A PHASE 1 OPEN-LABEL PHARMACOKINETICS STUDY OF PALBOCICLIB, A CYCLIN-DEPENDENT KINASE 4 AND 6 (CDK4/6) INHIBITOR, IN POSTMENOPAUSAL CHINESE WOMEN WITH ER (+), HER2 (-) ADVANCED BREAST CANCER
Phase: PHASE1
Conditions: Advanced Breast Cancer
Sponsor: Pfizer

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1
A P H A S E 1 O P E N -L A B E L P H A R M A C O KI N E TI C S S T U D Y O F P A L B O CI C LI B , A 
C Y C LI N -D E P E N D E N T KI N A S E 4 A N D 6 ( C D K 4/ 6) I N HI BI T O R, I N
P O S T M E N O P A U S A L C HI N E S E W O M E N WI T H E R ( +), H E R 2 ( -) A D V A N C E D 
B R E A S T C A N C E R
C o m p o u n d:
P D - 0 3 3 2 9 9 1
C o m p o u n d N a me:
Pal b ocicli b
U S I N D N u m ber:
6 9, 3 2 4
E ur o pe a n Cli nic al Tri al D at a b ase 
( E u dr a C T) N u m ber:
N ot A p plica ble
Pr ot oc ol N u m ber:
A 5 4 8 1 0 1 9
P h ase:
P hase 1
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n bel o n gi n g t o Pfizer.  E xce pt as ot her w ise a gree d t o i n writi n g, 
b y acce pti n g or re v ie wi n g t his d oc u me nt, y o u a gree t o h ol d t his i nf or mati o n i n c o nfi de nce a n d n ot c o p y or 
discl ose it t o ot hers (e xce pt w here re q uire d b y a p plica ble la w) or use it f or u na ut h orize d p ur p oses.  I n t he e ve nt 
of a n y act ual or s us pecte d breac h of t his o bli gati o n, Pfizer m ust be pr o m ptl y n otifie d.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
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D oc u me nt Hist or y
D oc u me nt  
Versi o n D ate
S u m m ar y of C h a n ges
A me n d me nt 3
1 6 Ja n uar y  2 0 1 9 
1.
Secti o n 1. 2. Bac k gr o u n d a n d Rati o nal: u p date d 
bac k gr o u n d a n d rati o nal secti o ns wit h t he m ost 
rece nt data/i nf or mati o n a vaila ble; a d de d
rati o nal f or c ha n ges i n A me n d me nt 3. 
2.
A d de d A p pe n di x 9: Pr o vi de d Sc he d ule of 
Acti vities t o be f oll o we d f or patie nts 
c o nti n ui n g t o recei ve acti ve treat me nt after 
I RB/I E C a p pr o val of A me n d me nt 3. 
3.
Secti o n 3 St u d y  Desi g n Disease Assess me nt 
u p date d: U p o n a p pr o val of A me n d me nt 3, 
t u m or assess me nts ma y be perf or me d e ver y 
6 c ycles ( ± 7 da ys) or as rec o m me n de d b y  t he 
p h y sicia n acc or di n g t o t he patie nt’s cli nical 
c o n diti o ns.   R E CI S T 1. 1 ma y  c o nti n ue t o be 
use d t o e val uate i ma gi n g assess me nts at t he 
i n vesti gat or’s discreti o n b ut will n o l o n ger be 
ma n dat or y .  Assess me nts of t u m or lesi o ns will 
n o l o n ger be rec or de d i n t he C R F, n or will t he 
R E CI S T assess me nts.  O nl y  t he date of 
pr o gressi o n of disease will be rec or de d. 
4.
Secti o n 5. 2. 4. 2. 2. D ose Dela y a n d Secti o n 6. 3 
Acti ve Treat me nt P hase: Re q uire me nt f or 
re petiti o n of c ycle Da y 1 pr oce d ures u p date d, 
n o l o n ger nee de d t o be wit hi n 7 da ys. 
5.
Secti o n 5. 4 u p date d: dr u gs k n o w n t o pr ol o n g 
Q T i nter val were re m o ve d fr o m t he 
“ Pr o hi bite d Me dicati o ns” Secti o n 5. 4. 1 a n d 
a d de d u n der Per m itte d Me dicati o ns Secti o n 
5. 4. 3 t o reflect res ults fr o m St u d y  A 5 4 8 1 0 0 8 
s h o wi n g t hat pal b ocicli b, w he n a d de d t o 
letr oz ole, di d n ot pr ol o n g Q T i nter val t o a 
cli nicall y mea ni n gf ul e xte nt.
6.
Secti o n 6. 4 E n d of Treat me nt visit, Secti o n 6. 6 
Patie nt Wit h dra wal, a n d Secti o n 7. 2. 1 T u m or 
Assess me nt u p date d acc or di n g t o t he St u d y  
desi g n u p date t o reflect c ha n ges, t hat t he t u m or 
R E CI S T v. 1. 1 assess me nt n o l o n ger re q uire d 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3
a n d t he assess me nt fre q ue nc y  re d uce d.
7.
Secti o n 6. 5 a n d A p pe n di x 9 : Clarifie d 
f oll o w-u p d urati o n after disc o nti n uati o n of 
st u d y treat me nt, u p t o 2 8 da ys ( ± 7 da ys) fr o m 
t he last d ose of st u d y treat me nt or i nitiati o n of 
a n y ne w a nti-ca ncer t hera p y, w hic he ver occ urs 
earlier.
8.
Secti o n 7. 3. 2 L a b orat or y Safet y Assess me nt: 
U p o n I R B/I E C a p pr o val of A me n d me nt 3, 
bl o o d c he mistr y  will o nl y nee d t o be m o nit ore d 
e ver y 3 c ycles a n d at e n d of treat me nt visit; 
he m o gl o bi n A 1c will n o l o n ger be re q uire d t o 
be meas ure d e ver y  3 m o nt hs b ut is re q uire d t o 
be c ollecte d at t he e n d of treat me nt visit.  
A d diti o nal u nsc he d ule d bl o o d c h e mistr y pa nels 
ma y  be c ollecte d as cli nicall y i n dicate d a n d 
res ults will be rec or de d o n t he a p pr o priate 
C R F.
9.
Secti o n 7. 3. 3. E C G: O nce A me n d me nt 3 is 
I RB /IE C a p pr o ve d, E C G will be perf or me d as 
cli nicall y i n dicate d be yo n d C y cle 1 0 b y  
referri n g t o A p pe n di x 9.
1 0. Secti o n 8 A d verse E ve nt Re p orti n g u p date d t o 
be c o nsiste nt wit h Pfizer te m plate.  
Acc o r di n gly, 1 7. 3 A p pe n di x 3 was u p date d
a n d 1 7. 8 A p pe n di x 8 C ollecti o n of Pre g na nc y  
I nf or mati o n was a d de d
1 1. Secti o n 1 5. 1 C o m m u nicati o n of Res ults b y  
Pfizer was u p date d t o be c o nsiste nt wit h Pfizer 
te m plate.
1 2. Secti o n 1 6 Refere nces: M ore refere nces were
a d de d f or ne w u p dates. 
1 3. T hr o u g h o ut t he d oc u me nt: E dit orial c ha n ges 
ma de f or better rea da bilit y a n d clarificati o n.
A me n d me nt 2
2 4 J ul y  2 0 1 5 
1. D ue t o re g ulat or y  reas o n i n C hi na, C D K 6
ge n ot y pi n g test is n o w re m o ve d fr o m t his 
st u d y. T heref ore, a si n gle 4 m L  bl o o d sa m ple 
Pre p D 1 ( K 2E D T A w h ole bl o o d c ollecti o n 
o pti mize d f or D N A a nal y sis) will n ot be 
 

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A 5 4 8 1 0 1 9
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c ollecte d pre-d ose o n Da y  - 1. ( Sc he d ule of 
Acti vities/ Secti o n 3 St u d y Desi g n/ Secti o n 7 
Assess me nts)
2.
Ta ble 1 Sc he d ule of Acti vities: All o we d st u d y  
visit wi n d o w is a d de d i n t he r o w f or 
St u d y Da y .
3.
Ta ble 1 Sc he d ule of Acti vities: “( o nl y  f or 
C y cle 2)” is re m o ve d fr o m Da y  1 of C ycles 2 
f or Vital Si g ns a n d P hys ical E xa mi nati o n, 
si nce s ym pt o m -direct e d p h ysical e xa mi nati o ns, 
bl o o d press ure a n d p ulse rate will be still 
perf or me d after t he first t w o c y cles. 
4.
Ta ble 1 Sc he d ule of Acti vities a n d f o ot n ote p: 
Clarificati o n is a d de d t o i n dicate t he 
ra n d o mizati o n of patie nts i nt o 2 gr o u ps will 
occ ur o n Da y  - 1 f or differe nt bi o ps y sc he d ules 
i n Lea d-i n p hase a n d Cyc le 1. 
5.
Ta ble 2 Sc he d ule of Acti vities: A pre -d ose P K 
sa m ple is a d de d i n t he si n gle d ose P K part o n 
Da y 1 of Lea d -i n p hase t o meet t he re g ulat or y 
re q uire me nt.
6.
Ta ble 2 Sc he d ule of Acti vities: C y cle n u m ber 
( C 1) is a d de d i n t he ta ble a n d clarifie d i n 
f o ot n ote i. Clarificati o n is als o a d de d t o 
f o ot n ote c t o e m p hasize t he pre-d ose P K 
c ollecti o n o n C ycle 1 Da y 1 is f or p ost si n gle 
d ose P K sa m ple at 1 2 0 hrs. 
7.
Secti o n 1. 2. 1. 3 Cli nical S u m mar y : U p dates are 
a d de d as m ore data bec o me a vaila ble. 
8.
Secti o n 7. 1 Bl o o d V ol u me: Mi n or u p date is 
a d de d. 
9.
Secti o n 3 St u d y  Desi g n/ Secti o n 7. 2. 1 T u m or 
Assess me nt: A d de d t he te xt a b o ut c o n diti o nal 
acce pta nce f or patie nts t o c o nti n ue t he st u d y  
treat me nt be yo n d t he ti me of R E CI S T -defi ne d 
disease pr o gressi o n. 
1 0. Secti o n 3 St u d y  Desi g n/Secti o n 7. 2. 1 T u m or 
Assess me nt/ Ta ble 1 a n d Ta ble 3 f o ot n ote b: 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
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Base d o n c urre nt i ma gi n g practice f or sta n dar d 
of care f or a d va nce d breast ca ncer patie nt 
p o p ulati o n, t he fre q ue nc y  of p ost-baseli ne 
t u m or assess me nts is c ha n ge d t o e ver y 
1 2 wee ks ( 7 d a y s) fr o m C ycle 1 Da y 1.
1 1. Secti o n 4. 1 I ncl usi o n Criteria: A d de d 
clarificati o ns o n defi niti o n of p ost me n o pa usal 
w o me n. 
1 2. Secti o n 4. 2 E xcl usi o n Criteria: C o m mercial kit 
assa ys t o test H E R 2 stat us be yo n d t he s p o ns or 
a p pr o ve d o nes ca n be als o acce pte d f or 
e nr oll me nt criteria, gi ve n t he e xtre mel y  l o w 
pr o ba bilit y  of false H E R 2 ne gati ve res ults.
1 3. Secti o n 4. 3 Ra n d o mizati o n Criteria is a d de d.
1 4. Secti o n 4. 4 L ife St yle G ui deli nes: Clarificati o n 
is a d de d t o i n dicate a n alc o h ol breath test is n ot 
re q uire d b ut ma y be c o n d ucte d at t he discreti o n 
of t he i n vesti gat or.
1 5. Secti o n 5. 2. 2 Pre parati o n a n d Dis pe nsi n g: 
A d de d sa me re q uire me nt f or letr oz ole as 
pal b ocicli b.
1 6. Secti o n 5. 2. 3. 1 Pal b ocicli b: I f i nte nsi ve P K 
assess me nts are c o n d ucte d i n a la ter c ycle f or 
a n y reas o n, t he sa me re q uire me nt f or brea kfast 
i nta ke is a p plie d.
1 7. Secti o n 5. 2. 3. 1 Pal b ocicli b: Safet y  e val uati o n 
( vital si g ns, la b orat or y safet y a n d E C G) s h o ul d 
be c o n d ucte d bef ore f o o d i nta ke.
1 8. Secti o n 5. 2. 3. 1 Pal b ocicli b: Secti o n 5. 2. 4. 2 was
referre d f or d ose m o dificati o n t hat is nee de d 
f or patie nts e x perie nci n g i n vesti gati o nal 
pr o d uct relate d t o xicit y .
1 9. Secti o n 5. 2. 6 C o m plia nce/ Secti o n 5. 3 Dr u g 
St ora ge a n d Dr u g Acc o u nta bilit y : Clarificati o n 
is a d de d t o re q uire patie nts t o ret ur n t he 
c o m plete d patie nt diar y .
2 0. Secti o n 5. 3 Dr u g St ora ge a n d Dr u g 
 

Pal b ocicli b
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Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
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Acc o u nta bilit y : Re q uire me nt is a d de d t o re p ort 
a n y e xc ursi o ns of dr u g st ora ge c o n diti o n t o 
s p o ns or.
2 1. Secti o n 5. 4. 1 Pr o hi bite d Me dicati o ns: 
E mer gi n g data fr o m t w o dr u g i nteracti o n 
st u dies is a d de d i n s u bsectio n f or C Y P 3 A 
i n hi bit ors/i n d ucers.
2 2. Secti o n 5. 4. 2 Me dicati o ns N ot Rec o m me n de d: 
Re q uire me nt is a d de d t o rec or d a n y usa ge of 
C hi nese or ot her her bal me dici nes.
2 3. Secti o n 6. 1 Scree ni n g: O p ht hal mic pr oce d ures 
at scree ni n g are a d de d f or all le ns gra di n g 
e val ua ble p atie nts ( n o a d diti o nal pr oce d ures; 
o nl y  clarificati o ns). 
2 4. Secti o n 6. 1. 1 Scree n Fail ure is a d de d. 
2 5. Secti o n 6. 5 Patie nt Wit h dra wal: Clarificati o n is 
a d de d t o i n dicate “ wit h dra wal of c o nse nt” 
s h o ul d n ot be t he reas o n f or disc o nti n uati o n if 
a patie nt o pts t o d isc o nti n ue fr o m t he acti ve 
treat me nt p hase as a res ult of a n u nacce pta ble 
a d verse dr u g reacti o n. 
2 6. Secti o n 7. 3. 2 L a b orat or y Safet y Assess me nts/ 
Ta ble 1 Sc he d ule of Acti vities f o ot n ote d: 
Clarificati o n is a d de d t o i n dicate H g b A 1c, 
fasti n g li pi d pa nel, fasti ng gl uc ose a n d fasti n g 
i ns uli n will be a nal yze d at a ce ntral la b orat or y 
desi g nate d b y t he s p o ns or.
2 7. Secti o n 7. 3. 2 La b orat or y Safet y 
Assess me nts/ Ta ble 1 Sc he d ule of Acti vities 
f o ot n ote d: W he n all of t hese assess me nts are 
c o n d ucte d t o get her, t he y  s h o ul d be d one bef ore 
f o o d i nta ke. 
2 8. Secti o n 7. 3. 3 Electr ocar di o gra m ( E C G): Heart 
rate s h o ul d be als o rec or de d t o get her wit h ot her 
E C G meas ure me nts at t he sc he d ule d 
meas ure me nt ti me p oi nts. 
2 9. Secti o n 7. 3. 3 Electr ocar di o gra m 
( E C G)/ Ta ble 1 Sc he d ule of Acti vities f o ot n ote 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
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i: E C G e val uati o n s h o ul d be c o n d ucte d bef ore 
f o o d i nta ke.
3 0. Secti o n 7. 3. 3 Electr ocar di o gra m ( E C G): T he 
c ut off val ue of Q Tc pr ol o n gati o n a n d 
ass ociate d g ui da nce w he n Q Tc pr ol o n gati o n 
occ urs are u p date d. 
3 1. Secti o n 7. 3. 4. 1 Vis ual Ac uit y  a n d Refracti o n: 
I n a d ditio n t o S nelle n n otati o n , ot her met h o ds 
are all o we d t o be use d a n d t he met h o d bei n g 
use d s h o ul d be i n dicate d o n t he C R F pa ges.
T he ori gi nal res ults s h o ul d be rec or de d wit h 
t he res pecti ve u nits i n dicate d.  C o n versi o n t o 
S nelle n n otati o n will n ot be nee de d.
3 2. S ecti o n 7. 3. 4. 2 I ntra oc ular Press ure 
Meas ure me nt: A n o n -c o ntact met h o d 
( T o n o pe n, Sc hi otz or Re b o u n d t o n o meter) is 
all o we d t o be use d f or i ntra oc ular press ure 
(I O P) meas ure me nt. T he I O P data ma y  be 
p o ole d t o get her f or a nal ysis. 
3 3. Secti o n 7. 4 P har mac o ki netic Assess me nts: 
A d diti o nal clarificati o n is a d de d t o e m p hasize 
t hat t he d osi n g ti mes b ot h pri or t o a n d after 
eac h sa m ple c ollecti o n s h o ul d be ca pt ure d i n 
t he C R F pa ges. T w o e xa m ples are als o gi ve n.
3 4. Secti o n 7. 4 P har mac o ki netic Assess me nts: 
Re q uire me nts o n a d m i nistrati o n of st u d y dr u gs 
bef ore a n d after eac h pre -d ose P K sa m ple are 
a d de d.
3 5. Secti o n 7. 4. 1 Plas ma f or A nal y sis of 
Pal b ocicli b ( P D -0 3 3 2 9 9 1): D uri n g t he 
o ut patie nt visits o n Da ys 1, 1 9 a n d 2 0 i n 
C y cle 1 a n d Da y 1 i n C ycle 2, patie nts s h o ul d 
be i nstr ucte d t o bri n g t he dr u g s u p pl y a n d 
a d mi nister t he dr u gs i n t he C R U after 
c o m pleti o n of P K c ollecti o n o n t hat da y . 
3 6. Secti o n 7. 5 Bi o mar ker Assess me nts: 
A d diti o nal clarificati o ns are a d de d t o 
e m p hasize t hat t he c ollecti o ns of bi o mar ker 
sa m ples s h o ul d be d o ne as cl ose as p ossi ble 
 

Pal b ocicli b
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wit h t he c ollecti o n of P K sa m ples. Sa m ple 
c ollecti o ns f or T K a nal ys is s h o ul d occ ur 
i m me diatel y after t he c o m pleti o n of P K 
sa m pli n gs ( wit hi n 1 5 mi n utes) a n d s ki n bi o ps y  
sa m pli n gs s h o ul d be c o n d ucte d wit hi n 
3 0 mi n utes after t he c o m pleti o n of P K 
sa m pli n gs. 
3 7. Secti o n 7. 5. 1 S ki n Bi o ps y : Rare c o ntra dicti o ns 
a n d rele va nt preca uti o ns of s ki n bi o ps y  are 
descri be d. 
3 8. Secti o n 8 A d verse E ve nt Re p orti n g u p date d t o 
be c o nsiste nt wit h Pfizer te m plate.
3 9. Secti o n 9. 2. 1 A nal y sis P o p ulati o ns: T he P K 
e val ua ble a nal y sis set is a d de d f or P K a nalys is 
pla n. 
4 0. Secti o n 9. 2. 2 Deri vati o n of P har mac o ki netic 
Para meters Pri or t o A nal ysis: S u m mar y  of P K 
para meters will be f or P K para meter a nal ys is 
set a n d P K e val ua ble a nal ysis set.
4 1. Secti o n 9. 4 A nal y sis of Ot her E n d p oi nts is 
a d de d.
4 2. Secti o n 9. 5. 3 A nal y sis of Electr ocar di o gra m 
meas ure me nts: T he c ut off val ue of Q Tc 
pr ol o n gati o n is u p date d t o be c o nsiste nt wit h 
Secti o n 7.
4 3. Secti o n 1 5. 1 C o m m u nicati o n of Res ults b y  
Pfizer was u p date d t o be c o nsiste nt wit h Pfizer 
te m plate.
4 4. A p pe n di x 7 is a d de d f or Wisc o nsi n 
A ge -Relate d E y e Disease St u d y ( A R E D S) 
2 0 0 8 Cli nical L e ns O pacit y Gra di n g 
Pr oce d ure.
4 5. Secti o n 1 6 Refere nces: M ore refere nces are 
a d de d f or ne w u p dates. 
4 6. T hr o u g h o ut t he d oc u me nt: E dit orial c ha n ges 
ma de f or better rea da bilit y a n d clarificati o n.  
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9
A me n d me nt 1
0 6 N o ve m ber 
2 0 1 4
1.
Secti o n 1 I ntr o d ucti o n: u p date d t he 
n o n -cli nical s u m mar y, i n vi v o a n d i n vitr o 
safety p har mac ol o g y, cli nical s u m mar y  a n d 
safety secti o ns wit h t he m ost rece nt 
data/i nf or mati o n a vaila ble.
2.
Secti o n 1. 2. 3. 2 Rati o nale f or Pal b o cicli b D ose: 
re m o ve d rati o nale f or si n gle-d ose st u d y  gi ve n 
m ulti ple d osi n g P K assess me nt is i ncl u de d i n 
t his st u d y, a n d als o a d de d a cli nical data 
s u m mar y base d o n t he c urre nt I n vesti gat or’s 
Br oc h ure ( 2 0 1 3).
3.
Secti o n 1. 2. 3. 2 Rati o nale f or Pal b ocicli b 
D ose/ S ecti o n 3 St u d y Desi g n/ Secti o n 9. 1 
Sa m ple Size Deter mi nati o n: re vise d t he criteria 
f or patie nt re place me nt gi ve n t hat 8-1 2 s u bjects 
are re q uire d f or P K st u d y b y C hi na C F D A.
4.
T hr o u g h o ut t he w h ole d oc u me nt: re m o ve d 
“st u d y peri o d” t o a v oi d a n y c o nf usi o n si nce 
there are n o differe nt peri o ds i n t his st u d y .
5.
Secti o n 2: a d de d bi o mar ker a nal ys is as a n ot her 
sec o n dar y o bjecti ve a n d a d de d bi o mar kers as 
a d diti o nal sec o n dar y e n d p oi nts. 
6.
Secti o n 2. 2/ Secti o n 9. 2: a d de d Vz/ F as o ne of 
t he pri mar y e n d p oi nts f or m ulti ple-d ose P K t o 
be c o nsiste nt wit h t hat f or si n gle -d ose P K 
assess me nt; re vise d P K para meter ta ble per 
re q uest fr o m Pfizer P K a nal yst f or t his st u d y. 
7.
Secti o n 2. 2: a d de d 1 -ye ar P F S pr o ba bilit y as 
a n ot her sec o n dar y efficac y e n d p oi nts.
8.
Sc he d ule of Acti vities/ Secti o n 3 S t u d y Desi g n: 
c ha n ge d t o kee p patie nts i n t he cli nical u nit f or 
at least 7 2 h o urs after pal b ocicli b d osi n g f or 
b ot h si n gle - a n d m ulti ple -d ose P K assess me nts 
t o re d uce t he n u m ber of o ut patie nt visits t o 
i m pr o ve t he c o m plia nce wit h st u d y c o n d uct.
9.
Secti o n 3 St u d y  Desi g n: a d de d t w o para gra p hs 
t o disc uss t he rati o nale f or bi o mar ker 
assess me nts a n d p har mac o ge n o mic a nal ys es, 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0
res pecti vely.
1 0. Sc he d ule of Acti vities/t hr o u g h o ut t he w h ole 
d oc u me nt: u p date d t he st u d y  da y n u m bers t o 
a v oi d a n y c o nf usi o n bet wee n Lea d -i n p hase
( Da y 1 t o Da y 5) a n d Cycles ≥1 ( Da y s ≥1) 
acti vities.  T he da y  n u m ber f or pre-d ose 
pr oce d ures a n d a d missi o n of patie nts t o cli nical 
u nit was c ha n ge d t o Da y  - 1.
1 1. Sc he d ule of Acti vities/ Secti o n 4. 3. 2 a n d 
5. 2. 3. 1: re m o ve d fasti n g re q uire me nt fr o m 
pal b ocicli b d osi n g i nstr ucti o ns, a n d a d de d 
re q uire me nt t hat pal b ocicli b s h o ul d n o w be 
ta ke n wit h meals.  O n da ys wit h i nte nsi ve P K 
c ollecti o ns ( o nl y D a y 1 i n Lea d-i n p hase a n d 
Da y  2 1 i n C ycle 1), t he c o nte nt re q uire me nt of 
pr o vi de d brea kfasts was a d de d.
1 2. Sc he d ule of Act i vities/ Secti o n 7. 3. 2: a d de d 
m ore la b orat or y  tests i n t he bl o o d c he mistr y 
pa nel ( he m o gl o bi n A 1c, fasti n g gl uc ose, 
fasti n g i ns uli n a n d fasti n g li pi d pa nel) t o 
e val uate w het her or n ot pal b ocicli b affects 
gl uc ose meta b olis m.
1 3. Sc he d ule of Acti vities: re m o ve d se veral P K 
sa m ple c ollecti o ns. 
1 4. Sc he d ule of Acti vities: i ncrease d t he fre q ue nc y  
of he mat ol o g y  assess me nts.  T he sc he d ule of 
he mat ol o g y  assess me nts i n Lea d-i n p hase a n d 
C y cle 1 was m o ve d t o Ta ble 2 f or clarificati o n.
1 5. Sc he d ule of Acti vities/ Secti o n 7. 3. 3: u p da te d 
E C G e val uati o n sc he d ule a n d a d de d pr oce d ure 
re q uire me nt i n Ta ble 1 a n d re m o ve d t he E C G 
part fr o m Ta ble 2.
1 6. Sc he d ule of Acti vities/ Secti o n 7. 3. 4: a d de d 
o p ht hal mic pr oce d ures f or all e val ua ble 
patie nts t o assess t he p ote ntial ris k of 
pal b ocicli b -ass ociated cr y stalli ne le ns c ha n ges.
1 7. Sc he d ule of Acti vities/ Secti o n 7. 4: a d de d 
re q uire me nt f or stea dy state P K sa m ple 
c ollecti o n ( wit h o ut d osi n g i nterr u pti o n f or at 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1
least 8 da ys pri or t o sa m ple c ollecti o n).
1 8. Sc he d ule of Acti vities/ Secti o n 7. 4. 1: a d de d 
clarificati o n o n de viati o n fr o m re q uire d 
c ollecti o n ti me f or P K sa m ples a n d i nstr ucti o ns 
f or c ollecti o n of pre-d ose P K sa m ples; a d de d 
i nstr ucti o ns re gar di n g dr u g a d mi nistrati o n t o 
e ns ure t he c ollecti o n of pre- d ose P K sa m ples.
1 9. Sc he d ule of Acti vities/ Secti o n 7. 4. 1: t he bl o o d 
v ol u me c ollecte d f or eac h P K sa m ple was 
re d uce d t o 2 m L fr o m 3 m L.
2 0. Sc he d ule of Acti vities/ Secti o n 7. 5: a d de d 
se parate bl o o d sa m ple f or p har mac o ge n o mic 
a nal ys is ( C D K 6 p ol ym or p his m [ S N P rs 4 4 5]).
2 1. Sc he d ule of Acti vities/ Secti o n 7. 6: a d de d s ki n 
p u nc h bi o ps y pr oce d ure a n d bl o o d test f or 
bi o mar ker assess me nts.  T he detaile d ti me 
p oi nts were descri be d i n Ta ble 2.
2 2. Sc he d ule of Acti vities: re m o ve d uri ne dr u g test 
a n d alc o h ol breat h test beca use t hese tests are 
i na p pr o priate i n a st u dy i n ca ncer patie nts.
2 3. Sc he d ule of Acti vities: a d de d clarificati o n t hat 
s o me pre- d ose pr oce d ures will n ot be re q uire d 
o n Da y  -1 if alrea d y perf or me d wit h acce pta ble 
res ults wit hi n 7 da ys pri or t o Da y - 1.
2 4. Secti o n 5. 2. 1 F or m ulati o n a n d Pac ka gi n g: 
u p date d me dicati o n i nf or mati o n f or letr oz o le t o 
i n dicate t hat it will be s o urce d l ocall y at C hi na 
sites.
2 5. Secti o n 5. 2. 2: a d de d m ore detaile d i nstr ucti o n 
f or dr u g pre parati o n/ dis pe nsi n g.
2 6. Secti o n 5. 2. 3. 2: a d de d clarificati o n t hat 
letr oz ole will be a d mi nistere d al o ne fr o m D a y  
2 t o 5 i n L ea d -i n p hase, d uri n g t he pal b ocicli b 
off -treat me nt wee k i n e ver y c ycle, a n d i n t he 
e ve nt of pal b ocicli b d osi n g i nterr u pti o n.
2 7. Secti o n 5. 2. 4. 2. 2. D ose Dela y  (f or 
pal b ocicli b)/ Secti o n 6. 3. Acti ve Treat me nt 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2
P hase: a d de d o ne para gra p h t o clarif y  t he 
pr oce d ures re q uire d o n Da y 1 of a ne w c y cle 
w he n t he start of a ne w c y cle is dela ye d d ue t o 
treat me nt-relate d t o xicit y.
2 8. Secti o n 5. 2. 4. 2. 3. D ose Re d ucti o ns: a d de d 
Ta ble 7 t o clarif y t he rec o m me n de d pal b ocicli b 
d ose m o dificati o n f or he mat ol o gic t o xicities b y  
C T C A E gra de a n d treat me n t da y.  T his ta ble 
was a d de d i n a gree me nt wit h t he pal b ocicli b 
Ris k Ma na ge me nt C o m mittee’s re visi o n of t he 
bl o o d c o u nts m o nit ori n g pla n.
2 9. Secti o n 5. 4. 1. Pr o hi bite d Me dicati o ns: 
e m p hasize t hat C Y P 3 A i n hi bit or/i n d ucers 
s h o ul d be pr o hi bite d wit hi n 7 da ys or 
5 half -li ves ( w hic he ver is l o n ger) pri or t o t he 
first P K sa m ple u ntil t he c o m pleti o n of all 
re q uire d P K sa m pli n gs; e dit orial c ha n ges t o 
differe ntiate bet wee n str o n g a n d m o derate 
C Y P 3 A i n d ucers/i n hi bit ors. 
3 0. Secti o n 5. 4. 1. Pr o hi bite d Me dicati o ns: a d de d 
pr o hi bi ti o n of ta ki n g pr ot o n-p u m p i n hi bit or 
( P PI).  Acc or di n g t o ne w a vaila ble data fr o m a 
dr u g i nteracti o n st u d y, t he t otal pal b ocicli b 
e x p os ure ( A U C i nf) was re d uce d o nly b y 
a p pr o xi matel y 1 3 % u n der fe d c o n diti o ns w he n 
c oa d mi nistere d wit h P PI.  T heref ore, P PIs will 
be pr o hi bite d o nl y  f or P K assess me nts (fr o m at 
least 1 0 da ys bef ore t he c ollecti o n of t he first 
P K sa m ple u ntil t he c o m pleti o n of all t he 
re q uire d P K sa m pli n gs).
3 1. Secti o n 5. 4. 3. Per mitte d Me dicati o ns: a d de d 
rec o m me n dati o n t o use l ocal a ntaci ds as well 
as H 2-rece pt or a nta g o nists as alter nati ve 
treat me nts f or patie nts re q uiri n g 
gastr o pr otecti ve treat me nt.  Sta g gere d d osi n g 
re gi me ns will be re q uire d o nl y o n P K sa m pli n g 
da y s.  D osi n g of pal b ocicli b s h o ul d occ ur at 
least 1 0 h o urs after H2-rece pt or a nta g o nists 
e ve ni n g d ose a n d 2 h o urs bef ore t he 
H 2-rece pt or a nta g o nists m or ni n g d ose.  L ocal 
a ntaci ds s h o ul d be gi ve n at least 2 h o urs bef ore 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 3
or 2 h o urs after a d mi nistrati o n of pal b ocicli b.
3 2. Secti o n 5. 4. 3. Per mitte d Me dicati o ns: a d de d 
clarificati o n f or all o wi n g aci d re d uci n g a ge nts 
t o be use d after t he c o m pleti o n of P K 
e val uati o ns.
3 3. Secti o n 5. 4. 2. Me dicati o ns N ot Rec o m me n de d: 
re m o ve d c oa d mi nistrati o n of C Y P 3 A 
s u bstrates wit h pal b ocicli b fr o m Secti o n 5. 4. 2 
base d o n ne w a vaila ble data t hat s h o we d 
pal b ocicli b is a wea k C Y P 3 A i n hi bit or.
3 4. Secti o n 6. 5: a d de d clarificati o ns o n patie nt 
wit h dra wal.
3 5. Secti o n 7. 1: u p date d bl o o d v ol u me secti o n a n d 
Ta ble 9 t o o nl y pr o vi de t he esti mati o n of bl o o d 
a m o u nt d uri n g t he Lea d -i n p hase a n d Cycle 1 
w here t he a m o u nt of c ollecte d bl o o d will be 
m uc h lar ger t ha n ot her c ycles.  T he t otal bl o o d 
sa m pli n g v ol u me d uri n g t he w h ole st u d y 
ca n n ot be esti mate d beca use t he trial d urati o n 
is deter mi ne d by disease pr o gressi o n, 
u nacce pta ble t o xicit y , wit h dra wal of c o nse nt, 
or patie nt deat h.
3 6. Secti o n 8. A d verse E ve nt Re p orti n g: ma de 
c ha n ges t o c o m pl y wit h t he c urre nt versi o n of 
pr ot oc ol te m plate. 
3 7. Secti o n 9. 2. 1. A nal y sis P o p ulati o ns: ma de 
c ha n ges o n t he defi niti o ns of P K c o nce ntrati o n 
p o p ulati o n a n d P K para meter a nal ys is 
p o p ulati o n t o be c o nsiste nt wit h t he P K desi g n.
3 8. Secti o n 9. 2. 2. Deri vati o n of P har mac o ki netic 
Para meters Pri or t o A nal ysis: ma de c ha n ges t o 
a v oi d a n y c o nf usi o n.
3 9. Secti o n 9. 3. Efficac y  A nal ysis: a d de d 
defi niti o n of efficac y  a nal ysis set; a d de d 
descri pti o n a b o ut ce ns ori n g pr o gressi o n -free 
s ur vi val a n d d urati o n of res p o nse; a d de d 
descri pti o ns f or calc ulati n g t he 1 -ye ar P F S 
pr o ba bilit y .
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 4
4 0. Secti o n 9. 4. Safet y  A nal ysis: c ha n ge d t he 
i nstr ucti o n t o i ncl u de t he me dical hist or y, 
p h y sical e xa mi nati o n of patie nts i nt o t he st u d y 
data base; a d de d scree ni n g val ues of la b o rat or y 
data, E C Gs, a n d vital si g ns i nt o t he st u d y  
data base as baseli ne le vels.
4 1. Secti o n 9. 4. 2: a d de d brief descri pti o n of 
a nal ys is f or oc ular e ve nts.
4 2. Secti o n 9. 4. 3: a d de d clarificati o ns a n d re m o ve d 
re peate d para gra p hs a b o ut E C G a nal ysis.
4 3. Secti o n 1 0/ Secti o n 1 1: re m o ve d P C R U -relate d 
parts gi ve n t hat t he st u d y will be c o n d ucte d at 
e xter nal sites i n C hi na.
4 4. Secti o n 1 5: ma de c ha n ges t o c o m pl y  wit h t he 
c urre nt versi o n of pr ot oc ol te m plate.
4 5. Secti o n 1 6: a d de d m ore refere nces t o s u p p ort 
t he i ncl u de d data a n d i nf or mati o n.
4 6. E dit orial c ha n ges ma de t o c orrect t y p os a n d 
f or matti n g iss ues.
Ori gi nal P r ot oc ol
1 0 A P R 2 0 1 3  
N/ A
T his a me n d me nt i nc or p orates all re visi o ns t o date, i ncl u di n g a me n d me nts ma de at t he 
re q uest of c o u ntr y healt h a ut h orities, i nstit uti o nal re vie w b oar ds/ethics c o m mittees 
(I RBs/ E Cs), etc .
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5
T a ble 1 .
S C H E D U L E O F A C TI VI TI E S
T he Sc he d ule of Acti vities ta ble pr o vi des a n o ver vie w of t he pr ot oc ol visits a n d pr oce d ures.  Refer t o t he S T U D Y P R O C E D U R E S
a n d A S S E S S M E N T S secti o ns of t he pr ot oc ol f or detaile d i nf or mati o n o n eac h pr oce d ure a n d assess me nt re q uire d f or c o m plia nce wit h 
t he pr ot oc ol. 
T he i n vesti gat or ma y  sc he d ule visits ( u n pla n ne d visits) i n a d diti o n t o t h ose liste d o n t he sc he d ule of acti vities, i n or der t o c o n d uct 
e val uati o ns or assess me nts re q uire d t o pr otect t he well bei n g of t he s u bject. 
Pr ot oc ol Acti vit y
Scree ni n g
(2 8 d a ys 
pri or t o 
st u d y 
e ntr y )
Si n gle - D ose 
P K ( Le a d -i n 
p h ase D a ys 
1- 5)
M uti ple D os e P K
(C ycle 1 )
C ycles 2
E n d of 
Tre at me nt 
/ Wit h dr a w al 
( E O T)r
F oll o w
-u p
St u d y D a y
D a y - 1a
Fr o m 
Da y -4 t o 
Da y - 1
D a ys 1 ~ 5
Fr o m 
Da y -3 t o 
Da y 1
D a y 
1
D a y 
1 4
D a y 
2 1
D a y 1
(2 d, o nl y 
f or c ycle
> 2)
D a y 1 4
(2 d)
D a y 2 1
(2 d)
7
B aseli ne D oc u me nt ati o n
I nf or me d C o nse nt
X
Me dical / O nc ol o g y
Hist or y 
X  
X
Baseli ne 
Si g ns/ S y m pt o ms b
X  
X
Vital Si g n s a n d P h ysical 
E xa mi nati o n c
X  
X
X
X
X
E C O G Perf or ma nce 
Stat us
X
X
X
X
L a b or at ory Tests 
He mat ol o g y d
X  
X
See Ta ble 2 f or detaile d ti me p oi nts
X
X ( o nl y f or 
C y cle 2)
X
Bl o o d C he mistr y d
X  
X
X  
X
X
X ( o nl y f or 
C y cle 2)
X
H g b A 1c d
X
C y cle 4 Da y 1 a n d e ver y 3 m o nt hs t h ereafter
X
Fasti n g Gl uc ose a n d 
Fasti n g I ns uli n d
X
X
X ( o nl y f or 
C y cle 2)
X
Fasti n g Li pi d Pa nel d
X
X
Uri nal ysis e
X  
X
X
C oa g ulati o n f
X  
X
X
H bs A g , a nti- H C V g
X
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 6
Pr ot oc ol Acti vit y
Scree ni n g
(2 8 d a ys 
pri or t o 
st u d y 
e ntr y )
Si n gle - D ose 
P K ( Le a d -i n 
p h ase D a ys 
1- 5)
M uti ple D os e P K
(C ycle 1 )
C ycles 2
E n d of 
Tre at me nt 
/ Wit h dr a w al 
( E O T)r
F oll o w
-u p
St u d y D a y
D a y - 1a
Fr o m 
Da y -4 t o 
Da y - 1
D a ys 1 ~ 5
Fr o m 
Da y -3 t o 
Da y 1
D a y 
1
D a y 
1 4
D a y 
2 1
D a y 1
(2 d, o nl y 
f or c ycle
> 2)
D a y 1 4
(2 d)
D a y 2 1
(2 d)
7
HI V test h
X
E C G (i n tri pl icate)i
X  
X
X  
X
X
X ( o nl y f or 
C y cle 2)
X
Oc ular Assess me nt j
X
See f o ot n ote f or details
X
St u dy Tre at me nt
Letr oz ole
O nce dail y c o nti n u o usl y (fr o m Lea d -i n p hase Da y 1)
Pal b oci bli b k
X
( O nl y Da y 1)
O nce dail y o n Da y 1 t o Da y 2 1 of  eac h c ycle f oll o we d b y 7 da ys off
D ise ase A ssess me ntsl
C T/ M RI Sca ns of C hes t, 
A b d o me n, Pel vis, a n y 
cli nicall y i n dicate d sites 
of disease, a n d of b o ne 
lesi o ns; Cli nical
e val uati o n of s u perficial 
disease
X
Perf or me d e ver y 1 2 wee ks 
(7 da ys) fr o m C 1 D 1
X
Ra di o n ucli de B o ne Sca n, 
W h ole B o d y
X
Perf or me d e ver y 2 4 wee ks 
( ± 7 days) fr o m C 1 D 1
X
Ot her Cli nic al 
Assess me nts
Dr u g C o m plia nce m
X
X
A d verse E ve nt Re p orti n g n
X  
X
Assesse d t hr o u g h o ut t he st u d y
X
X
C o nc o mita nt
M e dicati o n s/ Treat me ntso
X  
X
Assesse d t hr o u g h o ut t he st u d y
X
X
P h ar m ac o ki netic B l o o d 
S a m pli n g
See Ta ble 2 f or detaile d ti me p oi nts
S ki n Bi o psy p
X
See Ta ble 2 f or detaile d ti me p oi nts
Ra n d o mizati o n p
X
T hy mi di ne Ki n ase Bl o o d 
Test q
X
See Ta ble 2 f or detaile d ti me p oi nts
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 7
a.
D a y -1: Patie nts w ill be a d mitte d t o t he Cli nical Researc h U nit ( C R U) o n Da y -1 a n d will be re q uire d t o sta y i n t he u nit u ntil at least 7 2 h o urs ( o n Da y 4) 
f oll o wi n g si n gle d ose of pal b ocicli b base d o n t he a vaila bilit y of C R U.  I n t he case t hat scree ni n g a n d Da y -1 occ ur o n t he sa me da y, pr oce d ures sc he d ule d o n 
D a y  -1 d o n ot nee d t o be re peate d.
b.
B aseli ne Si g ns/ S y m pt o ms: Baseli ne t u m or relate d si g ns a n d s y m pt o ms will be rec or de d at t he scr ee ni n g a n d Da y -1 visit pri or t o d osi n g a n d t he n re p orte d 
as a d verse e ve nts d uri n g t he trial if t he y w orse n i n se verit y or i ncrease i n fre q ue nc y.
c.
Vit al Si g ns a n d P h ysic al E x a mi n ati o n : A f ull p h ysical e xa mi nati o n i ncl u di n g a n e xa mi nati o n of all maj or b o d y syste ms, hei g ht (at scree ni n g o nl y), wei g ht,
bl o o d press ure a n d p ulse rate, w hic h ma y be perf or me d b y a p h ysicia n, re gistere d n urse or ot her q ualifie d healt h care pr o vi de r, will be re q uire d at scree ni n g, 
D a y  -1, Da y 1 of C ycles 1 a n d 2 as w ell as t he e n d of treat me nt ( E O T).  P h ysical e xa mi nati o ns will n ot be re q uire d o n Da y -1 if a n acce pta ble scree ni n g 
e xa mi nati o n is perf or me d wit hi n 7 da ys pri or t o Da y -1.  S y m pt o m -directe d p h ysical e xa mi nati o ns, bl o o d press ure a n d p ulse rate will be perf or me d at 
s u bse q ue nt visits.
d.
H e m at ol o g y, a n d Bl o o d C he mistr y P a nel: He m at ol o g y i ncl u des he m o gl o bi n ( H b), W B C, a bs ol ute ne utr o p hils, platelet c o u nt a n d t he assess me nts will be 
c o n d ucte d re gar dless of f o o d i nta ke.  Bl o o d c he mistr y i ncl u des A S T/ A L T, al kali ne p h os p hatase, s o di u m , p otassi u m, ma g nesi u m, t otal calci u m, t otal 
bilir u bi n, B U N ( or urea), ser u m creati ni ne, al b u mi n, he m o gl o bi n A 1c ( H g b A 1c), fasti n g gl uc ose, fasti n g i ns uli n, a n d fasti n g l i pi d pa nel.  H g b A 1c 
assess me nts will be c o n d ucte d re gar dless of f o o d i nta ke; fasti n g g l uc ose, fasti n g i ns uli n a n d fasti n g li pi d pa nel will be assesse d f oll o wi n g a n o ver ni g ht fast 
(at least 1 0 h o urs); sa m ples f or ot her bl o o d c he mist y tests s h o ul d be c ollecte d f oll o wi n g at least a 4-h o ur fast.  T heref ore, if all of t hese assess me nts are 
c o n d ucte d t o get her, t he y s h o ul d be d o ne bef ore f o o d i nta ke.  T he he mat ol o g y a n d bl o o d c he mistr y assess me nt sc he d ules s h o ul d be ref erre d t o i n Ta ble 1 a n d 
Ta ble 2 .  A d diti o nal hemat ol o g y/c he mistr y pa nels ma y be perf or me d as cli nicall y i n dicate d.  H g b A 1c, fasti n g li pi d pa nel, fasti n g gl uc ose a n d fasti n g i ns uli n 
will be s hi p pe d t o a ce ntral la b orat or y desi g nate d b y t he S p o ns or f or a nal ysis.
e.
Uri n al ysis: Uri ne pr otei n a n d bl o o d.
Di ps tic k is acce pta ble.  If p ositi ve, micr osc o pic a nal ysis will be perf or me d a n d 2 4-hr uri ne sa m ples will be c ollecte d 
( o nl y f or pr otei n e xcreti o n).  T his assess me nt will n ot be re q uire d o n Da y -1 if a n acce pta ble scree ni n g assess me nt is perf or me d wit hi n 7 da y s pri or t o 
D a y -1.
f.
C o a g ul ati o n: P T or I N R, P T T or a P T T. A d diti o nal c oa g ulati o n st u dies ma y be perf or me d as cli nicall y i n dicate d .  T he assess me nt will n ot be re q uire d o n 
D a y  -1 if a n acce pta ble scree ni n g assess me nt is perf or me d wit hi n 7 da ys pri or t o Da y -1.
g.
H bs A g , a nti -H C V : He patitis B s urface a nti ge n ( H bs A g) a n d a nti b o d y a gai nst he patitis C vir us (a nti -H C V) tests.
h.
HI V test : H u ma n I m m u n o deficie nc y Vir us test.
i.
E C G: At eac h sc he d ule d E C G e val uati o n, 3 c o nsec uti ve 1 2 -lea d pre-d ose E C Gs will be perf or me d a p pr o xi matel y 2 mi n utes a part t o deter mi ne t he mea n 
Q T c i nter val.  All t he assess me nts will be ma de after at least a 1 0 -mi n ute rest i n a s u pi ne p ositi o n.  If E C G a n d P K c ollecti o ns are sc he d ule d o n t he sa me da y 
( C ycle 2 Da y 1), pre-d ose E C G assess me nts s h o ul d occ ur bef ore P K c ollecti o ns.  All E C G e val uati o ns s h o ul d be c o n d ucte d bef ore f o o d i nta ke.
j.
Oc ul ar Assess me nt : Oc ular assess me nts s h o ul d be c o n d ucte d at scree ni n g a n d o n st u d y treat me nt after 3 m o nt hs ( C ycle 4 Da y 1), 6 m o nt hs ( C ycle 7 
D a y 1), 1 2 m o nt hs ( C yc le 1 3 Da y 1), e ver y 1 2 m o nt hs ( Da y 1 of C ycles 2 5, 3 7 etc.) t hereafter, as well as at t he E O T.  A d diti o nal oc ular assess me nts ma y be 
perf or me d d uri n g t he st u d y as cli nicall y i n dicate d.  T he oc ular assess me nts will i ncl u de: best c orrecte d dista nt vis ual ac u it y, refracti ve err or ass ociate d wit h 
best c orrecte d dista nt vis ual ac uit y, i ntra oc ular press ure (I O P – o ne rea di n g), slit -la mp bi o micr osc o p y of t he a nteri or se g me nt i ncl u di n g cell c o u nt a n d flare 
gra di n g, cr ystalli ne le ns gra di n g usi n g t he Wisc o nsi n A ge - Relate d E ye Disease St u d y ( A R E D S), 2 0 0 8 Cli nical Le ns O pacit y Gra di n g pr oce d ure, a n d 
f u n d osc o p y.  All oc ular assess me nts will be perf or me d b y o p ht hal m ol o gists.
k.
St u d y Tre at me nt A d mi nistr ati o n: Pal b ocicli b a n d letr oz ole s h o ul d be a d mi nistere d t o get her wit h f o o d.  O n Da y 1 i n Lea d -i n p hase a n d Da y 2 1 i n C ycle 
1(i nte nsi ve P K sa m pli n g da ys), si milar brea kfast will be pr o vi de d t o patie nts a p pr o xi matel y 3 0 mi n utes pri or t o t he a d mi nistr ati o n of pal b ocicli b ( brea kfast 
starte d at a p pr o xi matel y 0 9 3 0 A M).  Brea kfast will be c o ns u me d wit hi n a 2 0-mi n ute peri o d w it h st u d y dr u gs a d mi nistere d a p pr o xi matel y 1 0 mi n utes after 
c o m pleti o n of t he meal.  At least 8 0 % of t he pr o vi de d brea kfast s h o ul d be c o ns u me d pri or t o pal b ocicli b a d mi nistrati o n.  T he pr o vi de d brea kfast s h o ul d be 
m o derate -fat sta n dar d-cal orie meal (a p pr o xi matel y 1 5 % pr otei n, 5 0 % car b o h y drate, 3 5 % fat diet f or a t otal of 5 0 0 -7 0 0 cal ories).
0
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 8
l.
Dise ase Assess me nts: R efer t o t he t u m or assess me nt re q uire me nt fl o wc hart (Ta ble 3 ) f or details a n d ti mi n g of pr oce d ures.
m.
Dr u g C o m pli a nce: Patie nts will be re q uire d t o ret ur n t he c o m plete d patie nt d osi n g diar y a n d all b ottles of p al b ocicli b a n d letr oz ole i ncl u di n g a n y u n use d 
ca ps ules/ta blets t o t he cli nic f or dr u g acc o u nta bilit y at t he be gi n ni n g of eac h c ycle. Dr u g acc o u nta bilit y will be perf or me d o n Da y 1 of e ver y c ycle pri or t o 
dis pe nsi n g dr u g s u p pl y f or t he ne xt c ycle.
n.
A d verse E ve nts: F or S A Es, t he acti ve re p orti n g peri o d be gi ns fr o m t he ti me t hat t he patie nt pr o vi des i nf or me d c o nse nt t hr o u g h a n d i ncl u di n g 2 8 cale n dar 
da ys after t he last a d mi nistrati o n of t he i n vesti gati o nal pr o d uct.  Seri o us a d verse e ve nts occ urri n g t o a patie nt after t he a cti ve re p orti n g peri o d has e n de d 
s h o ul d be re p orte d t o t he S p o ns or if t he i n vesti gat or bec o mes a ware of t he m; at a mi ni m u m, all seri o us a d verse e ve nts t hat t he i n vesti gat or belie ves ha ve at 
least a reas o na ble p ossi bilit y of bei n g relate d t o st u d y dr u g are t o be re p orte d t o t he S p o ns or.  A Es (seri o us a n d n o n seri o us) s h o ul d be rec or de d fr o m t he 
ti me t he patie nt has ta ke n at least o ne d ose of st u d y treat me nt t hr o u g h last patie nt visit.
o.
C o nc o m it a nt Me dic ati o ns/ Tre at me nts: C o nc o mita nt me dicati o ns a n d treat me nts will be rec or de d fr o m 2 8 da ys pri or t o t he start of st u d y treat me nt a n d u p 
t o 2 8 da ys after t he last d ose of st u d y treat me nt.
N o C hi nese or ot her her bal me dici nes will be all o w e d d uri n g P K p orti o n.  N o C hi nese a nti -ca ncer her bal 
me dici nes will be all o we d after t he P K p orti o n ( C ycle 1). T he use of her bal me dici nes is n ot rec o m m de d fr o m C ycle 2. A n y us a ge of C hi nese or ot her 
her bal me dici ne s h o ul d be rec or de d.
p.
S ki n Bi o ps y: S ki n tiss ue sa m ples are re q uire d t o be c ollecte d fr o m e nr olle d patie nts at pre -d ose o n Da y -1.  O n Da y -1, patie nts will be ra n d o mize d i nt o 
2 gr o u ps f or differe nt c ollecti o n sc he d ules i n Lea d-i n p hase a n d C ycle 1. Refer t o Ta ble 2 f or ti mi n g details of p ost-d ose pr oce d ures.
q.
T h y mi di ne Ki n ase Bl o o d Test: Bl o o d sa m ples will be c ollecte d f or a nal ysis of t h y mi di ne ki nase ( T K) acti vit y at pre -d ose o n Da y -1. Refer t o Ta ble 2 f or 
ti mi n g details of p ost-d ose pr oce d ures.
r.
E n d of Tre at me nt/ Wit h dr a w al : O btai n t hese assess me nts if n ot c o m plete d d uri n g t he pre vi o us 4 wee ks ( or wit hi n t he pre vi o us 8 wee ks f or disease
assess me nts).
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 9
T a ble 2 .
Bl o o d S a m pli n g T i me P oi nts f or P K, He m at ol o g y a n d Bi o m ar ker E v al u ati o ns D uri n g Si n gle -D ose a n d 
M ulti ple - D ose P K P orti o n
Si n gle - or  
M ulti ple -D ose 
P K a
Si n gle -D ose P K ( Le a d -i n p h ase)
C 1 i
M ulti ple -D ose P K i n C ycle 1 f
C ycle 2
St u d y D a y
1
2 
3 
4 
5 
1
1 4 
1 9 
2 0
2 1
2 2 
2 3 
2 4 
2 5 
2 6
1
H o ur p ost d ose
0 b
2 
4 
6 
8
1 0
2 4 
4 8 
7 2 
9 6
1 2 0 b ,c
0 
0 b
0 b
0 b
2 
4 
6 
8
1 0 
2 4 
4 8 
7 2 
9 6 
1 2 0
0 b
P K bl o o d 
c ollecti o n f or 
pa b ocicli b d
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P K bl o o d 
c ollecti o n f or 
letr ozole d
X  
X  
X
X
H e m at ol o g y e
X  
X  
X
X
X
X
S ki n Bi o ps y g
X  
X
X  
X  
X  
X  
X  
X
Bl o o d Sa m ples 
f or T K testh
X  
X  
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X
C o nfi ne me nt
→ 
→
→ 
→
→ 
→ 
→ 
→ 
X
X  
→ 
→ 
→
→
→ 
→ 
→ 
→ 
X
Disc har ge fr o m 
C R U
X
X
O ut patie nt V isit
X  
X  
X  
X
X  
X  
X
a.
F or b ot h si n gle -d ose a n d m ulti ple -d ose P K c ollecti o n s, patie nts will be re q uire d t o sta y i n t he C R U f or at leas t 7 2 h o urs f oll o wi n g pal b ocicli b d osi n g base d 
o n t he a vaila bilit y of C R U, a n d c o me bac k f or o ut patie nt visits t o pr o vi de P K sa m ples as sc he d ule d.  F or P K c ollecti o ns sc he d ule d bef ore 2 4 h o urs p ost -d ose 
i n C R U, de viati o n of re q uire d c ollecti o n ti me wit hi n 10 % of t he n o mi nal ti me (e g, wit hi n 6 mi n utes of a 6 0 -mi n ute sa m ple) fr o m d osi n g will n ot be ca pt ure d 
as a pr ot oc ol de viati o n, as l o n g as t he act ual c ollecti o n ti me is rec or de d.  F or sa m ples sc he d ule d after 2 4 h o urs p ost -d ose, c ollecti o ns o btai ne d wit hi n 1 0 % of 
t he sa m pli n g i nter val (ie, 2 4 h o urs i n t his st u d y) will n ot be ca pt ure d as a pr ot oc ol de viati o n as l o n g as t he act ual c ollecti o n ti me is rec or de d.  F or t he P K 
sa m ples c ollecte d d uri n g o ut patie nt visits, de viati o n of re q uire d c ollecti o n ti me lar ger t ha n 1 0 % of sa m pli n g i nter val (ie, 2 4 h o urs i n t his st u d y) ma y be 
acce pta ble as l o n g as t he act ual c ollecti o n ti me is rec or de d.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0
b.
Pr e -d ose P K sa m ples s h o ul d be ta ke n i m me diatel y pri or t o a n y pal b ocicli b a n d letr oz ole m or ni n g d osi n g o n t hat da y ( wit hi n a p pr o xi ma tel y 1 5 mi n utes pri or 
t o t he d osi n g).  O n t hese da ys, a d mi nistrati o n of pal b ocicli b a n d letr oz ole s h o ul d occ ur i n t he C R U t o e ns ure t he pre-d ose P K sa m ples ca n be c ollecte d; o n 
D a y s 1, 1 9 a n d 2 0 i n C ycle 1 a n d Da y 1 i n C ycle 2, patie nts s h o ul d be i nstr ucte d t o bri n g t he dr u g s u p pl y a n d a d mi nister t he dr u gs i n t he C R U after 
c o m pleti o n of P K c ollecti o n o n t hat da y. 
c.
O n C ycle 1 Da y 1, t he p ost si n gle d ose P K sa m ple at 1 2 0 hrs w ill be ta ke n pri or t o d osi n g.
d.
2 m L of w h ole bl o o d will be dra w n i nt o a t u be c o ntai ni n g K 2E D T A f or eac h ti me p oi nt.
e.
H e m at ol o g y assess me nts will be e val uate d at scree ni n g a n d/ or Da y -1, o n Da y 4 bef ore disc har ge i n Lea d -i n p hase, o n C ycle 1 Da y 1 bef ore d osi n g of 
pal b ocicli b, o n C ycle 1 Da y 1 4, 2 1, 2 4 i n C ycle 1, o n C ycle 2 Da y 1 a n d 2 1 as we ll as Da y 1 i n C ycles 3.  O n Da y 1 of eac h c ycle (at least f or 4 s u bse q ue nt 
c ycles after t he first 2 c ycles), t he assess me nts s h o ul d be c o n d ucte d bef ore d osi n g t o e ns ure t he t olera bilit y of patie nts.  Act ual ti me of assess me nts m ust be 
d oc u me nte d.  O nce c o mplete bl o o d c o u nt has sta bilize d, f urt her m o nit ori n g s h o ul d be c o n d ucte d as cli nicall y i n dicate d.
f.
P K sa m ple c ollecti o ns sc he d ule d after m ulti ple d osi n g of pal b ocicli b s h o ul d be c o n d ucte d gi ve n t hat t here is n o d osi n g i nterr u pti o n f or at least 8 da ys pr i or 
t o sa m ple c ollecti o n.  If t he sa m ple c ollecti o n is misse d f or a n y reas o n, or if t he P K data c ollecte d are dee me d n ot e val ua ble b y t he S p o ns or, t he n t he P K 
sa m ple c ollecti o n ma y be re peate d d uri n g a later c ycle.
g.
S ki n bi o ps y f or bi o mar ker assess me nts wil l be c o n d ucte d.  Sa m ples will be c ollecte d fr o m all e nr olle d patie nts at pre-d ose o n Da y -1.  I n Lea d -i n p hase a n d 
C y cle 1, patie nts will be ra n d o mize d i nt o 2 gr o u ps f or differe nt c ollecti o n sc he d ules: patie nts fr o m Gr o u p 1 will be re q uire d t o pr o vi de sa m p les o n Da y 2 
( 2 4 h o urs p ost d ose) i n Lea d -i n p hase, Da ys 2 2, 2 4 a n d 2 6 i n C ycle 1; patie nts fr o m Gr o u p 2 will be re q uire d t o pr o vi de sa m ples o n Da y 1 ( 1 0 h o urs p ost 
d ose) i n Lea d -i n p hase, Da ys 2 1 ( 1 0 h o urs p ost-d ose), 2 3 a n d 2 5 i n C ycle 1.  T he bi o mar ker sa m ple c ollecti o n s h o ul d be c o n d ucte d t o get her wit h P K 
c ollecti o n, a n d t he act ual c ollecti o n ti me m ust be d oc u me nte d.
h.
3 m L of w h ole bl o o d will be dra w n i nt o a t u be at eac h sc he d ule d ti me p oi nt ri g ht after c ollecti o n of P K sa m ples ( n o nee d t o perf or m ve ni p u nct ure a gai n at 
t he sa me ti me p oi nt).  Act ual c ollecti o n ti me s h o ul d be rec or de d.
i.
C 1 re prese nt C ycle 1.
N O T E: 
D uri n g t he peri o ds of i nte nsi ve P K bl o o d dra ws, an i n d welli n g cat heter is all o we d if t here is a nee d.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1
T a ble 3 .
T u m or As sess me nt Re q uire me nts Fl o w C h art
Scree ni n g a
Tre at m e nt Peri o d b
E n d of Tre at me nt Visit c
C T d or M RI of c hest, a b d o me n, 
a n d pel vis ( C A P) 
Re q uire d e
Re q uire d 
Re q uire d 
C T d or M RI of a n y ot her site of 
disease, as cli nicall y i n dicate d 
Re q uire d e,f
Re q uire d f or sites of disease 
i de ntifie d at scree ni n g 
Re q uire d f or sites of disease i de ntifie d at scree ni n g, u nless 
disease pr o gressi o n has bee n c o nfir me d else w he re 
Ra di o n ucli de b o ne sca n ( w h ole 
b o d y) a n d c orrelati ve b o ne 
i ma gi n g 
Re q uire d g ,h
Re q uire d f or sites of disease 
i de ntifie d at scree ni n g or if 
cli nicall y i n dicate d i
Re q uire d f or sites of disease i de ntifie d at scree ni n g, u nless 
disease pr o gressi o n has bee n c o nfir me d else w here 
P h ot o gra p hs of all s u perficial 
lesi o ns as a p plica blej
Re q uire d 
Re q uire d f or sites of disease 
i de ntifie d at scree ni n g 
Re q uire d f or sites of disease i de ntifie d at scree ni n g, u nless 
disease pr o gressi o n has bee n c o nfir me d else w here 
a.
Scree ni n g sca ns m ust occ ur wit hi n 4 w ee ks (ie, 2 8 da ys) pri or t o st u d y e ntr y u nless ot her wise s pecifie d. 
b.
T u m or assess me nt m ust be d o ne d uri n g t he treat me nt peri o d, e ver y 1 2 we e ks( 7 da ys) fr o m C 1 D 1, b o ne sca ns (as a p plica ble) e ver y 2 4 wee ks ( 7 da ys) 
fr o m C 1 D 1 u ntil ra di o gra p hicall y a n d/ or cli nicall y (ie,f or p h ot o gra p he d or pal pa bl e lesi o ns) d oc u me nte d P D as per R E CI S T v. 1. 1, st u d y treat me nt 
disc o nti n uati o n (f or patie nts c o nti n ui n g treat me nt be y o n d R E CI S T -defi ne d disease pr o gressi o n), i nitiati o n of ne w a ntica ncer t hera p y or disc o nti n uati o n of 
patie nt fr o m o verall st u d y partici pati o n (e g, deat h, patie nt's re q uest, l ost t o f oll o w u p), w hic he ver occ urs first.  T he sc he d ule of assess me nts s h o ul d be fi xe d 
acc or di n g t o t he cale n dar, re gar dless of treat me nt dela ys/i nterr u pti o ns.  I ma gi n g assess me nts are t o be sc he d ule d usi n g t he C 1 D 1 date a s t he refere nce date 
f or all ti me-p oi nts a n d are N O T t o be sc he d ule d base d o n t he date of t he pre vi o us i ma gi n g ti me -p oi nt.  I ma gi n g assess me nt dela y t o c o nf or m t o treat me nt 
dela y is n ot per mitte d.  T he sa me t u m or assess me nt tec h ni q ue M U S T be use d t hr o u g h o u t t he st u d y f or a gi ve n lesi o n/ patie nt. 
c.
Patie nts w h o ha ve alrea d y de m o nstrate d o bjecti ve disease pr o gressi o n as per R E CI S T v. 1. 1 d o n ot nee d t o ha ve sca ns re peate d a t t he e n d of treat me nt visit. 
d.
T he C T sca ns, i ncl u di n g brai n C T sca n if a p plica ble, s h o ul d be perf or me d wit h c o ntrast a ge nts u nless c o ntrai n dicate d f or me dical reas o ns.  If I V c o ntrast is 
me dicall y c o ntrai n dicate d, t he i ma gi n g m o dalit y t o be use d t o f oll o w  t he disease (eit her C T wit h o ut c o ntrast or M RI) s h o ul d be t he m o dalit y w hic h best 
e val uates t he disease, a n d t he c h oice s h o ul d be deter mi ne d b y t he i n vesti gat or i n c o nj u ncti o n wit h t he l ocal ra di ol o gist.  M RI of t h e a b d o me n a n d pel vis ca n 
be s u bstit ute d f or C T if M RI a de q uatel y de picts t he disease.  H o w e ver, M RI of t he c hest s h o ul d n ot be s u bs tit ute d f or C T of c hest e ve n if I V c o ntrast is 
c o ntrai n dicate d.   I n s uc h case C T will be perf or me d wit h o ut c o ntrast. If M RI is use d t o f oll o w-u p b o ne lesi o n(s) it m ust be perf or me d a fe w da ys bef ore a n y
treat me nt t hat ma y affect b o ne-marr o w  cell ularit y (eg, G- C S F).
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2
e.
Ra di o gra p hic assess me nts o btai ne d per t he patie nt’s sta n dar d of care pri or t o st u d y e ntr y d o n ot nee d t o be re peate d a n d are acce pta ble t o use as baseli ne 
e val uati o ns, if ( 1) o btai ne d wit hi n 2 8 da ys bef ore st u d y e ntr y, ( 2) t he y were perf or me d usi n g t he met h o d re q uire me nts o utli ne d i n R E CI S T v. 1. 1 ( 3) t he sa me 
tec h ni q ue/ m o dalit y s h o ul d be use d t o f oll o w i de ntifie d lesi o ns t hr o u g h o ut t he trial f or a gi ve n patie nt, a n d ( 4) a p pr o priate d oc u me ntati o n i n dicati n g t hat 
t hese ra di o gra p hic t u m or assess me nts were perf or me d as sta n dar d of care is a vaila ble i n t he patie nt ’s s o urce n otes.
f.
Baseli ne brai n sca ns are o nl y re q uire d if si g ns a n d s y m pt o ms s u g gest prese nce of metastatic brai n disease.  Brai n sca ns perf o r me d bef ore t he si g ni n g of
i nf or me d c o nse nt as r o uti ne pr oce d ures ( b ut wit hi n 6 wee ks bef ore st u d y e ntr y) d o n ot nee d t o be re peate d a n d ma y be use d as baseli ne assess me nts as l o n g 
as ( 1) tests were perf or me d usi n g t he met h o d re q uire me nts o utli ne d i n R E CI S T v. 1. 1 ( 2) t he sa me tec h ni q ue/ m o dalit y s h o ul d be use d t o f oll o w i de ntifie d 
lesi o ns t hr o u g h o ut t he trial f or a gi ve n patie nt ( 3) a p pr o priate d oc u me ntati o n i n dicati n g t hat t hese ra di o gra p hic t u m or assess me nts were perf or me d as 
sta n dar d of care is a vaila ble i n t he patie nt’s s o urce n otes.  P ost-baseli ne re pe at brai n sca ns will o nl y be re q uire d o nl y if metastases are s us pecte d.
g.
B o ne sca ns will be carrie d o ut at baseli ne f or all patie nts wit hi n 1 2 wee ks pri or t o st u d y e ntr y i n or der t o detect b o n y sites of disease.  B o ne sca ns perf or m e d 
bef ore t he si g ni n g of i n f or me d c o nse nt as r o uti ne pr oce d ures ( b ut wit hi n 1 2 wee ks bef ore st u d y e ntr y) d o n ot nee d t o be re peate d a n d ma y be use d as 
baseli ne assess me nts as l o n g as ( 1) tests w ere perf or me d usi n g t he met h o d re q uire me nts o utli ne d i n R E CI S T v. 1. 1 ( 2) t he sa me tec h ni que/ m o dalit y s h o ul d be 
use d t o f oll o w i de ntifie d lesi o ns t hr o u g h o ut t he trial f or a gi ve n patie nt ( 3) a p pr o priate d oc u me ntati o n i n dicati n g t hat t hes e ra di o gra p hic t u m or assess me nts 
were perf or me d as sta n dar d of care is a vaila ble i n t he patie nt’s s o urce n otes.
h.
A n y s us pici o us a b n or malities (ie, h ots p ots) i de ntifie d o n t he b o ne sca ns at baseli ne a n d o n s u bse q ue nt b o ne sca ns M U S T be c o n fir me d b y X-r a y, C T sca n 
wit h b o ne wi n d o ws or M RI.  T he sa me m o dalit y m ust be use d t hr o u g h o ut t he trial f or c o nfir mati o n f or a g i ve n lesi o n/ patie nt.  B o ne lesi o ns i de ntifie d at 
baseli ne will be f oll o w e d u p acc or di n g t o t he sa me assess me nt sc he d ule (ie, e ver y 1 2 w ee ks ± 7 da ys fr o m C 1 D 1) as f or all ot her lesi o ns.  Areas t hat ha ve 
recei ve d palliati ve ra di ot hera p y ca n n ot be use d t o assess res p o nse t o st u d y treat me nt.
i.
If b o ne lesi o ns were i de ntifie d at baseli ne, t he n b o ne sca ns will be re peate d d uri n g t he acti ve treat me nt p hase e ver y 2 4 wee k ( ± 7 da ys) fr o m t he date of
C 1 D 1 a n d at t he ti me of c o nfir mati o n of C R.  If n o b o ne lesi o ns were i de ntifie d at baseli ne, t he n b o ne sca ns will o nl y be re peate d d uri n g t he acti ve treat me nt 
p hase w he n cli nicall y i n dicate d (ie, patie nt descri bes ne w  or w orse ni n g b o ne pai n, or has i ncreasi n g al kali ne p h os p hatase le vel, or ot her si g ns a n d s y m pt o ms 
of ne w/ pr o gressi n g b o ne metastases) b ut are re q uire d at t he ti me of c o nfir mati o n of C R.  Ne w  Ab n or m alities f o u n d o n s u bse q ue nt b o ne sca ns m ust als o be 
c o nfir me d b y X -ra y, C T sca n wit h b o ne wi n d o ws or M RI.
j.
Cli nical assess me nt of s u perficial disease m ust be carrie d o u t o n t he sa me date as t he i ma gi n g st u dies a n d will i ncl u de p h ot o gra p hs of all s u perficial
metastatic lesi o ns.  All lesi o n meas ure me nts m ust be rec or de d i n t he case re p ort f or m ( C R F).
N otes:
- Ra di o gra p hic t u m or assess me nts ma y be d o ne at a n y ti me if t here is cli nical s us pici o n of disease pr o gressi o n at t he discreti o n of t he i n vesti gat or.  If
pr o gressi ve disease is c o nfir me d per R E CI S T v. 1. 1, patie nts are e x pecte d t o disc o nti n ue st u d y t hera p y.  H o w e ver, patie nts ma y c o nti n ue treat me nt as 
assi g ne d be y o n d t he ti me of R E CI S T-defi ne d P D at t he discreti o n of t he i n vesti gat or if t hat is c o nsi dere d t o be i n t he best i nterest of t he patie nt a n d as 
l o n g as n o ne w a ntica ncer treat me nt is i nitiate d.
- U p o n a p pr o v al of A m e n d me nt 3, t u mor assess me nts m a y be perf or m e d e ver y 6 c ycles ( ± 7 d a ys) or as rec o m me n de d b y t he p h ysici a n 
acc or di n g t o t he p atie nt’s cli nic al c o n diti o ns. R E CI S T 1. 1 m a y c o nti n ue t o be use d t o e v al u ate i m a gi n g assess me nts at t he i n vesti g at or’s 
discreti o n b ut will n o l o n ger be m a n d at or y. Assess me nts of t u m o r lesi o ns will n o l o n ger be rec or de d i n t he C R F, n or will t he R E CI S T 
assess me nts.   O nl y t he d ate of pr o gressi o n of dise ase will be rec or de d.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3
T A B L E O F C O N T E N T S
LI S T O F T A B L E S ...................................................................................................................2 7
1. I N T R O D U C TI O N ...............................................................................................................2 8
1. 1. I n dicati o n .................................................................................................................2 8
1. 2. Bac k gr o u n d a n d Rati o nale................................ ......................................................2 8
1. 2. 1. O ver vie w of Pal b ocicli b .............................................................................2 9
1. 2. 1. 1. N o n - Cli nical P har mac o ki netic a n d Meta b olis m of 
Pal b ocicli b................................ .........................................................2 9
1. 2. 1. 2. I n Vi v o a n d I n Vitr o Safet y  P har mac ol o g y of Pal b ocicli b .......3 0
1. 2. 1. 3. Cli nical S u m mar y ......................................................................3 2
1. 2. 2. Safet y.......................................................................................................... 3 5
1. 2. 3. St u d y  Rati o nale........................................................................................... 3 6
1. 2. 3. 1. Rati o nale f or Pal b ocicli b A d mi nistrati o n Sc he d ule ..................3 6
1. 2. 3. 2. Rati o nale f or Pal b ocicli b D ose................................ ..................3 7
1. 2. 4. Rati o nale f or C ha n ges i n A me n d me nt 3, 1 6 Ja n uar y  2 0 1 9........................3 8
2. S T U D Y O BJ E C TI V E S A N D E N D P OI N T S .......................................................................4 0
2. 1. O bjecti ves ................................................................................................................4 0
2. 2. E n d p oi nts .................................................................................................................4 0
3. S T U D Y D E SI G N .................................................................................................................4 1
4. P A TI E N T S E L E C TI O N ......................................................................................................4 2
4. 1. I ncl usi o n Criteria................................ .....................................................................4 3
4. 2. E xcl usi o n Criteria ....................................................................................................4 4
4. 3. Ra n d o mizati o n Criteria................................ ...........................................................4 6
4. 4. Li fe St yle G ui deli nes...............................................................................................4 6
4. 4. 1. Alc o h ol, Caffei ne , C hi nese Her bal Me dici ne a n d E xercise f or P K 
E val uati o n ........................................................................................................4 6
4. 4. 2. Meals a n d Dietar y  Restricti o ns f or P K E val uati o n .....................................4 7
4. 5. S p o ns or Q ualifie d Me dical Pers o n nel .....................................................................4 7
5. S T U D Y T R E A T M E N T S .....................................................................................................4 8
5. 1. All ocati o n t o Treat me nt ................................ ..........................................................4 8
5. 2. Dr u g S u p plies................................ ..........................................................................4 8
5. 2. 1. F or m ulati o n a n d Pac ka gi n g ........................................................................4 8
5. 2. 1. 1. Pal b ocicli b................................ .................................................4 8
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 4
5. 2. 1. 2. Letr oz ole ....................................................................................4 8
5. 2. 2. Pre parati o n a n d Dis pe nsi n g ........................................................................4 9
5. 2. 2. 1. Pal b ocicli b................................ .................................................4 9
5. 2. 2. 2. Letr oz ole ....................................................................................4 9
5. 2. 3. A d mi nistrati o n ............................................................................................4 9
5. 2. 3. 1. Pal b ocicli b................................ .................................................4 9
5. 2. 3. 2. Letr oz ole ....................................................................................5 0
5. 2. 3. 3. Ge neral r ules .............................................................................5 0
5. 2. 4. Rec o m me n de d D ose M o dificati o n .............................................................5 0
5. 2. 4. 1. Letr oz ole ....................................................................................5 1
5. 2. 4. 2. P al b ocicli b .................................................................................5 1
5. 2. 5. Me dicati o n Err ors a n d O ver d ose ................................................................5 6
5. 2. 6. C o m plia nce .................................................................................................5 7
5. 3. Dr u g St ora ge a n d Dr u g Acc o u nta bilit y ...................................................................5 7
5. 3. 1. Pal b ocicli b.................................................................................................. 5 8
5. 3. 2. L etr oz ole .....................................................................................................5 8
5. 4. C o nc o mita nt Me dicati o ns .......................................................................................5 8
5. 4. 1. Pr o hi bite d Me dicati o ns............................................................................... 5 9
5. 4. 2. Me dicati o ns N ot Rec o m me n de d .................................................................6 0
5. 4. 3. Per mitte d Me dicati o ns ................................................................................6 0
5. 5. C o nc o mita nt Ra di ot hera p y or S ur ger y ....................................................................6 2
6. S T U D Y P R O C E D U R E S................................ .....................................................................6 2
6. 1. Scree ni n g .................................................................................................................6 2
6. 1. 1. Scree n Fail ure .............................................................................................6 3
6. 2. P har mac o ki netics ....................................................................................................6 3
6. 3. Acti ve Treat me nt P hase ..........................................................................................6 4
6. 4. E n d of Treat me nt Visit................................ ............................................................6 4
6. 5. P ost Treat me nt F oll o w - u p.......................................................................................6 4
6. 6. Patie nt Wit h dra wal................................ ..................................................................6 4
7. A S S E S S M E N T S ..................................................................................................................6 6
7. 1. Bl o o d V ol u mes ........................................................................................................6 6
7. 2. Efficac y  Assess me nts ..............................................................................................6 7
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 5
7. 2. 1. T u m or Ass ess me nt ......................................................................................6 7
7. 3. Safet y Assess me nts .................................................................................................7 0
7. 3. 1. A d verse E ve nts ...........................................................................................7 0
7 . 3. 2. La b orat or y Safety Assess me nts ..................................................................7 0
7. 3. 3. Electr ocar di o gra m ( E C G) ...........................................................................7 1
7. 3. 4. Oc ular Safet y Assess me nts .........................................................................7 2
7. 3. 4. 1. Vis ual Ac uit y a n d Refracti o n ....................................................7 2
7. 3. 4. 2. I ntra oc ular Press ure Meas ure me nt ............................................7 3
7. 3. 4. 3. Slit -La m p Bi o micr osc o p y................................ .........................7 3
7. 3. 4. 4. Le ns Gra di n g................................ .............................................7 4
7. 3. 4. 5. F u n d usc o p y ( O p ht hal m osc o p y ) ................................................ 7 4
7. 3. 5. Ot her Safet y Assess me nts ...........................................................................7 5
7. 4. P har mac o ki netic Assess me nts................................ .................................................7 5
7. 4. 1. Plas ma f or A nal ys is of Pal b ocicli b ( P D-0 3 3 2 9 9 1) .....................................7 6
7. 4. 2. Plas ma f or A nal ys is of Letr oz ole ...............................................................7 6
7. 4. 3. S hi p me nt of P har mac o ki netic Sa m ples ......................................................7 7
7. 5. Bi o mar ker Assess me nts ................................ ..........................................................7 7
7. 5. 1. S ki n Bi o ps y .................................................................................................7 7
7. 5. 2. T h y mi di ne Ki nase Bl o o d Test ....................................................................7 8
8. A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S ............................................7 8
8. 1. Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A E a n d S A E I nf or mati o n ...................7 9
8. 1. 1. Re p orti n g S A Es t o Pfizer Safet y ................................................................7 9
8. 1. 2. Rec or di n g N o nseri o us A Es a n d S A Es o n t he C R F.................................... 8 0
8. 2. Met h o d of Detecti n g A Es a n d S A Es .......................................................................8 0
8. 3. F oll o w -u p of A Es a n d S A Es ...................................................................................8 0
8. 4. Re g ulat or y  Re p orti n g Re q uire me nts f or S A Es.......................................................8 0
8. 4. 1. E x p os ure D uri n g Pre g na nc y  or Breastfee di n g, a n d Occ u pati o nal 
E x p os ure ..........................................................................................................8 1
8. 4. 2. E x p os ure D uri n g Pre g na nc y .......................................................................8 1
8. 4. 3. E x p os ure D uri n g Breastfee di n g ..................................................................8 1
8. 4. 4. Occ u pati o nal E x p os ure ...............................................................................8 1
8. 5. Disease -Relate d E ve nts a n d/ or Disease -Relate d O utc o mes N ot Q ualif y i n g as 
A Es or S A Es ..............................................................................................................8 2
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 6
8. 6. Me dicati o n Err ors ....................................................................................................8 2
8. 7. Treat me nt of O ver d ose................................ ............................................................8 3
9. D A T A A N A L Y SI S/ S T A TI S TI C A L M E T H O D S ...............................................................8 4
9. 1. Sa m ple Size Det er mi nati o n .....................................................................................8 4
9. 2. A nal y sis of P har mac o ki netics .................................................................................8 4
9. 2. 1. A nal y sis P o p ulati o ns ..................................................................................8 4
9. 2. 2. Deri vati o n of P har mac o ki netic Para meters Pri or t o A nal y sis ....................8 5
9. 3. Efficac y  A nalys is ....................................................................................................8 7
9. 4. A nal y sis of Ot her E n d p oi nts ...................................................................................8 8
9. 5. Safet y A nal ys is........................................................................................................8 8
9. 5. 1. A nal y sis of A d verse E ve nts a n d La b orat or y A b n or malities ......................8 9
9. 5. 2. Oc ular E ve nts ..............................................................................................8 9
9. 5. 3. A nal y sis of Electr ocar di o gra m Meas ure me nts ...........................................8 9
9. 6. Data M o nit ori n g C o m mittee ...................................................................................9 0
1 0. Q U A LI T Y C O N T R O L  A N D Q U A LI T Y A S S U R A N C E................................................. 9 0
1 1. D A T A H A N D LI N G A N D R E C O R D K E E PI N G .............................................................9 1
1 1. 1. Case Re p ort F or ms/ Electr o nic Data Rec or d .........................................................9 1
1 1. 2. Rec or d Rete nti o n ...................................................................................................9 1
1 2. E T HI C S ..............................................................................................................................9 2
1 2. 1. I nstit uti o nal Re vie w B oar d (I R B)/I n de pe n de nt Et hics C o m mittee (I E C) ............9 2
1 2. 2. Et hical C o n d uct of t he St u d y ................................................................................9 2
1 2. 3. S u bject I nf or mati o n a n d C o nse nt ..........................................................................9 2
1 2. 4. S u bject Recr uit me nt ..............................................................................................9 3
1 2. 5. Re p orti n g of Safet y I ss ues a n d Seri o us Breac hes of t he Pr ot oc ol or I C H 
G C P ...........................................................................................................................9 3
1 3. D E FI NI TI O N O F E N D O F T RI A L ...................................................................................9 3
1 3. 1 . E n d of Trial i n All Partici pati n g C o u ntries ...........................................................9 3
1 4. S P O N S O R DI S C O N TI N U A TI O N C RI T E RI A ................................................................9 3
1 5. P U B LI C A TI O N O F S T U D Y R E S U L T S ..........................................................................9 4
1 5. 1. C o m m u nicati o n of Res ults b y  Pfizer ....................................................................9 4
1 5. 2. P u blicati o ns b y  In vesti gat ors ................................................................................9 5
1 6. R E F E R E N C E S ..................................................................................................................9 7
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 7
1 7. A P P E N DI X ......................................................................................................................1 0 0
1 7. 1. A p pe n di x 1. A b bre viati o ns .................................................................................1 0 0
1 7. 2. A p pe n di x 2. R E CI S T ( Res p o nse E val uati o n Criteria I n S oli d T u m ors) 
versi o n 1. 1 G ui deli nes .............................................................................................1 0 3
1 7. 3. A p pe n di x 3. A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g ....................................................................1 0 8
1 7. 3. 1. - Defi niti o n of A E ....................................................................................1 0 8
1 7. 3. 2. Defi niti o n of S A E................................................................................... 1 0 9
1 7. 3. 3. Rec or di n g/ Re p orti n g a n d F oll o w- u p of A Es a n d/ or S A Es .....................1 1 1
1 7. 3. 4. Re p orti n g of S A Es.................................................................................. 1 1 3
1 7. 4. A p pe n di x 4. E C O G Perf or ma nce Stat us * ...........................................................1 1 4
1 7. 5. A p pe n di x 5. B o ne Marr o w Reser ve i n A d ult...................................................... 1 1 5
1 7. 6. A p pe n di x 6. Li st of Dr u gs K n o w n t o Pre dis p ose t o T orsa de de P oi ntes............ 1 1 7
1 7. 7. A p pe n di x 7. Wisc o nsi n A ge -Relate d E y e Disease St u d y ( A R E D S) 2 0 0 8 
Cli nical L e ns O pacit y Gra di n g Pr oce d ure ...............................................................1 1 8
1 7. 8. A p pe n di x 8. C ollecti o n of Pre g na nc y  Inf or mati o n .............................................1 2 0
1 7. 9. A p pe n di x 9. Sc he d ule Sc he d ule of Acti vities f or Patie nts C o nti n ui n g t o 
Recei ve Acti ve Treat me nt After I R B/I E C A p pr o val of A me n d me nt 3.................. 1 2 2
LI S T O F T A B L E S
Ta ble 1.
S C H E D U L E O F A C TI VI TI E S ................................................................1 5
Ta ble 2. 
Bl o o d S a m pli n g T i me P oi nts f or P K, He mat ol o g y  a n d Bi o mar ker 
E val uati o ns D uri n g Si n gle -D ose a n d M ulti ple -D ose P K P orti o n ............1 9
Ta ble 3.
T u m or Assess me nt Re q uire me nts Fl o w C hart .........................................2 1
Ta ble 4.
P al b ocicli b Ca ps ule C haracteristics ..........................................................4 8
Ta ble 5.
A vaila ble D ose Le vels ..............................................................................5 3
Ta ble 6.
Pal b ocicli b D ose M o dificati o ns f or Treat me nt Relate d T o xicities 
Re q uiri n g Treat me nt I nterr u pti o n/ Dela y or Persisti n g Des pite 
O pti mal Me dical Treat me nt ......................................................................5 4
Ta ble 7
Pal b ocicli b D ose M o dificati o ns f or He mat ol o gic T o xicities ( b y  
C T C A E Gra de a n d o n Da y  of Treat me nt)a...............................................5 5
Ta ble 8.
Pal b ocicli b D ose M o dificati o ns i n t he E ve nt of Q Tc Pr ol o n gati o n......... 5 6
Ta ble 9.
Bl o o d V ol u me ...........................................................................................6 6
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 8
1. I N T R O D U C TI O N
1. 1. I n dic ati o n
Estr o ge n rece pt or -p ositi ve ( E R( +)), H E R 2 - ne gati ve ( H E R 2(-)) A d va nce d Breast Ca ncer 
( A B C) i n C hi nese patie nts w h o h a ve n ot receive d a n y pri or s yste mic a nti-ca ncer t hera p y f or 
t heir a d va nce d disease
1. 2. B ac k gr o u n d a n d R ati o n ale
Breast Ca ncer is t he m ost c o m m o n i n vasi ve ca ncer i n w o me n, wit h m ore t ha n 1. 3 milli o n 
cases a n d o ver 4 5 0, 0 0 0 deat hs occ urri n g w orl d wi de a n n uall y.  I n C hi na, t he i nci de nce of 
breast ca ncer is 2 1. 6 per 1 0 0, 0 0 0 i n di vi d uals , t he m ortalit y rate is 5. 7 per 1 0 0, 0 0 0 i n di vi d uals. 1
Alt h o u g h a ge-a dj uste d m ortalit y fr o m breast ca ncer has bee n decreasi n g si nce 1 9 9 0, the 
me dia n s ur vi val f or patie nts wit h metastatic disease is still o nl y a p pr o xi matel y 1 8 t o 2 4 
m o nt hs 2 a n d t he me dical nee d f or m ore acti ve a ge nts i n t his cli nical setti n g re mai ns ver y 
hi g h.
Pal b ocicli b, a n orall y acti ve p yri d o p yri mi di ne, is a p ote nt a n d hi g hl y selecti ve re versi ble
i n hi bit or of c ycli n-de pe n de nt ki nase ( C D K) 4 a n d C D K 6. T he c o m p o u n d pre ve nts cell ular
D N A s y nt hesis b y pr o hi biti n g pr o gressi o n of t he cell c ycle fr o m G 1 i nt o t he S p hase, as
de m o nstrate d i n la b orat or y  m o dels a n d earl y cli nical trials. Pal b ocicli b precli nical data
i n dicate t hat it ma y be e x pecte d t o ha ve direct effect o n gr o wt h arrest as well as p ote ntial
sec o n dar y c yt ore d ucti ve acti vit y. Treat me nt of c ult ure d t u m or cells ( M D A-M B -4 3 5 br east 
ca ncer cell li ne a n d C ol o- 2 0 5 c ol o n ca ncer cell li ne) wit h pal b ocicli b ca uses gr o wt h arrest 
t hat is acc o m pa nie d by t he i n hi biti o n of s pecific reti n o blast o ma ( R b) p h os p h or y lati 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.  C o nse q ue ntl y , t he p h os p h or y lati o n 
stat us of t hese sites ser ves as s pecific bi o mar kers of C D K 4/ 6 i n hi biti o n b y  pal b ocicli b.
T he o nl y  k n o w n nat ural s u bstrate f or C D K 4/ 6 ki nase acti vit y is t he reti n o blast o ma ( R b) 
pr otei n.  I n a s mall p orti o n of t u m ors (e g, reti n o blast o ma, s m all-cell l u n g ca ncer), c o ntr ol of 
G 1/ S pr o gressi o n is l ost b y R b ge ne m utati o n.3 ,4 ,5  I n m ore c o m m o n t u m ors, h o we ver, ot h er 
ge netic a n d e pi ge netic c ha n ges lea d t o i ncreases i n C D K 4/ 6 acti vit y  w hic h c o ntri b utes t o 
t u m or cell gr o wt h.  T h us, t u m or cell pr oliferati o n i n t hese t u m ors ma y  be partic ularly 
se nsiti ve t o selecti ve i n hi bit ors of C D K 4/ 6.
T he r ole of estr o ge ns i n breast ca ncer eti ol o g y a n d pr o gressi o n is well esta blis he d.  
M o dificati o n of estr o ge n acti vit y  or sy nt hesis re prese nts t he treat me nt of c h oice f or
p ost me n o pa usal w o me n wit h h or m o nal rece pt or p ositi ve a d va nce d breast ca ncer, partic ularl y
f or t h ose wit h sl o wl y pr o gressi ve disease a n d li mite d t u m or-relate d sy m pt o ms.  L etr oz ole is 
a n oral n o nster oi dal ar o matase i n hi bit or a n d it is a p pr o ve d w orl d wi de f or t he first-li ne 
treat me nt of p ost me n o pa usal w o me n wit h h or m o ne rece pt or-p ositi ve a d va nce d breast ca ncer 
( A B C).
As me n ti o ne d, pal b ocicli b pre ve nts cell c ycle pr o gressi o n fr o m G 1 t o S p hase a n d has s h o w n 
a ntit u m or acti vit y i n m ulti ple precli nical m o dels, i ncl u di n g i n estr o ge n rece pt or-p ositi ve 
( E R +) l u mi nal breast ca ncer cell li nes. 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 9
F urt her m ore, pre -cli nical e x pl orati o n usi n g a breast ca ncer cell li ne pa nel has de m o nstrate d 
prese nce of reti n o blast o ma ( R b) pr otei n a n d u pre g ulati o n of c y cli n D 1 as well as decrease d 
C D K N 2 A ( p 1 6) t hat were ass ociate d wit h se nsiti vit y  t o pal b ocicli b as well as wit h its effects 
u p o n cell c ycle a n d gr o wt h i n hi biti o n.  T hese ge ne e x pressi o n fi n di n gs were als o ass ociate d 
wit h t he l u mi nal s u bt y pe vers us basal -li ke s u bty pe of B C. 
T hese res ults, t o get her wit h p u blis he d data o n t he i nteracti o n of estr o ge ns a n d C D Ks a n d t he 
i m p orta nt r ole of cell c ycl e-relate d pr otei ns i n t he ge nesis a n d mai nte na nce of breast ca ncer, 
s u p p ort t o t he cli nical de vel o p me nt of pal b ocicli b i n c o m bi nati o n wit h a n ar o matase i n hi bit or 
( AI) li ke letr oz ole i n t he first-li ne treat me nt of E R( +)/ H E R 2(-) A B C patie nts. 
1. 2. 1. O ver vie w of P al b ocicli b 
Oral pal b ocicli b is a hi g hl y  selecti ve, re versi ble i n hi bit or of C D K 4 a n d 6.  I n hi biti o n of 
C D K 4/ 6 bl oc ks D N A s y nt hesis b y  pr o hi biti n g pr o gressi o n of t he cell c ycle fr o m G 1 t o 
S p hase.  Data fr o m n o ncli nical st u dies i n dicate t hat pal b ocicli b ma y  ha ve c y t ore d ucti ve as 
well as c y t ostatic effects.
1. 2. 1. 1. N o n - Cli nic al P h ar m ac o ki netic a n d Met a b olis m of P al b ocicli b
I n n o ncli nical s pecies (rat, d o g, a n d m o n ke y), pal b ocicli b e x hi bits l o w t o m o derate plas ma 
cleara nce, lar ge v ol u me of distri b uti o n, a n d m o derate or al bi oa vaila bilit y ra n gi n g fr o m 
2 3 % t o 5 6 %. 
Plas ma pr otei n bi n di n g of pal b ocicli b is m o derate i n m o use, rat, d o g, a n d h u ma n plas ma.  
Plas ma pr otei n bi n di n g was n ot f o u n d t o be sat ura ble o ver t he teste d c o nce ntrati o n ra n ge of 
0. 5 t o 5. 0 μ g/ m L .  Mea n fracti o n u n b o u n d (f u) i n h u ma n plas ma ra n ge d fr o m 0. 1 3 7 t o 0. 1 6 1.  
Pal b ocicli b s h o ws a m o dest prefere ntial distri b uti o n t o re d bl o o d cells ( R B Cs) o ver plas ma i n 
h u ma ns wi t h a c o nce ntrati o n rati o of bl o o d/ plas ma of 1. 6 3, b ut si milar distri b uti o n bet wee n 
re d bl o o d cells a n d plas ma i n n o ncli nical s pecies.
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 m es.  I n vitr o, pal b ocicli b is pri maril y  meta b olize d b y 
s ulf otra nsferase ( S U L T) 2 A 1 a n d C Y P 3 A e nz ymes.  O ne of pri mar y  meta b olites o bser ve d i n 
i n vitr o a n d a ni mal s yste ms is a n acti ve lacta m meta b olite desi g nate d P F-0 5 0 8 9 3 2 6. 
I n vitr o, pal b ocicli b is n ot a n i n hi bit or of C Y P 1 A 2, 2 A 6, 2 B 6, 2 C 8, 2 C 9, 2 C 1 9, a n d 2 D 6, a n d 
is n ot a n i n d ucer of C Y P 1 A 2, 2 B 6, 2 C 8, a n d 3 A 4 at cli nicall y rele va nt c o nce ntrati o ns a n d 
t h us, s h o we d l o w p ote ntial f or C Y P- me diate d p har mac o ki netic dr u g i nteracti o ns.  H o we ver, 
pal b ocicli b a n d P F -0 5 0 8 9 3 2 6 ca use d ti me -de pe n de nt i n hi biti o n of C Y P 3 A mi daz ola m 
1’- h y dr o x yl ase a n d test oster o ne 6 -h y dr o x yl ase acti vities wit h K i a n d k i nact val ues f or 
pal b ocicli b of 1 0 M, 0. 0 3 6 mi n
- 1 a n d 1 9 M, 0. 0 8 7 mi n
- 1 a n d f or P F-0 5 0 8 9 3 2 6 of 7. 0 M, 
0. 0 9 4 mi n - 1 a n d 6. 4 M, 0. 1 5 mi n
- 1, res pecti vel y.  T heref ore, pal b ocicli b a n d its meta b olite 
ma y  ha ve t he p ote ntial f or p har mac o ki netic dr u g i nteracti o ns wit h c o m p o u n ds f or w hic h 
C Y P 3 A -me diate d meta b olis m c o nstit utes t he pri mar y  mec ha nis m of cleara nce.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 0
E x peri me nts i n Ma di n -Dar b y ca ni ne ki d ne y ( M D C K) cells tra nsfecte d wit h P -gl yc o pr otei n 
( P-g p) or breast ca ncer resista nt pr otei n ( B C R P) i n dicate d t hat pal b ocicli b was a m o derate 
s u bstrate f or b ot h.  T he effl u x of pal b ocicli b was f o u n d t o be c o nce ntrati o n de pe n de nt a n d 
a p peared t o be sat ura ble wit h effl u x rati os less t ha n 2 w he n pal b ocicli b c o nce ntrati o ns were 
greater t ha n 0. 5 2 a n d 1. 9 6 M f or P -g p a n d B C R P, res pecti vel y .  Pal b ocicli b i n hi bite d P-g p 
a n d B C R P i n M D C KII - m ulti ple dr u g resista nce ( M D R) 1 a n d M D C KII-B C R P cells wit h a
5 0 % i n hi bit or y c o nce ntrati o n (I C 5 0) of > 3 2 M ( > ~ 1 4. 3 g/ m L), i n dicati n g a l o w p ote ntial 
f or pal b ocicli b t o i n hi bit t hese tra ns p orters at cli nicall y rele va nt c o nce ntrati o ns.  In vitr o, 
pal b ocicli b, at c o nce ntrati o ns u p t o ~ 3 2 M, di d n ot i n hi bit or ga nic c ati o n tra ns p orter 
( O C T)- 2, or ga nic a ni o n tra ns p orters ( O A T)-1 a n d 3, or ga nic a ni o n tra ns p orti n g p ol y pe pti de 
( O A T P)-1 B 1 a n d 1 B 3, a n d bile -salt e x p ort p u m p ( B S E P).
He patic u pta ke a n d biliar y e xcreti o n of pal b ocicli b was i n vesti gate d i n vitr o usi n g a 
sa n d wic h c ult ure h u ma n he pat oc yte m o del i n t he prese nce a n d a bse nce of rifa myci n S V a n d 
di vale nt cati o ns.  Pal b ocicli b s h o we d hi g h passi ve per mea bilit y  t o h u ma n he pat oc ytes a n d 
tra ns p orter-me diate d u pta ke was o bser ve d at a b o ut 1 5 % of t he t otal u pta ke i nt o he pat oc y tes.  
Biliar y  e xcreti o n of pal b ocicli b was c o nsi dere d mi ni mal as acc u m ulati o n i n prese nce a n d 
a bse nce of di vale nt cati o ns was si milar.  Pal b ocicli b acc u m ulati o n i n t he prese nce a n d 
a bse nce of rifa m yci n S V were si milar i n dicati n g a mi n or r ole, if a n y , f or OA T P 1 B 1 a n d 
O A T P 1 B 3 i n pal b ocicli b tra ns p ort.
1. 2. 1. 2. I n Vi v o a n d I n Vitr o S afet y P h ar m ac ol o g y of P al b ocicli b
I n precli nical st u dies, pal b ocicli b ca use d decreases i n heart rate ( H R; u p t o 8 beats per mi n ute 
[ b p m]) t hat c orres p o n de d wit h i ncreases i n res pirat or y rate ( R R) i nter val ( u p t o 
7 3 millisec o n ds [ msec]) a n d i ncreases i n s ys t olic bl o o d press ure ( u p t o 6 m m H g) i n d o gs 
gi ve n a si n gle oral d ose of 1 0 a n d 3 0 m g / k g bet wee n 4. 5 a n d 2 0 h o urs p ost d ose ( 1 4 0 n g/ m L  
u n b o u n d).  I n a d diti o n, i ncreases i n t he ti me bet wee n t he start of t he Q wa ve a n d t he e n d of 
t he T wa ve i n t he heart's electrical c ycle ( Q T; u p t o 1 4 msec) a n d heart rate c orrecte d Q T 
( Q Tc; u p t o 9 msec) i nter val were i de ntifie d i n t he d o g at 3 m g / k g wit h a t hres h ol d 
c o nce ntrati o n of 6 7 n g/ m L ( u n b o u n d) res ulti n g i n a 3. 7 -f ol d a b o ve h u ma n cli nical e x p os ure 
at 1 2 5 m g o nce a da y  ( Q D).  Pal b ocicli b i n hi bite d h E R G c urre nt i n h u ma n e m br yo nic ki d ne y  
2 9 3 ( H E K 2 9 3) cells wit h a n o bser ve d I C5 0 of 3. 2 M ( 1 4 3 2
n g/ m L).  I n t he P ur ki nje fi ber 
assa y pal b ocicli b ha d n o effect o n t he resti n g me m bra ne p ote ntial, acti o n p ote ntial a m plit u de, 
V ma x , a n d acti o n p ote ntial d urati o n at 5 0 % re p olarizati o n ( A P D5 0) at 0. 1 a n d 1 M; h o we ver, 
a statisticall y si g nifica nt 8. 2 % i ncrease i n acti o n p ote ntial d urati o n at 9 0 % re p olarizati o n 
( A P D9 0) occ urre d at 1 0 M ( 4 4 7 5
n g/ m L).  I n t he h E R G assa y wit h t he o xi dati ve meta b olite 
of pal b ocicli b, P F -0 5 0 8 9 3 2 6, t he I C 5 0 was n ot ac hie ve d at 1 0 M t hat was t he ma xi m u m 
c o nce ntrati o n teste d d ue t o t he c o m p o u n d s ol u bilit y  li mit.
I n re peat- d ose rat a n d d o g t o xicit y st u dies of u p t o 1 5 wee ks i n d urati o n, t he pri mar y  
pal b ocicli b -relate d t o xicities were o bser ve d i n t he b o ne marr o w, ly m p h oi d tiss ues, a n d testes.  
Decrease d cell ularit y i n t he b o ne marr o w a n d l y m p h oi d tiss ues, a n d i ncrease d ir o n pi g me nt 
i n t he b o ne marr o w, li ver, a n d s plee n were ass ociate d wit h t he prese nce of he mat ol o gical 
c ha n ges t hat i ncl u de d decreases i n re d bl o o d cell para meters a n d le u k oc y tes.  Partial t o 
c o m plete re versi bilit y of t hese t o xicities was de m o nstrate d f oll o wi n g a 4 wee k rec o ver y  
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 1
per i o d, wit h t he e xce pti o n of t he testic ular a n d e pi di d ymal c ha n ges f or w hic h re versal was 
n ot o bser ve d i n t he d o g.  T hese t o xicities occ urre 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 (ie, cell c y cle i n hibiti o n). 6 ,7 ,8
I n a n o n g oi n g 2 7-wee k re peat -d ose rat t o xicit y  st u d y, cataracts were i de ntifie d i n male rats at 
3 0 m g/ k g/ d a y a n d c orrelate d micr osc o picall y wit h le ns de ge nerati o n.  Alt h o u g h cataracts 
were n ot i de ntifie d fr o m o p ht hal mic e val uati o ns at 1 0 m g/ k g/ da y  i n males or at a n y d ose i n 
fe males, le ns de ge nerati o n was n ote d micr osc o picall y i n male rats at 1 0 m g/ k g/ da y  
( 7 5 0 n g· hr/ m L , u n b o u n d) a n d i n fe male rats at 5 0 a n d 1 0 0 m g/ k g/ da y  ( 3 3 1 n g· hr/ m L, 
u n b o u n d).  T hese micr osc o pic effects were see n at e x p os ures t hat are c o m para ble t o cli nical 
e x p os ure at t he rec o m me n de d h u ma n d ose of 1 2 5 m g Q D.
T he mec ha nis m f or cataract f or mat i o n i n pal b ocicli b-treate d rats is u n k n o w n; h o we ver, 
e mer ge nt data fr o m t he 2 7- wee k rat t o xicit y  st u d y s u g gests its pat h o ge nesis ma y be relate d t o 
altere d gl uc ose meta b olis m.  Te n of 1 1 male rats wit h le ns de ge nerati o n were s h o w n t o ha ve 
gl yc os uria ( + 2 or + 3) a n d/ or i ncrease d ser u m gl uc ose (c o m pare d t o t he u p per ra n ge of 
c o ntr ol val ues) ( u nsc he d ule d deat hs n ot i ncl u de d d ue t o t he lac k of cli nical c he mistr y  data).  
O ne of 3 fe male rats wit h le ns de ge nerati o n als o ha d glyc os uria a n d h y p er gl yce mia.  I n 
a d diti on t o t he c orrelati o n o bser ve d bet wee n altere d gl uc ose meta b olis m a n d le ns 
de ge nerati o n, a c orrelati o n bet wee n altere d gl uc ose meta b olis m a n d pa ncreatic islet cell 
va u olati o n was i de ntifie d i n all ( 1 0 of 1 0) male a ni mals wit h t he hist ol o gical c ha n ge.  I n 
females, t he o ne fe male wit h le ns de ge nerati o n t hat c orrelate d wit h gl yc os uria a n d 
h y per gl y ce mia als o ha d pa ncreatic islet cell vac u olati o n. 
Mater nal a n d fetal effects were o bser ve d i n e m br y ofetal de vel o p me nt st u dies c o n d ucte d i n 
t he rat a n d ra b bit wit h palb ocicli b. Mater nal b o d y wei g ht gai n a n d f o o d i nta ke were re d uce d 
at 3 0 0 a n d 2 0 m g/ k g/ da y  i n pre g na nt rats a n d ra b bits, res pecti vely.  Re d uce d fetal b o d y 
wei g hts ( 9 5 % of c o ntr ol) were i de ntifie d i n rats o nl y  at 3 0 0 m g / k g/ da y.  A l o w i nci de nce of 
s mall p hala n ges o n t he f ore pa ws were n ote d ( 3 fet uses fr o m 2 litters; s keletal variati o n) at 
2 0 m g/ k g/ da y  i n ra b bits.
T he ge n ot o xic p ote ntial of pal b ocicli b was assesse d i n a batter y  of i n vitr o a n d i n viv o tests.  
Pal b ocicli b teste d ne gati ve i n t he micr o bial re vers e m utati o n assa y w he n teste d u p t o 
5 m g/ plate i n t he prese nce a n d a bse nce of e x o ge n o us meta b olic acti vati o n.  H o we ver, 
pal b ocicli b teste d p ositi ve i n a n e x pl orat or y  i n vitr o micr o n ucle us assa y  w he n teste d i n a 
2 4 -h o ur test.  I n a s u bse q ue nt i n vitr o micr o n ucle us test, ki net oc h ore- stai ni n g was use d t o 
discri mi nate micr o n uclei i n d uce d b y c hr o m os o mal brea ka ge fr o m t h ose i n d uce d b y 
c hr o m os o mal l oss.  T he res ults fr o m t his st u d y s h o w t hat pal b ocicli b i n d uces pre d o mi na ntl y  
micr o n uclei c o ntai ni n g w h ole c hr o m os o mes a n d is t heref ore c o nsi dere d a ne u ge nic i n t he i n 
vitr o test s yste m.  T he lac k of clast o ge nic p ote ntial was f urt her c o nfir me d i n t he h u ma n 
l ym p h oc y te a berrati o n assa y w he n teste d i n 3- a n d 2 4- h o ur tests wit h o ut meta b olic 
acti vati o n, a n d i n a 3-h o ur test wit h meta b olic acti vati o n u p t o c o nce ntrati o ns li mite d b y  
c yt ot o xicit y.  Pal b ocicli b was als o teste d i n a n i n viv o b o ne marr o w micr o n ucle us assa y  i n 
rats at u p t o ma xi mall y t olerate d d oses of 5 0, 1 0 0 a n d 2 0 0 m g/ k g i n males a n d 1 0 0, 2 0 0, 
4 0 0 m g/ k g i n fe males f oll o wi n g o nce dail y oral d osi n g f or 3 wee ks.  Pal b ocicli b i n d uce d 
micr o n uclei i n t he p ol y c hr o matic b o ne marr o w er yt hr oc ytes of male rats at 1 0 0 a n d 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 2
2 0 0 m g/ k g b ut n ot at 5 0 m g/ k g or i n fe male rats w he n teste d u p t o ma xi mall y  t olerate d d oses.  
S y ste mic Da y 2 1 area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve ( A U C) e x p os ure at 
t he n o-o bser ve d effect le vels ( N O E L) of 5 0 m g/ k g i n males a n d 4 0 0 m g / k g i n fe males was 
1 7 3 0 0 a n d 1 1 1 0 0 n g• hr/ m L , res pecti vely.  Base d o n t he lac k of direct D N A i nteracti o n a n d 
t he e xpecte d safet y  mar gi n f or a ne u ge nic acti vit y, t here are n o percei ve d ge netic t o xicit y 
ris ks t o h u ma ns at d oses u p t o 1 2 5 m g Q D all o wi n g f or d osi n g i n healt h y  v ol u nteers.
C o m plete i nf or mati o n o n t he precli nical t o xic ol o g y of pal b ocicli b ca n be f o u n d i n t he 
In vesti gat or’s Br oc h ure. 
1. 2. 1. 3. Cli nic al S u m m ar y
As of J ul y 2 0 1 8, t he cli nical pr o gra m wit h pal b ocicli b i ncl u de d 1 0 o n g oi n g a n d 4 c o m plete d 
st u dies i n a d va nce d ca ncer patie nts. 
T w o ( 2) P hase 1 st u dies i n a d ult ca ncer patie nts (s oli d t u m ors or l y m p h o mas [ A 5 4 8 1 0 0 1, 
c o m plete d] a n d ma ntle cell l y m p h o ma [ A 5 4 8 1 0 0 2, c o m plete d]) ha ve bee n c o n d ucte d.  T w o 
( 2) P hase 1/ 2 st u dies ha ve c o m plete d, 1 i n A B C ( A 5 4 8 1 0 0 3, i n c o m bi nati o n wit h letr oz ole) 
a n d 1 i n rela pse d/refract or y  m ulti ple m yel o ma ( A 5 4 8 1 0 0 4, i n c o m bi nati o n wit h b o rtez o mi b 
a n d de xa met has o ne).  A P hase 1/ 2 d ose -escalati o n st u d y i n Ja pa nese patie nts wit h A B C 
( A 5 4 8 1 0 1 0, i n c o m bi nati o n wit h letr oz ole) is o n g oi n g. A P hase 3 st u d ies i n A B C 
( A 5 4 8 1 0 0 8, i n c o m bi nati o n wit h letr oz ole) a n d a P hase 3 st u d y  i n A B C ( A 5 4 8 1 0 2 3, i n
c o m bi nati o n wit h f ul vestra nt [ wit h or wit h o ut g osereli n]) ha ve ac hie ve d c o m pleti o n of t he 
pri mar y  e n d p oi nt a n d is o n g oi n g.  A P hase 3 st u d y ( A 5 4 8 1 0 2 7, i n c o m bi nati o n wit h 
letr oz ole) c o n d ucte d i n Asia n patie nts wit h A B C has c o m plete d e nr oll me nt a n d is o n g o i n g.  
T w o ( 2) e x pa n de d access st u dies i n A B C ( A 5 4 8 1 0 3 7 a n d A 5 4 8 1 0 5 3, i n c o m bi nati o n wit h 
letr oz ole) are o n g oi n g.  I n a d diti o n, a P hase 2 st u d y i n patie nts wit h a d va nce d s q ua m o us cell 
carci n o ma of t he hea d a n d nec k ( A 5 4 8 1 0 4 4, i n c o m bi nati o n wit h cet u xi ma b) is o n g oi n g a n d 
a P hase 1 st u d y i n patie nts wit h a d va nce d pa ncreatic d uctal a de n ocarci n o ma ( A 5 4 8 1 0 5 9, i n 
c o m bi nati o n wit h na b- paclita xel) is o n g oi n g.  As of Dece m ber 2 0 1 4, p har mac o ki netic ( P K) 
data ha ve als o bee n c ollecte d i n 1 5 c o m plete d cli nical p har mac ol o g y  st u dies fr o m healt h y 
v ol u nteers ( A 5 4 8 1 0 0 9, A 5 4 8 1 0 1 1, A 5 4 8 1 0 1 2, A 5 4 8 1 0 1 5, A 5 4 8 1 0 1 6, A 5 4 8 1 0 1 7, 
A 5 4 8 1 0 1 8, A 5 4 8 1 0 2 0, A 5 4 8 1 0 2 1, A 5 4 8 1 0 2 2, A 5 4 8 1 0 2 6, A 5 4 8 1 0 3 2, A 5 4 8 1 0 3 6, 
A 5 4 8 1 0 3 8, a n d A 5 4 8 1 0 4 0).  As of 3 1 J ul y  2 0 1 8, p har mac o ki netic ( P K) data ha ve bee n 
c ollecte d i n 1 1 st u dies ( A 5 4 8 1 0 0 1, A 5 4 8 1 0 0 2, A 5 4 8 1 0 0 3, A 5 4 8 1 0 0 4, A 5 4 8 1 0 0 8, 
A 5 4 8 1 0 1 0, A 5 4 8 1 0 1 9, A 5 4 8 1 0 2 3, A 5 4 8 1 0 2 7, A 5 4 8 1 0 4 4 a n d A 5 4 8 1 0 5 9) fr o m a d ult 
a d va nce d ca ncer patie nts.  St u dies A 5 4 8 1 0 0 1, A 5 4 8 1 0 0 2, A 5 4 8 1 0 0 3, A 5 4 8 1 0 0 4, A 5 4 8 1 0 0 8, 
a n d A 5 4 8 1 0 2 3 ha ve c o m plete d t heir pri mar y  e n d p oi nts a n d fi nal P K data are a vaila ble.  I n 
a d diti o n, P K data ha ve bee n c ollecte d i n 2 0 cli nical p har mac ol o g y  st u dies i n a t otal of 5 4 5 
healt h y  v ol u nteers.
O n 0 3 Fe br uar y  2 0 1 5, a n accelerate d a p pr o val f or pal b ocicli b was recei ve d f or t he first-li ne 
treat me nt of E R( +),H E R 2 - ne gati ve ( H E R 2(-)) A B C i n p ost me n o pa usal w o me n i n t he U nite d 
States base d o n t he res ults of P hase 1/ 2 st u d y  ( A 5 4 8 1 0 0 3) desi g ne d t o assess t he efficac y, 
safety, a n d P K of letr oz ole 2. 5 m g a d mi nistere d o nce dail y ( 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 wit h sc he d ule of 3 wee ks o n treat me nt/ 1 wee k 
off -treat me nt ( 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 his 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 3
i n dicati o n.  T he fi nal efficac y res ults fr o m t he P hase 2 p orti o n of t he st u d y s h o we d t hat t he 
me dia n pr o gressi o n -free s ur vi val ( P F S) was si g nifica ntl y l o n ger i n t he pal b ocicli b pl us 
letr oz ole ar m t ha n i n t he letr oz ole al o ne ar m ( 2 0. 2 m o nt hs vers us 1 0. 2 m o nt hs) wit h a hazar d 
rati o of 0. 4 8 8 ( 9 0 % c o nfi de nce i nter vals [ CIs]: 0. 3 1 9, 0. 7 4 8) i n fa v or of pal b ocicli b pl us 
letr oz ole ( p = 0. 0 0 0 4).  St u d y A 5 4 8 1 0 0 8, as a lar ge P hase 3 trial, met its pri mar y o bjecti ve of 
i m pr o vi n g P F S wit h hazar d rati o as 0. 5 7 6 ( 9 5 % CIs: 0. 4 6 3, 0. 7 1 8; stratifie d 1 -si de d p-val ue 
< 0. 0 0 0 0 0 1) i n fa v or of pal b oci cli b pl us letr oz ole relati ve t o place b o pl us letr oz ole.  T he 
p ositi ve o utc o me pr o vi de d c o nfir mat or y  e vi de nce f or a n i m pr o ve me nt i n P F S f or pal b ocicli b 
i n c o m bi nati o n wit h letr oz ole i n t he first-li ne setti n g, w hic h was first de m o nstrate d i n St u d y 
A 5 4 8 1 0 0 3. A n ot her c o m plete d P hase 3 St u d y  A 5 4 8 1 0 2 3 als o de m o nstrate d t hat pal b ocicli b 
c o m bi ne d wit h f ul vestra nt, a selecti ve E R de gra der, res ulte d i n a l o n ger P F S ( 9. 2 m o nt hs) 
t ha n place b o pl us f ul vestra nt ( 3. 8 m o nt hs; hazar d rati o : 0. 4 2; 9 5 % CIs: 0. 3 2 – 0. 5 6; p < 0. 0 0 1) 
a m o n g patie nts wit h h or m o ne rece pt or p ositi ve metastatic breast ca ncer w h o e x perie nce d 
disease pr o gressi o n d uri n g pri or e n d ocri ne t hera p y.
- P har mac o ki netic ( P K) para meters are a vaila ble fr o m all 7 4 patie nts e nr olle d i n Pr ot oc ol 
A 5 4 8 1 0 0 1 f oll o wi n g a si n gle -d ose ( Da y  1 of Cycl e 1), a n d fr o m 5 1 patie nts f oll o wi n g 
m ulti ple -d ose a d mi nistrati o n ( Da y 8 of C ycle 1) of o nce 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 o n Sc he d ules 3/ 1 a n d 2/ 1.  I n a d diti o n, P K para meters are als o 
a vaila ble f or 9 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) a n d 4 patie nts 
o n Da y  2 1 of Cycle 1 (fr o m patie nts o n Sc he d ule 3/ 1).  T he e x p os ure ( A U C ( 0-1 0 hr) (area u n der 
t he plas ma c o nce ntrati o n) a n d C ma x ( ma xi m u m plas ma c o nce ntrati o n)) i ncrease d i n a 
d ose -pr o p or ti o nal ma n ner o ver t he d ose ra n ge of 2 5-2 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 y cle 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 bser ve d partic ularl y at t he 1 5 0 m g Q D d ose le vel. 9
P K data fr o m S t u d y A 5 4 8 1 0 0 2 ( ma ntle cell ly m p h o ma p o p ulati o n) i n dicate d t hat pal b ocicli b 
e x p os ure at stea d y state i n ma ntle cell l y m p h o ma patie nts was si milar t o t hat o bser ve d i n 
patie nts wit h s oli d t u m or or l y m p h o ma ( Pr ot oc ol A 5 4 8 1 0 0 1). 1 0
P K a nal y sis of data fr o m t he P hase 1 p orti o n of S t u d y A 5 4 8 1 0 0 3 ( breast ca ncer, c o m bi nati o n 
wit h letr oz ole) was c o n d ucte d t o e val uate t he p ote ntial f or dr u g -dr u g i nteracti o n ( D DI) 
bet wee n pal b ocicli b a n d letr oz ole.  Letr oz ole is pri maril y meta b olize d b y C Y P 2 A 6, a n d 
C Y P 3 A re prese nts a mi n or pat h wa y  of eli mi nati o n.  T he res ults i n dicate a lac k of D DI 
bet wee n pal b ocicli b a n d letr oz ole w he n a d mi nistere d i n c o m bi nati o n. Res ults fr o m t he 
P hase 2 p orti o n of t he s t u d y de m o nstrate d t he a d diti o n of pal b ocicli b t o letr oz ole res ulte d i n 
statisticall y si g nifica nt, r o b ust, a n d cli nicall y mea ni n gf ul i m pr o ve me nt i n pr o gressi o n-free 
s ur vi val ( P F S) as c o m pare d wit h letr oz ole al o ne i n t he treat me nt of p ost me n o pa usal w o me n 
wit h E R -p ositi ve, H E R 2 - ne gati ve a d va nce d breast ca ncer ( 2 0. 2 m o nt hs vers us 1 0. 2 m o nt hs).  
O bjecti ve res p o nse a n d cli nical be nefit rates ( 4 2. 9 % vs. 3 3. 3 % a n d 8 1. 0 % vs. 5 8 %, 
res pecti vely) were als o s u peri or wit h t he c o m bi nati o n.  T he safet y pr ofile of t he pal b o cicli b 
pl us letr oz ole c o m bi nati o n was t olera ble a n d ma na gea ble wit h u nc o m plicate d Ne utr o pe nia 
a n d Le u k o pe nia as t he m ost c o m m o n a d verse e ve nts a n d cli nicall y i nsi g nifica nt effects o n 
Q Tc i nter val w he n c o m pare d t o letr oz ole al o ne. 1 1
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 4
P K data fr o m St u dies A 5 4 8 1 0 0 1, A 5 4 8 1 0 0 3, a n d A 5 4 8 1 0 1 0 i n dicate t hat pal b ocicli b is 
sl o wl y a bs or be d wit h a me dia n ti me of ma xi m u m c o nce ntrati o n ( Tma x ) bet wee n 4 a n d 8 h o urs 
p ost -d ose, a n d is sl o wl y  eli mi nate d wit h a n eli mi nati o n half-life (t1/ 2) ra n gi n g fr o m 
2 3. 2 h o urs t o 2 8. 8 h o urs.  Pal b ocicli b acc u m ulates after re peate d dail y d osi n g ( me dia n Rac 
ra n ge d fr o m 1. 9 t o 2. 4), w hic h was c o nsiste nt wit h its ter mi nal t1/ 2. I n St u d y A 5 4 8 1 0 1 0, t he 
me dia n R ss (t he pre dicte d acc u m ulati o n t o esti mate li nearit y) was 1. 1, i n dicati n g t hat 
pal b ocicli b cleara nce d oes n ot c ha n ge o ver ti me.  I n St u d y  A 5 4 8 1 0 0 3, pal b ocicli b was s h o w n 
t o ac hie ve stea dy- state c o nce ntrati o ns f oll o wi n g 8 da y s of Q D d osi n g.  T he pal b ocicli b 
ge o metric mea n v ol u me of distri b uti o n ( Vz/ F) was 2 5 8 3 L i n w o me n wit h a d va nce d breast 
ca ncer ( St u d y A 5 4 8 1 0 0 3), w hic h is si g nifica ntl y greater t ha n t otal b o d y water ( 4 2 L), 
i n dicati n g t hat pal b ocicli b e xte nsi vel y distri b utes t o peri p heral tiss ues.
Res ults fr o m pal b ocicli b h u ma n mass bala nce st u d y ( A 5 4 8 1 0 1 1) s u g geste d t he maj or r o ute 
of [ 1 4C] -pal b ocicli b eli mi nati o n was mai nl y via fecal e xcreti o n ( 7 4. 1 % of d ose) wit h 
1 7. 5 % of d ose e xcrete d i n uri ne.  T he pare nt dr u g was t he m ost a b u n da nt circ ulati n g e ntit y  
f oll o wi n g oral a d mi nistrati o n of [1 4C] - pal b ocicli b.  T he maj or circ ulati n g meta b olite was a 
gl uc ur o ni de c o nj u gate of pal b ocicli b ( M 2 2), a n d 3 maj or meta b olites rec o vere d i n feces 
i ncl u de d a s ulfa mic aci d of pal b ocicli b ( M 1 1, P F-0 6 7 5 4 2 3 3), a car b o x yl ic aci d ( M 1 6) a n d a 
c ycl o pe nt yl  ri n g-h y dr o x ylat e d meta b olite of t he lacta m ( M 1 7, P F -0 5 0 8 9 3 2 6).  I n vitr o 
st u dies s u g geste d t hat c yt oc hr o me P 4 5 0 ( C Y P) 3 A a n d s ulf otra nsferase ( S U L T) 2 A 1 were t he 
maj or e nz y mes res p o nsi ble f or pal b ocicli b meta b olis m.  P F -0 5 0 8 9 3 2 6 was s u g geste d t o be 
a p pr o xi matel y a n e q ui p ote nt i n hi bit or of C D K-4/ 6 relati ve t o pal b ocicli b i n vitr o a n d prese nt 
at 1 8 % a n d 1 0 % of pare nt dr u g base d o n C ma x a n d A U C i nf, res pecti vel y.1 2  Si nce t he s ys te mic 
e x p os ure of P F- 0 5 0 8 9 3 2 6 was o nl y a p pr o xi matel y  10 % of pare nt dr u g, a n d it als o s h o we d a 
l o wer u n b o u n d fracti o n t ha n pal b ocicli b, t he P K of t his meta b olite was n ot c haracterize d i n 
s u bse q ue nt cli nical st u dies.
Pal b ocicli b D DI st u d y  A 5 4 8 1 0 1 2 s u g geste d pal b ocicli b is c o nsi dere d t o be a wea k 
ti me-de pe n de nt i n hi bit or of C Y P 3 A base d o n t he res ults t hat c oa d mi nistrati o n of pal b ocicli b 
i ncrease d mi daz ola m A U Ci nf a n d C ma x b y  6 1 % a n d 3 7 % res pecti vel y.1 3  Res ults fr o m st u d y  
A 5 4 8 1 0 1 7 s h o we d c oa d mi nistrati o n of str o n g C Y P 3 A i n d ucer rifa m pi n decrease d 
pal b ocicli b A U C i nf a n d C ma x b y  8 5 % a n d 7 0 % res pecti vely, relati ve t o t h ose w he n pal b ocicli b 
was gi ve n al o ne. 1 4 Res ults fr o m a D DI st u d y of pal b ocicli b wit h str o n g C Y P 3 A i n hi bit or 
itrac o naz ole ( A 5 4 8 1 0 1 6) s u g geste d c oa d mi nistrati o n of itrac o naz ole i ncrease d t he 
pal b ocicli b A U C i nf a n d C ma x b y  a p pr o xi matel y 8 7 % a n d 3 4 %, res pecti vely. 1 5
T he effect of f o o d o n t he e x p os ure of pal b ocicli b w he n a d mi nistere d as t he c o m mercial free 
base ca ps ule was e val uate d i n healt h y s u bjects ( A 5 4 8 1 0 2 1).  C o m pare d t o pal b ocicli b gi ve n 
u n der o ver ni g ht faste d c o n diti o ns, t he A U C i nf a n d C ma x of pal b ocicli b i ncrease d b y 2 1 % a n d 
3 8 % w he n gi ve n wit h hi g h -fat f o o d, by 1 2 % a n d 2 7 % w he n gi ve n wit h l o w -fat f o o d, a n d by 
1 3 % a n d 2 4 % w he n m o derate -fat f o o d was gi ve n 1 h o ur bef ore a n d 2 h o urs after pal b ocicli b 
d osi n g.  I n a d diti o n, f o o d i nta ke si g nifica ntl y  re d uce d t he i nters u bject a n d i ntras u bject 
varia bilit y of pal b ocicli b e x p os ure.  Base d o n t hese res ults, pal b ocicli b c o m mercial free base 
ca ps ules s h o ul d be ta ke n wit h f o o d. 1 6
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 5
Res ults fr o m pal b ocicli b relati ve bi oa vaila bilit y st u d y ( A 5 4 8 1 0 3 6) s h o we d t he fi nal P hase 
3/c o m mercial free base ca ps ules a d mi nistere d wit h m o derate-fat f o o d are bi oe q ui vale nt t o 
t he iset hi o nate ca ps ules gi ve n u n der a n o ver ni g ht faste d c o n diti o n a n d a mi ni mal faste d 
c o n diti o n, w hic h re prese nt t he 2 e xtre me sce nari os f or c o m plia nt pal b ocicli b d osi n g wit h 
re gar d t o f o o d i nta ke i n St u d y A 5 4 8 1 0 0 3.1 7  T his fi n di n g s u p p orts t he rec o m me n dati o n t hat 
pal b ocicli b fi nal P hase 3/c o m mercial free base ca ps ules s h o ul d be a d mi nistere d wit h f o o d i n 
all o n g oi n g a n d f ut ure st u dies.
T he s ol u bilit y  of t he pal b ocicli b free base 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 matically decreases 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 ncrease gastric p H ca n alter t he s ol u bili t y a n d a bs or pti o n of 
pal b ocicli b free base f or m ulati o ns.
A pal b ocicli b D DI st u d y ( A 5 4 8 1 0 3 8) was c o n d ucte d t o i n vesti gate t he effect of a 
pr ot o n -p u m p i n hi bit or ( P PI ), a H2-rece pt or a nta g o nist ( H2R A) a n d a l ocal a ntaci d o n 
bi oa vaila bilit y  of pal b ocicli b wit h t he fi nal P hase 3/c o m mercial free base ca ps ule 
f or u m ulati o n u n der fe d c o n diti o n i n healt h y v ol u nteers.  T he res ults de m o nstrate d t hat a 
H 2R A fa m oti di ne gi ve n 1 0 h o urs bef ore a n d 2 h o urs after pal b ocicli b, or a l ocal a ntaci d 
Mi -Aci d Ma xi m u m Stre n gt h Li q ui d gi ve n 2 h o urs bef ore or 2 h o urs after pal b ocicli b, ha d n o 
i m pact o n t he e x p os ure of pal b ocicli b. Ra be praz ole, a P PI  gi ve n dail y f or 6 da ys bef ore a n d 
4 h o urs pri or t o pal b ocicli b res ulte d i n a p pr o xi matel y  4 1 % decrease i n Cma x , b ut ha d li mite d 
effect ( 1 3 % ) o n A U Ci nf.1 8  I n a n ot her healt hy s u bject st u d y, c oa d mi nistrati o n of a si n gle d ose 
of c o m mercial free base ca ps ule wit h m ulti ple d oses of t he P PI  ra be praz ole u n der faste d 
c o n diti o ns decrease d pal b ocicli b A U C i nf a n d C ma x b y  6 2 % a n d 8 0 %, res pecti vel y, w he n 
c o m pare d t o a si n gle d ose of pal b ocicli b a d mi nistere d al o ne.  C ollecti vel y , t hese a ntaci d D DI 
data f urt her s u p p ort t he re q uire me nt t hat t he free base ca ps ule of pal b ocicli b s h o ul d be ta ke n 
wit h f o o d. 1 9 Base d u p o n t hese data, u n der fe d c o n diti o ns, t he use of H 2-rece pt or a nta g o nist 
or l ocal a ntaci ds or P PI s is n o w per mitte d as defi ne d i n Secti o n 5. 4. 3 .
1. 2. 2. S afe t y
I n St u dies A 5 4 8 1 0 0 1 a n d A 5 4 8 1 0 0 2, t he m ost c o m m o nl y re p orte d treat me nt relate d 
treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) (≥2 0 % of patie nts) of a n y  gra de, re gar dless of 
ca usalit y were fati g ue ( 5 2. 7 % of patie nts); ne utr o pe nia ( 4 8. 4 %); na usea ( 3 5. 2 %); diarr hea 
a n d a ne mia ( 3 0. 8 % eac h); c o nsti pati o n ( 2 6. 4 %); decrease d a p petite ( 2 2. 0 %); a n d v o miti n g
a n d t hr o m b oc yt o pe nia ( 2 0. 9 % eac h).  I n St u d y A 5 4 8 1 0 0 3, t he m ost c o m m o nl y re p orte d 
T E A E of a n y gra de, re gar dless of ca usalit y  were ne utr o pe nia ( 7 3. 7 %); fati g ue ( 4 6. 3 %); 
le u k o pe nia ( 4 4. 2 %); a ne mia ( 3 4. 7 %); na usea ( 2 8. 4 %); diarr hea a n d art hral gia ( 2 4. 2 % f or 
eac h); a n d h ot fl us h ( 2 1. 1 %). 2 0  Ne utr o pe nia, le u k o pe nia, a n d a ne mia were t he m ost fre q ue nt 
treat me nt-relate d Gra de 3/ 4 A d verse E ve nts ( A Es ) i n patie nts treate d wit h t he c o m bi nati o n 
t hera py of pal b ocicli b pl us l etr oz ole i n St u d y A 5 4 8 1 0 0 3.  H o we ver, t he re p orte d A Es were 
re versi ble, n o n-c u m ulati ve, a n d cli nically ma na gea ble.  Gi ve n t he k n o w n a nti pr oliferati ve 
mec ha nis m of acti o n of pal b ocicli b as a cell c y cle i n hi bit or, m yel os u p pressi o n is t he 
o n -tar get he mat ol o gic t o xicit y.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 6
T he preli mi nar y  res ults fr o m a n o n g oi n g P hase 1 st u d y i n Ja pa nese patie nts ( A 5 4 8 1 0 1 0) 
s h o we d t hat t he safet y pr ofile wit h si n gle-a ge nt pal b ocicli b i n Ja pa nese was si milar t o t hat i n 
n o n -Ja pa nese patie nts; a d diti o nall y, n o ne w safety si g nals were i de ntifie d i n Ja pa nese 
patie nts w h o recei ve d pal b ocicli b i n c o m bi nati o n wit h letr oz ole.
A q ua ntitati ve a nal ys is of t he relati o ns hi p bet wee n t he Q Tc i nter val a n d t he plas ma 
c o nce ntrati o ns of pal b ocicli b i n patie nts wit h a d va nce d ca ncer was c o n d ucte d usi n g data 
fr o m St u dies A 5 4 8 1 0 0 1, A 5 4 8 1 0 0 2, a n d A 5 4 8 1 0 0 3 f oll o wi n g stea dy state d oses ra n gi n g 
fr o m 2 5-2 2 5 m g.   At t he mea n or me dia n stea d y  state Cma x of pal b ocicli b f oll o wi n g a 
t hera pe utic d osi n g sc he d ule ( 1 2 5 m g Q D o n sc he d ule of 3 wee ks o n treat me nt/ 1 wee k off 
treat me nt), t he mea n st u d y-c orrecte d Q Tc ( Q Tc S) i ncrease was 5. 6 msec, wit h t he u p per 
b o u n d of t he o ne -si de d 9 5 % CI falli n g bel o w 1 0 msec, s u g gesti n g t hat Q T i nter val 
pr ol o n gati o n is n ot a safet y  c o ncer n wit h pal b ocicli b treat me nt wit h t he rec o m me n de d d osi n g 
re gi me n.  P al b ocicli b ha d n o effect o n heart rate eit her.2 1 I n St u d y  A 5 4 8 1 0 0 8, res ults fr o m 
St u d y  A 5 4 8 1 0 0 8 s h o we d t hat i n t he Q Tc a nalys is p o p ulati o n, n o patie nts ha d a p ost baseli ne 
a bs ol ute mea n ma xi m u m Q Tc F ( Fri dericia’s c orrecti o n met h o d) or Q Tc S of 5 0 0 msec or a 
ma xi m u m i ncrease fr o m Q Tc F or Q Tc S baseli ne of 6 0 msec d uri n g t he i nte nsi ve Q Tc 
assess me nt peri o d. A ra n d o m effect a nalys is of t he Q Tc data i n t he Q Tc a nal ysis p o p ulati o n 
de m o nstrate d t hat t he u p per b o u n ds of t he 1- si de d 9 5 % CI f or t he mea n c ha n ge ti me-matc he d 
fr o m baseli ne f or Q Tc F, Q Tc S a n d Q Tc B (Bazett ’s c orrecti o n met h o d) were < 1 0 msec at all 
ti me p oi nts i n t he Q Tc assess me nt peri o d, i n dicati n g t hat pal b ocicli b, w he n a d de d t o 
letr oz ole at t he rec o m me n de d d osi n g re gi me n, di d n ot pr ol o n g Q T i nter val t o a cli nicall y  
mea ni n gf ul e xte nt. 2 9
C o m plete i nf or mati o n f or pal b ocicli b ma y  be f o u n d i n t he Si n gle Refere nce Safety 
D oc u me nt ( S R S D), w hic h f or t his st u d y is t he I n vesti gat or’s Br oc h ure.
1. 2. 3. St u d y R ati o n al e
T his P hase 1 C hi na -o nl y P K st u d y ( A 5 4 8 1 0 19) is i nte n de d t o s u p p ort t he C F D A re g ulat or y 
fili n g re q uire me nt of pal b ocicli b , a n d is desi g ne d t o e val uate t he P K pr ofile a n d safety of 
pal b ocicli b as c o m bi n ati o n t hera p y wit h letr oz ole i n C hi nese patie nts wit h E R( +), H E R 2(-)
A B C . I n a d diti o n, efficac y will be e val uate d as o ne of t he sec o n dar y o bjecti ves.
1. 2. 3. 1. R ati o n ale f or P al b ocicli b A d mi nistr ati o n Sc he d ule
Pal b ocicli b has bee n a d mi nistere d a n d e xa mi ne d i n a P h ase 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 ncer. T w o d osi n g sc he d ules were e val uate d: 
Sc he d ule 3/ 1 ( 3 wee ks o n treat me nt/ 1 wee k off treat 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).
O verall, t he a d verse e v e nts ( A Es) re p orte d i n t his st u d y were ma na gea ble a n d re versi ble.  
T he d ose -li miti n g t o xicities ( D L Ts) t hat occ urre d d uri n g t his st u d y were si milar bet wee n t he 
t w o d osi n g sc he d ules a n d c o nsiste d of m yel ot o xic e ve nts, ie , ne utr o pe nia, t hr o m b oc yt o pe nia, 
a n d/or a ne mia.  T he m ye l os u p pressi o n was n ot irre versi ble, c u m ulati ve, or c o m plicate d, a n d 
it res ulte d i n per ma ne nt treat me nt disc o nti n uati o n i n o nl y 1 patie nt.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 7
F or patie nts w h o recei ve d pal b ocicli b Q D a d mi nistere d o n Sc he d ule 3/ 1, 3 7 patie nts were 
e val ua ble for res p o nse, 1 3 patie nts ( 3 5 %) ha d a n o verall best res p o nse of sta ble disease f or at 
least 2 c ycles.  Sta ble disease laste d 4 c y cles i n 1 0 patie nts ( 2 7 %) a n d 1 0 c ycles i n 
6 patie nts ( 1 6. 2 %). 
F or t he patie nts w h o recei ve d pal b ocicli b Q D a d mi nistere d o n S c he d ule 2/ 1, 3 1 of t he 
3 3 patie nts were e val ua ble f or res p o nse.  O ne patie nt wit h testic ular ca ncer ha d a partial 
res p o nse ( P R) t o pal b ocicli b 2 0 0 m g Q D.  Si x patie nts ( 1 9 %) mai ntai ne d sta ble disease f or 
4 c ycles, a n d 3 patie nts ( 1 0 %) mai ntai ne d sta ble di sease f or 1 0 c y cles.
W hile t he safet y  pr ofiles of t he t w o sc he d ules were c o m para ble, greater l o n g -ter m a ntit u m or 
acti vit y was o bser ve d wit h Sc he d ule 3/ 1; t heref ore t his re gi me n was selecte d f or f urt her 
cli nical de vel o p me nt.  T he R P 2 D f or Sc he d ule 3/ 1 was deter mi ne d t o be 1 2 5 m g Q D.
St u d y  A 5 4 8 1 0 0 2 was c o n d ucte d t o e val uate t he p har mac o d yna mics, cli nical acti vit y  a n d 
safety of pal b ocicli b a d mi nistere d at 1 2 5 m g Q D usi n g Sc he d ule 3/ 1 i n patie nts wit h 
pre vi o usl y  treate d ma ntle cell l ym p h o ma ( M C L).  Se ve ntee n p atie nts ha ve bee n e nr olle d i n 
t his st u d y i n w hic h 1 c o m plete res p o nse a n d 2 partial res p o nses were o bser ve d.  P E T -C T was 
use d i n t his st u d y  al o n g wit h rele va nt t u m or tiss ue bi o mar kers t o c o nfir m t he pr o of of 
mec ha nis m of acti o n of pal b ocicli b as M C L
is a disease c haracterize d b y o vere x pressi o n of 
C y cli ne D 1.  T he safet y pr ofile was si milar t o t hat o bser ve d i n t he d ose escalati o n st u d y .
Base d o n t he a b o ve data, Sc he d ule 3/ 1 was selecte d f or S t u d y A 5 4 8 1 0 1 9.
1. 2. 3. 2. R ati o n ale f or P al b ocicli b D ose
Pal b ocicli b was e val uate d i n a series of i n vitr o a n d i n vi v o ge netic t o xicit y st u dies.   
Pal b ocicli b was n ot m uta ge nic i n bacteria or clast o ge nic i n t he str uct ural c hr o m os o me 
a berrati o n assa y.  Ki net oc h ore stai ni n g i n a n i n vitr o micr o n ucle us assa y deter mi ne d t hat 
p ositi ve mi cr o n ucle us res ults i n vitr o a n d i n vi v o were d ue t o a ne u ge nicit y.   It is well 
acce pte d t hat a ne u ge ns i n d uce t heir effect b y  a t hres h ol d mec ha nis m2 2 ,2 3 ,2 4 f or w hic h a 
N O E L ca n be defi ne d.  A N O E L f or micr o n ucle us i n d ucti o n was i de ntifie d fr o m a n i n vi v o 
b o ne marr o w rat micr o n ucle us assa y  wit h pal b ocicli b.  Si g nifica nt i ncreases i n 
micr o n ucleate d p ol yc hr o matic er y t hr oc ytes were i de ntifie d at d oses 1 0 0 m g/ k g/ da y  i n t he 
male o nl y ; a N O E L f or micr o n uclei f or mati o n was i de ntifie d at 5 0 m g/ k g/ da y i n males a n d 
4 0 0 m g/ k g/ da y  i n fe males gi ve n pal b ocicli b f or 3 wee ks, wit h ass ociate d s yste mic Da y 2 1 
u n b o u n d A U C val ues of 2 1 6 3 a n d 1 3 8 8 n g• hr/ m L, res pecti vel y, offeri n g u p t o a n 8 -f ol d 
mar gi n o ver u n b o u n d s ys te mic A U C e x p os ure relate d t o t he h u ma n cli nical d ose of 1 2 5 m g 
Q D ( 2 7 4 n g• hr/ m L) w hic h will be a d mi nistere d i n t his st u d y .  Base d o n t he lac k of direct 
D N A i nteracti o n a n d t he e x pecte d safet y mar gi n f or a ne u ge nic acti vit y, t here are n o 
percei ve d ge netic t o xicit y  ris ks t o h u ma ns at d oses u p t o 1 2 5 m g Q D, all o wi n g f or m ulti ple 
d osi n g i n healt h y v ol u nteers a n d ca ncer patie nts.
Base d o n P hase 1 St u d y  A 5 4 8 1 0 0 1 i n ca ncer patie nts, 1 2 5 m g Q D of pal b ocicli b was 
deter mi ne d t o be t he ma xi mall y  t olerate d d ose ( M T D) a n d t he rec o m me n de d Phase 2 d ose 
( R P 2 D) o n t he 3/ 1 sc he d ule.  In St u d y  A 5 4 8 1 0 0 1, a t otal of 2 2 a d va nce d ca ncer patie nts were 
e nr olle d o n t he 3/ 1 sc he d ule t o t he 1 2 5 m g Q D c o h orts.  As o f 9/ 1/ 2 0 1 3, pal b ocicli b has bee n 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 8
a d mi nistere d c hr o nicall y t o o ver 2 7 0 a d va nce d ca ncer patie nts i n Pfizer-s p o ns ore d trials at 
d oses ra n gi n g fr o m 2 5 – 2 2 5 m g/ da y , i ncl u di n g 7 4 patie nts i n St u d y A 5 4 8 1 0 0 1, 1 7 patie nts 
i n St u d y A 5 4 8 1 0 0 2, 9 5 patie nts i n St u d y A 54 8 1 0 0 3, 5 1 patie nts i n St u d y  A 5 4 8 1 0 0 4, 
4 2 patie nts i n St u d y  A 5 4 8 1 0 0 8 (i ncl u des b ot h patie nts treate d wit h pal b ocicli b a n d place b o 
i n t his d o u ble-bli n d, place b o -c o ntr olle d st u d y), a n d 1 7 patie nts i n St u d y  A 5 4 8 1 0 1 0.  O ver 
1 5 0 of t h ose patie nts recei ve d dail y d oses of at least 1 2 5 m g/ da y .  I n a d diti o n, 1 2 5 m g was 
t he d ose use d i n pi v otal P hase 2 St u d y A 5 4 8 1 0 0 3 f or E R( +) H E R 2(-) a d va nce d breast 
ca ncer.
Base d o n t he safet y  data of pal b ocicli b a n d pri or cli nical e x perie nce as descri be d a b o ve, a 
d ose of 1 2 5 m g/ da y of pal b ocicli b as a si n gle d ose or o nce dail y at t he 3/ 1 sc he d ule is 
selecte d t o be a d mi nistere d i n c o m bi nati o n wit h letr oz ole i n C hi nese patie nts wit h a d va nce d 
breast ca ncer i n t his st u d y. A mi ni m u m of a p pr o xi matel y 2 5 patie nts will be e nr olle d t o t he 
st u d y.  Patie nts ma y be re place d if t here are less t ha n 1 2 patie nts c o m pleti n g t he si n gle-d ose 
a n d m ulti ple- d ose P K sa m ple c ollecti o ns wit h o ut d osi n g i nterr u pti o n or d ose m o dificati o n.  
F or si n gle -d ose P K asesse me nt, o n Da y  1 of Lea d-i n p hase, patie nts will recei ve oral si n gle 
d ose of 1 2 5 m g pal b ocicli b i n c o m bi nati o n wit h 2. 5 m g letr oz ole; letr oz ole d osi n g Q D will 
c o nti n ue fr o m Da y 2 - D a y  5. Fr o m Da y  1 of Cyc le 1 a n d t hereafter, patie nts will recei ve 
pal b ocicli b 1 2 5 m g orall y o nce dail y f or 3 wee ks f oll o w e d b y 1 wee k off treat me nt i n 
c o m bi nati o n wit h 2. 5 m g letr oz ole orall y  o nce dail y c o nti n u o usly i n 2 8 -d a y  c ycles.
1. 2. 4. R ati o n ale f or C h a n ges i n A me n d me nt 3, 1 6 J a n u ar y 2 0 1 9
T he prese nt st u d y met all t he e n d p oi nts i ncl u di n g P K a nal y sis, safety, a n d 
i n vesti gat or-assesse d P F S a nal ysis at t he rece nt pri mar y c o m pleti o n date cli nical st u d y re p ort 
( data c ut off of 3 1 J ul 2 0 1 8 ), de m o nstrati n g t hat i n C hi nese p ost me n o pa usal w o me n wit h 
E R -p ositi ve/ H E R 2 -ne gati ve A B C w h o ha d n ot recei ve d a n y pri or s ys te mic a ntica ncer
t hera pies f or t heir a d va nce d/ metastatic disease, t he a d diti o n of pal b ocicli b t o letr oz ole
s h o we d c o nsiste nt P K pr ofile wi t h gl o bal st u dies a n d t olera ble a n d ma na gea ble t o xicit y.
F oll o wi n g si n gle -d ose a d mi nistrati o n of pal b ocicli b 1 2 5 m g + letr oz ole 2. 5 m g Q D oral
d oses i n C hi nese patie nts, t he ge o metric mea n pal b ocicli b A U C i nf a n d C ma x were 2 3 8 6 
n g• hr/ m L a n d 8 2. 1 4 n g/ m L , res pecti vely.  Me dia n T ma x was o bser ve d at 7. 9 4 h o urs p ost d ose.  
Pal b ocicli b was eli mi nate d sl o wl y  wit h a n arit h metic mea n t½ of 2 3. 4 6 h o urs, a n d a 
ge o metric mea n C L/ F ( A p pare nt Cleara nce ) of 5 2. 4 0 L / hr, a n d t he 
 L, i n dicati n g t hat pal b ocicli b e xte nsi vel y 
distri b utes t o peri p heral tiss ues. F oll o wi n g m ulti ple- d ose a d mi nistrati o n of pal b ocicli b 
1 2 5 m g + letr oz ole 2. 5 m g Q D oral d oses t o stea d y state i n C hi nese patie nts, t he ge o metric 
mea n pal b ocicli b A U C τ a n d C ma x were 2 5 0 1 n g• hr/ m L  a n d 1 3 9. 7 n g/ m L, res pecti vely, wit h 
t he me dia n Tma x at 6. 0 5 h o urs p ost d ose.  At stea d y  state, t he e x p os ure of pal b ocicli b 
i ncrease d by a p pr o xi matel y 2 -f ol d c o m pare d t o t hat of si n gle-d ose.  Pal b ocicli b e x hi bite d 
li near P K after m ulti ple d osi n g.  T he ge o metric mea n C L/ F a n d 
 f oll o wi n g m ulti ple 
d osi n g were 4 9. 9 7 L/ hr a n d  
 L , res pecti vel y, a n d t he mea n h a lf life was 2 7. 2 6 h o urs.
 
C CI
C CI
C CI

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 9
Me dia n tr o u g h c o nce ntrati o ns f or plas ma letr oz ole ra n ge d fr o m 8 3. 7 0 n g/ m L t o 9 7. 4 0
n g/ m L 
f oll o wi n g m ulti ple-d ose Q D a d mi nistrati o n of pal b ocicli b 1 2 5 m g + letr oz ole 2. 5 m g oral 
d osi n g.
T he o n -tar get effect of pal b ocicli b meas ure d b y  p har mac o d y n a mic mar kers ( Ki 6 7 a n d p R b of 
s ki n a n d t h ymi di ne ki nase acti vit y of ser u m) c o nsiste ntl y s h o we d re d ucti o ns d uri n g 3 wee ks 
treat me nt of pal b ocicli b + letr oz ole a n d re b o u n de d d uri n g 1 wee k off-treat me nt wee k, 
s u g gesti n g C K K 4/ 6 C D K 4/ 6 i n hi biti o n a n d s u bse q ue nt pr o hi biti o n of cell c ycle pr o gressi o n 
b y  pal b ocicli b.
T he t o xicit y  of pal b ocicli b i n c o m bi nati o n wit h letr oz ole treat me nt was t olera ble a n d 
ma na gea ble i n C hi nese fe male patie nts wit h E R( +)/ H E R 2(- ) A B C i n t his st u d y.  T he m ost 
c o m m o n cl ustered treat me nt-e mer ge nt a d verse e ve nts ( T E A Es ) o bser ve d f oll o wi n g treat me nt 
wit h pal b ocicli b pl us letr oz ole were N E U T R O P E NI A, L E U K O P E NI A, A N E MI A a n d 
T H R O M B O P E NI A.
T he m ost c o m m o n Gra de 3/ 4 T E A Es o bser ve d f oll o wi n g treat me nt 
wit h pal b ocicli b pl us letr oz ole we re N E U T R O P E NI A a n d L E U K O P E NI A.
 
T he efficac y  res ult of A 5 4 8 1 0 1 9 is c o m para ble wit h gl o bal st u dies.3 0 O ne ( 1) patie nt 
ac hie ve d a c o m plete res p o nse.  F o ur ( 4) patie nts ac hie ve d a c o nfir me d partial res p o nse a n d 
1 5 patie nts ha d sta ble disease a m o n g t he 2 6 patie nts wit h A B C e val uate d i n t his st u d y .  T he 
o bjecti ve res p o nse rate was 1 9. 2 % ( 9 5 % CI: 6. 6, 3 9. 4) a n d t he disease c o ntr ol rate was 
6 5. 4 % ( 9 5 % CI: 4 4. 3, 8 2. 8).  T here were 6 5. 4 % patie nts ac hie ve d a P F S e ve nt a n d me dia n 
P F S was 1 8. 6 m o nt hs .
Gi ve n t he c o m pleti o n of t he pri mar y  o bjecti ve a n d all of t he sec o n dar y o bjecti ve s of t he 
st u d y, t he ma na ge me nt of patie nts w h o are still recei vi n g acti ve treat me nt will be m o difie d.
U p o n I R B/I E C a p pr o val of A me n d me nt 3, cli nical assess me nts will be re d uce d i n sc o pe a n d 
t he re q uire d sc he d ule of acti vities is pr o vi de d i n A p pe n di x 9 .  G ui da nce o n ma na ge me nt of 
t hese patie nts is s u m marize d bel o w.
U p o n a p pr o val of A me n d me nt 3 , t u m or assess me nts will be perf or me d at e ver y 6 c ycles
(7 d a y s), a differe nt sc he d ule t ha n t he ori ginal pr ot oc ol , or as i n dicate d b y  t he p h ysicia n 
acc or di n g t o t he patie nt’s cli nical c o n diti o ns. Selecti o n of i ma gi n g st u dies will de pe n d o n 
treati n g p hys icia n a n d ra di ol o gist as per l ocal i nstit uti o nal practice. Res p o nse E val uati o n 
Criteria i n S oli d T u m or s (R E CI S T ) 1. 1 ma y  c o nti n ue t o be use d t o e val uate i ma gi n g 
assess me nts at t he i n vesti gat or’s discreti o n b ut will n o l o n ger be ma n dat or y. Assess me nts of 
t u m or lesi o ns [ie, tar get lesi o n(s), n o n-tar get lesi o n(s) a n d tar get l ym p h n o de(s)] will n o 
l o n ger be rec or de d i n t he Case Re p ort F or m ( C R F ), n or will t he R E CIS T assess me nts. O nl y  
t he date of pr o gressi o n of disease will be rec or de d.
C o nsi deri n g t hat t he res ults fr o m t he safet y a nal yses fr o m t his st u d y ha ve bee n c o nsiste nt
wit h t he k n o w n safet y pr ofile of p al b ocicli b a n d n o ne w safet y fi n di n gs ha ve bee n i de ntifie d,
u p o n I R B/I E C a p pr o val of A me n d me nt 3 , bl o o d c he mistr y will o nl y nee d t o be m o nit ore d o n
D a y  1 of e ver y 3 c ycles. A d diti o nall y , he m o gl o bi n A 1c will n o l o n ger be re q uire d t o be 
 
C CI

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 0
meas ure d e ver y  3 m o nt hs fr o m t he date of ra n d o mizati o n (ie, C 4 D 1, C 7 D 1, etc.) b ut is 
re q uire d t o be c ollecte d at t he e n d of treat me nt visit. A d diti o nal u nsc he d ule d he mat ol o g y  
a n d bl o o d c he mistr y pa nels ma y be c ollecte d as cli nicall y i n dicate d a n d res ults will be 
rec or de d o n t he a p pr o priate C R F.
Fi nall y , dr u gs k n o w n t o pr ol o n g Q T i nter val were re m o ve d fr o m t he “ Pr o hi bite d 
Me dicati o ns” Secti o n 5. 4. 1 a n d a d de d u n der Per mitte d Me dicati o ns Secti o n 5. 4. 3 t o reflect 
res ults fr o m St u d y A 5 4 8 1 0 0 8 s h o wi n g t hat pal b ocicli b, w he n a d de d t o letr oz ole, di d n ot 
pr ol o n g Q T i nter val t o a cli nicall y  mea ni n gf ul e xte nt.2 9
2. S T U D Y O B J E C TI V E S A N D E N D P O I N T S
2. 1. O bjecti ves
Pri m ar y O bjecti ve

T o deter mi ne si n gle -d ose a n d m ulti ple - d ose P K pr ofiles of pal b ocicli b i n c o m bi nati o n 
wit h letr oz ole i n C hi nese patie nts wit h E R( +)/ H E R 2( -) a d va nce d breast ca ncer w h o 
ha ve n ot recei ve d a n y pri or s yste mic a nti-ca ncer t hera p y f or t heir a d va nce d disease. 
Sec o n d ar y O bjecti ves

T o e val uate safet y of pal b ocicli b i n c o m bi nati o n wit h letr oz ole i n t his patie nt 
p o p ulati o n.

T o e val uate efficac y  of pal b ocicli b i n c o m bi nati o n wit h letr oz ole i n t his patie nt 
p o p ulati o n.

T o e val uate tr o u g h plas ma c o nce ntrati o n of letr oz ole after m ulti ple d osi n g.

T o e val uate bi o mar ker c ha n ges p ost pal b ocicli b treat me nt a n d t heir c orrelati o n wit h 
dr u g e x p os ure a n d efficac y  e n d p oi nts if data per mit.
2. 2. E n d p oi nts
Pri m ar y E n d p oi nt

Si n gle -d ose ( S D ) P K para meters: C ma x , A U C1 0, A U C2 4 ( = A U C s d,τ), A U Clast, A U Ci nf, 
T ma x , Vz/ F, Kel, t1/ 2, M R T, C L/ F.

M ulti ple -d ose ( M D) P K para meters : C ss, mi n, Css, ma x, Css,a v, A U Css,τ, Tss, ma x, Vz/ F, t1/ 2, 
C L / F, P T F ( = D F), Rac, a n d Rss.
Sec o n d ar y E n d p oi nts

A d verse eve nts as c haracterize d b y ty pe, fre q ue nc y, se verit y (as gra de d b y 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 ) v. 4. 0) , ti mi n g, 
seri o us ness a n d relati o ns hi p t o st u d y t hera p y;
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 1

La b orat or y  a b n or malities as c haracterize d b y ty pe, fre q ue nc y, se verit y ( as gra de d b y 
N CI  C T C A E v. 4 .0 ) a n d ti mi n g;

C orrecte d Q T i nter val ( Q Tc);

Pr o gressi o n -Free S ur vi val ( P F S); 

O bjecti ve Res p o nse ( O R: C o m plete Res p o nse [ C R] or Partial Res p o nse [ P R]); 

Disease C o ntr ol ( D C: C R + P R + Sta ble disease 2 4 wee ks);

D urati o n of Res p o nse ( D R) ;

1 -ye ar P F S Pr o ba bilit y;

Tr o u g h plas ma c o nce ntrati o n of letr oz ole;

S ki n bi o mar kers p h os p h or y late d reti n o blast o ma pr otei n ( p R b) a n d Ki 6 7 e x pressi o n; 
bl o o d bi o mar ker t h y m i di ne ki nase [ T K] acti vit y.
3. S T U D Y D E SI G N
T his is a si n gle -c o u ntr y, n o n-ra n d o mize d, o pe n-la bel, si n gle-ar m, m ultice nter P hase 1 
cli nical trial w hic h will e val uate P K, safet y a n d efficac y of pal b ocicli b i n c o m bi nati o n wit h 
letr oz ole i n p ost me n o pa usal C hi nese w o me n wit h E R( +)/ H E R 2 ( -) A B C.
A mi ni m u m of a p pr o xi matel y 2 5 patie nts will be e nr olle d t o t he st u d y a n d patie nts ma y  be 
re place d if t here are less t ha n 1 2 patie nts c o m pleti n g t he si n gle-d ose a n d m ulti ple -d ose P K 
sa m ple c ollecti o ns wit h o ut d osi n g i nterr u pti o n or d ose m o dificati o n.
Si n gle -d ose P K ( Lea d -i n p hase, t otal 5 da ys) will be c o n d ucte d pri or t o m ul ti ple-d ose P K 
( C ycle 1). O n D a y  1 of t he si n gle-d ose P K part ( Lea d -i n p hase), patie nts will recei ve a 
si n gle oral d ose of pal b ocicli b 1 2 5 m g a n d letr oz ole 2. 5 m g.  Fr o m Da y 2 t o Da y 5, patie nts 
will recei ve letr oz ole 2. 5 m g al o ne o n ce dail y as a bac k gr o u n d t hera p y. Fr o m C y cle 1 D a y 1 
( C 1 D 1), patie nts will recei ve pal b ocicli b 1 2 5 m g o nce daily orall y f or 3 wee ks f oll o we d b y 
1 wee k off treat me nt a n d letr oz ole 2. 5 m g o nce dail y  orally c o nti n u o usl y.  Patie nts wil l 
re mai n o n st u d y treat me nt wit h c o m bi nati o n treat me nt of pal b ocicli b a n d letr oz ole u ntil 
disease pr o gressi o n, u nacce pta ble t o xicit y , wit h dra wal of c o nse nt, or deat h , w hic he ver occ urs 
first. H o we ver, patie nts ma y  c o nti n ue t he st u d y treat me nt be yo n d t he ti me of 
R E CI S T -defi ne d dis ease pr o gressi o n at t he discreti o n of t he i n vesti gat or if t hat is c o nsi dere d 
t o be i n t he best i nterest of t he patie nt a n d as l o n g as n o ne w a ntica ncer treat me nt is i nitiate d.  
I n t his case, t he patie nt w o ul d c o nti n ue wit h r o uti ne safety rele va nt assess me n ts as per t he 
Sc he d ule of Acti vities f or t he acti ve treat me nt peri o d. 
Patie nts will be scree ne d wit hi n 2 8 da y s of t he first d ose of st u d y me dicati o n.  Patie nts will 
be a d mitte d t o t he cli nical researc h u nit ( C R U) at least 1 2 h o urs p ri or t o Da y 1 d osi n g i n 
Lea d -i n p hase a n d re mai n i n t he C R U u ntil at least 7 2 h o urs p ost-d ose o n Da y  4 i n Lea d-i n 
p hase f or P K sa m pli n gs bef ore disc har ge (t he d urati o n of c o nfi ne me nt is s u bject t o c ha n ge 
gi ve n t he a vaila bilit y  of C R U).  Patie nts will ret urn t o t he C R U as o ut patie nt visits o n Da y 5 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 2
( Lea d-i n p hase) f or m or ni n g P K sa m ple c ollecti o n at 9 6 h o urs p ost-d ose a n d o n C 1 D 1 f or 
pre d ose m or ni n g P K sa m ple c ollecti o n ( 1 2 0 h o urs p ost si n gle d ose).  D uri n g C ycle 1, 
patie nts will visit t he C R U f or he mat ol o g y e val uati o n o n Da y 1 4 a n d tr o u g h P K sa m ple 
c ollecti o n ( pre d ose) o n Da y 1 9.  Patie nts will ret ur n t o t he C R U o n C 1 D 2 0 f or tr o u g h P K 
sa m ple c ollecti o n ( pre d ose) a n d re mai n i n t he C R U u ntil C 1 D 2 4 f or P K sa m ple c ollecti o n 
bef ore disc har ge (t he d urati o n of c o nf i ne me nt is s u bject t o c ha n ge gi ve n t he a vaila bilit y of 
C R U).  Patie nts will visit t he C R U o n Da ys 2 5, 2 6 of C y cle 1a n d C 2 D 1 f or m or ni n g tr o u g h 
P K sa m ple c ollecti o n ( pre d ose).
Bl o o d sa m ples f or deter mi nati o n of pal b ocicli b c o nce ntrati o ns will be c ollecte d a t 2, 4, 6, 8, 
1 0, 2 4, 4 8, 7 2, 9 6, a n d 1 2 0 h o urs after si n gle -d ose pal b ocicli b a d mi nistrati o n f or si n gle -d ose 
P K i n L ea d-i n p hase a n d after pal b ocicli b d ose o n C 1 D 2 1 f or m ulti ple-d ose P K.  Tr o u g h 
bl o o d sa m ples ( pre d ose) f or b ot h pal b ocicli b a n d letr oz ole wi ll be c ollecte d o n Da ys 1 9-2 1 of 
C y cle 1.  A n a d diti o nal tr o u g h bl o o d sa m ple ( pre d ose) f or letr oz ole will be c ollecte d o n 
C 2 D 1.
U p o n a p pr o val of A me n d me nt 3, t u m or assess me nts will be perf or me d e ver y  6 c ycles or as 
rec o m me n de d by t he p h ysicia n acc or di n g t o t he patie nt’s cli nical c o n diti o ns w hic h ma y  be 
differe nt fr o m t he ori gi nal pr ot oc ol . Selecti o n of i ma gi n g st u dies will de pe n d o n treati n g 
p h y sicia n a n d ra di ol o gist as per l ocal practice. R E CI S T 1. 1 ma y  c o nti n ue t o be use d t o 
e val uate i ma gi n g assess me nts at t he i n vesti gat or’s discreti o n b ut will n o l o n ger be ma n dat or y.  
Assess me nts of t u m or lesi o ns [ie, tar get lesi o n(s), n o n -tar get lesi o n(s) a n d tar get ly m p h 
n o de(s)] will n o l o n ger be rec or de d i n t he C R F, n or will t he R E CI S T assess me nts. O nl y  t he 
date of pr o gressi o n of disease will be rec or de d.   T u m or assess me nts will be perf or me d u ntil 
ra di o gra p hicall y a n d/ or cli nicall y (ie, f or p h ot o gra p he d or pal pa ble lesi o ns) d oc u me nte d 
disease pr o gressi o n, st u d y treat me nt disc o nti n uati o n (f or patie nts c o nti n ui n g trea t me nt 
be y o n d - disease pr o gressi o n), i nitiati o n of ne w a ntica ncer t hera p y or disc o nti n uati o n of 
patie nt fr o m o verall st u d y  partici pati o n (e g, deat h, patie nt's re q uest, l ost t o f oll o w-u p), 
w hic he ver occ urs first.  A series of i nc o m plete disease assess me nts w ill res ult i n ce ns ori n g of 
P F S bac k t o t he ti me of t he last f ull assess me nt t hat di d n ot s h o w disease pr o gressi o n. 
T he st u d y  als o i ncl u des tra nslati o nal c o m p o ne nts ai me d at c haracterizi n g alterati o ns i n 
pr otei ns rele va nt t o t he cell c y cle, dr u g tar gets, a n d patie nt res p o nse o ver ti me. L o n git u di nal 
m o nit ori n g of pal b ocicli b p har mac o d y n a mic mar ker m o d ulati o n, s uc h as p h os p h or y late d 
reti n o blast o ma pr otei n ( p R b) a n d Ki 6 7 e x pressi o n usi n g s ki n bi o psies a n d t h ymi di ne ki nase 
( T K) acti vit y usi n g ser u m sa m ples will all o w c haracterizi n g t he relati o ns hi p a m o n g P K, 
bi o mar ker, a n d patie nt cli nical res p o nse.  T he d urati o n a n d ma g nit u de of cell c y cle i n hi biti o n 
after pal b ocicli b treat me nt ma y als o be o btai ne d.  T his bi o mar ker a nal ysis will be critical f or 
better u n dersta n di n g of t he mec ha nis m of acti o n of pal b ocicli b i n breast ca ncer patie nts, a n d 
ma y  als o p ote ntiall y i de ntif y patie nts wit h better res p o nse t o pal b ocicli b treat me nt.
4. P A TI E N T S E L E C TI O N
T his st u d y  ca n f ulfill its o bjecti ves o nl y if a p pr o priate patie nts are enr olle d.  T he f oll o wi n g 
eli gi bilit y criteria are desi g ne d t o select patie nts f or w h o m pr ot oc ol treat me nt is c o nsi dere d 
a p pr o priate.  All rele va nt me dical a n d n o n -me dical c o n diti o ns s h o ul d be ta ke n i nt o 
c o nsi derati o n w he n deci di n g w het her t his pr ot oc ol is s uita ble f or a partic ular patie nt.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 3
4. 1. I ncl usi o n Criteri a
Patie nt eli gi bilit y  s h o ul d be re vie we d a n d d oc u me nte d b y a n a p pr o priately q ualifie d me m ber 
of t he i n vesti gat or’s st u d y  tea m bef ore patie nts are i ncl u de d i n t he st u d y. Patie nts m ust meet 
all of t he f oll owi n g i ncl usi o n criteria t o be eli gi ble f or e nr oll me nt i nt o t he st u d y :
1.
P ost me n o pa usal a d ult (a ges 1 8 -6 5 y ears, i ncl usi ve) C hi nese w o me n wit h pr o ve n 
dia g n osis of a de n ocarci n o ma of t he breast wit h e vi de nce of l oc ore gi o nall y rec urre nt or 
metastatic disease n ot a me na ble t o resecti o n or ra diati o n t hera p y wit h c urati ve i nte nt a n d 
f or w h o m c he m ot hera py is n ot cli nicall y i n dicate d.  T he details of criteria are s pecifie d 
bel o w:
a.
P ost me n o pa usal w o me n defi ne d as w o me n w h o ha ve u n der g o ne:
i.
Pri or d oc u me nte d bilateral s ur gi cal o o p h orect o m y; or 
ii.
S p o nta ne o us cessati o n of re g ular me nses f or at least 1 2 c o nsec uti ve m o nt hs wit h 
n o alter nati ve pat h ol o gical or p h ysi ol o gical ca use, c o nfir me d wit h 
f ollicle-sti m ulati n g h or m o ne ( F S H) a n d estra di ol bl o o d le vels i n t heir res pecti ve 
p ost m e n o pa usal ra n ges .
b.
D oc u me ntati o n of hist ol o gicall y  or c yt ol o gically c o nfir me d dia g n osis of E R( +) breast 
ca ncer base d o n l ocal la b orat or y  res ults.
c.
D oc u me ntati o n of H E R 2( -) breast ca ncer base d o n l ocal la b orat or y res ults.
d.
Pre vi o usl y  u ntreate d wit h a n y  sys te mic a nti-ca ncer t hera p y f or t heir l oc ore gi o nall y 
rec urre nt or metastatic E R + disease.
2.
Meas ura ble disease as defi ne d per R E CI S T v. 1. 1 or b o ne- o nl y disease ( wit h b o ne lesi o ns 
c o nfir me d b y c o m p ute d t o m o gra p h y [ C T], Ma g netic Res o na nce I ma gi n g [ M RI ] or b o ne 
X- ray) .  T u m or lesi o ns pre vi o usl y irra diate d or s u bjecte d t o ot her l oc ore gi o nal t hera p y 
will o nl y  be dee me d meas ura ble if disease pr o gressi o n at t he treate d site after c o m pleti o n 
of t hera p y is clearl y d oc u me nte d.
3.
Easter n C o o perati ve O nc ol o g y  Gr o u p perf or ma nce stat us 0- 1.
4.
A de q uate or ga n a n d marr o w f u ncti o n defi ne d as f oll o ws:

A N C 1, 5 0 0/ m m 3 ( 1. 5 x 1 0 9 / L);

Platelets 1 0 0, 0 0 0/ m m 3 ( 1 0 0 x 1 0 9 / L);

He m o gl o bi n 9 g/ d L ( 9 0 g/ L);

Ser u m creati ni ne 1. 5 x U L N (U p per Li mit of N or mal ) or esti mate d creati ni ne 
cleara nce ≥6 0 m L / mi n as calc ulate d usi n g t he met h o d sta n dar d f or t he i nstit uti o n;

T otal ser u m bilir u bi n 1. 5 x U L N (3. 0 x U L N if Gil bert’s disease);
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 4

A S T a n d/ or A L T 3 x U L N (5. 0 x U L N if li ver metastases prese nt);

Al kali ne p h os p hatase 2. 5 x U L N ( 5. 0 x U L N if b o ne or li ver metastases prese nt). 
5.
Res ol uti o n of all ac ute t o xic effects of pri or a nti -ca ncer t hera p y or s ur gical pr oce d ures t o 
baseli ne se verit y  or N CI C T C A E versi o n 4. 0 Gra de 1 (e xce pt al o pecia or ot her 
t o xicities n ot c o nsi dere d a safety ris k f or t he patie nt at i n vesti gat or's discreti o n)
6.
Willi n g ness a n d a bilit y  t o c o m pl y wit h sc he d ule d visits, treat me nt pla n, la b orat or y tests, 
a n d ot her trial pr oce d ures.
7.
E vi de nce of a pers o nall y  si g ne d a n d date d i nf or me d c o nse nt d oc u me nt i n dicati n g t hat t he 
patie nt has bee n i n f or me d of all t he perti ne nt as pects of t he trial pri or t o e nr oll me nt.
4. 2. E xcl usi o n Criteri a
Patie nts prese nti n g wit h a n y  of t he f oll o wi n g will n ot be i ncl u de d i n t he st u d y:
1.
H E R 2 -p ositi ve t u m or as defi ne d b y d oc u me ntati o n of er b B -2 ge ne a m plificati o n b y  
FI S H (as defi ne d by a H E R 2/ C E P 1 7 rati o 2) or c hr o m o ge nic i n sit u h y bri dizati o n 
( CIS H, as defi ne d b y  t he ma n ufact urer’s kit i nstr ucti o n) or d oc u me ntati o n of 
H E R 2 -o vere x pressi o n b y I H C ( defi ne d as I H C 3 +, or I H C 2 + wit h FI S H or CI S H 
c o nfir mati o n) base d o n l ocal la b orat or y  res ults. 
2.
P atie nts wit h a d va nce d, s y m pt o matic, visceral s prea d, t hat are at ris k of 
life-t hreate ni n g c o m plicati o ns i n t he s h ort ter m (i ncl u di n g patie nts wit h massi ve 
u nc o ntr olle d eff usi o ns [ ple ural, pericar dial, perit o neal], p ul m o nar y l y m p ha n gitis , a n d 
o ver 5 0 % li ver i n v ol ve me nt).
3.
K n o w n a cti ve u nc o ntr olle d or s y m pt o matic C N S metastases, as i n dicate d b y cli nical 
s ym pt o ms, cere bral e de ma, s pi nal c or d c o m pressi o n, carci n o mat o us me ni n gitis, 
le pt o me ni n geal disease a n d/ or pr o gressi ve gr o wt h.  Patie nts wi t h a hist or y of C N S 
metastases or c or d c o m pressi o n are eli gi ble if t he y ha ve bee n defi niti vel y treate d a n d 
are cli nicall y sta ble off a ntic o n v ulsa nts a n d ster oi ds f or at least 4 wee ks bef ore t he 
first d ose of pal b ocicli b.
4.
P ri or ne oa dj u va nt or a dj u va nt treatme nt wit h a n o n -ster oi dal ar o matase i n hi bit or 
(ie, a nastr oz ole or letr oz ole) wit h disease pr o gressi o n or rec urre nce w hile o n or 
wit hi n 1 2 m o nt hs fr o m c o m pleti n g treat me nt.
5.
P ri or treat me nt wit h a ny C D K 4/ 6 i n hi bit or.
6.
K n o w n mala bs or pti o n s y n dr o me or ot her c o n diti o n t hat ma y  i m pair a bs or pti o n of 
pal b ocicli b .
7.
P atie nts treate d wit hi n t he last 7 da ys pri or t o st u d y e ntr y wit h: 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 5

F o o d or dr u gs t hat are k n o w n t o be str o n g C Y P 3 A 4 i n hi bit ors (ie, a m pre na vir, 
ataza na vir, b oce pre vir, clarit hr o m y ci n, c o ni va pta n, dela vir di ne, diltiaze m, 
er yt hr o m y ci n, f osa m pre na vir, i n di na vir, itrac o naz ole, ket oc o naz ole, l o pi na vir, 
mi befra dil, mic o naz ole, nefaz o d o ne, nelfi na vir, p osac o naz ole, rit o na vir, 
sa q ui na vir, tela pre vir, telit hr o m yci n, vera pa mil, v oric o naz ole, a n d gra pefr uit or 
gra pefr uit j uice) .

Dr u gs t hat are k n o w n t o be str o n g C Y P 3 A 4 i n d ucers (ie, car ba maze pi ne, 
fel ba mate, ne vira pi ne, p he n o bar bital, p he nyt 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). 

Dr u gs t hat are k n o w n t o pr ol o n g t he Q T i nter val. 
8.
Maj or s ur ger y , c he m ot hera p y, ra di ot hera py, a n y i n vesti gati o nal a ge nts, or ot her 
a nti-ca ncer t hera p y wit hi n 2 wee ks bef ore st u d y e ntr y.  Patie nts w h o recei ve d pri or 
ra di ot hera py t o 2 5 % of b o ne marr o w are n ot eli gi ble i n de pe n de nt of w he n it was 
recei ve d (see 1 7. 5 A p pe n di x 5 ).
9.
Dia g n osis of a n y ot her mali g na nc y wit hi n 3 years pri or t o st u d y e ntr y, e xce pt f or 
a de q uatel y treate d basal cell or s q ua m o us cell s ki n ca ncer, or carci n o ma i n sit u of t he 
cer vi x.
1 0. Q Tc i nter val > 4 8 0 msec ( base d o n t he mea n val ue of t he tri plicate scree ni n g 
electr ocar di o gra m [ E C Gs]); fa mil y or pers o nal hist or y of l o n g or s h ort Q T s yn dr o me; 
hist or y  of cli nicall y si g nifica nt ve ntric ular d ysr hyt h mias, or c urre ntl y u n der treat me nt 
wit h a nti- arr h yt h mic me dicati o n or i m pla nte d defi brillati o n de vice f or ve ntric ular 
d y sr hyt h mias .
1 1. U nc o ntr olle d electr ol yt e dis or ders t hat ca n c o m p o u n d t he effects of a Q Tc -pr ol o n gi n g 
dr u g (e g, h y p ocalce mia, h y p o kale mia, h y p o ma g nese mia).
1 2. A n y  of t he f oll owi n g wit hi n 6 m o nt hs of st u d y e ntr y: my ocar dial i nfarcti o n, 
se vere/ u nsta ble a n gi na, o n g oi n g car diac dys r hyt h mias of N CI  C T C A E versi o n 4. 0 
Gra de 2, atrial fi brillati o n of a n y  gra de, c or o nar y/ peri p heral arter y b ypass graft, 
s ym pt o matic c o n gesti ve heart fail ure, cere br o vasc ular acci de nt i ncl u di n g tra nsie nt 
isc he mic attac k, or s ym pt o matic p ul m o nar y  e m b olis m.
1 3. Acti ve i nfla m mat or y  b o wel disease or c hr o nic diarr hea, s h ort b o wel sy n dr o me, or a n y 
u p per gastr oi ntesti nal s ur ger y  i ncl u di n g gastric resecti o n.
1 4. K n o w n h y p e rse nsiti vit y t o letr oz ole, or a n y of its e xci pie nts, or t o a n y pal b ocicli b
e xci pie nts.
1 5. Acti ve a n d cli nicall y si g nifica nt bacterial, f u n gal or viral i nfecti o n i ncl u di n g he patitis 
B ( H B V), he patitis C ( H C V), k n o w n h u ma n i m m u n o deficie nc y vir us ( HI V) or 
ac q uire d i m m u n o deficie nc y sy n dr o me ( AI D S) -relate d ill ness.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 6
1 6. Ot her se vere ac ute or c hr o nic me dical or ps yc hi atric c o n diti o n or la b orat or y 
a b n or malit y t hat ma y i ncrease t he ris k ass ociate d wit h st u d y partici pati o n or 
i n vesti gati o nal pr o d uct a d mi nistrati o n or ma y i nterfere wit h t he i nter pretati o n of 
st u d y res ults a n d, i n t he j u d g me nt of t he i n vesti gat or, w o ul d ma ke t he patie nt 
i na p pr o priate f or e ntr y i nt o t his st u d y.
1 7. Patie nts w h o are i n vesti gati o nal site staff me m bers directl y i n v ol ve d i n t he c o n d uct of 
t he st u d y a n d t heir fa mil y me m bers, site staff me m bers ot her wise s u per vise d b y t he 
I n vesti gat or, or patie nts w h o are Pfizer e m pl oye es directl y i n v ol ve d i n t he c o n d uct of 
t he trial.
1 8. Partici pati o n i n a n y ot her st u dies wit hi n 4 wee ks bef ore st u d y e ntr y a n d/ or d uri n g 
parti ci pati o n i n t he acti ve treat me nt p hase of t he trial.
1 9. Rece nt or acti ve s uici dal i deati o n or be ha vi or. 
4. 3. R a n d o miz ati o n Criteri a

Patie nts will be ra n d o mize d o n Da y  -1 i nt o t w o gr o u ps ass ociate d wit h differe nt s ki n 
bi o ps y  sc he d ules, pr o vi de d t he y ha ve satisfie d all patie nt selecti o n criteria.

T he i n vesti gat ors or t heir pre -s pecifie d desi g nee will ra n d o mize eli gi ble patie nts b y 
i nteracti ve ra n d o mizati o n tec h n ol o g y (IR T) as descri be d i n t he St u d y  Refere nce 
Ma n ual.

T he ce ntral c o m p uterize d s y ste m will pr o vi de t he ra n d o mizati o n n u m ber a n d 
assi g n me nt of s ki n bi o ps y sc he d ule.
4. 4. Life St yle G ui deli nes
T he f oll o wi n g g ui deli nes are pr o vi de d:
4. 4. 1. Alc o h ol, C affei ne , C hi nese Her b al Me dici ne a n d E xercise f or P K E v al u ati o n

Patie nt s will a bstai n fr o m alc o h ol f or 2 4 h o urs pri or t o a d missi o n t o t he C R U a n d 
c o nti n ue a bstai ni n g fr o m alc o h ol u ntil c ollecti o n of t he last p har mac o ki netic sa m ple.   
A n alc o h ol breat h test is n ot re q uire d b ut ma y  be c o n d ucte d at t he discreti o n of t he 
i n vesti gat or.

Patie nt s will a bstai n fr o m caffei ne-c o ntai ni n g p r o d ucts f or 2 4 h o urs pri or t o t he start 
of d osi n g u ntil c ollecti o n of t he last p har mac o ki netic sa m ple. 

Patie nt s will a bstai n fr o m stre n u o us e xercise (e g, hea vy lifti n g, wei g ht trai ni n g, 
calist he nics, aer o bics) f or at least 4 8 h o urs pri or t o eac h bl o o d c ol lecti o n f or cli nical 
la b orat or y tests.  Wal ki n g at a n or mal pace will be per mitte d.

N o C hi nese her bal me dici nes will be all o we d d uri n g P K p orti o n. 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 7
4. 4. 2. Me als a n d Diet ar y Restricti o ns f or P K E v al u ati o n

Pal b ocicli b a n d letr oz ole s h o ul d be a d mi nistere d t o get her w it h f o o d.

O n Da y  1 i n Lea d-i n p hase a n d Da y 2 1 i n Cycle 1 w he n i nte nsi ve P K sa m ples are 
c ollecte d, si milar brea kfast s h o ul d be pr o vi de d t o patie nts a p pr o xi matel y  3 0 mi n utes 
pri or t o t he a d mi nistrati o n of pal b ocicli b ( brea kfast starte d at a p pr o xi matel y 
0 9 3 0 A M).  Brea kfast will be c o ns u me d wit hi n a 2 0- mi n ute peri o d wit h st u d y  dr u gs 
a d mi nistere d a p pr o xi matel y 1 0 mi n utes after c o m pleti o n of t he meal.  At least 8 0 % of 
t he pr o vi de d brea kfast s h o ul d be c o ns u me d pri or t o pal b ocicli b a d mi nistrati o n.  T he 
pr o vi de d b rea kfast s h o ul d be m o derate-fat sta n dar d-cal orie meal (a p pr o xi matel y 
1 5 % pr otei n, 5 0 % car b o h y drate, 3 5 % fat diet f or a t otal of 5 0 0 -7 0 0 cal ories).  L u nc h 
a n d di n ner will be pr o vi de d a p pr o xi matel y  4 h o urs a n d 9 h o urs after pal b ocicli b 
d osi n g.

N o n -caffei nated dri n ks (e xce pt gra pefr uit or gra pefr uit- relate d citr us fr uit j uices – see 
bel o w) ma y  be c o ns u me d wit h meals a n d t he e ve ni n g s nac k.

A n e ve ni n g s nac k ma y  be per mitte d.

Patie nts will n ot be all o we d t o eat or dri n k gra pefr uit or gra pefr uit- relate d citr us fr uits 
(e g, Se ville ora n ges, p o mel os) fr o m 7 da ys pri or t o t he first d ose of st u d y me dicati o n 
u ntil c ollecti o n of t he last P K bl o o d sa m ple. 

W hile c o nfi ne d, t he rec o m me n de d t otal dail y  n utriti o nal c o m p ositi o n s h o ul d be 
a p pr o xi matel y 5 0 % car b o h ydrate, 3 5 % fat a n d 1 5 % pr otei n.  T he dail y cal oric i nta ke 
per patie nt s h o ul d n ot e xcee d a p pr o xi matel y 3 2 0 0 kcal.
4. 5. S p o ns or Q u alifie d Me dic al Pers o n nel
T he c o ntact i nf or mati o n f or t he s p o ns or's a p pr o priatel y q ualifie d me dical pers o n nel f or t he 
st u d y is d oc u me nte d i n t he stu d y  c o ntact list i n t he tea m s hare p oi nt st u d y p ortal s pace.  T o 
facilitate access t o a p pr o priatel y q ualifie d me dical pers o n nel o n st u d y relate d me dical 
q uesti o ns or pr o ble ms, patie nts are pr o vi de d wit h a c o ntact car d.  T he c o ntact car d c o ntai ns, 
at a mi ni m u m, pr ot oc ol a n d i n vesti gati o nal c o m p o u n d i de ntifiers, patie nt st u d y  n u m ber, 
c o ntact i nf or mati o n f or t he i n vesti gati o nal site a n d c o ntact details f or a hel p des k i n t he e ve nt 
t hat t he i n vesti gati o nal site staff ca n n ot be reac he d t o pr o vi de a d vice o n a me dical q uesti o n 
or pr o ble m ori gi nati n g fr o m a n ot her healt hcare pr ofessi o nal n ot i n v ol ve d i n t he patie nts 
partici pati o n i n t he st u d y .  T he hel p des k n u m ber ca n als o be use d b y i n vesti gati o nal staff if 
t he y are see ki n g a d vice o n me dical q uesti o ns or pr o ble ms, h o we ver it s h o ul d o nl y be use d i n 
t he e ve nt t hat t he esta blis he d c o m m u nicati o n pat h wa ys bet wee n t he i n vesti gati o nal site a n d 
t he st u d y tea m are n ot a vaila ble.  It is t heref ore i nte n de d t o a u g me nt, b ut n ot re place t he 
esta blis he d c o m m u nicati o n pat h wa y s bet wee n t he i n vesti gati o nal site a n d st u d y  tea m f or 
a d vice o n me dical q uesti o ns or pr o ble ms t hat ma y arise d uri n g t he st u d y.  T he hel p des k 
n u m ber is n ot i nte n de d f or use b y t he patie nt directl y a n d if a patie nt calls t hat n u m ber t he y 
will be directe d bac k t o t he i n vesti gati o nal site.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 8
5. S T U D Y T R E A T M E N T S
5. 1. All oc ati o n t o Tre at me nt
T he i n vesti gat or’s k n o wle d ge of t he treat me nt s h o ul d n ot i nfl ue nce t he decisi o n t o e nr oll a 
partic ular patie nt or affect t he or der i n w hic h patie nts are e nr olle d. T he i n vesti gat or will 
assig n patie nt n u m bers se q ue ntiall y  t o t he patie nts as t he y are scree ne d f or t he st u d y.
T he st u d y  will ha ve 1 treat me nt gr o u p.  O n Da y  1 i n t he Le a d-i n p hase (si n gle-d ose P K part ), 
patie nts will recei ve a si n gle oral d ose of pal b ocicli b 1 2 5 m g a n d letr oz ole 2 . 5 m g. Fr o m 
D a y 2 t o Da y  5, patie nts will recei ve letr oz ole 2. 5 m g al o ne o nce dail y as a bac k gr o u n d 
t hera py.  O n C ycle 1 Da y 1 ( C 1 D 1), patie nts will start t he first c ycle of c o m bi nati o n 
treat me nt, pal b ocicli b 1 2 5 m g o nce daily orall y f or 3 wee ks f oll o we d b y  1 wee k off treat me nt 
a n d letr oz ole 2. 5 m g o nce dail y orally c o nti n u o usl y. Patie nts wil l re mai n o n st u d y treat me nt 
wit h c o m bi nati o n treat me nt of pal b ocicli b a n d letr oz ole u ntil disease pr o gressi o n, 
u nacce pta ble t o xicit y , wit h dra wal of c o nse nt, or deat h , w hic he ver occ urs first .
5. 2. Dr u g S u p plies
T he i n vesti gati o nal dr u g use d i n t he c o urse of t his trial is pal b ocicli b.  I n a d diti o n, all patie nts 
will recei ve letr oz ole.  B ot h of t he me dicati o ns will be s u p plie d b y  t he s p o ns or. St u d y  
Ce nters will recei ve a s u p pl y  of t he a p pr o priate i n vesti gati o nal pr o d uct after site acti vati o n.  
Re -s u p plies will be ma de d uri n g t he c o urse of t he st u d y.  T he st u dy m o nit or s h o ul d be 
c o ntacte d f or a n y iss ues relate d t o i n vesti gati o nal pr o d uct s u p plies.
5. 2. 1. F or m ul ati o n a n d P ac k a gi n g
5. 2. 1. 1. P al b ocicli b 
Pal b ocicli b will be s u p plie d as ca ps ules c o ntai ni n g 7 5 m g, 1 0 0 m g, or 1 2 5 m g e q ui vale nts of 
pal b ocicli b free base.  T he s p o ns or will s u p pl y t he oral dr u g f or m ulati o n t o sites i n H D P E 
b ottles c o ntai ni n g 7 5 m g, 1 0 0 m g, or 1 2 5 m g ca ps ules.  T he ca ps ules ca n be differe ntiate d b y  
t heir size a n d c ol or (see bel o w).
T a ble 4. 
P al b ocicli b C a ps ule C h ar acteristics
D os a ge
C a ps ule c ol or
C a ps ule size
7 5 m g
S u nset Yell o w/ S u nset Yell o w
2
1 0 0 m g 
Cara mel/ S u nset Yell o w
1
1 2 5 m g
Cara mel/ Car a mel
0
5. 2. 1. 2. Letr oz ole
C o m merciall y  a vaila ble letr oz ole 2. 5 m g fil m -c oate d ta blets will be s o urce d l ocall y .  
C o m plete i nf or mati o n a b o ut letr oz ole f or m ulati o n ca n be f o u n d i n t he l ocal pac ka ge i nsert.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 9
5. 2. 2. Pre p ar ati o n a n d Dis pe nsi n g
5. 2. 2. 1. P al b ocicli b
Pal b ocicli b will be pr o vi de d i n n o n- patie nt s pecific b ottles c o ntai ni n g eit her 7 5 m g, 1 0 0 m g  
or 1 2 5 m g ca ps ules.  T he patie nt n u m ber s h o ul d be rec or de d o n t he b ottle la bel 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 patie nt. Site pers o n nel m ust e ns ure
t hat patie nts clearly u n dersta n d t he directi o ns f or self -me dicati o n.  Patie nts s h o ul d be gi ve n a 
s ufficie nt s u p pl y t o last u ntil t heir ne xt st u d y visit.  U n use d dr u g a n d/ or e m pt y b ottles s h o ul d 
be ret ur ne d t o t he site at t he ne xt st u d y  visit.  Ret ur ne d u nuse d me dicati o n M U S T N O T be 
re-dis pe nse d t o t he patie nt. Detail i nf or mati o n is pr o vi de d i n t he st u d y  ma n ual.
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.  Patie nts s h o ul d be 
i nstr ucte d t o kee p t heir me dicati o n i n t he b ottles pro vi de d a n d n ot tra nsfer it t o a n y  ot her 
c o ntai ner.  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 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 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 dificati o n, re q uest s h o ul d be ma de of t he patie nt t o ret ur n all pre vi o usl y  
dis pe nse d me dicati o n t o t he cli nic, a n d ne w ca ps ules will be dis pe nse d.
O nl y  q ualifie d pers o n nel w h o are fa miliar wit h pr oce d ures t hat mi ni mize u n d ue e x p os ure t o 
t he msel ves a n d t o t he e n vir o n me nt s h o ul d u n derta ke t he pre parati o n, ha n dli n g, a n d safe 
dis p osal of c he m ot hera pe utic a ge nts.
5. 2. 2. 2. Letr oz ole
Letr oz ole s h o ul d be pre pare d a n d dis pe nse d acc or di n g t o t he pac ka ge i nsert or sta n dar d 
practice at t he st u d y site .  T he patie nt n u m ber s h o ul d be rec or de d o n t he b ottle la bel i n t he 
s paces pr o vi de d by site pers o n nel at t he ti me of assi g n me nt t o patie nt.  Site pers o n nel m ust 
e ns ure t hat patie nts clearl y u n dersta n d t he directi o ns f or self -me dicati o n.  Patie nts s h o ul d be 
gi ve n a s ufficie nt s u p pl y t o last u ntil t heir ne xt st u d y visit.  U n use d dr u g a n d/ or e m pt y b ottles 
s h o ul d be ret ur ne d t o t he site at t he ne xt st u d y visit.
O n l y q ualifie d pers o n nel w h o are fa miliar wit h pr oce d ures t hat mi ni mize u n d ue e x p os ure t o 
t he msel ves a n d t o t he e n vir o n me nt s h o ul d u n derta ke t he pre parati o n, ha n dli n g, a n d safe 
dis p osal of c he m ot hera pe utic a ge nts.
5. 2. 3. A d mi nistr ati o n
5. 2. 3. 1. P al b ocicli b
Pal b ocicli b will be orall y a d mi nistere d dail y f or 3 wee ks f oll o we d by 1 wee k off treat me nt
( Sc he d ule 3/ 1), defi ni n g a treat me nt C y cle t hat is 2 8 da y s i n d urati o n. 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 0
Pal b ocicli b will be orall y a d mi nistere d o nce dail y i n t he m or ni n g wit h f o o d.  O n t he i nte nsi ve 
P K da y s ( Da y 1 i n Lea d-i n p hase a n d Da y 2 1 i n C ycle 1), si milar brea kfast wit h m o derate fat 
a n d sta n dar d cal ories s h o ul d be pr o vi de d t o patie nts a p pr o xi matel y  3 0 mi n utes pri or t o 
a d mi nistrati o n of pal b ocicli b ( brea kfast starte d at a p pr o xi matel y  0 9 3 0 A M).  Brea kfast will
be c o ns u me d wit hi n a 2 0 -mi n ute peri o d wit h st u d y  dr u gs a d mi nistere d a p pr o xi matel y 
1 0 mi n utes after c o m pleti o n of t he meal.  At least 8 0 % of t he pr o vi de d brea kfast s h o ul d be 
c o ns u me d pri or t o pal b ocicli b a d mi nistrati o n.  T he pr o vi de d brea kfast s h o ul d be m o derate -fat 
sta n dar d-cal orie meal (a p pr o xi matel y 1 5 % pr otei n, 5 0 % car b o h ydrate, 3 5 % fat diet f or a t otal 
of 5 0 0 -7 0 0 cal ories).   L u nc h a n d di n ner will be pr o vi de d a p pr o xi matel y  4 h o urs a n d 9 h o urs 
after pal b ocicli b d osi n g.  If i nte nsi ve P K assess me nts are c o n d ucte d i n a later c y cle f or a n y 
reas o n, t he sa me re q uire me nt f or brea kfast i nta ke is a p plie d.  Safety e val uati o n ( vital si g ns, 
la b orat or y safety a n d E C G) s h o ul d be c o n d ucte d bef ore f o o d i nta ke.
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 w h ole 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 s h o ul d be i n geste d if it is br o ke n, crac ke d, or ot her wise n ot 
i ntact.  Patie nts s h o ul d be e nc o ura ge d t o ta ke t heir d ose at a p pr o xi matel y t he sa me ti me eac h 
da y .  Patie nts s h o ul d be i nstr ucte d t o rec or d daily a d mi nistrati o n of t he st u d y dr u gs i n a 
patie nt diar y .
Patie nts e x perie nci n g i n vesti gati o nal pr o d uct relate d t o xicit y  ma y ha ve t heir d ose m o difie d 
acc or di n g t o Secti o n 5. 2. 4. 2 . 
5. 2. 3. 2. Letr oz ole
Letr oz ole will be a d mi nistere d orall y o nce dail y c o nti n u o usl y  t o get her wit h pal b ocicli b.  
Fr o m Da y 2 t o 5 i n Lea d -i n p hase, d uri n g t he off-treat me nt wee k of pal b ocicli b, a n d i n t he 
e ve nt of pal b ocicli b d osi n g i nterr u pti o n, letr oz ole al o ne will be a d mi nistere d. 
5. 2. 3. 3. Ge ner al r ules
F or b ot h pal b ocicli b a n d letr oz ole: 

Patie nts w h o miss a da y ’s d ose e ntirely m ust be i nstr ucte d N O T t o “ ma ke it u p” t he 
ne xt da y .

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 “ ma ke it 
u p,” a n d t o res u me treat me nt t he ne xt da y  as prescri be d. 

Patie nts w h o i na d verte ntl y  ta ke 1 e xtra d ose d uri n g a da y m ust be i nstr ucte d t o s ki p 
t he ne xt da y’s d ose.  Als o refer t o Secti o n 5. 2. 5 f or f urt her details o n me dicati o n 
err ors a n d o ver d ose.
5. 2. 4. Rec o m me n de d D ose M o dific ati o n
E ver y  eff ort s h o ul d be ma de t o a d mi nister st u d y treat me nt o n t he pla n ne d d ose a n d sc he d ule.  
H o we ver, i n t he e ve nt of si g nifica nt treat me nt -relate d t o xicit y, a d mi nistrati o n of st u d y dr u gs 
( pal b ocicli b or letr oz ole) ma y nee d t o be a dj uste d as descri be d i n t he f oll o wi n g secti o ns.  
De pe n di n g o n t he nat ure of t he t o xicit y  o bser ve d, d osi n g a dj ust me nt ma y be re q uire d f or j ust 
o ne or b ot h st u d y  dr u gs i n t he c o m bi nati o n.  In t he e ve nt treat me nt i nterr u pti o n is dee me d 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 1
necessar y  f or j ust o ne of t he st u d y dr u gs i n t he c o m bi nati o n, treat me nt wit h t he ot her st u d y 
dr u g will c o nti n ue as pla n ne d. 
5. 2. 4. 1. Letr oz ole 
N o d ose a dj ust me nt f or letr oz ole is per mitte d b ut d osi n g i nterr u pt i o ns are all o we d.  
Treat me nt i nterr u pti o n f or letr oz ole-relate d t o xicities will be perf or me d as per t he 
i n vesti gat or’s best me dical j u d g me nt. 
Patie nts disc o nti n ui n g letr oz ole treat me nt d ue t o treat me nt -relate d t o xicit y will be 
disc o nti n ue d fr o m t he st u d y.
5. 2. 4. 2. P al b ocicli b
I n t he e ve nt of si g nifica nt treat me nt-relate d t o xicit y, pal b ocicli b d osi n g ma y be i nterr u pte d or 
dela y e d a n d/ or re d uce d as descri be d bel o w.  I n t he e ve nt of m ulti ple t o xicities, d ose 
m o dificati o n s h o ul d be base d o n t he w orst t o xicit y  o bser ve d.  Patie nts are t o be i nstr ucte d t o 
n otif y  In vesti gat ors at t he first occ urre nce of a n y  a d verse si g n or sy m pt o m.
D ose m o dificati o ns ma y  occ ur i n t hree wa ys:

Wit hi n a c y cle: d osi n g i nterr u pti o n u ntil a de q uate rec o ver y a n d d ose re d ucti o n, if 
re q uire d, d uri n g a gi ve n treat me nt c ycle;

Bet wee n c y cles: ne xt c ycle a d mi nistrati o n ma y be dela ye d d ue t o persisti n g t o xicit y 
w he n a ne w c y cle is d ue t o start;

I n t he ne xt c ycle: d ose re d ucti o n ma y be re q uire d i n a s u bse q ue nt c ycle base d o n 
t o xicit y e x perie nce d i n t he previ o us c y cle.
5. 2. 4. 2. 1. D osi n g I nterr u pti o ns
Patie nts e x perie nci n g t he f oll o wi n g a d verse e ve nts s h o ul d ha ve t heir treat me nt 
i nterr u pte d/ dela ye d: 

U nc o m plicate d Gra de 3 ne utr o pe nia ( A N C < 1 0 0 0/ m m 3);

Gra de 3 ne utr o pe nia ( A N C < 1 0 0 0/ m m 3) ass ociate d wit h a d oc u me nte d i nfectio n or 
fe ver 3 8. 5 C;

Gra de 4 ne utr o pe nia ( A N C < 5 0 0/ m m 3);

Gra de 4 t hr o m b oc y t o pe nia ( Platelet c o u nt < 2 5, 0 0 0/ m m3);

Gra de 3 n o n- he mat ol o gic t o xicit y  (i ncl u di n g, na usea, v o miti n g, diarr hea, a n d 
h y perte nsi o n o nl y  if persisti n g des pite o pti mal me dical treat me nt);

Gra de 3 Q Tc pr ol o n gati o n ( Q Tc 5 0 1 msec o n at least t w o se parate E C Gs).
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 2
A p pr o priate f oll o w u p assess me nts s h o ul d be d o ne u ntil a de q uate rec o ver y occ urs as 
assesse d b y t he I n vesti gat or.  Criteria re q uire d bef ore treat me nt ca n res u me are descri be d i n 
Secti o n 5. 2. 4. 2. 2 . 
D oses ma y  be hel d as nee de d u ntil t o xicit y res ol uti o n.  De pe n di n g o n w he n t he a d verse e ve nt 
res ol ve d, a treat me nt i nterr u pti o n ma y lea d t o t he patie nt missi n g all s u bse q ue nt pla n ne d 
d oses wit hi n t hat sa me c y cle or e ve n t o dela y t he i nitiati o n of t he s u bse q ue nt c ycle. 
If t he a d verse e ve nt t hat le d t o t he treat me nt i nterr u pti o n rec o vers wit hi n t he sa me c ycle, t he n 
re-d osi n g i n t hat c y cle is all o we d.  D oses o mitte d f or t o xicit y  are n ot t o be re place d wit hi n 
t he sa me c ycle.  T he nee d f or a d ose re d ucti o n at t he ti me of treat me nt res u m pti o n s h o ul d be 
base d o n t he criteria defi ne d i n Secti o n 5. 2. 4. 2. 3 u nless e x pressl y  a gree d ot her wise f oll o wi n g 
disc ussi o n bet wee n t he i n vesti gat or a n d t he s p o ns or.  If a d ose re d ucti o n is a p plie d i n t he 
sa me c ycle, t he patie nt will nee d t o ret ur n t o t he cli nic t o recei ve ne w dr u g s u p pl y .
I n t he e ve nt of a treat me nt i nterr u pti o n f or reas o ns ot her t ha n treat me nt-relate d t o xicit y
(e g, n o n- ca ncer relate d s ur ger y) lasti n g > 2 wee ks, treat me nt res u m pti o n will be deci de d i n 
c o ns ultati o n wit h t he s p o ns or.
5. 2. 4. 2. 2. D ose Del a y
Retreat me nt f oll o wi n g treat me nt i nterr u pti o n f or treat me nt relate d t o xicit y  or at t he start of 
a n y ne w c ycle ma y n ot occ ur u ntil all of t he f oll o wi n g para meters ha ve bee n met:

Platelet c o u nt 5 0, 0 0 0/ m m 3; 

A N C 1 0 0 0/ m m 3 a n d n o fe ver;

Gra de 3 treat me nt -relate d n o n- he mat ol o gic A Es (i ncl u di n g, na usea, v o miti n g, 
di arr hea, a n d h y perte nsi o n o nl y if persisti n g des pite o pti mal me dical treat me nt), wit h 
t he e xce pti o n of al o pecia, ha ve rec o vere d t o Gra de 1 or baseli ne ( or, at t he 
i n vesti gat or’s discreti o n, Gra de 2 if n ot c o nsi dere d a safet y ris k f or t he patie nt) .

Q Tc < 5 0 1 msec a n d p ote ntial re versi ble ca uses (e g, electr ol yt e i m bala nce, 
c o nc o mita nt me dicati o ns k n o w n t o pr ol o n g Q Tc) c orrecte d.  If Q Tc re mai ns a b o ve 
4 8 0 msec, electr ocar di o gra m ( E C G) s h o ul d be m o nit ore d m ore fre q ue ntl y as per t he 
i n vesti gat or’s best me dical j u d ge me nt u ntil Q Tc 4 8 0 msec.
If a treat me nt dela y  res ults fr o m decli ne i n he mat ol o gic para meters, t he fre q ue nc y of bl o o d 
c o u nt assess me nts s h o ul d be i ncrease d as cli nicall y i n dicate d.
If t hese para meters are met wit hi n 2 wee ks of treat me nt i nterr u pti o n or c ycle dela y, 
pal b ocicli b ma y  be res u me d.  R efer t o Secti o n 5. 2. 4. 2. 3 D ose Re d ucti o ns f or a d verse e ve nts 
re q uiri n g d ose re d ucti o n at t he ti me of treat me nt res u m pti o n. 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 3
If t hese para meters ha ve n ot bee n met after 2 wee ks of d osi n g i nterr u pti o n (i ncl u di n g t he 
sc he d ule d 1 wee k off treat me nt) or 2 wee ks of c ycle dela y, per ma ne nt disc o nti n uati o n of 
pal b ocicli b treat me nt s h o ul d be c o nsi dere d.  Treat me nt res u m pti o n f or patie nts rec o ver i n g 
fr o m treat me nt-relate d t o xicit y after > 2 wee ks of treat me nt i nterr u pti o n or c ycle dela y w h o 
are deri vi n g cli nical be nefit per t he i n vesti gat or’s best me dical j u d g me nt is left at t he 
i n vesti gat or’s discreti o n.
I n t he e ve nt t hat t he start of a ne w c ycle is dela ye d d ue t o treat me nt -relate d t o xicit y, 
pr oce d ures re q uire d o n Da y  1 of t he gi ve n c ycle will be perf or me d w he n pal b ocicli b is 
res u me d.  Ne w c ycle Da y 1 pr oce d ures (ie, p h y sical e xa mi nati o n, E C O G perf or ma nce stat us, 
E C G, Q ualif y  of Life q uesti o n naires, bl o o d c he mistr y, he mat ol o g y) t hat were perf or me d 
pri or t o k n o wi n g t he nee d t o dela y  t he start of t he c ycle d o n ot nee d t o be re peate d u nless 
re q uire d t o c o nfir m t hat t he para meters necessar y f or st u d y dr u gs t o be res u me d are met.  
5. 2. 4. 2. 3. D ose Re d ucti o ns
F oll o w i n g d osi n g i nterr u pti o n or c ycle dela y t he pal b ocicli b d ose ma y nee d t o be re d uce d 
w he n treat me nt is res u me d.
N o s pecific d ose a dj ust me nts are rec o m me n de d f or Gra de 1/ 2 treat me nt -relate d t o xicit y.  
H o we ver, i n vesti gat ors s h o ul d al wa y s ma na ge t heir patie nts acc or di n g t o t heir me dical 
j u d g me nt base d o n t he partic ular cli nical circ u msta nces.
D ose re d ucti o n of pal b ocicli b b y  1 a n d, if nee de d, 2 d ose le vels (Ta ble 5 ) will be all o we d 
de pe n di n g o n t he t y pe a n d se verit y of t o xicit y e nc o u ntere d.  Patie nts re q uiri n g m ore t ha n 
2 d ose re d ucti o ns will be disc o nti n ue d fr o m t he st u d y . 
All d ose m o dificati o ns/a dj ust me nts m ust be clearl y d oc u me nte d i n t he patie nt's s o urce n otes 
a n d case re p ort f or m pa ges ( C R F) f or I n vesti gati o nal pr o d uct a d mi nistrati o n. 
O nce a d ose has bee n re d uce d f or a gi ve n patie nt, all s u bse q ue nt c y cles s h o ul d be 
a d mi nistere d at t hat d ose le vel, u nless f urt her d ose re d ucti o n is re q uire d.  D ose re -escalati o n 
is n ot all o we d.
T a ble 5.
A v ail a b le D ose Le vels 
D ose Le vel
P al b ocicli b f or 3 o ut of 4 wee ks ( 3/ 1 
sc he d ule)
Letr oz ole o n a c o nti n u o us d ail y d osi n g 
sc he d ule
Starti n g D ose
1 2 5 m g/ d
2. 5 m g/ d
- 1
1 0 0 m g/ d
2. 5 m g/ d
- 2
7 5 m g/ d *
2. 5 m g/ d
Disc o nti n ue St u d y Treat me nt
* Pal b ocicli b d ose re d uct i o n bel o w 7 5 m g/ d is n ot all o we d.
Pal b ocicli b rec o m me n de d d ose m o dificati o ns f or treat me nt relate d t o xicities re q uiri n g 
treat me nt i nterr u pti o n/ dela y or persisti n g des pite o pti mal me dical treat me nt are descri be d i n 
Ta ble 6 a n d Ta ble 7 . 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 4
T a ble 6.
P al b ocicli b D ose M o dific ati o ns f or Tre at me nt Rel ate d T o xicities Re q uiri n g 
Tre at me nt I nterr u pti o n/ Del a y or Persisti n g Des pite O pti m al Me dic al 
Tre at me nt
T y pe a n d Gr a de of T o xicit y
Rest art P al b ocicli b Tre at m e nt at:
U nc o m plic ate d Gr a de 3 ne utr o pe ni a
( 5 0 0/ m m3≤A N C < 1 0 0 0/ m m 3)
Sa m e d ose le vel
Gr a de 3 ne utr o pe ni a ( 5 0 0/ m m3≤A N C < 1 0 0 0/ m m 3) ass oci ate d 
wit h a d oc u m e nte d i nfecti o n or fe ver 3 8. 5 C
1 D ose Le vel
Gr a de 4 ne utr o pe ni a ( A N C < 5 0 0/ m m3)
1 D ose Le vel
Gr a de 4 t hr o m b oc yt o pe ni a ( Pl atelet c o u nt < 2 5, 0 0 0/ m m3)
1 D ose Le vel
Gr a de 3 n o n -he m at ol o gic t o xicit y (i ncl u di n g, n a use a, 
v o miti n g, di arr he a, a n d hy perte nsi o n o nly if persisti n g des pite 
o pti m al me dic al tre at me nt)
1 D ose Le vel
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 5
T a ble 7 
P al b ocicli b D ose M o dific ati o ns f or He m at ol o gic T o xicities ( b y C T C A E 
Gr a de a n d o n D a y of Tre at me nt) a
D a y of tre at m e nt
C T C A E Gr a de
D ose m o dific ati o ns
C y cle 1 Da y 1 4
G ra de 1, 2, a n d 3
N o d ose a dj ust me nt is re q uire d
Gra de 4 b
Gra de 3 c wit h 
d oc u me nte d i nfecti o n or 
fe ver 3 8. 5 C
Wit h h ol d u ntil rec o ver y t o Gra de 2, t he n res u me at ne x t 
l o wer d ose at start of ne xt c ycle
C y cle 1 Da y 2 1
Gra de 1, 2, a n d 3
N o d ose a dj ust me nt is re q uire d
Gra de 4 b
Gra de 3 c wit h 
d oc u me nte d i nfecti o n or 
fe ver 3 8. 5 C
W it h h ol d u ntil rec o ver y t o Gra de 2, t he n res u me at ne xt 
l o wer d ose at start of ne xt c ycle
C y cle 2 Da y 1
Gra de 1 a n d 2
N o d ose a dj ust me nt is re q uire d
Gra de 3 b
Wit h h ol d u ntil rec o ver y t o Gra de 2, t he n res u me a t 
c urre nt d ose
Gra de 4 b
Gra de 3 c wit h 
d oc u me nte d i nfecti o n or 
fe ver 3 8. 5 C
Wit h h ol d u ntil rec o ver y t o Gra de 2, t he n res u me at ne xt 
l o wer d ose
C y cle 2 Da y 2 1
Gra d e 1, 2, a n d 3
N o d ose a dj ust me nt is re q uire d
Gra de 4 b
Gra de 3 c wit h 
d oc u me nte d i nfecti o n or 
fe ver 3 8. 5 C
Wit h h ol d u ntil rec o ver y t o Gra de 2, t he n res u me at ne xt 
lo w er d ose at start of ne xt c ycle
D a y  1 of s u bse q ue nt 
c ycles
Gra de 1 a n d 2
N o d ose a dj ust me nt is re q uire d
Gra de 3 b
Wit h h ol d u ntil rec o ver y t o Gra de 2, t he n res u me at 
c urre nt d ose
Gra de 4 b
Gra de 3 c wit h 
d oc u me nte d i nfecti o n or 
fe ver 3 8. 5 C
Wit h h ol d u ntil rec o ver y t o Gra de ≤2, t he n res u me at ne xt 
l o wer d ose
Gra di n g acc or di n g t o C T C A E Versi o n 4. 0.
A N C =a bs ol ute ne utr o p hil c o u nt; C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts.
a.
M o nit or c o m plete bl o o d c o u nt pri or t o starti n g Pal b ocicli b a n d o n Da y 1 4 a n d 2 1 of t he first c ycle.   O btai n c o m plete 
bl o o d c o u nt at t he start of, a n d o n Da y 2 1 of t he sec o n d c ycle.   C o nti n ue m o n t hl y m o nit ori n g of c o m plete bl o o d 
c o u nt at t he be gi n ni n g of eac h c ycle f or at least 4 s u bse q ue nt c ycles.   O nce c o m plete bl o o d c o u nt has sta bilize d, 
m o nit or as cli nicall y i n dicate d.
b.
E xce pt l y m p h o pe nia ( u nless ass ociate d wit h cli nical e ve nts, e g, o p p ort u nist ic i nfecti o ns).
c.
Patie nts e x perie nci n g u nc o m plicate d Gra de 3 ne utr o pe nia ( A N C < 1 0 0 0/ m m 3) s h o ul d still ha ve t heir treat me nt 
i nterr u pte d/ dela ye d u ntil rec o ver y t o Gra de 2, t he n res u me at t he sa me c urre nt d ose.  Patie nts wit h Gra de 3 
ne utr o pe nia ( A N C < 1 0 0 0/ m m 3) ass ociate d wit h a d oc u me nte d i nfecti o n or fe ver 3 8. 5 C s h o ul d ha ve t heir treat me nt 
i nterr u pte d/ dela ye d u ntil rec o ver y t o Gra de 2 a n d fe ver is n o l o n ger prese nt, t he n res u me at ne xt l o wer d ose.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 6
Q Tc pr ol o n g ati o n m a n a ge me nt
I n t he e ve nt of Q Tc pr ol o n gati on, p ossi ble alter nati ve re versi ble ca uses s uc h as ser u m 
electr ol yt es a b n or malities, or usa ge of c o nc o mita nt me dicati o ns wit h t he p ote ntial t o pr ol o n g 
t he Q T i nter val s h o ul d be e val uate d. 
If s uc h re versi ble ca uses are i de ntifie d, t he n t he y s h o ul d be c orrecte d acc or di n gly 
(ie, c orrecti o n of electr ol yte a b n or malities wit h s u p ple me nts t o wit hi n n or mal li mits a n d/ or 
disc o nti n uati o n (if p ossi ble) of c o nc o mita nt me dicati o ns k n o w n t o pr ol o n g t he Q T i nter val). 
Rec o m me n de d d ose m o dificati o ns i n t he e ve nt of Q Tc pr o l o n gati o n are pr o vi de d i n Ta ble 8. 
T a ble 8. 
P al b ocicli b D ose M o dific ati o ns i n t he E ve nt of Q Tc Pr ol o n g ati o n
T o xicit y ( N CI C T C A E Gra de, Versi o n 4. 0)
Gr a de 2 Q Tc pr ol o n g ati o n
Gr a de 3 Q Tc p r ol o n g ati o n
Gr a de 4 Q Tc 
pr ol o n g ati o n
Re versi ble 
c a use 
i de ntifie d
Treat re versi ble ca use
I nitiate m ore fre q ue nt E C G 
m o nit ori n g acc or di n g t o 
i n vesti gat or’s best me dical 
j u d g me nt u ntil Q Tc 4 8 0 msec
C o nti n ue at t he sa me d ose le vel ( 1)
Treat re versi ble ca use
Wit h h ol d treat me nt u ntil Q Tc < 5 0 1 msec
Res u me treat me nt at t he sa me d ose le vel.
M o nit or E C G m ore fre q ue ntl y as per 
i n vesti gat or’s best me dical j u d g me nt u ntil 
Q T c 4 8 0 msec.
Per m a ne ntl y 
disc o nti n ue
N o re versi ble 
c a use 
i de ntifie d
I nitiate m ore fre q ue nt E C G 
m o nit ori n g acc or di n g t o 
i n vesti gat or’s best me dical 
j u d g me nt u ntil Q Tc≤4 8 0 msec
C o nti n ue at t he sa me d ose le vel ( 1)
Wit h h ol d treat me nt u ntil Q Tc < 5 0 1 msec
Res u me treat me nt at t he ne xt l o w er d ose
le vel( 2)
M o nit or E C G m ore fre q ue ntl y as per 
i n vesti gat or’s best me dical j u d g me nt u ntil 
Q T c 4 8 0 msec.
Per m a ne ntl y 
disc o nti n ue
1.
If t he Q Tc re mai ns a b o ve 4 8 0 msec m ore t ha n 2 c ycles or if Gra de 2 Q Tc pr ol o n gati o n rec urs i n t he a bse nce of ot her 
alter nati ve ca uses or des pite c orrecti o n of alter nati ve ca use s, d ose a dj ust me nt a n d/ or disc o nti n uati o n s h o ul d be 
c o nsi dere d i n c o ns ultati o n wit h a car di ol o gist a n d t he s p o ns or’s me dical m o nit or, ta ki n g i nt o acc o u nt t he e mer gi n g 
safet y data fr o m pal b ocicli b trials a n d t he i n vesti gat or’s best me dical j u d g me nt.
2.
If t he Gr a de 3 Q Tc pr ol o n gati o n occ urs a gai n after o ne d ose re d ucti o n, f urt her d ose a dj ust me nt a n d/ or disc o nti n uati o n 
s h o ul d be disc usse d wit h s p o ns or’s me dical m o nit or i n c o ns ultati o n wit h a car di ol o gist, ta ki n g i nt o c o nsi derati o n t he 
e mer gi n g safet y data fr o m p al b ocicli b trials a n d t he i n vesti gat or’s best me dical j u d g me nt.
5. 2. 5. Me dic ati o n Err ors a n d O ver d ose
Me dicati o n err ors ma y  res ult i n t his st u d y fr o m t he a d mi nistrati o n or c o ns u m pti o n of t he 
wr o n g pr o d uct, b y t he wr o n g patie nt, at t he wr o n g ti me, or at t he wr o n g d osa ge stre n gt h.  
S uc h me dicati o n err ors occ urri n g t o a st u d y partici pa nt are t o be ca pt ure d o n t he me dicati o n 
err or C R F w hic h is a s pecific versi o n of t he a d verse e ve nt ( A E) pa ge a n d o n t he Seri o us 
A d verse E ve nt ( S A E ) f or m w he n a p pr o priate.  I n t he e ve nt of me dicati o n d osi n g err or, t he 
s p o ns or s h o ul d be n otifie d i m me diatel y.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 7
Me dicati o n err ors are re p orta ble irres pecti ve of t he prese nce of a n ass ociate d A E/ S A E, 
i ncl u di n g:

Me dicati o n err ors i n v ol vi n g patie nt e x p os ure t o t he i n vesti gati o nal pr o d uct;

P ote ntia l me dicati o n err ors or uses o utsi de of w hat is f oresee n i n t he pr ot oc ol t hat d o 
or d o n ot i n v ol ve t he partici pati n g patie nt.
W het her or n ot a me dicati o n err or is acc o m pa nie d b y  a n A E, as deter mi ne d b y t he 
i n vesti gat or, t he me dicati o n err or is ca pt ure d o n the me dicati o n err or versi o n of t he a d verse 
e ve nt ( A E) pa ge a n d, if a p plica ble, a n y ass ociate d A Es are ca pt ure d o n a n A E C R F pa ge.
5. 2. 6. C o m pli a nce
Patie nts will be re q uire d t o ret ur n all b ottles of pal b ocicli b a n d ta blets of letr oz ole as well as 
t he c o m plete d patie nt d osi n g diar y at t he be gi n ni n g of eac h c ycle f or dr u g acc o u nta bilit y.  
Dr u g acc o u nta bilit y  will be perf or me d o n Da y 1 of e ver y  c ycle pri or t o dis pe nsi n g dr u g 
s u p pl y f or t he ne xt c ycle.  T he n u m ber of re mai ni n g ca ps ules a n d ta blets will be d oc u me nte d 
an d rec or de d. 
T o be c o nsi dere d c o m plia nt, eac h st u d y patie nt m ust ha ve recei ve d at least 8 0 % of t he 
pla n ne d n u m ber of d oses of pri mar y  t hera p y base d o n t he n u m ber of da ys of act ual d ose 
a d mi nistrati o n.  D ose a dj ust me nts m ust f oll o w i nstr ucti o ns pr o vi de d i n t he d ose a dj ust me nt 
g ui deli nes secti o n. 
5. 3. Dr u g St or a ge a n d Dr u g Acc o u nt a bilit y
St ora ge c o n diti o ns state d i n t he St u d y  Refere nce Safety D oc u me nt (ie, I n vesti gat or’s 
Br oc h ure (I B), or L ocal Pr o d uct D oc u me nt ( L P D)) will be s u perse de d b y t he la bel st ora ge.
I n vesti gat ors a n d site staff are re mi n de d t o c hec k te m perat ures dail y (ie, ma n uall y or by 
usi n g alar m s y ste m t o alert of a n y e xc ursi o ns) a n d e ns ure t hat t her m o meters are w or ki n g
c orrectl y as re q uire d f or pr o per st ora ge of i n vesti gati o nal pr o d ucts. T hese i ncl u de 
t her m o meters f or b ot h t he r o o m st ora ge a n d refri gerat or st ora ge.  A ny e xc ursi o ns s h o ul d be 
re p orte d t o t he s p o ns or a n d a d dresse d acc or di n g t o a p pr o priate sta n dar d o perati n g 
pr oce d ures . 
T he i n vesti gati o nal pr o d uct(s) m ust be st ore d as i n dicate d.  De via ti o ns fr o m t he st ora ge 
re q uire me nts, i ncl u di n g a n y acti o ns ta ke n, m ust be d oc u me nte d a n d re p orte d t o t he s p o ns or.  
O nce a de viati o n is i de ntifie d, t he i n vesti gati o nal pr o d uct ( pal b ocicli b or letr oz ole) M U S T be 
q uara nti ne d a n d n ot use d u ntil t he s p o ns or pr o vi des d oc u me ntati o n of per missi o n t o use t he 
i n vesti gati o nal pr o d uct.
At t he e n d of t he trial, t he s p o ns or will pr o vi de i nstr ucti o ns as t o dis p ositi o n of a n y u n use d 
i n vesti gati o nal pr o d uct.  If t he s p o ns or a ut h orizes destr ucti o n at t he trial site, t he i n vesti gat or 
m ust e ns ure t hat t he materials are destr o ye d i n c o m plia nce wit h a p plica ble e n vir o n me ntal 
re g ulati o ns, i nstit uti o nal p olic y, a n d a n y s pecial i nstr ucti o ns pr o vi de d b y t he s p o ns or.  
Destr ucti o n m ust be a de q uatel y  d oc u me nte d.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 8
5. 3. 1. P al b ocicli b
Pal b ocicli b ca ps ules 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) i n t heir 
ori gi nal c o ntai ner.
Me dicati o n s h o ul d be ke pt i n a sec ure d l oc ke d area at t he st u d y  site i n acc or da nce wit h 
a p plica ble re g ulat or y re q uire me nts.  Ret ur ne d me dicati o n s h o ul d be st ored se paratel y  fr o m 
me dicati o n t hat nee ds t o be dis pe nse d.
T o e ns ure a de q uate rec or ds, pal b ocicli b ca ps ules will be acc o u nte d f or as i nstr ucte d b y t he 
s p o ns or.  Patie nts are re q ueste d t o ret ur n pre vi o usl y dis pe nse d c o ntai ners as well as t heir 
c o m plete d patient d osi n g diar y  t o t he cli nic at eac h visit f or acc o u nta bilit y p ur p oses e ve n if 
t he y will n ot be iss ue d wit h ne w me dicati o n at t hat visit. 
5. 3. 2. Letr oz ole
Letr oz ole ta blets m ust be st ore d acc or di n g t o t he i nstr ucti o ns detaile d i n t he l ocal pac ka ge 
i nsert. 
Me di cati o n s h o ul d be ke pt i n a sec ure d l oc ke d area at t he st u d y  site i n acc or da nce wit h 
a p plica ble re g ulat or y re q uire me nts.  Ret ur ne d me dicati o n s h o ul d be st ore d se paratel y fr o m 
me dicati o n t hat nee ds t o be dis pe nse d.
T o e ns ure a de q uate rec or ds, letr oz ole ta ble ts will be acc o u nte d f or as i nstr ucte d by t he 
s p o ns or.  Patie nts are re q ueste d t o ret ur n pre vi o usl y dis pe nse d c o ntai ners as well as t heir 
c o m plete d patie nt diar y t o t he cli nic at eac h visit f or acc o u nta bilit y p ur p oses e ve n if t he y will 
n ot be iss ue d wit h n e w me dicati o n at t hat visit. 
5. 4. C o nc o mit a nt Me dic ati o ns
Patie nts m ust be i nstr ucte d n ot t o ta ke a n y a d diti o nal me dicati o ns ( o ver -t he-c o u nter or ot her 
pr o d ucts) d uri n g t he st u d y  wit h o ut pri or c o ns ultati o n wit h t he i n vesti gat or.  A n y me dicati o ns 
i ncl u di n g C hi n ese or ot her her bal me dici nes or s u p ple me nts, vita mi ns, or treat me nt ta ke n b y 
t he patie nt fr o m 2 8 d a y s pri or t o t he start of st u d y treat me nt a n d u p t o 2 8 da ys f oll o wi n g t he 
last d ose of i n vesti gati o nal pr o d uct a n d t he reas o n f or t heir a d mi nistrati o n m ust be rec or de d 
o n t he C R F. 
R o uti ne p ost o perati ve care, s uc h as dressi n g c ha n ges, s ut ure re m o val, drai n re m o val, or 
ve n o us access (ce ntral or peri p heral), d oes n ot nee d t o be rec or de d.  A nest hetics use d f or a n y 
s ur gical pr oce d ures perf or me d d uri n g t he patie nt’s partici pati o n i n t he st u d y ca n be rec or de d 
as “ u ns pecifie d a nest hesia” o n t he c o nc o mita nt treat me nt rec or ds; it is n ot necessar y  t o list 
t he s pecific a nest hetics.  Palliati ve a n d s u p p orti ve care f or ca ncer-relate d sy m pt o ms will be 
offere d t o all patie nts i n t his st u d y.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 9
5. 4. 1. Pr o hi bite d Me dic ati o ns
T he f oll o wi n g treat me nts are pr o hi bite d t hr o u g h o ut t he d urati o n of t he acti ve treat me nt 
p hase: 

A ntic a ncer a ge nts: N o a d diti o nal i n vesti gati o nal or c o m mercial a ntica ncer a ge nts 
s uc h as c he m ot hera py, i m m u n ot hera p y, tar gete d t hera p y, bi ol o gical res p o nse 
m o difiers, or e n d ocri ne t hera p y ot her t ha n letr oz ole will be per mitte d d uri n g t he 
acti ve treat me nt p hase.  I n ge neral, a n y dr u gs c o ntai ni n g “f or t he treat me nt of breast 
ca ncer” o n t he pr o d uct i nsert are n ot per mitte d o n s t u d y.

C Y P 3 A i n hi bit ors/i n d ucers: 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 ymes.  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 ge t he plas ma c o nce ntrati o ns 
of pal b ocicli b i n h u ma ns.  Data fr o m a dr u g -dr u g i nteracti o n ( D DI) st u d y  i n healt h y 
s u bjects i n dicate d t hat c oa d mi nistrati o n of m ulti ple 2 0 0-m g d oses of t he str o n g 
C Y P 3 A i n hi bit or i trac o naz ole wit h a si n gle 1 2 5-m g pal b ocicli b d ose i ncrease d 
pal b ocicli b t otal e x p os ure ( A U C i nf) a n d t he pea k e x p os ure ( Cma x ) b y a p pr o xi matel y 
8 7 % a n d 3 4 %, res pecti vel y , relati ve t o a si n gle 1 2 5- m g pal b ocicli b d ose gi ve n al o ne.  
Data fr o m a D DI st u d y i n hea lt h y s u bjects i n dicate d t hat c oa d mi nistrati o n of m ulti ple 
6 0 0 - m g d oses of t he str o n g C Y P 3 A i n d ucer rifa m pi n wit h a si n gle 1 2 5-m g 
pal b ocicli b d ose decrease d pal b ocicli b A U C i nf a n d C ma x b y  8 5 % a n d 7 0 %, 
res pecti vely, relati ve t o a si n gle 1 2 5 -m g  pal b ocicli b d ose gi ve n al o ne.  Use of f o o d or 
dr u g t hat are C Y P 3 A 4 i n hi bit or or i n d ucers are pr o hi bite d wit hi n 7 da y s or 
5 half -li ves ( w hic he ver is l o n ger) pri or t o t he first P K sa m ple u ntil t he c o m pleti o n of 
all re q uire d P K sa m pli n gs. After t he c o m pleti o n of all re q ui re d P K sa m ple 
c ollecti o ns, t he c o nc urre nt use of str o n g (i ncl u des s o me m o derate) C Y P 3 A 4 
i n hi bit ors/i n d ucers liste d bel o w is still n ot all o we d i n t he st u d y:

Str o n g C Y P 3 A i n hi bit ors , i ncl u di n g b ut n ot li mite d t o b oce pre vir, 
clarit hr o m yci n, c o ni va pta n, dela vi r di ne, i n di na vir, itrac o naz ole, ket oc o naz ole, 
l o pi na vir, mi befra dil, mic o naz ole, nefaz o d o ne, nelfi na vir, p osac o naz ole, 
rit o na vir, sa q ui na vir, s u b o x o ne, tela pre vir, telit hr o m yci n, v oric o naz ole, a n d 
gra pefr uit, gra pefr uit j uice or a n y pr o d uct c o ntai ni n g gra p efr uit. 

T he f oll o wi n g m o derate C Y P 3 A i n hi bit ors : a m pre na vir, ataza na vir, diltiaze m, 
er yt hr o m y ci n, f osa m pre na vir, a n d vera pa mil. 

Str o n g C Y P 3 A i n d ucers , i ncl u di n g b ut n ot li mite d t o car ba maze pi ne, p he n yt oi n, 
pri mi d o ne, rifa m pi n, rifa pe nti n, a n d St. J o h n’s w ort.

T he f oll o wi n g m o derate C Y P 3 A i n d ucers , fel ba mate, ne vira pi ne, p he n o bar bital, 
a n d rifa b uti n.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 6 0

H or m o ne re pl ace me nt t her a p y , t o pical estr o ge ns (i ncl u di n g a ny i ntra -va gi nal 
pre parati o ns), me gestr ol acet ate
a n d selecti ve estr o ge n-rece pt or m o d ul at ors
(e g, ral o xife ne) are pr o hi bite d d uri n g t he acti ve treat me nt p hase.

Pr ot o n -p u m p i n hi bit or ( P PI): t he c o nc o mita nt use of P PIs (i ncl u di n g b ut n ot 
li mite d t o, de xla ns o praz ole, es o me praz ole, la ns o praz ole, o me praz ole, pa nt o praz ole, 
ra be praz ole) wit h pal b ocicli b is pr ohi bite d fr o m at least 1 0 da y s bef ore t he first P K 
sa m ple u ntil t he c o m pleti o n of all re q uire d P K sa m pli n gs.  If a n aci d-l o weri n g a ge nt 
is nee de d d uri n g t his peri o d, H2-rece pt or a nta g o nists a n d l ocal a ntaci ds are all o we d 
wit h sta g gere d d osi n g re gi me ns.  Det aile d rec o m me n dati o ns a b o ut t he use of 
aci d-re d uci n g a ge nts are pr o vi de d u n der Secti o n 5. 4. 3 .

N o C hi nese or ot her her bal me dici nes will be all o we d d uri n g P K p orti o n.  N o 
C hi nes e a nti-ca ncer her bal me dici nes will be all o we d after t he P K p orti o n ( C y cle 1).
5. 4. 2.
Me dic ati o ns N ot Rec o m me n de d 
T he f oll o wi n g treat me nts are n ot rec o m me n de d t hr o u g h o ut t he d urati o n of t he acti ve 
treat me nt p hase.  Alter nati ve t hera pies s h o ul d be c o nsi dere d w he ne ver p ossi ble.  If usa ge of 
t he f oll o wi n g treat me nts is dee me d necessar y, c o ns ultati o n a n d a gree me nt wit h t he s p o ns or’s 
me dical m o nit or is re q uire d pri or t o treat me nt i nitiati o n . 

M o der ate C Y P 3 A I n d ucers: T he c o nc urre nt use of m o derate C Y P 3 A i n d ucers s uc h 
as de xa met has o ne or m o dafi nil is n ot rec o m me n de d. 

C hr o nic i m m u n os u p pressi ve t her a pies s h o ul d be a v oi de d, i ncl u di n g sys te mic 
c ortic oster oi ds.  Ster oi ds gi ve n f or p h ys i ol o gical re place me nt, as a nti-e metics or 
i n hale d as well as s h ort c o urse of oral/t o pical ster oi ds gi ve n f or aller gic reacti o ns or 
ast h ma flares are all o we d.

T he use of C hi nese or ot her her b al me dici ne is n ot rec o m me n de d d uri n g t he acti ve 
treat me nt p hase a n d is pr o hi bite d d uri n g P K p orti o n of t he st u d y . A n y usa ge of 
C hi nese or ot her her bal me dici nes s h o ul d be rec or de d. 
5. 4. 3. Per mitte d Me dic ati o ns
T he f oll o wi n g treat me nts are per mitte d t hr o u g h o ut t he d urati o n of t he acti ve treat me nt p hase: 

St a n d ar d t her a pies f or pre-e xisti n g me dical c o n diti o ns, me dical a n d/ or s ur gical 
c o m plicati o ns, a n d palliati o n. A n y  me dicati o n i nte n de d s olely f or s u p p orti ve care 
(e g, a nal gesics, a nti diarr heals, a nti de pressa nts) ma y als o be use d at t he i n vesti gat or’s 
discreti o n.  All me dicati o ns s h o ul d be rec or de d. 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 6 1

Bis p h os p h o n ates a n d rece pt or acti v at or of n ucle ar f act or k a p p a- B li g a n d 
( R A N K L) i n hi bit ors f or t he treat me nt of oste o p or osis or ma na ge me nt of e xisti n g 
b o ne metastases ma y  be c o nti n ue d f or patie nts w h o ha ve bee n recei vi n g t he m at a 
sta ble d ose f or at least 2 wee ks pri or t o st u d y e ntr y.  H o we ver t he nee d t o i nitiate or 
i ncrease t he d ose of t hese t hera pies d uri n g t he st u d y will be c o nsi dere d as i n dicati ve 
of disease pr o gressi o n lea di n g t o t he disc o nti n uati o n of patie nt u nless disease 
pr o gressi o n ca n be c o m pletel y  r ule d o ut a n d t he e xact reas o n f or t he use of t hese 
t hera pies clearl y d oc u me nte d i n t he patie nt’s s o urce d oc u me ntati o n.

He m at o p oietic gr o wt h f act ors (e g, gra n ul oc yte c ol o n y sti m ulati n g fact or [ G-C S F], 
gra n ul oc y te macr o p ha ge c ol o n y sti m ulati n g fact or [ G M-C S F]): Pri mar y  pr o p h ylactic 
use of gra n ul oc y t e-c ol o n y sti m ulatin g fact ors is n ot per mitte d b ut t he y  ma y be use d t o 
treat treat me nt-e mer ge nt ne utr o pe nia as i n dicate d b y t he c urre nt A merica n S ociet y of 
Cli nical O nc ol o g y  ( A S C O) g ui deli ne.2 5  If ne utr o pe nic c o m plicati o ns are o bser ve d i n 
a c ycle i n w hic h pri mar y pr o p h yla xis wit h C S Fs was n ot recei ve d, sec o n dar y 
pr o p h y la xis ma y be gi ve n at t he discreti o n of t he i n vesti gat or, b ut o nl y if d ose 
re d ucti o n or dela y are n ot c o nsi dere d t o be a reas o na ble alter nati ve.

Er yt hr o p oieti n ma y  be use d at t he i n vesti gat or's discreti o n f or t he s u p p orti ve 
treat me nt of a ne mia. 

H 2-Rece pt or A nt a g o nists (H 2R As) f or sy m pt o matic treat me nt of gastr oi ntesti nal 
dis or der (i ncl u di n g, b ut n ot li mite d t o fa m oti di ne, ra niti di ne, nizati di ne, ci meti di ne).  
Base d o n a vaila ble data, a d mi nistrati o n of H 2R A wit h a sta g gere d d osi n g re gi me n 
(t wice daily) d oes n ot affect a bs or pti o n or e x p os ure of pal b oicli b w he n pal b ocicli b is 
ta ke n wit h f o o d.  Bef ore t he c o m pleti o n of all re q uire d P K sa m pli n gs, if H2R A 
a d mi nistrati o n is nee de d , t he d osi n g of pal b ocicli b s h o ul d occ ur at least 1 0 h o urs after 
t he H2R A e ve ni n g d ose a n d 2 h o urs bef ore t he H 2R A m or ni n g d ose.

L oc al a nt aci ds f or s ym pt o matic treat me nt of gastr oi ntesti nal dis or der (e g, 
al u mi n u m/calci u m h ydr o xi de, al u mi n u m/calci u m c ar b o nate, bis m ut h s u bsalic ylate).  
Base d o n a vaila ble data, a d mi nistrati o n of l ocal a ntaci ds wit h a sta g gere d d osi n g 
re gi me n d oes n ot affect a bs or pti o n or e x p os ure of pal b oicli b w he n pal b ocicli b is 
ta ke n wit h f o o d.  Bef ore t he c o m pleti o n of all re q uire d P K sa m pli n gs, if 
a d mi nistrati o n of l ocal a ntaci ds is nee de d, l ocal a ntaci ds s h o ul d be gi ve n at least 
2 h o urs bef ore or 2 h o urs after a d mi nistrati o n of pal b ocicli b.

Aci d re d uci n g a ge nts (i ncl u di n g P PIs, H 2R As a n d l oc al a nt aci ds) ca n be use d f or 
s ym pt o matic tr eat me nt of gastr oi ntesti nal dis or der after t he c o m pleti o n of P K 
e val uati o ns.

Dr u gs k n o w n t o ca use Q T i nter val pr ol o n gati o n are per mitte d u p o n I R B/I E C
a p pr o val of A me n d me nt 3 .  Refer t o A p pe n di x 6 f or a list of dr u gs k n o w n t o
pre dis p ose t o T orsa de de P oi ntes .
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 6 2
5. 5. C o nc o mit a nt R a di ot her a p y or S ur ger y
A n y  c o nc urre nt ra di ot hera p y (e xce pt palliati ve ra di ot hera py as s pecifie d bel o w) or 
ca ncer-relate d s ur ger y are pr o hi bite d t hr o u g h o ut t he d urati o n of t he acti ve treat me nt p hase of 
t he st u dy.  Patie nts re q uiri n g a n y of t hese pr oce d ures will be disc o nti n ue d fr o m t he st u d y.
Palliati ve ra di ot hera p y is per mitte d f or t he treat me nt of pai nf ul b o n y lesi o ns pr o vi de d t hat t he 
lesi o ns were k n o w n t o be prese nt at t he ti me of st u d y e ntr y a n d t he i n vestigat or clearl y 
d oc u me nts t hat t he nee d f or palliati ve ra di ot hera p y is n ot i n dicati ve of disease pr o gressi o n.  
I n vie w of t he c urre nt lac k of data a b o ut t he i nteracti o n of pal b ocicli b wit h ra di ot hera py, 
pal b ocicli b treat me nt s h o ul d be i nterr u pte d d uri n g pall iati ve ra di ot hera py, st o p pi n g 1 d a y  
bef ore a n d res u mi n g treat me nt 1 wee k after.  F or patie nts wit h b o ne i n v ol ve me nt, it is 
s u g geste d t o i nstit ute palliati ve ra di ot hera py bef ore st u d y  i nitiati o n if p ossi ble a n d cli nically 
a p pr o priate (e g, lesi o ns at ris k f o r s p o nta ne o us micr o-fract ures or pai nf ul lesi o ns).  Palliati ve 
ra di ot hera py d uri n g t he acti ve treat me nt p hase will be c o nsi dere d alter nati ve ca ncer t hera p y 
a n d will res ult i n ce ns ori n g of t he P F S e n d p oi nt.  T he dates o n w hic h palliati ve ra di ot hera p y 
is a d mi nistere d s h o ul d be rec or de d o n t he a p pr o priate C R Fs. 
Ca uti o n is a d vise d o n t he oretical gr o u n ds f or a n y s ur gical pr oce d ures d uri n g t he st u d y.  T he 
a p pr o priate i nter val of ti me bet wee n s ur ger y  a n d pal b ocicli b re q uire d t o mi ni mize t he ris k of 
i m paire d w o u n d heali n g a n d blee di n g has n ot bee n deter mi ne d.  Base d o n t he a vaila ble 
p har mac o ki netic data, st o p pi n g pal b ocicli b is rec o m me n de d at least 7 da ys pri or t o electi ve 
s ur ger y.  P ost o perati vely,  t he decisi o n t o rei nitiate pal b ocicli b treat me nt s h o ul d be base d on a 
cli nical assess me nt of satisfact or y  w o u n d heali n g a n d rec o ver y fr o m s ur ger y.
6. S T U D Y P R O C E D U R E S 
All st u d y  pr oce d ures are descri be d i n S C H E D U L E O F A C TI VI TI E S .
6. 1. Scree ni n g
V ol u ntar y , writte n, date d, a n d si g ne d i nf orme d c o nse nt m ust be o btai ne d bef ore a n y st u d y 
s pecific pr oce d ures are perf or me d ( wit h t he e xce pti o n of certai n i ma gi n g assess me nts if 
meeti n g t he criteria defi ne d i n t his secti o n); h o we ver, it ma y  be o btai ne d m ore t ha n 2 8 d a y s 
bef ore e nr oll me nt. 
Ra di o gra p hic t u m or assess me nts (as d oc u me nte d o n t he Ta ble 3 T u m or Assess me nt 
Re q uire me nt Fl o wc hart ) t hat were perf or me d bef ore t he si g ni n g of t he i nf or me d c o nse nt 
f or m as r outi ne pr oce d ures ( b ut wit hi n 2 8 da ys pri or t o st u d y e ntr y) d o n ot nee d t o be 
re peate d a n d ma y be use d as baseli ne assess me nts, as l o n g as:

T he tests were perf or me d per t he met h o d re q uire me nts o utli ne d i n t he 
T u m or Assess me nt Re q uire me nt Fl o wc hart a n d Secti o n 7. 2 Efficac y  Assess me nt. 

A p pr o priate d oc u me ntati o n i n dicati n g t hat t hese ra di o gra p hic t u m or assess me nts 
were perf or me d as sta n dar d of care is a vaila ble i n t he patie nt’s s o u rce n otes.
B o ne sca ns perf or me d as r o uti ne pr oce d ures wit hi n 1 2 wee ks pri or t o e nr oll me nt ma y  als o be 
acce pte d as baseli ne assess me nt if t he y  meet t he sa me re q uire me nts liste d a b o ve.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 6 3
Brai n sca ns perf or me d as r o uti ne pr oce d ures wit hi n 6 wee ks pri or t o e nr oll me nt ma y  als o be 
acce pte d as baseli ne assess me nt if t he y  meet t he sa me re q uire me nts liste d a b o ve.
If scree ni n g a n d D a y -1 occ ur o n t he sa me da y , t he re q uire d assess me nts do n ot nee d t o be 
re peate d o n D a y - 1.
All le ns gra di n g e val ua ble patie nts will u n der g o t he f oll o wi n g o p ht hal mic pr oce d ures at 
scree ni n g:

Best c orrecte d dista nt vis ual ac uit y;

Refracti ve err or ass ociate d wit h best c orrecte d dista nt vis ual ac uit y ;

I ntra oc ular press ure (I O P-o ne rea di n g);

Slit la m p bi o micr osc o p y  of t he a nteri or se g me nt i ncl u di n g cell c o u nt a n d flare 
gra di n g;

Le ns gra di n g wit h t he Wisc o nsi n A ge- Relate d E y e Disease St u d y ( A R E D S) 
2 0 0 8 Cli nical L e ns O pacit y Gra di n g Pr oce d ures usi n g a la mi nate d refere nce p oc ket 
car d ( See 1 7. 7 ) - ( p u pil dilate d e xa mi nati o n);

F u n d usc o p y ( O p ht hal m osc o p y – p u pils m ust be dilate d).
Patie nts wit h o p ht hal mic c o n diti o ns (e g, a n o p ht hal m us, p ht hisis, a p ha kia, pse u d o p ha kia) t hat 
w o ul d pre ve nt gra di n g of t he le ns i n b ot h e y es will n ot be c o nsi dere d e val ua ble f or t his
o p ht hal mic assess me nt a n d d o n ot nee d t o u n der g o t hese o p ht hal mic pr oce d ures.  Reas o ns 
f or n ot bei n g e val ua ble m ust be clearl y d oc u me nte d i n t he patie nt s o urce n otes. 
All o p ht hal mic e xa mi nati o ns will be perf or me d b y a n o p ht hal m ol o gist. Refer t o Secti o n 
7. 3. 4 Oc ular Safet y Assess me nts f or f urt her details o n t hese pr oce d ures.
F or details o n baseli ne pr oce d ures, see t he Sc he d ule of Acti vities ta bles.
6. 1. 1. Scree n F ail ure 
Patie nts w h o c o m plete d t he i nf or me d c o nse nt pr ocess b ut d o N O T meet all eli gi bilit y  criteria 
a n d t heref ore are N O T e nr olle d t o t he st u d y will be c o nsi dere d as scree n fail ures. 
Cli nical sites m ust pr o vi de f or all scree n fail ures t he f oll o wi n g i nf or mati o n usi n g t he 
a p pr o priate C R F pa ges: scree ni n g n u m ber, de m o gra p hic data as well as t he fi nal s u bject 
s u m mar y i ncl u di n g t he reas o n f or scree ni n g fail ure.
6. 2. P h ar m ac o ki netics
D uri n g t he i nte nsi ve P K c ollecti o n parts, a n i n d welli n g cat heter i s all o we d if t here is a nee d.  
F or bl o o d sa m pli n g ti me p oi nts, see S C H E D U L E O F A C TI VI TI E S a n d Secti o n 7
A S S E S S M E N T S . 
 

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6. 3. Acti ve Tre at me nt P h ase
F or pr oce d ures d uri n g t his p hase, see S C H E D U L E O F A C TI VI TI E S a n d Secti o n 7
A S S E S S M E N T S .  Please refer t o A p pe n di x 9 f or t he Sc he d ule of Acti vities f or patie nts 
c o nti n ui n g t o recei ve acti ve treat me nt after I R B/I E C a p pr o val of A me n d me nt 3.
I n t he e ve nt t hat t he start of a ne w c ycle is dela ye d d ue t o treat me nt -relate d t o xicit y, 
pr oce d ures re q uire d o n Da y  1 of t he gi ve n c ycle will be perf or me d w he n pal b ocicli b is 
res u me d.  Ne w c ycle Da y 1 pr oce d ures t hat were perf or me d pri or t o k n o wi n g t he nee d t o 
dela y  t he start of t he c ycle d o n ot nee d t o be re peate d u nless re q uire d t o c o nfir m t hat t he 
para meters necessar y  f or st u d y dr u g t o be res u me d are met (see Secti o n 5. 2. 4. 2. 2 ).
6. 4. E n d of Tre at me nt Visit
If t he re q uire d assess me nts are n ot c o m plete d d uri n g t he pre vi o us 4 wee ks o n st u d y  ( or 
wit hi n t he pre vi o us 8 wee ks f or disease assess me nts) , t he assess me nts will be d o ne at t he e n d 
of treat me nt visit. T he e n d of treat me nt visit will be perf or me d as s o o n as p ossi ble b ut n o 
later t ha n 4 wee ks (ie, 2 8 da y s) ± 7 da ys fr o m last d ose of i n vesti gati o nal pr o d uct a n d pri or t o 
t he i nitiati o n of a n y ne w a ntica ncer t hera p y. Patie nts w h o ha ve alrea d y  de m o nstrate d 
o bjecti ve disease pr o gressi o n as per R E CI S T v. 1. 1 d o n ot nee d t o ha ve sca n s re peate d at t he 
e n d of treat me nt visit (U p o n a p pr o val of A me n d me nt 3 , R E CIS T v 1. 1 ma y  c o nti n ue t o be 
use d b ut will n o l o n ger be ma n dat or y ).
F or details o n pr oce d ures t o be perf or me d at t he E n d of Treat me nt visit, see t he S C H E D U L E 
O F A C TI VI TI E S ta bles. 
6. 5. P ost Tre at me nt F oll o w -u p
After disc o nti n uati o n of st u d y  treat me nt, p ost-treat me nt f oll o w-u p i nf or mati o n will be 
c ollecte d u p t o 2 8 da ys ( ± 7 da ys) fr o m t he last d ose of st u d y treat me nt or i nitiati o n of a n y 
ne w a nti -ca ncer t hera p y, w hic he ver occ urs earlier .
6. 6. P atie nt Wit h dr a w al
Patie nts ma y  wit h dra w fr o m treat me nt at a ny ti me at t heir o w n re q uest, or t he y  m a y be 
wit h dra w n at t he discreti o n of t he i n vesti gat or or s p o ns or f or safet y or be ha vi oral reas o ns, or 
t he i na bilit y of t he patie nt t o c o m pl y  wit h t he pr ot oc ol re q uire d sc he d ule of st u d y visits or 
pr oce d ures at a gi ve n st u d y  site.  T he reas o n f or disc o nti n uati o n fr o m treat me nt will be 
c ollecte d o n t he a p pr o priate C R F.
Reas o ns f or wit h dra wal of st u d y  treat me nt ma y i ncl u de:

T he patie nt wit h dra ws c o nse nt t o u n der g o f urt her treat me nt;
 

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
Disease p r o gressi o n as per R E CIS T v. 1. 1 ( u nless t here is reas o na ble e vi de nce of 
o n g oi n g cli nical be nefit t o j ustif y c o nti n uati o n o n pr ot oc ol acc or di n g t o t he 
i n vesti gat or after disc ussi o n wit h t he s p o ns or’s me dical m o nit or ) (( U p o n a p pr o val of 
A me n d me nt 3, R E CI S T v 1. 1 ma y  c o nti n ue t o be use d b ut will n o l o n ger be 
ma n dat or y ); 

Gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n wit h o ut o bjecti ve 
e vi de nce of disease pr o gressi o n as per R E CI S T v. 1. 1 (( U p o n a p pr o val of A me n d me nt 
3, R E CI S T v 1. 1 ma y  c o nti n ue t o be use d b ut will n o l o n ger be ma n dat or y);

Treat me nt dela y  f or m ore t ha n 2 wee ks f or treat me nt-relate d t o xicit y ( unless t here is 
reas o na ble e vi de nce of o n g oi n g cli nical be nefit t o j ustif y c o nti n uati o n o n pr ot oc ol; 
t his m ust be disc usse d wit h t he s p o ns or);

U nacce pta ble t o xicit y ;

T he patie nt is l ost t o f oll o w - u p;

P o or c o m plia nce wit h eit her pr ot oc ol pr oce d ures or wit h ta ki n g t he st u d y  
me dicati o ns;

T he patie nt n o l o n ger re q uires treat me nt (e g, patie nts ha vi n g e x perie nce d a t u m or 
re d ucti o n f oll o we d by resecti o n a n d n o l o n ger ha vi n g e val ua ble disease);

I nitiati o n of treat me nt wit h a n ot her a nti-ca ncer t hera p y n ot s pecifie d i n t he pr ot oc ol;

Si g nifica nt pr ot oc ol vi olati o n;

St u d y  ter mi nate d b y S p o ns or;

Deat h.
If a patie nt d oes n ot ret ur n f or a sc he d ule d visit, e ver y eff ort s h o ul d be ma de t o c o ntact t he 
patie nt.  T he I n vesti gat or s h o ul d atte m pt t o c o ntact t he s u bject t wice.  After t w o atte m pts, 
C R U staff ma y  se n d a re gistere d letter.  If n o res p o nse is recei ve d fr o m t he s u bject, t he 
s u bject will be c o nsi dere d l ost t o f oll o w u p.  All atte m pts t o c o ntact t he s u bject a n d 
i nf or mati o n recei ve d d uri n g c o ntact atte m pts m ust be d oc u me nte d i n t he s u bject’s me dical 
rec or d. I n a ny ci rc u msta nce, e ver y eff ort s h oul d be ma de t o d oc u me nt patie nt o utc o me, if 
p ossi ble.  T he i n vesti gat or s h o ul d i n q uire a b o ut t he reas o n f or wit h dra wal, re q uest t he 
patie nt s t o ret ur n f or a fi nal visit, if a p plica ble, a n d f oll o w-u p wit h t he patie nt re gar di n g a n y 
u nres ol ve d a d verse e ve nts.
Patie nt w h o disc o nti n ue fr o m t he acti ve treat me nt p hase m ust ha ve e n d of 
treat me nt/ wit h dra wal e val uati o ns perf or me d as s o o n as p ossi ble b ut n o later t ha n 4 wee ks 
after t he last d ose of i n vesti gati o nal pr o d uct a n d pri or t o i nitiati o n of a n y  ne w a ntica ncer 
t hera py.
 

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If t he patie nt wit h dra ws fr o m t he st u d y, a n d als o wit h dra ws c o nse nt f or discl os ure of f ut ure 
i nf or mati o n, n o f urt her e val uati o ns s h o ul d be perf or me d, a n d n o a d diti o nal data s h o ul d be 
c ollecte d.  T he S p o ns or ma y  retai n a n d c o nti n ue t o use a n y data c ollecte d bef ore s uc h 
wit h dra wal of c o nse nt.
If a patie nt o pts t o disc o nti n ue fr o m t he acti ve treat me nt p hase as a res ult of a n u nacce pta ble 
a d verse dr u g reacti o n, " wit h dra wal of c o nse nt" s h o ul d n ot be t he reas o n f or disc o nti n uati o n. 
I nstea d, t he reas o n for disc o nti n uati o n of acti ve treat me nt p hase, m ust be rec or de d as 
" U nacce pta ble t o xicit y" a n d a n a p pr o priate acti o n ta ke n m ust be assi g ne d o n t he A E C R F t o 
t he a d verse e ve nt lea di n g t o t he patie nt’s wit h dra wal of c o nse nt.
7. A S S E S S M E N T S
All st u d y  pr oce d ures are detaile d i n S C H E D U L E O F A C TI VI TI E S .
E ver y  eff ort s h o ul d be ma de t o e ns ure t hat t he pr ot oc ol re q uire d tests a n d pr oce d ures are 
c o m plete d as descri be d.  H o we ver it is a ntici pate d t hat fr o m ti me t o ti me t here ma y  be 
circ u msta nces, o utsi de of t he c o ntr ol of t he i n vesti gat or, t hat ma y  ma ke it u nfeasi ble t o 
perf or m t he test.  I n t hese cases t he i n vesti gat or will ta ke all ste ps necessar y t o e ns ure t he 
safety a n d well bei n g of t he patie nt.  W he n a pr ot oc ol re q uire d test ca n n ot be perf or me d t he 
i n vesti gat or will d oc u me nt t he reas o n f or t his a n d a n y c orrecti ve a n d pre ve nti ve acti o ns 
w hic h he/s he has ta ke n t o e ns ure t hat n or mal pr ocesses are a d here d t o as s o o n as p ossi ble.  
T he st u d y  tea m will be i nf or me d of t hese i nci de nts i n a ti mel y fas hi o n. 
7. 1. Bl o o d V ol u mes 
T he hi g hest t otal bl o o d sa m pli n g v ol u me f or i n di vi d ual patie nt s fr o m scree ni n g t o t he 
Lea d -i n p hase a n d Cycle 1 of t he st u d y  is a p pr o xi matel y 2 0 9 m L .  T he act ual c ollecti o n 
ti mes of bl o o d sa m pli n g ma y c ha n ge, b ut t he t otal bl o o d v ol u me c ollecte d will n ot i ncrease.  
Bl o o d v ol u me c ollecte d i n eac h of t he later c y cles s h o ul d be less t ha n t he t otal a m o u nt i n 
Lea d -i n p hase pl us C ycle 1.  A d diti o nal bl o o d sa m ples ma y be ta ke n f or safet y assess me nts 
d uri n g t he w h ole st u d y  at times s pecifie d b y t he s p o ns or, pr o vi de d t he t otal v ol u me ta ke n 
d uri n g t he st u d y d oes n ot e xcee d 5 5 0 m L  d uri n g a n y peri o d of 3 0 c o nsec uti ve da ys.
T a ble 9. 
Bl o o d V ol u me
S a m ple T y pe
S a m ple 
V ol u me ( m L)
N u m ber of S a m pli n g Ti m es
T ot al V ol u me  
( mL)
Scree ni n g/ Da y - 1
Lea d -i n P hase/ C ycle 1
Safet y La bs
1 5
1 or 2
5
1 0 5
P K
2
2 8
5 6
Bl o o d T K 
Acti vit y
3
1
1 5
4 8
T O T A L
2 0 9
T his t otal v ol u me d oes n ot i ncl u de discar de d bl o o d fr o m pre -dra ws use d t o re m o ve fl ui d fr o m fl us he d 
cat heters, if a p plica ble. 
 

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7. 2. Effic ac y Assess me nts
7. 2. 1. T u m or Assess me nt
T he i m p orta nce of ti mel y a n d c o m plete disease assess me nts i n t his st u d y  ca n n ot be 
u n derstate d.  Disease assess me nts m ust be perf or me d as sc he d ule d acc or di n g t o t he cale n dar, 
re gar dless of treat me nt dela ys resulti n g fr o m t o xicit y , t o pre ve nt t he i ntr o d ucti o n of bias i nt o 
t he assess me nt of efficac y.  Fail ure t o perf or m a n y of t he re q uire d disease assess me nts will 
res ult i n t he i na bilit y t o deter mi ne disease stat us f or t hat ti me p oi nt.  A series of i nc o m plete 
dis ease assess me nts will res ult i n ce ns ori n g of t he pri mar y  e n d p oi nt of P F S bac k t o t he ti me 
of t he last f ull assess me nt t hat di d n ot s h o w pr o gressi o n.  Fre q ue nt off sc he d ule or 
i nc o m plete disease assess me nts ha ve t he p ote ntial t o wea ke n t he c o ncl usi o n of t his cli nical 
trial.
Ra di o gra p hic t u m or assess me nts ma y  be d o ne at a n y ti me if t here is cli nical s us pici o n of 
disease pr o gressi o n at t he discreti o n of t he i n vesti gat or. If pr o gressi ve disease is c o nfir me d 
per R E CI S T v. 1. 1, patie nts are e x pecte d t o disc o nti n u e st u d y t hera p y. H o we ver, patie nts 
ma y  c o nti n ue t he st u d y treat me nt be yo n d t he ti me of R E CI S T -defi ne d pr o gressi ve disease 
( P D) at t he discreti o n of t he i n vesti gat or if t hat is c o nsi dere d t o be i n t he best i nterest of t he 
patie nt a n d as l o n g as n o ne w a nti ca ncer treat me nt is i nitiate d.
Scree ni n g/ b aseli ne t u m or assess me nt will be carrie d o ut wit hi n 4 wee ks (ie, 2 8 d a y s of
st u d y e ntr y ( u nless ot her wise s pecifie d bel o w). 
Disease assess me nt f or all patie nts at baseli ne will i ncl u de:

C T or M RI  sca n of t he c hest, a b d o me n, a n d pel vis ( C A P).

C T or M RI  sca n of a ny ot her sites of disease as cli nicall y  i n dicate d. 

Cli nical assess me nt of s u perficial disease w hic h will i ncl u de p h ot o gra p hs of all 
s u perficial metastatic lesi o ns.  All lesi o n meas ure me nts m ust be rec or de d i n t he C R F. 

B o ne sca ns i n or der t o detect b o n y  sites of disease.  A n y s us pici o us a b n or malities 
(ie, h ots p ots) i de ntifie d o n t he b o ne sca ns at baseli ne m ust be c o nfir me d b y X- ra y, C T 
sca n wit h b o ne wi n d o ws or M RI.  B o ne lesi o ns i de ntifie d at baseli ne will f oll o w t he 
sa me assess me nt sc he d ule as f or meas ura ble lesi o ns.  Baseli ne brai n C T or M RI are 
o nl y  re q uire d i n case si g ns a n d s ym pt o ms s u g gest t he prese nce of metastatic brai n 
disease.  Refer t o Secti o n 6. 1 f or f urt her details o n ti mi n g all o wa nce f or baseli ne 
brai n a n d b o ne sca ns. 
P ost -b aseli ne t u m or assess me nts will be perf or me d e ver y 1 2 wee ks (7 da y s) a n d b o ne 
sca ns (as a p plica ble) e ver y 2 4 wee ks (7 da y s) fr o m C 1 D 1 u ntil ra di o gra p hicall y a n d/ or 
cli nicall y (ie, f or p h ot o gra p he d or pal pa ble lesi o ns) d oc u me nte d P D as per R E CIS T v. 1. 1, 
st u d y treat me nt disc o nti n uati o n (f or patie nts c o nti n ui n g treat me nt be yo n d R E CI S T -defi ne d 
disease pr o gressi o n), i nitiati o n of ne w a ntica ncer t hera p y, or disc o nti n uati o n of patie nt fr o m 
o verall st u d y  partici pati o n (e g, deat h, patie nt's re q uest, l ost t o f oll o w- u p) w hic he ver occ urs 
 

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first.  Ima gi n g assess me nts are t o be sc he d ule d usi n g t he C 1 D 1 date as t he refere nce date f or 
all ti me-p oi nts a n d are N O T t o be sc he d ule d base d o n t he date of t he pre vi o us i ma gi n g 
ti me-p oi nt.  I ma gi n g assess me nt dela y  t o c o nf or m t o treat me nt dela y is n ot per mitte d.
Please refer t o A p pe n di x 9 , f or t u m or assess me nt re q uire me nts f or patie nts c o nti n ui n g t o
recei ve acti ve treat me nt after I R B/I E C a p pr o val of A me n d me nt 3.
P ost - baseli ne t u m or assess me nts will i ncl u de:

C T or M RI  sca n of t he c hest, a b d o me n, a n d pel vis ( C A P).

C T or M RI  sca n of a ny ot her sites of disease i de ntifie d at baseli ne.

Cli nical asse ss me nt of sites of s u perficial disease i de ntifie d at baseli ne.  Cli nical 
assess me nt of s u perficial disease m ust c oi nci de wit h t he i ma gi n g st u dies a n d will 
i ncl u de p h ot o gra p hs of all s u perficial metastatic lesi o ns.  All lesi o n meas ure me nts 
m ust be rec or de d i n t he C R F. 

B o ne lesi o ns i ma gi n g:

If b o ne lesi o ns were i de ntifie d at baseli ne t he f oll o wi n g assess me nt m ust be 
perf or me d:

X- ra y/ C T sca n/ M RI e ver y 1 2 wee ks ( ± 7 da ys) fr o m t he date of C 1 D 1 usi n g 
t he sa me m o dalit y use d t o c o nfir m t he b o ne lesi o ns at baseli ne.  Areas t hat 
ha ve recei ve d palliati ve ra di ot hera p y o n st u d y ca n n ot be use d t o assess 
res p o nse t o st u d y treat me nt.

B o ne sca ns e ver y  2 4 wee ks ( ± 7 da ys) fr o m t he date of C 1 D 1 a n d t o c o nfir m 
c o m plete res p o nse.  A b n or malities f o u n d o n s u bse q ue nt b o ne sca ns m ust als o 
be c o nfir me d b y X- r a y, C T sca n, or M RI.

If n o b o ne lesi o ns were i de ntifie d at baseli ne, b o ne sca ns s h o ul d be perf or me d as 
cli nicall y i n dicate d (ie, patie nt descri bes ne w or w orse ni n g b o ne pai n, or has 
i ncreasi n g al kali ne p h os p hatase le vel, or ot her si g ns a n d s ym pt o ms of 
ne w/ pr o gressi n g b o ne metastases) b ut are re q uire d t o c o nfir m c o m plete res p o nse.  
A b n or malities f o u n d o n s u bse q ue nt b o ne sca ns m ust als o be c o nfir me d b y X- ra y, 
C T sca n, or M RI.

Re peat brai n sca ns will be re q uire d o nl y  if metastases are s us pecte d.
T he C T sca ns, i ncl u di n g brai n C T sca n if a p plica ble, s h o ul d be perf or me d wit h c o ntrast 
a ge nts u nless c o ntrai n dicate d f or me dical reas o ns.  If I V c o ntrast is me dicall y  
c o ntrai n dicate d, t he i ma gi n g m o dalit y t o be use d t o f oll o w t he disease (eit her C T wit h o ut 
c o ntrast or M RI) s h o ul d be t he m o dalit y  w hic h best e val uates t he disease, a n d t he c h oice 
s h o ul d be deter mi ne d by t he i n vesti gat or i n c o nj u ncti o n wit h t he l ocal ra di ol o gist.  M RI of 
t he a b d o me n a n d pel vis ca n be s u bstit ute d f or C T if M RI a de quatel y  de picts t he disease.
 

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H o we ver, M RI  of t he c hest s h o ul d n ot be s u bstit ute d f or C T of c hest e ve n if I V c o ntrast is 
c o ntrai n dicate d.  I n s uc h case C T will be perf or me d wit h o ut c o ntrast.  If M RI is use d t o 
f oll o w-u p b o ne lesi o n(s) it m ust be perf or me d a fe w da ys bef ore a ny treat me nt t hat ma y  
affect b o ne -marr o w cell ularit y  (e g, G-C S F).
T he sa me met h o d a n d tec h ni q ue m ust be use d t o c haracterize eac h lesi o n i de ntifie d a n d 
re p orte d at baseli ne, d uri n g t he st u dy treat me nt peri o d a n d d uri n g f oll o w -u p.  T he use of 
plai n -fil m X-ra ys ( wit h t he e xce pti o n of b o ne X-ra ys as detaile d a b o ve) is disc o ura ge d.  T he 
use of p ositr o n e missi o n t o m o gra p h y ( P E T) i ma gi n g as t he o nl y i ma gi n g m o dalit y is n ot 
per mitte d.
F or patie nts ha vi n g eff usi o ns or ascites, cases ha vi n g c y t ol o gical pr o of of mali g na nc y s h o ul d 
be rec or de d as n o n -tar get lesi o ns o n t he t u m or assess me nt C R Fs.  Eff usi o ns t hat ha ve n ot 
bee n e val uate d usi n g c y t ol o g y or were f o u n d t o be n o n-mali g na nt s h o ul d n ot be rec or de d o n 
t he n o n-tar get lesi o n C R F. 
O bjecti ve t u m or r es p o nse will be meas ure d usi n g t he Res p o nse E val uati o n Criteria i n S oli d 
T u m ors ( R E CI S T Versi o n 1. 1, see htt p:// w w w.e ortc. be/recist/ defa ult. ht m).  Als o please refer 
t o 1 7. 2 A p pe n di x 2 .  All meas ure me nts s h o ul d be rec or de d i n metric n otati o n usi n g a r uler or 
cali pers. 
N ote, u p o n a p pr o val of A me n d me nt 3, t u m or assess me nts ma y  be perf or me d e ver y 6 c ycles 
( ± 7 da ys) or as rec o m me n de d b y t he p h ysicia n acc or di n g t o t he patie nt’s cli nical c o n diti o ns.   
R E CI S T 1. 1 ma y  c o nti n ue t o be use d t o e val uate i ma gi n g assess me nts at t he i n vesti gat or’s 
discreti o n b ut will n o l o n ger be ma n dat or y .  Assess me nts of t u m or lesi o ns will n o l o n ger be 
rec or de d i n t he C R F, n or will t he R E CIS T assess me nts.   O nl y  t he date of pr o gressi o n of 
disease will be rec or de d.
F or p atie nts wit h b o ne -o nl y dise ase: 

Treat me nt o utc o me will be rec or de d i n t he C R F as c o m plete res p o nse ( C R), sta ble 
disease ( S D) or pr o gressi o n ( P D). 
I nter pretati o n will be P D if:

T he mali g na nt nat ure of o ne or m ore ne w lesi o ns i de ntifie d wit h b o ne sca n is 
c o nfir me d wit h X-ra y, or C T, or M RI sca n, 

Flare o bser ve d i n b o ne sca n is f oll o we d b y c o nfir mati o n of pr o gressi o n wit h ot her 
i ma gi n g m o dalities,

Cli nical w orse ni n g of t he disease is assesse d b y b o ne s ca n a n d disease pr o gressi o n 
(ie, ne w lesi o n(s)) is c o nfir me d wit h ot her i ma gi n g m o dalities.

U ne q ui v ocal pr o gressi o n of e xisti n g b o ne lesi o ns.
 

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I nter pretati o n will be S D if:

T he mali g na nt nat ure of all t he ne w lesi o ns i de ntifie d wit h b o ne sca n is n ot 
c o nfir me d.
I n t he f oll o wi n g cases t he patie nt will be ce ns ore d at t he date of pri or t u m or assess me nt wit h 
n o P D: 1) o n- st u d y fract ure; 2) o n-st u d y ma na ge me nt of pai n ( palliati ve ra diati o n t hera p y, 
palliati ve s ur ger y), 3) cli nical w orse ni n g n ot o bjecti vel y  c o nfir me d; 4) o n -st u d y c ha n ge of 
t hera py.  I n all t he ce ns ore d cases ( n o o bjecti vel y d oc u me nte d P D) t u m or assess me nt will be 
perf or me d u ntil P D.  Als o, it will be at t he discreti o n of t he i n vesti gat or t o disc o nti n ue t he 
st u d y treat me nt.
It is s u g geste d t o i nstit ute palliati ve ra di ot hera py (e g, lesi o ns at ris k f or s p o nta ne o us 
micr o -fract ures or pai nf ul lesi o ns) bef ore st u dy i nitiati o n as well as palliati ve s ur ger y if 
p ossi ble a n d cli nicall y  a p pr o priate.
7. 3. S afet y Assess me nts
7. 3. 1. A d verse E ve nts
Assess me nt of a d verse e ve nts will i ncl u de t y pe, i nci de nce, se verit y ( gra de d b y t he Nati o nal 
Ca ncer I nstit ute [ 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 4 . 0, see 1 7. 3 A p pe n di x 3 Nati o nal Ca ncer I nstit ute ( 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)), ti mi n g, seri o us ness, a n d relate d ness; a n d la b orat or y 
a b n or malities.
Baseli ne t u m or -relate d si g ns a n d sy m pt o ms will be rec or de d pri or t o st u d y  e ntr y a n d t he n 
re p orte d as a dverse e ve nts d uri n g t he trial if t he y  w orse n i n se verit y or i ncrease i n fre q ue nc y.
7. 3. 2. L a b or at or y S afet y Assess me nts
Bl o o d tests i ncl u de:

He mat ol o g y : w hite bl o o d cell c o u nt , platelet c o u nt, he m o gl o bi n ( H b), a n d w hite 
bl o o d cell differe ntial ( ne utr o p hils, e osi n o p hils, bas o p hils, l y m p h oc y tes, m o n oc ytes).

Bl o o d c he mistr y : As partate a mi n otra nsferase ( A S T)/ala ni ne a mi n otra nsferase ( A L T), 
al kali ne p h os p hatase, s o di u m, p otassi u m, ma g nesi u m, t otal calci u m, t otal bilir u bi n, 
B U N ( or urea), ser u m creati ni ne, al b u mi n, fast i n g li pi d pa nel (t otal c h olester ol, hi g h 
de nsit y  li p o pr otei n [ H D L], l o w de nsit y li p o pr otei n [ L D L] a n d tri glyc eri des), 
he m o gl o bi n A 1c ( H g b A 1c), fasti n g gl uc ose a n d fasti n g i ns uli n.

C oa g ulati o n: P T or I nter nati o nal N or malize d Rati o (I N R), P T T or a P T T.  A d di ti o nal 
c oa g ulati o n st u dies ma y be perf or me d as cli nicall y i n dicate d.

H bs A g , a nti-H C V , HI V tests.
 

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He mat ol o g y  a n d bl o o d c he mistr y will be dra w n at t he ti me p oi nts descri be d i n S C H E D U L E 
O F A C TI VI TI E S a n d a nal yze d at l ocal la b orat ories, e xce pt H g b A 1c, fasti n g li pi d pa nel, 
fasti n g gl uc ose a n d fasti n g i ns uli n t hat will be a nal y ze d at a ce ntral la b orat or y desi g nate d b y 
t he S p o ns or.  U p o n I R B/I E C a p pr o val of A me n d me nt 3, bl o o d c he mistr y  will o nl y nee d t o be 
m o nit ore d e ver y 3 c y cles d uri n g acti ve treat me nt a n d at e n d of treat me nt visit; h e m o gl o bi n 
A 1c will n o l o n ger be re q uire d t o be meas ure d e ver y  3 m o nt hs b ut is re q uire d t o be c ollecte d 
at t he e n d of treat me nt visit.  A d diti o nal u nsc he d ule d bl o o d c he mistr y  pa nels ma y be 
c ollecte d as cli nicall y i n dicate d a n d res ults will be rec or de d o n t he a p pr o priate C R F.
He mat ol o g y  assess me nts will be c o n d ucte d re gar dless of f o o d i nta ke.  H g b A 1c assess me nts 
will be c o n d ucte d re gar dless of f o o d i nta ke; fasti n g gl uc ose, fasti n g i ns uli n a n d fasti n g li pi d 
pa nel will be assesse d f oll o wi n g a n o ver ni g ht fast (at least 1 0 h o urs); sa m ples f or ot her bl o o d 
c he mist y tests s h o ul d be c ollecte d f oll o wi n g at least a 4-h o ur fast.  T heref ore, w he n all of 
t hese assess me nts are c o n d ucte d t o get her, t he y s h o ul d be d o ne bef ore f o o d i nta ke.  
A d diti o nal he mat ol o g y /c he mistry pa nels ma y  be perf or me d at t he discreti o n of i n vesti gat ors 
as cli nicall y i n dicate d f or pla n ni n g treat me nt a d mi nistrati o n, d ose m o dificati o n, or f urt her 
e val uati o n of a d verse e ve nts.
Uri nal y sis w ill i ncl u de pr otei n a n d bl o o d.   Di pstic k is acce pta ble.   If p ositi ve, c ollect 2 4-hr 
uri ne (f or pr otei n e xcreti o n) a n d perf or m micr osc o pic a nal ys is of t he uri ne.
7. 3. 3. Electr oc ar di o gr a m ( E C G)
Electr ocar di o gra ms ( E C Gs) s h o ul d be c ollecte d at pre- d ose o n t he da y s specifie d i n t he 
S T U D Y P R O C E D U R E S secti o n of t his pr ot oc ol.  E C G meas ure me nts will i ncl u de P R 
i nter val, Q T i nter val, R R i nter val, a n d Q R S c o m ple x.  Heart rate s h o ul d be meas ure d a n d 
rec or de d as well.  It is prefera ble t hat t he mac hi ne use d has a ca pacit y t o calc ulate t he 
sta n dar d i nter vals a ut o maticall y.  A d diti o nal E C Gs ma y  be perf or me d as cli nicall y i n dicate d.
1 2 -lea d tri plicate E C Gs m o nit ori n g will be u n derta ke n i n all patie nts e nr olle d i n t he trial.  At 
eac h ti me p oi nt (see S C H E D U L E O F A C TI VI TI E S a n d Ta ble 1 , a n d refer t o A p pe n di x 9 , f or 
t u m or assess me nt re q uire me nts f or patie nts c o nti n ui n g t o recei ve acti ve treat me nt after 
I RB/I E C a p pr o val of A me n d me nt 3 ), 3 c o nsec uti ve E C Gs will be perf or me d a p pr o xi matel y  
2 mi n utes a part t o deter mi ne t he mea n Q Tc i nter val.  All sc he d ule d E C Gs s h o ul d be 
perf or me d after t he s u bject has reste d q uietl y f or at least 1 0 mi n utes i n a s u pi ne p ositi o n.  
W he n t he E C G sc he d ule is matc he d wit h P K sa m pli n g, E C G m ust be carrie d o ut bef ore P K 
sa m ple dra wi n g s uc h t hat t he P K sa m ples are c ollecte d at t he n o mi nal ti me (ie, t he ti mi n g of 
t he P K c ollecti o ns o ver ri des t he ti mi n g of t he E C G c ollecti o ns).  E C G e val uati o n s h o ul d be 
c o n d ucte d bef ore f o o d i nta ke. 
If t he mea n Q Tc i nter val is pr ol o n ge d ( > 5 0 0 msec), t he n t he E C Gs s h o ul d be re -e val uate d b y 
a q ualifie d pers o n at t he site f or c o nfir mati o n as s o o n as t he fi n di n g is ma de, i ncl u di n g 
verificati o n t hat t he mac hi ne rea di n g is acc urate.  If t he pr ol o n ge d mea n Q Tc is c o nfir me d, 
i m me diate searc h f or re versi ble ca uses (i ncl u di n g electr olyt e a b n or malities, h yp o xia, a n d 
c o nc o mita nt me dicati o ns f or dr u gs wit h t he p ote ntial t o pr ol o n g t he Q T i nter val) s h o ul d be 
perf or me d b y i n vesti gat or a n d s p o ns or.  I n a d diti o n, re peat E C Gs s h o ul d be i m me diatel y 
perf or me d h o url y f or at least 3 h o urs u ntil t he Q Tc falls bel o w 5 0 1 msec. 
 

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
If Q Tc i nter val re verts t o less t ha n 5 0 1 msec, a n d i n t he j u d g me nt of i n vesti gat or(s) i n 
c o ns ultati o n wit h t he s p o ns or t he ca use is deter mi ne d t o be ot her t ha n st u d y dr u g, 
treat me nt ma y be c o nti n ue d wit h re g ular E C G m o nit ori n g u n der h os pital s u per visi o n.

If i n t hat ti mefra me t he Q Tc i nter vals re mai n a b o ve 5 0 1 msec t he st u d y dr u g will be 
hel d u ntil t he Q Tc i nter val decreases t o < 5 0 1 msec.
Pri or t o c o ncl u di n g t hat a n e pis o de of Q Tc pr ol o n gati o n is d ue t o st u d y  dr u g, t h or o u g h 
c o nsi derati o n s h o ul d be gi ve n t o p ote ntial preci pitati n g fact ors (e g, c ha n ge i n patie nt cli nical 
c o n diti o n, effect of c o nc urre nt me dicati o n, electr ol y te dist ur ba nce) a n d p ossi ble e val uati o n 
b y  a s pecialist. 
If i n vesti gati o nal pr o d uct ca usalit y ca n n ot be r ule d o ut, i n vesti gati o nal pr o d uct d ose 
a dj ust me nt a n d/ or disc o nti n uati o n s h o ul d be perf or me d acc or di n g t o i nstr ucti o ns pr o vi de d i n
Secti o n 5. 2. 4 Rec o m me de d D ose M o dificati o n. A d diti o nal tri plicate E C Gs ma y  be 
perf or me d as cli nicall y i n dicate d.
7. 3. 4. Oc ul ar S afet y Assess me nts
Oc ular assess me nts will be perf or me d at t he ti me p oi nts descri be d i n S C H E D U L E O F 
A C TI VI TI E S b y  o p ht hal m ol o gists.
7. 3. 4. 1. Vis u al Ac uit y a n d Refr acti o n
Vis ual ac uit y  will be assesse d b y usi n g a sta n dar d wall or pr ojecti o n c hart bef ore 
i m ple me nti n g a n y pr oce d ures t hat ca n affect visi o n (eg, p u pil dilati o n, t o n o metr y , a n d 
g o ni osc o p y).  S nelle n n otati o n a n d ot her met h o ds are all o we d t o be use d a n d t he met h o d 
bei n g use d s h o ul d be i n dicate d o n t he C R F pa ges.  T he ori gi nal res ults s h o ul d be rec or de d 
wit h t he res pecti ve u nits ( meter or feet, or left bla n k f or fracti o n n u m ber) o n t he C R F pa ges. 
C o n versi o n t o S nelle n n otati o n will n ot be nee de d.
T he sa me o pt ot y pe will be use d t hr o u g h o ut t he st u d y f or a s pecific patie nt, a n d t he ri g ht e ye 
s h o ul d be teste d first.  T he refracti ve err or will be deter mi ne d at t he Scree ni n g visit.  T he 
e xa mi ner s h o ul d e ns ure t hat patie nts are seate d c o mf orta bl y  a n d t hat t he y d o n ot m o ve t heir 
hea d f or war d or bac k war d d uri n g testi n g.  Patie nts will be t ol d t hat t he c hart c o ntai ns o nl y  
letters.
T he li ne rea d wit h 2 or fe wer err ors will be rec or de d.  If 3 of t he 5 letters o n a li ne are rea d 
c orrectl y, t he patie nt will be gi ve n cre dit f or t hat li ne.  F or e xa m ple, if t he patie nt rea ds 
2 0/ 2 5 + 3, 2 0/ 2 0 will be rec or de d. 
A decrease i n best -c orrecte d vis ual ac uit y of 3 li nes or m ore fr o m t he Scree ni n g visit will be 
re p orte d as a n a d verse e ve nt.  A n a d verse e ve nt of vis ual ac uit y will be c o u nte d fr o m t he 
f oll o wi n g li nes: 2 0/ 2 0 or better, 2 0/ 2 5, 2 0/ 3 0, 2 0/ 4 0, 2 0/ 5 0, 2 0/ 6 0, 2 0/ 7 0, 2 0/ 8 0, 2 0/ 1 0 0, 
2 0/ 1 2 5, 2 0/ 1 5 0, a n d 2 0/ 2 0 0.  If t he ac uit y  at scree ni n g is better t ha n 2 0/ 2 0, t he decrease will 
be calc ulate d fr o m 2 0/ 2 0. 
 

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I n t he e ve nt of a decrease i n vis ual ac uit y of 3 li nes or m ore fr o m scree ni n g, refracti o n will 
be rec hec ke d at all s u bse q ue nt st u d y  visits.  A c ha n ge i n refracti o n p o wer (s p herical or 
c yli n drical) of ± 1. 2 5 di o pters c o m pare d wit h t he scree ni n g e xa mi nati o n will be re p orte d as 
a n a d verse e ve nt.
7. 3. 4. 2. I ntr a oc ul ar Press ure Me as ure me nt
I ntra oc ular press ure (I O P) will be meas ure d usi n g a cali brate d G ol d ma n n a p pla nati o n 
t on o meter or a n o n - c o ntact met h o d ( p uff) wit h t he T o n o pe n, Sc hi otz or Re b o u n d t o n o meter.  
I O P data ma y be p o ole d t o get her f or a nalys is.  B ot h e yes will be teste d, wit h t he ri g ht e ye 
prece di n g t he left e y e.  T he o perat or will i nitiall y set t he dial at 1 0 m m H g, t he n l o o k t hr o u g h 
t he slit la m p a n d a dj ust t he dial t o ta ke t he rea di n g, a n d t he n rec or d t he res ults, i ncl u di n g t he 
ti me assess me nt is ma de. 
A n y  IO P i ncrease of greater t ha n 1 0 m m H g a b o ve baseli ne or a n y I O P t hat i ncreases a b o ve 
2 5 m m H g will be re p ort e d as a n a d verse e ve nt ( A E).
7. 3. 4. 3. Slit - L a m p Bi o micr osc o p y
Slit -la m p bi o micr osc o p y wit h fl u orescei n will be perf or me d.  At eac h sc he d ule d visit, 
de p ositi o n of pi g me nt o n t he c or neal e n d ot helial la y er or t he le ns ca ps ule or a n y 
a b n or malities of t he li ds, c o nj u nct i vae, c or nea, a nteri or c ha m ber, iris, or le ns (see Le ns 
Gra di n g) will be gra de d as mil d, m o derate, or se vere.  Slit -la m p bi o micr osc o p y s h o ul d 
prece de I O P meas ure me nt a n d t he a d mi nistrati o n of a n y p u pil -dilati n g a ge nt f or 
o p ht hal m osc o p y .
Cells a n d flare i n t he a nteri or c ha m ber s h o ul d be n ote d d uri n g t he slit-la m p e xa mi nati o n.
I ntra oc ular I nfla m mati o n Gra di n g Scale f or Bi o micr osc o py:
 
C CI

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D uri n g t he st u d y , a n y ne w fi n di n g or deteri orati o n fr o m baseli ne fi n di n gs s h o ul d be re p orte d 
as a n a d verse e ve nt.
7. 3. 4. 4. Le ns Gr a di n g
W he n d oi n g le ns gra di n g, gra ders m ust be a ware of t heir bias, eit her c o nsci o us or 
u nc o nsci o us, t hat cataract is a u ni directi o nal disease t hat stea dil y  gets w orse wit h a ge.  
Beca use of t his bias, if o ne k n o ws t he baseli ne or a n y  pri or le ns gra de, it is li kely t hat t he 
gra de assi g ne d at a f oll o w- u p visit will be hi g her.   T o a v oi d t his p ote ntial o bser vati o n bias, 
t he gra der will re mai n mas ke d t o earlier le ns gra di n g a n d s h o ul d al wa ys start wit h a bla n k 
case re p ort f or m ( C R F).  T he Wisc o nsi n A R E D S 2 0 0 8 Cli nical Le ns O pacit y  Gra di n g 
Pr oce d ure will be use d. 2 7  O nce t he p u pils are dilate d t o at least 5 m m, use slit la m p wit h 
~ 1 0 X ma g nificati o n a n d bri g htest bea m i nte nsit y .

N uclear o pacit y.

Orie nt bea m at 4 5° t o vie wi n g a xis .

A dj ust slit bea m t o sta n dar d para meters: 8 m m hei g ht a n d 0. 3 m m wi dt h .

C o m pare o palesce nce of n ucle us wit h t h ose o n t he pr o vi de d p oc ket car d of 
sta n dar d p h ot os.

C ortical a n d P osteri or S u bca ps ular Cataract ( P S C) o pacities .

Select wi de slit bea m setti n g o pti m u m f or retr o -ill u mi nati o n of le ns.

Vis ualize le ns o pacities a gai nst re d f u n d us refle x bac k gr o u n d .

C o u nt o nl y  o pacities defi nitel y visi ble a gai nst re d refle x.

Me ntall y  c o m bi ne all c ortical o pacities i nt o o ne c o nti g u o us area.

C o m pare t otal o pacit y area wit h t h ose o n t he pr o vi de d p oc ket car d of sta n dar d 
p h ot os .

Gra de eac h t y p e of o pacit y i n half ste ps fr o m < 1 t o > 3 ( 1 = mil d, 2 = m o derate a n d 
3 =se vere) usi n g t he scale defi ne d o n t he pr o vi de d p oc ket car d of sta n dar d p h ot os .
7. 3. 4. 5. F u n d usc o p y ( O p ht h al m osc o p y)
F u n d usc o p y  ( O p ht hal m osc o p y) will be perf or me d after dilati o n of t he p u pils t o e xa mi ne t he 
vitre o us b o d y , reti na, a n d o ptic ner ve hea d.  At scree ni n g, a ny a b n or malities a n d pat h ol o gic 
fi n di n gs will be gra de d as mil d, m o derate, or se vere. 
A n y  ne w fi n di n gs or deteri orati o n fr o m baseli ne fi n di n gs will be re p orte d as a n a d verse 
e ve nt.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 7 5
7. 3. 5. Ot her S afet y Assess me nts
A f ull p h y sical e xa mi nati o n i ncl u di n g a n e xa mi nati o n of all maj or b o d y sys te ms, hei g ht (at 
scree ni n g o nly), wei g ht, bl o o d press ure a n d p ulse rate w hic h ma y be pe rf or me d b y a 
p h y sicia n, re gistere d n urse or ot her q ualifie d healt h care pr o vi der, will be re q uire d at 
scree ni n g, Da y -1, Da y  1 of C y cles 1 a n d 2 , a n d at t he e n d of treat me nt. 
S y m pt o m directe d p h y sical e xa mi nati o ns, bl o o d press ure a n d p ulse rate will be perf or me d at 
s u bse q ue nt visits.
Perf or ma nce Stat us: T he Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) perf or ma nce stat us 
scale will be use d (see 1 7. 4 A p pe n di x 4 ). 
7. 4. P h ar m ac o ki netic Assess me nts 
Bl o o d sa m ples will be c ollecte d f or i nte nsi ve P K assess me nts of pal b ocicli b d uri n g t he 
si n gle-d ose P K part i n Lea d -i n p hase a n d m ultip le-d ose P K part i n C y cle 1 as o utli ne d i n t he 
S C H E D U L E O F A C TI VI TI E S .  S parse P K sa m ples will be c ollecte d f or deter mi nati o n of 
letr oz ole c o nce ntrati o n at pre d ose i n Cycles 1 a n d 2 as o utli ne d i n t he S C H E D U L E O F 
A C TI VI TI E S .  A d diti o nal bl o o d sa m ples ma y be c ollecte d at discreti o n of i n vesti gat ors. 
All eff orts will be ma de t o o btai n t he P K sa m ples at t he sc he d ule d n o mi nal ti me relati ve t o 
d osi n g.  T he act ual ti me of t he sa m ple c ollecti o n a n d t he m ost rece nt d osi n g ti me b ot h pri or 
t o a n d after eac h sa m ple c ollecti o n will be rec or de d i n t he C R F.  F or i nstance, d osi n g ti mes 
o n b ot h C y cle 1 Da y 1 8 a n d Da y 1 9 s h o ul d be rec or de d f or P K sa m ple c ollecti o n o n Da y 1 9; 
d osi n g ti mes of letr oz ole o n b ot h C y cle 1 Da y 2 8 a n d C ycle 2 Da y 1 s h o ul d be rec or de d f or 
P K sa m ple c ollecti o n of letr oz ole o n C y cle 2 Da y 1. I n case t hat t he sa m ples ha ve t o be 
c ollecte d i n a later c ycle, t he sa me r ule s h o ul d be a p plie d.  T he date of a n y misse d d oses 
s h o ul d als o be rec or de d i n t he C R F.
P K sa m ple c ollecti o ns sc he d ule d at stea d y state after m ulti ple d osi n g of pal b ocicli b s h o ul d 
be c o n d ucte d gi ve n t hat t here is n o d osi n g i nterr u pti o n f or at least 8 da y s pri or t o sa m ple 
c ollecti o n.  If t he sa m ple c ollecti o n is misse d f or a n y  reas o n or if t he P K data c ollecte d are 
dee me d n ot e val ua ble b y t he S p o ns or, t he P K sa m ple c ollecti o n ma y be re peated d uri n g a 
later c ycle.  Patie nts m ust be i nstr ucte d t o wit h h ol d t heir dail y  d ose of st u d y dr u gs o n 
P K sa m pli n g da ys u ntil safety assess me nts (ie , he mat ol o g y , bl o o d c he mistr y, a n d E C Gs) a n d 
pre - d ose P K sa m ple c ollecti o n ha ve bee n c o m plete d.  It is al wa ys rec o m me n de d t hat 
self-a d mi nistrati o n of st u d y dr u gs s h o ul d occ ur i n t he m or ni n g, es pecially o n Da y s 1 8, 1 9, 
2 0 a n d 2 8 of C ycle 1 w he n pre -d ose P K sa m ples will be ta ke n o n t he ne xt da y , t o e ns ure 
pre - d ose P K sa m ples are c ollecte d at least 2 0 h o urs after t he pre vi o us d ose a n d i m me diatel y  
bef ore t he ne xt d ose.
P K bl o o d sa m ples will be assa y e d f or pal b ocicli b a n d letr oz ole usi n g a vali date d a nal yt ical 
met h o d i n c o m plia nce wit h Pfizer sta n dar d o perati n g pr oce d ures.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 7 6
7. 4. 1. Pl as m a f or A n al ysis of P al b ocicli b ( P D -0 3 3 2 9 9 1)
D uri n g all st u d y  peri o ds, bl o o d sa m ples ( 2 m L) t o pr o vi de a mi ni m u m of 0. 5 m L plas ma f or 
p har mac o ki netic a nal ys is will be c ollecte d i nt o a p pr o priately la bele d t u bes c o ntai ni n g 
K 2E D T A at ti mes s pecifie d i n t he S T U D Y P R O C E D U R E S secti o n of t he pr ot oc ol.
T he act ual ti mes ma y  c ha n ge b ut t he n u m ber of sa m ples will re mai n t he sa me.  All eff orts 
will be ma de t o o btai n t he p har mac o ki netic sa m ples at t he e xact n o mi nal ti me relati ve t o 
d osi n g. Pre d ose sa m ples s h o ul d be o btai n e d i m me diatel y pri or t o t he m or ni n g d ose ( wit hi n 
1 5 mi n utes pri or t o d osi n g).  O n t hese da y s, a d mi nistrati o n of pal b ocicli b a n d letr oz ole 
s h o ul d occ ur i n t he C R U t o e ns ure t he pre-d ose P K sa m ples ca n be c ollecte d, s o d uri n g t he 
o ut patie nt visits o n Da y s 1, 1 9 a n d 2 0 i n C y cle 1 a n d Da y 1 i n C ycle 2, patie nts s h o ul d be 
i nstr ucte d t o bri n g t he dr u g s u p ply a n d a d mi nister t he dr u gs i n t he C R U after c o m pleti o n of 
P K c ollecti o n o n t hat da y .
F or P K c ollecti o ns sc he d ule d bef ore 2 4 h o urs p ost - d ose i n C R U, de viati o n of re q uire d 
c ollecti o n ti me wit hi n 1 0 % of t he n o mi nal ti me (e g, wit hi n 6 mi n utes of a 6 0 -mi n ute sa m ple) 
fr o m d osi n g will n ot be ca pt ure d as a pr ot oc ol de viati o n, as l o n g as t he act ual c ollecti o n ti me 
is rec or de d.  F or sa m ples sc he d ule d after 2 4 h o urs p ost-d ose, c ollecti o ns o btai ne d wit hi n 
1 0 % of t he sa m pli n g i nter val (ie, 2 4 h o urs i n t his st u d y ) will n ot be ca pt ure d as a pr ot oc ol 
de viati o n as l o n g as t he act ual c ollecti o n ti me is rec or de d.  F or t he P K sa m ples c ollecte d 
d uri n g o ut patie nt visits, de viati o n of re q uire d c ollecti o n ti me larger t ha n 1 0 % of sa m pli n g 
i nter val (ie, 2 4 h o urs i n t his st u d y) ma y be acce pta ble as l o n g as t he act ual c ollecti o n ti me is 
rec or de d.

Sa m ples will be ce ntrif u ge d at a p pr o xi matel y  1 7 0 0 x g f or a b o ut 1 0 mi n utes at 4° C.  
T he plas ma will be st ore d i n a p pr o priatel y la bele d scre w -ca p pe d p ol y pr o p yle ne t u bes 
at a p pr o xi matel y -2 0° C wit hi n 1 h o ur of c ollecti o n.

Sa m ples will be a nal y ze d f or pal b ocicli b (P D -0 3 3 2 9 9 1 ) usi n g a vali date d a nal y tical 
met h o d i n c o m plia nce wit h Pfizer sta n dar d o perat i n g pr oce d ures. 


Refer t o t he La b orat or y  Ma n ual f or detaile d c ollecti o n, pr ocessi n g a n d s hi p pi ng pr oce d ures.
7. 4. 2. Pl as m a f or A n al ysis of Letr oz ole
D uri n g all st u d y  peri o ds, bl o o d sa m ples ( 2 m L) t o pr o vi de a mi ni m u m of 0. 5 m L plas ma f or 
p har mac o ki netic a nal ys is will be c ollecte d i nt o a p pr o priately la bele d t u bes c o ntai ni n g 
K 2E D T A at ti mes s pecifie d i n t he S T U D Y P R O C E D U R E S secti o n of t he pr ot oc ol.
 
C CI

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 7 7
T he act ual ti mes ma y  c ha n ge b ut t he n u m ber of sa m ples will re mai n t he sa me.  All 
eff orts will be ma de t o o btai n t he p har mac o ki netic sa m ples at t he e xact n o mi nal ti me relati v e 
t o d osi n g.  H o we ver, sa m ples o btai ne d wit hi n 1 0 % of t he n o mi nal ti me (e g, wit hi n 6 mi n utes 
of a 6 0 mi n ute sa m ple) fr o m d osi n g will n ot be ca pt ure d as a pr ot oc ol de viati o n, as l o n g as 
t he e xact ti me of t he sa m ple c ollecti o n is n ote d o n t he s o urce d oc u me nt a n d data c ollecti o n 
t o ol (e g, C R F).  Pre d ose sa m ples s h o ul d be o btai ne d i m me diatel y pri or t o t he m or ni n g d ose.

Sa m ples will be ce ntrif u ge d at a p pr o xi matel y  1 7 0 0 x g f or a b o ut 1 0 mi n utes at 4° C.  
T he plas ma will be st ore d i n a p pr o priatel y la bele d scre w -ca ppe d p ol y pr o p yle ne t u bes 
at a p pr o xi matel y -2 0° C wit hi n 1 h o ur of c ollecti o n. 

Sa m ples will be a nal y ze d f or letr oz ole usi n g a vali date d a nal yt ical met h o d i n 
c o m plia nce wit h Pfizer sta n dar d o perati n g pr oce d ures.


Refer t o t he La b orat or y  Ma n ual f or detaile d c ollecti o n, pr ocessi n g a n d s hi p pi n g pr oce d ures.
7. 4. 3. S hi p me nt of P h ar m ac o ki netic S a m ples
T he s hi p me nt a d dress a n d assa y la b c o ntact i nf or mati o n will be pr o vi de d t o t he i n vesti gat or 
site pri or t o i nitiati o n of t he st u d y.
7. 5. Bi o m ar ker Assess me nts
S ki n bi o ps y  tiss ues a n d bl o o d sa m ples will be c ollecte d f or bi o mar ker assess me nts of 
pal b ocicli b at pre -d ose a n d d ur i n g t he si n gle a n d m ulti ple d ose P K parts as descri be d i n 
S C H E D U L E O F A C TI VI TI E S .  All t he bi o mar ker sa m pli n gs are sc he d ule d at t he sa me ti me 
wit h s o me of t he P K sa m pli n gs.   All eff orts s h o ul d be ma de t o c o or di nate bi o mar ker sa m ple 
c ollecti o ns i m me diatel y after t he c o m pleti o n of P K sa m pli n gs wit h t he act ual P K c ollecti o n 
ti me bei n g t he cl osest t o t he n o mi nal ti mes.  If P K sa m pli n gs sc he d ule d at stea d y state are 
c o n d ucte d i n a later c ycle f or a n y reas o n, sa m ples f or bi o mar ker assess me nts s h o ul d be als o 
c ollecte d at t he sa me ti me t o e ns ure t he c ollecti o ns are ti me- matc he d bet wee n P K a n d 
bi o mar ker.  T he act ual ti me of t he sa m ple c ollecti o ns will be rec or de d o n t he s o urce 
d oc u me nts a n d C R F.
7. 5. 1. S ki n Bi o ps y
S ki n p u nc h bi o ps y  tiss ues are re q uire d fr o m e nr olle d patie nts f or bi o mar ker assess me nts 
( p R b a n d Ki 6 7) a n d will be c ollecte d o n t he pla n ne d da ys descri be d i n S C H E D U L E O F 
A C TI VI TI E S .  I n or der t o a v oi d i nte nsi ve c ollecti o ns, patie nts will be ra n d o mize d i nt o 
2 gr o u ps ass ociate d wit h differe nt sc he d ules i n Lea d -i n p hase a n d C y cle 1, as i n dicate d i n t he 
 
C CI

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 7 8
f o ot n ote of S C H E D U L E O F A C TI VI TI E S . W he ne ver p ossi ble, all eff orts s h o ul d be ma de t o 
c o n d uct s ki n tiss ue c ollecti o n wit hi n 3 0 mi n utes after t he c o m pleti o n of P K sa m pli n gs. 
Bi o ps y  at areas wit h c ol ore d ( pi g me nte d) s ki n c o nt o ur s h o ul d be a v oi de d.  S ki n bi o ps y  is 
rarely c o ntrai n dicate d.  Preca uti o ns s h o ul d be ta ke n if a patie nt has a hist or y  of a n aller g y t o 
l ocal or t o pical a nest hetics, a n d ot her materials t o be use d f or bi o ps y pr oce d ure , or has 
e vi de nce of a n acti ve i nfecti o n at t he bi o ps y  site.  Pre bi o ps y e val uati o n s h o ul d als o i ncl u de a 
hist or y  f or a n y blee di n g dis or ders, c oa g ul o pat h y, a n d me dicati o ns t hat mi g ht affect 
he m ostasis t hr o u g h t heir a ntic oa g ulati ve effects, or pri or hist or y  of blee di n g pr o ble ms after a 
s ur ger y or pr oce d ure, w hic h ma y i n dicate a n i ntri nsic cl otti n g fact or deficie nc y. S uc h fact ors 
d o n ot precl u de s ki n bi o ps y , b ut ma y pr ol o n g or c o m plicate he m ostasis. I n s o me rare 
c o n diti o ns, kel oi d mi g ht de vel o p, es peciall y f or patie nts w h o ha ve hist or y  of disse mi nate d 
kel oi d .
Most c o m plicati o ns of s ki n bi o ps y , if w o ul d de vel o p, are mi n or a n d te m p orar y.  If 
t he patie nt e x perie nce se vere br uisi n g, te n der ness, i nfecti o n or u nc o ntr olle d blee di n g as well 
as relate d c o n diti o ns n ote d b y  i n vesti gat ors after c o n d ucti n g t he pr oce d ure, i n vesti gat ors 
s h o ul d re p ort t o t he s p o ns or i m me diatel y.  Base d o n me dical discreti o n a n d disc ussi o n wit h 
s p o ns or, if t he patie nt is c o nsi dere d as i na p pr o priate t o c o nti n ue t he s ki n bi o ps y pr oce d ure, 
i n vesti gat ors c o ul d c o nsi der wit h h ol di n g te m p oraril y or ca ncelli n g t he f oll o wi n g sc he d ule d 
bi o psies.
Retr os pecti ve testi n g of f or mali n fi xe d paraffi n e m be d de d ( F F P E) tiss ue sa m ples f or p R b a n d 
Ki 6 7 e x pressi o n will be perf or me d i n a ce ntral la b orat or y  desi g nate d by t he s p o ns or.  Res ults 
fr o m t his assa y will be use d f or e x pl orat or y a nalys es bet wee n P K a n d p har mac o d y na mics 
mar kers.
Detaile d i nf or mati o n a b o ut bi o mar ker sa m ple c ollecti o n, pre parati o n, st ora ge, la beli n g, a n d 
s hi p me nt is i n dicate d i n t he La b orat or y Ma n ual.
7. 5. 2. T h y mi di ne Ki n ase Bl o o d Test
Bl o o d sa m ples ( 3 m L) t o pr o vi de a mi ni m u m of 1 m L  ser u m will be c ollecte d fr o m all t he 
e nr olle d patie nts i nt o a p pr o priatel y la bele d t u bes f or assess me nts of t h ymi di ne ki nase ( T K) 
acti vit y at ti me p oi nts descri be d i n S C H E D U L E O F A C TI VI TI E S .  All t he sa m ple 
c ollecti o ns f or T K a nal ys is s h o ul d occ ur i m me diatel y after t he c o m pleti o n of P K sa m pli n gs 
wit h o ut perf or mi n g ve ni p u nct ure a gai n at t he sa me ti me p oi nt.  T K sa m ples c ollecte d wit hi n 
1 5 mi n utes after t he c o m pleti o n of P K sa m pli n gs will be c o nsi dere d as pr ot oc ol c o m plia nt. 
Retr os pecti ve testi n g of ser u m sa m ples f or T K acti vit y  will be perf or me d in a ce ntral 
la b orat or y desi g nate d b y t he s p o ns or.  Res ults fr o m t his testi n g will be use d f or e x pl orat or y 
a nal ys is bet wee n P K a n d p har mac o d yna mics mar kers.
Detaile d i nf or mati o n a b o ut bi o mar ker sa m ple c ollecti o n, pre parati o n, st ora ge, la beli n g, a n d 
s hi p me nt is i n dicate d i n t he La b orat or y Ma n ual.
8. A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S
T he defi niti o ns of a n A E a n d a n S A E ca n be f o u n d i n A p pe n di x 3 .
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 7 9
A Es will be re p orte d b y t he partici pa nt ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or 
t he partici pa nt's le gally a ut h orize d re prese ntati ve).
T he i n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble t o p urs ue 
a n d o btai n a de q uate i nf or mati o n b ot h t o deter mi ne t he o utc o me a n d t o assess w het her it 
meets t he criteria f or classificati o n as a n S A E or t hat ca use d t he partici pa nt t o disc o nti n ue t he 
st u d y i nter ve nti o n (see Secti o n 6 ). 
I n a d diti o n, t he i n vesti gat or ma y be re q ueste d b y Pfizer Safety t o o btai n s pecific f oll o w - u p 
i nf or mati o n i n a n e x pe dite d fas hi o n.
8. 1. Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d S A E I nf or m ati o n
T he ti me peri o d f or acti vel y  elicitin g a n d c ollecti n g A Es a n d S A Es (“acti ve c ollecti o n 
peri o d”) f or eac h partici pa nt be gi ns fr o m t he ti me t he partici pa nt pr o vi des i nf or me d c o nse nt, 
w hic h is o btai ne d bef ore t he partici pa nt’s partici pati o n i n t he st u d y  (ie, bef ore u n der g oi n g 
a n y st u d y-relate d pr oce d ure a n d/ or recei vi n g i n vesti gati o nal pr o d uct), t hr o u g h a n d i ncl u di n g 
a mi ni m u m of 2 8 cale n dar da y s after t he last a d mi nistrati o n of t he i n vesti gati o nal pr o d uct.
F or partici pa nts w h o are scree n fail ures, t he acti ve c ollecti o n peri o d e n ds w he n scree n f ail ure 
stat us is deter mi ne d.
Me dical occ urre nces t hat be gi n bef ore t he start of st u d y  i nter ve nti o n b ut after o btai ni n g 
i nf or me d c o nse nt will be rec or de d o n t he Me dical Hist or y/ C urre nt Me dical C o n diti o ns 
secti o n of t he case re p ort f or m ( C R F), n ot t he A E secti o n.
F oll o w -u p b y  t he i n vesti gat or c o nti n ues t hr o u g h o ut a n d after t he acti ve c ollecti o n peri o d a n d 
u ntil t he e ve nt or its se q uelae res ol ve or sta bilize at a le vel acce pta ble t o t he i n vesti gat or, a n d 
Pfizer c o nc urs wit h t hat assess me nt.
I n vesti gat ors are not o bli gate d t o acti vel y see k A Es or S A Es after c o ncl usi o n of t he st u d y 
partici pati o n.  H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a deat h, at a n y ti me 
after a partici pa nt has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt t o be 
reas o na bly relate d t o t he st u d y  i nter ve nti o n or st u d y partici pati o n, t he i n vesti gat or m ust 
pr o m ptl y  n otif y t he s p o ns or.
8. 1. 1. Re p orti n g S A Es t o Pfizer S afet y
All S A Es occ urri n g i n a partici pa nt d uri n g t he acti ve c ollecti o n peri o d are re p orte d t o Pfizer 
Safet y o n t he Cli nical Trial S A E Re p ort F or m i m me diatel y  a n d u n der n o circ u msta nce 
s h o ul d t his e xcee d 2 4 h o urs, as i n dicate d i n A p pe n di x 3 .  T he i n vesti gat or will s u b mit a n y 
u p date d S A E data t o t he s p o ns or wit hi n 2 4 h o urs of it be i n g a vaila ble.
If a partici pa nt be gi ns a ne w a ntica ncer t hera py, S A Es occ urri n g d uri n g t he a b o ve- i n dicate d 
acti ve c ollecti o n peri o d m ust still be re p orte d t o Pfizer Safet y  irres pecti ve of a n y i nter ve ni n g 
treat me nt.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 0
S A Es occ urri n g i n a partici pa nt after t he acti ve c ollecti o n peri o d has e n de d are re p orte d t o 
Pfizer Safet y  if t he i n vesti gat or bec o mes a ware of t he m; at a mi ni m u m, all S A Es t hat t he 
i n vesti gat or belie ves ha ve at least a reas o na ble p ossi bilit y of bei n g relate d t o i n vesti gati o nal 
pr o d uct m ust be re p orte d t o Pfizer Safet y .
8. 1. 2. Rec or di n g N o nseri o us A Es a n d S A Es o n t he C R F
D uri n g t he acti ve c ollecti o n peri o d, b ot h n o nseri o us A Es a n d S A Es are rec or de d o n t he C R F.
If a partici pa nt be gi ns a ne w a ntica ncer t hera py, S A Es occ urri n g d uri n g t he a b o ve i n dicate d 
acti ve c ollecti o n peri o d m ust still be re p orte d t o Pfizer Safet y irres pecti ve of a n y i nter ve ni n g 
treat me nt.
S A Es occ urri n g i n a partici pa nt after t he acti ve c ollecti o n peri o d has e n de d are re p orte d t o 
Pfizer Safet y  if t he i n vesti gat or bec o mes a ware of t he m; at a mi ni m u m, all S A Es t hat t he 
i n vesti gat or belie ves ha ve at least a reas o na ble p ossi bilit y of bei n g relate d t o i n vesti gati o nal 
pr o d uct m ust be re p orte d t o Pfizer Safet y .
8. 2. Met h o d of Detecti n g A Es a n d S A Es
T he met h o d of rec or di n g, e val uati n g, a n d assessi n g c a usalit y of A Es a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n A p pe n di x 3 .
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A Es a n d/ or S A Es.  O pe n -e n de d a n d 
n o nlea di n g ver bal q u esti o ni n g of t he partici pa nt is t he preferre d met h o d t o i n q uire a b o ut 
A E occ urre nces.
8. 3. F oll o w - u p of A Es a n d S A Es
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h 
partici pa nt at s u bse q ue nt visits/c o ntacts.  F or eac h e ve nt, t he i n vesti gat or m ust p urs ue a n d 
o btai n a de q uate i nf or mati o n u ntil res ol uti o n, sta bilizati o n, t he e ve nt is ot her wise e x plai ne d, 
or t he partici pa nt is l ost t o f oll o w- u p (as defi ne d i n Secti o n 6. 6 ).
I n ge neral, f oll o w- u p i nf or mati o n will i ncl u de a descri pti o n of t he e ve nt i n s ufficie nt detail t o 
all o w f or a c o m plete me dical assess me nt of t he case a n d i n de pe n de nt deter mi nati o n of 
p ossi ble ca usalit y .  A ny i nf or mati o n rele va nt t o t he e ve nt, s uc h as c o nc o mita nt me dicati o ns 
a n d ill nesses, m ust be pr o vi de d.  I n t he case of a partici pa nt deat h, a s u m mar y of a vaila ble 
a ut o ps y fi n di n gs m ust be s u b mitte d as s o o n as p ossi ble t o Pfizer Safet y. 
F urt her i nf or mati o n o n f oll o w -u p pr oce d ures is gi ve n i n A p pe n di x 3 .
8. 4. Re g ul at or y Re p orti n g Re q uire me nts f or S A Es
Pr o m pt n otificati o n b y  t he i n vesti gat or t o t he s p o ns or of a n S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of partici pa nts a n d t he safety of a 
st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met.
0
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 1
T he s p o ns or has a le gal res p o nsi bilit y  t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a ge ncies a b o ut t he safety of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n.  T he 
s p o ns or will c o m pl y wit h c o u ntr y-s pecific re g ulat or y re q uire me nts relati n g t o safety 
re p orti n g t o t he re g ulat or y a ut h ority, i nstit uti o nal re vie w b oar ds (I R Bs)/et hics c o m mittees 
( E Cs), a n d i n vesti gat ors.
I n vesti gat or safet y re p orts m ust be pre pare d f or s us pecte d u ne x pecte d seri o us a d verse 
reacti o ns ( S U S A Rs) acc or di n g t o l ocal re g ulat or y re q uire me nts a n d s p o ns or p olic y a n d 
f or war de d t o i n vesti gat ors as necessar y.
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a n S A E or ot her 
s pecific safet y i nf or mati o n (e g, s u m mar y or listi n g of S A Es) fr o m t he s p o ns or will re vie w 
a n d t he n file it al o n g wit h t he i n vesti gat or’s br oc h ure a n d will n otif y  t he I R B/ E C, if 
a p pr o priate acc or di n g t o l ocal re q uire me nts.
8. 4. 1. E x p os ure D uri n g Pre g n a nc y or Bre astfee di n g, a n d Occ u p ati o n al E x p os ure
E x p os ure t o t he i n vesti gati o nal pr o d uct u n der st u d y  d uri n g pre g na nc y or breastfee di n g a n d 
occ u pati o nal e x p os ure are re p orta ble t o Pfizer Safet y  wit hi n 2 4 h o urs of i n vesti gat or 
a ware ness.
8. 4. 2. E x p os ure D uri n g Pre g n a nc y
Details of all pre g na ncies i n fe male partici pa nts will be c ollecte d after t he start of st u d y  
i nter ve nti o n a n d u ntil 2 8 da y s after disc o nti n ui n g t he st u d y i nter ve nti o ns. 
If a pre g na nc y is re p orte d, t he i n vesti gat or s h o ul d i nf or m t he s p o ns or wit hi n [ 2 4 h o urs] of 
lear ni n g of t he pre g na nc y  a n d s h o ul d f oll o w t he pr oce d ures o utli ne d i n A p pe n di x 8 .
A b n or mal pre g na nc y  o utc o mes (e g, s p o nta ne o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g na nc y ) are c o nsi dere d S A Es.
8. 4. 3. E x p os ure D uri n g Bre astfee di n g
Sce nari os of e x p os ure d uri n g breastfee di n g m ust be re p orte d, irres pecti ve of t he prese nce of 
a n ass ociate d S A E, t o Pfizer Safet y wit hi n 2 4 h o urs of t he i n vesti gat or’s a ware ness, usi n g t he 
C T S A E Re p ort F or m.  A n e x p os ure d uri n g breast fee di n g re p ort is n ot create d w he n a Pfizer 
dr u g s pecificall y  a p pr o ve d f or use i n breastfee di n g w o me n (e g, vita mi ns) is a d mi nistere d i n 
acc or d wit h a ut h orize d use.  H o we ver, if t he i nfa nt e x perie nces a n S A E ass ociate d wit h s uc h 
a dr u g’s a d mi nistrati o n, t he S A E is re p orte d t o get her wit h t he e x p os ure d uri n g breastfee di n g.
8. 4. 4. Occ u p ati o n al E x p os ure
A n occ u pati o nal e x p os ure occ urs w he n, d uri n g t he perf or ma nce of j o b d uties, a pers o n 
( w het her a healt hcare pr ofessi o nal or ot her wise) gets i n u n pla n ne d direct c o ntact wit h t he 
pr o d uct, w hic h ma y  or ma y n ot lea d t o t he occ urre nce of a n A E.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 2
A n occ u pati o nal e x p os ure is re p orte d t o Pfizer Safet y  wit hi n 2 4 h o urs of t he i n vesti gat or’s 
a ware ness, usi n g t he C T S A E Re p ort F or m, re gar dless of w het her t here is a n ass ociate d 
S A E.  S i nce t he i nf or mati o n d oes n ot pertai n t o a partici pa nt e nr olle d i n t he st u d y, t he 
i nf or mati o n is n ot rec or de d o n a C R F; h o we ver, a c o p y of t he c o m plete d C T S A E Re p ort 
F or m is mai ntai ne d i n t he i n vesti gat or site file.
8. 5. Dise ase -Rel ate d E ve nts a n d/ or Dise ase - Rel ate d O utc o mes N ot Q u alif yi n g as A Es or 
S A Es
T he f oll o wi n g disease -relate d e ve nts ( D R Es) are c o m m o n i n partici pa nts wit h ca ncer a n d ca n 
be seri o us/life t hreate ni n g:
Pr o gressi o n of t he mali g na nc y  u n der st u dy (i ncl u di n g si g ns a n d sy m pt o ms of 
pr o gressi o n) wi ll n ot be re p orte d as S A Es u nless t he o utc o me is fatal wit hi n t he safety 
re p orti n g peri o d.
Disease pr o gressi o n relate d e ve nts t hat are fatal will n ot be re p orte d i n di vi d uall y  i n a n 
e x pe dite d ma n ner beca use t he y are a ntici pate d t o occ ur i n t he st u dy p o p ulat i o n.
Beca use t hese e ve nts are t y picall y ass ociate d wit h t he disease u n der st u d y, t he y will n ot be 
re p orte d acc or di n g t o t he sta n dar d pr ocess f or e x pe dite d re p orti n g of S A Es e ve n t h o u g h t he 
e ve nt ma y meet t he defi niti o n of a n S A E.  T hese e ve nts will be rec or de d o n t he 
c orres p o n di n g C R F pa ge i n t he partici pa nt’s C R F wit hi n t he a p pr o priate ti me fra me. 
N O T E: H o we ver, if eit her of t he f oll o wi n g c o n diti o ns a p plies, t he n t he e ve nt m ust be 
rec or de d a n d re p orte d as a n S A E (i nstea d of a D R E):
T he e ve nt is, i n t he i n vesti gat or’s o pi ni o n, of greater i nte nsit y , fre q ue nc y, or d urati o n 
t ha n e x pecte d f or t he i n di vi d ual partici pa nt.
O R
T he i n vesti gat or c o nsi ders t hat t here is a reas o na ble p ossi bilit y  t hat t he e ve nt was 
relate d t o st u dy i nter ve nti o n.
8. 6. Me dic ati o n Err ors
Me dica ti o n err ors ma y res ult fr o m t he a d mi nistrati o n or c o ns u m pti o n of t he i n vesti gati o nal 
pr o d uct b y t he wr o n g partici pa nt, or at t he wr o n g ti me, or at t he wr o n g d osa ge stre n gt h. 
E x p os ures t o t he i n vesti gati o nal pr o d uct u n der st u d y  ma y occ ur i n cli nical trial setti n gs, s uc h 
as me dicati o n err ors.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 3
S afet y E ve nt
Rec or de d o n t he C R F
Re p orte d o n t he C T S A E Re p ort 
F or m t o Pfizer S afet y Wit hi n 
2 4 H o urs of A w are ness
Me dicati o n err ors 
All (re gar dless of w het her 
ass ociate d wit h a n A E)
O nl y  if ass ociate d wit h a n S A E
Me dicati o n err ors i ncl u de:

Me dicati o n err ors i n v ol vi n g partici pa nt e x p os ure t o t he i n vesti gati o nal pr o d uct;

P ote ntial me dicati o n err ors or uses o utsi de of w hat is f oresee n i n t he pr ot oc ol t hat d o 
or d o n ot i n v ol ve t he st u d y  partici pa nt.
S uc h me dicati o n err or s occ urri n g t o a st u d y partici pa nt are t o be ca pt ure d o n t he me dicati o n 
err or pa ge of t he C R F, w hic h is a s pecific versi o n of t he A E pa ge.
I n t he e ve nt of a me dicati o n d osi n g err or, t he s p o ns or s h o ul d be n otifie d i m me diatel y.
W het her or n ot t he me dicati o n err or is acc o m pa nie d b y a n A E, as deter mi ne d b y t he 
i n vesti gat or, t he me dicati o n err or is rec or de d o n t he me dicati o n err or pa ge of t he C R F a n d, if 
a p plica ble, a n y ass ociate d A E(s), seri o us a n d n o nseri o us, are rec or de d o n a n A E pa ge of t he 
C R F.
Me dicati o n
err ors s h o ul d be re p orte d t o Pfizer Safet y  wit hi n 2 4 h o urs o n a C T S A E Re p ort 
F or m o nl y w he n ass oci ate d wit h a n S A E .
8. 7. Tre at me nt of O ver d ose
F or t his st u d y , a n y d ose of pal b ocicli b greater t ha n 1 2 5 m g or 1 0 0 m g (after d ose re d ucti o n) or 
7 5 m g (after t w o d ose r e d ucti o n) wit hi n a 2 4 -h o ur ti me peri o d will be c o nsi dere d a n 
o ver d ose.
S p o ns or d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose.  Patie nts w h o i na d verte ntl y 
ta ke 1 e xtra d ose d uri n g a da y m ust be i nstr ucte d t o s ki p t he ne xt da y’s d ose. 
I n t he e ve nt of a n o ver d ose ( m ore t ha n o ne e xtra d ose), t he i n vesti gat or/treati n g p h ysicia n 
s h o ul d:
1.
C o ntact t he me dical m o nit or i m me diatel y .
2.
Cl osel y  m o nit or t he partici pa nt f or a ny A Es/ S A Es a n d la b orat or y  a b n or malities u ntil 
Pal b ocicli b ca n n o l o n ger be detecte d s yste micall y (at least 5 half -lifes or 7 da y s).
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 4
3.
O btai n a bl o o d sa m ple f or P K a nal ys is wit hi n 7 da ys fr o m t he date of t he last d ose of 
st u d y i nter ve nti o n if re q ueste d b y t he me dical m o nit or ( deter mi ne d o n a case-b y -case 
basis).
4.
D oc u me nt t he q ua ntit y of t he e xcess d ose as well as t he d urati o n of t he o ver d ose i n 
t he C R F.
5.
O ver d ose is re p orta ble t o Safet y  o nl y w he n ass ociate d wit h a n S A E.
Decisi o ns re gar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y  t he i n vesti gat or i n 
c o ns ultati o n wit h t he me dical m o nit or base d o n t he cli nical e val uati o n of t he partici pa nt.
9. D A T A A N A L Y SI S/ S T A TI S TI C A L M E T H O D S
Detaile d met h o d ol o g y  f or s u m mar y a n d statistical a nalys es of t he data c ollecte d i n t his st u d y  
will be d oc u me nte d i n a Statistical A nal y sis Pla n, w hic h will be mai ntai ne d b y  t he S p o ns or.  
T his d oc u me nt ma y  m o dif y t he pla ns o utli ne d i n t he pr ot oc ol; h o we ver, a n y maj or 
m o dificati o ns of t he pri mar y  e n d p oi nt defi niti o n a n d/ or its a nal ysis will als o be reflecte d i n a 
pr ot oc ol a me n d me nt.
9. 1. S a m ple Size Deter mi n ati o n
A mi ni m u m of a p pr o xi matel y 2 5 patie nts will be e nr olle d t o t he st u d y a n d t his sa m ple size 
was selecte d t o satisf y  re g ulat or y re q uire me nt b y C F D A i n ter ms of P K e val uati o n i n 
C hi nese p o p ulati o n a n d pr o vi de mea ni ni n gf ul data f or sec o n dar y  e n d p oi nt a nal ysis.  Patie nts 
ma y  be re place d if t here are less t ha n 1 2 patie nts c o m pleti n g t he si n gle-d ose a n d 
m ulti ple - d ose P K sa m ple c ollecti o ns wit h o ut d osi n g i nterr u pti o n or d ose m o dificati o n.
9. 2. A n al ysis of P h ar m ac o ki netics
9. 2. 1. A n al ysis P o p ul ati o ns
T he P K c o nce ntrati o n p o p ulati o n is defi ne d as all patie nt s e nr olle d a n d treate d w h o ha ve at 
least 1 P K c o nce ntrati o n i n t he si n gle-d ose a n d/ or m ulti ple -d ose P K part.
T he P K para meter a nal ys is p o p ulati o n is defi ne d as all patie nt s e nr olle d a n d treate d w h o ha ve 
at least 1 of t he P K para meters of pri m ar y i nterest i n t he si n gle -d ose a n d/ or m ulti ple -d ose P K 
part.
T he P K e val ua ble a nal ys is set is defi ne d as all patie nts i n t he P K para meter a nalys is set w h o 
c o m plete b ot h t he si n gle d ose P K a n d m ulti ple d ose P K parts wit h o ut maj or pr ot oc ol 
de viati o ns.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 5
9. 2. 2. Deri v ati o n of P h ar m ac o ki netic P ar a meters Pri or t o A n al ysis
P K para meters of pal b ocicli b f oll o wi n g si n gle d ose a d mi nistrati o n will be deri ve d fr o m t he 
c o nce ntrati o n-ti me pr ofiles as s h o w n i n t he ta ble bel o w.
P ar a meter
Defi niti o n
Met h o d of Deter mi n ati o n
A U C 1 0
Ar ea u n der t he plas ma 
c o nce ntrati o n vers us ti me c ur ve 
fr o m ti me zer o t o t he ti me 
1 0 h o urs
Li near/ L o g tra pez oi dal met h o d
A U C 2 4
( = A U Cs d,τ)
Area u n der t he plas ma 
c o nce ntrati o n vers us ti me c ur ve 
fr o m ti me zer o t o t he ti me 
2 4 h o urs ( = a d osi n g i nter val of τ)
Li n ear/ L o g tra pez oi dal met h o d
A U C last
Area u n der t he plas ma 
c o nce ntrati o n vers us ti me c ur ve 
fr o m ti me zer o t o t he ti me of t he 
last q ua ntifia ble c o nce ntrati o n 
( Clast)
Li near/ L o g tra pez oi dal met h o d
A U C i nf
Area u n der t he plas ma 
c o nce ntrati o n vers us ti me c ur ve 
fr o m ti me zer o e xtra p olate d t o 
i nfi nite ti me
A U C last + ( C last/ kel), w here Clast is t he 
pre dicte d plas ma c o nce ntrati o n at t he 
last q ua ntifia ble ti me p oi nt esti mate d 
fr o m t he l o g-li near re gressi o n a nal ysis; 
k el is t he ter mi nal p hase rate c o nsta nt 
calc ulate d b y  a li near re gressi o n of t he 
l o g-li near c o nce ntrati o n-ti me c ur ve.
C ma x
Ma xi m u m plas ma c o nce ntrati o n
O bser ve directl y fr o m data
T ma x
Ti me f or C ma x
O bser ve directl y fr o m data as ti me of 
first occ urre nce
C L / F
A p pare nt oral cleara nce
D ose/ A U C i nf
t½
Ter mi n al plas ma half -life
L o g e( 2)/ kel, w here kel is t he ter mi nal 
p hase rate c o nsta nt calc ulate d b y  a 
li near re gressi o n of t he l o g-li near 
c o nce ntrati o n-ti me c ur ve.
M R T
Mea n resi de nce ti me
A U M C i nf/ A U Ci nf, w here A U M Ci nf is 
area u n der t he first m o me nt c ur ve 
fr o m zer o ti me t o i nfi nit y.
Vz/ F
A p pare nt v ol u me of distri b uti o n
D ose/( A U C i nf * k el)
k el
Rate c o nsta nt f or ter mi nal p hase
Calc ulate d b y a li near re gressi o n of t he 
l o g-li near c o nce ntrati o n-ti me c ur ve
P K para meters of pal b ocicli b f oll o wi n g m ulti ple d ose a d mi nistr ati o n will be deri ve d fr o m t he 
c o nce ntrati o n -ti me pr ofiles as s h o w n i n t he ta ble bel o w.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 6
P ar a meter
Defi niti o n
Met h o d of Deter mi n ati o n
A U C ss,
Area u n der t he plas ma 
c o nce ntrati o n vers us ti me c ur ve 
wit hi n a d osi n g i nter val of τ 
( = 2 4 hr) at stea d y state
Li near/ L o g tra pez oi dal met h o d
C ss, ma x
Ma xi m u m plas ma c o nce ntrati o n 
at stea d y state
O bser ve directl y fr o m data
C ss, mi n
Mi ni m u m plas ma c o nce ntrati o n at 
stea d y state
O bser ve directl y fr o m data
C ss,a v
A vera ge plas ma c o nce ntrati o n at 
stea d y state
C ss,a v= A U C ss,/
T ss, ma x
Ti me f or C ss, ma x
O bser ve directl y fr o m data as ti me of 
first occ urre nce wit hi n at stea d y state
C L / F
A p pare nt cleara nce
D ose/ A U C ss,
Vz/ F
A p pare nt v ol u me of distri b uti o n
D ose/ ( A U C ss,* k el)
t½
Ter mi nal half -life
l n ( 2)/ kel,
W here k
el is t he ter mi nal p hase rate 
c o nsta nt f oll o wi n g M D calc ulate d b y a 
li near re gressi o n of t he l o g-li near 
c o nce ntrati o n-ti me c ur ve.
P T F ( D F)
Pea k t o tr o u g h fl uct uati o n at 
stea d y state ( = D F)
( Css, ma x- Css, mi n)/ Css,a v
R ac
O bser ve d acc u m ulati o n rati o   
R ac= A U C ss,τ / A U Cs d,τ, w here A U Cs d,τ is 
A U C 2 4
R ss
Stea d y -state acc u m ulati o n rati o
R ss= A U C ss,τ / A U Ci nf, w here A U Ci nf is 
fr o m si n gle d ose.
Act ual P K sa m pli n g ti mes will be use d i n t he deri vati o n of P K para meters.
S u m mar y  of p har mac o ki netic para meters will be f or P K para meter a nal ysis set a n d P K
e val ua ble a nal ys is set. T he P K para meters A U C 1 0, A U C2 4, A U Clast, A U Ci nf, Cma x , Tma x , 
C L / F, t1/ 2, M R T, Vz/ F a n d Kel o f pal b ocicli b f oll o wi n g si n gle d ose a d mi nistrati o n of 
pal b ocicli b will be liste d a n d s u m marize d descri pti vel y  f or Lea d-i n p hase. T he P K 
para meters A U C ss,, Css, ma x, Css, mi n, Css,a v, Tss, ma x, C L/ F, Vz/ F, t1/ 2, P T F, Rac, a n d Rss of 
pal b ocicli b f oll o wi n g m ulti ple d ose oral a d mi nistrati o n of pal b ocicli b will be liste d a n d 
s u m marize d descri pti vel y. 
T he plas ma c o nce ntrati o n data f or pal b ocicli b a n d letr oz ole will be liste d a n d s u m marize d 
descri pti vel y b y da y a n d n o mi nal P K sa m pli n g ti me f or s u bjects i n t he P K c o nce ntrati o n 
a nal ys is set.  O verla y m ulti ple patie nt pr ofiles of t he plas ma c o nce ntrati o n-ti me data f or 
pal b ocicli b will be pl otte d usi n g act ual P K sa m pli n g ti me (se parate pl ots f or si n gle a n d 
m ulti ple d ose P K).  F or mea n a n d me dia n pl ots of pal b ocicli b pl as ma c o nce ntrati o n-ti me, t he 
n o mi nal P K sa m pli n g ti me will be use d.  Mea n a n d me dia n pr ofiles will be prese nte d o n b ot h 
li near-li near a n d l o g-li near scales.  F or i n di vi d ual patie nt pl ots of pal b ocicli b, t he act ual 
P K sa m pli n g ti me will be use d, w hile t he pre d ose ti me will be set t o zer o. 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 7
T he tr o u g h plas ma c o nce ntrati o n of pal b ocicli b o n Da y s 1 9-2 1 i n C y cle 1 will als o be pl otte d 
f or vis ual i ns pecti o n of stea dy- state c o n diti o n.  T he tr o u g h plas ma c o nce ntrati o n of letr oz ole 
o n Da y s 1 9-2 1 a n d C ycl e 2 Da y 1 will als o be pl otte d f or vis ual i ns pecti o n of m ulti ple d ose 
le vel.
9. 3. Effic ac y A n al ysis 
T he efficac y a nal ys is set is defi ne d as all e nr olle d patie nts w h o start t he treat me nt of C ycle 1. 
T he a nal ys is of efficac y e n d p oi nts de pe n de nt o n disease assess me nt ( P F S, D C , O R a n d D R) 
will be base d o n i n vesti gat or assess me nt of disease res p o nse a n d pr o gressi o n.
Ce ns ori n g f or ti me- t o-e ve nt e n d p oi nts will be detaile d i n t he S A P.
Pr o gressi o n -free s ur vi val ( P F S)
Pr o gressi o n -free s ur vi val is t he ti me fr o m C 1 D 1 t o date of first d oc u me ntati o n of disease 
pr o gressi o n or deat h d ue t o a n y  ca use, w hic he ver occ urs first.  D oc u me ntati o n of pr o gressi o n 
m ust be b y  o bjecti ve disease assess me nt as defi ne d b y t he Res p o nse E val uati o n Criteria i n 
S oli d T u m ors ( R E CI S T versi o n 1. 1).  P F S data will be ce ns ore d o n t he date of t he last t u m or 
assess me nt o n st u d y f or patie nts w h o d o n ot ha ve o bjecti ve t u m or pr o gressi o n a n d w h o d o 
n ot die w hile o n st u d y .  A d diti o nall y, patie nts w h o start a ne w a nti-ca ncer t hera p y pri or t o 
d oc u me nte d disease pr o gressi o n will be ce ns ore d at t he date of t he last t u m or assess me nt 
pri or t o t he start of t he ne w t hera p y. 
P F S will be s u m marize d i n t he efficac y a nal ysis set usi n g t he Ka pla n -Meier met h o d a n d 
dis pla y e d gra p hicall y. Me dia n e ve nt ti me a n d 9 5 % c o nfi de nce i nter val f or t he me dia n will 
be pr o vi de d .
O bjecti ve Res p o nse ( O R)
O bjecti ve res p o nse is defi ne d as a c o m plete res p o nse ( C R) or partial res p o nse ( P R) acc or di n g 
t o t he R E CIS T rec or de d fr o m C 1 D 1 u ntil disease pr o gressi o n or deat h d ue t o a n y  ca use. 
A patie nt will be c o nsi dere d t o ha ve ac hie ve d a n O R if t he patie nt has a s ustai ne d c o m plete 
res p o nse ( C R) or partial res p o nse ( P R) acc or di n g t o R E CIS T v. 1. 1 defi niti o ns.  Ot her wise, 
t he patie nt will be c o nsi dere d as n o n-res p o n ders i n t he O R rate a nalys is.  A d diti o nall y, 
pati e nts wit h i na de q uate data f or t u m or assess me nt (e g, n o baseli ne assess me nt or n o 
f oll o w- u p assess me nts) will be c o nsi dere d as n o n-res p o n ders i n t he O R rate a nalys is. 
T he O R rate ( O R R) will be esti mate d b y di vi di n g t he n u m ber of patie nts wit h o bjecti ve
resp o nse ( C R or P R) b y  t he n u m ber of patie nts i n t he efficac y a nalys is set (res p o nse rate).  A 
9 5 % c o nfi de nce i nter val ( CI) will be pr o vi de d f or t he O R R .
I n a d diti o n, t he best o verall res p o nse f or eac h patie nt will be s u m marize d.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 8
Disease C o ntr ol (D C )
Disease c o ntr ol ( D C) is defi ne d as c o m plete res p o nse ( C R), partial res p o nse ( P R), or sta ble 
disease ( S D) 2 4 wee ks acc or di n g t o R E CI S T versi o n 1. 1 rec or de d i n t he ti me peri o d 
bet wee n C 1 D 1 a n d disease pr o gressi o n or deat h d ue t o a ny ca use. 
T he D C rate ( D C R) will b e esti mate d b y di vi di n g t he n u m ber of patie nts wit h C R, P R, or S D 
2 4 wee ks b y t he n u m ber of patie nts i n t he efficac y a nalys is set. A 9 5 % CI  f or t he D C R will 
be pr o vi de d.
D urati o n of Res p o nse ( D R)
F or patie nts wit h a n o bjecti ve res p o nse ( C R or P R), d urati o n of res p o nse ( D R) is t he ti me 
fr o m first d oc u me ntati o n of C R or P R t o date of first d oc u me ntati o n of o bjecti ve pr o gressi o n 
or deat h.  Date of first d oc u me ntati o n of P D a n d date of first d oc u me ntati o n of C R or P R will 
be base d o n i n vesti gat or assess me nt o f res p o nse.  D R data will be ce ns ore d o n t he date of t he 
last t u m or assess me nt o n st u d y f or patie nts w h o d o n ot ha ve o bjecti ve t u m or pr o gressi o n a n d 
w h o d o n ot die d ue t o a n y  ca use w hile o n st u d y.  D R will o nl y be calc ulate d f or t he s u b gr o u p 
of patie nts wi t h a n o bjecti ve res p o nse.
D R will be s u m marize d i n t he efficac y a nalys is set usi n g t he Ka pla n -Meier met h o d a n d 
dis pla y e d gra p hicall y. Me dia n e ve nt ti me a n d 9 5 % c o nfi de nce i nter val f or t he me dia n will 
be pr o vi de d .
1 -ye ar P F S Pr o ba bilit y
T he 1 -ye ar P F S pr o b a bilit y will be esti mate d usi n g t he Ka pla n-Meier met h o d a n d a 2 -si de d 
9 5 % CI  f or t he l o g [-l o g( 1 year P F S pr o ba bilit y)] will be calc ulate d usi n g a n or mal 
a p pr o xi mati o n, a n d t he n bac k tra nsf or me d t o gi ve a CI  f or t he 1-ye ar P F S pr o ba bilit y itself.
9. 4. A n al ysis of Ot her E n d p oi nts
Descri pti ve statistics will be use d t o s u m marize all patie nt c haracteristics, treat me nt 
a d mi nistrati o n/c o m plia nce, pri or a n d c o nc o mita nt me dicati o ns a n d n o n -dr u g treat me nts, a n d 
bi o mar kers. Data will als o be dis pla y e d gra p hicall y, w here a p pr o priate.
I n a d diti o n, t he relati o ns hi p bet wee n e x p os ure, bi o mar ker e x pressi o n, efficac y/safty 
e n d p oi nts will be e x pl ore d if e mer gi n g data all o ws.  T he res ults of t hese e x pl orat or y  a nalys es 
ma y  be re p orte d se paratel y fr o m t he cli nical st u d y re p ort.
9. 5. S a fet y A n al ysis
T he safet y a nal ys is set i ncl u des all e nr olle d patie nts w h o recei ve at least o ne d ose of st u d y 
me dicati o n .
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 8 9
A d verse e ve nts, E C Gs, bl o o d press ure, p ulse rate, c o nti n u o us car diac m o nit ori n g, a n d safet y  
la b orat or y data will be re vie we d a n d s u m marize d o n a n o n g oi n g basis d uri n g t he st u d y t o 
e val uate t he safet y of patie nt s.  A n y cli nical la b orat or y, E C G, B P, a n d P R a b n or malities of 
p ote ntial cli nical c o ncer n as defi ne d will be descri be d.  Safet y data will be prese nte d i n 
ta b ular a n d/ or gra p hical f ormat a n d s u m marize d descri pti vel y, w here a p pr o priate.
Me dical hist or y  a n d p h ysical e xa mi nati o n, i ncl u di n g ne ur ol o gic e xa mi nati o n, i nf or mati o n 
c ollecte d d uri n g t he c o urse of t he st u d y will be ca pt ure d f or i ncl usi o n i nt o t he st u d y data base, 
u nless ot her wise n ote d.  A n y  u nt o war d fi n di n gs i de ntifie d o n p h ysical a n d/ or ne ur ol o gic 
e xa mi nati o ns c o n d ucte d after t he a d mi nistrati o n of t he first d ose of st u d y me dicati o n will be 
ca pt ure d as a n a d verse e ve nt, if t h ose fi n di n gs meet t he defi niti o n of a n a d verse e ve nt.  Da ta 
c ollecte d at Scree ni n g t hat is use d f or i ncl usi o n/e xcl usi o n criteria, s uc h as la b orat or y  data, 
E C Gs, a n d vital si g ns will be c o nsi dere d s o urce data a n d i ncl u de d i nt o t he st u d y  data base.  
De m o gra p hic data c ollecte d at Scree ni n g will be i ncl u de d i n t he st u d y  data base.
9. 5. 1. A n al ysis of A d verse E ve nts a n d L a b or at or y A b n or m alities
A d verse E ve nts ( A Es) will be gra de d b y t he i n vesti gat or 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 ve nts ( C T C A E) versi o n 4. 0 a n d c o de d usi n g t he Me dical 
Dicti o nar y  f or Re gulat or y  Acti vities ( Me d D R A).  T he f oc us of A E s u m maries will be o n 
Treat me nt -E mer ge nt A d verse E ve nts ( T E A Es), t h ose wit h i nitial o nset or i ncreasi n g i n 
se verity after t he first d ose of st u d y treat me nt.  T he n u m ber a n d perce nta ge of patie nts w h o 
e x perie nce d a n y A E, seri o us A E ( S A E), treat me nt -relate d A E, a n d treat me nt-relate d S A E 
will be s u m marize d acc or di n g t o w orst t o xicit y  gra des.  T he s u m maries will prese nt A Es 
b ot h o n t he e ntire st u d y  peri o d a n d b y c ycle ( C ycl e 1 a n d C ycles > 1) as well as b y  
relate d ness t o trial treat me nt. 
T he n u m ber a n d perce nta ge of patie nts w h o e x perie nce d la b orat or y  test a b n or malities will be 
s u m marize d acc or di n g t o w orst t o xicit y gra de o bser ve d f or eac h la b orat or y assa y base d o n 
t he N CI C T C A E v 4. 0 se verit y gra de.  T he a nal yses will s u m marize la b orat or y tests b ot h o n 
t he e ntire st u dy peri o d a n d b y c ycle ( C ycl e 1 a n d C y cles > 1). F or la b orat or y  tests wit h o ut 
C T C A E gra de defi niti o ns, res ults will be cate g orize d as n or mal, a b n or mal or n ot d o ne.
9. 5. 2. Oc ul ar E ve nts
Oc ular e ve nts will be re p ort e d as part of t he a d verse e ve nt a nal ysis descri be d a b o ve.
A d diti o nall y , c ha n ges i n le ns gra di n g w hile o n st u d y treat me nt will be a nal yze d as descri be d
i n t he Statistical A nal ysis Pla n.
9. 5. 3. A n al ysis of Electr oc ar di o gr a m Me as ure me nts 
All E C Gs o btai ne d d uri n g t h e st u d y will be e val uate d f or safet y.  T he a vera ge of t he 
tri plicate E C G meas ure me nts will be use d f or t he statistical a nal ysis a n d all data 
prese ntati o ns.  A n y data o btai ne d fr o m E C Gs re peate d f or safet y reas o ns after t he n o mi nal 
ti me-p oi nts will n ot be a vera ge d al o n g wit h t he prece di n g tri plicates.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 0
If a ny of t he t hree i n di vi d ual E C G traci n gs has a Q Tc i nter val > 5 0 0 msec, b ut t he mea n of 
t he tri plicates is n ot > 5 0 0 msec, t he data fr o m t he s u bject’s i n di vi d ual traci n g will be 
descri be d i n a safet y secti o n o f t he st u d y re p ort i n or der t o place t he > 5 0 0 msec val ue i n 
a p pr o priate cli nical c o nte xt.  H o we ver, val ues fr o m i n di vi d ual traci n gs wit hi n tri plicate 
meas ure me nts t hat are > 5 0 0 msec will n ot be i ncl u de d i n t he cate g orical a nal y sis u nless t he 
a vera ge fr o m t he tri plicate meas ure me nts is als o > 5 0 0 msec.  C ha n ges fr o m baseli ne will be 
defi ne d as t he c ha n ge of Q Tc p ost d ose fr o m t he a vera ge of t he pre - d ose tri plicate val ues.
Q T i nter vals will be c orrecte d f or heart rate ( Q Tc) usi n g sta n dar d c orrecti o n fact ors 
(ie, Bazett’s, Fri dericia’s a n d p ossi bl y  a st u dy s pecific fact or).  Data will be s u m marize d a n d 
liste d f or Q T, H R, R R, P R, Q R S a n d Q Tc b y  ti me.  Descri pti ve statistics ( n, mea n, me dia n, 
sta n dar d de viati o n, mi ni m u m, a n d ma xi m u m) will be use d t o s u m marize t he a bs ol ute Q Tc 
val ue a n d c ha n ges fr o m baseli ne i n Q Tc after treat me nt b y  da y a n d ti me p oi nt.  F or eac h 
patie nt, t he ma xi m u m c ha n ge fr o m baseli ne will be calc ulate d as well as t he ma xi m u m 
p ost -baseli ne val ue acr oss ti me p oi nts. Cate g orical a nal ysis of t he Q T c data will be 
c o n d ucte d a n d s u m marize d as f oll o ws:
T he n u m ber of patie nts wit h ma xi m u m c ha n ge fr o m baseli ne i n Q Tc ( < 3 0, 3 0 -5 9, a n d 
6 0 m sec);
T he n u m ber of patie nts wit h ma xi m u m p ost -d ose ( p ost -baseli ne) Q Tc ( < 4 5 0, 4 5 0 -< 4 8 0, 
4 8 0 -5 0 0, a n d > 5 0 0 m sec).
9. 6. D at a M o nit ori n g C o m mittee 
T his st u d y  will n ot use a Data M o nit ori n g C o m mittee.
1 0. Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E
D uri n g st u d y c o n d uct, Pfizer or its a ge nt will c o n d uct peri o dic m o nit ori n g visits f or st u dies 
c o n d ucte d o utsi de of Pfizer Cli nical Researc h U nits t o e ns ure t hat t he pr ot oc ol a n d G o o d 
Cli nical Practices ( G C Ps) are bei n g f oll o we d.  T he m o nit ors ma y  re vie w s o urce d oc u me nts 
t o c o nfir m t hat t he data rec or de d o n C R Fs is acc urate.  T he i n vesti gat or a n d i nstit uti o n will 
all o w Pfizer m o nit ors /a u dit ors or its a ge nts a n d a p pr o priate re g ulat or y  a ut h orities direct 
access t o s o urce d oc u me nts t o perf or m t his verificati o n.
T he st u d y  site ma y be s u bject t o re vie w by t he I nstit uti o nal Re vie w B oar d (I R B)/I n de pe n de nt 
Et hics C o m mittee (I E C), a n d/ or t o q ualit y  ass ura nce a u dits perf or me d b y P fizer, or 
c o m pa nies w or ki n g wit h or o n be half of Pfizer, a n d/ or t o i ns pecti o n b y  a p pr o priate 
re g ulat or y a ut h orities.
F or st u dies c o n d ucte d o utsi de of t he Pfizer Cli nical Researc h U nits, it is i m p orta nt t hat t he 
i n vesti gat or(s) a n d t heir rele va nt pers o n nel are a vaila ble d uri n g t he m o nit ori n g visits a n d 
p ossi ble a u dits or i ns pecti o ns a n d t hat s ufficie nt ti me is de v ote d t o t he pr ocess.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 1
1 1. D A T A H A N D LI N G A N D R E C O R D K E E PI N G
1 1. 1. C ase Re p ort F or ms/ Electr o nic D at a Rec or d
As use d i n t his pr ot oc ol, t he ter m C R F s h o ul d be u n derst o o d t o refer t o eit her a pa per f or m or 
a n electr o nic data rec or d or b ot h, de pe n di n g o n t he data c ollecti o n met h o d use d i n t his st u d y .
A C R F is re q uire d a n d s h o ul d be c o m plete d f or eac h i ncl u de d patie nt.  T he c o m plete d 
ori gi na l C R Fs are t he s ole pr o perty of Pfizer a n d s h o ul d n ot be ma de a vaila ble i n a n y f or m t o 
t hir d parties, e xce pt f or a ut h orize d re prese ntati ves of Pfizer or a p pr o priate re g ulat or y 
a ut h orities, wit h o ut writte n per missi o n fr o m Pfizer.
T he i n vesti gat or has ulti ma te res p o nsi bilit y f or t he c ollecti o n a n d re p orti n g of all cli nical, 
safety a n d la b orat or y data e ntere d o n t he C R Fs a n d a n y ot her data c ollecti o n f or ms (s o urce 
d oc u me nts) a n d e ns uri n g t hat t he y are acc urate, a ut he ntic / ori gi nal, attri b uta ble, c o m plete, 
c o nsiste nt, le gi ble, ti mel y (c o nte m p ora ne o us), e n d uri n g a n d a vaila ble w he n re q uire d.  T he 
C R Fs m ust be si g ne d b y t he i n vesti gat or or by a n a ut h orize d staff me m ber t o attest t hat t he 
data c o ntai ne d o n t he C R Fs is tr ue.  A n y c orrecti o ns t o e ntries ma de i n t he C R Fs, s o urce 
d oc u me nts m ust be date d, i nitiale d a n d e x plai ne d (if necessar y ) a n d s h o ul d n ot o bsc ure t he 
ori gi nal e ntr y . 
I n m ost cases, t he s o urce d oc u me nts are t he h os pital's or t he p hys icia n's patie nt c hart.  I n 
t hese cases data c ollecte d o n t he C R Fs m ust matc h t he data i n t h ose c harts. 
I n s o me cases, t he C R F, or part of t he C R F, ma y als o ser ve as s o urce d oc u me nts.  I n t hese 
cases, a d oc u me nt s h o ul d be a vaila ble at t he i n vesti gat or’s site as well as at Pfizer a n d clearl y 
i de ntif y t h ose data t hat will be rec or de d i n t he C R F, a n d f or w hic h t he C R F will sta n d as t he 
s o urce d oc u me nt.
1 1. 2. Rec or d Rete nti o n
T o e na ble e val uati o ns a n d/ or a u dits fr o m re g ulat or y  a ut h orities or Pfizer, t he i n vesti gat or 
a grees t o kee p rec or ds, i ncl u di n g t he i de ntit y of all partici pati n g pa tie nts (s ufficie nt 
i nf or mati o n t o li n k rec or ds, e g, C R Fs a n d h os pital rec or ds), all ori gi nal si g ne d i nf or me d 
c o nse nt d oc u me nts, c o pies of all C R Fs, safet y  re p orti n g f or ms, s o urce d oc u me nts, a n d 
detaile d rec or ds of treat me nt dis p ositi o n, a n d a de q uate d oc u me ntati o n of rele va nt 
c orres p o n de nce (e g, letters, meeti n g mi n utes, tele p h o ne calls re p orts).  T he rec or ds s h o ul d be 
retai ne d by t he i n vesti gat or acc or di n g t o I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H), 
l ocal re g ulati o ns, or as s pecifie d i n t he Cli nical St u d y  A gree me nt ( C S A), w hic he ver is 
l o n ger.
If t he i n vesti gat or bec o mes u na ble f or a ny reas o n t o c o nti n ue t o retai n st u d y rec or ds f or t he 
re q uire d peri o d (e g, retire me nt, rel ocati o n), Pfizer s h o ul d be pr os pecti vely n otifie d.  T he 
st u d y rec or ds m ust be transferre d t o a desi g nee acce pta ble t o Pfizer, s uc h as a n ot her 
i n vesti gat or, a n ot her i nstit uti o n, or t o a n i n de pe n de nt t hir d party arra n ge d b y Pfizer.  
I n vesti gat or rec or ds m ust be ke pt f or a mi ni m u m of 1 5 years after c o m pleti o n or 
disc o nti n uati o n of t he st u d y  or f or l o n ger if re q uire d b y a p plica ble l ocal re g ulati o ns.
 

Pal b ocicli b
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T he i n vesti gat or m ust o btai n Pfizer's writte n per missi o n bef ore dis p osi n g of a n y rec or ds, 
e ve n if rete nti o n re q uire me nts ha ve bee n met.
1 2. E T HI C S
1 2. 1. I nstit uti o n al Re vie w B o ar d (I R B)/I n de pe n de nt Et hics C o m mittee (I E C)
It is t he res p o nsi bilit y of t he i n vesti gat or t o ha ve pr os pecti ve a p pr o val of t he st u d y pr ot oc ol, 
pr ot oc ol a me n d me nts, i nf or me d c o nse nt d oc u me nts, a n d ot her rele va nt d oc u me nts, e g, 
recr uit me nt a d vertise me nts, if a p plica ble, fr o m t he IR B/I E C .  All c orres p o n de nce wit h t he 
I RB/I E C s h o ul d be retai ne d i n t he I n vesti gat or File.  C o pies of I R B/I E C a p pr o vals s h o ul d be 
f or war de d t o Pfizer.
T he o nl y  circ u msta nce i n w hic h a n a me n d me nt ma y be i nitiate d pri or t o I R B/I E C a p pr o val is 
w here t he c ha n ge is ne cessar y t o eli mi nate a p pare nt i m me diate hazar ds t o t he patie nts.  I n 
t hat e ve nt, t he i n vesti gat or m ust n otif y t he I R B/I E C a n d Pfizer i n writi n g i m me diatel y after 
t he i m ple me ntati o n.
1 2. 2. Et hic al C o n d uct of t he St u d y
T he st u d y  will be c o n d ucte d i n acc or da nce with le gal a n d re g ulat or y  re q uire me nts, as well as 
t he ge neral pri nci ples set f ort h i n t he I nter nati o nal Et hical G ui deli nes f or Bi o me dical 
Researc h I n v ol vi n g H u ma n Patie nts ( C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces 2 0 0 2), G ui deli nes f or G C P (I C H 1 9 9 6), a n d t he Declarati o n of Helsi n ki ( W orl d 
Me dical Ass ociati o n 2 0 0 8). 
I n a d diti o n, t he st u d y will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol, t he IC H g ui deli ne 
o n G C P, a n d a p plica ble l ocal re g ulat or y  re q uire me nts a n d la ws.
1 2. 3. S u bject I nf or m ati o n an d C o nse nt
All parties will e ns ure pr otecti o n of patie nt pers o nal data a n d will n ot i ncl u de patie nt na mes 
o n a n y  s p o ns or f or ms, re p orts, p u blicati o ns, or i n a n y ot her discl os ures, e xce pt w here 
re q uire d by la ws. 
Patie nt na mes, a d dress, birt h date a n d ot her i de ntifia ble data will be re place d b y a n u merical 
c o de c o nsisti n g of a n u m beri n g s ys te m pr o vi de d b y Pfizer i n or der t o de-i de ntif y t he st u d y 
patie nt.  I n case of data tra nsfer, Pfizer will mai ntai n hi g h sta n dar ds of c o nfi de ntialit y  a n d 
pr otecti o n of patie nt pers o nal data.
T he i nf or me d c o nse nt d oc u me nt m ust be i n c o m plia nce wit h I C H G C P, l ocal re g ulat or y  
re q uire me nts, a n d le gal re q uire me nts.
T he i nf or me d c o nse nt d oc u me nt(s) use d d uri n g t he i nf or me d c o nse nt pr ocess m ust be 
re vie we d by t he s p o ns or, a p pr o ve d b y t he I RB/I E C bef ore use, a n d a vaila ble f or i ns pecti o n.
T he i n vesti gat or m ust e ns ure t hat eac h st u d y  patie nt, or his/ her le gal re prese ntati ve, is f ull y 
i nf or me d a b o ut t he nat ure a n d o bjecti ves of t he st u d y a n d p ossi ble ris ks ass ociate d wit h 
partici pati o n. 
 

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T he i n vesti gat or, or a pers o n desi g nate d b y t he i n vesti gat or, will o btai n writte n i nf or me d 
c o nse nt fr o m eac h patie nt or t he patie nt's le gal re prese ntati ve bef ore a n y st u d y -s pecific 
acti vit y is perf or me d. T he i n vesti gat or will retai n t he ori gi nal of eac h patie nt's si g ne d 
c o nse nt d oc u me nt.  T he patie nt will be pr o vi de d wit h a c o p y of t he si g ne d i nf or me d c o nse nt 
f or m.
1 2. 4. S u bject Recr uit me nt
A d vertise me nts a p pr o ve d b y  et hics c o m mittees a n d i n vesti gat or data bases ma y be use d as 
recr uit me nt pr oce d ures.
1 2. 5. Re p orti n g of S afet y Iss ues a n d Seri o us Bre ac hes of t he Pr ot oc ol or I C H G C P
I n t he e ve nt of a ny pr o hi biti o n or restricti o n i m p ose d (ie, cli nical h ol d) b y a n a p plica ble 
C o m pete nt A ut h orit y  i n a n y area of t he W orl d, or if t he i n vesti gat or is a ware of a n y ne w 
i nf or mati on w hic h mi g ht i nfl ue nce t he e val uati o n of t he be nefits a n d ris ks of t he 
i n vesti gati o nal pr o d uct, Pfizer s h o ul d be i nf or me d i m me diatel y. 
I n a d diti o n, t he i n vesti gat or will i nf or m Pfizer i m me diatel y of a n y ur ge nt safety meas ures 
ta ke n by t he i n vesti gat or t o pr otect t he st u d y  patie nts a gai nst a n y i m me diate hazar d, a n d of 
a n y seri o us breac hes of t his pr ot oc ol or of I C H G C P t hat t he i n vesti gat or bec o mes a ware of.
1 3. D E FI NI TI O N O F E N D O F T RI A L
1 3. 1. E n d of Tri al i n All P artici p ati n g C o u ntries
E n d of Trial i n all partici p ati n g c o u ntries is defi ne d as t he ti me w hic h:

E nr oll me nt is c o m plete d a n d; 

Assess me nts a n d re q uire me nts u p t o 2 8 da ys after per ma ne nt disc o nti n uati o n of 
treat me nt of t he last patie nt are c o m plete d as per pr ot oc ol a n d all data are s u b mitte d 
f or all patie nts.
1 4. S P O N S O R DI S C O N TI N U A T I O N C RI T E RI A
Pre mat ure ter mi nati o n of t his st u d y  ma y occ ur beca use of a re g ulat or y a ut h orit y decisi o n, 
c ha n ge i n o pi ni o n of t he I R B/I E C, dr u g safet y pr o ble ms, or at t he discreti o n of Pfizer.  I n 
a d diti o n, Pfizer retai ns t he ri g ht t o disc o nti n ue de vel o p me nt of pal b ocicli b at a n y ti me.
If a st u dy is pre mat urel y ter mi nate d or disc o nti n ue d, Pfizer will pr o m ptl y n otif y t he 
i n vesti gat or.  After n otificati o n, t he i n vesti gat or m ust c o ntact all partici pati n g patie nts a n d 
t he h os pital p har mac y (if a p plica ble) wit hi n 7 da ys .  As directe d by Pfizer, all st u d y  materials 
m ust be c ollecte d a n d all C R Fs c o m plete d t o t he greatest e xte nt p ossi ble.
 

Pal b ocicli b
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Pa ge 9 4
1 5. P U B LI C A TI O N O F S T U D Y R E S U L T S
1 5. 1. C o m m u nic ati o n of Res ults b y Pfizer
Pfizer f ulfills its c o m mit me nt t o p u blicl y  discl ose cli nical st u d y  res ults t hr o u g h p osti n g t he 
res ults of st u dies o n w w w.cli nicaltrials. g o v ( Cli nical Trials. g o v), t he E ur o pea n Cli nical Trials 
Data base ( E u dra C T), a n d/ or w w w. pfizer.c o m, a n d ot her p u blic re gistries i n acc or da nce wit h 
a p plica ble l ocal l a ws/re g ulati o ns.  I n a d diti o n, Pfizer re p orts st u d y res ults o utsi de of t he 
re q uire me nts of l ocal la ws/re g ulati o ns p urs ua nt t o its Sta n dar d O perati n g P r oce d ures ( S O Ps).
I n all cases, st u dy res ults are re p orte d b y Pfizer i n a n o bjecti ve, acc urate, bala nce d, a n d 
c o m plete ma n ner a n d are re p orte d re gar dless of t he o utc o me of t he st u d y or t he c o u ntr y i n 
w hic h t he st u d y  was c o n d ucte d.
w w w.cli nicaltrials. g o v
Pfizer p osts cli nical trial U S Basic Res ults o n w w w.cli nicaltrials. g o v f or all Pfizer -s p o ns ore d 
i nter ve nti o nal st u dies c o n d ucte d i n patie nts t hat e val uate t he safet y a n d/ or efficac y of a Pfizer 
pr o d uct, re gar dless of t he ge o gra p hical l ocati o n i n w hic h t he st u d y is c o n d ucte d.  U S Basic 
Res ults are s u b mitte d f or p osti n g wit hi n 1 ye ar of t he pri mar y c o m pleti o n date f or st u dies i n 
a d ult p o p ulati o ns or wit hi n 6 m o nt hs of t he pri mar y c o m pleti o n date f or st u dies i n pe diatric 
p o p ulati o ns.
Pri mar y  C o m pleti o n Date is defi ne d as t he date t hat t he fi nal patie nt was e xa mi ne d or 
recei ve d a n i nter ve nti o n f or t he p ur p oses of fi nal c ollecti o n of data f or t he pri mar y o utc o me, 
w het her t he cli nical st u d y c o ncl u de d acc or di n g t o t he pre -s pecifie d pr ot oc ol or was 
ter mi nate d.
E u dra C T
Pfizer p osts E U Basic Res ults o n E u dra C T f or all Pfizer -s p o ns ore d i nter ve nti o nal st u dies t hat 
are i n sc o p e of E U re q uire me nts.  E U Basic Res ults are s u b mitte d f or p osti n g wit hi n 1 year 
of t he pri mar y  c o m pleti o n date f or st u dies i n a d ult p o p ulati o ns or wit hi n 6 m o nt hs of t he 
pri mar y  c o m pleti o n date f or st u dies i n pe diatric p o p ulati o ns.
w w w. pfizer.c o m
Pfizer p o sts P u blic Discl os ure S yn o pses (cli nical st u d y  re p ort s yn o pses i n w hic h a n y  data 
t hat c o ul d be use d t o i de ntif y i n di vi d ual patie nts has bee n re m o ve d) o n w w w. pfizer.c o m f or 
Pfizer -s p o ns ore d i nter ve nti o nal st u dies at t he sa me ti me t he U S Basic Res ults d oc u ment is 
p oste d t o w w w.cli nicaltrials. g o v .
D oc u me nts wit hi n mar keti n g a ut h orizati o n pac ka ges/s u b missi o ns .
Pfizer c o m plies wit h t he E ur o pea n U ni o n P olic y  0 0 7 0, t he pr oacti ve p u blicati o n of cli nical 
data t o t he E ur o pea n Me dici nes A ge nc y  ( E M A) we bsite.  Cli nical data, u n der P hase 1 of t his 
p olic y , i ncl u des cli nical o ver vie ws, cli nical s u m maries, Cli nical St u d y  Re p orts (C S Rs ), a n d 
a p pe n dices c o ntai ni n g t he pr ot oc ol a n d pr ot oc ol a me n d me nts, sa m ple C R Fs, a n d statistical 
 

Pal b ocicli b
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Pa ge 9 5
met h o ds.  Cli nical data, u n der P hase 2 of t his p olic y , i ncl u des t he p u blis hi n g of i n di vi d ual 
partici pa nt data.  P olic y  0 0 7 0 a p plies t o ne w mar keti n g a ut h orizati o n a p plicati o ns s u b mitte d 
via t he ce ntralize d pr oce d ure si nce 0 1 Ja n uar y  2 0 1 5 a n d a p plicati o ns f or li ne e xte nsi o ns a n d 
f or ne w i n dicati o ns s u bmitte d via t he ce ntralize d pr oce d ure si nce 0 1 J ul y  2 0 1 5.
Data S hari n g
Pfizer pr o vi des researc hers sec ure access t o patie nt le vel data or f ull C S Rs f or t he p ur p oses 
of “ b o na fi de scie ntific researc h” t hat c o ntri b ute t o t he scie ntific u n dersta n di n g of t he disease, 
tar get, or c o m p o u n d class.  Pfizer will ma ke a vaila ble data fr o m t hese trials 2 4 m o nt hs after 
st u d y c o m pleti o n.  Patie nt le vel data will be a n o n y mize d i n acc or da nce wit h a p plica ble 
pri vac y  la ws a n d re g ulati o ns.  C S Rs will ha ve pers o nall y i de ntifia ble i nf or mati o n re dacte d.
Data re q uests are c o nsi dere d fr o m q ualifie d researc hers wit h t he a p pr o priate c o m pete ncies t o 
perf or m t he pr o p ose d a nal yses.  Researc h tea ms m ust i ncl u de a bi ostatisticia n.  Data will n ot 
be pr o vi de d t o a p plica nts wit h si g nifica nt c o nflicts of i nterest, i ncl u di n g i n di vi d uals 
re q uesti n g access f or c o m mercial/c o m petiti ve or le gal p ur p oses.
1 5. 2. P u blic ati o ns b y I n vesti g at ors
Pfizer has n o o bjecti o n t o p u blicati o n b y  In vesti gat or of a n y  i nf or mati o n c ollecte d or 
ge nerate d b y I n vesti gat or, w het her or n ot t he res ults are fa v ora ble t o t he I nvesti gati o nal 
Dr u g.  H o we ver, t o e ns ure a gai nst i na d verte nt discl os ure of C o nfi de ntial I nf or mati o n or 
u n pr otecte d I n ve nti o ns, I n vesti gat or will pr o vi de Pfizer a n o p p ort u nit y  t o re vie w a ny 
pr o p ose d p u blicati o n or ot her t y pe of discl os ure bef ore it is s u b mitte d or ot her wise discl ose d.
I n vesti gat or will pr o vi de ma n uscri pts, a bstracts, or t he f ull te xt of a n y ot her i nte n de d 
discl os ure ( p oster prese ntati o n, i n vite d s pea ker or g uest lect urer prese ntati o n, etc.) t o Pfiz er 
at least 3 0 d a y s bef ore t he y are s u b mitte d f or p u blicati o n or ot her wise discl ose d.  If a ny 
pate nt acti o n is re q uire d t o pr otect i ntellect ual pr o pert y ri g hts, I n vesti gat or a grees t o dela y  
t he discl os ure f or a peri o d n ot t o e xcee d a n a d diti o nal 6 0 d a y s.
T he i n vesti gat or will, o n re q uest, re m o ve a n y pre vi o usl y  u n discl ose d c o nfi de ntial 
i nf or mati o n ( ot her t ha n t he st u d y res ults t he msel ves) bef ore discl os ure.
If t he St u d y is part of a m ulti-ce ntre st u d y, t he i n vesti gat or a grees t hat t he first p u blicati o n is 
t o be a j oi nt p u blicati o n c o veri n g all ce nters.  H o we ver, if a j oi nt ma n uscri pt has n ot bee n 
s u b mitte d f or p u blicati o n wit hi n 1 2 m o nt hs of c o m pleti o n or ter mi nati o n of t he st u d y at all 
partici pati n g sites, t he i n vesti gat or is free t o p u blis h se paratel y, pati e nt t o t he ot her 
re q uire me nts of t his secti o n.
F or all p u blicati o ns relati n g t o t he st u d y, i nstit uti o n will c o m pl y wit h rec o g nize d et hical 
sta n dar ds c o ncer ni n g p u blicati o ns a n d a ut h ors hi p, i ncl u di n g Secti o n II - “ Et hical 
C o nsi derati o ns i n t he C o n d uct a n d R e p orti n g of Researc h” of t he U nif or m Re q uire me nts f or 
Ma n uscri pts S u b mitte d t o Bi o me dical J o ur nals, htt p:// w w w.ic mje. or g/i n de x. ht ml #a ut h ors hi p,
esta blis he d b y t he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors.
 

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P u blicati o n of st u d y  res ults is als o pr o vi de d f or i n t he Cli nical St u d y A gree me nt bet wee n 
Pfizer a n d t he i nstit uti o n.  I n t his secti o n e ntitle d P u blicati o ns b y  In vesti gat ors , t he defi ne d 
ter ms s hall ha ve t he mea ni n gs gi ve n t o t he m i n t he Cli nical St u d y A gree me nt.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 7
1 6. R E F E R E N C E S
1.
G L O B A L C A N 2 0 0 8 C A N C E R F A C T S H E E T .
2.  
W o o d W C, M uss H B, S oli n L J, Ol o pa de OI. Mali g na nt T u m ors of t he Breast. In: De 
Vita V T Jr, Hell ma n n S, R ose n ber g S A, e dit ors. Ca ncer, Pri nci ple a n d Practice of 
O nc ol o g y , 7t h E diti o n, Li p pi nc ott Willia ms a n d Wil ki ns; 2 00 5; 1 4 1 5 - 7 7.
3.
Wei n ber g, R A. T he reti n o blast o ma pr otei n a n d cell c ycle c o ntr ol. Cell 1 9 9 5; 8 1: 3 2 3 - 3 0.
4.
Se ki d o Y, F o n g K M, Mi n na J D.  M olec ular bi ol o g y  of l u n g ca ncer.  I n: De Vita V T, 
Hell ma n S, R ose n ber g S A, e dit ors.  Ca ncer: Pri nci ples & Practice of O nc ol o g y . 6t h e d.  
P hila del p hia: L i p pi nc ott Willia ms & Wil ki ns; 2 0 0 1: 9 1 7- 2 5.
5.
K a y e FJ.  R B a n d c yli n de pe n de nt ki nase pat h wa ys: Defi ni n g a disti ncti o n bet wee n R B 
a n d p 1 6 l oss i n l u n g ca ncer. O nc o ge ne 2 0 0 2; 2 1: 6 9 0 8 - 1 4.
6.
Ar g uell o, F., et al., Fla v o piri d ol i n d uces a p o pt o sis of n or mal l ym p h oi d cells, ca uses 
i m m u n os u p pressi o n, a n d has p ote nt a ntit u m or acti vit y In vi v o a gai nst h u ma n le u ke mia 
a n d l ym p h o ma xe n o grafts.  Bl o o d, 1 9 9 8. 9 1 ( 7): p. 2 4 8 2- 9 0.
7.
Bart k o va, J., et al., Dere g ulati o n of t he R B pat h wa y i n h u ma n testic ular ger m cell 
t u m o urs. J Pat h ol, 2 0 0 3. 2 0 0 ( 2): p. 1 4 9- 5 6.
8.
Fi n k, J. R. a n d T. W. L e Bie n, N o vel e x pressi o n of c y cli n-de pe n de nt ki nase i n hi bit ors i n 
h u ma n B -cell prec urs ors. E x p He mat ol, 2 0 0 1. 2 9 ( 4): p. 4 9 0- 8.
9. 
C S R A 5 4 8 1 0 0 1.  A p hase 1 cli nical, p har mac o ki netic, a n d p ha r mac o d yna mic 
e val uati o n of 2 sc he d ules of oral P D 0 3 3 2 9 9 1, a c ycli n -de pe n de nt ki nase i n hi bit or, i n 
patie nts wit h a d va nce d ca ncer.  2 6 Marc h 2 0 0 9.
1 0.
C S R A 5 4 8 1 0 0 2.  A pil ot st u d y of P D 0 3 3 2 9 9 1 i n patie nts wit h pre vi o usl y  treate d 
ma ntle cell l y m p h o ma.  1 2 Se pte m ber 2 0 0 6.
1 1.
C S R A 5 4 8 1 0 0 3.  P hase ½, o pe n -la bel, ra n d o mize d st u d y of t he safety, efficac y , a n d 
p har mac o ki netics of letr oz ole pl us P D 0 3 3 2 9 9 1 ( oral C D K 4/ 6 i n hi bit or) a n d letr oz ole 
si n gle a ge nt f or t he first-li ne treat me nt of E R p ositi ve, Her 2 ne gati ve a d va nce d breast 
ca ncer i n p ost me n o pa usal w o me n.  0 2 Ma y  2 0 1 4.
1 2.
C S R A 5 4 8 1 0 1 1.  A P hase 1 o pe n -la bel si n gle-ra di ola bele d d ose st u dy t o i n vesti gate t he 
a bs or pti o n, meta b olis m, a n d e xcreti o n of [1 4C] -P D -0 3 3 2 9 9 1 i n h ealt h y m ale v ol u nteers .  
0 9 A pril 2 0 1 4.
1 3.
C S R A 5 4 8 1 0 1 2 .  A P hase 1 ra n d o mize d, o pe n-la bel, 2-se q ue nce, 2-peri o d cr oss o ver 
st u d y of t he effect of m ulti ple d oses of P D-0 3 3 2 9 9 1 o n mi daz ola m p har mac o ki netics i n 
healt h y  w o me n of n o n-c hil d beari n g p ote ntial.  1 1 J ul y 2 0 1 3.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 8
1 4.
C S R A 5 4 8 1 0 1 7. A P hase 1, o pe n- la bel, fi xe d-se q ue nce 2-peri o d st u d y  t o i n vesti gate t he 
effect of m ulti ple d oses of rifa m pi n o n pal b ocicli b ( P D- 0 3 3 2 9 9 1) p har mac o ki netics i n 
healt h y  v ol u nteers.  2 1 A pril 2 0 1 4.
1 5.
C S R A 5 4 8 1 0 1 6. A P hase 1, o pe n- la bel, fi xe d-se q ue nce 2-peri o d st u d y  t o i n vesti gate t he 
effect of m ulti ple d oses of itrac o naz ole o n t he si n gle d ose p har mac o ki netics of 
pal b ocicli b ( P D -0 3 3 2 9 9 1) i n healt h y  v ol u nteers.  2 6 Se pte m ber 2 0 1 4.
1 6.
C S R A 5 4 8 1 0 2 1. A P hase 1, o pe n- la bel, 4 se q ue ne 4 peri o d cr oss-o ver st u d y of 
pal b ocicli b ( P D -0 3 3 2 9 9 1) i n healt h y  v ol u nteers t o esti mate t he effect of f o o d o n t he 
bi oa vaila bilit y  of pal b ocicli b.  2 3 A pril 2 0 1 4.
1 7.
C S R A 5 4 8 1 0 3 6.  A P hase 1, o pe n -la bel 6-se q ue nce 3-peri o d cr oss o ver st u d y  of 
pal b ocicli b ( P D -0 3 3 2 9 9 1) i n healt h y  v ol u nteers t o esti mate t he relati ve bi oa vaila bilit y 
of pal b ocicli b f or m ulati o ns.  3 0 A pril 2 0 1 4.
1 8.
C S R A 5 4 8 1 0 3 8.  A P hase 1, o pe n -la bel, 3-peri o d st u d y  of t he effect of a n a ntaci d, a 
pr ot o n p u m p i n hi bit or a n d a n H 2-rece pt or a nta g o nist o n pal b ocicli b ( P D-0 3 3 2 9 9 1)  
bi oa vaila bilit y  u n der fe d c o n diti o ns i n healt h y v ol u nteers.  1 5 A u gest 2 0 1 4. 
1 9.
C S R A 5 4 8 1 0 1 8. A P hase 1, o pe n- la bel, fi xe d-se q ue nce 2-peri o d cr oss o ver st u d y  of 
pal b ocicli b i n healt h y  s u bjects t o i n vesti gate t he p ote ntial effect of a ntaci d treat me nt o n 
t he p har mac o ki netics of a si n gle oral d ose a d mi nistere d u n der faste d c o n diti o ns.  
2 5 A pril 2 0 1 4.
2 0.
I n vesti gat or’s Br oc h ure, A 5 4 8 ( Pal b ocicli b, P D- 0 3 3 2 9 9 1).  Dece m ber 2 0 1 3.
2 1.
P M A R -E Q D D -A 5 4 8 b -D P 4 -2 8 7.  Pal b ocicli b Q Tc -c o nce ntrati o n a nal ys is i n ca ncer 
patie nts.  2 4 A pril 2 0 1 4.
2 2.
El haj o uji A, Va n H u m mele n P, Kirsc h -V ol ders M.  I n dicati o ns f or a t hres h ol d of 
c he micall y- i n d uce d a ne u pl oi d y i n vitr o i n h u ma n l ym p h oc y tes.  E n vir o n me ntal a n d 
M olec ular M uta ge nesis 1 9 9 5; 2 6( 4): 2 9 2 - 3 0 4.
2 3.
Parr y  J M, Fiel der RJ, Mc D o nal d A.  T hres h ol ds f or a ne u pl oi d y-i n d uci n g c he micals.  
M uta g e nesis 1 9 9 4; 9( 6): 5 0 3 - 4.
2 4.
Be ntle y  K S, Kir kla n d D, M ur p h y M, et al.  E val uati o n of t hres h ol ds f or be n o m yl- a n d 
car be n dazi m- i n d uce d a ne u pl oi d y i n c ult ure d h u ma n l ym p h oc y tes usi n g fl u oresce nce i n 
sit u h ybri dizati o n.  M utati o n Researc h 2 0 0 0; 4 6 4( 1): 4 1 - 5 1.
2 5.
S mi t h TJ, K hatc heressia n J, L yma n G H, et al. 2 0 0 6 U p date of Rec o m me n dati o ns f or t he 
Use of W hite Bl o o d Cell Gr o wt h Fact ors: A n E vi de nce - Base d Cli nical Practice 
G ui deli ne. J o ur nal of Cli nical O nc ol o g y  2 0 0 6; 2 4, 1 9: 3 1 8 7- 2 0 5.
2 6.
H o ga n MJ, Ki m ura SJ, T h y ges o n P: Si g ns a n d s y m pt o ms of u veitis: I . A nteri or u veitis. 
A m J O p ht hal m ol 1 9 5 9; 4 7: 1 5 5 - 7 0.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 9
2 7.
C he w E Y, Ki m J, S per d ut o R D, Datiles M B 3r d, C ole ma n H R, T h o m ps o n DJ, Milt o n 
R C, Cla y t o n J A, H u b bar d LD, Da nis R P, Ferris F L 3r d. E val uati o n of t he a ge -relate d 
e ye disease s t u d y cli nical le ns gra di n g sys te m A R E D S re p ort N o. 3 1. O p ht hal m ol o g y. 
2 0 1 0 N o v; 1 1 7( 1 1): 2 1 1 2 - 9.
2 8.
O ka da Y, Hir ota T, Ka mata ni Y,et al.  I de ntificati o n of Ni ne N o vel L oci Ass ociate d 
wit h W hite Bl o o d Cell S u bt y pe i n a Ja pa nese P o p ulati o n.  P L o S Ge net 2 0 1 1; 7( 6) : 1- 1 0.
2 9.
D urairaj C, R uiz - Garcia A, Ga ut hier E R, et al. Pal b ocicli b has n o cli nically rele va nt
effect o n t he Q Tc i nter val i n patie nts wit h a d va nce d breast ca ncer. A nti -Ca ncer Dr u gs;
2 0 1 8, 2 9 ( 3): 2 7 1 – 8 0.
3 0.
C S R A 5 4 8 1 0 1 9. A p hase 1 o pe n -la bel p har mac o ki netics st u d y of Pal b ocicli b, a 
c ycli n- de pe n de nt ki nase 4 a n d 6 ( C D K 4/ 6) i n hi bit or, i n p ost me n o pa usal C hi nese 
w o me n wit h E R ( +), H E R 2 ( -) a d va nce d breast ca ncer 2 5 Fe b. 2 0 1 9 .
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 0
1 7. A P P E N DI X
1 7. 1. A p pe n di x 1. A b bre vi ati o ns
A B C
A d va nce d Breast Ca ncer
A S C O
A merica n S ociet y of C li nical O nc ol o g y
A E
A d vers e E ve nt
AI
A r o matase In hi bit or
A L P  
A l kali ne P h os p hatase
A L T
Ala ni ne A mi n otra nsferases 
A N C
A bs ol ute Ne utr o p hil C o u nt
A U C 1 0
Area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o 
t he ti me 1 0 h o urs
A U C 2 4
Area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o 
t he ti me 2 4 h o urs
A U C last
Area u n der t he plas ma c o nce ntrati o n vers us ti me c ur ve fr o m ti me zer o t o 
t he ti me of t he last q ua ntifia ble c o nce ntrati o n ( Clast)
A U C i nf
Area u n der t he plas ma c o n ce ntrati o n vers us ti me c ur ve fr o m ti me zer o 
e xtra p olate d t o i nfi nite ti me
a P P T
acti vate d P artial T hr o m b o plasti n T i me
A S T
As partate A mi n otra nsferases 
A U C
Area U n der t he C ur ve
B U N
Bl o o d Urea Nitr o ge n
C 1 D 1
C y cle 1 Da y 1
C D K
C y cli n- De pe n de nt K i nase
C L / F
A p pare nt C leara nce
CI
C o nfi de ntial I nter val
C ma x
Ma xi m u m P las ma C o nce ntrati o n
C m i n
Mi ni m u m P las ma C o nce ntrati o n
C last
T he last q ua ntifia ble c o nce ntrati o n
C N S
Ce ntral Ner v o us S ys te m
C R
C o m plete Res p o nse
C R F
Case Re p ort F or m
C S A
Cli nical St u d y  A gree me nt
C S F
C ol o n y - Sti m ulati n g F act ors
C S R
Cli nical St u d y  Re p ort
C T
C o m p ute d T o m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C Y P
C y t oc hr o me P- 4 5 0
D L T
D ose L i miti n g T o xicity
D N A
De o x yri b o n ucleic A ci d
D R
D urati o n of Res p o nse
D R E
D isease- Relate d E ve nt
E C G
Electr ocar di o gra m 
E C O G
Easter n C o o perati ve O nc ol o g y  Gr o u p
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 1
E D T A
E t h yle ne dia mi netetraacetic aci d
EI U
E x p os ure I n Uter o
E M A
E ur o pea n Me dici nes A ge nc y
E R
E str o ge n R ece pt or
F D A A A
U S F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act
G C P
G o o d Cli nical Practice
H 2R A
H 2-Rece pt or A nta g o nist
H b
H e m o gl o bi n
H E K 2 9 3
H u ma n e m br y o nic Ki d ne y  2 9 3
H E R
H u ma n E pi der mal G r o wt h F act or R ece pt or
H R
Heart R ate
Ht
H e mat ocrit
I C 5 0
C o nce ntrati o n of 5 0 % I n hi biti o n 
I C D
I nf or me d Co nse nt D oc u me nt
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n of Tec h nical Re q uire me nts f or 
Re gistrati o n of P har mace uticals f or H u ma n Use
I E C
I n de pe n de nt Et hics C o m mittee
I N R
Inter nati o nal N or malize d R ati o
I RB 
I nstit uti o nal Re vie w B oar d
K el
Rate c o nsta nt f or ter mi nal p hase
Ki
I n hi biti o n c oefficie nt
L D H
Lactate D e h y dr o ge nase 
L F T
Li ver F u ncti o n Test
LI P
Lea d -i n P hase
L S L V
L ast S u bject L ast V isit
M A D
Ma xi m u m A d mi nistere d D ose
M C L
M a ntle C ell L y m p h o ma
M D C K
Ma di n -Dar b y Ca ni ne Ki d ne y
M D R
M ulti ple Dr u g Resista nce
Me d D R A
Me dic al Dicti o nar y f or Re g ulat or y Acti vities
M RI
Ma g netic Res o na nce I ma gi n g
M T D  
Ma xi m u m T olerate d D ose
N A
N ot A p plica ble
N CI
Nati o nal Ca ncer I nstit ute
N O E L
N o -O bser ve d Effect Le vel
O R R
O verall R es p o nse R ate
P C D
P ri mar y Outc o me C o m pleti o n D ate
P D
Pr o gres si ve Disease
P E T
P ositr o n E missi o n T o m o gra p h y
P F S
Pr o gressi o n Free S ur vi val
P K
P har mac o ki netic 
P P T
Partial T hr o m b o plasti n Ti me
P R
Partial Res p o nse or Pr o gester o ne Rece pt or ( de pe n di n g o n c o nte xt)
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 2
P R
T he P R i nter val is meas ure d fr o m t he be gi n ni n g of t he P wa ve t o t he 
be gi n ni n g of t he Q R S c o m ple x.
P S
Perf or ma nce Stat us
P T
Pr ot hr o m bi n T i me
Q D
Q ua q ue Die ( o nce dail y )
Q R S
T he Q R S c o m ple x is a na me f or t he c o m bi nati o n of t hree of t he gra p hical 
deflecti o ns see n o n a t y pical electr ocar di o gra m .
T he Q R S c o m ple x reflects t he ra pi d de p olarizati o n of t he ri g ht a n d left 
ve ntricles.
Q T
Ti me bet wee n t he start of t he Q wa ve a n d t he e n d of t he T wa ve i n t he 
heart's electrical c y cle
Q T c
Q T I nter val C orrecte d b y  heart rate
Q Tc B
T he Q T i nter val c orrecte d f or heart r ate usi n g Baz ett'sf o m ula
Q Tc F
T he Q T i nter val c orrecte d f or heart rate usi n g Fri dericia's f o m ula
Q Tc S
T he Q T i nter val c orrecte d f or heart rate usi n g a st u d y-s pecific c orrecti o n 
met h o d
R B/ R b
Reti n o blast o ma
R E CI S T
Res p o nse E val uati o n Criteria i n S oli d T u m ors
R P 2 D
Rec o m me n de d P hase 2 D ose
R R
T he i nter val bet wee n a n R wa ve a n d t he ne xt R wa ve
R ac
A cc u m ulati o n R ati o
R ss
Stea d y -state acc u m ulati o n rati o
S A E
Seri o us A d verse E ve nt
S CI D
Se vere C o m bi ne d I m m u n o deficie nc y
S C L C
S mall C ell L u n g C a ncer
S D
Sta b le Disease or Sta n dar d De viati o n ( de pe n di n g o n c o nte xt)
S N P
Si n gle n ucle oti de p ol y m or p his m
S O P
Sta n dar d O perati n g Pr oce d ure
S U S A R
S us pecte d U ne x pecte d S eri o us A d verse R eacti o n
t½
Ter mi nal E li mi nati o n H alf-life
T E A E
Treat me nt -E mer ge nt A d verse E ve nt
T m a x
Ti me f or C ma x
U L N
U p per Li mit of N or mal
V z/ F
A p pare nt V ol u me of D istri b uti o n
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 3
1 7. 2. A p pe n di x 2. R E CI S T ( Res p o nse E v al u ati o n Criteri a I n S oli d T u m ors) versi o n 1. 1 
G ui deli nes
A d a pte d fr o m E. A. Eise n h a uer, et al: Ne w res p o nse ev al u ati o n criteri a i n s oli d t u m o u rs: 
Revise d R E CI S T g ui deli ne (versi o n 1. 1). E ur o pe a n J o ur n al of C a ncer 4 5 ( 2 0 0 9) 2 2 8– 2 4 7. 
C A T E G O RI ZI N G L E SI O N A T B A S E LI N E
Me as ur a ble Lesi o ns
Lesi o ns t hat ca n be acc uratel y  meas ure d i n at least o ne di me nsi o n.

Lesi o ns wit h l o n gest dia meter t wice t he slice t hic k ness a n d at least 1 0 m m or greater 
w he n assesse d b y C T or M RI  (slice t hic k ness 5-8 m m).

Lesi o ns wit h l o n gest dia meter at least 2 0 m m w he n assesse d b y C hest X -ra y. 

S u perficial lesi o ns wit h l o n gest dia meter 1 0 m m or greater w he n assesse d b y cali per.

M ali g na nt l y m p h n o des wit h t he s h ort a xis 1 5 m m or greater w he n assesse d b y  C T.
N O T E: T he s h ortest a xis is use d as t he di a meter f or m ali g n a nt l y m p h n o des, l o n gest 
a xis f or all ot her me as ur a ble lesi o ns. 
N o n - meas ura ble disease 
N o n -meas ura ble disease i ncl u de s lesi o ns t o o s mall t o be c o nsi dere d meas ura ble (i ncl u di n g 
n o des wit h s h ort a xis bet wee n 1 0 a n d 1 4. 9 m m) a n d tr ul y  n o n- meas ura ble disease s uc h as
ple ural or pericar dial eff usi o ns, ascites, i nfla m mat or y breast disease, le pt o me ni n geal disease, 
l ym p ha n gitic i n v ol ve me nt of s ki n or l u n g, cli nical lesi o ns t hat ca n n ot be acc uratel y  meas ure d 
wit h cali pers, a b d o mi nal masses i de ntifie d by p h ysical e xa m t hat are n ot meas ura ble b y 
re pr o d uci ble i ma gi n g tec h ni q ues.

B o ne disease: B o ne disease is n o n- meas ura ble wit h t he e x ce pti o n of s oft tiss ue 
c o m p o ne nts t hat ca n be e val uate d b y C T or M RI a n d meet t he defi niti o n of 
meas ura bilit y  at baseli ne. 

Pre vi o us l ocal treat me nt: A pre vi o usl y  irra diate d lesi o n ( or lesi o n patie nte d t o ot her 
l ocal treat me nt) is n o n-meas ura ble u nless it has pr o gresse d si nce c o m pleti o n of 
treat me nt.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 4
N or m al sites

C y stic lesi o ns: Si m ple c ysts s h o ul d n ot be c o nsi dere d as mali g na nt lesi o ns a n d s h o ul d 
n ot be rec or de d eit her as tar get or n o n -tar get disease.  C ystic lesi o ns t h o u g ht t o 
re prese nt c ystic metastases ca n be meas ura ble lesi o ns, if t he y  meet t he s pecific 
defi niti o n a b o ve.  If n o n -c ystic lesi o ns are als o prese nt, t hese are preferre d as tar get 
lesi o ns.

N or mal n o des: N o des wit h s h ort a xis < 1 0 m m are c o nsi dere d n or mal a n d s h o ul d n ot 
be rec or de d or f oll o we d e it her as meas ura ble or n o n-meas ura ble disease.
Rec or di n g T u m or Assess me nts 
All sites of disease m ust be assesse d at baseli ne.  Baseli ne assess me nts s h o ul d be d o ne as 
cl ose as p ossi ble pri or t o st u d y  start.  F or a n a de q uate baseli ne assess me nt, all re q uired sca ns 
m ust be d o ne wit hi n 2 8 da ys pri or t o treat me nt a n d all disease m ust be d oc u me nte d 
a p pr o priatel y.  If baseli ne assess me nt is i na de q uate, s u bse q ue nt stat uses ge nerall y s h o ul d be 
i n deter mi nate. 
T ar get lesi o ns
All meas ura ble lesi o ns u p t o a ma xi m u m of 2 lesi o ns per or ga n, 5 lesi o ns i n t otal, 
re prese ntati ve of all i n v ol ve d or ga ns, s h o ul d be i de ntifie d as tar get lesi o ns at baseli ne.  
Tar get lesi o ns s h o ul d be selecte d o n t he basis of size (l o n gest lesi o ns) a n d s uita bilit y  f or 
acc urate re peate d meas ure me nt s.  Rec or d t he l o n gest dia meter f or eac h lesi o n, e xce pt i n t he 
case of pat h ol o gical l y m p h n o des f or w hic h t he s h ort a xis s h o ul d be rec or de d.  T he s u m of 
t he dia meters (l o n gest f or n o n- n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or all tar get lesi o ns 
at baseli ne will be t he basis f or c o m paris o n t o assess me nts perf or me d o n st u d y . 

If t w o tar get lesi o ns c oalesce t he meas ure me nt of t he c oalesce d mass is use d.  If a 
lar ge tar get lesi o n s plits, t he s u m of t he parts is use d.

Meas ure me nts f or tar get lesi o ns t hat bec o me s mall s h o ul d c o nti n ue t o be rec or de d.  If 
a tar get lesi o n bec o mes t o o s mall t o meas ure, 0 m m s h o ul d be rec or de d if t he lesi o n is 
c o nsi dere d t o ha ve disa p peare d; ot her wise a defa ult val ue of 5 m m s h o ul d be 
rec or de d.
N O T E: W he n n o d al lesi o ns decre ase t o < 1 0 m m ( n or m al), t he act u al me as ure me nt 
s h o ul d still be rec or de d.
N o n -t ar get dise ase 
All n o n - meas ura ble disease is n o n-tar get.  All meas ura ble lesi o ns n ot i de ntifie d as tar get 
lesi o ns are als o i ncl u de d as n o n-tar get disease.  Meas ure me nts are n ot re q ui re d b ut rat her 
assess me nts will be e x presse d as A B S E N T, I N D E T E R MI N A T E, P R E S E N T/ N O T 
I N C R E A S E D, I N C R E A S E D.  M ulti ple n o n-tar get lesi o ns i n o ne or ga n ma y be rec or de d as a 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 0 5
si n gle ite m o n t he case re p ort f or m (e g, ‘ m ulti ple e nlar ge d pel vic ly m p h n o des’ or ‘ m ulti ple 
li ver metastases’).
O B J E C TI V E R E S P O N S E S T A T U S A T E A C H E V A L U A TI O N .
Disease sites m ust be assesse d usi n g t he sa me tec h ni q ue as baseli ne, i ncl u di n g c o nsiste nt 
a d mi nistrati o n of c o ntrast a n d ti mi n g of sca n ni n g.  I f a c ha n ge nee ds t o be ma de t he case 
m ust be disc usse d wit h t he ra di ol o gist t o deter mi ne if s u bstit uti o n is p ossi ble.  If n ot, 
s u bse q ue nt o bjecti ve stat uses are i n deter mi nate. 
Tar get disease

C o m plete Res p o nse ( C R): C o m plete disa p peara nce of all tar get lesi o ns wit h t he 
e xce pti o n of n o dal disease. All tar get n o des m ust decrease t o n or mal size (s h ort a xis 
< 1 0 m m).  All tar get lesi o ns m ust be assesse d.

Partial Res p o nse ( P R): Greater t ha n or e q ual t o 3 0 % decrease u n der baseli ne of t he 
s u m of dia meters of all tar get meas ura ble lesi o ns.  T he s h ort dia meter is use d i n t he 
s u m f or tar get n o des, w hile t he l o n gest dia meter is use d i n t he s u m f or all ot her tar get 
lesi o ns.  All tar get lesi o ns m ust be assesse d. 

Sta ble: D oes n ot q ualif y  f or C R, P R or Pr o gressi o n.  All tar get lesi o ns m ust be 
assesse d.  Sta ble ca n f oll o w P R o nl y  i n t he rare case t hat t he s u m i ncreases b y less 
t ha n 2 0 % fr o m t he na dir, b ut e n o u g h t hat a pre vi o usl y d oc u me nte d 3 0 % decrease n o 
l o n ger h ol ds. 

O bjecti ve Pr o gressi o n ( P D): 2 0 % i ncrease i n t he s u m of dia meters of tar get 
meas ura ble lesi o ns a b o ve t he s mallest s u m o bser ve d ( o ver baseli ne if n o decrease i n 
t he s u m is o bser ve d d uri n g t hera py), wit h a mi ni m u m a bs ol ute i ncrease of 5 m m. 

I n deter mi nate.  Pr o gressi o n has n ot bee n d oc u me nte d, a n d 

O ne or m ore tar get meas ura ble lesi o ns ha ve n ot bee n as sesse d; 

O r assess me nt met h o ds use d were i nc o nsiste nt wit h t h ose use d at baseli ne;

O r o ne or m ore tar get lesi o ns ca n n ot be meas ure d acc urately (e g, p o orl y visi ble 
u nless d ue t o bei n g t o o s mall t o meas ure);

O r o ne or m ore tar get lesi o ns were e xcise d or irradiate d a n d ha ve n ot rea p peare d 
or i ncrease d. 
N o n -tar get disease

C R: Disa p peara nce of all n o n- tar get lesi o ns a n d n or malizati o n of t u m or mar ker 
le vels.  All l y m p h n o des m ust be ‘ n or mal’ i n size ( < 1 0 m m s h ort a xis).
 

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
N o n -C R/ N o n -P D: Persiste nce of a n y n o n -tar get lesi o ns a n d/ or t u m or mar ker le vel 
a b o ve t he n or mal li mits. 

P D: U ne q ui v ocal pr o gressi o n of pre- e xisti n g lesi o ns.  Ge nerall y t he o verall t u m or 
b ur de n m ust i ncrease s ufficie ntl y  t o merit disc o nti n uati o n of t hera p y.  I n t he prese nce 
of S D or P R i n tar get d isease, pr o gressi o n d ue t o u ne q ui v ocal i ncrease i n n o n-tar get 
disease s h o ul d be rare. 

I n deter mi nate: Pr o gressi o n has n ot bee n deter mi ne d a n d o ne or m ore n o n-tar get sites 
were n ot assesse d or assess me nt met h o ds were i nc o nsiste nt wit h t h ose use d at 
baseli ne .
Ne w Lesi o ns 
T he a p peara nce of a n y ne w u ne q ui v ocal mali g na nt lesi o n i n dicates P D.  If a ne w lesi o n is 
e q ui v ocal, f or e xa m ple d ue t o its s mall size, c o nti n ue d assess me nt will clarif y  t he eti ol o g y.  
If re peat assess me nts c o nfir m t he lesi o n, t he n pr o gressi on s h o ul d be rec or de d o n t he date of 
t he i nitial assess me nt.  A lesi o n i de ntifie d i n a n area n ot pre vi o usl y sca n ne d will be 
c o nsi dere d a ne w lesi o n.
S u p ple me ntal I n vesti gati o ns

If C R deter mi nati o n de pe n ds o n a resi d ual lesi o n t hat decrease d i n size b ut di d n ot 
disa p pear c o m pletel y, it is rec o m me n de d t he resi d ual lesi o n be i n vesti gate d wit h 
bi o ps y  or fi ne nee dle as pirate.  If n o disease is i de ntifie d, o bjecti ve stat us is C R.

If pr o gressi o n deter mi nati o n de pe n ds o n a lesi o n wit h a n i ncrease p ossi bl y d ue t o 
nec r osis, t he lesi o n ma y be i n vesti gate d wit h bi o ps y or fi ne nee dle as pirate t o clarif y 
stat us. 
S u bjecti ve pr o gressi o n
Patie nts re q uiri n g disc o nti n uati o n of treat me nt wit h o ut o bjecti ve e vi de nce of disease 
pr o gressi o n s h o ul d n ot be re p orte d as P D o n t u m or ass ess me nt C R Fs.  T his s h o ul d be 
i n dicate d o n t he e n d of treat me nt C R F as off treat me nt d ue t o Gl o bal Deteri orati o n of Healt h 
Stat us.  E ver y  eff ort s h o ul d be ma de t o d oc u me nt o bjecti ve pr o gressi o n e ve n after 
disc o nti n uati o n of treat me nt. 
 

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T a ble 1. O bjecti ve R es p o nse St at us at e ac h E v al u ati o n
T ar get Lesi o ns
N o n -t ar get Dise ase
Ne w Lesi o ns
O bjecti ve st at us
C R
C R
N o
C R
C R
N o n -C R/ N o n -P D
N o
P R
C R
I n deter mi nate or 
Missi n g 
N o
P R
P R
N o n -C R/ N o n -P D, 
I n deter mi nate, or 
Missi n g
N o
P R
S D
N o n -C R/ N o n -P D, 
I n deter mi nate, or 
Missi n g
N o
Sta ble
I n deter mi nate or 
Missi n g
N o n -P D
N o
I n deter mi nate
P D
A n y
Yes or N o
P D
A n y
P D
Yes or N o
P D
A n y
A n y
Yes
P D
T a ble 2. O bjecti ve Res p o nse St at us at e ac h E v al u ati o n f or P atie nts wit h N o n -T ar get 
Dise ase O nl y
N o n -t ar get Dise ase
Ne w Lesi o n s
O bjecti ve st at us
C R
N o
C R
N o n -C R/ N o n -P D
N o
N o n -C R/ N o n -P D
I n deter mi nate
N o
I n deter mi nate
U ne q ui v ocal pr o gressi o n
Yes or N o
P D
A n y
Yes
P D
 

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1 7. 3. A p pe n di x 3. A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g
1 7. 3. 1. - Def i niti o n of A E
A E Defi niti o n

A n A E is a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical st u d y 
partici pa nt, te m p orall y ass ociate d wit h t he use of st u d y i nter ve nti o n, w het her or n ot 
c o nsi dere d relate d t o t he st u d y  i nter ve nti o n.

N O T E: A n A E ca n t heref o re be a ny u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), sy m pt o m, or disease ( ne w or e xacer bate d) te m p orall y  
ass ociate d wit h t he use of st u d y  i nter ve nti o n.
E ve nts Meeti n g t he A E Defi niti o n
A n y  a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or 
ot her safet y assess me nts (e g, E C G, ra di ol o gical sca ns, vital si g n meas ure me nts), i ncl u di n g 
t h ose t hat w orse n fr o m baseli ne, c o nsi dere d cli nicall y si g nifica nt i n t he me dical a n d 
scie ntific j u d g me nt of t he i n vesti gat or (ie, n ot relate d t o pr o gressi o n of u n derl yi n g 
disease).
E xacer bati o n of a c hr o nic or i nter mitte nt pree xisti n g c o n diti o n i ncl u di n g eit her a n i ncrease 
i n fre q ue nc y a n d/ or i nte nsit y of t he c o n diti o n.
Ne w c o n diti o ns detecte d or dia g n ose d after st u d y  i nter ve nti o n a d mi nistrati o n e ve n t h o u g h 
it ma y ha ve bee n prese nt bef ore t he start of t he st u d y.
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y 
i nter ve nti o n or a c o nc o mita nt me dicati o n.  O ver d ose per se will n ot be re p orte d as a n 
A E/ S A E u nless it is a n i nte nti o nal o ver d ose ta ke n wit h p ossi ble s uici dal/self -har mi n g 
i nte nt.  S uc h o ver d oses s h o ul d be re p orte d re gar dless of se q uelae.
“ Lac k of ef ficac y” or “fail ure of e x pecte d p har mac ol o gical acti o n” per se will n ot be 
re p orte d as a n A E or S A E.  S uc h i nsta nces will be ca pt ure d i n t he efficac y assess me nts.  
H o we ver, t he si g ns, s y m pt o ms, a n d/ or cli nical se q uelae res ulti n g fr o m lac k of efficac y  will 
be re p orte d as a n A E or S A E if t he y  f ulfill t he defi niti o n of a n A E or S A E.
E ve nts N O T Meeti n g t he A E Defi niti o n
A n y  cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs or ot her a b n or mal safety 
assess me nts w hic h are ass ociate d wit h t he u n derl yi n g diseas e, u nless j u d ge d b y t he 
 

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i n vesti gat or t o be m ore se vere t ha n e x pecte d f or t he partici pa nt’s c o n diti o n.
T he disease/ dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o ms of t he 
disease/ dis or der bei n g st u die d, u nless m ore se vere t ha n e x pecte d f or t he partici pa nt’s 
c o n diti o n.
Me dical or s ur gical pr oce d ure (e g, e n d osc o p y, a p pe n dect o m y): t he c o n diti o n t hat lea ds t o 
t he pr oce d ure is t he A E.
Sit uati o ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pi tal).
A ntici pate d da y -t o-d a y  fl uct uati o ns of pree xisti n g disease(s) or c o n diti o n(s) prese nt or 
detecte d at t he start of t he st u d y  t hat d o n ot w orse n.
W orse ni n g of si g ns a n d s y m pt o ms of t he mali g na nc y  u n der st u d y s h o ul d be rec or de d as 
A Es i n t he a p pr o priate secti o n of t he C R F.  Disease pr o gressi o n assesse d b y meas ure me nt 
of mali g na nt lesi o ns o n ra di o gra p hs or ot her met h o ds s h o ul d n ot be re p orte d as A Es.
1 7. 3. 2. Defi niti o n of S A E
If a n e ve nt is n ot a n A E per defi niti o n a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us
c o n diti o ns are met (e g, h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n der st u d y , deat h 
d ue t o pr o gressi o n of disease).
A n S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:
a.
Res ults i n de at h
b.
Is life-t hre ate ni n g
T he ter m “life -t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h t he 
partici pa nt was at ris k of deat h at t he ti me of t he e ve nt.  I t d oes n ot refer t o a n e ve nt t hat 
h y p ot heticall y  mi g ht ha ve ca use d deat h if it were m ore se vere.
c.
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
I n ge neral, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n detai ne d ( us uall y 
i n v ol vi n g at least a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or o bser vati o n 
a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h ys icia n’s office or 
o ut patie nt setti n g.  C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are A Es.  If a 
c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, t he e ve nt is 
seri o us.  W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was necessar y, t he A E 
s h o ul d be c o nsi dere d seri o us.
H os pitalizati o n f or electi ve treat me nt of a pree xisti n g c o n diti o n t hat di d n ot w orse n fr o m 
baseli ne is n ot c o nsi dere d a n A E.
 

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d.
Res ults i n persiste nt dis a bilit y/i nc a p acit y
T he ter m disa bilit y mea ns 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 f u ncti o ns.
T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, a n d 
acci de ntal tra u ma (e g, s prai ne d a n kle) w hic h ma y  i nterfere wit h or pre ve nt e ver yd a y  life 
f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n.
e.
Is a c o n ge nit al a n o m al y/ birt h defect
f.
Ot her sit u ati o ns:
Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E re p orti n g is 
a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat ma y  n ot be 
i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he 
partici pa nt or ma y  re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he ot her 
o utc o mes liste d i n t he a b o ve defi niti o n.  T hese e ve nts s h o ul d us uall y  be c o nsi dere d 
seri o us.
E xa m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, 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 f or aller gic br o nc h os pas m, bl o o d d yscrasias or c o n v ulsi o ns 
t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.
Pr o gressi o n of t he mali g na nc y  u n der st u dy (i ncl u di n g si g ns a n d sy m pt o ms of pr o gressi o n) 
s h o ul d n ot be re p orte d as a n S A E u nless t he o utc o me is fatal wit hi n t he acti ve c ollecti o n 
peri o d.  H os pitalizati o n d ue t o si g ns a n d s y m pt o ms of disease pr o gressi o n s h o ul d n ot be 
re p orte d as a n S A E.  If t he mali g na nc y has a fatal o utc o me d uri n g t he st u d y or wit hi n t he 
acti ve c ollecti o n peri o d, t he n t he e ve nt lea di n g t o deat h m ust be rec or de d as a n A E o n t he 
C R F, a n d as a n S A E wit h 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) 
Gra de 5 (see t he Assess me nt of I nte nsit y  secti o n).
 

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1 7. 3. 3. Rec or di n g/ Re p orti n g a n d F oll o w -u p of A Es a n d/ or S A Es
A E a n d S A E Rec or di n g/ Re p orti n g
T he ta ble bel o w s u m marizes t he re q uire me nts f or rec or di n g a d verse e ve nts o n t he C R F a n d 
f or re p orti n g seri o us a d verse e ve nts o n t he Cli nical Trial ( C T) Seri o us A d verse E ve nt 
( S A E) Re p ort F or m t o Pfizer Safet y.  T hese re q uire me nts are deli neate d f or 3 t ypes of 
e ve nts: ( 1) S A Es; ( 2) n o nseri o us a d verse e ve nts ( A Es); a n d ( 3) e x p os ure t o t he 
i n vesti gati o nal pr o d uct u n der st u d y d uri n g pre g na nc y or breastfee di n g, a n d occ u pati o nal 
e x p os ure. 
It s h o ul d be n ote d t hat t he C T S A E Re p ort F or m f or re p orti n g of S A E i nf or mati o n is n ot 
t he sa me as t he A E pa ge of t he C R F.  W he n t he sa me data are c ollecte d, t he f or ms m ust be 
c o m plete d i n a c o nsiste nt ma n ner.  A Es s h o ul d be rec or de d usi n g c o ncise me dical 
ter mi n ol o gy a n d t he sa me A E ter m s h o ul d be use d o n b ot h t he C R F a n d t he C T S A E 
Re p ort F or m f or re p orti n g of S A E i nf or mati o n.
S afet y E ve nt
Rec or de d o n t he C R F
Re p orte d o n t he C T S A E 
Re p ort F or m t o Pfizer 
S afet y Wit hi n 2 4 H o urs of 
A w are ness
S A E
All
All
N o nseri o us A E
All
N o ne
E x p os ure t o t he 
i n vesti gati o nal pr o d uct 
u n der st u d y  d uri n g 
pre g na nc y  or 
breastfee di n g, a n d 
occ u pati o nal e x p os ure
N o ne
All (a n d e x p os ure d uri n g 
pre g na nc y  [ E D P] 
s u p ple me ntal f or m f or 
E D P)  
W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y  of t he i n vesti gat or t o re vie w all 
d oc u me ntati o n (e g, h os pital pr o gress n otes, la b orat or y  re p orts, a n d dia g n ostic re p orts) 
relate d t o t he e ve nt.
T he i n vesti gat or will t he n rec or d all rele va nt A E/ S A E i nf or mati o n i n t he C R F.
It is n ot acce pta ble f or t he i n vesti gat or t o se n d p h ot oc o pies of t he partici pa nt’s me dical 
rec or ds t o Pfizer Safet y i n lie u of c o m pleti o n of t he C T S A E Re p ort F or m/ A E/ S A E C R F 
pa ge.
T here ma y  be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are re q ueste d b y 
Pfizer Safet y .  I n t his case, all partici pa nt i de ntifiers, wit h t he e xce pti o n of t he partici pa nt 
n u m ber, will be re dacte d o n t he c o pies of t he me dical rec or ds bef ore s u b missi o n t o Pfizer 
Safet y .
T he i n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
 

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s ym p t o ms, a n d/ or ot her cli nical i nf or mati o n.  W he ne ver p ossi ble, t he dia g n osis ( n ot t he 
i n di vi d ual si g ns/s ym pt o ms) will be d oc u me nte d as t he A E/ S A E.
Assess me nt of I nte nsit y
A d verse e ve nts occ urri n g d uri n g t his st u d y  will be gra de d i n acc or da nce wit h Gra de 0 t o 
Gra de 5 scale prese nte d bel o w.  T he detaile d defi niti o ns are i n acc or da nce wit h Nati o nal 
Ca n cer I nstit ute 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 4. 0.  
D oc u me ntati o n of A E gra di n g i n t he s o urce d oc u me nts a n d C R F m ust be c o nsiste nt wit h 
pr o vi de d defi niti o ns .
T he N CI C T C A E ( Versi o n 4. 0 date Ma y  2 9, 2 0 0 9) has bee n place d i n t he St u d y Ma n ual 
f or t his pr ot oc ol.  Alter nati vel y, t he N CI C T C A E ma y be re vie we d o n-li ne at t he f oll o wi n g 
N CI  we bsite: htt p://cte p.ca ncer. g o v/re p orti n g/ctc. ht ml.
N ote t he disti ncti o n bet wee n t he se verit y a n d t he seri o us ness of a n A E.  A se vere e ve nt is 
n ot necessaril y a n S A E.  F or e xa m ple, a hea dac he ma y be se vere (i nterferes si g nifica ntl y 
wit h t he s u bject's us ual f u ncti o n) b ut w o ul d n ot be classifie d as seri o us u n less it met o ne of 
t he criteria f or S A Es, liste d a b o ve.
G R A D E
Cli nic al Descri pti o n of Se verit y
1
MI L D a d verse e ve nt
2
M O D E R A T E a d verse e ve nt
3
S E V E R E a d verse e ve nt
4
LI F E -T H R E A T E NI N G c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d
5
D E A T H R E L A T E D T O a d ver se e ve nt
Assess me nt of C a us alit y
T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n a n d eac h 
occ urre nce of eac h A E/ S A E.
A “reas o na ble p ossi bilit y” of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, a n d/ or 
ar g u ments t o s u g gest a ca usal relati o ns hi p, rat her t ha n a relati o ns hi p ca n n ot be r ule d o ut.
T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.
Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k 
fact ors, as well as t he te m p oral relati o ns hi p of t he e ve nt t o st u d y  i nter ve nti o n 
a d mi nistrati o n will be c o nsi dere d a n d i n vesti gate d.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 3
T he i n vesti gat or will als o c o ns ult t he i n vesti gat or’s br oc h ure (I B) a n d/ or pr o d uct 
i nf or mati o n, f or mar kete d pr o d ucts, i n his/ her assess me nt.
F or eac h A E/ S A E, t he i n vesti gat or m ust d oc u me nt i n t he me dical n otes t hat he/s he has 
re vie we d t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usality.
T here ma y  be sit uati o ns i n w hic h a n S A E has occ urre d a n d t he i n vesti gat or has mi ni mal 
i nf or matio n t o i ncl u de i n t he i nitial re p ort t o t he s p o ns or.  H o we ver, it is ver y i m p ort a nt 
t h at t he i n vesti g at or al w a ys m a ke a n assess me nt of c a us alit y f or e ver y e ve nt bef ore 
t he i niti al tr a ns missi o n of t he S A E d at a t o t he s p o ns or.
T he i n vesti gat or ma y  c ha n ge his/her o pi ni o n of ca usalit y  i n li g ht of f oll o w-u p i nf or mati o n 
a n d se n d a n S A E f oll o w- u p re p ort wit h t he u p date d ca usalit y assess me nt.
T he ca usalit y  assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y re p orti n g 
re q uire me nts.
If t he i n vesti gat or d oes n ot k n o w w het her or n ot t he i n vesti gati o nal pr o d uct ca use d t he 
e ve nt, t he n t he e ve nt will be ha n dle d as “relate d t o i n vesti gati o nal pr o d uct” f or re p orti n g 
p ur p oses, as defi ne d b y t he s p o ns or.  I n a d diti o n, if t he i n vesti gat or deter mi nes t hat a n 
S A E is ass ociate d wit h st u d y pr oce d ures, t he i n vesti gat or m ust rec or d t his ca usal 
relati o ns hi p i n t he s o urce d oc u me nts a n d C R F, a n d re p ort s uc h a n assess me nt i n t he 
de dicate d secti o n of t he C T S A E Re p ort F or m a n d i n acc or da nce wit h t he S A E re p orti n g 
re q uire me nts.
F oll o w - u p of A Es a n d S A Es
T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as me dicall y  i n dicate d or as re q ueste d b y t he s p o ns or t o 
el uci date t he nat ure a n d/ or ca usalit y of t he A E or S A E as f ull y  as p ossi ble.  T his ma y 
i ncl u de a d diti o nal la b orat or y tests or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns, or 
c o ns ultati o n wit h ot her healt hcare pr ofessi o nals.
Ne w or u p date d i nf or mati o n will be rec or de d i n t he ori gi nall y  c o m plete d C R F.
T he i n vesti gat or will s u b mit a n y u p date d S A E data t o t he s p o ns or wit hi n 2 4 h o urs of 
recei pt of t he i nf or mati o n.
1 7. 3. 4. Re p orti n g of S A Es
S A E Re p orti n g t o Pfizer S afet y vi a a n Electr o nic D at a C ollecti o n T o ol
T he pri mar y  mec ha nis m f or re p orti n g a n S A E t o Pfizer Safety will be t he electr o nic data 
c ollecti o n t o ol.
If t he electr o nic sys te m is u na vaila ble, t he n t he site will use t he pa per S A E data c ollecti o n 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 4
t o ol (see ne xt secti o n) i n or der t o re p ort t he e ve nt wit hi n 2 4 h o urs.
T he site will e nter t he S A E data i nt o t he ele ctr o nic s yste m as s o o n as t he data bec o me 
a vaila ble.
After t he st u d y is c o m plete d at a gi ve n site, t he electr o nic data c ollecti o n t o ol will be ta ke n 
off -li ne t o pre ve nt t he e ntr y of ne w data or c ha n ges t o e xisti n g data.
If a site recei ves a re p ort of a ne w S A E fr o m a st u d y  partici pa nt or recei ves u p date d data 
o n a pre vi o usl y re p orte d S A E after t he electr o nic data c ollecti o n t o ol has bee n ta ke n 
off -li ne, t he n t he site ca n re p ort t his i nf or mati o n o n a pa per S A E f or m (see ne xt secti o n) or 
t o Pfizer Safet y b y tele p h o ne.
S A E Re p orti n g t o Pfizer S afet y vi a C T S A E Re p ort F or m
Facsi mile tra ns missi o n of t he C T S A E Re p ort F or m is t he preferre d met h o d t o tra ns mit 
t his i nf or mati o n t o Pfizer Safet y.
I n circ u msta nces w he n t he facsi mile is n ot w or ki n g, n otificati o n by t ele p h o ne is acce pta ble 
wit h a c o p y of t he C T S A E Re p ort F or m se nt b y o ver ni g ht mail or c o urier ser vice.
I nitial n otificati o n via tele p h o ne d oes n ot re place t he nee d f or t he i n vesti gat or t o c o m plete 
a n d si g n t he C T S A E Re p ort F or m pa ges wit hi n t he desi g nate d re p orti n g ti me fra mes.
1 7. 4. A p pe n di x 4. E C O G Perf or m a nce St at us *
Gr a de
E C O G
0
F ull y  acti ve, a ble t o carr y o n all pre-disease perf or ma nce wit h o ut restricti o n.
1
Restricte d i n p h y sicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut 
w or k of a li g ht or se de ntar y  nat ure, e g, li g ht h o use w or k, office w or k.
2
A m b ulat or y  a n d ca pa ble of all self-care b ut u na ble t o carr y o ut a ny w or k 
acti vities.  U p a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs.
3
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
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.
5
Dea d.
* As p u blis he d i n A m J Cli n O nc ol 5: 6 4 9 -6 5 5, 1 9 8 2.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 5
1 7. 5. A p pe n di x 5. B o ne M arr o w Reser ve i n A d ult
A d a pte d fr o m R. E. E L LI S : T he Distri buti o n of Active B o ne M arr o w i n t he A d ult, P hy. Me d. 
Bi ol.  5 , 2 5 5-2 5 8, 1 9 6 1
M A R R O W DI S T RI B U TI O N O F T H E A D U L T
SI T E
M A R R O W
wt. ( g)
F R A C TI O N 
R E D 
M A R R O W
A G E 4 0
R E D 
M A R R O W
wt. ( g)
A G E 4 0
% T O T A L
R E D M A R R O W
C R A NI U M
Hea d:
1 3 6. 6
A N D
Cra ni u m
1 6 5. 8
0. 7 5
1 2 4. 3
1 3. 1
1 3. 1
M A N DI B L E
Ma n di ble
1 6. 4
0. 7 5
1 2. 3
U p per Li m b Gir dle :
8 6. 7
H U M E RI,
S C A P U L A E,
2 H u mer us, 
hea d & nec k
2 6. 5
0. 7 5
2 0. 0
8. 3
8. 3
C L A VI C L E S
2 Sca p ulae 
6 7. 4
0. 7 5
5 0. 5
2 Cla vicles
2 1. 6
0. 7 5
1 6. 2
Ster n u m
3 9. 0
0. 6
2 3. 4
2. 3
Ri b s: 
8 2. 6
1 pair
1 0. 2
All 0. 4
4. 1
2 
1 2. 6
5. 0
3
1 6. 0
6. 4
S T E R N U M
4
1 8. 6
7. 4
A N D
5
2 3. 8
9. 5
7. 9
1 0. 2
RI B S
6
2 3. 6
9. 4
7
2 5. 0
1 0. 0
8
2 4. 0
9. 6
9
2 1. 2
8. 5
1 0
1 6. 0
6. 4
1 1
1 1. 2
4. 5
1 2
4. 6
1. 8
Sacr u m 
1 9 4. 0
0. 7 5
1 4 5. 6
1 3. 9
P E L VI C 
B O N E S
2 os c o xae
3 1 0. 6
0. 7 5
2 3 3. 0
2 2. 3
3 6. 2
F E M U R
2 Fe m oral hea d 
a n d nec k
5 3. 0
0. 7 5
4 0. 0
3. 8
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 6
M A R R O W DI S T RI B U TI O N O F T H E A D U L T ( C O N T' D)
SI T E
M A R R O W
wt. ( g)
F R A C TI O N R E D 
M A R R O W
A G E 4 0
R E D 
M A R R O W
wt. ( g)
A G E 4 0
% T O T A L
R E D M A R R O W
Verte brae
( Cer vical):
3 5. 8
1
6. 6
All 0. 7 5
5. 0
2
8. 4
6. 3
3
5. 4
4. 1
3. 4
4
5. 7
4. 3
5
5. 8
4. 4
6
7. 0
5. 3
7
8. 5
6. 4
Verte brae
( T h oracic):
1 4 7. 9
1 pair
1 0. 8
All 0. 7 5
8. 1
2
1 1. 7
8. 8
3
1 1. 4
8. 5
4
1 2. 2
9. 1
V E R T E B R A E
5
1 3. 4
1 0. 1 
1 4. 1
2 8. 4
6
1 5. 3
1 1. 5
7
1 6. 1
1 2. 1
8
1 8. 5
1 3. 9
9
1 9. 7
1 4. 8
1 0
2 1. 2
1 5. 9
1 1
2 1. 7
1 6. 3
1 2
2 5. 0
1 8. 8
Verte brae
( L u m bar):
1 1 4. 1
1 pair
2 7. 8
All 0. 7 5
2 0. 8
2
2 9. 1
2 1. 8
1 0. 9
3
3 1. 8
2 3. 8
4
3 2. 1
2 4. 1
5
3 1. 4
2 3. 6
T O T A L
1 4 9 7. 7
1 0 4 5. 7
1 0 0. 0
1 0 0. 0
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 7
1 7. 6. A p pe n di x 6. List of Dr u gs K n o w n t o Pre dis p ose t o T ors a de de P oi ntes
Ge neric N a me
Br a n d N a me(s)
A mi o dar o ne
C or dar o ne , Pacer o ne
Arse nic tri o xi de
Trise n o x 
Aste mi z ole
His ma nal 
Azit hr o m y ci n
Zit hr o ma x 
Be pri dil
Vasc or 
C hl or o q ui ne
Arale n 
C hl or pr o mazi ne
T h orazi ne 
Cisa pri de
Pr o p ulsi d 
Cital o pra m
Cele xa 
Clarit hr o m y ci n
Bia xi n 
Dis o p y ra mi de
N or pace 
D ofetili de
Ti k os y n 
D o m peri d o ne
M otili u m

Dr o peri d ol
I na psi ne
Er y t hr o myci n
Er y t hr oci n, E. E. S.
Flecai ni de
Ta m b oc or 
Hal ofa ntri ne
Halfa n 
Hal o peri d ol
Hal d ol 
I b utili de
C or vert 
Le v o met ha d yl
Orlaa m 
Mes ori dazi ne
Sere ntil 
Met ha d o ne
D ol o p hi ne , Met ha d ose
M o xifl o xaci n
A vel o x 
Pe nta mi di ne
Pe nta m Ne b u Pe nt 
Pi m ozi de
Ora p 
Pr o b uc ol
L orelc o 
Pr ocai na mi de
Pr o nest y l, Pr oca n
Q ui ni di ne
Car di o q ui n , Q ui na gl ute
S otal ol
Beta pace 
S parfl o xaci n
Za ga m 
Terfe na di ne
Sel da ne 
T hi ori dazi ne
Mellaril

Va n deta ni b
Ca prelsa 
A da pte d fr o m t he U ni versit y of Ariz o na C a ncer Ce nter f or E d ucati o n a n d Researc h o n T hera pe utics: " T orsa des 
List: Dr u gs wit h a Ris k of T orsa des de P oi ntes," dr u gs t hat are ge nerall y acce pte d b y t he Q T dr u gs. or g A d vis or y 
B oar d t o carr y a ris k of T orsa des de P oi ntes o n t he U ni versit y of Ariz o na C E R T we bsite: 
htt p:// w w w.azcert. or g/ me dical -pr os/ dr u g -lists/ b ycate g or y.cf m #.  T his list is n ot mea nt t o be c o nsi dere d all 
i ncl usi ve.  See we bsite f or c urre nt list. 
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 8
1 7. 7. A p pe n di x 7. Wisc o nsi n A ge -Rel ate d E ye Dise ase St u d y ( A R E D S) 2 0 0 8 Cli nic al 
Le ns O p acit y Gr a di n g Pr oce d ure

Dilate p u pils t o at least 5 m m dia meter.

Use slit la m p wit h ~ 1 0 X ma g nificati o n.

Use bri g htest bea m i nte nsit y .

N uclear o pacit y.

Orie nt bea m at 4 5° t o vie wi n g a xis .

A dj ust slit bea m t o sta n dar d para meters: 8 m m hei g ht a n d 0. 3 m m wi dt h .

C o m pare o p alesce nce of n ucle us wit h t hat i n sta n dar d p h ot os.

C ortical a n d P S C o pacities .

Select wi de slit bea m setti n g o pti m u m f or retr o -ill u mi nati o n of le ns.

Vis ualize le ns o pacities a gai nst re d f u n d us refle x bac k gr o u n d .

C o u nt o nl y  o pacities defi nitel y visi ble a gainst re d refle x .

Me ntall y  c o m bi ne all c ortical o pacities i nt o o ne c o nti g u o us area.

C o m pare t otal o pacit y area wit h t hat i n sta n dar d p h ot os .

Classif y  eac h o pacit y wit h scale defi ne d b y 3 sta n dar d p h ot os.

Select nearest half -ste p.

Si milar t o sta n dar d or bet we e n t w o sta n dar ds .

O b vi o usl y  less t ha n mil dest sta n dar d or greater t ha n m ost se vere.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 9
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 0
1 7. 8. A p pe n di x 8. C ollecti o n of Pre g n a nc y I nf or m ati o n
F or b ot h u na p pr o ve d/ u nlice nse d pr o d ucts a n d f or mar kete d pr o d ucts, a n e x p os ure d uri n g 
pre g na nc y  ( E D P) occ urs if:

A fe mal e bec o mes, or is f o u n d t o be, pre g na nt eit her w hile recei vi n g or ha vi n g bee n 
e x p ose d (e g, beca use of treat me nt or e n vir o n me ntal e x p os ure) t o t he i n vesti gati o nal 
pr o d uct; or t he fe male bec o mes or is f o u n d t o be pre g na nt after disc o nti n ui n g a n d/ or 
bei n g e x p o se d t o t he i n vesti gati o nal pr o d uct;

A n e xa m ple of e n vir o n me ntal e x p os ure w o ul d be a case i n v ol vi n g direct c o ntact 
wit h a Pfizer pr o d uct i n a pre g na nt w o ma n (e g, a n urse re p orts t hat s he is pre g na nt 
a n d has bee n e x p ose d t o c he m ot hera pe utic pr o d ucts).

A male has bee n e x p ose d (e g, beca use of treat me nt or e n vir o n me ntal e x p os ure) t o t he 
i n vesti gati o nal pr o d uct pri or t o or ar o u n d t he ti me of c o nce pti o n a n d/ or is e x p ose d 
d uri n g his part ner’s pre g na nc y .
If a partici pa nt or partici pa nt’s part ner bec o mes or is f o u n d t o be pre g na nt d uri n g t he 
partici pa nt’s treat me nt wit h t he i n vesti gati o nal pr o d uct, t he i n vesti gat or m ust re p ort t his 
i nf or mati o n t o Pfizer Safet y o n t he C T S A E Re p ort F or m a n d a n E D P s u p ple me ntal f or m, 
re gar dless of w het her a n S A E has occ urre d.  I n a d ditio n, t he i n vesti gat or m ust s u b mit 
i nf or mati o n re gar di n g e n vir o n me ntal e x p os ure t o a Pfizer pr o d uct i n a pre g na nt w o ma n (e g, a 
partici pa nt re p orts t hat s he is pre g na nt a n d has bee n e x p ose d t o a c yt ot o xic pr o d uct b y 
i n halati o n or s pilla ge) t o Pfizer Safet y usi n g t he E D P s u p ple me ntal f or m.  T his m ust be d o ne 
irres pecti ve of w het her a n A E has occ urre d a n d wit hi n 2 4 h o urs of a ware ness of t he 
e x p os ure.  T he i nf or mati o n s u b mitte d s h o ul d i ncl u de t he a ntici pate d date of deli ver y  (see 
bel o w f or i nf or mati o n relate d t o ter mi nati o n of pre g na nc y).
F oll o w -u p is c o n d ucte d t o o btai n ge neral i nf or mati o n o n t he pre g na nc y  a n d its o utc o me f or 
all E D P re p orts wit h a n u n k n o w n o utc o me.  T he i n vesti gat or will f oll o w t he pre g na nc y  u ntil 
c o m pleti o n ( or u ntil pre g na nc y  ter mi nati o n) a n d n otif y  Pfizer Safety of t he o utc o me as a 
f oll o w- u p t o t he i nitial E D P s u p ple me ntal f or m.  I n t he case of a li ve birt h, t he str uct ural 
i nte grity of t he ne o nate ca n be assesse d at t he ti me of birt h.  I n t he e ve nt of a ter mi nati o n, t he 
reas o n(s) f or ter mi natio n s h o ul d be s pecifie d a n d, if cli nicall y p ossi ble, t he str uct ural 
i nte grity of t he ter mi nate d fet us s h o ul d be assesse d b y gr oss vis ual i ns pecti o n ( u nless 
pre pr oce d ure test fi n di n gs are c o ncl usi ve f or a c o n ge nital a n o mal y a n d t he fi n di n gs are 
re p orte d).
If t he o utc o me of t he pre g na nc y meets t he criteria f or a n S A E (ie, ect o pic pre g na nc y, 
s p o nta ne o us a b orti o n, i ntra uteri ne fetal de mise, ne o natal deat h, or c o n ge nital a n o mal y [i n a 
li ve-b or n ba b y, a ter mi nate d fet us, a n i ntra uteri ne fetal de mise, or a ne o natal deat h]), t he 
i n vesti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g S A Es.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 1
A d diti o nal i nf or mati o n a b o ut pre g na nc y  o utc o mes t hat are re p orte d t o Pfizer Safety as S A Es 
f oll o ws: 

S p o nta ne o us a b orti o n i ncl u des miscarria ge a n d misse d a b orti o n;

Ne o natal deat hs t hat occ ur wit hi n 1 m o nt h of birt h s h o ul d be re p orte d, wit h o ut re gar d 
t o ca usalit y, as S A Es.  I n a d diti o n, i nfa nt deat hs after 1 m o nt h s h o ul d be re p orte d as 
S A Es w he n t he i n vesti gat or assesses t he i nfa nt deat h as relate d or p ossi bl y  relate d t o 
e x p os ure t o t he i n vesti gati o nal pr o d uct. 
A d diti o nal i nf or mati o n re gar di n g t he E D P ma y  be re q ueste d b y t he s p o ns or.  F urt her 
f oll o w- u p of birt h o utc o mes will be ha n dle d o n a case-b y -case basis (e g, f oll o w- u p o n 
preter m i nfa nts t o i de ntif y de vel o p me ntal dela y s).  In t h e case of pater nal e x p os ure, t he 
i n vesti gat or will pr o vi de t he partici pa nt wit h t he Pre g na nt Part ner Release of I nf or mati o n 
F or m t o deli ver t o his part ner.  T he i n vesti gat or m ust d oc u me nt i n t he s o urce d oc u me nts t hat 
t he partici pa nt was gi ve n t he Pre g na nt Part ner Release of I nf or mati o n F or m t o pr o vi de t o his 
part ner.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 2
1 7. 9. A p pe n di x 9 . Sc he d ule Sc he d ule of Acti vities f or P atie nts C o nti n ui n g t o Recei ve 
Acti ve Tre at me nt After I R B/I E C A p pr o v al of A me n d me nt 3.
U p o n I R B/I E C a p pr o val of A me n d me nt 3 , cli nical assess me nts will be re d uce d i n sc o pe a n d
t he re q uire d sc he d ule of acti vities is re vise d as s h o w n i n t his a p pe n di x.
T he f oll o wi n g re d uce d Sc he d ule of Acti vities descri bes t he ti mi n g of pr oce d ures t o be
perf or me d d uri n g treat me nt f or p atie nts recei vi n g st u d y dr u g after I RB/I E C a p pr o val of
A me n d me nt 3 .
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 3
A 5 4 8 1 0 1 9 Sc he d ule of Acti vities:
Pr ot oc ol Acti vit y
Acti ve Tre at me nt P h ase a
– O ne c ycle = 2 8 d a ys all 
c ycles
E n d of Tre at me nt 
/ Wit h dr a w al ( E O T)b
P ost -tre at me nt-F oll o w
-u p c
St u d y D a y
D a y 1 ( 2 d) d
7 d
Vital Si g ns /P h y sical 
E xa mi nati o n e
X
X
E C O G Perf or ma nce Stat us
X
X
He mat ol o g y
X a n d as cli nicall y 
i n dicate d
X
Bl o o d C he mistr y f
Assesse d e ver y 3 c ycles 
a n d as cli nicall y i n dicate d
X
H g b A 1c g
X
Fasti n g Gl uc ose a n d Fasti n g 
I ns uli n
X
Fasti n g Li pi d Pa nel
X
Uri nal ysis
X
C oa g ulati o n
X
E C G (i n tri plicate) h
P erf or me d as cli nicall y 
i n dicated be y o n d C ycle 1 0 
X
Oc ular Assess me nt i
Perf or me d e ver y 1 2 m o nt hs
X
Disease assess me nt: T u m or 
i ma gi n g i ncl u di n g Ra di o n ucli de 
B o ne Sca n j
Perf or me d e ver y 6 c ycles
(7 da ys) or as cli nicall y 
i n dicate d
X
Dr u g C o m plia nce
X
A d verse E ve nt Re p orti n g
X
X
X
C o nc o mita nt M e dicati o ns/ 
Treat me nts
X
X
X
St u d y Tre at me nt
Letr oz ole
O nce dail y c o nti n u o usl y
Pal b oci bli b
O nce dail y o n Da y 1 t o Da y 
2 1 of eac h c ycle f oll o we d 
b y 7 da ys off
a.
Acti ve Tre at me nt P h ase: All assess me nts s h o ul d be perf or me d pri or t o d osi n g wit h st u d y me dicati o ns o n t he visit da y 
u nless ot her wise i n dicate d. Acce pta ble ti me wi n d o ws f or perf or mi n g eac h assess me nt are descri be d i n t he c ol u m n 
hea ders. F or t he p ur p oses of t his t rial 1 c ycle is 2 8 da ys. A c ycle c o ul d be l o n ger t ha n 2 8 da ys if persiste nt t o xicit y 
dela ys t he i nitiati o n of t he s u bse q ue nt c ycle.
b.
E n d of Tre at me nt/ Wit h dr a w al: E n d of Treat me nt/ Wit h dra wal e val uati o ns will be perf or me d as s o o n as p ossi ble b ut 
n o later t ha n 4 wee ks (ie, 2 8 da ys) ± 7 da ys fr o m last d ose of st u d y treat me nt a n d pri or t o t he initiati o n of a n y ne w 
a nti-ca ncer t hera p y. O btai n t hese assess me nts if n ot c o m plete d d uri n g t he pre vi o us 4 wee ks o n st u d y.
c.
P ost Tre at me nt F oll o w -u p: Aft er disc o nti n uati o n of st u d y treat me nt, p ost-treat me nt f oll o w-u p i nf or mati o n will be 
c ollecte d u p t o 2 8 da ys ( ± 7 da ys) fr o m t he last d ose of st u d y treat me nt or i nititi o n of a n y ne w a nti -ca ncer t hera p y, 
w hic he ver occ urs earlier . 
d.
C ycle X, D a y 1: I n t he e ve nt t hat t he start of a ne w c ycle is dela ye d d ue t o treat me nt relate d t o xicit y, pr oce d ures 
re q uire d o n Da y 1 of t he gi ve n c ycle will be perf or me d w he n P D- 0 3 3 2 9 9 1/ place b o is res u me d. Ne w c ycle Da y 1 
pr oce d ures (ie, p h ysical e xa mi nati o n, E C O G perf or ma nce stat us, E C G, bl o o d c he mistr y, he mat ol o g y) t hat were 
perf or me d pri or t o k n o wi n g t he nee d t o dela y t he start of t he c ycle d o n ot nee d t o be re peate d u nless re q uire d t o 
c o nfir m t hat t he para meters necessar y f or st u d y dr u g t o be res u me d are met.
e.
P h ysic al E x a m i n ati o n/ Vit al si g ns: S y m pt o m -directe d p h ysical e xa mi nati o ns, bl o o d press ure a n d p ulse rate will be 
perf or me d .
f.
Bl o o d C he mistr y P a nel: Bl o o d c he mistr y i ncl u des A S T/ A L T, al kali ne p h os p hatase, s o di u m, p otassi u m, ma g nesi u m,
t otal calci u m, t otal bilir u bi n, B U N ( or urea), ser u m creati ni ne, a n d al b u mi n. U p o n I R B/I E C a p pr o val of A me n d me nt 3 , 
bl o o d c he mistr y will o nl y nee d t o be m o nit ore d e ver y 3 c ycles. A d diti o nal u nsc he d ule d bl o o d c he mistr y pa nels ma y be 
c ollecte d as cli nicall y i n dicate d a n d res ults will be rec or de d o n t he a p pr o priate C R F.
 

Pal b ocicli b
A 5 4 8 1 0 1 9
Fi nal Pr ot oc ol A me n d me nt 3 , 1 6 Ja n uar y 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 4
g.
H e mo gl o bi n A 1c: He m o gl o bi n A 1c will n o l o n ger be re q uire d t o be meas ure d e ver y 3 m o nt hs b ut is re q uire d t o be 
c ollecte d at t he e n d of treat me nt visit. A d diti o nal u nsc he d ule d he m o gl o bi n A 1 c ma y be c ollecte d as cli nicall y 
i n dicate d a n d res ults will be rec or de d o n t he a p pr o priate C R F.
h.
E C G: O nce A me n d me nt # 3 is I R B a p pr o ve d , E C G is perf or me d as cli nicall y i n dicate d be y o n d C ycle 1 0 .
i.
O p ht h al mic E x a mi n ati o ns: O nce A me n d me nt # 3 is I R B a p pr o ve d , all t he patie nts i n acti ve treat me nt p hase are 
alrea d y after 1 2 m o nt hs’ treat me nt, t heref ore oc ular e xa mi nati o n fre q ue nc y is t he sa me as t hat f oll o wi n g 
A me n d me nt # 2.
j.
Dise ase Assess me nts: U p o n a p pr o val of A me n d me nt 3 , t u m or assess me nts ma y be perf or me d e ver y 6 c ycles ( ± 7 da ys) 
or as rec o m me n de d b y t he p h ysicia n acc or di n g t o t h e patie nt’s cli nical c o n diti o ns. Selecti o n of i ma gi n g st u dies will 
de pe n d o n treati n g p h ysicia n a n d ra di ol o gist as per l ocal practice. R E CI S T 1. 1 ma y c o nti n ue t o be use d t o e val uate 
i ma gi n g assess me nts at t he i n vesti gat or’s discreti o n b ut will n o l o n ger be ma n dat or y. Assess me nts of t u m or lesi o ns [ie, 
tar get lesi o n(s), n o n-tar get lesi o n(s) a n d tar get l y m p h n o de(s)] will n o l o n ger be rec or de d i n t he C R F, n or will t he 
R E CI S T assess me nts.
O nl y t he date of pr o gressi o n of disease will be rec or de d .