ol (i.e. a bsti ne nce) t o a v oi d pre g na nc y w hile recei vi n g st u d y 
treat me nt. 
1 0.  Ac ute pr o m yel oc ytic l e u ke mia ( A P L)  
 
4. 3  
I ncl usi o n of W o m e n a n d Mi n orities  
Me n, w o me n  a n d me m bers of all races a n d et h nic gr o u ps are eli gi ble f or t his trial. 
 

  
  
  
 
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5. 0  
Re gistr ati o n  
All s u bjects w h o ha v e bee n c o nse nte d are t o be re gistere d i n t he O n C ore ™ Data bas e. F or 
t h ose s u bjects w h o are c o nse nte d, b ut n ot e nr olle d, t he reas o n f or e xcl usi o n m ust be 
rec or d e d. 
All s u bjects will be re gistere d t hr o u g h Cle vel a n d Cli nic  a n d will be pr o vi de d a st u d y 
n u m ber b y c o ntacti n g t he st u d y c o or di nat or liste d.  
 
6. 0  
Tre at m e nt Pl a n  
6. 1 
Tre at m e nt Re gi m e n O ver vie w  
I n d ucti o n 
Pal b ocicli b will be a d mi nistere d orall y o n da y - 2  a n d  - 1 starti n g at le vel 1 ( please see 
sc he ma  bel o w)  d uri n g  t he  p hase I p orti o n. D a y 0 will  be  rest  a n d  t he n  C P X - 3 5 1 
( da u n or u bici n 4 4 m g/ m2 a n d c ytara bi ne 1 0 0 m g/ m 2) will be starte d o n d a ys 1, 3 , a n d 5 
al o n g wit h Pal b ocicli b  da y 2, 4, a n d 6 f oll o we d b y rest/ m o nit ori n g peri o d ( da ys 7- 3 5). 
Patie nts will be treate d wit h C P X - 3 5 1 base d o n a calc ulati o n det er mi ne d fr o m t he 
patie nt's b o d y s urface ar ea ( B S A). B S A will be calc ulate d bef ore eac h c o urse a n d will be 
base d o n t he p atie nt's hei g ht ( meas ure d at baseli n e) a n d w ei g ht ( meas ure d eac h c y cle).  If 
a patie nt’s Q Tc B is a b o ve 4 8 0 ms  o n a da y of pal b ocicli b, d osi n g will be s ki p pe d f or t hat 
da y . T he d ose s h o ul d n ot be ma de u p a n d treat me nt s h o ul d c o nti n ue as pla n ne d t he ne xt 
da y.  
A b o ne marr o w bi o ps y a n d as pirate s h o ul d b e o bt ai ne d o n da y 1 4  ( + 3 da y wi n d o w ) 
after starti n g C P X -3 5 1. If resi d ual le u k e mia is prese nt ( blasts perce nta g e  > 5 %), p er t he 
discreti o n  of  t he  treati n g  p h ysicia n,  a n ot her  i n d ucti o n  c o urse  of  t he  c o m bi nati o n  of  
Pal b ocicli b a n d C P X- 3 5 1 is p ossi ble a n d will be a d mi nistere d  as f oll o ws: 
Pal b ocicli b will be starte d at desi g nate d d ose le vel  o n da y - 2 a n d - 1 , da y 0 is rest 
a n d C P X- 3 5 1 will be starte d at ( da u n or u bici n 4 4 m g/ m2 a n d c ytara bi ne 1 0 0 m g/ m 2) o n da y 
1 a n d 3 a n d P alb ocicli b o n da y 2 a n d 4. 

  
  
  
 
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Patie nt wit h F L T 3 -I T D w h o are e nr olle d o n t he st u d y will be gi vi n g t he o pti o n t o 
c o nti n ue o n t he st u d y wit h o ut recei vi n g mi d osta uri n or will be ta ke n off t h e st u d y t o start 
mi d osta uri n . 
St u d y Sc he m a  
 
 
 

  
  
  
 
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H y drea wit h a d ose at t he discreti o n of treati n g p h ysicia n is all o we d f or patie nts wit h W B C 
> 2 5, 0 0 0 a n d tr eat me nt wit h Pal b ocicli b a n d C P X -3 5 1 ca n n ot b e starte d u ntil W B C is less 
< 2 5, 0 0 0 t o pre ve nt o vert t u m or l ysis s y n dr o me. Pr o p h yla xis f or t u m or l ysis is re q uire d 
d uri n g t his peri o d. Pr o p h ylactic a nti bi otics are all o we d at t he discreti o n of t he treati n g 
p h ysicia n a n d i n acc or da nce wit h t he i nstit uti o nal g ui deli nes.  
 
6. 1. 1 
Na me of I n vesti g ati o n al A ge nt A d mi nistrati o n  
Patie nts will recei ve Pal b ocicli b orall y at desi g nate d d ose le vel  base d o n d osi n g sc he d ule 
descri be d i n t he st u d y cale n dar. 
 
6. 1. 2 
Na me of I n vesti g ati o n al A ge nt A d mi nistrati o n  
Patie nts will recei ve C P X -3 5 1 i ntra ve n o usl y at d a u n or u bici n 4 4 m g/ m 2 a n d c ytara bi ne 1 0 0 
m g/ m 2. D osi n g Sc he d ule is descri be d i n st u d y cale n dar. 
 
6. 2 
Defi niti o n of D ose -Li miti n g T o xicit y ( A p plic a ble f or d ose esc al ati o n st u dies 
o nl y) 
D ose li miti n g t o xicities will be acc or di n g t o t he N CI C T E P criteria. A n o n - he mat ol o gic 
d ose-li miti n g t o xicit y ( D L T) is defi ne d as Gra d e 3 or 4 a d vers e e ve nt or a b n or mal 
la b orat or y val u e (acc or di n g t o C T C A E criteria) assesse d b y treati n g p h ysicia n as at least 
p ossi bl y relate d t o eit her/ b ot h st u d y dr u g(s), u nless clearl y a n d i n c o ntr o verti bl y relate d t o 
acti ve A M L or i nterc urre nt ill ness, d uri n g treat me nt or wit hi n 2 8 da ys after t he last d ose 
of P al b ocicli b, a n d d oes n ot res ol ve t o bel o w gra d e 3 wit hi n 2 8 da ys of o ns et. 
E xcl usi o n of t hese criteri a ma y i ncl u de: 
                                            i.     Gra de 3 f ati g ue, ast he nia, fe v er, a n ore xi a, or c o nsti pati o n 
                                           ii.     Gra de 3 na us ea, v o miti n g or diarr hea n ot re q uiri n g t u be fee di n g, t otal 
pare nteral n utriti o n, or re q uiri n g or pr ol o n gi n g h os pitalizati o n 
                                          iii.     I nfecti o n, blee di n g, or ot her e x pecte d direct c o m plicati o n of c yt o p e nias d ue 
t o acti ve u n derl yi n g le u k e mia 

  
  
  
 
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                                          i v.     Gra de 3 i nf usi o n reacti o n i ncl u di n g c yt o ki ne releas e s y n dr o me ( C R S), if 
s uccessf ull y ma na g e d a n d w hic h res ol ves wit hi n 7 2 h o urs 
                                           v.     Gra de 3 or 4 t u m or l ysis s y n dr o me ( T L S) if it is s uccessf ull y ma na ge d 
cli nicall y a n d res ol ves wit hi n 7 da ys wit h o ut e n d- or ga n da ma g e.  
                                          vi.     Gra de 3 or 4 is olate d electr ol yte a b n or malities t hat last < 7 2 h o urs will n ot 
be c o nsi der e d D L T. 
A he mat ol o gic d ose- li miti n g t o xicit y is defi ne d as se vere m y el os u p pressi o n wit h a 
h y p o plastic marr o w wit h less t ha n 5 % cell ularit y a n d n o e vi de nce of le u k e mia 4 5 da ys 
fr o m start of t her a p y. T his will defi ne se vere a n d d ela ye d m yel os u p pressi o n n ot relate d t o 
persiste nt le u ke mia a n d li kel y relate d t o treat me nt.  
N o n -he mat ol o gic t o xicities will be c o u nte d as D L Ts if t he y are “at least p ossi bl y relate d 
t o t he st u d y dr u gs. A n y treat me nt relate d deat h or c o nfir m e d H y’s la w cases will be 
c o nsi dere d D L Ts.  
H y’s la w cases satisf y eac h of t he f oll o wi n g 3 c o m p o ne nts: 
a. T he dr u g ca uses he p at ocell ular i nj ur y, defi ne d as a n ele vat e d A L T or A S T ≥ 3 
ti mes t he u p per li mit of n or mal. 
b.  T he y als o ha ve ele vati o n of t heir ser u m t otal bilir u bi n > 2 ti mes t he u p per 
li mit of n or mal, wit h o ut fi n di n gs of c h olestasis ( ofte n defi ne d as s er u m 
al kali ne p h os p hatase acti vit y < 2 ti mes t he u p per li mit of n or mal).  
c. N o ot her reas o n ca n be f o u n d t o e x plai n t he c o m bi nati o n of i ncreas e d 
a mi n otra nsfer ase a n d s er u m t otal bilir u bi n, s uc h as viral he patitis, alc o h ol 
a b use, isc he mia, pr ee xisti n g li ver disease, or a n ot her dr u g ca pa ble of ca usi n g 
t he o bser ve d i nj ur y. 
 
It is ass u me d t hat l o w c o u nts at dia g n osis are d ue t o i n v ol ve me nt b y t he disease pr o cess 
a n d re q uir e t hera p y f or i m pr o ve me nt.  
6. 3 
Ge ner al C o nc o mit a nt Me dic ati o ns a n d S u p p orti ve C are G ui deli nes  
Necess ar y s u p p orti ve meas ures f or o pti mal me dical care will be gi ve n t hr o u g h o ut t he 
treat me nt as deter mi ne d b y t he treati n g p h ysicia n a n d t he patie nt’s me dical nee d. N o 

  
  
  
 
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c o nc o mita nt c he m ot her a p y, i m m u n ot hera p y, or t hera p y wit h m o n ocl o nal a nti b o dies will 
be all o we d d uri n g t he st u d y wit h t he e xce pti o n of h y dr o x y urea or c ortic oster oi ds f or 
c o ntr ol of bl o o d c o u nts. 
Use of a c ol o n y-sti m ulati n g fact or or c o m bi nati o ns t here of (e. g. G- C S F, G M -
C S F, or er yt hr o p oieti n) are at t he discreti o n of t he treati n g p h ysicia n a n d is per mitte d if 
j u d ge d i n t he patie nt’s best me dical i nterest. 
Pr o p h ylactic a nti bi otics , a ntif u n gal, a n d a nti viral a ge nts (e. g. le v ofl o xaci n, 
valac ycl o vir, etc.) are str o n gl y rec o m me n de d; h o we ver, t he us e of t hes e or ot her dr u gs 
will be left t o i nstit uti o nal g ui deli nes.  
Misse d d oses of Pal b ocicli b will n ot be ma de u p.  Patie nts w h o v o mit a n y ti me 
after ta ki n g a d ose m ust be i nstr ucte d N O T t o “ m a ke it u p,” a n d t o res u me treat me nt as 
per sc he d ul e.  
P al b ocicli b is meta b olize d t o m ulti ple meta b olites i n a q ualitati vel y si milar 
ma n ner i n rat, d o g a n d h u ma n li ver micr os o mes. I n vitr o, Pal b ocicli b is pri maril y 
meta b olize d b y C Y P 3 A 4 e nz y mes. C o-a d mi nistrati o n wit h dr u gs t hat are C Y P 3 A 
i n hi bit ors a n d i n d ucers ma y c ha n g e t he plas ma c o nce ntrati o ns of Pal b ocicli b i n h u ma ns. 
T he c o nc urre nt use of C Y P 3 A i n hi bit ors, i ncl u di n g a m pre na vir, ataza na vir, b oce pre vir, 
clarit hr o m yci n, c o ni va pt a n, dela vir di ne, diltiaze m, er yt hr o m yci n, f osa m pre na vir, 
i n di na vir, itrac o naz ole, k et oc o naz ol e, l o pi na vir, mi befra dil, mic o naz ole, nefaz o d o ne, 
nelfi na vir, p osac o n az ole, rit o na vir, sa q ui na vir, tel a pre vir, telit hr o m yci n, vera pa mil, 
v oric o naz ole, a n d gr a pefr uit, gra pefr uit j uice or a n y pr o d uct c o ntai ni n g gra pefr uit, are n ot 
all o we d d uri n g t he ti me t hat pal b ocicli b is a d mi nistere d . T he c o nc urre nt us e of C Y P 3 A 
i n d ucers, i ncl u di n g car ba maze pi ne, fel ba mate, n e vira pi ne, p he n o bar bital, p he n yt oi n, 
pri mi d o ne, rifa b uti n, rifa m pi n, rifa pe nti n, a n d St. J o h n’s w ort, are n ot all o we d i n d uri n g 
t he ti me t hat pal b ocicli b is a d mi nistere d.   
H y drea wit h a d ose at t h e discreti o n of treati n g p h ysicia n is all o we d f or p atie nts 
wit h W B C  > 2 5, 0 0 0 a n d treat me nt wit h Pal b oci cli b a n d C P X -3 5 1 ca n n ot be starte d u ntil 
W B C is less < 2 5, 0 0 0 t o pre ve nt o v ert t u m or l ysis s y n dr o me. Pr o p h yla xis f or t u m or l ysis 
is re q uire d d uri n g t his peri o d. Pr o p h ylactic a nti bi otics are all o we d at t he discreti o n of t he 
treati n g p h ysicia n a n d i n acc or d a nce wit h t he i nstit uti o nal g ui deli nes.  

  
  
  
 
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6. 4 
Criteri a f or R e m o v al fr o m St u d y  
I n t he a bse nce of treat me nt dela ys d ue t o a d verse e ve nts treat me nt ca n c o nti n ue u ntil o ne 
of t he criteri a a p plies  f or earl y r e m o val (see a p pe n di x II). 
6. 5  
D ur ati o n of F oll o w U p  
F oll o wi n g c o m pleti o n of acti ve treat me nt, patie nts will be f oll o we d f or s ur vi val a n d A M L -
relate d tr eat me nt e ver y 6 m o nt hs f or u p t o 2 y ears as part of sta n dar d of f or C C F le u ke mia 
patie nts . T his f oll o w u p will be c o m plet e d bas e d o n w hat is a vaila ble i n t he patie nt’s 
me dical rec or d.  
 
7. 0   
D ose Del a ys/ D ose M o dific ati o ns 
If a patie nt’s Q Tc B is a b o ve 4 8 0 ms o n a da y of p al b ocicli b, d osi n g will be s ki p pe d f or 
t hat da y. T he d ose s h o ul d n ot be ma de u p a n d treat me nt s h o ul d c o nti n ue as pla n ne d t he 
ne xt da y. 
 
8. 0  
P ote nti al Ris ks a n d A d verse E ve nts  
8. 1  
P al b ocicli b  
C O M M O N, S O M E M A Y B E S E RI O U S  
I n 1 0 0 p e o ple r ecei vi n g Pal b ocicli b m ore t ha n 2 0 a n d u p t o 1 0 0 ma y ha ve: 
 A ne mia  
 Ne utr o pe nia 
 Fati g ue 
 Diarr hea  
 Na usea  
 
 

  
  
  
 
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O C C A SI O N A L, S O M E M A Y B E S E RI O U S  
I n 1 0 0 p e o ple r ecei vi n g Pal b ocicli b fr o m 5 t o 1 0 ma y ha ve: 
 Decr ease d a p petite  
 C o nsti pati o n 
 V o miti n g  
 Ras h  
 Flat ule nce  
 A b d o mi nal pai n  
 S h ort ness of breat h 
 Fe ver  
 C o u g h 
 Bac k pai n  
 
R A R E, A N D S E RI O U S  
I n 1 0 0 p e o ple r ecei vi n g Pal b ocicli b 5 or fe w er m a y ha ve: 
 Hair l oss  
 Hea dac he  
 N ose blee d  
 M uscle s pas m  
 U p per r es pirat or y tract i nfecti o n  
 Dr y m o ut h 
 Itc hi n g 
 Dizzi ness  
 A b d o mi nal s welli n g  
 C hills  
 R u n n y n ose 
 
 
 
 
 

  
  
  
 
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Infl a m m ati o n of t he l u n gs  
Pal b ocicli b — use d t o treat s o me patie nts wit h a d va nce d breast ca ncer — ma y ca use rare b ut 
se vere i nfla m mati o n of t he l u n gs. Acc or di n g t o t he F D A, patie nts s h o ul d n otif y t heir 
healt h -care pr ofessi o nal ri g ht a wa y if t he y ha v e a n y ne w or w ors e ni n g s y m pt o ms i n v ol vi n g 
t heir l u n gs, as t he y ma y i n dicate a rare b ut life-t hreate ni n g c o n diti o n. S y m pt o ms t o watc h 
f or i ncl u de diffic ult y or disc o mf ort wit h breat hi n g a n d s h ort ness of breat h w hile at rest or 
wit h l o w acti vit y.  

  
  
  
 
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8. 2  
C P X - 3 5 1 
C O M M O N, S O M E M A Y B E S E RI O U S  
I n 1 0 0 p e o ple r ecei vi n g C P X-3 5 1 m ore t ha n 1 0 a n d u p t o 1 0 0 ma y ha ve:  
 A ne mia  
 Ne utr o pe nia 
 Fati g ue 
 Diarr hea  
 Na usea  
 C o nsti pati o n 
 He m orr ha g e  
 Ras h  
 E de ma  
 M uc ositis  
 M usc ul os keletal pai n  
 A b d o mi nal Pai n 
 C o u g h 
 Hea dac he  
 D ys p nea 
 Arr h yt h mia 
 P ne u m o nia 
 Slee p Dis or der  
 C hills  
 Dizzi ness  
 N o n -c o n d ucti o n
 Car di ot o xicit y
 (car di ot o xicit y
 ca use d
 b y
 t h e
 
a nt hrac ylci n e d o x or u bici n) 
 F u n gal i nfecti o n 
 U p per r es pirat or y i n d ucti o n (e xcl u di n g f u n gal) 
 H y p o xia 
 H y perte nsi o n 
 H y p ote nsi o n 
 V o miti n g  

  
  
  
 
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 C hest Pai n  
 Decr ease d a p petite  
 Bactere mia (e xcl u di n g se psis) 
 Deliri u m  
 P yre xia 
 Ple ural eff usi o n  
 A n xiet y 
 Pr urit us  
 Se psis (e xcl u di n g f u n gal) 
 He m orr h oi ds 
 Petec hiae  
 Re nal i ns ufficie nc y  
 Tra nsf usi o n reacti o ns 
 Vis ual i m pair me nt (e xce pt blee di n g)  
 Cat heter/ de vice/i njecti o n site reacti o n  
 Pr ol o n ge d l o w platelets 
 Pr ol o n ge d l o w ne utr o p hil c o u nt 
 Hair l oss  
 
O C C A SI O N A L, S O M E M A Y B E S E RI O U S  
I n 1 0 0 p e o ple r ecei vi n g C P X-3 5 1 m ore t ha n 5  ma y ha ve : 
 H y p o natre mia 
 H y p o kale mia 
 H y p oal b u mi ne mia 
 H y per bilir u bi ne mia 
 Ala ni ne a mi n otra nsferas e a b n or malities  
 
O C C A SI O N A L, S O M E M A Y B E S E RI O U S  
I n 1 0 0 p e o ple r ecei vi n g C P X-3 5 1 less t ha n 1 0 ma y ha ve : 
 Ear a n d la b yri nt h dis or ders: Deaf n ess, Deaf ness u nilateral  

  
  
  
 
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 E ye Dis or ders: E ye c o nj u ncti vitis, Dr y e ye, E ye e de ma, E ye s welli n g, 
E ye irritati o n, E ye pai n, Oc ular disc o mf ort, Oc ular h y pere mia, Peri or bital 
e de ma, Scler al h y pere mia  
 Gastr oi ntesti nal dis or ders: D ys pe psia 
 Ps yc hiatric dis or ders: Hall uci nati o ns  
 Res pirat or y, t h oraci c a n d me diasti nal dis or ders: P ne u m o nitis 
 
8. 3 
Defi niti o ns  
8. 3. 1 
A d verse E ve nt   
A n  a d verse e ve nt  ( A E) is a n y u nf a v ora bl e or u ni nte n de d e v e nt, p h ysical or ps yc h ol o gical, 
ass ociate d wit h a researc h st u d y, w hic h ca uses h ar m or i nj ur y t o a researc h partici pa nt as 
a  res ult  of  t h e  partici p a nt’s  i n v ol ve me nt  i n  a  researc h  st u d y.  T he  e ve nt  ca n  i ncl u de  
a b n or mal la b orat or y fi n di n gs, s y m pt o ms, or disease ass ociate d wit h t he researc h st u d y. 
T he e ve nt d o es n ot necessaril y ha ve t o ha v e a ca usal relati o ns hi p wit h t he researc h, a n y 
ris k ass ociate d wit h t he r esear c h, t he researc h i nter ve nti o n, or t he res earc h assess me nts.  
A d verse e ve nts ma y b e t he res ult of t he i nter ve nti o ns a n d i nteracti o ns use d i n t he 
researc h; t he c ollecti o n of i de ntifia ble pri vate i nf or mati o n i n t he researc h; a n u n derl yi n g 
disease, dis or der, or c o n diti o n of t he s u bject; a n d/ or ot her circ u msta nces u nrelate d t o t he 
researc h or a n y u n derl yi n g disease, dis or der, or c o n diti o n of t he s u bject.  
 
8. 3. 2   Seri o us A d verse E ve nts  
A seri o us a d verse e ve nt ( S A E) is a n y a d verse e x p erie nce occ urri n g at a n y d ose t hat res ults 
i n a n y of t he f oll o wi n g o utc o mes:  
•  Res ults i n de at h.   
•  Is  a  lif e-t hre ate ni n g a d verse e x perie nce.   T h e ter m  life -t hreate ni n g i n  t he 
defi niti o n of seri o us ref ers t o a n a d v erse e ve nt i n w hic h t he s u bject was at ris k 
of deat h at t he ti me of t h e e ve nt.  It d o es n ot refer t o a n a d vers e e v e nt w hic h 
h y p ot heticall y mi g ht ha ve ca use d d eat h if it were m ore se vere.  

  
  
  
 
Pa ge 3 8     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
•  Re q uires 
i n p atie nt
 h os pit aliz ati o n
 or
 pr ol o n g ati o n
 of
 e xisti n g
 
h os pit aliz ati o n .  A n y a d verse e ve nt lea di n g t o h os pitalizati o n or pr ol o n gati o n 
of h os pitalizati o n will be c o nsi dere d as Seri o us, U N L E S S at least o ne of t he 
f oll o wi n g e x pectati o ns is met: 
o  T he a d missi o n res ults i n a h os pital sta y of less t ha n 2 4 h o urs O R  
o  T he a d missi o n is pre -pla n ne d (e. g., electi ve or s c he d ule d s ur g er y 
arra n g e d pri or t o t he start of t he st u d y) O R  
o  T he a d missi o n is n ot ass ociate d wit h a n a d v erse e ve nt (e. g., s ocial 
h os pitalizati o n f or p ur p oses of res pite care.  
H o we ver , it s h o ul d be n ote d t hat i n vasi ve treat me nt d uri n g a n y h os pitalizati o n ma y 
f ulfill t he criteria of “ me dicall y i m p orta nt” a n d as s uc h ma y be re p orta ble as a 
seri o us a d verse e ve nt de pe n dent o n cli nical j u d g me nt.  I n a d diti o n w here l ocal 
re g ulat or y a ut h orities s pecificall y re q uire a m ore stri n ge nt defi niti o n, t he l ocal 
re g ulati o n ta kes pr ece d e nt.  
•  Res ults i n persiste nt or si g nific a nt dis a bilit y/i nc a p acit y .  T h e defi niti o n of 
disa bilit y is a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life’s 
f u ncti o ns. 
•  Is a c o n ge nit al a n o m al y/ birt h defect .  
•  Is a n i m p ort a nt m e dic al e ve nt.  I m p orta nt me dical e ve nts t hat ma y n ot res ult 
deat h, be life -t hreat e ni n g, or re q uire h os pitalizati o n ma y be c o nsi dere d a s eri o us 
a d verse e x perie n ce w h e n, base d u p o n a p pr o priat e me dical j u d g me nt, t he y ma y 
je o par dize  t he s u bject  a n d ma y re q uire me dical  or s ur gical  i nter ve nti o n t o 
pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n.  E xa m ples of s uc h m e dical 
e ve nts  i ncl u de  aller gic  br o nc h os pas m  re q uiri n g  i nte nsi ve  treat me nt  i n  a n  
e mer ge n c y r o o m or at h o me, bl o o d disease or dis or ders, or c o n v ulsi o ns t hat d o 
n ot res ult i n i n patie nt h os pitalizati o n, or t he de v el o p me nt of dr u g d e pe n de nc y 
or dr u g a b use. T h e de v el o p me nt of a ne w ca n cer is al wa ys c o nsi dere d a n 
i m p orta nt me dical e ve nt. 
 

  
  
  
 
Pa ge 3 9     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
8. 3. 3  A d verse E ve nt E v al u ati o n  
T he i n vesti gat or or desi g nee is r es p o nsi ble f or e ns uri n g t hat all a d v erse e ve nts ( b ot h seri o us 
a n d n o n-seri o us) o bser ve d b y t he cli nical tea m or re p orte d b y t he s u bject w hic h occ ur after 
t he s u bject h as si g ne d t he i nf or me d c o ns e nt are f ull y rec or d e d i n t h e s u bj ect’s me di cal 
rec or ds. S o ur ce d oc u m e ntati o n m ust be a vaila ble t o s u p p ort all a d verse e ve nts.  
 
A la b orat or y t est  a b n or malit y c o nsi dere d cli nicall y rele va nt  as  dee m e d  b y  t he 
treati n g p h ysicia n s h o ul d be re p ort e d as a n a d vers e e ve nt.   
 
T he i n vesti gat or or s u b-i n vesti gat or (treati n g p h ysicia n if a p plica ble) will pr o vi de 
t he f oll o wi n g f or all a d verse e ve nts ( b ot h s eri o us a n d n o n-seri o us): 
•  E ve nt ter m (as p er C T C A E  5. 0) 
•  Descri pti o n of t he e v e nt 
•  Date of o nset a n d res ol uti o n 
•  E x pecte d ness of t he t o xicit y  
•  Gr a de of t o xicit y  
•  Attri b uti o n of rel ate d ness t o t he i n vesti g ati o n al a ge nt - (t his m ust be assi g ne d 
b y a n i n vesti g at or, s u b-i n vesti g at or, or tre ati n g p h ysici a n) 
•  Acti o n ta ke n as a r es ult of t he e v e nt, i ncl u di n g b ut n ot li mite d t o; n o c ha n ges, d ose 
i nterr u pte d, re d u ce d, disc o nti n ue d, etc. or acti o n ta ke n wit h re gar d t o t he e v e nt, i.e. 
n o acti o n, recei ve d c o n m e d or ot her i nter v e nti o n, etc. 
•  O utc o me of e v e nt  
 
Descri pti o ns a n d gr a di n g sc ales  f o u n d i n t he N CI C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts ( C T C A E) versi o n 5 will be utilize d f or A E re p orti n g.  
A n e x pect e d a d verse e v e nt  is a n e ve nt pre vi o usl y k n o w n or a ntici pate d t o res ult 
fr o m partici pati o n i n t he researc h st u d y or a n y u n derl yi n g disease, dis or d er, or c o n diti o n 
of t he s u bject. T he e ve nt is us uall y liste d i n t he I n v esti gat or Br oc h ure, c o nse nt f or m or 
researc h pr ot o c ol.  

  
  
  
 
Pa ge 4 0     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
A n  u ne x pecte d  a d verse  e ve nt  is a n  a d verse  e ve nt  n ot  pre vi o usl y  k n o w n  or  
a ntici pate d  t o  res ult  fr o m  t he  researc h  st u d y  or  a n y  u n derl yi n g  disease,  dis or der,  or  
c o n diti o n of t he s u bject.  
  
 
Attri b uti o n *  is t he relati o ns hi p bet wee n a n a d v erse e ve nt or seri o us a d v ers e e ve nt 
a n d t he st u d y dr u g.  Attri b uti o n will be assi g ne d as f oll o ws: 
 
•  Defi nite – T he A E is clearly relate d  t o t he st u d y dr u g. 
•  Pr o ba ble – T he A E is li k el y relate d t o t he st u d y dr u g. 
•  P ossi ble – T he A E ma y be relate d  t o t he st u d y dr u g. 
•  U nli kel y – T he A E is d o u btf ull y relate d t o t he st u d y dr u g. 
•  U nrelate d – T h e A E is cl earl y N O T  relate d t o t he st u d y dr u g. 
  
  
* Attri b uti o n is re q uire d f or eac h i n di vi d ual c o m p o ne nts of t he treat me nt re gi me n.  
8. 4  
S A E Re p ort F or m  
S A Es will be r ec or d e d o n t he F D A F or m 3 5 0 0 A ( Me d Wat c h) a n d St u d y S A E c o vers h eet 
b ut s h o ul d o nl y be re p orte d as i nstr ucte d bel o w.  T he electr o nic F D A S A E re p orti n g f or ms 
s h o ul d n ot be use d.   
 
8. 5  
Re p orti n g Pr oce d ures f or Seri o us A d verse E ve nts  
F or t h e p ur p os es of safet y re p orti n g, all a d v erse e ve nts will be re p orte d t hat occ ur t hr o u g h 
3 0 da ys after t he fi nal d ose of st u d y dr u g. A d verse e v e nts, b ot h seri o us a n d n o n -seri o us, 
a n d deat hs t hat occ ur d uri n g t his peri o d will be rec or de d i n t he s o urce d oc u me nts. All S A Es 
s h o ul d be m o nit ore d u ntil t he y are res ol v e d or are clearl y d eter mi ne d t o be d ue t o a 
s u bject’s  sta ble  or  c hr o nic  c o n diti o n  or  i nterc urre nt  ill ness(es).  Relate d  A Es  will  be  
f oll o we d u ntil res ol uti o n t o baseli ne or gra d e 1 or sta bilizati o n.  
 
8. 5. 1 
S A E Re p orti n g Re q uire m e nts  

  
  
  
 
Pa ge 4 1     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
•  Partici pati n g i n vesti gat ors (all sites) m ust re p ort all seri o us a d verse e ve nts t o t he 
Lea d Site Pri nci p al I n vesti gat or (e. g. S p o ns or -I n vesti gat or) wit hi n 2 4 h o urs   of 
disc o ver y or n otificati o n of t he e v e nt. T he p arti ci pati n g i n vesti gat or m ust als o 
pr o vi de f oll o w- u p i nf or m ati o n o n t he S A E u ntil fi nal res ol uti o n.  
•  T he Lea d Site  Pri nci pal I n v esti gat or will re vie w t he S A E a n d re p ort t he e ve nt t o 
t he F D A, e xter n al c olla b orat or(s), a n d I R B as a p plica ble. 
•  It is t he S p o ns or-I n vesti g at or’s res p o nsi bilit y (e. g. lea d site PI) t o e ns ure t hat A L L 
seri o us a d vers e e ve nts t h at occ ur o n t he st u d y (e. g. A L L S A Es t hat occ ur at eac h 
e nr olli n g i nstit uti o n) are re p orte d t o all partici pati n g sites.  
Dr u g S u p plier / M a n uf act urer / Fi n a nci al S u p p orter R e p orti n g Re q uire me nts:  
•  Dr u gs ( C P X - 3 5 1, will be s u p plie d b y Jazz P har mace uticals a n d Pal b oci cli b 
p urc hase will be f u n de d b y Jazz P har m ace uticals ). T he trial will be s u p p ort e d b y 
Jazz P har m ace uticals.  T he S p o ns or-I n vesti gat or (e. g. lea d site PI) will be 
res p o nsi ble f or r e p orti n g all S A Es t hat are treat me nt-e mer ge nt f or C P X - 3 5 1 t o 
Jazz P har m ace uticals wit hi n 1 b usi ness da y of t heir a ware ness of t he S A E via 
e mail at A E Re p orti n g @jazz p h ar ma.c o m .  
 
I nstit uti o n al Re vie w B o ar d Re p orti n g Re q uire me nts: 
•  I n v esti gati ve sites will r e p ort a d verse e ve nts t o t h eir res pecti ve I R B acc or di n g t o 
t he l ocal I R B’s p olicies a n d pr oce d ures i n re p orti n g a d verse e ve nts.  
 
8. 6 
S A Es a n d O n C ore  
•  All S A Es will be e ntere d i nt o O n C ore.   
•  A c o p y of t he S A E f or m(s) s u b mitte d t o t he s p o ns or -i n vesti gat or is als o u pl oa de d 
i nt o O nc ore. 
 
8. 7   
D at a S afet y a n d T o xicit y C o m mittee  

  
  
  
 
Pa ge 4 2     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
It is t he res p o nsi bilit y of eac h site PI t o e ns ure t hat A L L S A Es occ urri n g o n t his trial 
(i nter nal or e xter nal) are re p orte d t o t he Case C o m pre he nsi ve Ca ncer Ce nter’s Data a n d 
Safet y T o xicit y C o m mittee. T his s u b missi o n is si m ulta ne o us wit h t heir s u b missi o n  t o Jazz 
P har mace uticals a n d/ or ot her re g ulat or y b o di es.  
T he  s p o ns or -i n vesti gat or  is  res p o nsi ble  f or  s u b mitti n g  a n  a n n ual  re p ort  t o  t he  
D S T C as per C C C C Data a n d Safet y M o nit ori n g Pla n. 
  
8. 8  
D at a a n d S afet y M o nit o ri n g Pl a n ( D S M P)  
T his pr ot oc ol will a d here t o t he p olicies of t he Cas e C o m pre he nsi ve Ca n cer Ce nter Data 
a n d Safet y M o nit ori n g Pla n i n acc or da nce wit h N CI g ui deli nes.  
 
9. 0 
P H A R M A C E U TI C A L I N F O R M A TI O N  
 
9. 1 I n vesti g ati o n al A ge nts 
9. 1. 1  Na me of A g e nt  
Palc ocicli b  
Ot her Na mes:   
I B R A N C E 
Pr o d uct descri pti o n:   
Pal b ocicli b will be s u p plie d as ca ps ul es or ta blets  c o ntai ni n g 1 2 5 m g e q ui vale nts of 
Pal b ocicli b free b ase. Ca ps ules will be s u p plie d i n H D P E b ottles c o ntai ni n g 2 3 ca ps ules. 
Please see t he c hart b el o w re gar di n g t he me dicati o n i n ca ps ule f or m.   
 
D os a g e  
C ol or  
S h a p e  
1 2 5 m g  
C ar a m el/ C ar a m el  O v al  
 
 

  
  
  
 
Pa ge 4 3     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
T a blets will be s u p plie d i n b lister p ac ks of 2 1 t a blets . Ple ase see t he c h art bel o w 
re g ar di n g t he m e dic ati o n i n t a blet f or m . 
D os a g e  
C ol or  
S h a p e  
1 2 5 m g  
Li g ht Pi n k 
O v al  
 
Pre p ar ati o n a n d Dis pe nse:   
Pal b ocicli b will be pr o vi de d i n n o n- patie nt -s p ecific b ottles or blister pac ks. T he patie nt 
na me  s h o ul d be rec or de d o n t he b ottle la bel or o n t he pac ki n g i n t he s paces pr o vi de d b y 
site pers o n nel at t he ti me of assi g n me nt t o p atie nt. Pal b ocicli b will be a d mi nistere d  b y t he 
researc h  a n d/ or  i n patie nt  staff  a n d  t he  dis pe nsi n g  will  be  rec or d e d  o n  t he  patie nt’s 
electr o nic m e dical r ec or d.  Ret ur ne d u n use d m e dicati o n M U S T N O T be re -dis pe nse d t o a 
patie nt.  
St or a ge re q uire m e nts:   
Pal b ocicli b is a n a ge nt t hat m ust be ha n dle d a n d a d mi nistere d wit h care. D ue t o p ossi ble 
u n k n o w n hazar ds ass ociate d wit h t o pical a n d e n vir o n me ntal e x p os ure t o e x peri me ntal 
a ge nts, ca ps ules  a n d ta bl ets  m ust n ot be o pe ne d a n d/ or e m ptie d i nt o a n y ve hicle f or oral 
i n gesti o n; ca ps ules m ust be s wall o we d i ntact. O nl y o ne ca ps ule or ta blet stre n gt h will be 
dis pe nse d t o t he patie nt at eac h dis pe nsi n g visit. I n t he e ve nt of d ose m o difi cati o n, ne w 
ca ps ules  or ta blets  will b e dis pe nse d. 
R o ute of a d mi nistr ati o n:   
Pal b ocicli b will be a d mi nistere d at t he d ose a n d s c he d ule des cri be d i n secti o n 6. Patie nts 
s h o ul d ta ke Pal b ocicli b wit h f o o d. Patie nts s h o ul d be i nstr ucte d t o s wall o w pal b ocicli b 
ca ps ules or ta blets w h ol e a n d n ot t o c he w t he m pri or t o s wall o wi n g. N o ca ps ule or ta blet 
s h o ul d be i n geste d if it is br o ke n, crac k e d, or ot her wise n ot i ntact. Patie nts s h o ul d be 
e nc o ura g e d t o ta ke t heir d ose at a p pr o xi matel y t h e sa me ti me eac h da y.  
Dr u g Pr oc ure m e nt:   

  
  
  
 
Pa ge 4 4     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
Pal b ocicli b  will  n ot  be  directl y  s u p plie d  b y Jazz  P har mace uticals,  h o we ver  J azz  
P har mace uticals will pr o vi di n g f u n ds t o p urc hase Pal b ocicli b f or t he st u d y.   
P ac ki n g, l a beli n g, a n d dr u g Acc o u nt a bilit y:  
Pal b ocicli b ca ps ules  a n d ta blets  s h o ul d be st ore d at c o ntr olle d r o o m te m perat ure ( 1 5- 3 0 
C, 5 9- 8 6 F) i n t heir ori gi nal c o ntai ner.  
Dr u g Destr ucti o n :  
At t he c o m pleti o n of t he st u d y, t here will be a fi nal rec o n ciliati o n of dr u g s hi p pe d, dr u g 
c o ns u me d,  a n d  dr u g  r e mai ni n g.  T his  rec o nciliati o n  will  be  l o g ge d  o n  t he  dr u g  
rec o nciliati o n  f or m,  si g ne d  a n d  d ate d.  A n y  discre pa n cies  n ote d  will  b e  i n vesti gate d,  
resol ve d,  a n d  d oc u me nt e d  pri or  t o  ret ur n  or  d estr ucti o n  of  u n use d  st u d y  dr u g.  Dr u g  
destr o ye d o n site will be d oc u me nte d i n t he st u d y files. 
 
9. 2   
I n vesti g ati o n al A ge nt s 
9. 2. 2 
Na me of A g e nt  
C P X - 3 5 1 
Ot her Na mes:   
V Y X E O S  
Pr o d uct descri pti o n:  C P X -3 5 1 ( da u n or u bi ci n a n d c ytara bi ne) li p os o me f or i njecti o n is a 
c o m bi nati o n of da u n or u bici n a n d c ytara bi ne i n a 1: 5 m olar rati o e nca ps ulat e d i n li p os o mes 
f or
 i ntra v e n o us
 a d mi nistrati o n.
 T he
 li p os o me
 me m bra n e
 is
 c o m p ose d
 of
 
distear o yl p h os p hati d ylc h oli ne  ( D S P C),  distear o 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.  
S ol uti o n pre p ar ati o n:  T he a p pr o pri ate n u m ber of vials of C P X- 3 5 1 
(c ytar a bi ne: da u n or u bici n) Li p os o me I njecti o n s h o ul d be re m o ve d fr o m t he refri gerat or 
pri or t o rec o nstit uti o n. Rec o nstit ute wit h 1 9 m L of sterile water f or i njecti o n usi n g a 2 0 
m L s yri n ge. D o n ot heat C P X- 3 5 1 (c ytara bi n e: da u n or u bici n) Li p os o me I njecti o n. After 
rec o nstit uti o n, i n vert vials ge ntl y 3- 4 ti mes a n d let rest f or 1 5 mi n utes a n d re peat vial 
i n versi o n pri or t o wit h dra wi n g dr u g f or dil uti o n. T he c o nce ntrati o n of t he rec o nstit ute d 
dis persi o n is 5 u/ m L. 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 s h o ul d be 
dil ute d i n a p pr o xi matel y 5 0 0 m L of s o di u m c hl ori de i njecti o n or de xtr ose i njecti o n. 

  
  
  
 
Pa ge 4 5     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
T he I V ba gs a n d i nf usi o n sets m ust be n o n- D E H P. Ase ptic tec h ni q ue m ust be strictl y 
o bser ve d t hr o u g h o ut t he ha n dli n g 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 si nce n o bacteri ostatic a ge nt or preser v ati ve is prese nt. T he i nf usi o n of C P X- 
3 5 1 (c ytar a bi ne: da u n or u bici n) Li p os o me I njecti o n m ust be starte d wit hi n 4 h o urs of 
dil uti o n. Vials are f or si n gle use. U n use d material s h o ul d be rec or de d as s u c h a n d 
discar de d acc or di n g t o i nstit uti o nal p olicies. Pr oce d ures f or pr o per h a n dli n g a n d dis p osal 
of a ntica ncer dr u gs s h o ul d be i m ple me nte d. 
St or a ge re q uire m e nts:  St ore u nrec o nstit ute d V Y X E O S vials i n a refri gerat or at 2° C t o 
8° C ( 3 6° F t o 4 6° F) i n a n u pri g ht p ositi o n. T he vial s h o ul d be st ore d i n its ori gi nal cart o n 
t o pr otect fr o m li g ht. 
St a bilit y:  If t he dil ute d i nf usi o n s ol uti o n is n ot use d i m me diatel y, st ore i n refri gerat or at 
2º C t o 8º C f or u p t o 4 h o urs. 
R o ute of a d mi nistr ati o n:  T he i nf usi o n of C P X- 3 5 1 (c ytara bi ne: da u n or u bi ci n) Li p os o me 
I njecti o n will be perf or m e d t hr o u g h a ce ntral ve n o us cat heter, usi n g a n i nf usi o n p u m p t o 
e ns ure t hat t he dr u g is i nf use d o ver t he s p ecifie d ti me peri o d. N o n- D E H P c o ntai ni n g 
a d mi nistrati o n sets s h o u l d be use d. D o n ot use a n i n- li ne filter. C P X - 3 5 1 s h o ul d ne ver 
be gi ve n b y t he i ntra m us c ular or s u bc ut a ne o us r o ute. A d mi nister C P X- 3 5 1 o ver 
a p pr o xi matel y 9 0 mi n utes via a n i nf usi o n p u m p. Fl us h t he li ne t o e ns ure a d mi nistrati o n 
of t he f ull d ose. T he d osa ge (t otal u nits a n d u/ m 2), start/st o p ti me of t he i nf usi o n, t otal 
v ol u me i nf use d, m ust be d oc u me nte d i n t he patie nt’s c hart. 
Dr u g Pr oc ure m e nt:  C P X - 3 5 1 will be s u p plie d f or t his st u d y b y Jazz P har mace uticals.  
Dr u g Acc o u nt a bilit y: T he st u d y p har macist or d esi g nee m ust mai ntai n rec or ds of t he 
deli ver y of C P X- 3 5 1 t o t he st u d y site, t he i n ve nt or y at t he site, t he use b y eac h patie nt, 
a n d t he dis p ositi o n of u n use d pr o d uct. T hes e rec or ds s h o ul d i ncl u de dates, q ua ntities, l ot 
n u m bers, e x p irati o n dates a n d patie nt i de ntificati o ns. I nstit uti o ns s h o ul d mai ntai n rec or ds 
t hat d oc u me nt a de q u atel y t hat t he patie nts were pr o vi de d t he d oses s pecifie d b y t he 
pr ot oc ol a n d rec o ncile all i n vesti gati o nal pr o d uct recei ve d fr o m Jazz P har m ace uticals. 
Rec or ds of st ora g e c o n diti o ns (te m perat ure l o gs) m ust be ke pt f or t he e ntire peri o d t hat 
C P X -3 5 1 is mai ntai ne d at t he i nstit uti o n.  

  
  
  
 
Pa ge 4 6     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
Dr u g Destr ucti o n : At t he c o m pleti o n of t he st u d y, t here will be a fi nal rec o nciliati o n of 
dr u g s hi p pe d, dr u g c o ns u me d, a n d dr u g re m ai ni n g. T his rec o nciliati o n will be l o g ge d o n 
t he  dr u g  r ec o nciliati o n  f or m,  si g ne d  a n d  dat e d.  A n y  discre pa n cies  n ote d  will  be  
i n vesti gate d, res ol ve d, a n d d oc u me nte d pri or t o ret ur n or destr u cti o n of u n use d st u d y dr u g. 
Dr u g destr o ye d o n site will be d oc u me nte d i n t he st u d y files. 
 
1 0. 0 
E X P L O R A T O R Y or C O R R E L A TI V E  S T U DI E S  
Peri p heral bl o o d sa m ples will be c ollecte d pri or t o starti n g treat me nt f or f ut ure 
c orrel ati ve st u dies.  
C A S E 1 9 1 8 : List of S peci me ns E x pecte d t o C ollect 
 
Scree ni n g  
T u bes E x pecte d  
Peri p heral Bl o o d  
1 0 m L S o di u m He pari n Gree n T o p T u be ( 2)  
 
C C F P R O C E D U R E  
 
1.  If dra w n at Ca ncer Ce nter, Pa ge 2 6 7 8 1 f or pi c k u p 
2.  If dra w n else w h ere, t u b e t o Ca ncer Ce nter a n d pa g e 2 6 7 8 1 o n sa m ple arri val 
3.  E mail 
 wit h a n y q uesti o ns 
 
 
1 1. 0  
S T U D Y P A R A M E T E R S A N D C A L E N D A R  
1 1. 1 
St u d y P ar a m eters  
1 1. 1. 1 Scree ni n g E val u ati o n   
Hist or y a n d p h ysical (i ncl u di n g wei g ht a n d bl o o d press ure), vitals, C B C wit h differe ntial 
a n d platelets, c he mistr y pr ofile (t otal bilir u bi n, ser u m creati ni ne, S G P T or S G O T, uric 
aci d, L D H, p h os p h or us, p otassi u m, ma g nesi u m, gl uc ose), E C H O, a n d a n E C G s h o ul d be 
perf or me d wit hi n 1 4 da ys of t hera p y start. Ser u m or uri ne H C G s h o ul d be o btai ne d at 
scree ni n g wit hi n 3 da ys pri or of treat me nt start. 

  
  
  
 
Pa ge 4 7     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
A b o ne marr o w as pirat e a n d/ or bi o ps y s h o ul d be perf or me d wit hi n 2 8 da ys of t hera p y 
start. T he b o ne marr o w e val uati o n will i ncl u de i m m u n o p he n ot y pi n g b y fl o w c yt o metr y 
a n d c yt o ge netic st u dies. 
 
1 1. 1. 2 Treat me nt Peri o d  
C B C wit h differe ntial a n d c he mistr y pr ofile will b e m o nit ore d per i nstit uti o nal sta n dar d 
of car e u ntil re missi o n.  La bs t hat are dra w n i n t his ti me fra me will be ca pt ure d i n t he 
data base.  
 
1 1. 1. 3 Re -i n d ucti o n Peri o d  
If a patie nt u n d er g oes r e-i n d ucti o n t hera p y aft er t h e Da y 1 4 bi o ps y ( + 3 d a y wi n d o w ), t he 
re-i n d ucti o n sc he d ul e of e ve nts s h o ul d t he n be f oll o we d starti n g wit h Da y - 2. 
 
1 1. 1. 4 E n d of Treat me nt ( E O T)  
E O T pr oce d ures s h o ul d be perf or me d at least wit hi n 7 da ys of t he Da y 3 5 b o ne marr o w 
bi o ps y/as pirate ta ki n g place. If a s u bject h as met criteria f or earl y re m o val fr o m t he 
st u d y, E O T pr oce d ures m ust be perf or me d wit hi n 7 da ys.

  
  
  
 
Pa ge 4 8     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
1 1. 2 
I n d ucti o n C ale n d ar  
Peri o d  
Scree ni n g  
Peri o d A   
Tre at m e nt Peri o d  
E n d Of 
Tre at me nt  
( E O T) 
F oll o w 
u p H 
 
 
 
 
D a y  
 
- 2M  
- 1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0  
1 1  
1 2  
1 3  
1 4  
1 5 -3 5  
 
 
I nf or me d c o nse nt f or m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hist or y a n d p h ysical e xa m D 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
C o nc o mita nt Me dicati o n B 
 X  
 
E C O G perf or ma nce stat us C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
He mat ol o g y D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X K  
 
Ser u m C he mistr y D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X K  
 
Uric Aci d  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
P h os p hate Le vel  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Ma g nesi u m Le vel  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Pre g na nc y test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E C G J 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
E C H O or M U G A  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital si g n  
X 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
X L  
 
X K  
 
B o ne marr o w bi o ps y  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X F  
X G 
 
 
B o ne marr o w as pirate  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X F  
X G 
 
 
S ur vi val F oll o w u p  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Rec or d R B C/ platelets tra nsf usi o n  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease res p o nse assess me nt  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X E  
 
 
Disease relat e d f oll o w u p  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
C orrelati ve Sa m ples  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
  
  
 
Pa ge 4 9     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
L D H/ T u m or L ysis S y n dr o me  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A E Assess m e nt I 
 X  
 
St u d y Dr u gs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pal b ocicli b  
 
X 
X 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
C P X -3 5 1  
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
A:  Scree ni n g peri o d is defi ne d as t he ti me peri o d fr o m t he da y of c o ns e nt t o start of st u d y t hera p y. 
B: C o n Me ds will be c ollecte d f or me dicati o ns t hat were a d mi nistere d beca use of a n A E or me dical hist or y 
C: See A p pe n di x I f or gr a di n g criteria 
D: See A p pe n di x I V f or r e q uire d tests 
E: See A p pe n di x III f or r es p o nse assess me nt criteria  
F: Da y 1 4 b o ne m arr o w bi o ps y/as pirate ha ve a + 3 da y s wi n d o w; t his is n ot re q uire d d uri n g re-i n d ucti o n 
G: Da y 3 5 b o ne marr o w bi o ps y/as pirate ha ve a +/- 7 da ys wi n d o w 
H: F oll o w u p occ urs e ver y 6 m o nt hs ( +/- 7 da ys wi n d o w) f or 2 years after E O T visit 
I: S A E f oll o w u p m ust b e re p ort e d t hr o u g h 3 0 da ys after last d ose 
J: S ki p pal b ocicli b d ose if Q Tc B > 4 8 0 ms 
K: D oes n ot nee d t o be re peate d at E O T if bei n g d o ne sa me da y as Da y 3 5 b o ne marr o w bi o ps y /as pirate 
L: T o be perf or me d o n sa me da y as Da y 3 5 bi o ps y 
M: Da y - 2 pre- d ose ass ess me nts d o n ot nee d t o be re peat e d if bei n g d o ne s a me da y as scree ni n g. If t he sa me assess m e nts are bei n g 
use d f or b ot h scr ee ni n g a n d da y - 2, t he data s h o ul d be e ntere d at scree ni n g i n t he data base. 
 

  
  
  
 
Pa ge 5 0     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
1 1. 3 Re -i n d ucti o n C ale n d ar 
 
Peri o d  
Tre at m e nt Peri o d  
E n d Of 
Tre at me nt  
( E O T) 
F oll o w 
u p H 
 
 
 
D a y  
- 2 
- 1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0  
1 1  
1 2  
1 3  
1 4  
1 5 -3 5  
 
 
Hist or y a n d p h ysical e x a m D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
C o nc o mita nt Me dicati o n B 
 X  
 
E C O G perf or ma nce stat us C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
He mat ol o g y D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X K  
 
Ser u m C he mistr y D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X K  
 
Uric Aci d  
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h os p hate Le vel  
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ma g nesi u m Le vel  
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
E C G J 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital si g n  
X 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X L  
 
X K  
 
B o ne marr o w bi o ps y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X G 
 
 
B o ne marr o w as pirate  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X G 
 
 
S ur vi val F oll o w u p  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Disease res p o nse assess me nt  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X E  
 
 
Disease relat e d f oll o w u p  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
A E Assess m e nt I 
 X  
 
St u d y Dr u gs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pal b ocicli b  
X 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
C P X -3 5 1  
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

  
  
  
 
Pa ge 5 1     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
1 2. 0  
M E A S U R E M E N T O F E F F E C T  
Res p o nse criteria will be defi ne d b y C hes o n et al 2 0 0 3 ( 1 1 ). Patie nts will be assesse d f or 
res p o nse at t he e n d of i n d ucti o n ( or at t he e n d of re-i n d ucti o n if a p plica ble). O verall 
res p o nse r ate i ncl u des C R  a n d C Ri.  
Res p o nse criteri a will be defi ne d as f oll o w: 
Res p o nse  
Defi niti o n  
C o m plete re missi o n  
( C R) 
B o ne marr o w blasts < 5 %; a bse nce of  
circ ulati n g blasts a n d blasts wit h A uer  
r o ds; a bse nce of e xtra me d ullar y 
disease; a bs ol ute ne utr o p hil c o u nt > 1. 0 
x 1 0 9/ L ( 1, 0 0 0/ μ L); platelet c o u nt > 1 0 0 x  
1 0 9/ L ( 1 0 0, 0 0 0/ μ L)  
C R wit h i nc o m plete  
he mat ol o gic 
rec o ver y 
( C Ri) 
All C R criteria e xce pt f or resi d ual  
ne utr o pe nia [ < 1. 0 x 1 0 9/ L ( 1, 0 0 0/ μ L)] or  
t hr o m b oc yt o pe nia [ < 1 0 0 x 1 0 9/ L 
( 1 0 0, 0 0 0/ μ L)] 
M or p h ol o gic 
le u ke mia-fr ee state 
( M L F S) 
B o ne marr o w blasts < 5 %; a bse nce of  
blasts wit h A uer r o ds; a bse nce of 
e xtra me d ullar y disease; n o he mat ol o gic 
rec o ver y re q uire d 
Partial re missi o n  
( P R) 
All he mat ol o gic criteria of C R; decreas e  
of b o ne marr o w blast perce nta ge t o 5 % 
t o 2 5 %; a n d decrease of pretreat me nt 

  
  
  
 
Pa ge 5 2     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
b o ne marr o w bl ast perce nta ge b y at  
least 5 0 % 
Sta ble disease  
A bse nce of C R M R D -, C R, C Ri, P R, 
M L F S; a n d criteri a f or P D n ot met  
Pr o gressi ve disease  
( P D) 
E vi de nce f or a n i ncreas e i n b o ne 
marr o w blast perce nt a ge a n d/ or 
i ncreas e of a bs ol ute blast c o u nts i n t he 
bl o o d: 
• > 5 0 % i ncrease i n marr o w blasts  
o ver baseli ne (a mi ni m u m 1 5 % p oi nt 
i ncreas e is re q uire d i n cases wit h 
< 3 0 % blasts at baseli ne; or  
persiste nt marr o w blast p erce nt a ge  
of > 7 0 % o ver at least 3 m o nt hs; 
wit h o ut at least a 1 0 0 % 
i m pr o ve me nt i n a bs ol ute ne utr o p hil 
c o u nt ( A N C) t o a n a bs ol ute le vel  
[ > 0. 5 x 1 0 9/ L ( 5 0 0/ μ L), a n d/ or 
platelet c o u nt t o > 5 0 x 1 0 9/ L 
( 5 0, 0 0 0/ μ L) n o n-tra nsf us e d]; or 
• > 5 0 % i ncrease i n peri p heral blasts 
( W B C x % blasts) t o > 2 5 x 1 0 9/ L 
( > 2 5, 0 0 0/ μl) (i n t he a bse nce of 

  
  
  
 
Pa ge 5 3     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
differe ntiati o n s y n dr o me); or  
• Ne w e xtra me d ullar y dis ease  
 
1 3. 0 
D A T A R E P O R T I N G / R E G U L A T O R Y C O N SI D E R A TI O N S  
A d verse e ve nt lists, g ui deli nes, a n d i nstr u cti o ns f or A E re p orti n g ca n be f o u n d i n Secti o n 
8. 0 ( A d vers e E ve nts: List a n d Re p orti n g Re q uire m e nts). 
 
1 3. 1 
D at a Re p orti n g  
T he F ort e E D C ™ 
a n d  O n C ore™ 
data b ases  will  be utilize d,  as  re q uire d  b y  t he Case 
C o m pre he nsi ve Ca ncer Ce nter a n d Cle v ela n d Cli nic, t o pr o vi de data c ollecti o n f or b ot h 
accr u al e ntr y a n d trial d ata ma na g e me nt. F ort e E D C a n d O n C ore ™ 
are Cli nical Trials 
Ma na ge me nt S yste ms h o use d o n sec ure ser v ers. Access t o data t hr o u g h F orte E D C a n d 
O n C ore ™ is restricte d b y user acc o u nts a n d assi g ne d r oles. O nce l o g ge d i nt o t he F orte 
E D C or O n C ore ™ s yste m wit h a user I D a n d pass w or d, F ort e E D C™ a n d O n C ore™ defi ne 
r oles f or eac h us er w hic h li mits access t o a p pr o priate data. User i nf or mati o n a n d pass w or d 
ca n  be  o btai ne d  b y  c o ntacti n g  t he  O n C ore ™ 
A d mi nistrat or  at  O n C ore-
re gistrati o n @cas e.e d u f or O n C ore™ access, a n d t a ussi g o nc ore @ ccf. or g f or F orte E D C™ 
access. 
F orte E D C ™ is desig ne d wit h t he ca pa bilit y f or st u d y set u p, acti vati o n, trac ki n g, re p orti n g, 
data m o nit ori n g a n d re vie w, a n d eli gi bilit y verificati o n.  W he n pr o perl y utilize d, F orte 
E D C ™ 
is 2 1 C F R 1 1 c o m plia nt.  T his st u d y will utilize electr o nic Cas e Re p ort F or m 
c o m pleti o n i n t he F orte E D C ™ 
data base. A cale n dar of e ve nts a n d re q uire d f or ms are 
a vaila ble i n F orte E D C ™. 
 
1 3. 2 
Re g ul at or y C o nsi der ati o ns 
T he st u d y will be c o n d u cte d i n c o m plia nce wit h I C H g ui deli nes a n d wit h all a p plica ble 
fe der al (i ncl u di n g 2 1 C F R parts 5 6 & 5 0), state or l ocal la ws. 

  
  
  
 
Pa ge 5 4     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
1 3. 2. 1  Writte n I nf or m e d c o nse nt  
Pr o visi o n  of  writte n  i nf or me d  c o ns e nt  m ust  be  o btai ne d  pri or  t o  a n y  st u d y -relate d 
pr oce d ur es.  T he  Pri nci p al  I n v esti gat or  will  e ns ure  t hat  t he  s u bject  is  gi ve n  f ull  a n d  
a de q uate oral a n d writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p ossi ble ris ks a n d be ne fits 
of t he st u d y as well as t h e s u bject’s fi na n cial res p o nsi bilit y. S u bjects m ust als o be n otifie d 
t hat t he y are fr ee t o disc o nti n ue fr o m t he st u d y at a n y ti me. T h e s u bject s h o ul d be gi ve n 
t he o p p ort u nit y t o as k q uesti o ns a n d be all o we d ti me t o c o nsi der t he i nf or mati o n pr o vi de d.  
T he ori gi nal, si g ne d writte n I nf or me d C o nse nt F or m m ust be ke pt wit h t he Researc h C h art 
i n c o nf or ma nce wit h t he i nstit uti o n’s sta n dar d o perati n g pr oce d ures. A c o p y of t he si g ne d 
writte n I nf or m e d C o nse nt F or m m ust be gi ve n t o t he s u bject. A d diti o nall y, d oc u me ntati o n 
of t he c o nse nti n g pr ocess s h o ul d be l ocate d i n t he researc h c h art. 
1 3. 2. 2 S u bject Data Pr otecti o n  
I n acc or da n ce wit h t he H ealt h I nf or m ati o n P orta bilit y a n d Acc o u nta bilit y A ct ( HI P A A), a 
s u bject m ust si g n a n a ut h orizati o n t o rel ease me dical i nf or mati o n t o t he s p o ns or a n d/ or 
all o w t he s p o ns or, a re g ulat or y a ut h orit y, or I nstit uti o nal Re vie w B oar d access t o s u bject’s 
me dical i nf or mati o n t hat i ncl u des all h os pital rec or ds rele v a nt t o t he st u d y, i ncl u di n g 
s u bjects’ me dical hist or y.  
1 3. 2. 3  Rete nti o n of rec or ds  
T he  Pri nci pal  I n v esti gat or  of  T he  Case  C o m pre he nsi ve  Ca ncer  Ce nter  s u per vises  t he  
rete nti o n  of  all  d oc u me ntati o n  of  a d v erse  e ve nts,  rec or ds  of  st u d y  dr u g  recei pt  a n d  
dis pe nsati o n, a n d all I R B c orres p o n de n ce f or as l o n g as nee de d t o c o m pl y wit h l ocal, 
nati o nal a n d i nter nati o nal re g ulati o ns. N o rec or ds will be destr o ye d u ntil t he Pri nci pal 
I n v esti gat or c o nfir ms d estr ucti o n is per mitte d.  
1 3. 2. 4  A u dits a n d i ns pecti o ns  
A ut h orize d re prese nt ati ves of t he s p o ns or, a re g ulat or y a ut h orit y, a n I n de pe n de nt Et hics 
C o m mittee (I E C) or a n I nstit uti o nal Re vie w B oar d (I R B) ma y visit t he site t o perf or m 
a u dits  or  i ns pecti o ns,  i n cl u di n g  s o urce  d ata  v erificati o n.  T he  p ur p os e  of  a n  a u dit  or 
i ns pecti o n is t o s yste maticall y a n d i n de pe n de ntl y e xa mi ne all st u d y-relate d acti vities a n d 
d oc u me nts t o deter mi ne w het her t h ese acti vities were c o n d u cte d, a n d data were rec or de d, 

  
  
  
 
Pa ge 5 5     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
a nal yse d, a n d acc uratel y re p orte d acc or di n g t o t he pr ot oc ol, G o o d Cli nical Practice ( G C P), 
g ui deli nes of t he I nt er nati o nal C o nfere nce o n H ar m o nizati o n (I C H), a n d a n y a p plica ble 
re g ulat or y r e q uire me nts.  F or m ulti-ce nter st u dies, partici pati n g sites m ust i n f or m t he 
s p o ns or-i n vesti gat or of p e n di n g a u dits.  
 
1 4. 0 S T A TI S TI C A L  C O N SI D E R A TI O N S   
T his  p hase  I -II  st u d y  is  de vise d  t o  e val uate  t he  safet y  a n d  preli mi nar y  efficac y  of  
Pal b ocicli b i n c o m bi nati o n wit h C P X - 3 5 1 f or treat me nt of A M L i n a t otal of 3 5 patie nts.   
P hase I will i de ntif y t he  M T D a n d rec o m me n de d p hase 2 d ose ( R P 2 D) of Pal b ocicli b w he n 
a d mi nistere d wit h C P X - 3 5 1 usi n g a c o n ve nti o nal 3 + 3 desi g n wit h 3 d os e le vels. D os e 
escalati o n will pr o cee d wit hi n eac h c o h ort acc or di n g t o t he f oll o wi n g s c he me. D os e -
li miti n g t o xicities ( D L T) are defi ne d i n secti o n 6. 2.  
 
N u m ber of S u bjects wit h D L T 
at a Gi ve n D ose Le vel 
Esc al ati o n Decisi o n R ule 
0 o ut of 3  
E nter 3 s u bjects at t he n e xt d ose le vel.  
1 o ut of 3  
E nter 3 m ore s u bjects at t his d ose le vel.  
•  If 0 of t hese 3 s u bj ects e x perie nce D L T, 
pr ocee d t o t he n e xt d ose le vel. 
•  If 1 or m ore of t his gr o u p s uffer D L T, t he n 
d ose escal ati o n is st o p pe d, a n d t his d ose is 
declare d t he ma xi mall y a d mi nistere d d ose. 
T hree ( 3) a d diti o nal s u bjects will be e ntere d 
at t he ne xt l o west d ose le vel if o nl y 3 
s u bjects were treat e d pre vi o usl y at t hat d ose. 
> 2  
D ose escalati o n will be st o p pe d. T his d ose le vel 
will be declare d t he ma xi mall y a d mi nistere d 
d ose ( hi g hest d ose a d mi nistere d). T hree ( 3) 
a d diti o nal s u bjects will be e ntere d at t he ne xt 

  
  
  
 
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l o west d ose le vel if o nl y 3 s u bjects were treat e d 
pre vi o usl y at t hat d ose. 
< 1 o ut of 6 or 0 o ut of 3 at 
hi g hest d ose le vel bel o w t he 
ma xi mall y a d mi nistere d d ose  
T his is ge nerall y t he rec o m me n de d ma xi mall y 
t olerate d d ose. 
 
After  c o m pleti o n  of  p h ase I,  t he  st u d y  will  pr ocee d  t o p has e  II  wit h  Pal b ocicli b  
a d mi nistere d at t he rec o m me n de d p hase 2 d ose ( R P 2 D). P hase II will e val uate b ot h t he 
safet y a n d t olera bilit y as well as preli mi nar y effi cac y of Pal b ocicli b i n c o m bi nati o n wit h 
C P X - 3 5 1 as meas ure d b y o ver all res p o ns e rate ( O R R), defi ne d as c o m plete res p o nse ( C R) 
a n d C R wit h i nc o m plete bl o o d c o u nt rec o ver y ( C Ri) b y 2 0 0 3 I W G criteri a. A d verse E v e nts 
will  be assesse d acc or di n g t o t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E v e nts 
( C T C A E) versi o n 5. 0).  
 
1 4. 1 P h ase II Effic ac y M o nit ori n g  
P hase II will use Si m o n ’s t w o-sta ge desi g n ( Si m o n, 1 9 8 9). T he n ull h y p ot hesis t hat t he 
tr ue O R R after i n d ucti o n < 0. 6 0 will be teste d a gai nst a o ne -si de d alter nati ve h y p ot hesis 
t hat t he O R R > 0. 8 0 wit h t y pe I err or 0. 1 a n d p o w er 0. 8 0 . T he p has e II part  h as a m a xi m u m 
sa m ple size of 2 6 patie nt s, wit h 1 4 patie nts i n sta ge I. F utilit y st o p pi n g r ules a n d desi g n 
o perati n g c h aracteristics are pr o vi d e d i n Ta ble 1 4. 1 . 
Ta ble 1 4. 1  F utilit y st o p pi n g b o u n daries f or effi cac y a n d o perati n g c h aracteristics of t he 
t w o-sta ge Si m o n desi g n wit h t y pe I err or 0. 1 a n d p o wer of 0. 8. N 1 is t he s a m ple size i n 
t he first sta ge. R 1 is t he dr u g rejecti o n n u m ber i n t he first sta ge. R is t he fi n al rejecti o n 
n u m ber s h o ul d t he trial pr ocee d t o f ull accr ual. P E T is t he pr o ba bilit y of earl y 
ter mi nati o n of t he st u d y u n der t he n ull h y p ot hesis. 
P hase II sa m ple size  
N 1  
R 1  
R 
P E T  
u n der n ull 
2 6  
1 4  
9  
1 8  
0. 7 2  
 

  
  
  
 
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T he trial will accr ue 1 4 patie nts i n sta ge I, if 9 or less patie nts ac hi e ve O R t he n t he tr ial 
will st o p earl y f or f utilit y. Ot her wise, t he trial will accr ue a d diti o nal 1 2 patie nts t o f ull 
sa m ple size of 2 6. T h e c o m bi nati o n will be c o nsi dere d effecti ve if 1 9 or m ore o ut of 2 6 
patie nts ac hie ve d O R.  
 
1 4. 2 P h ase II S afet y M o nit ori n g  
Safet y m o nit ori n g will c o nti n ue i n p hase II w h ere a  ma xi m u m of  2 6 patie nts will be 
e nr olle d. T he pri mar y e n d p oi nt f or safet y m o nit ori n g is t he occ urre n ce of a D L T d uri n g 
t he e ntire treat me nt peri o d of 1- 2 c ycl es of i n d ucti o n t hera p y. T he m et h o d of T hall et al 
( 1 9 9 5) (1 2 ) will be us e d t o m o nit or t he safet y of t h e c o m bi ne d re gi me n. T he safet y 
m o nit ori n g sc he me was de vise d t o pa use t he st u d y f or re vie w of t o xicities gi ve n 
s ufficie nt e vi de n ce t hat t he D L T rat e e xcee ds 0. 2 0. S pecificall y, t he trial will pa use f or 
t o xicit y re vie w if t he p osteri or pr o ba bilit y is 0. 8 or hi g her, i.e. Pr  ( T o xicit y Rate > 0. 2 0 | 
data) > 0. 8 0. A d diti o nall y, it is ass u me d t hat t he pri or pr o ba bilit y of e x perie nci n g a D L T 
is distri b ute d i n acc or da n ce wit h a n o n- i nf or mati ve pri or Beta ( 0. 2, 0. 8 ) distri b uti o n wit h 
effecti ve sa m ple size of 1. M o nit ori n g will be carri e d o ut i n c o h orts of 5 patie nts a n d will 
i nitiate fr o m t he 5 t h patie nt. Ta ble 1 4. 2 s u m marizes t he res ulta nt st o p pi n g b o u n daries. 
Ta ble 1 4. 3 s u m marizes t he trial’s o perati n g c haracteristics wit h t he Ba yesi a n desi g n. 
 
Ta ble 1 4. 2. S u m mar y of earl y st o p pi n g b o u n daries i n c o h ort s of 5  starti n g fr o m t he 5 t h patie nt. 
F or e x a m ple, i f 3 or m or e patie nts e x perie nce a D L T  o ut of t he first 5 patie nts, t he trial will st o p 
earl y d ue t o t o xicit y.  
 
St o p Earl y if # Patie nts E x perie nce d 
T o xicit y  
 
3- 5 
4- 1 0 
5- 1 5 
6- 2 0 
 
T otal # Patie nts Treate d  
 
5 
1 0 
1 5 
2 0 
 

  
  
  
 
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Ta ble 1 4. 3. S u m mar y of o perati n g c haracteristics base d o n 1 0, 0 0 0 si m ulati o ns usi n g b o u n daries i n 
Ta ble 1 4. 2 f or earl y st o p pi n g. F or e x a m ple, if t he tr ue t o xicit y rate is 2 0 %, t he pr o ba bilit y of earl y 
st o p pi n g is 0. 2 6. If t he tr ue t o xicit y rate is 4 0 %, t he pr o ba bilit y of earl y st o p pi n g is 0. 9 0. 
Sce nari o  
Tr ue T o xicit y 
Rate  
Pr( Earl y 
St o p) 
A vera g e # Patie nts 
Treate d  
A vera g e 
# T o xicities  
1  
0. 1 0  
0. 0 3  
2 4. 6  
2. 5  
2  
0. 2 0  
0. 2 6  
2 1. 7  
4. 3  
3  
0. 3 0  
0. 6 4  
1 6. 5  
4 . 9 
4  
0. 4 0  
0. 9 0  
1 1. 7  
4. 7  
 
 
 
1 4. 3 A n al ysis Pl a n 
Descri pti ve  statistical  a nal ysis  will  be  calc ulate d,  i ncl u di n g  hist o gra ms  or  b o x - pl ots, 
pr o p orti o ns, ra n ge, mea ns a n d sta n dar d de viati o ns. Fis her’s e xact test a n d Wilc o x o n ra n k 
test  will  be  us e d  i n  u ni variate  a nal yses  of  cate g orical  a n d  c o nti n u o us  varia bles,  
res pecti vel y.  S u m mar y  statistics  of  t o xicities  will  be  pr o vi de d  i n  fre q ue ncies  a n d  
perce nt a ges. T o xicit y rat e  a n d O R R  will be esti mate d al o n g wit h 9 5 % CIs. Ot her statistical 
a nal yses will be carrie d o ut as a p pr o priate. All p - v al ues prese nt e d will be n o mi nal.  
 
 
 
 
 
 
 
 
 
 
 
 
 

  
  
  
 
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R E F E R E N C E S  
1.  
D o h ner H, Este y E, Gri m wa de D, A m a d ori S, A p p el ba u m F R, B uc h ner T, et al. 
Dia g n osis a n d ma na ge m e nt of A M L i n a d ults: 2 0 1 7 E L N rec o m me n d ati o ns fr o m a n 
i nter nati o nal e x pert pa nel. Bl o o d. 2 0 1 7 Ja n 2 6; 1 2 9( 4): 4 2 4- 4 7. P u b Me d P MI D: 2 7 8 9 5 0 5 8. 
P u b me d Ce ntral P M CI D: P M C 5 2 9 1 9 6 5. E p u b 2 0 1 6/ 1 1/ 3 0. e n g. 
2.  
Ra va n di F, C ortes J, Fa d erl S, O' Brie n S, Garci a- Ma ner o G, V erst o vse k S, et al. 
C haracteristics a n d o utc o me of patie nts wit h ac ute m yel oi d le u ke mia refract or y t o 1 c ycle 
of hi g h- d ose c ytara bi ne- base d i n d ucti o n c he m ot h era p y. Bl o o d. 2 0 1 0; 1 1 6( 2 6): 5 8 1 8- 2 3. 
3.  
Ki m H P, Ger har d B, H ar as y m T O, Ma yer L D, H o g ge D E. 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 ut e m yel oi d le u ke mia pr o g e nit ors as c o m pare d t o a n al o g o us 
n or mal he mat o p oietic cells . E x peri me ntal he mat ol o g y. 2 0 1 1 J ul; 3 9( 7): 7 4 1- 5 0. P u b Me d 
P MI D: 2 1 5 3 0 6 0 9. E p u b 2 0 1 1/ 0 5/ 0 3. e n g. 
4.  
Fel d ma n EJ, La n cet J E, K olitz J E, Ritc hie E K, R o b oz GJ, List A F, 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 ut e m yel oi d le u kemia. 
J o ur nal of cli nical o nc ol o g y : official j o ur nal of t h e A merica n S ociet y of Cli nical 
O nc ol o g y. 2 0 1 1 Mar 1 0; 2 9( 8): 9 7 9- 8 5. P u b Me d P MI D: 2 1 2 8 2 5 4 1. P u b me d Ce ntral 
P M CI D: P M C 4 5 2 0 9 2 7. E p u b 2 0 1 1/ 0 2/ 0 2. e n g. 
5.  
C ortes J E, G ol d ber g S L, Fel d ma n EJ, Rizzeri D A, H o g ge D E, Lars o n M, 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. 2 0 1 5 
Jan 1 5; 1 2 1( 2): 2 3 4- 4 2. P u b Me d P MI D: 2 5 2 2 3 5 8 3. P u b me d Ce ntral P M CI D: 
P M C 5 5 4 2 8 5 7. E p u b 2 0 1 4/ 0 9/ 1 7. e n g. 
6. 
Me deir os B C, La ncet J E, C ortes J E, Ne well L F, Li n T L, Ritc hie E K, et al. 
A nal ysis of Efficac y B y A ge f or Patie nts A g e d 6 0- 7 5 wit h U ntreate d Sec o n dar y Ac ute 
M yel oi d Le u ke mia ( A M L) Treate d wit h C P X- 3 5 1 Li p os o me I njecti o n Vers us 
C o n ve nti o nal C ytara bi ne a n d Da u n or u bi ci n i n a P hase III Trial. Bl o o d. 
2 0 1 6; 1 2 8( 2 2): 9 0 2-. 
7.  
La ncet J E, U y G L, C ortes J E, Ne well L F, Li n T L, Ritc hie E K, et al. C P X - 3 5 1 
(c ytar a bi ne a n d d a u n or u bici n) Li p os o me f or I njecti o n Vers us C o n ve nti o nal C ytara bi ne 

  
  
  
 
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Pl us Da u n or u bici n i n Ol der Patie nts Wit h Ne wl y Dia g n ose d Sec o n d ar y Ac ute M yel oi d 
Le u ke mia. J o ur nal of cli nical o nc ol o g y : official j o ur nal of t he A merica n S ociet y of 
Cli nical O nc ol o g y. 2 0 1 8 J ul 1 9:J C O 2 0 1 7 7 7 6 1 1 2. P u b Me d P MI D: 3 0 0 2 4 7 8 4. E p u b 
2 0 1 8/ 0 7/ 2 0. e n g. 
8.  
K ufe D W, Maj or P P. St u dies o n t he mec ha nis m of acti o n of c yt osi ne ara bi n osi de. 
Me dical a n d pe di atric o n c ol o g y. 1 9 8 2; 1 0 S u p pl 1: 4 9- 6 7. P u b Me d P MI D: 6 7 6 1 5 6 9. E p u b 
1 9 8 2/ 0 1/ 0 1. e n g. 
9.  
Sc h nerc h D, Yalci nte pe J, Sc h mi dts A, Bec ker H, F oll o M, E n gel har dt M, et al. 
Cell c ycle c o ntr ol i n ac ut e m yel oi d le u ke mia. A m erica n J o ur n al of Ca ncer Researc h. 
2 0 1 2 0 8/ 2 0 
0 6/ 2 1/recei ve d 
0 7/ 2 7/acce pte d; 2( 5): 5 0 8- 2 8. P u b Me d P MI D: P M C 3 4 3 3 1 0 2. 
1 0. 
Alee m E, Ar ceci RJ. Tar geti n g cell c ycle re g ulat ors i n he mat ol o gic mali g na ncies. 
Fr o ntiers i n cell a n d de vel o p me ntal bi ol o g y. 2 0 1 5; 3: 1 6. P u b Me d P MI D: 2 5 9 1 4 8 8 4. 
P u b me d Ce ntral P M CI D: P M C 4 3 9 0 9 0 3. E p u b 2 0 1 5/ 0 4/ 2 9. e n g. 
1 1.  
C hes o n B D, Be n nett J M, K o pec k y KJ, B üc h n er T, Will ma n C L, Este y E H, et al. 
Re vise d Rec o m me n dati o ns of t he I nter n ati o nal W or ki n g Gr o u p f or Di a g n osis, 
Sta n dar dizati o n of Res p o nse Criteria, Treat me nt O utc o mes, a n d Re p orti n g Sta n dar ds f or 
T hera p e utic Trial s i n Ac ute M yel oi d Le u ke mia. J o ur nal of Cli nical O nc ol o g y. 
2 0 0 3; 2 1( 2 4): 4 6 4 2- 9. P u b Me d P MI D: 1 4 6 7 3 0 5 4. 
1 2.  
T hall P F, Si m o n R M, Este y E H. Ba yesia n s e q ue ntial m o nit ori n g desi g ns f or 
si n gle-ar m cli nical trials wit h m ulti ple o utc o mes. Statistics i n me dici ne. 1 9 9 5 Fe b 
2 8; 1 4( 4): 3 5 7- 7 9. P u b Me d P MI D: 7 7 4 6 9 7 7. E p u b 1 9 9 5/ 0 2/ 2 8. e n g. 
 
 
 
 
 
 
 

  
  
  
 
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A P P E N DI X I : E C O G / K A R N O F S K Y  P E R F O R M A N C E S T A T U S C RI T E RI A  
 
E C O G Perf or m a nce St at us Sc ale  
K ar n ofs k y Perf or m a nce Sc ale  
Gra de  
Descri pti o n  
Perce nt  
Descri pti o n  
 
0 
 
N or mal acti vit y. F ull acti ve, a ble 
t o carr y o n all pre-diseas e 
perf or ma n ce wit h o ut r estricti o n.  
 
1 0 0 
 
N or mal, n o c o m plai nts, n o 
e vi de nce of disease.  
 
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. 
 
1 
S y m pt o ms, b ut a m b ulat or y. 
Restricte d i n p h ysicall y 
stre n u o us acti vit y, b ut 
a m b ulat or y a n d a ble t o carr y o ut 
w or k of a li g ht or se d e ntar y 
nat ure ( e. g., li g ht h o use w or k, 
office w or k).  
 
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.  
 
7 0 
Cares f or s elf, u na ble t o carr y 
o n n or mal acti vit y or t o d o 
acti ve w or k.  
 
2 
I n b e d < 5 0 % of t he ti me.  
A m b ulat or y a n d ca p a ble of all 
self-care, b ut u na bl e 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 % if w a ki n g h o urs. 
 
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. 
 
5 0 
Re q uires c o nsi dera ble 
assista nce a n d fre q u e nt 
me dical care.  

  
  
  
 
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3 
I n b e d > 5 0 % of t he ti me.  
Ca pa ble of o nl y li mite d self -care, 
c o nfi ne d t o be d or c hair m ore 
t ha n 5 0 % of wa ki n g h o urs. 
 
4 0 
 
Disa ble d, re q uires s pecial care 
a n d assista nce.  
 
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.  
 
4 
1 0 0 % be dri d de n.  C o m pletel y 
disa ble d.  Ca n n ot carr y o n a n y 
self-care. T otall y c o nfi ne d t o be d 
or c hair.  
 
2 0 
Ver y sic k, h os pitalizati o n 
i n dicate d. Deat h n ot 
i m mi ne nt.  
 
1 0 
M ori b u n d, fatal pr ocesses 
pr o gressi n g ra pi dl y. 
5 
Dea d.  
0 
Dea d  
 
A P P E N DI X II: E A R L Y R E M O V A L  C RI T E RI A  
•  I nterc urre nt ill ness t hat pre ve nts f urt h er a d mi nistrati o n of treat me nt 
•  T he i n vesti gat or a n d/ or tr eati n g  p h ysicia n c o nsi ders it t o be i n t he best i nterest 
of t he s u bject t o per ma n e ntl y disc o nti n ue st u d y treat me nt 
o  T his i ncl u des if t he treat me nt is dee me d t o be of e xcessi ve t o xicit y t o 
t he patie nt b y t he treati n g p h ysicia n 
•  Patie nt decisi o n t o wit h dra w fr o m treat me nt ( p arti al c o nse nt) or fr o m t he st u d y 
(f ull c o nse nt) 
•  Pre g na nc y d uri n g t he c o urse of t he st u d y f or a c hil d- beari n g partici pa nt 
•  Deat h  

  
  
  
 
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•  U nacce pta ble a d vers e e v e nts defi ne d as f oll o wi n g:  
o  U nacce pta ble tr eat me nt relate d t o xicit y, N CI C T C A E versi o n 5. 0 
Gra de 3 or 4 t hat fails t o rec o ver t o baseli ne or < Gra de 3 i n t he a bse nce 
of treat me nt wit hi n 4 wee ks  
o  A n y t o xicit y or ot her iss ue t hat ca uses a dela y of st u d y dr u g 
a d mi nistrati o n b y m ore t ha n 4 wee ks  
 
 
A P P E N DI X III: R E S P O N S E C RI T E RI A  
Res p o nse  
Defi niti o n  
C o m plete re missi o n  
( C R) 
B o ne marr o w blasts < 5 %; a bse nce of  
circ ulati n g blasts a n d blasts wit h A uer  
r o ds; a bse nce of e xtra me d ullar y 
disease; a bs ol ute ne utr o p hil c o u nt > 1. 0 
x 1 0 9/ L ( 1, 0 0 0/ μ L); platelet c o u nt > 1 0 0 x  
1 0 9/ L ( 1 0 0, 0 0 0/ μ L)  
C R wit h i nc o m plete  
he mat ol o gic 
rec o ver y 
( C Ri) 
All C R criteria e xce pt f or resi d ual  
ne utr o pe nia [ < 1. 0 x 1 0 9/ L ( 1, 0 0 0/ μ L)] or  
t hr o m b oc yt o pe nia [ < 1 0 0 x 1 0 9/ L 
( 1 0 0, 0 0 0/ μ L)] 
M or p h ol o gic 
le u ke mia-fr ee state 
( M L F S) 
B o ne marr o w blasts < 5 %; a bse nce of  
blasts wit h A uer r o ds; a bse nce of 
e xtra me d ullar y disease; n o he mat ol o gic 

  
  
  
 
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rec o ver y re q uire d 
Partial re missi o n  
( P R) 
All he mat ol o gic criteria of C R; decreas e  
of b o ne marr o w blast perce nta ge t o 5 % 
t o 2 5 %; a n d decrease of pretreat me nt 
b o ne marr o w bl ast perce nta ge b y at 
least 5 0 % 
Sta ble disease  
A bse nce of C R M R D -, C R, C Ri, P R, 
M L F S; a n d criteri a f or P D n ot met  
Pr o gressi ve disease  
( P D) 
E vi de nce f or a n i ncreas e i n b o ne 
marr o w blast perce nt a ge a n d/ or 
i ncreas e of a bs ol ute blast c o u nts i n t he 
bl o o d: 
• > 5 0 % i ncrease i n marr o w blasts 
o ver baseli ne (a mi ni m u m 1 5 % p oi nt 
i ncreas e is re q uire d i n cases wit h 
< 3 0 % blasts at baseli ne; or  
persiste nt marr o w blast p erce nt a ge  
of > 7 0 % o ver at least 3 m o nt hs; 
wit h o ut at least a 1 0 0 % 
i m pr o ve me nt i n a bs ol ute ne utr o p hil 
c o u nt ( A N C) t o a n a bs ol ute le vel 
[ > 0. 5 x 1 0 9/ L ( 5 0 0/ μ L), a n d/ or 
platelet c o u nt t o > 5 0 x 1 0 9/ L 

  
  
  
 
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( 5 0, 0 0 0/ μ L) n o n -tra nsf us e d]; or 
• > 5 0 % i ncrease i n peri p heral blasts 
( W B C x % blasts) t o > 2 5 x 1 0 9/ L 
( > 2 5, 0 0 0/ μl) (i n t he a bse nce of 
differe ntiati o n s y n dr o me); or 
• Ne w e xtra me d ullar y dis ease 
 
A P P E N DI X I V: C LI NI C A L L A B O R A T O R Y P A R A M E T E R S 
He mat ol o g y 
Ser u m C he mistr y  Vitals  
P h ysical E xa m  B o ne Marr o w Bi o ps y & 
As pirati o n  
Re d bl o o d cell c o u nt  S o di u m  
Te m p  
Hei g ht ( o nl y at 
C 1 D 1) 
Marr o w blast perce nt 
He m o gl o bi n  
P otassi u m  
P ulse 
Wei g ht  
Marr o w Cell ularit y  
He mat ocrit  
C hl ori de  
Res p  
 
A uer R o ds 
W hite bl o o d cell 
c o u nt  
Bicar b o nate  
Bl o o d 
Press ure  
 
D ys plasia 
Ne utr o p hil 
B U N  
S p O 2 * 
 
C yt o ge netics ( n ot re q uire d 
o n D 1 4 bi o ps y ( + 3 da y 
wi n d o w) 
Platelets  
Gl uc ose ( n o n-
fasti n g)  
 
 
 
Blasts perce nt  
Al b u mi n  
 
 
 
M C V  
A S T  
 
 
 

  
  
  
 
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M C H C  
A L T  
 
 
 
E osi n o p hils  
Ser u m creati ni ne  
 
 
 
Bas o p hils  
Pr otei n  
 
 
 
M o n oc ytes  
 Calci u m  
 
 
 
L y m p h oc yte 
Bilir u bi n  
 
 
 
 
Al kali ne 
p h os p hate 
 
 
 
 
A P P E N DI X V: W H O cl assific ati o n of m yel oi d ne o pl as ms a n d ac ute le u ke mi a  
Ar ber et al, 2 0 1 6 
 
W H O m yel oi d ne o pl as m a n d ac ute le u ke mi a cl assific ati o n 
M yel o pr olifer ati ve  ne o pl as ms  ( M P N) 
  C hr o nic m yel oi d le u ke mia ( C M L), B C R -A B L 1 +  
  C hr o nic ne utr o p hilic le u ke mia ( C N L) 
 P ol yc yt he mia vera ( P V)  
 Pri mar y m yel ofi br osis ( P M F)  
    P M F, prefi br otic/earl y sta ge 

  
  
  
 
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W H O m yel oi d ne o pl as m a n d ac ute le u ke mi a cl assific ati o n 
    P M F, o vert fi br otic sta ge 
 Esse ntial t hr o m b oc yt he mia ( E T)  
  C hr o nic e osi n o p hilic le u ke mia, n ot ot her wise s pecifie d ( N O S) 
  M P N, u nclassifia ble 
Mast oc yt osis 
M yel oi d/l y m p h oi d  ne o pl as ms wit h  e osi n o p hili a  a n d re arr a n ge me nt  
of P D G F R A , P D G F R B , orF G F R 1,  or wit h  P C M 1 -J A K 2  
  M yel oi d/l y m p h oi d ne o plas ms wit h P D G F R A  rearra n g e me nt 
  M yel oi d/l y m p h oi d ne o plas ms wit h P D G F R B  rearra n g e me nt 
  M yel oi d/l y m p h oi d ne o plas ms wit h F G F R 1  rearra n ge me nt 
 Pr ovisi o n al e ntity: Myel oi d/ly m p h oi d ne o pl as ms wit h  P C M 1 -J A K 2 
M yel o d ys pl astic/ m yel o pr olifer ati ve ne o pl as ms ( M D S/ M P N) 
  C hr o nic m yel o m o n oc ytic le u ke mia ( C M M L) 
  At y pical c hr o nic m yel oi d le u ke mia (a C M L), B C R -A B L 1 − 
  J u ve nile m yel o m o n oc ytic le u ke mia (J M M L) 

  
  
  
 
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W H O m yel oi d ne o pl as m a n d ac ute le u ke mi a cl assific ati o n 
  M D S/ M P N wit h ri n g si der o blasts a n d t hr o m b oc yt osis ( M D S/ M P N-R S -T)  
 M D S/ M P N, u nclassifia ble  
M yel o d ys pl astic s y n dr o m es ( M D S) 
  M D S wit h si n gle li nea ge d ys plasia 
  M D S wit h ri n g si der o blasts ( M D S-R S)  
   M D S - R S a n d si n gle li nea ge d ys plasia 
   M D S - R S a n d m ultili nea ge d ys plasia 
 M D S wit h m ultili nea ge d ys plasia  
 M D S wit h e xcess blasts  
  M D S wit h is olate d del( 5 q) 
  M D S, u nclassifia ble 
 Pr ovisi o n al e ntity: Refr act ory  cyt o pe ni a of c hil d h o o d 
M yel oi d ne o plas ms wit h ger m li ne pre dis p ositi o n 
Ac ute  m yel oi d le u ke mi a ( A M L) a n d rel ate d  ne o pl as ms 

  
  
  
 
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W H O m yel oi d ne o pl as m a n d ac ute le u ke mi a cl assific ati o n 
 A M L wit h rec urre nt g e netic a b n or m alities  
    A M L wit h t( 8; 2 1)( q 2 2; q 2 2. 1);R U N X 1 -R U N X 1 T 1  
    A M L wit h i n v( 1 6)( p 1 3. 1 q 2 2) or t( 1 6; 1 6)( p 1 3. 1; q 2 2);C B F B -M Y H 1 1  
   A P L wit h  P M L -R A R A  
    A M L wit h t( 9; 1 1)( p 2 1. 3; q 2 3. 3);M L L T 3 -K M T 2 A  
    A M L wit h t( 6; 9)( p 2 3; q 3 4. 1);D E K - N U P 2 1 4 
   A M L wit h i n v( 3)( q 2 1. 3 q 2 6. 2) or t( 3; 3)( q 2 1. 3; q 2 6. 2); G A T A 2 , M E C O M  
    A M L ( me ga k ar y o bl astic) wit h t( 1; 2 2)( p 1 3. 3; q 1 3. 3);R B M 1 5 -M K L 1  
   Pr ovisi o n al e ntity: A M L  wit h  B C R -A B L 1  
   A M L wit h m utate d  N P M 1  
   A M L wit h biallelic m utati o ns of  C E B P A  
   Pr ovisi o n al e ntity: A M L  wit h  m ut ate d R U N X 1  
  A M L wit h m yel o d ys plasia-rel ate d c h a n ges 
 T hera p y -relat e d m yel oi d ne o plas ms 

  
  
  
 
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W H O m yel oi d ne o pl as m a n d ac ute le u ke mi a cl assific ati o n 
 A M L, N O S  
   A M L wit h mi ni mal differe ntiati o n  
   A M L wit h o ut mat urati o n  
   A M L wit h mat urati o n  
    Ac ute m yel o m o n oc ytic le u ke mia 
   Ac ute m o n o blastic/ m o n oc ytic le u ke mia  
    P ure er yt hr oi d le u ke mia 
   Ac ute me ga k ar y o bl astic le u ke mia  
   Ac ute bas o p hilic le u ke mia  
    Ac ute pa n m yel osis wit h m yel ofi br osis 
  M yel oi d sarc o ma 
  M yel oi d pr oliferati o ns relate d t o D o w n s y n dr o me 
    Tra nsie nt a b n or m al m yel o p oiesis ( T A M) 
    M yel oi d le u ke mia ass ociate d wit h D o w n s y n dr o me 

  
  
  
 
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W H O m yel oi d ne o pl as m a n d ac ute le u ke mi a cl assific ati o n 
Bl astic  pl as m ac yt oi d de n dritic  cell ne o pl as m