Clinical trial NCT03844997
Conditions: Acute Myeloid Leukemia AML
Sponsor: Sudipto Mukherjee, MD, PhD, MPH
Start date: 2019-06-06; Completion date: 2024-01-24
Enrollment: 35 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of Palbociclib in combination with investigational (experimental) drug, CPX-351 and evaluate the efficacy of Palbociclib in combination with chemotherapy as measured by overall response rate (ORR), i.e. complete response (CR) and CR with incomplete blood count recovery (CRi) by 2003 IWG criteria.

Detailed description:
The objectives of this study are to evaluate the safety and tolerability of Palbociclibin combination with CPX-351, and to evaluate the efficacy of Palbociclibin combination with chemotherapy as measured by overall response rate (ORR), i.e. complete response (CR) and CR with incomplete blood count recovery (CRi) by IWG criteria.

CPX-351 is an investigational drug that works as formulation of a fixed combination of the antineoplastic (acting to prevent, inhibit or halt the development of a neoplasm (a tumor)) drugs cytarabine and daunorubicin.

Palbociclibis an investigational drug that works to induce early G1 arrest by inhibiting CDK4/6, which are two types of CDKs that are overexpressed in AML cell cancer lines.

CPX-351 and Palbociclib is experimental because it is not approved by the Food and Drug Administration (FDA).

This is a single arm, open label study of the combination of Palbociclib with CPX-351 in adults with AML. The trial consists of two components: phase I to evaluate the safety with dose escalation of Palbociclib in combination with CPX-351 and phase II to evaluate the overall response rate of the combination in the targeted participant population.

Arms: arm 1: Palbociclib will be administered orally on day -1 and -2 at 125 mg PO during the phase IIaportion (dose level 0).Day 0 will be rest and then CPX-351 at 100 u/m2 will be started on days 1, 3, and 5 along with Palbociclib day 2, 4, and 6 followed by rest/monitoring period (day 7-28).

If Grade 3-4 non-hematologic toxicity is observed in 1 or less of 6 patients treated, the study will move to Phase IIb. If Grade 3-4 non-hematologic toxicity is observed in 2 or more of 6 patients treated, 6 additional patients will be treated on the Phase IIa portion at a lower dose level (100 mg po) until a Phase IIb safe dose schedule is defined at which 1 or less out of 6 patients on the Phase IIa experience Grade 3-4 non-hematologic toxicity. After the Phase IIa portion ensures safety, the study will proceed with phase IIb. The phase IIb component is a Simon 2-stage design trial whose objective is to assess the clinical efficacy of the combination of Palbociclib and CPX-351.
Interventions: intervention 1: Palcociclib intervention 2: CPX-351
Intervention descriptions: intervention 1: Palbociclib is an investigational (experimental) drug that works to induce early G1 arrest by inhibiting CDK4/6, which are two types of CDKs that are overexpressed in AML cell cancer lines. Palbociclib is experimental because it is not approved by the Food and Drug Administration (FDA).

Palbociclib will be supplied as capsules or tablets containing 125 mg equivalents of Palbociclib free base intervention 2: CPX-351 (daunorubicin and cytarabine) liposome for injection is a combination of daunorubicin and cytarabine in a 1:5 molar ratio encapsulated in liposomes for intravenous administration. CPX-351 is an investigational (experimental) drug that works as formulation of a fixed combination of the antineoplastic drugs cytarabine and daunorubicin. CPX-351 is experimental because it is not approved by the Food and Drug Administration (FDA).

Protocol documents:
Prot_SAP_000.pdf: 


  
  
  
 
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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 
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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  


  
  
  
 
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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  


  
  
  
 
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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) 
 


  
  
  
 
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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  


  
  
  
 
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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. 
 


  
  
  
 
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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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Versi o n date:  1/ 2 5/ 2 0 2 2 
 
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     
  
 
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•  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. 
 


  
  
  
 
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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.  


  
  
  
 
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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     
  
 
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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, 


  
  
  
 
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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  


  
  
  
 
Pa ge 6 3     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
•  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 


  
  
  
 
Pa ge 6 4     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
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 


  
  
  
 
Pa ge 6 5     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
( 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  
 
 
 


  
  
  
 
Pa ge 6 6     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
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 


  
  
  
 
Pa ge 6 7     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
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) 


  
  
  
 
Pa ge 6 8     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
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 


  
  
  
 
Pa ge 6 9     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
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 


  
  
  
 
Pa ge 7 0     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
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 


  
  
  
 
Pa ge 7 1     
  
 
Versi o n date:  1/ 2 5/ 2 0 2 2 
 
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 
 

ICF_001.pdf: 
CCF IRB #: 19-347  
Approval Date: 8/26/2021  
Expiration Date: 3/28/2022 
The Cleveland Clinic Foundation  
Consent to Participate in a Cancer Research Study  
Study title: CASE 1918; Phase I/II Trial of CPX-351 + Palbociclib in Patients with Acute Myeloid  
Leukemia  
Sponsor: Case Comprehensive Cancer Center; Jazz Pharmaceuticals  
Principal Investigators: Sudipto Mukherjee, MD – 216-444-0506 (Cleveland Clinic) After 
hours phone contact #: (216) 444-2200 or toll free at (800) 223-2273, and ask for the  
oncologist (cancer doctor) that is on call for Cleveland Clinic.   
Cancer research studies are coordinated by physicians and scientists from Cleveland Clinic,  
University Hospitals and Case Western Reserve University (CWRU) through the NIH National  
Cancer Institute (NCI) designated Case Comprehensive Cancer Center (Case CCC). The goal of this  
collaboration is to enhance cancer treatment and research in Northeast Ohio. This study is being  
offered at Cleveland Clinic (CC).  
Conflict of Interest Disclosure:  
One or more of the Investigators conducting this study serve as paid speakers, consultants or  
advisory committee members for the company that is paying for this research or a company that  
makes products used in this study. These financial interests are within permissible limits established  
by the Cleveland Clinic Conflict of Interest Policy. If you have any questions regarding conflicts of  
interest, please ask your study doctor or call the Institutional Review Board at 216-444-2924.  
KEY INFORMATION  
The following is a short summary of this research study to help you decide whether or not to be 
a part of this research study. More detailed information is included later on in this document.  
What should I know about a research study?  
• Someone will explain this research study to you.  
• You can choose whether or not to take part.  
• You can agree to take part and then later change your mind.  
• Your decision whether or not to participate will not be held against you.  
• You can ask all the questions you want before you decide.  
What is the purpose, procedures and duration of this study?   
We invite you to take part in a research study because you have been diagnosed with acute myeloid  
leukemia. The purpose of this study is to test the safety and efficacy of the combination of  
palbociclib plus CPX-351 in patients with acute myeloid leukemia.  
CPX-351 is an investigational (experimental) drug that works as formulation of a fixed combination  
of the antineoplastic drugs cytarabine and daunorubicin. CPX-351 is experimental because it is only  
FDA approved for the treatment adults with two types of acute myeloid leukemia (AML): newly  
diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML 
MRC).  
Palbociclib is an investigational (experimental) drug that works by arresting the cancer cell in early  
stage of its cell cycle. It is approved by the FDA for use in breast cancer, but, in this study, is being   
1  
CASE 1918  
Consent Version: 7/21/2021  
CCF IRB #: 19-347  


Approval Date: 8/26/2021  
Expiration Date: 3/28/2022 
evaluated in a different population of subjects (AML patients), so is considered an investigational  
(experimental) drug. Palbociclib is experimental because it is not approved by the Food and Drug 
Administration (FDA) for AML patients.   
You will be asked to provide one blood draw for a correlative study. There will be no additional  
research procedures performed.  
Your participation in the research will last about 45 days. After you finish the combination of  
palbociclib and CPX-351, your doctor will continue to watch you for side effects and follow your  
condition bimonthly for up to 2 years, depending on your condition.   
More detailed information can be found under the section labeled: “Information on the 
Research.” Why might you choose not to participate in this research study?  
There may be discomforts, side effects, and risks to using the palbociclib plus CPX-351 treatment  
combination that we do not know yet. Sometimes during a study, the sponsor may learn new  
information about the study drug and the risks, which the study doctor/staff will tell you about in a  
timely manner. This new information might make you change your mind about being in the study.  The 
study drugs may not be better, and could possibly be worse than the usual approach for your  cancer. 
Additionally, you may lose time at work or home and spend more time in the hospital or the  doctor’s 
office than usual. You also may be asked sensitive or private questions which you normally  do not 
discuss.   
More detailed information about the risks of this study can be found in the section labeled 
“Risks.” Why might you choose to volunteer for this study?  
We cannot know if you will have any benefit as a result of your participation in the study; it is  
possible the study treatment may improve your condition, which may give you relief from some  
symptoms or improve your quality of life. However, it is possible that your condition could worsen.  
Your participation in this study will help to obtain information about treating subjects with acute  
myeloid leukemia.  
More detailed information about the benefits of this study can be found in the section labeled  
“Benefits.”  
What are my other choices if I do not take part in this study?  
If you do not wish to take part in this research study, your study doctor will discuss 
alternative treatment options with you, including their benefits and risks. These may include:   
∙ The usual approach to treating acute leukemia  
∙ Taking part in other investigational studies if they are available  
∙ Supportive care which does not treat the leukemia but treats the symptoms  
DETAILED INFORMATION  
2  
CASE 1918  
Consent Version: 7/21/2021  
CCF IRB #: 19-347  
Approval Date: 8/26/2021  


Expiration Date: 3/28/2022 
The following is more detailed information about this study in addition to the information listed  
above.  
1. INFORMATION ON THE RESEARCH  
Why is the research study being done?  
The purpose of this study is to evaluate the safety and tolerability of Palbociclib in combination with  
CPX-351 and evaluate the effectiveness of Palbociclib in combination with chemotherapy as  
measured by overall response rate (ORR), i.e. complete response (CR) and CR with incomplete  
blood count recovery (CRi). Complete response (CR) is considered when the blasts percentage in the  
bone marrow < 5% and counts improved to certain level. CR with incomplete blood count recovery  
(CRi) is considered one the blasts are <5% but the counts did not meet criteria for complete  
remission. Both terms confirm remission.  
How Many People Will Take Part in this Study?  
Approximately 35 people will take part in this study at Cleveland Clinic.  
What is involved if you decide to take part in this research study?  
Phase 1 Dose Escalation Studies  
This portion of the study has been completed. The recommended safe dose of Palbociclib, the study  
drug, when given with chemotherapy was identified (125 mg) and will be used for treatment in the  
Phase II portion of the study.  
Phase II  
This portion of the study will evaluate how well Palbociclib, the study drug, when given with  
chemotherapy, will effectively treat the leukemia. Each patient in this part of the study will receive  
the same dose of Palbociclib.  
To find out what will happen to you during this study read the charts below. Start reading at the left  
side and read across to the right, following the lines and arrows. Your first course of treatment, or  
“induction”, will be completed as shown below. Depending on your response to this treatment, you  
may or may not have a second course, or “re-induction”. Please ask your study doctor any questions  
you may have regarding this treatment plan.   
3  
CASE 1918  
Consent Version: 7/21/2021  
CCF IRB #: 19-347  
Approval Date: 8/26/2021  


Expiration Date: 3/28/2022 
 
All study participants in Phase II will get the same study intervention. It will include the usual  
chemotherapy (CPX-351). All study participants will also get the study drug (Palbociclib) based on  
the Phase 1 findings.  
4  
CASE 1918  
Consent Version: 7/21/2021 
Induction Calendar 
Period 
Screening  
PeriodA  
Treatment Period 


 
 
 
D a y  
 
-2 J 
-1  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
I nf or me d c o nse nt f or m 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Hist or y a n d p h ysical e x a m  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nc o mita nt Me dicati o n B  
� X � 
E C O G perf or ma n ce stat us  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
He mat ol o g y  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ser u m C he mistr y  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Uric Aci d  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
P h os p hate Le v el  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
Ma g nesi u m Le v el  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
Pre g na nc y test  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
E C G G  
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  
 
 
 
 
B o ne marr o w bi o ps y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
B o ne marr o w as pirate  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
S ur vi val F oll o w u p  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rec or d R B C/ platelets tra nsf usi o n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease res p o nse assess me nt  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease relat e d f oll o w u p  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C orrelati ve Sa m ples  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
L D H/ T u m or L ysis S y n dr o me  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
A E Assess m e nt F  
� X � 
St u d y Dr u gs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5  
C A S E 1 9 1 8  
C o nse nt Versi o n: 7/ 2 1/ 2 0 2 1  


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 nse 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: Da y 1 4 b o ne marr o w bi o ps y/as pirate ha ve a + 3 da ys 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  
D: 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  
E: 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  
F: S A E f oll o w u p m ust be re p orte d t hr o u g h 3 0 da ys after last d ose  
G: S ki p pal b ocicli b d ose if Q Tc B > 4 8 0 ms  
H: 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  
I: T o be perf or me d o n sa me da y as Da y 3 5 bi o ps y  
J: Da y -2 pre -d ose assess me nts d o n ot nee d t o be re peate d if bei n g d o ne sa me da y as scree ni n g. If t he sa me assess me nts 
are bei n g use d f or b ot h scree 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.  
6  
C A S E 1 9 1 8  
C o nse nt Versi o n: 7/ 2 1/ 2 0 2 1  
Re -I n d ucti o n C ale n d ar 
Peri o d  
Tre at m e nt Peri o d  
 
 
D a y  
-2  
-1  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
Hist or y a n d p h ysical e x a m  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nc o mita nt Me dicati o n B  
� X � 
E C O G perf or ma n ce stat us  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


He mat ol o g y  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ser u m C he mistr y  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Uric Aci d  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
 
 
P h os p hate Le v el  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
 
 
Ma g nesi u m Le v el  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
 
 
E C G G  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
 
 
Vital si g n  
X  
X  
 
 
X  
 
X  
 
 
 
 
 
 
 
 
 
B o ne marr o w bi o ps y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B o ne marr o w as pirate  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S ur vi val F oll o w u p  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease res p o nse assess me nt  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease relat e d f oll o w u p  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A E Assess m e nt F  
� X � 
St u d y Dr u gs  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pal b ocicli b  
X  
X  
 
 
X  
 
X  
 
 
 
 
 
 
 
 
 
C P X -3 5 1  
 
 
 
X  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
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St u d y pr oce d ures  
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A p pr o val Date: 
8/ 2 6/ 2 0 2 1 E x pirati o n 
Date: 3/ 2 8/ 2 0 2 2
T he f oll o wi n g d escri b es all t he pr oce d ures y o u ca n e x p ect t o ha ve d uri n g t he st u d y. N ot all  
pr oce d ur es will b e d o ne at e ver y visit. T he st u d y d oct or/st u d y staff will disc uss t his wit h y o u i n  
m ore detail.  
I nf or m e d C o nse nt:   


The study doctor/staff will talk to you about the study and you will decide if you want to 
join. This will be done during the Screening visit.  
Review medical history:   
You will discuss your current and past health with the study doctor/staff. This will be done  
during the Screening visit.   
Review of medications:   
You will talk with the study doctor/staff about any medicines you take. This will be done during  
the Screening, Treatment and Follow Up visits.  
Physical examination:   
The study doctor/staff will check your body for general health. This will be done during the 
Screening and Treatment visits.   
Vital signs:   
The study doctor/staff will take your pulse, temperature, and blood pressure. This will be 
done during the Screening and Treatment visits.  
ECG (Electrocardiogram):   
Sticky patches that are connected to a machine that shows the electrical activity of your heart, are 
placed on your chest, arms and legs. This will be done during the Screening visit and maybe  
during Treatment visits if your Study Doctor advises you need this test.  
Blood draw/tests:   
 
 
 
 
 
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The study doctor/staff will draw blood from a vein in your arm, or may draw blood samples from  
a central catheter placed in the upper chest. You may get a bruise or irritation at the place where  
the needle goes into your skin. Some participants may faint and, in rare cases, can get an  infection.  
Sometimes you will need to repeat a blood test.   
Your blood will be used to check for:   
∙ Your general health  
∙ Disease evaluations  
∙ How your body handles the study drug  
∙ Pregnancy (if you are a female who could get pregnant.)  
∙ Scientific Research  
o 10mL of your blood will be taken for exploratory studies  
Bone Marrow Aspirate/Biopsy:   
An area of bone (usually pelvis) will be made numb by injecting a local anesthetic, and then a  
needle will be inserted into the bone. A small amount of bone and bone marrow will be  
removed. The bone marrow aspirate/biopsy will be used for disease evaluations, as well as  
Scientific/Genetic Research. This will be done during the Screening, Treatment and possibly  
Follow Up visits.  
How will my specimens be used?   
Your samples collected for this research will be analyzed for the study. As part of the analysis,  the 
research might include whole genomic sequencing. This means that researchers may look at  your 
sample to learn about your genes (DNA). There are different ways to look at your DNA.  
Researchers often use a technology called sequencing to look at your DNA. Sequencing “reads”  
each letter of the DNA and finds changes (also called “variations” or “mutations”) in your genes  
that may cause disease or affect how your body reacts to a certain disease.  
The research done with your blood may lead to the development of new products in the future.  
You will not receive, either now or in the future, any compensation, royalty, or other financial  
benefits resulting from any product, procedure, or other items developed from studying your  
sample(s).  
Will I be notified of the results of the tests/studies on my samples?   
When samples are collected and analyzed, there is the chance of finding something that may be  
important for your care. You will be informed of any results that are relevant to your clinical  
care.   
The research may find that you have an abnormal gene or gene product (RNA or protein) which  
indicates a risk for developing a disease at some time in the future. These results may also  
indirectly provide information about your entire family. This information will be provided to you   
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and your physician. A genetic counselor is available to you to discuss the results. The cost of a  
genetic counselor WILL NOT be paid by the research.   
2. RISKS  
What are the risks of participating in the research study?  
Your medical and genetic information is unique to you. There is a risk that someone outside of  
the research study could get access to your study records or trace information in a database back  
to you. They could use that information in a way that could harm you. While the chance that  
someone could access and misuse your information is believed to currently be very small, it is  
possible that the risk may increase in the future as people find new ways to access information.  
Side effects from the drugs are listed below. Some side effects are temporary, some long-lasting  
or permanent, some are mild and some may be severe, and some may lead to death.   
Possible side effects of CPX-351:  
COMMON, SOME MAY BE SERIOUS  
In 100 people receiving CPX-351 more than 10 and up to 100 may have: 
▪ Anemia (even requiring blood transfusions)  
▪ Neutropenia (low white blood cell count, which increases risk of infection) 
▪ Fatigue  
▪ Diarrhea  
▪ Nausea  
▪ Constipation  
▪ Hemorrhage  
▪ Rash  
▪ Edema (swelling)  
▪ Mucositis (irritation of mucous membranes, like in the mouth, nose, or vagina) 
▪ Musculoskeletal pain 
 
 
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▪ Abdominal Pain  
▪ Cough  
▪ Headache  
▪ Dyspnea (shortness of breath) ▪ Arrhythmia  
▪ Pneumonia  
▪ Sleep Disorder  
▪ Chills  
▪ Dizziness  
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▪ Non-conduction Cardiotoxicity (cardiotoxicity or damage to the heart caused by  the 
anthracylcine doxorubicin)  
▪ Fungal infection  
▪ Upper respiratory infection (excluding fungal)  
▪ Hypoxia (low amount of oxygen in the blood)  
▪ Hypertension  
▪ Hypotension  
▪ Vomiting  


▪ Chest Pain  
▪ Decreased appetite  
▪ Bacteremia (infection in the bloodstream, excluding sepsis)  
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▪ Delirium  
▪ Pyrexia (fever)  
▪ Pleural effusion (fluid around the lungs)  
▪ Anxiety  
▪ Pruritus (itching)  
▪ Sepsis (excluding fungal)  
▪ Hemorrhoids  
▪ Petechiae (red spots on the skin)  
▪ Renal (kidney) insufficiency, even to the point of needing dialysis  
▪ Transfusion reactions  
▪ Visual impairment (except bleeding)  
▪ Catheter/device/injection site reaction  
▪ Prolonged low platelets (increased risk for bleeding, and may need platelet  
transfusions)  
▪ Prolonged low neutrophil count  
▪ Hair loss 
 
 


OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving CPX-351 more than 5 may have: 
 
 
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▪ Hyponatremia (low sodium)  
▪ Hypokalemia (low potassium)  
▪ Hypoalbuminemia (low albumin)  
▪ Hyperbilirubinemia (jaundice)  
▪ Alanine aminotransferase abnormalities (indicating liver damage) 
 
 
OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving CPX-351 less than 10 may have: 
▪ Ear and labyrinth disorders: Deafness, Deafness unilateral   
▪ Eye Disorders: Eye conjunctivitis, Dry eye, Eye edema, Eye swelling, Eye  
irritation, Eye pain, Ocular discomfort, Ocular hyperemia (redness of the  
eyes), Periorbital edema (swelling around the eyes), Scleral hyperemia  
(redness of the white part of the eyes)  
▪ Gastrointestinal disorders: Dyspepsia (upset stomach)  
▪ Psychiatric disorders: Hallucinations   
▪ Respiratory, thoracic and mediastinal disorders: Pneumonitis (irritation of the  
lungs) 
 
 
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In addition to side effects outlined above, you may also experience the possible side effects of  
Palbociclib listed below.  
COMMON, SOME MAY BE SERIOUS  
In 100 people receiving Palbociclib more than 20 and up to 100 may have: 
▪ Anemia  
▪ Neutropenia  
▪ Fatigue  
▪ Diarrhea  
▪ Nausea 
 
 
OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving Palbociclib from 5 to 10 may have: 


▪ Decreased appetite  
▪ Constipation  
▪ Vomiting  
▪ Rash  
▪ Flatulence  
▪ Abdominal pain   
▪ Shortness of breath  
▪ Fever 
 
 
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OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving Palbociclib from 5 to 10 may have: 
▪ Cough  
▪ Back pain 
 
 
RARE, AND SERIOUS  
In 100 people receiving Palbociclib 5 or fewer may have: 


▪ Hair loss  
▪ Headache  
▪ Nosebleed  
▪ Muscle spasm  
▪ Upper respiratory tract infection  
▪ Dry mouth  
▪ Itching  
▪ Dizziness  
▪ Abdominal swelling  
▪ Chills  
▪ Runny nose 
 
 
Inflammation of the lungs  
Palbociclib—used to treat some patients with advanced breast cancer—may cause rare but severe  
inflammation of the lungs. According to the FDA, patients should notify their health-care   
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professional right away if they have any new or worsening symptoms involving their lungs, as  
they may indicate a rare but life-threatening condition. Symptoms to watch for include difficulty  
or discomfort with breathing and shortness of breath while at rest or with low activity.  
Posterior Reversible Encephalopathy Syndrome (PRES)  
PRES is a disorder characterized by headaches, mental status changes, visual disturbances, 
and/or seizures. PRES often occurs in patients with renal disease, such as hypertension, vascular  
and autoimmune diseases, exposure to immunosuppressive drugs (for example chemotherapy),  
and organ transplantation. If recognized and treated quickly, symptoms usually resolve within a  
week, and the changes seen in magnetic resonance imaging (MRI) resolve in a matter of days to  
weeks. A patient on this clinical trial developed this complication and it was determined to be  
possibly related to the combination of study drugs.  
Unknown Risks  


There may be risks or side effects related to the study drug/device that are unknown at this time.  
You will be notified of any significant new findings that become known that may affect your  
willingness to continue in the study.   
Reproductive Risks  
There may be unforeseen risks to an unborn child associated with your taking palbociclib and  
CPX-351. Therefore, if you are capable of giving birth to or fathering a child, you and your  
sexual partner should use adequate birth control measures while you are in the study. These  
measures may include abstinence, oral contraceptives (birth control pills), IUD, diaphragm,  
approved hormone injections, condoms, or documentation of medical sterilization. Discuss with  
your doctor which birth control measures are acceptable.   
If you are unwilling to do this, we ask that you not participate in this study. Pregnancy tests will  
be performed on all women of child-bearing potential before beginning the study and during the  
study each day for the first eight days. If you or your sexual partner become pregnant while  
taking part in this study you must notify the study doctor immediately.  
Confidentiality Risks  
There is a potential risk of loss of confidentiality of your data. Efforts will be made to keep your  
information confidential through the use of the following safeguards: use of codes, storage in a  
password protected computer accessible only by the research team. If you decide to be in this  
study, the study researchers will get information that identifies you and your personal health  
information. This may include information that might directly identify you, such as your name  
and address. This information will be kept for the length of the study. After that time it will be  
destroyed or de-identified, meaning we will replace your identifying information with a code that  
does not directly identify you. The principal investigator will keep a link that identifies you to  
your coded information, but this link will be kept secure and available only to the principal  
investigator or selected members of the research team. Any information that can identify you  
will remain confidential. Any personal information that could identify you will be removed or  
changed before files are shared with other researchers or results are made public.  
Blood Draw  
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The insertion of the needle to draw blood can be painful; however, the discomfort is brief. For  
most people, needle punctures to get blood samples do not cause any serious problems; however,  
they may cause bleeding, bruising, discomfort, infections, dizziness, or fainting.  
Bone Marrow Biopsy  
There are also risks associated with taking samples of your bone marrow. Your study doctor will  
insert a needle into your hip or breast bone to withdraw a sample of fluid containing bone  
marrow cells. The risks of bone marrow sampling commonly include discomfort, pain, redness,  
swelling, and/or bruising where the sample is taken from your hip or chest. Sometimes bleeding  
can occur at the place where the sample is drawn. Fainting and infection can happen, but rarely.  
Many patients also experience soreness or stiffness in the hips for several days after the  
procedure.  
 3. BENEFITS  
Participation in this study may help to improve your condition, but it is also possible that your  


condition may worsen. There is no guarantee that you will personally benefit by participating in  
this research study. Your participation in this study may provide information that may help other  
people who have a similar medical problem in the future.  
4. COSTS  
Are there any costs to you if you participate in this study?  
The following research study activities are being done only because you are participating in this  
research study and will be paid for by the study sponsor and will not be billed to you or your  
health insurance plan. These “research only” activities include: additional bone marrow biopsies  
outside of protocol requirements; electrocardiograms on scheduled days between day -2 and day  
14 (see study calendar); administration of the study drugs; correlative blood sample and the bone  
marrow send out at screening.  
Some of the services you will receive during this research study are considered to be  
conventional routine clinical services that you would have received even if you were not  
participating in the research study and will be billed to you or your health insurance plan.  
Examples of these routine services include: all blood samples used for labs such as complete  
blood count, complete metabolic panel, magnesium, phosphorus, uric acid, and pregnancy tests  
(if applicable); select bone marrow biopsies at screening and at end of treatment; any additional  
medication outside of the study drug, hospitalizations, and any radiographic tests. You are  
responsible for paying any deductibles, copayments or co-insurance that are a normal part of  
your health insurance plan.  
5. RESEARCH RELATED INJURY  
What will happen if you are injured as a result of taking part in the research?  
If you believe that you are injured as a result of the research procedures being performed, please  
immediately contact the study doctor.  
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If injury occurs as a result of your involvement in this research, medical treatment is available  
from Cleveland Clinic or another medical facility but you/your medical insurance will be  
responsible for the cost of this treatment. A research injury is an injury that happens as a result of  
taking part in this research study. If you are injured by a medical treatment or procedure that you  
would have received even if you weren’t in the study, that is not considered a “research injury”.  
There are no plans for payment of medical expenses or other payments, including lost wages, for  
any research related injury. To help avoid injury, it is very important to follow all study  
directions.  
Further information about research-related injuries is available by contacting the Cleveland  
Clinic Institutional Review Board at (216) 444-2924.  
6. HIPAA AUTHORIZATION  
Authorization to Use or Disclose (Release) Health Information that Identifies You for a  
Research Study  


If you volunteer to participate in this research, your protected health information (PHI) that  
identifies you will be used or disclosed to Sudipto Mukherjee, MD, and the research study staff  
at Cleveland Clinic for the purposes of this research and to Case Western Reserve University for  
administration.  
The PHI that we may use or disclose (release) for this research may include your name, address,  
phone number, date of birth, Social Security number, information from your medical record, lab  
tests, or certain information relating to your health or condition..  
Some of the tests and procedures done solely for this research study may also be placed in your  
medical record so other doctors know you are in this study. Upon completion of the study, you  
may have access to the research information that is contained in your medical record.   
In addition to the investigators and research staff listed above, your PHI may be looked at by  
other groups involved with the study such as the Cleveland Clinic Institutional Review Board  
and the Case Comprehensive Cancer Center Protocol Review and Monitoring Committee. Your  
PHI may also be used by and/or disclosed (released) to:  
▪ Cleveland Clinic, its study monitors and representatives  
▪ Funding/Drug Support: Jazz Pharmaceuticals  
▪ Case Comprehensive Cancer Center members and collaborators  
▪ The Food and Drug Administration;  
▪ The Department of Health and Human Services;  
▪ The National Cancer Institute (NCI);  
▪ Other Institutional Review Boards;   
▪ Data Safety and Monitoring Boards;  
Once your personal health information is released it may be re-disclosed and no longer protected  
by privacy laws.  
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Your research information may be used and disclosed indefinitely, but you may stop these uses  
and disclosures at any time by writing to:  
Sudipto Mukherjee, MD  
Case Comprehensive Cancer Center  
Cleveland Clinic  
9500 Euclid Ave.  
, OH 44195  
Your participation in the research will stop, but any information previously recorded about you  
cannot be removed from the records and will continue to be used as part of this research. Also,  
information already disclosed outside the Cleveland cannot be retrieved. This will not affect  
your rights to treatment or benefits outside the research study.   
The Cleveland Clinic will not use your information collected in this study for another research  
purpose without your written permission; unless the Cleveland Clinic Institutional Review Board  


(IRB) assures your privacy and confidentiality is protected. The IRB is a committee whose job it  
is to protect the safety and welfare of research subjects.  
By signing this informed consent form, you are authorizing such access to your research and  
medical record information. If you choose not to sign this consent form, you will not be able to  
participate in this research study. This Authorization does not have an expiration date.  
What will happen to your information that is collected for this research?  
Cleveland Clinic may share your study information, without anyone knowing that it is related to  
you specifically, with others or use it for research projects not listed in this form. Your data may  
be stored and shared for future research without additional informed consent if identifiable  
private information, such as your name and medical record number, are removed. If your  
identifying information is removed from your data, we will no longer be able to identify and  
destroy them.  
Study results may be shared in medical journals, at scientific meetings, and in other mediums  
without your identifying information. Your records will be confidential and your identity will not  
be shared in medical journals, at scientific meetings, and in other mediums without your express  
consent.   
Clinical Trials Language  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required  
by U. S. law. This Website will not include information that can identify you. At most, the  
Website will include a summary of the results. You can search the Website at any time.  
7. QUESTIONS  
Who do you call if you have any questions or problems?  
If you have any questions, you can ask the Principal Investigator and/or research staff at 
216- 444-0506.  
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Emergency or after-hours contact information   
If you are a Cleveland Clinic patient, you should contact the page operator at (216) 444-2200 or  
toll free at (800) 223-2273, and ask for the oncologist (cancer doctor) that is on call.  
Where Can I Get More Information?  
If the researchers cannot be reached, or if you would like to talk to someone other than the  
researcher(s) about: concerns regarding the study, research participant’s rights; research-related  
injury; or other human subjects issues, you may contact the Institutional Review Board (IRB) at  
Cleveland Clinic IRB 216-444-2924.   
You may call the National Cancer Institute's Cancer Information Service 
at: 1-800-4-CANCER (1-800-422-6237)   
You may also visit the NCI Web site at http://cancer.gov/  


▪ For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ ▪ For 
NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/  
You will get a copy of this form. If you want more information about this study, ask your study  
doctor.  
8. VOLUNTARY PARTICIPATION  
What are your rights as a research participant?  
Your participation in this research study is voluntary. Choosing not to participate will not alter  
your usual health care or involve any penalty or loss of benefits to which you are otherwise  
entitled. If you decide to join the study, you may withdraw at any time and for any reason  
without penalty or loss of benefits. If information generated from this study is published or  
presented, your identity will not be revealed.   
In the event new information becomes available that may affect the risks or benefits associated  
with this study or your willingness to participate in it, you will be notified so that you can decide  
whether or not to continue participating.  
Can I withdraw my samples?  
If you agree to allow your blood to be kept for future research with identifying information that  
could link your sample to you, you are free to change your mind at any time. We ask that you  
contact the Principal Investigator in writing and ask to withdraw your permission for your  
identifiable blood to be used for future research. The mailing address is,  
Sudipto Mukherjee  
9500 Euclid Ave, CA60  
Cleveland, OH 44195  
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At that time we will ask you to indicate in writing if you want the unused identifiable blood 
destroyed or if your samples (having all identifying information removed that would link the  
sample to you) could be used for other research.  
9. SIGNATURES  
Statement of Participant  
I have read and have had verbally explained to me the above information and have had all my  
questions answered to my satisfaction. I understand that my participation is voluntary and that I  
may stop my participation in the study at any time. Signing this form does not waive any of my  
legal rights. I understand that a copy of this consent will be provided to me. By signing below,  I 
agree to take part in this research study.   
_____________________________  


 Printed name of Participant  
_____________________________ ___________  
 Participant Signature Date  
Statement of Person Conducting Informed Consent Discussion  
I have discussed the information contained in this document with the participant and it is my  
opinion that the participant understands the risks, benefits, alternatives and procedures involved  
with this research study.  
_____________________________  
Printed name of person obtaining consent  
_____________________________ ___________  
Signature of person obtaining consent Date  
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