Palbociclib and Endocrine Therapy for LObular Breast Cancer Preoperative Study (PELOPS): A Randomized Phase II Study of Palbociclib With Letrozole Versus Letrozole Alone for Invasive Lobular Carcinoma and Invasive Ductal Carcinoma
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: Dana-Farber Cancer Institute



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2
S C H E M A
N = 1 9 5
 
Eli gi bilit y:

T u m or size 
≥1. 5c m  

E R a n d/ or P R- 
p ositi ve,  
H E R 2- ne gati ve
   
Breast 
S ur ger y
S ur ger y 
S peci me n 
C ollecti o n
Ar m A: 
Ta m o xife n 
Ar m C: 
E n d ocri ne 
T hera p y + 
Pal b ocicli b
Stratificati o n Fact ors
1.
Hist ol o g y: i n vasi ve d uctal carci n o ma vs. I n vasi ve l o b ular carci n o ma 
2.
Me n o pa usal Stat us: pre vs. P ost me n o pa usal 
3.
I nitial l y m p h n o de stat us: P ositi ve vs. Ne gati ve
4.
Pre-treat me nt t u m or size: T 1- 2 vs. T 3- T 4
R
A
N
D
O
M
I
Z
A
T
I
O
N
Researc h 
bi o ps y
Dia g n ostic 
S peci me n 
C ollecti o n
2: 1
Ar m B: 
Letr oz ole 
R
A
N
D
O
M
I
Z
A
T
I
O
N
F oll o w u p 
f or 
rec urre nce 
a n d s ur vi val 
f or 1 0 years
Researc h bi o psies f or 
patie nts w h o start wit h 
Treat me nt P hase O nl y:

Pre-treat me nt

2 wee ks
Wi n d o w P hase
( 2 wee ks)
Treat me nt P hase
( 2 4 wee ks)
1: 1
F urt her 
treat me nt 
offere d at t he 
discreti o n of 
t he treati n g 
o nc ol o gist
Ar m D: 
E n d ocri ne 
T hera p y
Researc h 
bi o ps y

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T A B L E O F C O N T E N T S
S C H E M A......................................................................................................................................... 2
1.  
O BJ E C TI V E S...................................................................................................................... 7
1. 1 
St u d y Desi g n............................................................................................................ 7
1. 2 
Pri mar y O bjecti ve.................................................................................................... 7
1. 3 
Sec o n dar y O bjecti ves............................................................................................... 8
1. 4 
C orrelati ve Scie nce O bjecti ves................................................................................ 8
2. 
B A C K G R O U N D................................................................................................................. 9
2. 1 
St u d y Disease(s)....................................................................................................... 9
2. 2 
Rati o nale................................................................................................................ 1 4
2. 3 
Rati o nale - C orrelati ve St u dies.............................................................................. 1 6
3. 
P A R TI CI P A N T S E L E C TI O N........................................................................................... 2 1
3. 1 
Eli gi bilit y Criteria.................................................................................................. 2 1
3. 2 
E xcl usi o n Criteria.................................................................................................. 2 3
3. 3 
I ncl usi o n of W o me n a n d Mi n orities...................................................................... 2 4
4. 
R E GI S T R A TI O N P R O C E D U R E S ................................................................................... 2 4
4. 1  
Ge neral G ui deli nes f or D F/ H C C a n d D F/ P C C I nstit uti o ns................................... 2 5
4. 2 
Re gistrati o n Pr ocess f or D F/ H C C a n d D F/ P C C I nstit uti o ns................................. 2 5
4. 3  
Ge neral G ui deli nes f or Ot her I n vesti gati ve Sites.................................................. 2 5
4. 4 
Re gistrati o n Pr ocess f or Ot her I n vesti gati ve Sites................................................. 2 5
5. 
S T U D Y P R O C E D U R E S................................................................................................... 2 6
5. 1 
Pr oce d ures f or assi g ni n g patie nts i nt o t he st u d y.................................................... 2 6
5. 2  
Me dical Hist or y a n d De m o gra p hic Data............................................................... 2 7
5. 3 
P h ysical E xa mi nati o ns........................................................................................... 2 7
5. 4  
Vital si g ns.............................................................................................................. 2 7
5. 5 
La b orat or y assess me nts ......................................................................................... 2 7
5. 6 
T u m or Sta gi n g ....................................................................................................... 2 8
5. 7 
S ur gical Assess me nt.............................................................................................. 2 8
5. 8 
T u m or Tiss ue C ollecti o n........................................................................................ 2 8
5. 9 
Researc h Bl o o d Sa m ple C ollecti o n ....................................................................... 3 1
5. 1 0  
A ge nt A d mi nistrati o n............................................................................................. 3 3
5. 1 1  
Ge neral C o nc o mita nt Me dicati o n a n d S u p p orti ve Care G ui deli nes...................... 3 6
5. 1 2  
Defi niti ve Breast S ur ger y ...................................................................................... 3 8
5. 1 3 
P ost- o perati ve Ra di ot hera p y.................................................................................. 3 8
5. 1 4 
P ost- o perati ve A dj u va nt T hera p y.......................................................................... 3 8
5. 1 5 
Criteria f or Ta ki n g a Partici pa nt off Pr ot oc ol T hera p y.......................................... 3 9
5. 1 6  
D urati o n of F oll o w U p........................................................................................... 3 9
5. 1 7 
Criteria f or Ta ki n g a Partici pa nt off St u d y............................................................ 4 0
6. 
E X P E C T E D T O XI CI TI E S A N D D O SI N G D E L A Y S/ D O S E M O DI FI C A TI O N S ......... 4 1

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6. 1 
E n d ocri ne T hera p y................................................................................................. 4 1
6. 2 
Pal b ocicli b.............................................................................................................. 4 2
6. 3  
D ose M o dificati o n G ui deli nes............................................................................... 4 4
7.  
A D V E R S E E V E N T S:  LI S T A N D R E P O R TI N G R E Q UI R E M E N T S............................ 4 9
7. 1  
M o nit ori n g of A d verse E ve nts a n d Peri o d of O bser vati o n.................................... 4 9
7. 2 
E x pecte d T o xicities................................................................................................ 5 0
7. 3  
A d verse E ve nt C haracteristics............................................................................... 5 1
7. 4 
E x pe dite d A d verse E ve nt Re p orti n g...................................................................... 5 1
7. 5 
E x pe dite d Re p orti n g t o 
................................................................................ 5 2
7. 6 
E x pe dite d Re p orti n g t o H os pital Ris k Ma na ge me nt ............................................. 5 4
7. 7 
R o uti ne A d verse E ve nt Re p orti n g......................................................................... 5 4
8. 
P H A R M A C E U TI C A L I N F O R M A TI O N.......................................................................... 5 4
8. 1 
Ta m o xife n.............................................................................................................. 5 4
8. 2 
Letr oz ole................................................................................................................ 5 5
8. 3 
Pal b ocicli b.............................................................................................................. 5 6
9. 
BI O M A R K E R, C O R R E L A TI V E, A N D S P E CI A L S T U DI E S ........................................ 5 8
9. 1 
Bi o mar ker li n ke d t o st u d y pri mar y o bjecti ve........................................................ 5 8
9. 2 
Bi o mar kers li n ke d t o c orrelati ve st u dies................................................................ 5 9
1 0. 
S T U D Y C A L E N D A R ....................................................................................................... 6 0
1 1.  
M E A S U R E M E N T O F E F F E C T ....................................................................................... 6 3
1 1. 1  
A ntit u m or Effect – S oli d T u m ors.......................................................................... 6 3
1 1. 2 
Ra di o gra p hic assess me nt....................................................................................... 6 4
1 1. 3 
Cli nical assess me nts............................................................................................... 6 4
1 1. 4 
Pat h ol o gic Res p o nse.............................................................................................. 6 4
1 2.  
D A T A R E P O R TI N G / R E G U L A T O R Y R E Q UI R E M E N T S........................................... 6 5
1 2. 1  
Data Re p orti n g....................................................................................................... 6 5
1 2. 2  
Data Safet y M o nit ori n g.......................................................................................... 6 5
1 2. 3  
M ultice nter G ui deli nes........................................................................................... 6 6
1 2. 4 
C olla b orati ve Researc h a n d F ut ure Use of Data a n d Bi os peci me ns...................... 6 6
1 3. 
S T A TI S TI C A L C O N SI D E R A TI O N S............................................................................... 6 7
1 3. 1 
St u d y Desi g n/ E n d p oi nts ........................................................................................ 6 7
1 3. 2 
Sa m ple Size, Accr ual Rate a n d St u d y D urati o n.................................................... 6 7
1 3. 3 
I nteri m M o nit ori n g Pla n ........................................................................................ 6 8
1 3. 4  
A nal ysis of Pri mar y E n d p oi nts.............................................................................. 6 8
1 3. 5  
A nal ysis of Sec o n dar y E n d p oi nts.......................................................................... 6 9
1 3. 6 
C orrelati ve Scie nce O bjecti ves.............................................................................. 7 0
1 3. 7 
E x pl orat or y A xillar y L y m p h N o de S ur ger y O bjecti ves........................................ 7 0
1 3. 8 
Re p orti n g a n d E xcl usi o ns...................................................................................... 7 1
1 4. 
P U B LI C A TI O N P L A N ..................................................................................................... 7 1

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1 5. 
R E F E R E N C E S .................................................................................................................. 7 3
A P P E N DI X A 
P E R F O R M A N C E S T A T U S C RI T E RI A .................................................. 7 8
A P P E N DI X B 
S P E CI M E N R E Q UI SI TI O N F O R M......................................................... 7 9
A P P E N DI X C  
S T U D Y P A R TI CI P A N T D R U G DI A R Y- WI N D O W............................. 8 1
A P P E N DI X D  
S T U D Y P A R TI CI P A N T A D MI NI S T E R E D D R U G DI A R Y- 
T R E A T M E N T................................................................................................................... 8 3
A P P E N DI X E  
D F/ H C C M U L TI- C E N T E R D S M P........................................................... 8 7
1. 
I N T R O D U C TI O N............................................................................................................. 9 2
1. 1 
P ur p ose................................................................................................................... 9 2
1. 2  
M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n Defi niti o ns.................................. 9 2
2.  
G E N E R A L R O L E S A N D R E S P O N SI BI LI TI E S ............................................................. 9 3
2. 1  
D F/ H C C S p o ns or................................................................................................... 9 3
2. 2 
C o or di nati n g Ce nter............................................................................................... 9 4
2. 3 
Partici pati n g I nstit uti o n.......................................................................................... 9 4
3.  
D F/ H C C R E Q UI R E M E N T S F O R M U L TI- C E N T E R P R O T O C O L S ............................. 9 5
3. 1 
Pr ot oc ol Distri b uti o n.............................................................................................. 9 5
3. 2 
Pr ot oc ol Re visi o ns a n d Cl os ures ........................................................................... 9 5
3. 3 
I nf or me d C o nse nt Re q uire me nts........................................................................... 9 5
3. 4 
I R B D oc u me ntati o n............................................................................................... 9 6
3. 5 
I R B Re- A p pr o val................................................................................................... 9 6
3. 6 
Partici pa nt C o nfi de ntialit y a n d A ut h orizati o n State me nt...................................... 9 6
3. 7  
D F/ H C C M ulti- Ce nter Pr ot oc ol Re gistrati o n P olic y............................................. 9 7
3. 8  
D F/ H C C Pr ot oc ol Case N u m ber............................................................................ 9 7
3. 9 
Pr ot oc ol De viati o ns, E xce pti o ns a n d Vi olati o ns ................................................... 9 7
3. 1 0 
Safet y Assess me nts a n d T o xicit y M o nit ori n g....................................................... 9 8
3. 1 1  
Data Ma na ge me nt.................................................................................................. 9 9
4. 
R E Q UI SI TI O NI N G I N V E S TI G A TI O N A L D R U G........................................................ 1 0 0
5.  
M O NI T O RI N G: Q U A LI T Y C O N T R O L........................................................................ 1 0 0
5. 1  
O n g oi n g M o nit ori n g of Pr ot oc ol C o m plia nce..................................................... 1 0 0
5. 2  
M o nit ori n g Re p orts.............................................................................................. 1 0 1
5. 3  
Accr ual M o nit ori n g.............................................................................................. 1 0 1
6.  
A U DI TI N G: Q U A LI T Y A S S U R A N C E......................................................................... 1 0 1
6. 1  
A u dit Pla n: D F/ H C C S p o ns ore d Trials ............................................................... 1 0 2
6. 2  
A u dit N otificati o n................................................................................................ 1 0 2
6. 3  
A u dit Re p orts....................................................................................................... 1 0 2
6. 4 
Partici pati n g I nstit uti o n Perf or ma nce.................................................................. 1 0 2

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A P P E N DI X F  
Re p orta ble E ve nt C o ver S heet................................................................. 1 0 2
A P P E N DI X G  
A xillar y Ma na ge me nt after Ne oa dj u va nt E n d ocri ne T hera p y f or H or m o ne-
P ositi ve Breast Ca ncer ( S ur ge o n I nter vie w G ui de)......................................................... 1 0 5

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1.
O B J E C TI V E S
1. 1 
St u d y Desi g n
T his is a n o pe n la bel p hase II ne oa dj u va nt cli nical trial of Pal b ocicli b i n c o m bi nati o n wit h 
e n d ocri ne t hera p y f or E R + earl y-sta ge breast ca ncer. T he pla n ne d sa m ple size is u p t o 1 9 5 
partici pa nts. T he st u d y i ncl u des a “ wi n d o w of treat me nt” p hase f oll o we d b y a treat me nt p hase. I n 
t he wi n d o w p hase, patie nts will be treate d wit h a t w o- wee k c o urse of ta m o xife n ( Ar m A) or 
letr oz ole ( Ar m B). I n t he treat me nt p hase partici pa nts will be ra n d o mize d t o recei ve e n d ocri ne 
t hera p y i n c o m bi nati o n wit h pal b ocicli b ( Ar m C) or e n d ocri ne t hera p y al o ne ( Ar m D) f or a t otal 
d urati o n of 2 4 wee ks. 
St u d y e nr oll me nt will be perf or me d as f oll o ws: P ost me n o pa usal w o me n dia g n ose d wit h eit her 
i n vasi ve l o b ular carci n o ma ( n = 6 0) or i n vasi ve d uctal carci n o ma ( n = 6 0) will be e nr olle d i n t he 
wi n d o w p hase of t he st u d y. A researc h bi o ps y will be perf or me d bef ore starti n g a n d after 
c o m pleti n g t he t w o- wee k c o urse of e n d ocri ne t hera p y a n d patie nts will c o nti n ue o n st u d y i nt o t he 
treat me nt p hase. U p o n c o m pleti o n of e nr oll me nt of eit her t he i n vasi ve l o b ular carci n o ma or 
i n vasi ve d uctal carci n o ma s u bsets i n t he wi n d o w p hase, t he st u d y will be a me n de d s uc h t hat 
s u bse q ue nt p ost me n o pa usal patie nts will be eli gi ble t o e nr oll directl y i nt o t he treat me nt p hase of 
t he st u d y. Pre me n o pa usal patie nts wit h eit her i n vasi ve l o b ular or d uctal carci n o ma will be eli gi ble 
t o e nr oll directl y i nt o t he treat me nt p hase of t he st u d y. A researc h bi o ps y will be perf or me d bef ore 
starti n g a n d after t w o wee ks of treat me nt f or partici pa nts e nr olle d directl y i nt o t he treat me nt p hase. 
Partici pa nts w h o e nr oll t o t he wi n d o w p hase will be ra n d o mize d f or treat me nt assi g n me nt t o b ot h 
st u d y p hases at ti me of re gistrati o n. 
Disease res p o nse assess me nt will be e val uate d at baseli ne a n d pri or t o s ur ger y wit h i ma gi n g, a n d 
cli nicall y e ver y f o ur wee ks d uri n g st u d y t hera p y. R o uti ne i ma gi n g is n ot re q uire d d uri n g t he 
ne oa dj u va nt treat me nt, b ut is rec o m me n de d f or patie nts n ot e x perie nci n g a cli nical res p o nse. 
Defi niti ve breast ca ncer s ur ger y (e xcisi o n or mastect o m y) mar ks t he e n d of pr ot oc ol- ma n date d 
t hera p y. Pat h ol o gic res p o nse deter mi ne d b y t he Resi d ual Ca ncer B ur de n calc ulat or will be use d 
f or t he pri mar y e n d p oi nt of t his st u d y. T he treati n g o nc ol o gist will ma ke decisi o ns re gar di n g 
c h oice of p ost-s ur gical s yste mic t hera p y. H o we ver, partici pa nts e nr olle d i n t his st u d y a n d 
ra n d o mize d t o e n d ocri ne t hera p y o nl y will ha ve t he o pti o n t o recei ve e n d ocri ne t hera p y i n 
c o m bi nati o n wit h pal b ocicli b f or a t otal d urati o n of 6 m o nt hs i n t he a dj u va nt setti n g. 
1. 2 
Pri m ar y O bjecti ve
T he st u d y has t w o c o- pri mar y o bjecti ves: 
Wi n d o w p hase: T o e val uate t he differe nce i n a nti- pr oliferati ve acti vit y of letr oz ole vers us 
ta m o xife n meas ure d b y c ha n ges i n Ki 6 7 fr o m baseli ne t o researc h bi o ps y ( da y 1 5) wit hi n c o h orts 
of E R + breast ca ncer f or patie nts dia g n ose d wit h i n vasi ve l o b ular or i n vasi ve d uctal carci n o ma. 
 
Treat me nt p hase: T o c o m pare t he pat h ol o gic res p o nse of e n d ocri ne t hera p y pl us pal b ocicli b vers us 

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e n d ocri ne t hera p y al o ne i n breast ca ncer patie nts dia g n ose d wit h h or m o ne rece pt or p ositi ve 
i n vasi ve breast ca ncer, as deter mi ne d b y t he Resi d ual Ca ncer B ur de n ( R C B)  
1. 3 
Sec o n d ar y O bjecti ves

T o e val uate t he differe nce i n a nti- pr oliferati ve acti vit y of e n d ocri ne t hera p y pl us 
pal b ocicli b vers us e n d ocri ne t hera p y al o ne meas ure d b y c ha n ges i n Ki 6 7 fr o m baseli ne t o 
researc h bi o ps y ( da y 1 5) f or pre me n o pa usal patie nts e nr olle d i nt o t he treat me nt p hase of 
t he st u d y. 

T o c o m pare t he pat h ol o gic res p o nse of e n d ocri ne t hera p y pl us pal b ocicli b vers us e n d ocri ne 
t her pa y al o ne i n breast ca ncer patie nts as deter mi ne d b y t he m o difie d Pre o perati ve 
E n d ocri ne T hera p y Pr o g n ostic I n de x ( m P E PI)

T o deter mi ne t he cli nical res p o nse rate, defi ne d as t he n u m ber of partial a n d c o m plete 
res p o nses after pre o perati ve e n d ocri ne t hera p y pl us pal b ocicli b a n d of e n d ocri ne t hera p y 
al o ne i n breast ca ncer patie nts dia g n ose d wit h h or m o ne rece pt or p ositi ve i n vasi ve breast 
ca ncer 

T o c haracterize safet y a n d t olera bilit y of pal b ocicli b gi ve n i n c o m bi nati o n wit h e n d ocri ne 
t hera p y i n t he pre o perati ve setti n g 
1. 4  
C orrel ati ve Scie nce O bjecti ves 

T o i nterr o gate differe nces i n t he estr o ge n rece pt or tra nscri pti o nal re g ulati o n f or patie nts 
dia g n ose d wit h I L C a n d I D C

T o e x pl ore t he differe nces i n a nti- pr oliferati ve acti vit y of letr oz ole a n d ta m o xife n 
meas ure d b y c ha n ges i n Ki 6 7 fr o m baseli ne t o researc h bi o ps y ( da y 1 5) wit hi n c o h orts of 
L u mi nal A ( L A) a n d L u mi nal ( B) i n vasi ve breast ca ncer.  

T o e x pl ore t he c orrelati o n of R b p h os p h or ylati o n a n d Ki 6 7 c ha n ge fr o m baseli ne t o 
researc h bi o ps y ( da y 1 5) a m o n g patie nts treate d wit h e n d ocri ne t hera p y pl us pal b ocicli b or 
e n d ocri ne t hera p y al o ne (i.e. partici pa nts e nr olle d strai g ht i nt o t he treat me nt p hase of t he 
st u d y)

T o descri be t he ass ociati o n bet wee n w h ole e x o me se q ue nci n g a n d c o p y n u m ber fi n di n gs 
a n d p C R

T o e x pl ore w het her m olec ular feat ures of i n vasi ve l o b ular carci n o ma pre dicts f or greater 
se nsiti vit y t o pal b ocicli b w he n c o m pare d t o i n vasi ve d uctal carci n o ma. M olec ular feat ures 
of I L C i ncl u de b ut are n ot li mite d t o hi g her fre q ue nc y of c ycli n D 1 a m plificati o n, a n d 
e nric h me nt f or L u mi nal A s u bt y pe w he n c o m pare d t o I D C. 

T o c haracterize serial c ha n ges i n i m m u ne mar ker pr ofile i n peri p heral bl o o d m o n o n uclear 
cells ( P B M Cs) a m o n g patie nts treate d wit h e n d ocri ne t hera p y wit h or wit h o ut pal b ocicli b

T o e x pl ore w het her i n d ucti o n of c ha n ges i n t he i m m u n os u p pressi ve a n d/ or i m m u ne-
sti m ulati n g i m m u ne mar ker pr ofile i n P B M Cs c orrelates i m m u ne mar ker pr ofile c ha n ges 
i n t he researc h bi o psies 

T o deter mi ne w het her t he Rec urre nce Sc ore is ass ociate d wit h res p o nse t o ne oa dj u va nt 
e n d ocri ne t hera p y. 

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
T o deter mi ne w het her t he S E T 2, 3 i n de x is ass ociate d wit h res p o nse t o ne oa dj u va nt 
e n d ocri ne t hera p y. 

T o c o m pare rates a n d patter ns of pat h ol o gic n o dal res p o nse a m o n g patie nts treate d wit h 
e n d ocri ne t hera p y, wit h or wit h o ut pal b ocicli b. 

T o c haracterize a xillar y s ur gical ma na ge me nt base d o n v ol u me of resi d ual n o dal disease 
f oll o wi n g e n d ocri ne t hera p y, wit h or wit h o ut pal b ocicli b. 

T o deter mi ne o utc o mes base d o n defi niti ve a xillar y l y m p h n o de s ur ger y perf or me d 
f oll o wi n g e n d ocri ne t hera p y, wit h or wit h o ut pal b ocicli b. 

2.
B A C K G R O U N D
2. 1 
St u d y Dise ase(s)
I n vasi ve l o b ular carci n o ma (I L C) is t he sec o n d m ost hist ol o gical s u bt y pe of breast ca ncer 
acc o u nti n g f or 1 0- 1 5 % of all breast ca ncer cases [ 1- 3]. I L C differs fr o m i n vasi ve d uctal carci n o ma 
(I D C) 
wit h res pect t o e pi de mi ol o g y, cli nical 
prese ntati o n, 
hist ol o gical feat ures, a n d 
res p o nsi ve ness t o s yste mic treat me nts [ 4]. At t he m or p h ol o gical le vel, I L C are c o m m o nl y 
re prese nte d b y s mall cells lac ki n g c o hesi o n a n d arra n ge d i n si n gle file li near c or ds, a n d ge nerall y 
classifie d as h or m o ne rece pt or p ositi ve t u m ors ( E R +), H E R 2 ne gati ve, wit h l o w t o i nter me diate 
hist ol o gical gra de. I n a retr os pecti ve a nal ysis perf or me d usi n g data fr o m t he BI G 1- 9 8 st u d y, 
patie nts dia g n ose d wit h I L C ha d i nferi or o utc o me w he n treate d wit h ta m o xife n w he n c o m pare d t o 
patie nts dia g n ose d wit h I D C a n d als o treate d wit h ta m o xife n. Des pite t he rec o g nize d differe nces, 
cli nical trials ha ve n ot c o nsi dere d I L C as a disti nct disease s u bset. T he c urre nt st u d y i ncl u des 
patie nts dia g n ose d wit h I L C a n d I D C classifie d as h or m o ne rece pt or p ositi ve a n d H E R 2 ne gati ve. 
T he ne oa dj u va nt desi g n will all o w us t o i n vesti gate t he differe ntial effecti ve ness of ta m o xife n 
vers us letr oz ole after a s h ort t w o- wee k treat me nt e x p os ure. T he sec o n d part of t his st u d y will all o w 
us t o i n vesti gate t he efficac y of pal b ocicli b w he n c o m bi ne d wit h a dj u va nt e n d ocri ne t hera p y. 
Pal b ocicli b is n o w a n a p pr o ve d a ge nt f or patie nts f or patie nts dia g n ose d wit h a d va nce d estr o ge n 
rece pt or p ositi ve breast ca ncer. Pal b ocicli b is als o bei n g e val uate d i n c o m bi nati o n wit h e n d ocri ne 
t hera p y i n t he P A L L A S a dj u va nt cli nical trial.  
A ge nt(s)
T he use of Pal b ocicli b a n d Letr oz ole i n t he earl y-sta ge setti n g i n t he c urre nt st u d y f oll o ws safet y 
data pr o vi de d b y st u dies c o n d ucte d i n a d va nce d setti n g as s u m marize d bel o w.
2. 1. 1
Pal b ocicli b
P D- 0 3 3 2 9 9 1 ( pal b ocicli b), a n orall y acti ve p yri d o p yri mi di ne, is a p ote nt first-i n-class, hi g hl y 
selecti ve re versi ble i n hi bit or of C D K 4 a n d C D K 6 (I C 5 0 = 1 1 n M; Ki = 2 n M) wit h a m olec ular 
wei g ht of 4 4 7. 5 3. 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 yt ore d ucti ve 
as well as c yt ostatic effects o n t u m or cells. 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 b ot h i n 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
1 0
la b orat or y m o dels a n d i n earl y cli nical trials. C D K 4 a n d C D K 6 c o ntr ol G 1 t o S p hase tra nsit b y 
bi n di n g t o D-t y pe c ycli ns [ 5- 7].  T he C D K 4/ 6/ C ycli n D 1 c o m ple x p h os p h or ylates t he 
reti n o blast o ma s usce pti bilit y (R B 1 ) ge ne pr o d uct ( R b), releasi n g t he E 2 F a n d D P tra nscri pti o n 
fact ors t hat dri ve e x pressi o n of ge nes re q uire d f or S- p hase e ntr y. C D K acti vit y a n d G 1 
pr o gressi o n is ne gati vel y re g ulate d b y Ci p- Ki p ( P 2 7, P 2 1) a n d I N K 4 fa mil y, t y pifie d b y p 1 6 [ 8-
1 2]. O vere x pressi o n of p 1 6 i n cells wit h n or mal R b i n hi bits b ot h C D K 4-a n d C D K 6- ass ociate d 
ki nase acti vit y a n d R b p h os p h or ylati o n, wit h s u bse q ue nt cell c ycle arrest [ 1 3, 1 4].
T here is a str o n g li n k bet wee n t he acti o ns of estra di ol a n d t he G 1- S p hase tra nsiti o n, w here t he 
estra di ol effect or is t he c ycli n D 1- C D K 4/ 6- R b c o m ple x [ 1 5]. C ycli n D 1 is a direct tra nscri pti o nal 
tar get of E R [ 1 6, 1 7] a n d micr oi njecti o n of a nti b o dies t o c ycli n D 1 i n hi bits estr o ge n-i n d uce d S-
p hase e ntr y. I n a d diti o n, a nti -estr o ge n-i n d uce d gr o wt h arrest of E R + breast ca ncer cells is 
acc o m pa nie d b y decrease d c ycli n D 1 e x pressi o n [ 1 8], w hile e n d ocri ne resista nce is ass ociate d 
wit h persiste nt c ycli n D 1 e x pressi o n a n d R b p h os p h or ylati o n [ 1 9]. C o nsiste nt wit h t he n oti o n 
t hat t he mai n f u ncti o n of c ycli n D 1 is t o acti vate C D K 4/ 6, its o nc o ge nic acti vit y is de pe n de nt o n 
C D K 4/ 6-ass ociate d ki nase acti vit y [ 2 0] a n d C D K 4/ 6 i n hi bit ors are m ost effecti ve i n t u m ors wit h 
ge ne a m plificati o n a n d o vere x pressi o n of c ycli n D 1 [ 2 1- 2 3], w hic h is c o m m o n i n E R + breast 
ca ncer. Ge netic a berrati o ns lea di n g t o h y peracti vati o n of c ycli n D 1- C D K 4/ 6 is partic ularl y 
c o m m o n i n E R + breast ca ncer [ 2 4], c o nsiste nt wit h its critical r ole i n t he t u m ori ge nesis of t his 
ca ncer s u bt y pe, ma ki n g C D K 4/ 6 i n hi bit ors partic ularl y attracti ve a ge nts f or E R + breast ca ncer.
P al b ocicli b Precli nic al D at a
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. Si n gle a ge nt pal b ocicli b has s h o w n 
a nti pr oliferati ve effects (selecti ve G 1 arrest) o n R b- p ositi ve ca ncer cells i n vitr o a n d i n viv o [ 2 2] 
w here pal b ocicli b acti vit y was ass ociate d wit h re d uce d R b- p h os p h or ylati o n a n d decrease d 
e x pressi o n of t he cell pr oliferati o n mar ker Ki 6 7. Pal b ocicli b s h o we d n o acti vit y i n R b- ne gati ve 
t u m or cell xe n o grafts, c o nsiste nt wit h C D K 4/ 6 i n hi biti o n as t he s ole m o de of acti o n [ 2 2].
Treat me nt of c ult ure d t u m or cells wit h pal b ocicli b ca uses gr o wt h arrest t hat is acc o m pa nie d b y 
t he i n hi biti o n of s pecific p R b p h os p h or ylati o n b y C D K 4 or C D K 6 o n resi d ues seri ne - 7 8 0 a n d -
7 9 5 of p R b. T he I C 5 0 val ues f or re d ucti o n of p R b p h os p h or ylati o n at seri ne - 7 8 0 a n d - 7 9 5 i n 
M D A- M B- 4 3 5 breast carci n o ma cells were 0. 0 6 6 a n d 0. 0 6 3 μ M,  res pecti vel y. T he I C5 0 val ues 
f or re d ucti o n of p R b p h os p h or ylati o n are si milar t o t he I C5 0 val ues of i n hi biti o n of t h y mi di ne 
i nc or p orati o n acr oss a ra n ge of c ult ure d t u m or a n d n or mal cells. 
Pal b ocicli b was teste d i n vitr o o n m olec ularl y c haracterize d h u ma n breast ca ncer cell li nes. 
Res ults fr o m t hese e x peri me nts i n dicate t hat t h ose cell li nes t hat are m ore se nsiti ve t o pal b ocicli b 
(I C5 0 < 1 5 0 n M) ha ve l o w le vels of C D K N 2 A ( p 1 6) a n d hi g h le vels of R b 1, w hile resista nt cell 
li nes s h o w t he o p p osite c haracteristics. I n t his st u d y, E R + breast ca ncer see ms t o be partic ularl y 
a p pr o priate f or treat me nt wit h pal b ocicli b; se nsiti ve cell li nes i n t his pa nel re prese nt m ostl y t he 
l u mi nal E R + s u bt y pe [ 2 9]. T he c o m bi nati o n of pal b ocicli b wit h ta m o xife n has bee n teste d i n 
vitr o i n E R + breast ca ncer cell li nes i n dicati n g a s y ner gistic i nteracti o n a n d pr o vi de d a bi ol o gic 
rati o nale f or e val uati n g t he c o m bi nati o n of pal b ocicli b wit h a nti- h or m o nal t hera p y i n t he cli nic. 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
1 1
I n n o ncli nical st u dies, pal b ocicli b a n d its acti ve lacta m meta b olite, P F- 0 5 0 8 9 3 2 6, de m o nstrate d 
little or n o i n hi biti o n of c yt oc hr o me P 4 5 0 ( C Y P) 1 A 2, C Y P 2 B 6, C Y P 2 C 8, C Y P 2 C 9, C Y P 2 C 1 9, 
or C Y P 2 D 6 e nz y me acti vities a n d t h us, s h o we d l o w p ote ntial f or P K D DI wit h dr u gs t hat are 
s u bstrates f or t hese C Y Ps. H o we ver, pal b ocicli b a n d its meta b olite, 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- me diate d mi daz ola m 1’- h y dr o x ylase a n d test oster o ne 6 β-
h y dr o x ylase acti vities a n d, t heref ore, ma y ha ve t he p ote ntial f or P K D DI wit h dr u gs 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 di d 
n ot ca use i n d ucti o n of C Y P 1 A 2, C Y P 2 B 6, C Y P 2 C 8, or C Y P 3 A 4 messe n ger ri b o n ucleic aci d 
e x pressi o n a n d/ or e nz y me acti vit y i n vitr o i n h u ma n he pat oc ytes at c o nce ntrati o ns e xcee di n g 5 0-
f ol d of t he pal b ocicli b u n b o u n d stea d y-state plas ma Cma x  deter mi ne d at t hera pe utic d oses i n 
h u ma ns; t h us, t he p ote ntial f or pal b ocicli b t o i n d uce t hese e nz y mes is c o nsi dere d t o be l o w at 
cli nicall y rele va nt c o nce ntrati o ns. T he p ote ntial f or pal b ocicli b t o i n hi bit t he acti vities of selecte d 
uri di ne di p h os p hate gl uc ur o n os yltra nsferase ( U G T) e nz y mes ( U G T 1 A 1, U G T 1 A 4, U G T 1 A 6, 
U G T 1 A 9, a n d U G T 2 B 7) was als o assesse d, a n d t he li keli h o o d of D DI ass ociate d wit h i n hi biti o n 
of t hese P hase 2 e nz y mes at cli nicall y rele va nt c o nce ntrati o ns is c o nsi dere d l o w.
I n hi biti o n of effl u x tra ns p orters ( p- gl yc o pr otei n [ P- g p] a n d breast ca ncer resista nt pr otei n 
[ B C R P]), he patic u pta ke tra ns p orters ( 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 
O A T P 1 B 3), he patic effl u x tra ns p orter ( bile salt e x p ort p u m p [ B S E P]), a n d re nal tra ns p orters 
( or ga nic a ni o n tra ns p orter [ O A T] 1, O A T 3, a n d or ga nic cati o n tra ns p orter [ O C T] 2) b y 
pal b ocicli b was assesse d i n vitr o a n d was c o nsi dere d t o be u nli kel y at cli nicall y rele va nt 
pal b ocicli b c o nce ntrati o ns. 
I n vitr o, pal b ocicli b is meta b olize d mai nl y b y C Y P 3 A a n d s ulf otra nsferase 2 A 1 ( S U L T 2 A 1) 
e nz y mes. Dr u gs t hat are k n o w n t o i n d uce or i n hi bit t he acti vities of t hese e nz y mes ma y alter t he 
cleara nce a n d s yste mic e x p os ure of pal b ocicli b.
P al b ocicli b P h ar m ac o ki netic ( P K) D at a
T o date, p har mac o ki netic data ha ve bee n c ollecte d i n 8 cli nical st u dies f or a t otal of o ver 2 5 0 
a d va nce d ca ncer patie nts a n d 3 0 healt h y v ol u nteers ( 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 0 9, A 5 4 8 1 0 1 0, a n d A 5 4 8 1 0 1 1). I n t he FI P trial ( A 5 4 8 1 0 0 1) t he 
e x p os ure i ncrease d i n a d ose pr o p orti o nal ma n ner o ver t he d ose ra n ge of 2 5 t o 2 2 5 m g Q D 
f oll o wi n g pal b ocicli b a d mi nistrati o n o n Da ys 1 a n d 8 of C ycle 1, alt h o u g h s o me varia bilit y (l o w 
t o m o derate) ar o u n d t hese d oses was o bser ve d partic ularl y at t he 1 5 0 m g Q D d ose le vel. 
F oll o wi n g re peate d dail y d osi n g t o stea d y state, pal b ocicli b was a bs or be d wit h a me dia n T ma x of 
~ 4 h o urs. T he mea n pal b ocicli b Vz/ F was 2 5 8 3 L, 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 pe netrates i nt o peri p heral tiss ues. 
Pal b ocicli b was eli mi nate d sl o wl y; t he mea n eli mi nati o n half-life (t 1⁄ 2) was 2 8. 8 h o urs  a n d t he 
mea n C L/ F was 6 3. 1 L/ h o ur. Pal b ocicli b acc u m ulate d f oll o wi n g re peate d d osi n g wit h a me dia n 
R ac of 2. 4, w hic h is c o nsiste nt wit h t he ter mi nal half-life.
T he effect of f o o d o n t he bi oa vaila bilit y 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 i n vesti gate d i n St u d y A 5 4 8 1 0 2 1. T he a d mi nistrati o n of t he free base 
f or m ulati o n of pal b ocicli b wit h f o o d (i ncl u di n g a hi g h fat or a l o w fat meal gi ve n t o get her wit h 
pal b ocicli b, or m o derate fat meals gi ve n 1 h o ur bef ore a n d 2 h o urs after pal b ocicli b) res ulte d i n 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
1 2
m ore u nif or m dr u g a bs or pti o n a n d si g nifica ntl y re d uce d t he i nters u bject varia bilit y i n dr u g 
e x p os ure w he n c o m pare d t o t he a d mi nistrati o n of free base f or m ulati o n of pal b ocicli b i n a faste d 
state. T he relati ve bi oa vaila bilit y of t he c o m mercial free base ca ps ule a d mi nistere d wit h f o o d a n d 
t he iset hi o nate ca ps ule a d mi nistere d u n der o ver ni g ht a n d mi ni mal fasti n g c o n diti o ns was 
i n vesti gate d i n St u d y A 5 4 8 1 0 3 6. T he t w o fasti n g c o n diti o ns f or a d mi nistrati o n of iset hi o nate 
ca ps ules 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 t he pi v otal P hase 1/ 2 efficac y trial, St u d y A 5 4 8 1 0 0 3, i n w hic h patie nts were i nstr ucte d 
t o fast fr o m 1 h o ur bef ore u ntil 2 h o urs after pal b ocicli b d osi n g. T he a d mi nistrati o n of 
pal b ocicli b free base ca ps ule f or m ulati o n wit h f o o d was f o u n d t o be bi oe q ui vale nt t o pal b ocicli b 
iset hi o nate ca ps ule f or m ulati o n gi ve n u n der b ot h t he o ver ni g ht a n d mi ni mal fasti n g c o n diti o ns. 
As a res ult of t hese fi n di n gs, it is rec o m me n de d t hat free base f or m ulati o ns of pal b ocicli b be 
a d mi nistere d wit h f o o d.
P har mac o ki netic data are a vaila ble fr o m a n itrac o naz ole D DI st u d y w here t he effect of m ulti ple 
d osi n g of a p ote nt C Y P 3 A 4 i n hi bit or, itrac o naz ole ( 2 0 0 m g Q D), o n t he si n gle- d ose P K of 
pal b ocicli b ( 1 2 5 m g) was e val uate d i n 1 2 healt h y faste d s u bjects ( St u d y A 5 4 8 1 0 1 6). Me dia n 
pal b ocicli b plas ma c o nce ntrati o ns were hi g her i n t he prese nce of itrac o naz ole t ha n t h ose i n t he 
a bse nce of itrac o naz ole. Pal b ocicli b mea n plas ma A U C fr o m ti me 0 t o i nfi nit y ( A U C i nf ) a n d 
C ma x  val ues i ncrease d a p pr o xi matel y 8 7 % a n d 3 4 %, res pecti vel y, w he n a d mi nistere d i n 
c o m bi nati o n wit h itrac o naz ole c o m pare d t o w he n a d mi nistere d al o ne. T heref ore, c o nc o mita nt 
a d mi nistrati o n of a ge nts k n o w n t o be str o n g i n hi bit ors of C Y P 3 A is oe nz y mes (s uc h as 
ket oc o naz ole, mic o naz ole, itrac o naz ole, p osac o naz ole, clarit hr o m yci n, er yt hr o m yci n, 
telit hr o m yci n, nefaz o d o ne, diltiaze m, vera pa mil, i n di na vir, sa q ui na vir, rit o na vir, nelfi na vir, 
l o pi na vir, ataza na vir, a m pre na vir, f osa m pre na vir, a n d gra pefr uit j uice) s h o ul d be a v oi de d.
P har mac o ki netic data are a vaila ble fr o m a rifa m pi n D DI st u d y w here t he effect of m ulti ple 
d osi n g of a p ote nt C Y P 3 A 4 i n d ucer, rifa m pi n ( 6 0 0 m g Q D), o n t he si n gle- d ose P K of 
pal b ocicli b ( 1 2 5 m g) was e val uate d i n 1 5 healt h y faste d s u bjects ( St u d y A 5 4 8 1 0 1 7). Me dia n 
pal b ocicli b plas ma c o nce ntrati o ns were s u bsta ntiall y l o wer i n t he prese nce of rifa m pi n t ha n t h ose 
i n t he a bse nce of rifa m pi n. Pal b ocicli b mea n plas ma A U C fr o m ti me 0 t o i nfi nit y ( A U Ci nf ) a n d 
C ma x  val ues decrease d a p pr o xi matel y 8 5 % a n d 7 0 %, res pecti vel y, w he n a d mi nistere d i n 
c o m bi nati o n wit h rifa m pi n c o m pare d t o w he n a d mi nistere d al o ne. T heref ore, c o-a d mi nistrati o n 
of pal b ocicli b wit h str o n g C Y P 3 A i n d ucers (s uc h as p he n o bar bital, rifa m pi n, p he n yt oi n, 
car ba maze pi ne, rifa b uti n, rifa pe nti n, cle vi di pi ne, a n d St. J o h n’s W ort) s h o ul d be a v oi de d.
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 i n i n vitr o assa ys. 
P har mac o ki netic data are a vaila ble fr o m a mi daz ola m D DI st u d y w here t he effect of m ulti ple 
d osi n g of pal b ocicli b ( 1 2 5 m g Q D) o n t he si n gle- d ose P K of a se nsiti ve C Y P 3 A 4/ 5 pr o be 
s u bstrate, oral mi daz ola m ( 2 m g), was e val uate d i n 2 6 healt h y w o me n of n o n-c hil d beari n g 
p ote ntial ( St u d y A 5 4 8 1 0 1 2). W he n mi daz ola m was a d mi nistere d wit h pal b ocicli b 1 2 5 m g Q D at 
stea d y-state, t he mea n mi daz ola m plas ma C ma x  a n d A U Ci nf val ues i ncrease d a p pr o xi matel y 3 8 % 
a n d 6 1 %, res pecti vel y, as c o m pare d wit h t h ose deter mi ne d after a d mi nistrati o n of mi daz ola m 
al o ne. T hese res ults i n dicate t hat pal b ocicli b is a wea k ti me- de pe n de nt i n hi bit or of C Y P 3 A.
P al b ocicli b D ose R ati o n ale

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
1 3
Pal b ocicli b has bee n teste d i n a P hase 1 d ose escalati o n St u d y ( A 5 4 8 1 0 0 1) i n 7 4 patie nts wit h 
a d va nce d ca 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). All d ose 
li miti n g t o xicities ( D L Ts) o bser ve d i n t his st u d y were relate d t o m yel os u p pressi o n a n d mai nl y 
c o nsiste d of Gra de 3 ne utr o pe nia lasti n g m ore t ha n 7 da ys after t he e n d of t he treat me nt c ycle. 
H o we ver, ne utr o pe nia was re versi ble a n d n o n-c u m ulati ve. T he m ost c o m m o n n o n- he mat ol o gical 
a d verse e ve nts i ncl u de d fati g ue, a ne mia, diarr hea, c o nsti pati o n, v o miti n g a n d d ys p nea, all wit h 
mil d t o m o derate se verit y. A greater pr o p orti o n of patie nts o n t he 2/ 1 sc he d ule ha d treat me nt-
relate d T E A Es d uri n g a n d after C ycle 1 t ha n patie nts o n t he 3/ 1 sc he d ule alt h o u g h t he pr o p orti o n 
of patie nts wit h treat me nt-relate d ne utr o pe nia was si milar wit h res pect t o t he 2 d osi n g sc he d ules, 
b ot h d uri n g a n d after C ycle 1. O ne partial res p o nse ( P R) was re p orte d i n a patie nt wit h testic ular 
ca ncer. A t otal of 1 3/ 3 7 patie nts treate d wit h Sc he d ule 3/ 1 e val ua ble f or efficac y e x perie nce d 
sta ble disease ( S D), i ncl u di n g 6 patie nts wit h S D lasti n g 4 0 wee ks or l o n ger. O ne of t hese 
patie nts was a w o ma n wit h E R + breast ca ncer w h o ha d pre vi o usl y recei ve d 7 li nes of treat me nt 
f or her disease. T his patie nt re mai ne d o n treat me nt f or 8 0 wee ks ( 7 c ycles at 5 0 m g/ d a n d 1 3 
c ycles at 7 5 m g/ d) a n d e ve nt uall y disc o nti n ue d treat me nt d ue t o disease pr o gressi o n. Base d o n 
t he relati vel y i m pr o ve d safet y pr ofile of Sc he d ule 3/ 1, a n d t he efficac y res ults fr o m t his st u d y, 
t he Sc he d ule 3/ 1 has bee n selecte d f or f urt her cli nical de vel o p me nt a n d t he R P 2 D f or t his 
sc he d ule was deter mi ne d t o be 1 2 5 m g/ da y. T his sc he d ule a n d ass ociate d R P 2 D was f urt her 
e x pl ore d i n c o m bi nati o n wit h letr oz ole i n t he P hase I/II st u d y i n patie nts wit h a d va nce d breast 
ca ncer descri be d bel o w.
P al b ocicli b Cli nic al D at a
A p hase II st u d y wit h si n gle a ge nt pal b ocicli b i n 3 6 w o me n wit h a d va nce d breast ca ncer was 
re p orte d at t he A merica n S ociet y of Cli nical O nc ol o g y ( A S C O) 2 0 1 3 fr o m 2 8 w o me n w h o ha ve 
c o m plete d c ycle 1 [ 3 0].  Pal b ocicli b is gi ve n at 1 2 5 m g orall y, da ys 1- 2 1 of a 2 8- da y c ycle. Of 
t he 2 8 w o me n, 1 8 ( 6 4 %) w o me n are H R +/ H E R 2-, 2 ( 7 %) are H R +/ H E R 2 + a n d 8 ( 2 9 %) H R-
/ H E R 2- ne gati ve. 9 0 % ha d pri or c he m ot hera p y f or metastatic disease ( me dia n 3 li nes); 7 8 % ha d 
pri or h or m o nal t hera p y ( me dia n 2 li nes). Gra de 3/ 4 t o xicities were li mite d t o tra nsie nt 
ne utr o pe nia ( n = 1 4; 5 0 %) a n d t hr o m b oc yt o pe nia ( n = 6; 2 1 %). O ne e pis o de of fe brile ne utr o pe nia 
occ urre d i n a patie nt wit h si x pre vi o us c he m ot hera p y re gi me ns. All ot her t o xicities were gra de 
1/ 2. Treat me nt was i nterr u pte d i n 7 ( 2 5 %) a n d d ose re d uce d i n 1 3 ( 4 6 %) patie nts f or c yt o pe nias; 
2 7/ 2 8 patie nts disc o nti n ue d st u d y f or disease pr o gressi o n. ( P R + S D > 6 m o nt hs) was as f oll o ws: 
4 patie nts ( 2 3 %) i n H R +/ H E R 2- ne gati ve ( n = 1 8), 1 ( 5 0 %) i n H R +/ H E R 2 + ( n = 2), 1 ( 1 3 %) i n H R-
ne gati ve/ H E R 2- ne gati ve ( n = 8). I n c o ncl usi o n, t hera p y wit h pal b ocicli b al o ne is well-t olerate d, 
a n d de m o nstrates cli nical be nefit i n patie nts wit h all s u bt y pes of breast ca ncer a n d des pite 
pr o gressi o n o n pri or h or m o nal- a n d c he m ot hera p y. Tra nslati o nal st u dies e xa mi ni n g m olec ular 
pre dict ors of res p o nse are i n pr o gress.
A ra n d o mize d, m ultice nter acti ve-c o ntr olle d P hase I/II St u d y ( A 5 4 8 1 0 0 3) was desi g ne d t o assess 
t he efficac y, safet y a n d P K of letr oz ole 2. 5 m g Q D i n c o m bi nati o n wit h pal b ocicli b 1 2 5 m g Q D 
(sc he d ule 3/ 1) vers us si n gle a ge nt letr oz ole 2. 5 m g Q D f or t he first-li ne treat me nt of E R +/ 
H E R 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. Letr oz ole was selecte d as t he 
acti ve c o ntr ol base d o n its w orl d wi de a p pr o val a n d use as sta n dar d of care f or t he first-li ne 
h or m o nal treat me nt of p ost me n o pa usal w o me n wit h E R + a d va nce d breast ca ncer.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
1 4
St u d y A 5 4 8 1 0 0 3 i ncl u de d a li mite d P hase I p orti o n, ai me d at c o nfir mi n g t he safet y a n d 
t olera bilit y of t he c o m bi nati o n a n d e xcl u di n g a P K i nteracti o n wit h t he c o m bi nati o n, a n d a 
ra n d o mize d P hase II p orti o n ai me d at e val uati n g t he efficac y a n d safet y of letr oz ole i n 
c o m bi nati o n wit h pal b ocicli b w he n c o m pare d t o letr oz ole al o ne i n t he first-li ne treat me nt of 
p ost me n o pa usal patie nts wit h E R +/ H E R 2- ne gati ve a d va nce d breast ca ncer. T he P hase II p orti o n, 
als o calle d P A L O M A- 1, c o nsiste d of 2 parts [ 2 5]. I n Part 1, patie nt selecti o n was base d o nl y o n 
E R/ H E R 2 stat us. I n Part 2, patie nts were pr os pecti vel y selecte d als o ta ki n g i nt o acc o u nt t u m or 
C C N D 1 a m plificati o n a n d/ or p 1 6 l oss. A t otal of 1 7 7 patie nts were e nr olle d i n t he st u d y. T wel ve 
( 1 2) were e nr olle d i n t he P hase 1 p orti o n a n d 1 6 5 ( 6 6 a n d 9 9 i n Part 1 a n d 2, res pecti vel y) were 
e nr olle d i n t he P hase 2 p orti o n. Res ults fr o m t he P hase 1 p orti o n i n dicate d n o P K i nteracti o n 
bet wee n pal b ocicli b a n d letr oz ole. T he R P 2 D was deter mi ne d t o be 1 2 5 m g Q D o n Sc he d ule 3/ 1 
( 3 wee ks c o nti n u o us treat me nt f oll o we d b y 1 wee k off treat me nt) i n c o m bi nati o n wit h letr oz ole 
2. 5 m g Q D c o nti n u o usl y. P Rs were re p orte d f or 3 ( 3 3 %) o ut of 9 patie nts wit h meas ura ble 
disease ( 3 ha d b o ne- o nl y disease). A n ot her 5 patie nts ( 4 2 %) ha d sta ble disease f or ≥ 6 m o nt hs 
a n d t he cli nical be nefit rate ( P R + S D ≥ 6 m o nt hs) was 6 7 %. Ei g ht ( 8) patie nts disc o nti n ue d fr o m 
t he st u d y d ue t o disease pr o gressi o n, i ncl u di n g 2 patie nts wit h cli nical pr o gressi o n, 1 patie nt 
wit h dre w c o nse nt, a n d 3 patie nts are still o n g oi n g.
T w o i nteri m a nal yses f or t he P hase 2 p orti o n of t he st u d y ha ve bee n c o n d ucte d. T he res ults of 
t he i nteri m a nal yses s h o we d c o nsiste nt tre n d of cli nicall y mea ni n gf ul i m pr o ve me nts i n P F S 
( pri mar y e n d p oi nt). I n t he first i nteri m a nal ysis ( Part 1; N = 6 6), t he me dia n P F S f or t he 
pal b ocicli b pl us letr oz ole ar m was 1 8. 2 m o nt hs vers us 5. 7 m o nt hs f or t he letr oz ole al o ne ar m 
( H R = 0. 3 5; 9 5 % CI: 0. 1 7, 0. 7 2; p = 0. 0 0 6). T he sec o n d i nteri m a nal ysis ( N = 1 6 5) c o nti n ue d t o 
de m o nstrate a statisticall y si g nifica nt i m pr o ve me nt i n P F S ( 2 6. 1 vs. 7. 5 m o nt hs, res pecti vel y; 
H R = 0. 3 7; 9 5 % CI: 0. 2 1, 0. 6 3; p < 0. 0 0 1) [ 2 5].  M ore rece ntl y, t he fi nal a nal ysis
 de m o nstrate d a 
statisticall y si g nifica nt i m pr o ve me nt i n P F S f or t he pal b ocicli b pl us letr oz ole ar m ( 2 0. 2 m o nt hs) 
vers us t he letr oz ole ar m ( 1 0. 2 m o nt hs) wit h hazar d rati o ( H R = 0. 4 8 8; 9 5 % CI: 0. 3 1 9, 0. 7 4 8, 
p = 0. 0 0 0 4). T hese res ults i n dicate t hat t he c o m bi nati o n of pal b ocicli b wit h letr oz ole is well 
t olerate d wit h a safet y pr ofile si milar t o t hat see n wit h eit her pal b ocicli b or letr oz ole w he n 
a d mi nistere d al o ne. T he m ost fre q ue ntl y re p orte d treat me nt-relate d a d verse e ve nts i ncl u de d 
ne utr o pe nia, le u k o pe nia, a ne mia, a n d fati g ue. T here were n o cases of fe brile ne utr o pe nia 
re p orte d t o date i n t his st u d y. O verall, 8 patie nts i n t he c o m bi nati o n ar m were disc o nti n ue d fr o m 
t he st u d y treat me nt d ue t o a n a d verse e ve nt, of w hic h 5 were c o nsi dere d treat me nt-relate d ( gra de 
3 ne utr o pe nia [ n = 4] a n d isc he mic c olitis) a n d 1 patie nt fr o m t he letr oz ole al o ne ar m. 
A d diti o nall y, t he c o m bi nati o n de m o nstrate d a ntit u m or acti vit y, w hic h was c o nsiste nt wit h t he 
se nsiti vit y of E R + breast ca ncer o bser ve d i n t he precli nical m o dels. 
2. 2  
R ati o n ale  
I n vasi ve l o b ular carci n o ma has u ni q ue cli nical a n d bi ol o gical feat ures b ut has n ot bee n st u die d as 
a se parate disease s u bset i n pr os pecti ve cli nical trials. I n t he “ wi n d o w” p hase of t he st u d y we will 
i n vesti gate t he differe ntial effecti ve ness of ta m o xife n vers us letr oz ole f or patie nts dia g n ose d wit h 
i n vasi ve l o b ular carci n o ma (I L C) or i n vasi ve d uctal carci n o ma (I D C).  I n t he treat me nt p hase of 
t he st u d y we will i n vesti gate t he be nefit of pal b ocicli b i n c o m bi nati o n wit h e n d ocri ne t hera p y i n 
t he ne oa dj u va nt setti n g. We e x pect t hat t he treat me nt p hase will pr o vi de us wit h rele va nt i nsi g hts 
relate d t o t he efficac y of pal b ocicli b i n earl y-sta ge h or m o ne rece pt or p ositi ve disease. I n a d diti o n 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
1 5
t o t he pri mar y cli nical o bjecti ve, we pla n t o e x pl ore t he efficac y of pal b ocicli b + letr oz ole 
acc or di n g t o pat h ol o g y defi ne d s u bt y pes (i.e. I L C, I D C) a n d ge n o micall y defi ne d s u bt y pes (i.e. 
l u mi nal A vs. l u mi nal B). Pal b ocicli b is n o w u n der i n vesti gati o n i n a lar ge a dj u va nt p hase III st u d y 
a n d res ults fr o m t he ne oa dj u va nt setti n g ca n be i nf or mati ve f or f ut ure tra nslati o nal researc h eff orts 
usi n g sa m ples fr o m a lar ge a dj u va nt st u d y.
 
T he wi n d o w p hase of t he st u d y is b uilt f oll o wi n g o bser vati o ns fr o m a retr os pecti ve a nal ysis 
c o n d ucte d usi n g data fr o m t he BI G 1- 9 8 p hase III st u d y [ 2 6]. BI G 1- 9 8 was a ra n d o mize d, p hase 
III st u d y t hat c o m pare d fi ve years of ta m o xife n or letr oz ole ( m o n ot hera p y ar ms), or t heir se q ue nces 
i n p ost- me n o pa usal w o me n wit h h or m o ne rece pt or p ositi ve earl y-sta ge breast ca ncer. T here were 
4 9 2 2 patie nts e nr olle d i n t he m o n ot hera p y ar ms of BI G 1- 9 8. T he a nal ysis i ncl u de d patie nts w h o 
ha d ce ntrall y-re vie we d hist ol o g y data a n d classifie d as I D C a n d I L C ( n = 3 6 6 0). I n s u m mar y t he 
ma g nit u de of be nefit of a dj u va nt letr oz ole was hi g her i n t he I L C s u bset w he n c o m pare d t o I D C. 
Of i nterest, a n d i n c o ntrast t o I D C, L A I L C deri ve d a si g nifica nt be nefit i n fa v or of letr oz ole, w hile 
L A I L C treate d wit h ta m o xife n ha d t he w orse disease-free s ur vi val. I n t he L B s u bset ( Fi g 2) we 
o bser ve d a si g nifica nt be nefit i n fa v or of letr oz ole i n b ot h s u b gr o u ps. I n t he m ulti variate a nal yses 
c orrecti n g f or classic cli nic o- pat h ol o gic varia bles we o bser ve d a si g nifica nt be nefit i n fa v or of 
letr oz ole i n t he I L C s u bset f or b ot h disease-free s ur vi val a n d o verall s ur vi val. T he fi n di n gs fr o m 
t he BI G 1- 9 8 str o n gl y s u g gest t hat I L C is partiall y resista nt t o ta m o xife n. 
I n t he wi n d o w p hase of t he c urre nt st u d y, patie nts dia g n ose d wit h eit her I L C or I D C will be treate d 
wit h a 2- wee k c o urse of ta m o xife n or letr oz ole. T he s u p pressi o n of Ki 6 7 was selecte d as t he 
pri mar y e n d p oi nt f or t his i nitial p hase of t he st u d y f oll o wi n g data fr o m pre vi o us st u dies c o n d ucte d 
usi n g e n d ocri ne t hera p y i n t he ne oa dj u va nt setti n g.  I n t he I M P A C T trial, s u p pressi o n of Ki 6 7 
after 2 a n d 1 2 wee ks was si g nifica ntl y greater wit h a nastr oz ole t ha n wit h ta m o xife n ( P = 0. 0 0 4). 
I n t he P 0 2 4 trial, treat me nt-i n d uce d re d ucti o n i n ge o metric mea n Ki 6 7 was si g nifica ntl y greater 
wit h 4 m o nt hs of letr oz ole ( 8 7 %) t ha n ta m o xife n ( 7 5 %; a nal ysis of c o varia nce P = 0. 0 0 0 9). I n t he 
A C O S O G Z 1 0 3 1 trial, t he effects o n Ki 6 7 were si milar a m o n g all t hree AIs (a nastr oz ole 7 8 %, 
e xe mesta ne 8 1. 2 % a n d letr oz ole 8 7. 1 %). T he a vaila ble data i n dicates t hat Ki 6 7 m o d ulati o n i n t he 
ne oa dj u va nt setti n g ca n be use d as a r o b ust e n d p oi nt. 
I n a d diti o n t o Ki 6 7, le vels of estr o ge n ( E R) a n d/ or pr o gester o ne rece pt or ( P g R) e x pressi o n ha ve 
als o bee n ass ociate d wit h res p o nse t o ne oa dj u va nt e n d ocri ne t hera p y. I n t he I M P A C T st u d y t here 
was a p ositi ve c orrelati o n bet wee n E R le vel a n d de gree of Ki 6 7 s u p pressi o n at b ot h 2 a n d 1 2 
wee ks. I n t he sa me st u d y, a greater s u p pressi o n of Ki 6 7 was o bser ve d i n t he s u bset classifie d as 
P g R p ositi ve vers us P g R ne gati ve. I n a d diti o n t o si n gle bi o mar ker meas ure me nts, t he 
pre o perati ve e n d ocri ne pr o g n ostic i n de x ( P E PI) sc ore was pr o p ose d as a c o m bi nati o n of mar kers 
mar kers t hat ha ve bee n s h o w n t o ha ve pr o g n ostic utilit y a m o n g patie nts treate d wit h ne oa dj u va nt 
e n d ocri ne t hera p y. P E PI sc ore i ncl u des resi d ual Ki 6 7 a n d meas ures of o n-treat me nt E R, 
pat h ol o gical t u m or size a n d n o dal stat us. 
I n t he c urre nt st u d y, ce ntral assess me nt of Ki 6 7 at baseli ne, 2- wee ks a n d at t he e n d of treat me nt 
al o n g wit h meas ure me nt of E R a n d P g R will pr o vi de us wit h r o b ust scie ntific data t o e x pl ore t he 
pr o p ose d researc h q uesti o ns. I n a d diti o n t o esta blis he d mar kers t he c urre nt st u d y will i ncl u de 
i m m u n o hist oc he mistr y stai ni n g f or Reti n o blast o ma ( R b) a n d p h os p h o- R b. I n a pre vi o us st u d y 
e val uati n g t he efficac y of pal b ocicli b a m o n g patie nts dia g n ose d wit h ma ntle cell l y m p h o ma, t he 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
1 6
de gree of re d ucti o n of p h os p h o- R b was hi g hl y c orrelate d wit h t hat of Ki 6 7 (r = 0. 9 1). T he desi g n 
of t he c urre nt st u d y will all o ws t o i n vesti gate t he de gree of p h os p h o- R b s u p pressi o n a m o n g 
patie nts treate d wit h e n d ocri ne t hera p y pl us or mi n us pal b ocicli b. 
2. 3  
R ati o n ale - C orrel ati ve St u dies 
I n t he c urre nt st u d y we pla n t o e x pa n d u p o n pre vi o us fi n di n gs a n d f urt her i n vesti gate t he m olec ular 
u n der pi n ni n gs of i n vasi ve l o b ular carci n o ma a n d i n vasi ve d uctal carci n o ma i n t he c o nte xt of a 
cli nical trial.  T he mai n o bjecti ve of P E L O P S Tra nslati o nal Researc h pr o gra m is t o e val uate 
w het her t u m or- deri ve d m olec ular or ge n o mic alterati o ns pre dict be nefit fr o m t he pr o p ose d 
treat me nt i nter ve nti o ns.  ‘
I n t he wi n d o w p hase of t he st u d y, we will i n vesti gate t he mec ha nis ms dri vi n g t he differe ntial t he 
differe ntial effecti ve ness of e n d ocri ne t hera pies i n I L C w he n c o m pare d t o I D C t u m ors. As a n 
i nitial a p pr oac h t o t his q uesti o n, we pla n t o perf or m ge n o me- wi de a nal yses of estr o ge n rece pt or 
( E R)- bi n di n g sites ( k n o w n as t he E R cistr o me) i n I L C a n d I D C t u m or sa m ples treate d wit h a t w o-
wee k e x p os ure of ta m o xife n or letr oz ole. We h y p ot hesize t hat e pi ge netic feat ures of I L C ( E R-
bi n di n g a n d/ or e n ha ncer c ha n ges) will pr o vi de us wit h h y p ot hesis relate d t o t he differe ntial 
effecti ve ness of e n d ocri ne t hera pies f or patie nts dia g n ose d wit h I L C or I D C. 
T he i de ntificati o n of E R- bi n di n g sites or cistr o me was i nitiall y perf or me d i n I D C cell li nes usi n g 
c hr o mati n i m m u n o preci pitati o n ( C hI P) c o u ple d wit h massi vel y parallel se q ue nci n g ( C hI P-se q) 
[ 2 7]. S o far, t he m ost si g nifica nt fi n di n gs wit h C hi p-se q e x peri me nts i n cell li nes ca n be 
s u m marize d as: 1) E R fre q ue ntl y bi n ds distal e n ha ncers [ 2 7], 2) t he f or k hea d pr otei n F o x A 1 is 
necessar y f or E R-c hr o mati n i nteracti o ns [ 2 8, 2 9] a n d 3) acti vati o n of gr o wt h fact or rece pt or 
si g nali n g res ults i n t he re directi o n of E R bi n di n g [ 3 0]. R oss-I n nes a n d c ollea g ues perf or me d E R 
C hI P-se q e x peri me nts i n 1 5 E R + t u m ors (ei g ht wit h a g o o d pr o g n osis a n d se ve n wit h a p o or 
pr o g n osis) a n d t hree dista nt 
metastases [ 3 1]. Des pite s mall n u m bers t he st u d y s u g geste d 
differe ntial E R bi n di n g sites is ass ociate d wit h t he o utc o me of patie nts wit h breast ca ncer.  
M ore o ver, a n i nteresti n g fi n di n g of t his st u d y was t hat E R is still b o u n d t o D N A i n t u m ors resista nt 
t o h or m o nal t hera pies b ut was recr uite d t o n o vel sites i n t he ge n o me. T hese sites are f u ncti o nall y 
a n d bi ol o gicall y rele va nt si nce a ge ne e x pressi o n pre dict or base d o n ge nes wit hi n a 2 0- k b wi n d o w 
of t he bi n di n g sites was ass ociate d wit h s ur vi val i n E R + datasets.
I n a d diti o n t o CI S T R O M E relate d q uesti o ns, we will i n vesti gate t u m or feat ures usi n g t u m or-
deri ve d D N A, R N A a n d pr otei n e x pressi o n f or ge netic a n d m olec ular disc o ver y. 
R N A-se q ue nci n g ( R N A-se q) tec h n ol o g y will be use d t o defi ne t he s o-calle d i ntri nsic breast ca ncer 
s u bt y pes. T he defi niti o n of L A a n d L B s u bt y pes will be defi ne d usi n g pre-esta blis he d classifiers. 
I n a retr os pecti ve series [ 3 2] i ncl u di n g 1 6 6 I L C t u m ors pr ofile d b y Aff y metri x, t he pr oliferati o n-
base d ge ne si g nat ure Ge n o mic Gra de I n de x ( G GI) pr o vi de d us wit h rele va nt i nf or mati o n s h o wi n g 
t hat a si g nifica nt fracti o n of I L C is classifie d as hi g h ris k b y G GI. We s u bse q ue ntl y classifie d t he 
s u bset of I L C acc or di n g t o t he P A M 5 0 classifier [ 3 3]. I L C t u m ors were mai nl y c haracterize d as 
l u mi nal A ( L A), ( 7 6 %, n = 1 3 3) a n d l u mi nal B ( L B), ( 2 0 %, n = 3 4) f oll o we d b y a mi n orit y of H E R 2-
p ositi ve ( 2 %, n = 3), basal ( 1 %, n = 2) a n d n or mal-li ke ( 1 %, n = 2).  I n t he c urre nt st u d y we pla n t o 
i n vesti gate t he efficac y of pal b ocicli b i n t he L A a n d L B s u bt y pes. 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
1 7
D N A- base d se q ue nci n g assa ys ha ve descri be d t he s o-calle d “s o matic la n dsca pe of ge n o mic 
alterati o ns” f or earl y-sta ge I L C, b ut t here is li mite d i nf or mati o n li n ki n g “ ge n o mic scars” a n d 
treat me nt be nefit. I n t he c urre nt st u d y we pla n t o se q ue nce t u m ors usi n g eit her tar gete d se q ue nci n g 
a p pr oac h or m ore c o m pre he nsi ve a p pr oac hes (e. g. w h ole ge n o me or w h ole e x o me) a n d i nterr o gate 
w het her “ patter ns” of s o matic alterati o ns pre dict be nefit t o treat me nt. 
Preli mi nar y res ults fr o m se q ue nci n g st u dies a n d data fr o m p u blicl y a vaila ble re p osit ories i n dicate 
t hat I L C t u m ors ha ve a differe nt ge n o mic arc hitect ure w he n c o m pare d t o I D C t u m ors. I n a n earl y 
re p ort, S ha h et al. [ 3 4] descri be d t he ge n o mic arc hitect ure of a pri mar y I L C t u m or wit h its paire d 
meta static t u m or sa m ple ( ple ural eff usi o n) o btai ne d 9 years after t he pri mar y dia g n osis. I n t his 
a nal ysis, o ut of 3 2 s o matic alterati o ns f o u n d i n t he metastatic site, o nl y 1 1 were f o u n d i n t he 
pri mar y t u m or pr o vi di n g i nsi g hts i nt o t he nat ural hist or y of disease pr o gressi o n. S u bse q ue ntl y, a 
c o h ort of 1 9 2 a d diti o nal t u m ors ( 1 1 2 I L C a n d 8 0 d uctal) was scree ne d f or s o matic m utati o ns i n 
ni ne of t hese ge nes: P A L B 2, U S P 2 8, H A U S 3, KI A A 1 4 6 8  (f o u n d i n t he pri mar y t u m or a n d 
metastasis), E R B B 2, C D C 6, C H D 3, S P 1, D L G 4  ( metastasis-s pecific m utati o ns). O nl y t w o ge nes 
were f o u n d t o be m utate d i n t his c o h ort; E R B B 2  m utati o ns were i de ntifie d i n 3 cases ( 2 I L C, 1 
I D C) a n d H A U S 3 m utati o ns were detecte d i n 2 I L C cases.  I nitial data fr o m t he Ca ncer Ge n o me 
Atlas ( T C G A) [ 3 5], s h o we d m utati o ns i n t he ge ne e nc o di n g e-ca d heri n ( C D H 1) i n 3 0 o ut of 3 6 
sa m ples; a n d 4 of 8 s o matic varia nts i n H E R 2 were f o u n d i n I L C cases wit h t hree of t his m utati o ns 
prese nt wit hi n t he t yr osi ne ki nase d o mai n.  M ore rece ntl y, data fr o m t w o retr os pecti ve series 
pr o vi de d si g nifica nt i nf or mati o n relate d t o t he s o matic la n dsca pe of i n vasi ve l o b ular carci n o ma. 
T he lar gest series ( Des me dt, 
Metz ger et al. J C O i n press) i ncl u de 6 3 0 I L C t u m ors. O ur 
i n vesti gati o ns i ncl u de d hi g h-t hr o u g h p ut se q ue nci n g of 3 6 0 ca ncer-relate d ge nes; ge n o me- wi de 
c o p y n u m ber a berrati o n detecti o n, as well as t he assess me nt of d o w nstrea m tra nscri pt o me. T he 
n o vel a n d rele va nt fi n di n gs are s u m marize d as f oll o ws: 1) 5. 1 % i nci de nce of H E R 2 m utati o ns, 
3. 6 % of H E R 3 m utati o ns wit h a s u g gesti o n of i nferi or s ur vi val o utc o me a m o n g t h ose classifie d as 
H E R 2- m uta nt. 2) C o p y n u m ber gai ns of c hr o m os o me 6 q 2 5. 1, w hic h e nc o m passes E S R 1 was see n 
i n 2 5 % of cases. Of i m p orta nce, E S R 1 gai ns were ass ociate d wit h i ncrease d E S R 1 m R N A al o n g 
wit h i ncrease d e x pressi o n of E S R 1-tar get ge ne T F F 1 p oi nti n g t o war ds a f u ncti o nal r ole f or t his 
alterati o n i n l o b ular breast ca ncer. 3) Alterati o ns i n ke y ge nes relate d t o PI K 3 C A si g nali n g were 
prese nt i n 5 0 % of patie nts. PI K 3 C A ge ne m utati o ns were ass ociate d wit h l o w pr oliferati o n defi ne d 
b y Ki 6 7. A K T m utati o n was prese nt i n 4 % of patie nts wit h a s u g gesti o n of i nferi or s ur vi val 
o utc o me i n t his s u bset. I n a n ele ga nt w or k rece ntl y prese nte d b y t he T C G A net w or k [ 3 6]  a t otal 
of 8 1 7 breast t u m ors, i ncl u di n g 1 2 7 I L C, 4 9 0 d uctal, a n d 8 8 mi xe d I D C/I L C were pr ofile d. I n 
a d diti o n t o e-ca d heri n l oss, m utati o ns tar geti n g P T E N, T B X 3 a n d F O X A 1 were e nric he d i n t he 
I L C s u bset. P T E N l oss was ass ociate d wit h i ncrease d A K T p h os p h or ylati o n. I m p orta ntl y, t he 
c o m pre he nsi ve T C G A 
w or k s u g geste d t hat pr oliferati o n a n d i m m u ne-relate d si g nat ures 
deter mi ne d t hree I L C tra nscri pti o nal s u bt y pes ass ociate d wit h s ur vi val differe nces. 
Mi xe d 
I D C/I L C cases were m olec ularl y classifie d as I L C-li ke a n d I D C-li ke re veali n g n o tr ue h y bri d 
feat ures. 
R N A- a n d D N A- base d se q ue nci n g assa ys will be c o m ple me nt b y classic pat h ol o g y w he n 
necessar y. Mar kers ass ociate d wit h be nefit a n d/ or resista nce t o pal b ocicli b will i ncl u de b ut ma y 
n ot be li mite d t o ge nes, pr otei ns, a n d R N As rele va nt t o t he cell c ycle (e. g., C C N D 1 a m plificati o n, 
C D K N 2 A deleti o n), dr u g tar gets (e. g., C D K 4/ 6), a n d t u m or se nsiti vit y a n d/ or resista nce (c ycli n 
E, PI 3 K, p 1 6). Ki 6 7, R b, p h os p h o- R B, estr o ge n rece pt or a n d pr o gester o ne rece pt or will be 

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ce ntrall y e val uate d at t he Bri g ha m a n d W o me n’s Pat h ol o g y c ore. 
T he c urre nt st u d y als o i ncl u des a disc o ver y assa y de dicate d t o u n dersta n d t he efficac y of 
pal b ocicli b at a cell ular le vel. As part of a n i n vesti gati o nal pr ot oc ol c o n d ucte d at t he D F CI, 
researc h bi o psies will be stai ne d wit h m ulti ple mar kers (a p pr o x. 2 0 mar kers) si m ulta ne o usl y wit h 
a n ai m t o i n vesti gate w het her pal b ocicli b c ha n ges t he cell ular c o m p ositi o n of t he t u m or. 
I n a d diti o n t o t he a b o ve- me nti o ne d assa ys, t he c urre nt pr ot oc ol will i n vesti gate w het her m olec ular 
alterati o ns f o u n d i n t u m or bi o psies are detecta ble i n peri p heral circ ulati o n. T he fiel d of “li q ui d 
bi o psies” is e v ol vi n g q uic kl y a n d we e x pect t o use t he m ost u p date d se q ue nci n g a p pr oac h t o st u d y 
t he c ollecte d sa m ples. Sa m ples will be pr ocesse d f or cf D N A a n d ger mli ne D N A. 
S E T I n dex S u b-st u dy: 
Pr o g n ostic ge n o mic si g nat ures a p plie d t o F F P E sa m ples ha ve bec o me sta n dar d tests f or patie nts 
wit h Sta ge I breast ca ncer, b ut t heir a bs ol ute pr o g n ostic esti mates i n cli nical Sta ge II-III disease 
are less c o m pelli n g [ 3 7- 4 0]. T his raises t he c or ollar y of w het her a q ua ntitati ve scale of pre dicte d 
se nsiti vit y t o e n d ocri ne t hera p y ( S E T) w o ul d i nf or m t he selecti o n of o pti mal ca n di dates f or 
ne oa dj u va nt e n d ocri ne- base d treat me nt a n d w hic h e n d ocri ne a p pr oac h t o pr o p ose. E x pressi o n 
le vel of E R tra nscri pt ( E S R 1) is bi m o dall y distri b ute d i n breast ca ncers, c orres p o n di n g t o E R I H C 
stat us [ 4 1, 4 2] H o we ver, meas ure me nt of E S R 1 e x pressi o n le vel has o nl y m o dest a bilit y t o pre dict 
e n d ocri ne treat me nt be nefit [ 4 3].
T he S E T 2, 3 I n de x was desi g ne d t o meas ure t he S E T E R/ P R  i n de x of tra nscri pti o n 
c orrelate d wit h t he e x pressi o n of b ot h estr o ge n a n d pr o gester o ne rece pt ors ( b ut n ot 
pr oliferati o n), a n d a dj uste d f or a baseli ne pr o g n ostic i n de x ( B PI) base d o n cli nical t u m or a n d 
n o dal stat us at ti me of dia g n osis a n d a 4- ge ne classifier ( R N A 4) - a si m ple s u bt y pe classifier 
base d o n t he e x pressi o n of E S R 1 , P G R , E R B B 2  a n d A U R K A  ( D u et al, ma n uscri pt i n 
pre parati o n) [ 4 4- 4 7]. T h us, S E T 2, 3 i n de x is t he wei g hte d s u m of B PI i n de x a n d t he S E T E R/ P R  
i n de x. T he S E TE R/ P R  I n de x re prese nts a n i m pr o ve me nt o n t he p u blis he d S E T i n de x of E R-relate d 
ge ne e x pressi o n i n breast ca ncer[ 4 7]. It is calc ulate d as t he differe nce i n t he mea ns of e x pressi o n 
bet wee n t he 1 8 i nf or mati ve ge nes a n d 1 0 refere nce ge nes.
 T he S E TE R/ P R  i n de x was meas ure d fr o m a pre-treat me nt nee dle bi o ps y a n d c o m pare d 
wit h pat h ol o gic res p o nse a n d s ur vi val f oll o wi n g ne oa dj u va nt c he m ot hera p y (ta xa ne-
a nt hrac ycli ne re gi me ns) f oll o we d b y a dj u va nt h or m o nal t hera p y i n t w o lar ge st u dies – a 3 0 0-
patie nt c o h ort fr o m M D A C C a n d a 2 2 0- patie nt c o h ort fr o m t he I- S P Y 2 trial. N ote t hat all 
patie nts i n t hese st u dies ha d hi g h-ris k 7 0- ge ne pr o g n ostic sc ore ( Ma m ma Pri nt test i n t he I- S P Y 2 
trial) a n d 9 0 % of t he M D A C C c o h ort ha d 2 1- ge ne rec urre nce sc ore a b o ve 3 1 ( micr oarra y 
esti mate). T he 2 1- ge ne si g nat ure has n ot bee n e val uate d i n t he I- S P Y 2 trial. 
I n b ot h st u dies, a p pr o xi matel y 4 0 % ha d hi g h S E T 2, 3 (i n de x ≥1. 7 7)  a n d t heir s ur vi val was 
e xcelle nt irres pecti ve of t he resi d ual ca ncer b ur de n ( R C B) after ne oa dj u va nt c he m ot hera p y. O n 
t he ot her ha n d, a p pr o xi matel y 6 0 % i n b ot h st u dies ha d l o w S E T 2, 3 i n de x, a n d t he pr o g n ostic 
relati o ns hi p of R C B classes was e q ui vale nt t o t hat re p orte d f or E R- ne gati ve ca ncer. Fr o m t his, it 
see ms t hat patie nts wit h hi g h S E T 2, 3 i n de x c o ul d re prese nt a p o p ulati o n t o be offere d a 
ne oa dj u va nt e n d ocri ne- base d treat me nt, si nce res p o nse t o c he m ot hera p y w o ul d be 
u ni nf or mati ve, a n d t heir res p o nse t o e n d ocri ne treat me nt mi g ht g ui de s u bse q ue nt a dj u va nt 
treat me nt pla ns. T his p o p ulati o n mi g ht ha ve i m pr o ve d o utc o mes fr o m ne oa dj u va nt e n d ocri ne 

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Versi o n D ate: J uly 6, 2 0 2 2
1 9
t hera p y, a n d t his c o ul d be teste d i n t he c urre nt trial. 
T he S E T 2, 3 i n de x is meas ure d fr o m F F P E t u m or secti o ns, wit h o ut nee d f or R N A 
e xtracti o n, a n d is meas ure d usi n g a bea d- base d laser detecti o n tec h n ol o g y t hat is wi des prea d i n 
pr ote o mic cli nical testi n g ( L u mi ne x, A usti n, T X) wit h Q ua nti ge ne Ple x ( Q G P) oli g o n ucle oti de 
detecti o n a n d la beli n g ( T her m o Fis her, Walt ha m, M A). 
O nc ot y pe D x s u b st u d y  
T he p ur p ose of t his s u b-st u d y is t o e x pl ore t he use of t he O nc ot y pe D x Rec urre nce Sc ore i n 
patie nts e nr olle d o nt o a c o nte m p orar y ne oa dj u va nt e n d ocri ne t hera p y ( N E T) trial, P E L O P S. 
T he ris k stratificati o n of estr o ge n rece pt or ( E R)- p ositi ve breast ca ncers has greatl y i m pr o ve d i n 
rece nt years wit h t he wi des prea d a d o pti o n of ge ne e x pressi o n pr ofile ( G E P) assa ys i n cli nical 
practice. S uc h tests ha ve t heref ore bec o me a f u n da me ntal c o m p o ne nt of pr o g n ostic assess me nt 
a n d treat me nt g ui deli nes, ser vi n g t o assist i n decisi o ns a b o ut t he be nefit of c he m ot hera p y i n 
partic ular [ 4 8] Usi n g t he 2 1 -ge ne Bre ast Rec urre nce Sc ore , t he Trial Assi g ni n g I n di vi d ualize d 
O pti o ns f or Treat me nt ( T AI L O R x) o bser ve d a ver y l o w dista nt rec urre nce rate a m o n g w o me n 
wit h a Rec urre nce Sc ore res ult < 1 1 a n d de m o nstrate d n o be nefit fr o m t he a d diti o n of a dj u va nt 
c he m ot hera p y t o e n d ocri ne t hera p y f or w o me n wit h a n i nter me diate sc ore of 1 1- 2 5 [ 3 7] A m o n g 
t he 9, 7 1 9 w o me n i ncl u de d i n t he trial, 8 6 % ha d a sc ore ≤2 5  a n d t h us c o ul d p ote ntiall y be s pare d 
a dj u va nt c he m ot hera p y. N ota bl y, i n a s u b-a nal ysis, c he m ot hera p y be nefit varie d b y Rec urre nce 
Sc ore res ults a m o n g w o me n a ge < 5 0 years, wit h p ossi ble be nefit see n a m o n g w o me n wit h sc ores 
bet wee n 1 6- 2 0 a n d 2 1- 2 5 [ 4 9].  
Alt h o u g h t he 2 1- ge ne assa y was vali date d i n t he a dj u va nt setti n g, it ma y als o be 
re q ueste d u p o n i nitial dia g n osis t o facilitate c he m ot hera p y decisi o n ma ki n g pri or t o s ur ger y. I n a 
rece nt a nal ysis fr o m t he Nati o nal Ca ncer Data base ( N C D B), Rec urre nce Sc ore res ult re p orti n g 
a m o n g patie nts u n der g oi n g ne oa dj u va nt c he m ot hera p y ( N C T) i ncrease d fr o m 4. 9 % t o 8. 2 % 
bet wee n 2 0 1 0- 2 0 1 5 [ 4 9]. I n t his setti n g, t here is val ue f or t he a bilit y of a test t o pre dict res p o nse 
t o ne oa dj u va nt t hera p y i n or der t o facilitate s ur ger y, i n a d diti o n t o t he i m pact of c he m ot hera p y 
o n l o n g-ter m o utc o mes. 
C o m paris o ns of t he 2 1- ge ne assa y bet wee n s ur gical a n d c ore bi o ps y s peci me ns i n breast 
ca ncer patie nts are li mite d t h o u g h see m t o be cli nicall y acce pta ble. Se veral st u dies i n 
p ost me n o pa usal w o me n ha ve s h o w n a c orrelati o n bet wee n Rec urre nce Sc ore ( R S) < 1 8 a n d 
greater li keli h o o d of res p o nse t o N E T ra n gi n g fr o m 5 9- 6 4 % c o m pare d t o 2 0- 3 1 % f or R S  ≥ 3 1 
[ 5 0- 5 2]. C o n versel y pat h ol o gic res p o nse rates t o c he m ot hera p y see m t o be decrease d i n patie nts 
wit h l o w R S [ 5 3- 5 5]. I n a n N C D B a nal ysis of 9 8 9 E R +/ H E R 2- patie nts wit h a vaila ble R S 
u n der g oi n g N C T, 4. 3 % ac hie ve d a p C R wit h t he rate i ncreasi n g t o 9. 6 % i n R S  ≥ 3 11 3. O nc ot y pe 
R S was pr os pecti vel y use d t o g ui de ne oa dj u va nt s yste mic t hera p y decisi o ns a n d facilitate B C S i n 
a pr os pecti ve m ulti-ce nter pil ot st u d y 1 4. A m o n g 6 4 n o n- B C S eli gi ble w o me n, B C S rates were 
7 5 % i n R S < 1 1 a n d 7 2 % f or R S 1 1- 2 5 after N E T, c o m pare d t o 6 4 % f or R S 1 1 – 2 5 a n d 5 7 % f or 
R S > 2 5 after N C T. N ota bl y cli nical res p o nse rates ( ultras o u n d or p h ysical e xa mi nati o n) a m o n g 
w o me n wit h R S 1 1- 2 5 were si g nifica ntl y hi g her wit h N C T vs N E T ( 7 2. 7 % vs 5 0. 0 %). 
I n t his s u b st u d y we will i n vesti gate t he ass ociati o n bet wee n pre-treat me nt R S a n d 
res p o nse t o N E T wit h or wit h o ut c o nc o mita nt C D K 4/ 6 i n hi biti o n.  N ota bl y, t he P E L O P S trial 
i ncl u des a si g nifica nt s u b- p o p ulati o n ( n = 4 5) of pre me n o pa usal patie nts. Pre me n o pa usal w o me n 
ha ve bee n e xcl u de d fr o m m ost pre vi o us st u dies of N E T. T his a p pr oac h has bee n hist oricall y 
disre gar de d i n t his p o p ulati o n d ue t o c o ncer ns re gar di n g t he efficac y of p har mac ol o gic o varia n 

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Versi o n D ate: J uly 6, 2 0 2 2
2 0
f u ncti o n s u p pressi o n ( O F S) a n d t he ass u m pti o n t hat c he m ot hera p y is i n dicate d i n m ost 
pre me n o pa usal w o me n wit h t u m ors e xte nsi ve e n o u g h t o be nefit fr o m pre o perati ve d o w nsta gi n g. 
W hile pr ofessi o nal g ui deli nes, li ke N C C N, d o n ot directl y a d v ocate a gai nst t his a p pr oac h, it is 
ge nerall y c o nsi dere d e x peri me ntal 1 5, 1 6. A n ass ociati o n bet wee n R S a n d res p o nse t o N E T a m o n g 
pre me n o pa usal w o ul d be i m p orta nt f or t he pr o m oti o n of t his a p pr oac h a m o n g y o u n g w o me n i n 
nee d of ne oa dj u va nt t hera p y wit h l o w li keli h o o d of be nefiti n g fr o m N C T. 
A xill ar y L y m p h N o de s ur ger y s u b st u d y b ac k gr o u n d
T here is mi ni mal data re gar di n g a xillar y l y m p h n o de res p o nse a n d l y m p h n o de s ur ger y 
after ne oa dj u va nt e n d ocri ne t hera p y. M ost cli nical trials t o date ha ve re p orte d i n- breast t u m or 
res p o nse a n d breast c o nser vati o n rates. As a res ult, t he Nati o nal C o m pre he nsi ve Ca ncer Net w or k 
g ui deli nes lac k a n y a xillar y l y m p h n o de s ur ger y g ui deli nes f or patie nts treate d wit h ne oa dj u va nt 
e n d ocri ne t hera p y. I nstea d, t hese patie nts are gr o u pe d wit h ne oa dj u va nt c he m ot hera p y patie nts, 
b ut t he a xillar y strate gies use d after c he m ot hera p y, w het her it be a xillar y l y m p h n o de dissecti o n 
or a xillar y ra diati o n, ma y be o vertreat me nt i n t he e n d ocri ne-treate d p o p ulati o n.  S ur ge o ns are 
s u bse q ue ntl y left t o ma ke a xillar y s ur ger y decisi o ns f oll o wi n g e n d ocri ne t hera p y base d o n little 
data a n d treat me nts var y wi del y, i ncl u di n g i ncrease d perf or ma nce of a xillar y l y m p h n o de 
dissecti o n 6 3, w hic h is a m or bi d pr oce d ure t hat b ot h patie nts a n d pr o vi ders w o ul d li ke t o a v oi d. 
Preli mi nar y, h y p ot hesis- ge nerati n g w or k fr o m o ur gr o u p has re veale d t hat t he pr o g n ostic 
si g nifica nce of resi d ual n o dal disease after ne oa dj u va nt e n d ocri ne t hera p y is e q ui vale nt t o t hat of 
n o dal disease disc o vere d i n t he u pfr o nt s ur ger y p o p ulati o n. T he N C D B was q uerie d f or c T 1-
3 N 0- 1 H R- p ositi ve breast ca ncer patie nts treate d wit h ne oa dj u va nt e n d ocri ne t hera p y a n d 
a xillar y s ur ger y bet wee n 2 0 1 0 a n d 2 0 1 6. T he prese nce of s mall v ol u me resi d ual disease after 
ne oa dj u va nt e n d ocri ne t hera p y ( y p N 0, y p N 0[i +], a n d y p N 1 mi) ha d n o effect o n 5- year a dj uste d 
O S, si milar t o hist oric st u dies i n t he u pfr o nt s ur ger y p o p ulati o n 6 4. O S was i m pacte d b y t he 
prese nce of resi d ual macr o metastatic disease ( y p N 1) f oll o wi n g ne oa dj u va nt e n d ocri ne t hera p y. 
I n a pr o pe nsit y matc he d a nal ysis, 5- year O S was si milar bet wee n patie nts selecte d f or 
ne oa dj u va nt e n d ocri ne t hera p y a n d t h ose pr ocee di n g t o u pfr o nt s ur ger y a n d f o u n d t o ha ve l o w 
v ol u me n o dal disease 6 5. 
We t he n i n vesti gate d t he v ol u mes of resi d ual n o dal disease a n d i m pact of a xillar y s ur ger y 
a m o n g sta ge I-III H R- p ositi ve breast ca ncer patie nts w h o were treate d wit h ne oa dj u va nt 
e n d ocri ne t hera p y i n o ur pr os pecti vel y- mai ntai ne d si n gle-i nstit uti o n data base ( Dece m ber 2 0 1 5 – 
Se pte m ber 2 0 1 8; N = 9 5) a n d t he N C D B ( 2 0 1 2 – 2 0 1 6; N = 3, 6 4 0). Of t he c N 0 patie nts w h o 
u n der we nt a xillar y s ur ger y, m ost patie nts ha d a l o w v ol u me of resi d ual n o dal disease ( defi ne d as 
< 3 p ositi ve n o des): 9 6 % ( 4 4/ 4 6) i n t he i nstit uti o nal c o h ort a n d 9 1 % ( 2, 9 4 5/ 3, 2 2 7) i n t he N C D B 
c o h ort. I n t he N C D B c o h ort 6 6 t here was n o differe nce i n 5- year esti mate d O S b y t y pe of a xillar y 
s ur ger y (se nti nel l y m p h n o de bi o ps y vs a xillar y l y m p h n o de dissecti o n) i n a n y resi d ual n o dal 
disease b ur de n s u b gr o u p. T hese data s u g gest t hat m ost c N 0 patie nts selecte d f or ne oa dj u va nt 
e n d ocri ne t hera p y ha ve a l o w resi d ual n o dal disease b ur de n a n d c h oice of a xillar y s ur ger y ma y 
n ot i m pact s ur vi val, j ust as i n u pfr o nt s ur ger y patie nts 6 7.
I n s u m mar y, t hese fi n di n gs s u g gest t hat patie nts treate d wit h e n d ocri ne t hera p y ma y be 
safel y ma na ge d wit h a xillar y l y m p h n o de s ur ger y strate gies rese m bli n g t h ose esta blis he d f or 
patie nts treate d wit h u pfr o nt s ur ger y, i nstea d of t h ose f or patie nts treate d wit h ne oa dj u va nt 
c he m ot hera p y. We belie ve t hat t here is a n o p p ort u nit y t o de-escalate a xillar y s ur ger y a n d t he 
perf or ma nce of a xillar y l y m p h n o de dissecti o n i n patie nts w h o are treate d wit h e n d ocri ne 
t hera p y, b ut we are i n critical nee d of hi g h- q ualit y a xillar y n o dal res p o nse a n d ma na ge me nt data 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
2 1
f oll o wi n g e n d ocri ne t hera p y. T his trial ca n pr o vi de s uc h data. I n t his e x pl orat or y s u bst u d y, we 
will 1) e xa mi ne t he pat h ol o gic res p o nse of n o dal disease t o e n d ocri ne t hera p y +/- pal b ocicli b, 
a n d c orrelate res p o nse t o Ki 6 7 le vels w hic h were o btai ne d f or t he pri mar y e n d p oi nt; 2) 
c haracterize t he a xillar y s ur gical ma na ge me nt of t he patie nts treate d o n P E L O P S b y b ot h 
descri pti ve a n d mi xe d- met h o ds a nal yses; a n d 3) c o m pare o utc o mes of a xillar y s ur ger y (se nti nel 
l y m p h n o de bi o ps y vs a xillar y l y m p h n o de dissecti o n).
3.
P A R TI CI P A N T S E L E C TI O N
Baseli ne e val uati o ns (la b orat or y tests a n d ot her n o n-la b orat or y tests) m ust be perf or me d wit hi n 2 8 
da ys of st u d y e ntr y wit h t he e xce pti o n of t he f oll o wi n g tests: D oc u me ntati o n of 
M RI, 
ma m m o gra m, or ultras o u n d (i ncl u di n g D CI S a n d i n vasi ve ca ncer) of t he disease d breast perf or me d 
wit hi n 4 2 da ys pri or t o re gistrati o n. Ma m m o gra m f or t he u naffecte d c o ntralateral breast is re q uire d 
wit hi n 1 2 m o nt hs pri or t o re gistrati o n. Ser u m or uri ne pre g na nc y test m ust be ne gati ve i n w o me n 
j u d ge d pre me n o pa usal wit hi n 7 da ys of ra n d o mizati o n, or i n w o me n wit h a me n orr hea of less t ha n 
1 2 m o nt hs at ti me of ra n d o mizati o n (see criteria bel o w). 
3. 1 
Eli gi bilit y Criteri a 
3. 1. 1
Patie nts m ust ha ve Sta ge I t o III hist ol o gicall y c o nfir me d i n vasi ve carci n o ma of t he 
breast. A mi ni m u m t u m or size of at least 1. 5 c m deter mi ne d b y p h ysical e xa m or i ma gi n g 
( w hic he ver is lar ger) is re q uire d
3. 1. 2
Patie nts m ust ha ve hist ol o gicall y c o nfir me d h or m o ne rece pt or p ositi ve ( E R a n d/ or P R), 
H E R 2 ne gati ve, earl y i n vasi ve breast ca ncer.  E R, P R a n d H E R 2 meas ure me nts s h o ul d be 
perf or me d acc or di n g t o i nstit uti o nal g ui deli nes, i n a C LI A-a p pr o ve d setti n g i n t he U S or 
certifie d la b orat ories f or N o n- U S re gi o ns. C ut- off val ues f or p ositi ve/ ne gati ve stai ni n g 
s h o ul d be i n acc or da nce wit h c urre nt A S C O/ C A P ( A merica n S ociet y of Cli nical 
O nc ol o g y/ C olle ge of A merica n Pat h ol o gists) g ui deli nes. Ce ntral c o nfir mati o n is n ot 
re q uire d f or E R, P R, or H E R stat uses.
3. 1. 3
Patie nts wit h e q ui v ocal H E R 2 i n sit u h y bri dizati o n res ults acc or di n g t o c urre nt 
A S C O/ C A P g ui deli nes are all o we d, as l o n g as t he cli nicia n has deter mi ne d t hat t he y 
s h o ul d be treate d as H E R 2 ne gati ve.
3. 1. 4
F or t he wi n d o w p hase: Patie nts m ust ha ve hist ol o gicall y c o nfir me d i n vasi ve l o b ular 
carci n o ma or i n vasi ve d uctal carci n o ma. N o ce ntral c o nfir mati o n of hist ol o gical s u bt y pe 
is necessar y f or e nr oll me nt. Patie nts wit h mi xe d i n vasi ve d uctal a n d l o b ular carci n o ma 
are eli gi ble a n d will be stratifie d as d uctal. 
3. 1. 5
F or t he treat me nt p hase: Patie nts wit h a n y hist ol o gical s u bt y pe are eli gi ble.  Patie nts m ust 
be eli gi ble acc or di n g t o t he criteria i n 3. 1. 1 a n d 3. 1. 2.
3. 1. 6
W o me n  1 8 years of a ge. Me n are n ot eli gi ble.

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2 2
3. 1. 7
E C O G perf or ma nce stat us 0 or 1 
3. 1. 8
Re q uire d la b orat or y val ues: 

A bs ol ute ne utr o p hil c o u nt ≥ 1, 5 0 0/ m m 3

Platelets ≥ 1 0 0, 0 0 0/ m m 3

He m o gl o bi n ≥ 1 0 g/ d L

T otal ser u m bilir u bi n ≤ U L N; or t otal bilir u bi n ≤ 3. 0 × U L N wit h direct bilir u bi n 
wit hi n n or mal ra n ge i n patie nts wit h d oc u me nte d Gil bert’s S y n dr o me

As partate a mi n o tra nsferase ( A S T or S G O T) a n d ala ni ne a mi n o tra nsferase ( A L T or 
S G P T) ≤ 2. 0 × i nstit uti o nal U L N

Ser u m creati ni ne bel o w i nstit uti o nal u p per li mit of n or mal or creati ni ne cleara nce ≥ 
6 0 m L/ mi n/ 1. 7 3 m 2 f or patie nts wit h ser u m creati ni ne le vels a b o ve i nstit uti o nal 
U L N. 
3. 1. 9
P ost me n o pa usal is defi ne d eit her b y A ge > 6 0, Pri or bilateral o o p h orect o m y, or a ge < 6 0 
wit h i ntact uter us a n d n o s p o nta ne o us me nses o ver 1 2 c o nsec uti ve m o nt hs. F S H a n d L H 
will n ot be utilize d t o defi ne me n o pa usal stat us, u nless hist or y of pri or t otal 
h ysterect o m y. Pre me n o pa usal patie nts are eli gi ble t o partici pate. Me dicati o n-i n d uce d 
a me n orr hea will n ot cate g orize a patie nt as p ost- me n o pa usal; t hese patie nts s h o ul d be 
treate d as pre- me n o pa usal. Pre me n o pa usal a n d peri- me n o pa usal patie nts s h o ul d recei ve 
o n g oi n g treat me nt wit h L H R H a g o nists ( g oser oli n or le u pr oli de). Pre me n o pa usal patie nts 
m ust be e nr olle d directl y i nt o t he treat me nt p hase of t he st u d y. 
3. 1. 1 0 Patie nt m ust a gree t o t he re q uire d researc h bi o psies at baseli ne a n d after t he t w o- wee k 
treat me nt wit h e n d ocri ne t hera p y i n t he i nitial part of t he st u d y (“ wi n d o w p hase”); or at 
baseli ne a n d after t w o- wee k treate d wit h e n d ocri ne t hera p y pl us or mi n us pal b ocicli b f or 
t h ose patie nts e nr olle d directl y i nt o t he treat me nt p hase of t he st u d y.  
3. 1. 1 1 Patie nts m ust be a ble a n d willi n g t o s wall o w a n d retai n oral me dicati o n wit h o ut a 
c o n diti o n t hat w o ul d i nterfere wit h e nteric a bs or pti o n.
3. 1. 1 2
Breast i ma gi n g s h o ul d i ncl u de i ma gi n g of t he i psilateral a xilla. F or s u bjects wit h a 
cli nicall y ne gati ve a xilla, a se nti nel l y m p h n o de bi o ps y will be perf or me d eit her bef ore or 
after pre o perati ve t hera p y at t he discreti o n of t he s u bject’s p h ysicia ns. F or s u bjects wit h a 
cli nicall y p ositi ve a xilla, a nee dle as pirati o n, c ore bi o ps y or S L N pr oce d ure will be 
perf or me d t o deter mi ne t he prese nce of metastatic disease i n t he l y m p h n o des
3. 1. 1 3 Patie nts wit h m ultif ocal or m ulti-ce ntric disease are eli gi ble if t he treati n g cli nicia n has 
deter mi ne d t he patie nt s h o ul d be treate d as E R + a n d H E R 2- ne gati ve.  

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Versi o n D ate: J uly 6, 2 0 2 2
2 3
3. 1. 1 4
Bilateral breast ca ncers are all o we d if t he treati n g cli nicia n has deter mi ne d t he patie nt 
s h o ul d be treate d as E R + a n d H E R 2- ne gati ve.  
3. 1. 1 5 Ser u m or uri ne pre g na nc y test m ust be ne gati ve i n w o me n j u d ge d pre me n o pa usal wit hi n 
7 da ys of ra n d o mizati o n, or i n w o me n wit h a me n orr hea of less t ha n 1 2 m o nt hs at ti me of 
ra n d o mizati o n. Pre g na nc y testi n g d oes n ot nee d t o be p urs ue d i n patie nts w h o are j u d ge d 
as p ost me n o pa usal bef ore ra n d o mizati o n, as deter mi ne d b y l ocal practice, or w h o ha ve 
u n der g o ne bilateral o o p h orect o m y, t otal h ysterect o m y, or bilateral t u bal li gati o n. 
3. 1. 1 6 Pre me n o pa usal patie nts m ust a gree t o use a de q uate c o ntrace pti o n f or t he d urati o n of 
pr ot oc ol treat me nt a n d f or 6 m o nt hs after t he last treat me nt wit h pal b ocicli b. A de q uate 
c o ntrace pti o n is defi ne d as o ne hi g hl y effecti ve f or m (i.e. a bsti ne nce, male or fe male 
sterilizati o n) O R t w o effecti ve f or ms (e. g. n o n- h or m o nal I U D a n d c o n d o m/ occl usi ve ca p 
wit h s per mici dal f oa m / gel / fil m / crea m/ s u p p osit or y). H or m o nal c o ntrace pti ve 
met h o ds are n ot all o we d. Patie nts wit h h or m o nal I U D i n place are eli gi ble pr o vi de d t he 
h or m o nal I U D is re m o ve d or re place d b y a n o n- h or m o nal I U D pri or t o treat me nt 
i nitiati o n.
3. 1. 1 7 Patie nts wit h a hist or y of i psilateral or c o ntralateral D CI S are eli gi ble. 
3. 1. 1 8 Patie nts ma y c o nc urre ntl y recei ve bis p h os p h o nates or ra n k li ga n d i n hi bit ors w hile o n t his 
st u d y if necessar y f or treat me nt or pre ve nti o n of oste o pe nia or oste o p or osis. Pri or 
treat me nt wit h L H R H a g o nists is all o we d f or pre me n o pa usal w o me n. T o pical va gi nal 
estr o ge n t hera p y is all o wa ble.
3. 1. 1 9
A bilit y t o u n dersta n d a n d t he willi n g ness t o si g n a writte n i nf or me d c o nse nt d oc u me nt.
  
3. 2 
E xcl usi o n Criteri a
3. 2. 1
C o nc urre nt t hera p y wit h ot her I n vesti gati o nal Pr o d ucts.
3. 2. 2
Pri or t hera p y wit h a n y C D K i n hi bit or.
3. 2. 3
Patie nts wit h Sta ge I V breast ca ncer are n ot eli gi ble. Baseli ne sta gi n g t o d oc u me nt 
a bse nce of metastatic disease is n ot re q uire d, h o we ver is rec o m me n de d as deter mi ne d b y 
i nstit uti o nal practice (i n patie nts w here t here ma y be a reas o na ble s us pici o n of a d va nce d 
disease e. g., lar ge t u m ors, cli nicall y p ositi ve a xillar y l y m p h n o des, si g ns a n d s y m pt o ms). 
If perf or me d, re p orts of t hese e xa mi nati o ns m ust be a vaila ble. E xa mi nati o n t y pe f or 
sta gi n g, i.e. X-ra y, s o n o gra p h y, b o ne sca ns, C T, M RI, a n d/ or P E T- C T, is at t he discreti o n 
of t he i n vesti gat or.
3. 2. 4
Hist or y of aller gic reacti o ns attri b ute d t o c o m p o u n ds of c he mical or bi ol o gic c o m p ositi o n 
si milar t o pal b ocicli b.

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Versi o n D ate: J uly 6, 2 0 2 2
2 4
3. 2. 5
Patie nts recei vi n g a n y me dicati o ns or s u bsta nces t hat are p ote nt i n hi bit ors or i n d ucers of 
C Y P 3 A is oe nz y mes wit hi n 7 da ys of ra n d o mizati o n (see Secti o n 5. 1 1) f or list of C Y P 3 A 
i n hi bit ors a n d i n d ucers.
3. 2. 6
U nc o ntr olle d ill ness i ncl u di n g, b ut n ot li mite d t o, o n g oi n g or acti ve i nfecti o n, 
s y m pt o matic c o n gesti ve heart fail ure, u nsta ble a n gi na pect oris, car diac arr h yt h mia, 
dia betes, or ps yc hiatric ill ness/s ocial sit uati o ns t hat w o ul d li mit c o m plia nce wit h st u d y 
re q uire me nts.  A bilit y t o c o m pl y wit h st u d y re q uire me nts is t o be assesse d b y eac h 
i n vesti gat or at t he ti me of scree ni n g f or st u d y partici pati o n.
3. 2. 7
Pre g na nt w o me n, or w o me n of c hil d beari n g p ote ntial wit h o ut a ne gati ve pre g na nc y test 
(ser u m or uri ne) wit hi n 7 da ys pri or t o ra n d o mizati o n, irres pecti ve of t he met h o d of 
c o ntrace pti o n use d, are e xcl u de d fr o m t his st u d y beca use t he effect of pal b ocicli b o n a 
de vel o pi n g fet us is u n k n o w n. Breastfee di n g m ust be disc o nti n ue d pri or t o st u d y e ntr y.
3. 2. 8
Patie nts wit h a hist or y of mali g na nc y are i neli gi ble e xce pt f or t he f oll o wi n g 
circ u msta nces:

Patie nts wit h a hist or y of i n vasi ve breast ca ncer are eli gi ble if t he y ha ve bee n disease-
free f or a mi ni m u m of fi ve years

Patie nts wit h a mali g na nc y hist or y ot her t ha n i n vasi ve breast ca ncer are eli gi ble if 
t he y ha ve n o acti ve mali g na nc y a n d are dee me d b y t he i n vesti gat or t o be at l o w ris k 
f or rec urre nce of t hat mali g na nc y.

Patie nts wit h t he f oll o wi n g ca ncers are eli gi ble: d uctal carci n o ma i n sit u of t he breast, 
cer vical ca ncer i n sit u, a n d n o n- metastatic n o n- mela n o mat o us s ki n ca ncers.
3. 2. 9
Patie nts o n c o m bi nati o n a ntiretr o viral t hera p y, i.e. t h ose w h o are HI V- p ositi ve, are 
i neli gi ble beca use of t he p ote ntial f or p har mac o ki netic i nteracti o ns or i ncrease d 
i m m u n os u p pressi o n wit h pal b ocicli b.  HI V testi n g is n ot re q uire d, b ut patie nts m ust n ot 
be k n o w n t o be HI V- p ositi ve.
3. 2. 1 0 Patie nts recei vi n g c o nc urre nt e x o ge n o us h or m o ne t hera p y ( h or m o ne re place me nt 
t hera p y, oral or a n y ot her h or m o nal c o ntrace pti ves s uc h as h or m o nal c o ntrace pti ve c oil 
are n ot eli gi ble. 
3. 2. 1 1 Patie nts are n ot eli gi ble if t he y ha ve pre vi o usl y recei ve d c o nti n u o us e n d ocri ne t hera p y ( > 
3 0 da ys) wit hi n 5 years pri or t o dia g n osis of t he c urre nt mali g na nc y. T his i ncl u des use f or 
pr o p h ylactic reas o ns, i ncl u di n g treat me nt of oste o p or osis or ca ncer pre ve nti o n wit h 
ta m o xife n, ral o xife ne, or AI.
3. 3 
I ncl usi o n of W o me n a n d Mi n orities
W o me n of all races a n d et h nic gr o u ps are eli gi ble f or t his trial. 
4.
R E GI S T R A TI O N P R O C E D U R E S

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Versi o n D ate: J uly 6, 2 0 2 2
2 5
4. 1  
Ge ner al G ui deli nes f or D F/ H C C a n d D F/ P C C I nstit uti o ns
I nstit uti o ns will re gister eli gi ble partici pa nts i n t he Cli nical Trials Ma na ge me nt S yste m ( C T M S) 
O n C ore. Re gistrati o ns m ust occ ur pri or t o t he i nitiati o n of pr ot oc ol t hera p y. A n y partici pa nt n ot 
re gistere d t o t he pr ot oc ol bef ore pr ot oc ol t hera p y be gi ns will be c o nsi dere d i neli gi ble a n d 
re gistrati o n will be de nie d.
A n i n vesti gat or will c o nfir m eli gi bilit y criteria a n d a me m ber of t he st u d y tea m will c o m plete t he 
pr ot oc ol-s pecific eli gi bilit y c hec klist.
F oll o wi n g re gistrati o n, partici pa nts ma y be gi n pr ot oc ol t hera p y. Iss ues t hat w o ul d ca use 
treat me nt dela ys s h o ul d be disc usse d wit h t he O verall Pri nci pal I n vesti gat or ( PI). If a partici pa nt 
d oes n ot recei ve pr ot oc ol t hera p y f oll o wi n g re gistrati o n, t he partici pa nt’s re gistrati o n o n t he 
st u d y m ust be ca ncele d. Re gistrati o n ca ncellati o ns m ust be ma de i n O n C ore as s o o n as p ossi ble. 
4. 2  
Re gistr ati o n Pr ocess f or D F/ H C C a n d D F/ P C C I nstit uti o ns
D F/ H C C Sta n dar d O perati n g Pr oce d ure f or H u ma n S u bject Researc h Title d S u bject Pr ot oc ol 
Re gistr ati o n ( S O P #: R E GI S T- 1 0 1) m ust be f oll o we d.  
4. 3  
Ge ner al G ui deli nes f or Ot her I n vesti g ati ve Sites
Eli gi ble partici pa nts will be e ntere d o n st u d y ce ntrall y at t he Da na- Far ber Ca ncer I nstit ute  b y t he 
Pr oject Ma na ger.  All sites s h o ul d e mail t he d oc u me ntati o n liste d i n secti o n 4. 4 t o t he Pr oject 
Ma na ger  t o verif y sl ot a vaila bilit y.  
F oll o wi n g re gistrati o n, partici pa nts m ust be gi n pr ot oc ol treat me nt wit hi n 7 b usi ness da ys. Iss ues 
t hat w o ul d ca use treat me nt dela ys s h o ul d be disc usse d wit h t he O verall PI.  If a partici pa nt d oes 
n ot recei ve pr ot oc ol t hera p y f oll o wi n g re gistrati o n, t he partici pa nt’s re gistrati o n o n t he st u d y 
ma y be ca ncele d.  T he Pr oject Ma na ger s h o ul d be n otifie d of ca ncellati o ns as s o o n as p ossi ble.
4. 4  
Re gistr ati o n Pr ocess f or Ot her I n vesti g ati ve Sites
T o re gister a partici pa nt, t he researc h n urse or st u d y c o or di nat or s h o ul d fa x or a n d e mail t he 
f oll o wi n g d oc u me ntati o n t o 
:

Cli nic visit n ote d oc u me nti n g hist or y a n d p h ysical e xa m

Pat h ol o g y re p ort a n d d oc u me ntati o n of E R/ P R, a n d H E R 2 stat us

E mail or fa x re q uest a n d c o nfir mati o n of a vaila bilit y of dia g n ostic t u m or tiss ue 

Breast i ma gi n g re p ort ( M RI, Ma m m o gra m a n d/ or Ultras o u n d re p ort)

C T (c hest/a b d o me n/ pel vis) sca n re p ort f or patie nts wit h Sta ge III disease (if a p plica ble)

Re q uire d la b orat or y test res ults i ncl u di n g: He mat ol o g y ( C B C wit h differe ntial), ser u m 
c he mistries (creati ni ne a n d/ or creati ni ne cleara nce, bilir u bi n, A L T, a n d A S T) 

Si g ne d partici pa nt c o nse nt f or m

HI P A A a ut h orizati o n f or m (if se parate fr o m t he i nf or me d c o nse nt d oc u me nt)

C o m plete d Eli gi bilit y C hec klist

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
2 6
 
T o c o m plete t he re gistrati o n pr ocess, t he Pr oject Ma na ger will

f oll o w t he D F/ H C C Sta n dar d O perati n g Pr oce d ure f or H u ma n S u bject Researc h Title d 
S u bject Pr ot oc ol Re gistr ati o n ( S O P #: R E GI S T- 1 0 1) a n d re gister t he partici pa nt o n t he 
pr ot oc ol

call or e mail t he researc h n urse or data ma na ger at t he partici pati n g site wit h t he 
partici pa nt st u d y n u m ber, a n d t o c o nfir m re gistrati o n
N O T E: Re gistr ati o n c a n o nl y be c o n d ucte d d uri n g t he b usi ness h o urs of 8: 0 0 A M a n d 5: 0 0 
P M E aster n Ti me M o n d a y t hr o u g h Fri d a y.  Sa me da y treat me nt re gistrati o ns will o nl y be 
acce pte d wit h pri or n otice a n d disc ussi o n wit h t he D F/ H C C Pr oject Ma na ger. 
5.
S T U D Y P R O C E D U R E S
At t he ti me of re gistrati o n, t he eli gi bilit y c hec klist a n d s u p p orti n g d oc u me ntati o n t o verif y 
eli gi bilit y m ust be pr o vi de d pri or t o e nr oll me nt. Data will be c ollecte d a n d mai ntai ne d o n st u d y 
s pecific case re p ort f or ms. See Secti o n 1 0 St u d y Cale n dar f or a d diti o nal details.
Patie nts will be assesse d f or safet y, efficac y a n d bi o mar ker d uri n g t he st u d y. All patie nts will be 
cl osel y m o nit ore d f or safet y a n d t olera bilit y d uri n g st u d y treat me nt. Patie nts s h o ul d be assesse d 
f or t o xicit y pri or t o eac h c ycle; d osi n g will occ ur o nl y if t he cli nical assess me nt a n d l ocal 
la b orat or y test val ues are acce pta ble. 
5. 1 
Pr oce d ures f or assi g ni n g p atie nts i nt o t he st u d y
T he st u d y i ncl u des a “ wi n d o w of treat me nt” p hase f oll o we d b y a treat me nt p hase. Patie nts will 
be ra n d o mize d t o treat me nt assi g n me nt f or eac h p hase at ti me of re gistrati o n. I n t he wi n d o w 
p hase, patie nts will be ra n d o mize d i n a 1: 1 rati o t o recei ve a t w o- wee k c o urse of ta m o xife n or 
letr oz ole. I n t he treat me nt p hase partici pa nts will be ra n d o mize d i n a 2: 1 rati o t o recei ve 
e n d ocri ne t hera p y i n c o m bi nati o n wit h pal b ocicli b or e n d ocri ne t hera p y al o ne f or a t otal d urati o n 
of 2 4 wee ks.
St u d y e nr oll me nt will be perf or me d as f oll o ws: 
P ost me n o pa usal w o me n dia g n ose d wit h eit her i n vasi ve l o b ular carci n o ma ( n = 6 0) or i n vasi ve 
d uctal carci n o ma ( n = 6 0) will be e nr olle d i n t he wi n d o w p hase of t he st u d y. A researc h bi o ps y will 
be perf or me d bef ore starti n g a n d after c o m pleti n g t he t w o- wee k c o urse of e n d ocri ne t hera p y a n d 
patie nts will c o nti n ue o n st u d y i nt o t he treat me nt p hase. U p o n c o m pleti o n of e nr oll me nt of eit her 
t he i n vasi ve l o b ular carci n o ma or i n vasi ve d uctal carci n o ma s u bsets i n t he wi n d o w p hase, t he 
st u d y will be a me n de d s uc h t hat s u bse q ue nt p ost me n o pa usal patie nts will be eli gi ble t o e nr oll 
directl y i nt o t he treat me nt p hase of t he st u d y. 
P ost me n o pa usal patie nts ra n d o mize d t o recei ve letr oz ole i n t he wi n d o w p hase ma y recei ve 
c o nti n u o us letr oz ole d osi n g wit h o ut brea k bet wee n t he wi n d o w a n d treat me nt p hase. 
Pre me n o pa usal patie nts will be eli gi ble t o e nr oll directl y i nt o t he treat me nt p hase of t he st u d y. A 
researc h bi o ps y will be perf or me d bef ore starti n g a n d after t w o wee ks of treat me nt f or partici pa nts 
e nr olle d directl y i nt o t he treat me nt p hase. 

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2 7
Pre me n o pa usal a n d p ost me n o pa usal w o me n will be eli gi ble t o e nr oll i n t he treat me nt p hase of t he 
st u d y re gar dless of hist ol o gical s u bt y pe pr o vi de d t hat t u m ors are classifie d as h or m o ne rece pt or 
p ositi ve a n d H E R 2- ne gati ve as s pecifie d i n 3. 1. 1 a n d 3. 1. 2. 
5. 2  
Me dic al Hist or y a n d De m o gr a p hic D at a
Me dical hist or y i ncl u des past or c urre nt cli nicall y si g nifica nt c o n diti o ns, s ur geries, breast ca ncer 
s ur ger y a n d dia g n osis, re pr o d ucti ve stat us, a n d all me dicati o ns (e. g., prescri pti o n dr u gs, o ver t he 
c o u nter dr u gs, her bal or h o me o pat hic re me dies, n utriti o nal s u p ple me nts) use d b y t he patie nt wit hi n 
7 da ys pri or t o ra n d o mizati o n. De m o gra p hic data will i ncl u de a ge, se x, a n d self-re p orte d 
race/et h nicit y.
5. 3 
P h ysic al E x a mi n ati o ns
At t he i nitial visit p h ysical e xa mi nati o n s h o ul d i ncl u de hei g ht a n d wei g ht, breast a n d l ocal-re gi o nal 
l y m p hatics.  Cli nical T a n d N sta gi n g s h o ul d be d oc u me nte d. At s u bse q ue nt visits ( or as cli nicall y 
i n dicate d), breast e xa mi nati o n a n d e val uati o n of l ocal-re gi o nal l y m p hatics s h o ul d be perf or me d 
A d diti o nal p h ysical e xa mi nati o ns s h o ul d be f oc use d o n or ga n s yste ms relate d t o a d verse e ve nts. 
Wei g ht is t o be meas ure d o n Da y 1 of t he s pecifie d c ycles a n d c o m pare d wit h baseli ne. C ha n ges 
fr o m baseli ne a b n or malities s h o ul d be rec or de d i n patie nt n otes.  
5. 4  
Vit al si g ns
Vital si g ns will i ncl u de meas ure me nts of p ulse rate, a n d s yst olic a n d diast olic bl o o d press ures as 
well as te m perat ure.
5. 5 
L a b or at or y assess me nts 
Sa m ples f or t he f oll o wi n g la b orat or y tests will be acc or di n g t o t he St u d y Cale n dar:
He mat ol o g y 
He m o gl o bi n, he mat ocrit, platelet c o u nt, W B C c o u nt, a n d differe ntial i ncl u di n g a bs ol ute ne utr o p hil 
c o u nt
Ser u m c he mistr y
S o di u m, p otassi u m, c hl ori de, bicar b o nate, gl uc ose, B U N or urea, creati ni ne, t otal pr otei n, al b u mi n, 
T BI LI (a n d direct bilir u bi n w he n T BI LI > U L N), A L T, A S T, a n d A L P
Pre g na nc y test
Ser u m or uri ne pre g na nc y test m ust be ne gati ve i n w o me n j u d ge d pre me n o pa usal wit hi n 7 da ys of 
ra n d o mizati o n, or i n w o me n wit h a me n orr hea of less t ha n 1 2 m o nt hs at ti me of ra n d o mizati o n. 
Pre g na nc y testi n g d oes n ot nee d t o be p urs ue d i n patie nts w h o are j u d ge d as p ost me n o pa usal bef ore 
ra n d o mizati o n, as deter mi ne d b y l ocal practice, or w h o ha ve u n der g o ne bilateral o o p h orect o m y, 
t otal h ysterect o m y, or bilateral t u bal li gati o n. If a uri ne pre g na nc y test is p ositi ve, it m ust be 
c o nfir me d b y a ser u m pre g na nc y test.

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2 8
5. 6 
T u m or St a gi n g 
5. 6. 1
Breast a n d l oc ore gi o nal n o des 
All s u bjects are re q uire d t o ha ve a M RI, ma m m o gra m, or ultras o u n d perf or me d wit hi n 4 2 
da ys pri or t o re gistrati o n. Ma m m o gra m f or t he u naffecte d c o ntralateral breast is re q uire d 
wit hi n 1 2 m o nt hs pri or t o re gistrati o n. Breast i ma gi n g s h o ul d i ncl u de i ma gi n g of t he 
i psilateral a xilla. F or s u bjects wit h a cli nicall y ne gati ve a xilla, a se nti nel l y m p h n o de bi o ps y 
will be perf or me d eit her bef ore or after pre o perati ve t hera p y at t he discreti o n of t he 
s u bject’s p h ysicia ns. F or s u bjects wit h a cli nicall y p ositi ve a xilla, a nee dle as pirati o n, c ore 
bi o ps y or S L N pr oce d ure will be perf or me d t o deter mi ne t he prese nce of metastatic disease 
i n t he l y m p h n o des.  I ma gi n g of t he a xilla a n d/ or F N A ca n be perf or me d pri or t o 
re gistrati o n or d uri n g t he scree ni n g p hase of t he st u d y.
5. 6. 2
 C T sca ns 
It is rec o m me n de d t hat s u bjects wit h Sta ge III disease ha ve C T sca ns of c hest, a b d o me n 
a n d pel vis a n d/ or b o ne sca ns perf or me d d uri n g scree ni n g t o r ule o ut metastatic disease.
5. 7 
S ur gic al Assess me nt
All s u bjects will be see n a n d e xa mi ne d b y t he treati n g s ur ge o n at Scree ni n g a n d at t he Pre-
O perati ve Visit.  Eac h visit will i ncl u de a cli nical breast a n d l y m p h n o de e xa mi nati o n a n d re vie w 
of t he i ma gi n g st u dies ( ma m m o gra m, M RI, a n d a n y ot her ra di o gra p hic met h o d) of t he breast a n d 
a xilla. After e xa mi ni n g t he s u bject a n d re vie wi n g t he perti ne nt ra di o gra p hic st u dies at t he 
Scree ni n g visit, t he s ur ge o n will deter mi ne w het her t he s u bject is a ca n di date f or p ote ntiall y 
c urati ve s ur ger y. At b ot h t he Scree ni n g a n d Pre- O perati ve visits, t he s ur ge o n will als o deter mi ne 
w het her s u bject is eli gi ble f or breast c o nser vati o n s ur ger y. If t he s u bject is n ot a breast 
c o nser vati o n ca n di date, t he reas o n(s) will be d oc u me nte d i n t he C R F ( m ultice ntric t u m or, t u m or 
l ocati o n, t u m or size, ot her).
5. 8 
T u m or Tiss ue C ollecti o n
5. 8. 1
Dia g n ostic tiss ue
A bl oc k or mi ni m u m of 6 u nstai ne d sli des fr o m t he dia g n ostic bi o ps y will be c ollecte d at 
baseli ne f or a nal ysis of Ki 6 7 a n d a d diti o nal tests as part of t he c orrelati ve scie nce pla n. 
Partici pati n g sites s h o ul d c o nfir m a vaila bilit y of arc hi val tiss ue f or c orrelati ve a nal ysis 
pri or t o re gistrati o n. T his tiss ue m ust be se nt t o t he c o or di nat or ce nter after ra n d o mizati o n 
w he n s u bject n u m ber is assi g ne d; s hi p pi n g details are pr o vi de d bel o w i n secti o n 5. 8. 4.
5. 8. 2
I ma ge- g ui de d researc h bi o ps y  
Researc h breast c ore bi o psies of t he tar get lesi o n will be o btai ne d fr o m all partici pa nts at 
baseli ne a n d after a 2- wee k “ wi n d o w” of e n d ocri ne t hera p y wit h eit her ta m o xife n or 

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2 9
letr oz ole. F or patie nts e nr olle d directl y i nt o t he treat me nt p hase of t he st u d y, t he researc h 
c ore bi o psies will be perf or me d at baseli ne a n d after a 2- wee k treat me nt peri o d wit h eit her 
e n d ocri ne t hera p y al o ne or e n d ocri ne t hera p y i n c o m bi nati o n wit h pal b ocicli b. T he   
bi o psies re prese nt a n i nte grate d assa y t hat will be use d i n e val uati n g t he pri mar y o bjecti ve 
of t his st u d y, t h us j ustif yi n g t heir ma n dat or y c ollecti o n. 
It is str o n gl y rec o m me n de d t hat c ore bi o psies be i ma ge- g ui de d. T he re q uire d bi o psies 
i ncl u de t w o t o t hree c ore bi o psies place d i n 1 0 % b uffere d f or mali n (a si n gle pre-fille d 
f or mali n c o ntai ner is pr o vi de d i n t he kit t o h ol d b ot h c ores) a n d t w o t o t hree c ore bi o psies 
fr oze n i m me diatel y at be dsi de i n se parate O C T bl oc ks t o preser ve t he pr ote o me a n d 
tra nscri pt o me of t he t u m or. Bi o ps y cli ps are n ot re q uire d, b ut are per mitte d, per 
i nstit uti o nal g ui deli nes.  
I n a li mite d s u bset of partici pa nts e nr olle d at Da na- Far ber, 1 c ore of t he researc h bi o ps y 
will be tra nsferre d t o D M S O as o p p ose d t o O C T. 
T he preferre d or der of c ollecti o n is as f oll o ws: 
C ore 1 F or mali n
C ore 2 F or mali n
C ore 3 O C T
C ore 4 O C T
C ore 5 F or mali n
C ore 6 O C T
Researc h bi o ps y kits will be pr o vi de d b y t he st u d y.  Kits ma y be or dere d fr o m C ore 
Pr o g n oste x.  S peci me ns s h o ul d be s hi p pe d per t he g ui deli nes i n Secti o n 5. 8. 5. It is 
a ntici pate d t hat s o me patie nts will be hesita nt a b o ut c o m pleti n g t he researc h bi o psies.  
T heref ore, u p t o 1 0 % ma y o pt o ut o ne of t he researc h bi o psies wit h pri or a p pr o val fr o m 
t he o verall Pri nci pal I n vesti gat or.  D oc u me ntati o n of t his a p pr o val m ust be recei ve d pri or 
t o re gistrati o n.  T his e ve nt will n ot be c o nsi dere d a n eli gi bilit y e xce pti o n or maj or 
de viati o n. 
5. 8. 3
P ost-s ur gical t u m or sa m pli n g
F or mali n-fi xe d Paraffi n E m be d de d T u m or Bl oc ks
T he s peci me n ma y be bl oc ke d usi n g re g ular cassettes or lar ge cassettes. After t he 
hist ol o gical assess me nt of pat h ol o gic c o m plete res p o nse, bl oc ks s h o ul d be selecte d f or 
s u b missi o n acc or di n g t o t he f oll o wi n g criteria:

I n case of p C R: s u b mit t he bl oc k(s) relati ve t o t he area(s) cl osest t o t he bi o ps y(ies) 
site or t o t he cli p if cli ps are use d at t he ti me of bi o ps y 

I n case of resi d ual t u m or: s u b mit t he bl oc k(s) relati ve t o t he area(s) cl ose t o t he cli p t o  
pre vi o us bi o ps y(ies).  If t hese bl oc k(s) d o n ot i ncl u de ( or o nl y i ncl u de a mi ni mal 
p orti o n of) resi d ual t u m or, t he n s u b mit a n a d diti o nal bl oc k re prese ntati ve of t he mai n 
t u m or resi d ue. 

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3 3
  wit h t he sa m ple i nf or mati o n a n d trac ki n g 
i nf or mati o n t he da y bef ore s hi p pi n g s peci me ns. 
5. 1 0  
A ge nt A d mi nistr ati o n
Treat me nt will be a d mi nistere d o n a n o ut patie nt basis.  E x pecte d t o xicities a n d p ote ntial ris ks as 
well as d ose m o dificati o ns are descri be d i n Secti o n 6 ( E x pecte d T o xicities a n d D osi n g 
Dela ys/ D ose M o dificati o n). N o i n vesti gati o nal or c o m mercial a ge nts or t hera pies ot her t ha n 
t h ose descri be d bel o w ma y be a d mi nistere d wit h t he i nte nt t o treat t he partici pa nt’s mali g na nc y.
5. 1 0. 1
Wi n d o w P hase 
T he first part or wi n d o w p hase of t he st u d y will i ncl u de 1 2 0 p ost me n o pa usal w o me n 
dia g n ose d wit h eit her i n vasi ve l o b ular carci n o ma ( n = 6 0 partici pa nts) or i n vasi ve d uctal 
carci n o ma ( n = 6 0 partici pa nts).   T he treat me nt is descri be d bel o w i n Ta ble 2.  I n t he 
wi n d o w p hase, pati e nts will b e r a n d o mi z e d t o r e c ei v e eit h er t a m o xif e n ( Ar m A) or 
l etr o z ol e ( Ar m B) f or a t ot al d ur ati o n of t w o w e e ks. Ta m o xife n a n d Letr oz ole are 
c o m mercial a ge nts a n d will be bille d t o t he patie nt’s i ns ura nce.
Patie nts s h o ul d recei ve a mi ni m u m of 1 4 da ys of letr oz ole or ta m o xife n a n d treat me nt 
s h o ul d n ot be i nterr u pte d u ntil t he researc h bi o ps y is perf or me d (i.e. patie nts s h o ul d be o n 
treat me nt at t he ti me of researc h bi o ps y). 
Patie nts ra n d o mize d t o recei ve letr oz ole i n t he wi n d o w p hase ma y recei ve c o nti n u o us 
letr oz ole d osi n g wit h o ut brea k bet wee n t he wi n d o w a n d treat me nt p hase. 
T a bl e 2:  T r e at m e nt r e gi m e n – Wi n d o w P h as e
5. 1 0. 2
Treat me nt P hase
T he sec o n d part of t he st u d y – Treat me nt P hase – will i ncl u de u p t o 1 9 5 partici pa nts, 
c o m pr o mise d of 1 2 0 patie nts first treate d i n t he wi n d o w p hase, a n d t he rest of t he patie nts 
e nr olle d directl y i nt o t he treat me nt p hase of t he st u d y. Pre me n o pa usal patie nts will be 
e nr olle d directl y i nt o t he treat me nt p hase of t he st u d y.  T he treat me nt is descri be d bel o w 
A g e nt
P r e-
m e di c ati o ns
D os e
R o ut e
S c h e d ul e
C y cl e 
L e n gt h
A r m A
T a m o xif e n
N o r o uti n e 
pr e m e di c ati
o n r e q uir e d
2 0 m g
P O
O n c e D ail y o n 
d a ys 1- 1 4 
( c o nti n u o us)
1 4 d a ys
A r m B
L etr o z ol e
N o r o uti n e 
pr e m e di c ati
o n r e q uir e d
2. 5 m g 
P O
O n c e D ail y o n 
d a ys 1- 1 4 
( c o nti n u o us)
1 4 d a ys

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3 4
i n Ta ble 3. I n t h e tr e at m e nt p h as e of t h e st u d y p ati e nts will b e r a n d o mi z e d t o r e c ei v e 
Ar m C: e n d o cri n e t h er a p y pl us P al b o ci cli b or Ar m D: e n d o cri n e t h er a p y al o n e. 
P ost m e n o p a us al p ati e nts will r e c ei v e l etr o z ol e.  Pr e m e n o p a us al p ati e nts will r e c ei v e 
t a m o xif e n a n d o v ari a n s u p pr essi o n wit h L H R H a g o nist 
O ne c ycle is defi ne d as 4 wee ks ( 2 8 ± 3 da ys). Patie nts will be treate d f or a t otal of si x 
c ycles.  St u d y treat me nt will be a d mi nistere d i n 2 8- da y/ 4- wee k c ycles if n o a d diti o nal ti me 
is re q uire d f or re versal of t o xicit y.  If t he ti mi n g of a pr ot oc ol- ma n date d pr oce d ure 
c oi nci des wit h a h oli da y a n d/ or wee ke n d t hat precl u de perf or ma nce of t he pr oce d ure wit hi n 
t he all otte d 3- da y wi n d o w, t he pr oce d ure s h o ul d be perf or me d o n t he nearest f oll o wi n g 
date.
E n d ocri ne t hera p y ma y c o nti n ue after t he c o m pleti o n of 2 4 wee ks u ntil s ur ger y at t he 
discreti o n of t he treati n g i n vesti gat or. 
P ati e nts r a n d o mi z e d t o Ar m C will b e off er e d u p t o si x c y cl es of p al b o ci cli b wit h 
e n d o cri n e t h er a p y as p ost o p er ati v e ( a dj u v a nt) t h er a p y  (i n cl usi v e of n e o a dj u v a nt 
t h er a p y, t h e t ot al d ur ati o n is e q ui v al e nt t o 1 y e ar).. P ati e nts r a n d o mi z e d t o e n d o cri n e 
t h er a p y al o n e ( Ar m D) will b e off er e d p ost o p er ati v e ( a dj u v a nt) tr e at m e nt wit h 
p al b o ci cli b gi v e n i n c o m bi n ati o n wit h e n d o cri n e t h er a p y f or 1 2 c y cl es ( a t ot al d ur ati o n 
of 1 y e ar). S e e s e cti o n 5. 1 4 f or m or e i nf or m ati o n a b o ut pr es cri bi n g a dj u v a nt 
p al b o ci cli b.
T a bl e 3:  T r e at m e nt r e gi m e n – T r e at m e nt P h as e
A g e nt
P r e-
m e di c ati o ns; 
p r e c a uti o ns
D os e
R o ut e
S c h e d ul e
C y cl e 
L e n gt h
A r m C
P al b o ci cli b
Gi v e n wit h or 
wit h o ut f o o d
1 2 5 m g
P O
O n c e D ail y o n d a ys 
1- 2 1, f oll o w e d b y 
o n e w e e k off 
F or P ost m e n o p a us al P ati e nts
L etr o z ol e
N o r o uti n e 
pr e m e di c ati o n 
r e q uir e d
2. 5 m g 
P O
O n c e D ail y o n d a ys 
1- 2 8 ( c o nti n u o us)
F or Pr e m e n o p a us al P ati e nts
T a m o xif e n
N o r o uti n e 
pr e m e di c ati o n 
r e q uir e d
2 0 m g
P O
O n c e D ail y o n d a ys 
1- 2 8 ( c o nti n u o us)
2 8 d a ys
( 4 w e e ks)
A r m D
F or P ost m e n o p a us al P ati e nts 
L etr o z ol e
N o r o uti n e 
2. 5 m g 
P O
O n c e D ail y o n d a ys 
2 8 d a ys

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3 5
5. 1 0. 3
E n d ocri ne T hera p y – N o n I n vesti gati o nal Pr o d uct(s)
E n d ocri ne t hera p y (letr oz ole or ta m o xife n) s h o ul d be ta ke n orall y, o nce per da y, as per 
sta n dar d d osi n g. Patie nts s h o ul d be i nstr ucte d t o rec or d dail y a d mi nistrati o n of t he st u d y 
dr u gs i n a dr u g diar y ( A p pe n di x C f or t he Wi n d o w p orti o n, A p pe n di x D f or t he 
Treat me nt p orti o n). Or deri n g of e n d ocri ne t hera p y self-a d mi nistrati o n relati ve t o 
pal b ocicli b self-a d mi nistrati o n is as per patie nt prefere nce.  L H R H a g o nists will be 
a d mi nistere d t o pre me n o pa usal w o ma n i n t he treat me nt p hase acc or di n g t o sta n dar d 
i nstit uti o nal or re gi o nal practice. Ge nerics are all o we d, if l ocall y a vaila ble.
S pecific st ora ge c o n diti o ns, ha n dli n g dis pe nsati o n a n d a d mi nistrati o n i nstr ucti o ns ha ve t o 
be l ocall y f oll o we d acc or di n g t o l ocal re g ulati o ns a n d i n acc or da nce wit h res pecti ve l ocal 
pac ka ge i nserts a n d/ or l ocal S m P Cs.  E x pecte d t o xicities a n d p ote ntial ris ks ca n be 
o btai ne d fr o m res pecti ve l ocal pac k i nserts a n d or l ocal S m P Cs.  Misse d d oses of 
e n d ocri ne t hera p y s h o ul d n ot be ma de u p.
If pal b ocicli b is hel d or dela ye d f or t o xicit y, e n d ocri ne t hera p y s h o ul d c o nti n ue as 
pla n ne d.
E n d ocri ne t hera p y ma y c o nti n ue after t he c o m pleti o n of 2 4 wee ks u ntil s ur ger y at t he 
discreti o n of t he treati n g i n vesti gat or. 
A st u d y tea m me m ber s h o ul d re vie w t he dr u g diar y f or t he e n d ocri ne t hera p y b ut d oes 
n ot nee d t o perf or m a pill c o u nt f or letr oz ole or ta m o xife n.
5. 1 0. 4 Pal b ocicli b
Pal b ocicli b 1 2 5 m g s h o ul d be ta ke n orall y, o nce per da y, wit h or wit h o ut f o o d. If a d ose 
is v o mite d, a re place me nt d ose s h o ul d N O T be ta ke n. If a d ose is misse d, a n d it is less 
t ha n 6 h o urs fr o m us ual ti me of d osi n g, t he n patie nts ma y ta ke t hat d ose. Ot her wise t hat 
pr e m e di c ati o n 
r e q uir e d
1- 2 8 ( c o nti n u o us)
F or Pr e m e n o p a us al P ati e nts
T a m o xif e n
N o r o uti n e 
pr e m e di c ati o n 
r e q uir e d
2 0 m g
P O
O n c e D ail y o n d a ys 
1- 2 8 ( c o nti n u o us)
( 4 w e e ks)
M a n d at e d f or Pr e m e n o p a us al P ati e nts o n Ar m C a n d D
L H R H 
a g o nist 
N o r o uti n e 
pr e m e di c ati o n
D os e 
r e c o m m e n d e d 
b y t h e 
m a n uf a ct ur er
I M
R e c o m m e n d e d o n c e 
m o nt hl y d e p ot 
i nj e cti o n 
2 8 d a ys
( 4 w e e ks)

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
3 6
d ose s h o ul d be s ki p pe d a n d N O T reta ke n; patie nts s h o ul d res u me re g ular d osi n g t he 
f oll o wi n g da y.  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 s ki p t he 
ne xt da y’s d ose.  Patie nts s h o ul d be i nstr ucte d t o rec or d dail y a d mi nistrati o n of t he st u d y 
dr u gs i n a dr u g diar y ( A p pe n di x D). Treat me nt is c o nti n u o us dail y f or 2 1 da ys, a n d t he n 7 
da ys off, t o c o m plete a 2 8 da y c ycle. Partici pa nts m ust meet la b eli gi bilit y criteria f or 
C ycle 1 Da y 1. S u bse q ue nt c ycles m ust meet retreat me nt criteria o utli ne d i n Secti o n 
6. 3. 2.
O n da ys w he n patie nt is sc he d ule d f or a cli nic visit, t he patie nt ma y ta ke t he oral 
me dicati o ns at h o me or i n t he cli nic. I n a d diti o n, patie nts will bri n g blister pac ks t o visits, 
a n d pill c o u nts will be perf or me d as f oll o ws: Patie nts will be re q uire d t o ret ur n all blister 
pac ks of pal b ocicli b as well as t he c o m plete d dr u g diar y at eac h st u d y visit f or dr u g 
acc o u nta bilit y. Dr u g acc o u nta bilit y f or pal b ocicli b will be perf or me d at eac h st u d y visit 
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(s). T he n u m ber of re mai ni n g ta blets 
will be d oc u me nte d a n d rec or de d.
A st u d y tea m me m ber s h o ul d re vie w t he dr u g diar y f or t he e n d ocri ne t hera p y b ut d oes 
n ot nee d t o perf or m a pill c o u nt f or letr oz ole or ta m o xife n.
5. 1 1  
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p orti ve C are G ui deli nes
 Per mitte d A ncill ar y Me dic ati o ns
S u p p orti ve care me dicati o ns are all o we d at a n y ti me o n trial, as l o n g as t he y are n ot i ncl u de d i n 
t he list of pr o hi bite d me dicati o ns base d o n C Y P i n d ucti o n ( detaile d bel o w).
S pecificall y, t he f oll o wi n g a ge nts are per mitte d:

A ntie metics

A nti diarr heal t hera p y

A ntialler gic meas ures s uc h as c ortic oster oi ds a n d a nti hista mi nes

Bis p h os p h o nates: Patie nts bei n g treate d wit h bis p h os p h o nates f or ma na ge me nt of 
oste o p or osis w he n t he y e nter t he st u d y a n d ma y c o nti n ue t he me dicati o n as l o n g as t he 
d ose is sta ble. Patie nts ma y als o i nitiate bis p h os p h o nate t hera p y w hile o n pr ot oc ol 
t hera p y if me dicall y i n dicate d.

A ge nts t o assist i n ma na ge me nt of e n d ocri ne t hera p y-i n d uce d si de effects ( N o nster oi dal 
a nti-i nfla m mat or y dr u gs [ N S AI Ds], ga ba pe nti n, d ul o xeti ne, ve nlafa xi ne, etc.). 

Dia betes ma na ge me nt me dicati o n i ncl u di n g metf or mi n

Ra n k Li ga n d I n hi bit ors
N o n- breast s ur ger y is all o we d d uri n g pr ot oc ol t hera p y.  Patie nts p urs ui n g t his s ur ger y m ust h ol d 
pal b ocicli b t hera p y a p pr o xi matel y 7 da ys bef ore t he s ur ger y a n d u p t o 3 wee ks after s ur ger y. 
Patie nts ma y res u me pal b ocicli b t hera p y o nce satisfact or y w o u n d heali n g a n d rec o ver y ha ve 
occ urre d. Patie nts s h o ul d c o nti n ue e n d ocri ne t hera p y if pal b ocicli b is hel d f or s ur ger y.
 Pr o hi bite d C o nc o mit a nt Me dic ati o ns

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
3 7
Gr o wt h fact ors, i ncl u di n g Gra n ul oc yte C ol o n y Sti m ulati n g Fact or ( G- C S F), are n ot all o we d o n 
trial ( wit h t he e xce pti o n of sit uati o ns w here a patie nt bec o mes cli nicall y a n d me dicall y u nsta ble 
d ue t o ne utr o pe nia). T he use of c o nc urre nt i n vesti gati o nal or ot her a ntit u m or t hera pies, ot her 
t ha n e n d ocri ne t hera p y, is n ot per mitte d f or st u d y patie nts. If a s u bject m ust ta ke o ne of t he 
f oll o wi n g me dicati o ns d uri n g t he st u d y, a n d t here is n o alter nati ve, t he s u bject nee ds t o 
disc o nti n ue pal b ocicli b.
C Y P 3 A I n hi bit ors/I n d ucers 
P ote nt ( Str o n g/ M o derate) 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 y mes. C o-a d mi nistrati o n wit h dr u gs t hat are 
p ote nt 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. T he c o nc urre nt use of t he f oll o wi n g c o m p o u n ds is 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 d ucers, i ncl u di n g 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.

Str o n g C Y P 3 A i n hi bit ors, i ncl u di n g, b oce pre vir, clarit hr o m yci n, c o ni va pta n, dela vir 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 pefr uit.

M o derate C Y P 3 A i n hi bit ors i ncl u di n g a m pre na vir, ataza na vir, diltiaze m, er yt hr o m yci n, 
f osa m pre na vir, vera pa mil.

M o derate C Y P 3 A i n d ucers i ncl u di n g fel ba mate, ne vira pi ne, p he n o bar bital, rifa b uti n.
A ntica ncer T hera pies
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 p y, 
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, ra diati o n t hera p y or e n d ocri ne 
t hera p y ot her t ha n t h ose all o we d i n t he pr ot oc ol will be per mitte d d uri n g t he st u d y.  
H or m o ne re place me nt t hera p y, t o pical estr o ge ns ( b ut n ot i ntra- va gi nal pre parati o ns), me gestr ol 
acetate a n d selecti ve estr o ge n-rece pt or m o d ulat ors n ot i n dicate d i n t he pr ot oc ol desi g n, e. g. 
ral o xife ne, are pr o hi bite d d uri n g t he wi n d o w a n d treat me nt p hase.
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 st u d y. Alter nati ve 
t hera pies s h o ul d be c o nsi dere d w he ne ver p ossi ble:
T he c o nc urre nt use of de xa met has o ne is n ot rec o m me n de d.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
3 8
C hr o nic i m m u n os u p pressi ve t hera pies s h o ul d be a v oi de d, i ncl u di n g s yste mic c ortic oster oi ds. 
Ster oi ds gi ve n f or p h ysi 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 her bal me dici ne is n ot rec o m me n de d d uri n g t he st u d y.
C Y P 3 A S u bstrates wit h a Narr o w T hera pe utic I n de x: T he d ose of t he se nsiti ve C Y P 3 A 4 
s u bstrate wit h a narr o w t hera pe utic i n de x (e. g., alfe nta nil, c ycl os p ori ne, di h y dr oer g ota mi ne, 
er g ota mi ne, e ver oli m us, fe nta n yl, pi m ozi de, q ui ni di ne, sir oli m us a n d tacr oli m us) ma y nee d t o be 
re d uce d w he n gi ve n c o nc urre ntl y wit h pal b ocicli b as pal b ocicli b ma y i ncrease t heir e x p os ure.
5. 1 2  
Defi niti ve Bre ast S ur ger y
Defi niti ve breast s ur ger y (e xcisi o n a n d/ or mastect o m y) m ust be perf or me d n o later t ha n 4 2 da ys 
fr o m t he c o m pleti o n of si x c ycles ( 2 4 wee ks) of treat me nt i n t he treat me nt p hase of t he st u d y 
( wit hi n 4 2 da ys of C 6 D 2 8). If c o ntralateral mastect o m y is perf or me d c o nc urre ntl y, t he pat h ol o g y 
re p ort fr o m t he c o ntralateral breast m ust be re p orte d if i n vasi ve disease is i de ntifie d. 
5. 1 3 
P ost- o per ati ve R a di ot her a p y
Decisi o ns re gar di n g c h oice of p ost-s ur gical ra di ot hera p y will be ma de b y t he treati n g tea m. 
5. 1 4 
P ost- o per ati ve A dj u v a nt T her a p y
T he treati n g tea m will ma ke decisi o ns re gar di n g c h oice of p ost-s ur gical a dj u va nt t hera p y. 
Treati n g p h ysicia ns will be per mitte d t o prescri be pal b ocicli b fr o m i n vesti gati o nal s u p pl y as 
p ost- o perati ve a dj u va nt t hera p y u n der t he f oll o wi n g g ui deli nes: 
Ar m C: U p t o 6 c ycles of Pal b ocicli b i n c o m bi nati o n wit h e n d ocri ne t hera p y as a d diti o nal p ost-
s ur gical t hera p y f or patie nts ra n d o mize d t o Pal b ocicli b a n d e n d ocri ne t hera p y ( Ar m C) i n t he 
treat me nt p hase of t he st u d y.
•
It is rec o m me n de d t hat patie nts o n Ar m C be m o nit ore d f or ne utr o pe nia via C B C o n 
da y 1 of e ver y c ycle. Pal b ocicli b ma y be dis pe nse d u p t o 3 c ycles at a ti me 
•
Partici pa nts o n t his ar m s h o ul d start t hera p y at t he d ose a n d fre q ue nc y t he y were 
recei vi n g d uri n g t he ne oa dj u va nt p hase. D ose h ol ds/re d ucti o ns/i nterr u pti o ns are 
rec o m me n de d base d o n t he i n di vi d ual patie nt’s safet y a n d t olera bilit y, as assesse d b y 
t he treati n g p h ysicia n. 
Ar m D: U p t o 1 2 c ycles of Pal b ocicli b i n c o m bi nati o n wit h e n d ocri ne t hera p y as a d diti o nal p ost-
s ur gical t hera p y f or patie nts ra n d o mize d t o e n d ocri ne t hera p y al o ne ( Ar m D) i n t he treat me nt 
p hase of t he st u d y.
•
It is rec o m me n de d t hat patie nts o n Ar m D be m o nit ore d f or ne utr o pe nia via C B C o n 
da y 1 of e ver y c ycle a n d Da y 1 5 of C ycles 1 a n d 2. After t he c o m pleti o n of 2 c ycles, 
Pal b ocicli b ca n be dis pe nse d u p t o 3 c ycles at a ti me. 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
3 9
•
T he rec o m me n de d starti n g d ose is 1 2 5 m g b y m o ut h o nce a da y wit h f o o d f or 2 1 da ys 
f oll o we d b y 7 da ys off treat me nt. D ose h ol ds/re d ucti o ns/i nterr u pti o ns are 
rec o m me n de d base d o n t he i n di vi d ual patie nt’s safet y a n d t olera bilit y, as assesse d b y 
t he treati n g p h ysicia n. 
•
Pal b ocicli b will be pr o vi de d b y  
 at n o c ost.
•
T here is n o pr ot oc ol- ma n date d m o nit ori n g (la bs, assess me nts, t o xicit y, or dr u g c o m plia nce). 
All t hera p y will be prescri be d per i n vesti gat or discreti o n. Please refer t o t he Pal b ocicli b 
(I B R A N C E) pac ka ge i nsert f or a d diti o nal g ui da nce. 
•
Partici pa nts o n eit her ar m ma y be gi n t heir a dj u va nt pal b ocicli b at a n y ti me a n d t here is n o 
restricti o n o n w he n t hera p y ca n be gi n after s ur ger y. F or e xa m ple, it w o ul d be per missi ble f or 
a patie nt t o start t heir a dj u va nt t hera p y 6 or 1 2 m o nt hs after t heir s ur ger y. 
•
T o xicit y data relate d t o a dj u va nt Pal b ocicli b will n ot be rec or de d i n t he e C R Fs.
5. 1 5  
Criteri a f or T a ki n g a P artici p a nt off Pr ot oc ol T her a p y
D urati o n of t hera p y will de pe n d o n i n di vi d ual res p o nse, e vi de nce of disease pr o gressi o n a n d 
t olera nce. I n t he a bse nce of treat me nt dela ys d ue t o a d verse e ve nt(s), treat me nt ma y c o nti n ue f or 
6 c ycles ( 2 4 wee ks) or u ntil o ne of t he f oll o wi n g criteria a p plies:

Disease pr o gressi o n

I nterc urre nt ill ness t hat pre ve nts f urt her a d mi nistrati o n of treat me nt

U nacce pta ble a d verse e ve nt(s)

Partici pa nt de m o nstrates a n i na bilit y or u n willi n g ness t o c o m pl y wit h t he me dicati o n 
re gi me n a n d/ or d oc u me ntati o n re q uire me nts

Partici pa nt deci des t o wit h dra w fr o m t he pr ot oc ol t hera p y

Ge neral or s pecific c ha n ges i n t he partici pa nt's c o n diti o n re n der t he partici pa nt 
u nacce pta ble f or f urt her treat me nt i n t he j u d g me nt of t he treati n g i n vesti gat or
Partici pa nts will be re m o ve d fr o m t he pr ot oc ol t hera p y w he n a n y of t hese criteria a p pl y.  T he 
reas o n f or re m o val fr o m pr ot oc ol t hera p y, a n d t he date t he partici pa nt was re m o ve d, m ust be 
d oc u me nte d i n t he case re p ort f or m ( C R F). Alter nati ve care o pti o ns will be disc usse d wit h t he 
partici pa nt.
I n t he e ve nt of u n us ual or life-t hreate ni n g c o m plicati o ns, treati n g i n vesti gat ors m ust i m me diatel y 
n otif y t he O verall PI,  Ott o Metz ger, M D,
 
5. 1 6  
D ur ati o n of F oll o w U p
T he first p ost-s ur ger y f oll o w- u p visit will be c o nsi dere d t he s u bject's fi nal st u d y visit.  If breast 
s ur ger y is n ot perf or me d t he s u bject’s fi nal visit will be t he 3 0 da ys after t he last d ose of pr ot oc ol-
s pecifie d t hera p y.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
4 0
Si m plifie d p ost-s ur ger y f oll o w- u p a n d treat me nt i nf or mati o n will be s u bse q ue ntl y c ollecte d. 
Decisi o ns re gar di n g c h oice of p ost-s ur gical treat me nt a n d disease assess me nts will be at t he 
discreti o n of t he treati n g tea m a n d n ot ma n date d b y t he c urre nt pr ot oc ol. A d diti o nal p ost-s ur gical 
pal b ocicli b gi ve n i n c o m bi nati o n wit h e n d ocri ne t hera p y ma y be gi ve n at t he discreti o n of t he 
treati n g p h ysicia n, b ut t his is n ot ma n date d b y t he c urre nt pr ot oc ol. P h ysicia ns will be all o we d t o 
prescri be u p t o si x c ycles of pal b ocicli b i n c o m bi nati o n wit h e n d ocri ne t hera p y O N L Y f or patie nts 
ra n d o mize d t o recei ve e n d ocri ne t hera p y al o ne. T he i n vesti gat or is n ot re q uire d t o acti vel y m o nit or 
patie nts f or a d verse e ve nts after t he fi nal visit.  H o we ver, t he S p o ns or s h o ul d be n otifie d if t he 
i n vesti gat or bec o mes a ware of a n y deat h or ot her seri o us a d verse e ve nt t hat is c o nsi dere d relate d 
t o t he st u d y me dicati o n
P ost-s ur ger y f oll o w- u p i nf or mati o n will be c ollecte d at assess me nts e ver y year u ntil 1 0 years after 
s ur ger y, or u ntil a disease-free s ur vi val e ve nt. 
Disease-free s ur vi val ( D F S) will be defi ne d fr o m t he ti me of ra n d o mizati o n u ntil t he occ urre nce 
of t he first of t he f oll o wi n g e ve nts:

L ocal/re gi o nal rec urre nce: a rec urre nt or ne w i n vasi ve i psilateral breast ca ncer, i n vasi ve 
breast ca ncer i n t he a xilla, re gi o nal l y m p h n o des, c hest wall, or s ki n of t he i psilateral 
breast.

C o ntralateral i n vasi ve breast ca ncer

Dista nt rec urre nce: metastatic disease t hat has eit her bee n bi o ps y c o nfir me d or cli nicall y 
dia g n ose d as rec urre nt i n vasi ve breast ca ncer. A si n gle ne w lesi o n o n a b o ne sca n wit h o ut 
e vi de nce of l ytic disease o n x-ra y a n d wit h o ut s y m pt o ms d oes n ot i n a n d of itself 
c o nstit ute dista nt rec urre nce, b ut m ulti ple ne w b o ne lesi o ns, or i ncrease d is ot o pe u pta ke 
ass ociate d wit h ne w b o ne s y m pt o ms are m ore li kel y d ue t o metastases. B o ne metastases 
m ust be d oc u me nte d wit h x-ra ys a n d cli nical descri pti o n.

Deat h fr o m a n y ca use
I n sit u ca ncer is n ot i ncl u de d as a D F S e ve nt. If a patie nt has i n sit u breast ca ncer ( o n t he 
i psilateral or c o ntralateral si de) dia g n ose d d uri n g f oll o w- u p bef ore a n y of t he D F S e ve nts a b o ve, 
t he n t he patie nt s h o ul d c o nti n ue t o be f oll o we d f or D F S o n st u d y (e ve n if s he is gi ve n h or m o nal 
t hera p y after t he i n sit u dia g n osis). 
If a patie nt is dia g n ose d wit h a n o n- mela n o ma s ki n ca ncer or a va gi nal carci n o ma i n sit u, s he 
will c o nti n ue o n t his st u d y a n d c o nti n ue t o be f oll o we d f or D F S. 
It is rec o m me n de d t hat a n y disease-free s ur vi val e ve nt s h o ul d be bi o psie d t o c o nfir m rec urre nt 
disease. I nf or mati o n o n breast ca ncer stat us, ne w a nti-ca ncer t hera p y, a n d ne w o nset mali g na nc y 
dia g n oses will be c ollecte d via si m plifie d C R Fs.  F oll o wi n g a n D F S e ve nt, s ur vi val i nf or mati o n 
(i.e., date a n d ca use of deat h or last k n o w n ali ve date if n ot decease d a n d ne w o nset mali g na nc y 
i nf or mati o n) will be c ollecte d. All patie nts will be f oll o we d f or s ur vi val.  
5. 1 7  
Criteri a f or T a ki n g a P artici p a nt off St u d y
Partici pa nts will be re m o ve d fr o m st u d y bef ore st u d y c o m pleti o n w he n a n y of t he f oll o wi n g 
criteria a p pl y:

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
4 1

L ost t o f oll o w- u p

Wit h dra wal of c o nse nt f or data s u b missi o n

Deat h
T he reas o n f or ta ki n g a partici pa nt off st u d y, a n d t he date t he partici pa nt was re m o ve d, m ust be 
d oc u me nte d i n t he case re p ort f or m ( C R F).
I n t he e ve nt of u n us ual or life-t hreate ni n g c o m plicati o ns, treati n g i n vesti gat ors m ust i m me diatel y 
n otif y t he O verall PI, Ott o Metz ger, M D 
6.
E X P E C T E D T O XI CI TI E S A N D D O SI N G D E L A Y S/ D O S E M O DI FI C A TI O N S
A list of t he i m p orta nt a d verse e ve nts a n d p ote ntial ris ks ass ociate d wit h Pal b ocicli b a p pear 
bel o w a n d will deter mi ne w het her d ose dela ys a n d m o dificati o ns will be ma de a n d w het her t he 
e ve nt re q uires e x pe dite d re p orti n g i n a d diti o n t o r o uti ne re p orti n g.
6. 1 
E n d ocri ne T her a p y   
T he m ost c o m m o n a d verse e ve nts e x perie nce d wit h use of letr oz ole i ncl u de h ot flas hes, 
art hral gia, a n d gra d ual l oss of b o ne de nsit y. T he m ost c o m m o n a d verse e ve nts e x perie nce d wit h 
use of ta m o xife n i ncl u de h ot flas hes, ni g ht s weats, a n d va gi nal disc har ge. Ve n o us 
t hr o m b oe m b olic disease a n d e n d o metrial ca ncer are rare ris ks of ta m o xife n. A detaile d 
descri pti o n of A Es of t he c o m merciall y a vaila ble e n d ocri ne t hera p y a ge nts use d i n t his st u d y 
s h o ul d be o btai ne d fr o m t he partic ular pac ka ge i nserts ( S m P Cs) of t he l ocall y o btai ne d 
c o m mercial s u p plies.
6. 1. 1
E x pecte d T o xicities f or Letr oz ole 

H ot flas hes

H y per hi dr osis

Fati g ue

Hea dac he

I ns o m nia

H y perte nsi o n

A b d o mi nal pai n

Dizzi ness

Art hral gia

M yal gia

Wea k ness

A n ore xia

Na usea

E de ma

C o nsti pati o n

Wei g ht gai n 

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Versi o n D ate: J uly 6, 2 0 2 2
4 2

D ys p nea

C o u g h

Oste o pe nia

H y perc h olester ole mia

De pressi o n

A n xiet y

Diarr hea

Der matitis

M y ocar dial i nfarcti o n

Deat h d ue t o str o ke or heart fail ure
6. 1. 2
E x pecte d T o xicities f or Ta m o xife n 

Ni g ht s weati n g

Va gi nal disc har ge or dr y ness

Irre g ular me nses

V ul var itc hi n g

Na usea

E de ma

Der matitis

Hair t hi n ni n g

Ele vate d li ver e nz y mes

Oste o pe nia

T hr o m b us

Cataracts 

 A raise d se nsiti vit y t o bl o o d t hi n ners s uc h as C o u ma di n

E n d o metrial c ha n ges 
6. 2 
P al b ocicli b 
T he pri mar y a ntici pate d t o xicit y of pal b ocicli b is ne utr o pe nia. I n t he p hase I, d ose-escalati o n 
trial of pal b ocicli b al o ne i n a d va nce d ca ncers, ne utr o pe nia was t he o nl y d ose-li miti n g t o xicit y 
( D L T). Gra de 3 ne utr o pe nia d uri n g c ycle 1 was o bser ve d i n 3/ 2 2 patie nts recei vi n g pal b ocicli b 
1 2 5 m g P O dail y, wit h n o gra de 4 ne utr o pe nia e ve nts o bser ve d. Base d o n t his res ult, 1 2 5 m g P O 
dail y beca me t he rec o m me n de d p hase 2 d ose ( R P 2 D). Ot her he mat ol o gic A Es of gra de 3 or 
greater d uri n g c ycle 1 were a ne mia a n d le u k o pe nia, occ urri n g i n 1 a n d 4 of 4 1 patie nts, 
res pecti vel y. T he m ost c o m m o n n o n- he mat ol o gic A Es of gra de 3 or greater d uri n g c ycle 1 were 
fati g ue, na usea, a n d a b d o mi nal pai n (eac h occ urri n g i n 2 of 4 1 patie nts). Of n ote, t here were n o 
c o m plicate d he mat ol o gic A Es d oc u me nte d, a n d all he mat ol o gic A Es res ol ve d d uri n g t he off-
dr u g peri o d of a 3- wee k o n/ 1 wee k off sc he d ule, a n d were n o n-c u m ulati ve.
I n a p hase II trial of pal b ocicli b al o ne f or a d va nce d breast ca ncer, t he o nl y t o xicities > gra de 3 
o bser ve d were tra nsie nt ne utr o pe nia ( 5 0 %) a n d t hr o m b oc yt o pe nia ( 2 1 %)[ 5 6]. I n a p hase II trial 

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4 3
of pal b ocicli b pl us letr oz ole f or first-li ne t hera p y of h or m o ne rece pt or p ositi ve breast ca ncer, t he 
m ost c o m m o n A Es re p orte d were ne utr o pe nia, le u k o pe nia, a n d fati g ue[ 5 7, 5 8]. T he me dia n ti me 
t o first treat me nt dela y f or ne utr o pe nia was 5 8 da ys, a n d t he me dia n d urati o n of treat me nt dela y 
u ntil rec o ver y was 5 da ys (ra n ge 1- 1 6 da ys,  
 i nter nal data). I n ge neral, he mat ol o gic 
a b n or malities were a de q uatel y ma na ge d wit h sta n dar d s u p p orti ve care, were n ot c o m plicate d, 
a n d res ol ve d d uri n g t he dr u g h ol d wit h n o c u m ulati ve t o xicit y n ote d.
T he Si n gle Refere nce Safet y D oc u me nt f or Pal b ocicli b is t he I n vesti gat or’s Br oc h ure f or t he 
c o m p o u n d. 
6. 2. 1
E x pecte d T o xicities f or Pal b ocicli b 

Ne utr o pe nia

Decrease ne utr o p hil c o u nt ( wit h o ut fe ver)

Fati g ue

A ne mia

Diarr hea

Na usea

T hr o m b oc yt o pe nia

Decrease d a p petite

C o nsti pati o n 

M o ut h blisters/s ores

I nfecti o n of t he si n us or l u n g

V o miti n g

L oss of t o uc h or se nsati o n of pi ns a n d nee dles or n u m b ness o n t he s ki n

I nfla m mati o n of t he m o ut h

Pai n i ncl u di n g: A b d o mi nal pai n, m o ut h/t hr oat pai n, bac k pai n, fla n k pai n, m uscle pai n, 
b o ne pai n, pai n i n t he ha n ds a n d feet.

hair l oss

Ras h

C o u g h

S h ort ness of breat h

Hea dac he

Dizzi ness

H ot fl us h

I ns o m nia

Bl oati n g

S welli n g i n e xtre mities 

N ose blee d

M uscle s pas m or cra m ps

Fe ver

Dr y m o ut h 

Fe ver wit h da n ger o usl y l o w w hite bl o o d cell c o u nt

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4 4

A b n or mal taste 

A b d o mi nal pai n

I n di gesti o n 

Feeli n g wee k a n d ha vi n g n o e ner g y

Fl u-li ke ill ness

I ncrease i n bl o o d li ver e nz y mes

Dr y s ki n

Itc hi n g i n t he m o ut h or t hr oat

Hi g h bl o o d press ure

De pressi o n

I ncrease d ris k of fall

Irritati o n or s ores i n t he li ni n g of h oll o w or ga ns 

A b d o mi nal s welli n g

C hills

R u n n y N ose

Ni g ht S weats

Decrease d se nse of t o uc h or se nsati o n 

Wei g ht l oss

L o w bl o o d press ure

Hearts beats t hat are fast a n d har d

Bl urre d visi o n

I ncrease d teari n g

Dr y e ye

A b n or mal electrical c o n d ucti o n wit hi n t he heart 

P ul m o nar y e m b olis m 

P ne u m o nitis 
6. 3  
D ose M o dific ati o n G ui deli nes
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 pal b ocicli b 
a n d/ or e n d ocri ne t hera p y ma y nee d t o be a dj uste d.
I nci de nce, nat ure, a n d se verit y of a d verse e ve nts tri g geri n g d ose or st u d y treat me nt m o dificati o ns 
are t o be assesse d b y t he i n vesti gat or a n d gra de d acc or di n g t o Nati o nal Ca ncer 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, versi o n 4. 0 ( N CI C T C A E, v 4. 0) as A E relate d d ose 
a n d treat me nt m o dificati o n rec o m me n dati o ns are base d o n t his gra di n g scale. 
6. 3. 1
D ose M o dificati o ns / T o xicit y Ma na ge me nt – E n d ocri ne T hera p y
N o d ose re d ucti o n f or e n d ocri ne t hera p y is per mitte d. I n t he wi n d o w p hase of t he st u d y, n o 
treat me nt i nterr u pti o n is all o we d. I n t he treat me nt p hase of t he st u d y, e n d ocri ne treat me nt 
i nterr u pti o n is all o we d f or u p t o 4 c o nsec uti ve wee ks f or e n d ocri ne t hera p y-relate d t o xicities or 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
4 5
pers o nal reas o ns as per t he i n vesti gat or’s best me dical j u d g me nt. It is i m p orta nt t o n ote t hat if a 
patie nt e nc o u nters diffic ult y t olerati n g e n d ocri ne t hera p y, t he treati n g pr o vi der s h o ul d ma ke all 
p ossi ble eff orts t o c o nti n ue t he patie nt o n ne oa dj u va nt e n d ocri ne t hera p y, i ncl u di n g t he use of 
s u p p orti ve me dicati o n (e. g. i b u pr ofe n), w hile c o nti n ui n g treat me nt wit h pal b ocicli b. 
S u bjects missi n g m ore t ha n 4 c u m ulati ve wee ks of e n d ocri ne t hera p y will be re m o ve d fr o m   
treat me nt p hase of t he st u d y a n d will als o st o p pal b ocicli b (i.e. f or t h ose ra n d o mize d t o recei ve 
pal b ocicli b). Patie nts w h o disc o nti n ue e n d ocri ne t hera p y a n d/ or pal b ocicli b will c o nti n ue t o be 
f oll o we d acc or di n g t o p ost treat me nt f oll o w u p as defi ne d i n Sc he d ule of Assess me nts.
6. 3. 2
D ose M o dificati o ns / T o xicit y ma na ge me nt – Pal b ocicli b
D ose or treat me nt m o dificati o ns f or pal b ocicli b are all o wa ble a n d ma y occ ur as d ose 
i nterr u pti o ns ( wit hi n a c ycle), d ose del ays  ( bet wee n c ycles) or d ose re d ucti o ns .
I n t he e ve nt of si g nifica nt pal b ocicli b 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 ye d or re d uce d as descri be d wit hi n t his secti o n a n d acc or di n g t o ta ble 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 I n vesti gat ors at t he first occ urre nce of a n y 
a d verse si g n or s y m pt o m.
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 D ose Re d ucti o ns Secti o n 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, t he patie nt ma y 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.
P al b ocicli b D osi n g I nterr u pti o ns/ Del a ys
I n ge neral, c ycles s h o ul d be 2 8 da ys l o n g u nless t he start of a ne w c ycle is dela ye d. 
D oses misse d wit hi n a c ycle ( mea ni n g d ose i nterr u pti o ns) are n ot ma de u p. If, e. g. t he A E 
res ol ves bef ore t he e n d of t he c ycle, t he n t he patie nt ca n res u me ta ki n g t he pal b ocicli b f or t he 
re mai n der of t he c ycle b ut s h o ul d still st o p o n Da y 2 1 t o mai ntai n t he 7- da y brea k.
If a n a d verse e ve nt re q uiri n g a d ose h ol d has n ot res ol ve d b y Da y 1 of t he ne xt pla n ne d c ycle, t he 
start of t he ne w c ycle s h o ul d be dela ye d acc or di n g t o g ui deli nes wit hi n t his secti o n,.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
4 6
Patie nts o n pal b ocicli b ar m e x perie nci n g o ne or m ore of t he f oll o wi n g a d verse e ve nts descri be d 
bel o w s h o ul d ha ve t heir pal b ocicli b treat me nt i nterr u pte d/ dela ye d u ntil criteria f or retreat me nt 
are met:

U nc o m plicate d Gra de 3 or 4 ne utr o pe nia ( A N C < 1 0 0 0/ m m 3).

Gra de 3 or 4 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, 1 0 0. 4 F. 

Gra de 3 or 4 t hr o m b oc yt o pe nia ( Platelet c o u nt < 5 0, 0 0 0/ m m 3)

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 2 n o n- he mat ol o gic t o xicit y persisti n g des pite o pti mal me dical treat me nt, lasti n g 
m ore t ha n 3 wee ks, a n d u nacce pta ble t o patie nt a n d/ or pr o vi der.

I n case of c o nc urre nt occ urre nce of > 3 x U L N A L T a n d 2 x U L N T otal Bilir u bi n, at a n y 
ti me d uri n g t he trial, pal b ocicli b will be per ma ne ntl y disc o nti n ue d.
Patie nts s h o ul d n ot h ol d or disc o nti n ue pal b ocicli b f or si de effects p ote ntiall y or li kel y relate d t o 
c o nc o mita nt sta n dar d e n d ocri ne t hera p y (e. g., gra de 3 or l o n g lasti n g gra de 2 j oi nt pai n) as per 
t he i n vesti gat or’s j u d g me nt.
F oll o w u p assess me nts acc or di n g t o i n vesti gat or’s decisi o n s h o ul d be perf or me d u ntil a de q uate 
rec o ver y occ urs as assesse d b y t he I n vesti gat or.
S u bjects missi n g m ore t ha n 4 c u m ulati ve wee ks of e n d ocri ne t hera p y will be re m o ve d fr o m   
treat me nt p hase of t he st u d y a n d will als o st o p pal b ocicli b (i.e. f or t h ose ra n d o mize d t o recei ve 
pal b ocicli b). F or a patie nt w h o c h o oses t o st o p pal b ocicli b, it is str o n gl y rec o m me n de d t o 
e nc o ura ge t he patie nt t o c o nti n ue ne oa dj u va nt e n d ocri ne t hera p y f or a t otal d urati o n of si x 
c ycles. 
P al b ocicli b Retre at me nt Criteri a
Retreat me nt wit h pal b ocicli b f oll o wi n g treat me nt i nterr u pti o n or dela y f or treat me nt relate d 
t o xicit y 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 at t he start of a ne w 
c ycle:

Platelet c o u nt  7 5, 0 0 0/ m m3;

A N C  1 0 0 0/ m m3 a n d n o fe ver;

A n y persiste nt gra de 2, gra de 3 or hi g her treat me nt-relate d n o n- he mat ol o gic A Es 
c o nsi dere d relate d t o pal b ocicli b ha ve rec o vere d t o Gra de ≤ 1 or baseli ne.
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 a dj uste d as cli nicall y i n dicate d.
If t he retreat me nt para meters are met wit hi n 4 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.   
If t hese para meters ha ve n ot bee n met after 4 wee ks of d ose i nterr u pti o n (i ncl u di n g t he sc he d ule d 

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Versi o n D ate: J uly 6, 2 0 2 2
4 7
1 wee k off treat me nt) or c ycle dela y, t he patie nt s h o ul d per ma ne ntl y disc o nti n ue pal b ocicli b 
treat me nt. 
P al b ocicli b D ose Re d ucti o ns

T he pal b ocicli b d ose ma y nee d t o be re d uce d, f oll o wi n g a d ose i nterr u pti o n or c ycle 
dela y 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 or s h ort lasti n g Gra de 2 ( < 4 
wee ks) 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 ys 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 a n d d oc u me nt t he c ha n ges i n t he C R F.

F or pal b ocicli b relate d, Gra de 2 t o xicit y lasti n g f or ≥ 4 wee ks (e xcl u di n g al o pecia) or f or 
pal b ocicli b relate d Gra de 3 t o xicities ( des pite ma xi m u m s u p p orti ve care as j u d ge d b y t he 
i n vesti gat or), pal b ocicli b d ose re d ucti o n is rec o m me n de d f or all s u bse q ue nt c ycles. 
Ta ki n g pal b ocicli b acc or di n g t o rec o m me n dati o n (i.e., wit h f o o d) s h o ul d be rei nf orce d 
a n d c o nfir me d. D ose re d ucti o n of pal b ocicli b b y o ne d ose le vel, a n d, if nee de d, b y t w o 
d ose le vels as descri be d i n t he ta ble bel o w ma y be re q uire d de pe n di n g o n t y pe a n d 
se verit y of t he t o xicit y e nc o u ntere d. 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 ycles 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 of pal b ocicli b fr o m 1 0 0 m g t o 1 2 5 m g is n ot all o we d. 
Ca uti o us d ose re-escalati o n fr o m 7 5 m g t o 1 0 0 m g ca n be c o nsi dere d per i n vesti gat or 
discreti o n. Patie nts re q uiri n g m ore t ha n 2 d ose re d ucti o ns will disc o nti n ue pal b ocicli b 
treat me nt. 
T a ble 4: P al b ocicli b D ose Le vels a n d D ose Re d ucti o n Sc he d ule
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 5. 
D ose Le vel
P al b ocicli b o nce d ail y o n d a ys 1- 2 1, 
f oll o we d b y 7 d a ys off
Starti n g d ose
1 2 5 m g/ d
Le vel - 1 (first d ose re d ucti o n)
1 0 0 m g/ d
Le vel - 2 (sec o n d d ose 
re d ucti o n)
7 5 m g/ d
Disc o nti n ue pal b ocicli b treat me nt

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4 8
T a ble 5: A E tri g gere d D ose M o dific ati o ns a n d Tre at me nt M a n a ge me nt f or P al b ocicli b
C T C A E v. 4. 0
A d verse E ve nt
C T C A E v. 4. 0 
Gr a de
I nter ve nti o n wit h P al b ocicli b

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
4 9
Ne utr o pe nic fe ver
( A N C < 1 0 0 0/ m m 3 
ass oci ate d wit h fever 
3 8. 5 )
3, 4
H ol d u ntil cli nic ally st a ble, if A N C rec overs ( A N C 
≥ 1 0 0 0 m m3) a n d a bse nce of fever, t he n
1 st a p pe ar a nce: res u me at ne xt l o wer d ose 
2 n d a p pe ar a nce: res u me at ne xt l o wer d ose 
≥3 r d a p pe ar a nce: Disc o nti n ue
3
H ol d u ntil  1 0 0 0/ m m 3, t he n
1 st a p pe ar a nce: res u me at sa me d ose le vel
2 n d a p pe ar a nce: res u me at ne xt l o wer d ose  
3 r d a p pe ar a nce: res u me at ne xt l o wer d ose
Ne utr o p hil c o u nt 
decre ase d
( A N C < 1 0 0 0/ m m 3)
N ote: T he use of gr o wt h 
f act ors is n ot all o we d
4
H ol d u ntil  1 0 0 0/ m m3, t he n 
1 st a p pe ar a nce: res u me at ne xt l o wer d ose
2 n d a p pe ar a nce: res u me at ne xt l o wer d ose 
≥3 r d a p pe ar a nce: Disc o nti n ue
3
H ol d u ntil  7 5 0 0 0/ m m3, t he n
1 st a p pe ar a nce:  Mai ntai n d ose
2 n d a p pe ar a nce:  res u me at ne xt l o wer d ose 
3 r d a p pe ar a nce: res u me at ne xt l o wer d ose
Pl atelet c o u nt 
decre ase d
( platelet c o u nt < 
5 0, 0 0 0)
4
H ol d u ntil  7 5 0 0 0/ m m3, t he n 
1 st a p pe ar a nce:  res u me at ne xt l o wer d ose
2 n d a p pe ar a nce: res u me at ne xt l o wer d ose
≥3 r d a p pe ar a nce: Disc o nti n ue
A ne mi a 
( H g b < 8. 0 g/ d L)
3, 4
Re d uce t o next l o wer d ose o nly i n c ases of 
pr otr acte d sy m pt o m atic a ne mi a c o nsi dere d t o be 
rel ate d t o p al b ocicli b

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
5 0
Al a ni ne 
a mi n otr a nsfer ase 
( A L T)  i ncre ase d 
wit h t ot al bilir u bi n < 
2 X U L N (i n t he 
a bse nce of c h olest asis 
or he m ol ysis)
3
H ol d u ntil cli nic ally st a ble a n d rec overe d t o ≤ 
Gr a de 1 or t o b aseli ne,  t he n
1 st a p pe ar a nce:   res u me at sa me d ose  
2 n d a p pe ar a nce: res u me at ne xt l o wer d ose 
≥3 r d a p pe ar a nce: Disc o nti n ue
 (If gra de 3 A L T or A S T ele vati o n d oes n ot rec ur 
after at least 4 wee ks f oll o wi n g re-treat me nt wit h 
pal b ocicli b, t he d ose ma y be escalate d b y si n gle 
d ose le vel) 
4
H ol d u ntil cli nic ally st a ble a n d rec over t o ≤ Gr a de 
1 or h as ret ur ne d t o b aseli ne,  t he n
1 st a p pe ar a nce:   res u me at ne xt l o wer d ose   
2 n d a p pe ar a nce: disc o nti n ue 
C o nc urre nt > 3 X 
U L N A L T ( S G P T) a n d 
2 X U L N t ot al 
bilir u bi n 
Disc o nti n ue i m me diatel y
I nterst ati al L u n g 
Dise ase or 
P ne u m o nitits
2
H ol d u ntil cli nicall y sta ble a n d rec o vere d t o 
baseli ne
3, 4
Per ma ne ntl y disc o nti n ue pal b ocicli b
Ot her A Es re q uiri n g 
d ose m o dific ati o n per 
i n vesti g at or
( N ote: I nvesti g at or m ust 
deter mi ne attri b uti o n of 
A E a n d o nly f oll o w d ose 
m o dific ati o ns f or t he 
c a us al a ge nt .)
2
L asti n g Less t h a n 4 weeks :  Mai ntai n D ose
L asti n g 4 weeks (excl u di n g al o peci a) or m ore 
des pite m axi m al s u p p orti n g c are  u n acce pt a ble t o 
p atie nt a n d/ or i nvesti g at or, a n d t h o u g ht t o be 
rel ate d t o p al b ocicli b:  res u me at ne xt l o wer d ose
3, 4
If t he A E is relate d t o pal b ocicli b, wit h h ol d u ntil 
s y m pt o ms res ol ve t o:

≤ Gra de 1 or t o baseli ne 

≤ Gra de 2 (if n ot c o nsi dere d a safet y ris k 
f or t he patie nt)
Res u me at t he ne xt l o wer d ose le vel.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
5 1
7.
A D V E R S E E V E N T S:  LI S T A N D R E P O R TI N G R E Q UI R E M E N T S 
A d verse e ve nt ( A E) m o nit ori n g a n d re p orti n g is a r o uti ne part of e ver y cli nical trial.  
7. 1  
M o nit ori n g of A d verse E ve nts a n d Peri o d of O bser v ati o n
T he st u d y peri o d, d uri n g w hic h A Es a n d S A Es m ust be re p orte d, be gi ns after starti n g t he first 
d ose of st u d y treat me nt a n d e n ds 3 0 da ys f oll o wi n g t he last a d mi nistrati o n of st u d y treat me nt or 
st u d y disc o nti n uati o n/ter mi nati o n, w hic he ver is earlier. After t his peri o d, i n vesti gat ors s h o ul d 
o nl y re p ort S A Es t hat are attri b ute d t o st u d y treat me nt. 
All A Es a n d S A Es w het her v ol u nteere d b y t he s u bject, disc o vere d b y st u d y pers o n nel d uri n g 
q uesti o ni n g, or detecte d t hr o u g h p h ysical e xa mi nati o n, la b orat or y test, or ot her mea ns will be 
assesse d a n d re p orte d, w he n a p pr o priate. A b n or mal la b orat or y val ues will n ot be re p orte d u nless 
dee me d t o be cli nicall y si g nifica nt base d o n t he criteria liste d i n secti o n 7. 7. Eac h re p orte d A E or 
S A E will be descri be d b y its d urati o n (i.e., start a n d e n d dates), re g ulat or y seri o us ness criteria if 
a p plica ble, s us pecte d relati o ns hi p t o Pal b ocicli b or E n d ocri ne T hera p y, e x pecte d ness, a n d 
acti o ns ta ke n. T he f oll o wi n g list of e x pecte d t o xicities ( Secti o n 7. 2) a n d t he c haracteristics of a n 
o bser ve d A E ( Secti o n 7. 3) will deter mi ne w het her t he e ve nt re q uires e x pe dite d re p orti n g i n 
a d diti o n  t o r o uti ne re p orti n g.
7. 2 
E x pecte d T o xicities
7. 2. 1
E x pecte d t o xicities f or E n d ocri ne T hera p y 
T he m ost c o m m o n a d verse e ve nts e x perie nce d wit h use of letr oz ole i ncl u de h ot flas hes, 
art hral gia, a n d gra d ual l oss of b o ne de nsit y. T he m ost c o m m o n a d verse e ve nts 
e x perie nce d wit h use of ta m o xife n i ncl u de h ot flas hes, ni g ht s weats, a n d va gi nal 
disc har ge. Ve n o us t hr o m b oe m b olic disease a n d e n d o metrial ca ncer are rare ris ks of 
ta m o xife n. A list of e x pecte d t o xicities it a vaila ble i n pr ot oc ol secti o n 6. 1 or fr o m t he 
partic ular pac ka ge i nserts ( S m P Cs) of t he l ocall y o btai ne d c o m mercial s u p plies f or a 
m ore detaile d descri pti o n. 
7. 2. 2
E x pecte d t o xicities f or Pal b ocicli b
T he pri mar y a ntici pate d t o xicit y of pal b ocicli b is ne utr o pe nia. I n t he p hase I, d ose-
escalati o n trial of pal b ocicli b al o ne i n a d va nce d ca ncers, ne utr o pe nia was t he o nl y d ose-
li miti n g t o xicit y ( D L T). Gra de 3 ne utr o pe nia d uri n g c ycle 1 was o bser ve d i n 3/ 2 2 
patie nts recei vi n g pal b ocicli b 1 2 5 m g P O dail y, wit h n o gra de 4 ne utr o pe nic e ve nts 
o bser ve d. Base d o n t his res ult, 1 2 5 m g P O dail y beca me t he rec o m me n de d p hase 2 d ose 
( R P 2 D). Ot her he mat ol o gic A Es of gra de 3 or greater d uri n g c ycle 1 were a ne mia a n d 
le u k o pe nia, occ urri n g i n 1 a n d 4 of 4 1 patie nts, res pecti vel y. T he m ost c o m m o n n o n-
he mat ol o gic A Es of gra de 3 or greater d uri n g c ycle 1 were fati g ue, na usea, a n d 
a b d o mi nal pai n (eac h occ urri n g i n 2 of 4 1 patie nts). Of n ote, t here were n o c o m plicate d 
he mat ol o gic A Es d oc u me nte d, a n d all he mat ol o gic A Es res ol ve d d uri n g t he off dr u g 
peri o d of a 3 wee k o n/ 1 wee k off sc he d ule, a n d were n o n-c u m ulati ve.
A list of e x pecte d t o xicities it a vaila ble i n pr ot oc ol secti o n 6. 2.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
5 2
I n a p hase II trial of pal b ocicli b al o ne f or a d va nce d breast ca ncer, t he o nl y t o xicities > 
gra de 3 o bser ve d were tra nsie nt ne utr o pe nia ( 5 0 %) a n d t hr o m b oc yt o pe nia ( 2 1 %).  I n a 
p hase II trial of pal b ocicli b pl us letr oz ole f or first-li ne t hera p y of h or m o ne rece pt or 
p ositi ve breast ca ncer, t he m ost c o m m o n A Es re p orte d were ne utr o pe nia, le u k o pe nia, a n d 
fati g ue. T he me dia n ti me t o first treat me nt dela y f or ne utr o pe nia was 5 8 da ys, a n d t he 
me dia n d urati o n of treat me nt dela y u ntil rec o ver y was 5 da ys (ra n ge 1- 1 6 da ys).  
 
i nter nal data). I n ge neral, he mat ol o gic a b n or malities were a de q uatel y ma na ge d wit h 
sta n dar d s u p p orti ve care, were n ot c o m plicate d, a n d res ol ve d d uri n g t he dr u g h ol d wit h 
n o c u m ulati ve t o xicit y n ote d.
I n t he p hase I, d ose-escalati o n trial of pal b ocicli b al o ne i n a d va nce d ca ncers, Q T i nter val 
c ha n ges were als o e val uate d i n detail. W hile 2 6 of 4 1 patie nts ha d a ma xi m u m i ncrease 
of < 3 0 msec fr o m baseli ne Q Tc, zer o patie nts ha d a n o n-treat me nt val ue e xcee di n g 5 0 0 
msec.
7. 3  
A d verse E ve nt C h ar acteristics

C T C A E ter m ( A E descri pti o n) a n d gr a de:  T he descri pti o ns a n d gra di n g scales f o u n d 
i n t he re vise d N CI C o m m o n 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 will be utilize d f or A E re p orti n g.  All a p pr o priate treat me nt areas s h o ul d ha ve access 
t o a c o p y of t he C T C A E versi o n 4. 0.  A c o p y of t he C T C A E versi o n 4. 0 ca n be 
d o w nl oa de d fr o m t he C T E P we b site 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic a p plicati o ns/ctc. ht m .

F or e x pe dite d re p orti n g p ur p oses o nl y:  
-
A Es f or t he a ge nt(s) t hat are liste d a b o ve s h o ul d be re p orte d o nl y if t he a d verse e ve nt 
varies i n nat ure, i nte nsit y or fre q ue nc y fr o m t he e x pecte d t o xicit y i nf or mati o n w hic h 
is pr o vi de d.
-
Ot her A Es f or t he pr ot oc ol t hat d o n ot re q uire e x pe dite d re p orti n g are o utli ne d i n t he 
ne xt secti o n ( E x pe dite d A d verse E ve nt Re p orti n g) u n der t he s u b- hea di n g of Pr ot oc ol-
S pecific E x pe dite d A d verse E ve nt Re p orti n g E xcl usi o ns.

Attri b uti o n  of t he A E:
-
Defi nite – T he A E is cle arly rel ate d t o t he st u d y treat me nt.
-
Pr o ba ble – T he A E is likely rel ate d t o t he st u d y treat me nt.
-
P ossi ble – T he A E m ay be rel ate d  t o t he st u d y treat me nt.
-
U nli kel y – T he A E is d o u btf ully rel ate d t o t he st u d y treat me nt.
-
U nrelate d – T he A E is cle arly N O T rel ate d t o t he st u d y treat me nt.

E x pecte d ness:
E x pecte d a d verse e ve nts are t h ose a d verse e ve nts t hat are liste d or c haracterize d i n t he 
c urre nt a d verse e ve nt list, t he Pac ka ge I nsert, t he I n vesti gat or Br oc h ure or is i ncl u de d i n 
t he i nf or me d c o nse nt d oc u me nt as a p ote ntial ris k.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
5 3
U ne x pecte d a d verse e ve nts are t h ose n ot liste d i n t he Pac ka ge I nsert ( P.I.) or c urre nt 
I n vesti gat or Br oc h ure (I. B.) or n ot i de ntifie d. T his i ncl u des a d verse e ve nts f or w hic h t he 
s pecificit y or se verit y is n ot c o nsiste nt wit h t he descri pti o n i n t he P.I. or I. B. F or 
e xa m ple, u n der t his defi niti o n, he patic necr osis w o ul d be u ne x pecte d if t he P.I. or I. B. 
o nl y referre d t o ele vate d he patic e nz y mes or he patitis.
7. 4 
E x pe dite d A d verse E ve nt Re p orti n g 
7. 4. 1
I n vesti gat ors m ust  re p ort t o t he O verall PI a n y seri o us a d verse e ve nt ( S A E) t hat occ urs 
after t he i nitial d ose of st u d y treat me nt, d uri n g treat me nt, or wit hi n 3 0 da ys of t he last 
d ose of treat me nt o n t he l ocal i nstit uti o nal S A E f or m. 
7. 4. 2
F or m ulti-i nstit uti o n st u dies w here a D F/ H C C i n vesti gat or is ser vi n g as t he O verall 
Pri nci pal I n vesti gat or, eac h partici pati n g i nstit uti o n  m ust a bi de b y t he re p orti n g 
re q uire me nts set b y t he D F/ H C C. T his a p plies t o a n y me dical e ve nt e q ui vale nt t o a n 
u ne x pecte d gra de 2 or 3 wit h a p ossi ble, pr o ba ble or defi nite attri b uti o n, u ne x pecte d 
gra de 4 t o xicities, a n d gra de 5 ( deat h) re gar dless of st u d y p hase or attri b uti o n.
7. 4. 3
D F/ H C C E x pe dite d Re p orti n g G ui deli nes
I n vesti gati ve sites wit hi n D F/ H C C will re p ort A Es directl y t o t he D F CI Office f or 
H u ma n Researc h St u dies ( O H R S) per t he D F CI I R B re p orti n g p olic y. Ot her i n vesti gati ve 
sites will re p ort A Es t o t heir res pecti ve I R B acc or di n g t o t he l ocal I R B’s p olicies a n d 
pr oce d ures i n re p orti n g a d verse e ve nts i n a d diti o n t o t he D F/ H C C re p orti n g re q uire me nts 
bel o w.
A d diti o nall y, t he o verall PI s h o ul d be n otifie d of S A Es t hat meet t he D F/ H C C defi niti o n 
of a re p orta ble A E wit hi n t he ti mefra mes detaile d i n t he ta ble bel o w usi n g t he 
i nstit uti o nal S A E f or m.
T he C o or di nati n g Ce nter will s u b mit S A E re p orts fr o m o utsi de i nstit uti o ns t o t he D F CI 
O H R S acc or di n g t o D F CI I R B p olicies a n d pr oce d ures i n re p orti n g a d verse e ve nts. 
T a ble 6: D F/ H C C Re p ort a ble A d verse E ve nts
D F/ H C C R e p ort a bl e A E s
Attri b uti o n
Gr. 2 & 3 A E
E x p e ct e d
Gr. 2 & 3 A E 
U n e x p e ct e d
Gr. 4 A E E x p e ct e d
Gr. 4 A E
U n e x p e ct e d
Gr. 5 A E 
E x p e ct e d or 
U n e x p e ct e d
U nr el at e d
U nli k el y
N ot r e q uir e d
N ot r e q uir e d
5 c al e n d ar d a y s #
5 c al e n d ar d a y s
2 4 h o ur s*
P o s si bl e
Pr o b a bl e
D efi nit e
N ot r e q uir e d
5 c al e n d ar d a y s
5 c al e n d ar d a y s #
5 c al e n d ar d a y s
2 4 h o ur s*
# If li st e d i n pr ot o c ol a s e x p e ct e d a n d n ot r e q uiri n g e x p e dit e d r e p orti n g, e v e nt d o e s n ot n e e d t o b e r e p ort e d.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
5 4
* F or p arti ci p a nt s e nr oll e d a n d a cti v el y p arti ci p ati n g i n t h e st u d y or  f or A E s o c c urri n g wit hi n 3 0 d a y s of t h e l a st 
i nt er v e nti o n, t h e A E s h o ul d b e r e p ort e d wit hi n 1 b u si n e s s d a y of l e ar ni n g of t h e e v e nt.
7. 5 
E x pe dite d Re p orti n g t o
Wit hi n 2 4 b usi ness h o urs of first a ware ness of t he e ve nt (i m me diatel y if t he e ve nt is fatal or life 
t hreate ni n g), t he st u d y tea m fr o m t he site w here t he S A E t o o k place will re p ort t o  
b y 
facsi mile or e mail a n y Seri o us A d verse E ve nt (“ S A E,” as defi ne d bel o w) f or w hic h re p orti n g is 
re q uire d u n der t his pr o visi o n (as descri be d bel o w). S uc h S A Es are t o be re p orte d f or st u d y 
s u bjects or i n di vi d uals ot her wise e x p ose d t o  
 Pr o d uct as descri be d bel o w. S A Es s h o ul d 
be re p orte d as s o o n as t he y are deter mi ne d t o meet t he defi niti o n, e ve n if c o m plete i nf or mati o n is 
n ot yet a vaila ble.
I n vesti gat ors will re p ort S A Es usi n g F or m F D A 3 5 0 0 A ( Me d Watc h). T he Re p ort a ble
Eve nt F ax C over S heet  pr o vi de d b y  
m ust als o be i ncl u de d wit h eac h S A E s u b mitte d. T he 
Re p ort a ble Eve nt F ax C over S heet ca n be f o u n d i n A p pe n di x F. 
7. 5. 1
S A E Defi niti o n f or Re p orti n g t o 
A n S A E is a n y a d verse e ve nt, wit h o ut re gar d t o ca usalit y, t hat is life-t hreate ni n g (i.e., 
ca uses a n i m me diate ris k of deat h) or t hat res ults i n a n y of t he f oll o wi n g o utc o mes: 
deat h; i n- patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n; persiste nt or 
si g nifica nt disa bilit y or i nca pacit y (i.e. s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct 
n or mal life f u ncti o ns); or a c o n ge nital a n o mal y or birt h defect. A n y ot her me dical e ve nt 
t hat, i n t he me dical j u d g me nt of t he Pri nci pal I n vesti gat or, ma y je o par dize t he s u bject 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 o utc o mes liste d a b o ve 
is als o c o nsi dere d a n S A E. A pla n ne d me dical or s ur gical pr oce d ure is n ot, i n itself, a n 
S A E.
7. 5. 2
E x p os ure D uri n g Pre g na nc y, E x p os ure D uri n g Lactati o n, Occ u pati o nal E x p os ure
E ve n t h o u g h t here ma y n ot be a n ass ociate d S A E, e x p os ure t o Pal b ocicli b d uri n g 
pre g na nc y, e x p os ure t o Pal b ocicli b d uri n g lactati o n, a n d occ u pati o nal e x p os ure t o t he 
Pal b ocicli b are re p orta ble t
7. 5. 3
H y’s La w Cases 
Cases of p ote ntial dr u g-i n d uce d li ver i nj ur y as assesse d b y la b orat or y test val ues (“ H y’s 
La w Cases”) are als o re p orta ble t o  
 If a partici pa nt de vel o ps a b n or mal val ues i n 
as partate tra nsa mi nase ( A S T) or ala ni ne tra nsa mi nase or b ot h, c o nc urre nt wit h a b n or mal 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
5 5
ele vati o ns i n t otal bilir u bi n a n d n o ot her k n o w n ca use of li ver i nj ur y, t hat e ve nt w o ul d be 
classifie d as a H y’s La w Case.
7. 5. 4
S A E Re p orti n g Peri o d
T he S A Es t hat are s u bject t o t his re p orti n g pr o visi o n are t h ose t hat occ ur fr o m after t he 
first d ose of t he Pal b ocicli b t hr o u g h 3 0 cale n dar da ys after t he last a d mi nistrati o n of t he 
Pal b ocicli b, or l o n ger if s o s pecifie d i n t he Pr ot oc ol. I n a d diti o n, if a Pri nci pal 
I n vesti gat or bec o mes a ware of a n S A E occ urri n g a n y ti me after t he a d mi nistrati o n of t he 
last d ose of t he Pal b ocicli b, t he Pri nci pal I n vesti gat or s h o ul d re p ort t hat S A E t o  
 
t he Pri nci pal I n vesti gat or s us pects a ca usal relati o ns hi p bet wee n t he Pal b ocicli b a n d t he 
S A E.
7. 6 
E x pe dite d Re p orti n g t o H os pit al Ris k M a n a ge me nt
Partici pati n g i n vesti gat ors will re p ort t o t heir l ocal Ris k Ma na ge me nt office a n y partici pa nt 
safet y re p orts or se nti nel e ve nts t hat re q uire re p orti n g acc or di n g t o i nstit uti o nal p olic y. 
7. 7  
R o uti ne A d verse E ve nt Re p orti n g
All gra de 2 or hi g her a d verse e ve nts m ust  be re p orte d i n r o uti ne st u d y data s u b missi o ns t o t he 
O verall PI o n t he t o xicit y case re p ort f or ms. A b n or mal la b orat or y val ues or dia g n ostic tests will 
n ot be re p orte d o n t he case re p ort f or ms u nless t he y i n d uce cli nical si g ns or s y m pt o ms, re q uire 
treat me nt or f urt her dia g n ostic tests, or res ult i n a d ose h ol d or m o dificati o n. A Es re p orte d 
t hr o u g h e x pe dite d pr ocesses (e. g., re p orte d t o t he I R B, F D A, etc.) m ust als o be re p orte d i n 
r o uti ne st u d y d at a s u b missi o ns.
8.
P H A R M A C E U TI C A L I N F O R M A TI O N
A list of t he a d verse e ve nts a n d p ote ntial ris ks ass ociate d wit h t he i n vesti gati o nal or ot her a ge nts 
a d mi nistere d i n t his st u d y ca n be f o u n d i n Secti o ns 6 a n d 7. 2.
Refer t o t he I n vesti gat or’s Br oc h ure f or detaile d Pal b ocicli b i nf or mati o n a n d F D A a p pr o ve d 
pac ka ge i nserts f or m ore i nf or mati o n a b o ut c o m mercial a ge nts.
8. 1 
T a m o xife n
8. 1. 1
Descri pti o n
Ta m o xife n ta blets f or oral a d mi nistrati o n c o ntai n 3 0. 4 m g of ta m o xife n citrate w hic h is 
e q ui vale nt t o 2 0 m g of ta m o xife n, a n o nster oi dal a ntiestr o ge n. Ta m o xife n is t he tra ns-
is o mer of ari p he n ylet h yle ne deri vati ve. T he c he mical na me is ( Z) 2-[ 4-( 1, 2- di p he n yl- 1-
b ute n yl) p he n o x y] N, N- di met h ylet ha na mi ne 2- h y dr o x y- 1, 2, 3- pr o pa netricar b o x ylate 
( 1: 1). Ta m o xife n citrate has a m olec ular wei g ht of 5 6 3. 6 2, t he p Ka' is 8. 8 5, t he 
e q uili bri u m s ol u bilit y i n water at 3 7° C is 0. 5 m g/ m L a n d i n 0. 0 2 N H Cl at 3 7° C, it is 0. 2 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
5 6
m g/ m L.
8. 1. 2
F or m
Ta m o xife n is a vaila ble i n 2 0 m g ta blets.
8. 1. 3
St ora ge a n d Sta bilit y
St ore at c o ntr olle d r o o m te m perat ure, 2 0- 2 5° C ( 6 8- 7 7° F) [see U S P C o ntr olle d R o o m
Te m perat ure].
8. 1. 4
C o m pati bilit y
N o c o m pati bilit y iss ues e xist f or c o-a d mi nistrati o n of pal b ocicli b a n d ta m o xife n.
8. 1. 5
A vaila bilit y
Ta m o xife n is c o m merciall y a vaila ble.
8. 1. 6
A d mi nistrati o n
T he rec o m me n de d d ose of ta m o xife n is 2 0 m g o nce dail y.
8. 2 
Letr oz ole 
8. 2. 1
Descri pti o n
A letr oz ole ta blet f or oral a d mi nistrati o n c o ntai ns 2. 5 m g of letr oz ole, a n o nster oi dal 
ar o matase i n hi bit or (i n hi bit or of estr o ge n s y nt hesis). It is c he micall y descri be d as 4, 4'-
( 1 H- 1, 2, 4- Triaz ol- 1 yl met h yle ne) di be nz o nitrile, a n d its str uct ural f or m ula is Letr oz ole is 
a w hite t o yell o wis h cr ystalli ne p o w der, practicall y o d orless, freel y s ol u ble i n 
dic hl or o met ha ne, sli g htl y s ol u ble i n et ha n ol, a n d practicall y i ns ol u ble i n water. It has a 
m olec ular wei g ht of 2 8 5. 3 1, e m pirical f or m ula C 1 7 H 1 1 N 5, a n d a melti n g ra n ge of 
1 8 4° C- 1 8 5° C.
8. 2. 2
F or m
Letr oz ole is a vaila ble i n 2. 5 m g ta blets.
8. 2. 3
St ora ge a n d Sta bilit y
St ore at 2 5° C ( 7 7° F); e xc ursi o ns per mitte d t o 1 5- 3 0° C ( 5 9- 8 6° F) [see U S P C o ntr olle d 
R o o m Te m perat ure].
8. 2. 4
C o m pati bilit y

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
5 7
N o c o m pati bilit y iss ues e xist f or c o-a d mi nistrati o n of pal b ocicli b a n d letr oz ole.
8. 2. 5
A vaila bilit y
Letr oz ole is c o m merciall y a vaila ble.
8. 2. 6
A d mi nistrati o n
T he rec o m me n de d d ose of letr oz ole is o ne 2. 5 m g ta blet a d mi nistere d o nce a da y, wit h o ut 
re gar d t o meals.
8. 3 
P al b ocicli b
8. 3. 1
Descri pti o n
C he mical na me: 6-acet yl- 8-c ycl o pe nt yl- 5- met h yl- 2-( 5-( pi perazi n- 1- yl) p yri di n- 2-
yla mi n o) p yri d o[ 2, 3- d] p yri mi di n- 7( 8 H)- o ne.
C he mical f or m ula: C 2 4 H 2 9 N 7 O 2
M olec ular wei g ht: 4 4 7. 5 4.
Half life: ~ 2 9 h o urs.
Plas ma pr otei n bi n di n g of pal b ocicli b: ~ 8 5 %
Plas ma pr otei n bi n di n g of P F- 0 5 0 8 9 3 2 6 (t he lacta m of pal b ocicli b, o ne of t he mai n 
meta b olites prese nt i n plas ma): 9 5 %
Pal b ocicli b (I C 5 0 = 1 1 n M; Ki = 2 n M) 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 a n d S U L T 2 A 1 e nz y mes. I nf or mati o n o n p ote ntial 
dr u g i nteracti o ns ca n be f o u n d i n secti o n 5. 4.
8. 3. 2
F or m
Pal b ocicli b will be s u p plie d b y  
 as s m o ot h-c oate d ta blets 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.  
will s u p pl y t he oral dr u g 
f or m ulati o n t o sites i n m o nt hl y cart o ns of blister pac ks c o ntai ni n g 7 5 m g, 1 0 0 m g, or 1 2 5 
m g ta blets. Eac h cart o n will c o ntai n t hree blister pac ks eac h c o ntai ni n g a o ne- wee k 
s u p pl y of ta blets. T he ta blets ca n be differe ntiate d b y t heir size, c ol or, a n d cart o n c ol or.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
5 8
8. 3. 3
St ora ge a n d Sta bilit y
St ora ge c o n diti o ns state d i n t he Si n gle Refere nce Safet y D oc u me nt (i.e. I n vesti gat or’s 
Br oc h ure (I B), U nite d States Pac ka ge I nsert ( U S PI), S u m mar y of Pr o d uct C haracteristics 
( S P C), 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.
Pal b ocicli b ta blets s h o ul d be st ore d at c o ntr olle d r o o m te m perat ure ( 1 5- 3 0 °C, 5 9- 8 6 °F) i n 
t heir ori gi nal c o ntai ner.
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 (i.e. ma n uall y or b y 
usi n g alar m s yste ms 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 r o o m st ora ge. A n y te m perat ure e xc ursi o ns m ust be re p orte d t o  
 
T he i n vesti gati o nal pr o d ucts m ust be st ore d as i n dicate d. De viati 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 
O nce a de viati o n is i de ntifie d, t he i n vesti gati o nal pr o d ucts ( pal b ocicli b) m ust be 
q uara nti ne d a n d n ot use d u ntil  
 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.
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 ore d se paratel y 
fr o m me dicati o n t hat nee ds t o be dis pe nse d.
8. 3. 4
C o m pati bilit y
N o c o m pati bilit y iss ues e xist f or c o-a d mi nistrati o n of pal b ocicli b.
8. 3. 5
Ha n dli n g
Q ualifie d pers o n nel, 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 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 t he c he m ot hera pe utic a ge nt i n a self-c o ntai ne d a n d pr otecti ve e n vir o n me nt. 
8. 3. 6
A vaila bilit y
Pal b ocicli b will be s u p plie d free- of-c har ge fr o m  
 c o m mercial s u p pl y of dr u g.
8. 3. 7
A d mi nistrati o n
Pal b ocicli b will be pr o vi de d i n n o n- patie nt-s pecific cart o ns of blister pac ks 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.
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 blister pac ks s h o ul d be ret ur ne d t o t he site at t he ne xt st u d y 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
5 9
visit. U n use d ret ur ne d me dicati o n M U S T N O T be re- dis pe nse d t o patie nts.
Pal b ocicli b is a n a ge nt t hat m ust be ha n dle d a n d a d mi nistere d wit h care. 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 blister pac ks pr o 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, ta blets m ust n ot be cr us he d a n d/ or mi xe d 
i nt o a n y ve hicle f or oral i n gesti o n; ta blets m ust be s wall o we d i ntact.
O nl y a si n gle ta blet stre n gt h will be dis pe nse d t o t he patie nt at eac h dis pe nsi n g visit. I n 
t he e ve nt of d ose m o 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 ta blets will be dis pe nse d.
8. 3. 8
Or deri n g
Q ualifie d pers o n nel at partici pati n g sites will or der t he dr u g directl y fr o m  
 
8. 3. 9
Acc o u nta bilit y
T o e ns ure a de q uate rec or ds, pal b ocicli b ta blets will be acc o u nte d f or as i nstr ucte d b y 
 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 dr u 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.
T he i n vesti gat or, or a res p o nsi ble part y desi g nate d b y t he i n vesti gat or, s h o ul d mai ntai n a 
caref ul rec or d of t he i n ve nt or y a n d dis p ositi o n of t he a ge nt usi n g t he N CI Dr u g 
Acc o u nta bilit y Rec or d F or m ( D A R F) or a n ot her c o m para ble dr u g acc o u nta bilit y f or m.  
( See t he N CI I n vesti gat or’s Ha n d b o o k f or Pr oce d ures f or Dr u g Acc o u nta bilit y a n d 
St ora ge.)
9.
BI O M A R K E R, C O R R E L A TI V E, A N D S P E CI A L S T U DI E S
Bi o m ar ker A n al ysis
T u m or sa m ples o btai ne d fr o m dia g n ostic F F P E si des, c ore bi o psies, s ur gical s peci me n sa m pli n g, 
a n d li q ui d bi o psies will be use d t o assess t he p ote ntial pr o g n ostic or pre dicti ve val ue of ca n di date 
mar kers or bi o mar ker pa nels, i m pr o ve dia g n ostic tests, i m pr o ve u n dersta n di n g of breast ca ncer 
bi ol o g y, or disc o ver ne w bi o mar ker pr ofiles relate d t o treat me nt be nefit a n d/ or safet y or disease 
c haracteristics. Refer t o secti o n 5. 8 a n d 5. 9 f or tiss ue a n d bl o o d c ollecti o n, ha n dli n g a n d s hi p me nt 
i nstr ucti o ns. 
C orrelati ve sa m ples will be a nal yze d b y Da na- Far ber Ca ncer I nstit ute wit h c olla b orati o n fr o m t he 
partici pati n g i nstit uti o ns a n d t he Br oa d I nstit ute at MI T. 
9. 1 
Bi o m ar ker li n ke d t o st u d y pri m ar y o bjecti ve

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
6 0
9. 1. 1
Ce ntral Pat h ol o g y Assess me nts 
Ce ntral pat h ol o g y assess me nt will be perf or me d at t he Bri g ha m a n d W o me n’s Pat h ol o g y 
c ore. 
Ce ntral I H C stai ni n g f or Ki 6 7, estr o ge n ( E R) a n d pr o gester o ne rece pt or ( P g R) will be 
perf or me d f oll o wi n g c o nse ns us rec o m me n dati o ns [ 5 9, 6 0]. 
Ki 6 7 stai ni n g 
will be 
perf or me d i n t hree ti me p oi nts: dia g n ostic tiss ue, researc h bi o ps y tiss ue a n d resi d ual t u m or. 
H or m o ne rece pt ors will be assesse d at baseli ne a n d i n resi d ual t u m ors. 
E-ca d heri n/ p 1 2 0 stai ni n g will be perf or me d o n all sa m ples as pre vi o usl y re p orte d [ 6 1].  E-
ca d heri n is sc ore d as p ositi ve or ne gati ve me m bra ne stai ni n g a n d P 1 2 0 sc ore d as p ositi ve 
me m bra ne (i.e. o bser ve d i n I D C) or c yt o plas mic (I L C). E-ca d heri n/ p 1 2 0 stai ni n g will be 
perf or me d usi n g baseli ne dia g n ostic tiss ue or researc h bi o ps y s peci me n. 
9. 2 
Bi o m ar kers li n ke d t o c orrel ati ve st u dies
9. 2. 1
S oli d bi o psies 
D N A e xtracte d fr o m c ore bi o psies will be pr ofile d b y a h y bri d ca pt ure- base d tar gete d 
massi vel y parallel se q ue nci n g test a ble t o scree n f or c o di n g se q ue nci n g m utati o ns, i n dels, 
c o p y n u m ber alterati o ns, a n d selecte d rearra n ge me nts fr o m > 3 0 0 ge nes of i nterest. 
T he esse ntial feat ures of t he scree ni n g assa y are s u m marize d as f oll o ws: 

Be a ble t o test f or all p oi nt m utati o ns, i n dels, c o p y n u m ber c ha n ges, a n d selecte d 
rearra n ge me nts i n all t he ge nes of i nterest

Be a ble t o be r u n o n 1 0- 2 0 F F P E sli des

Ha ve de m o nstrate d hi g h se nsiti vit y a n d s pecificit y, es peciall y i n sa m ples wit h 
relati vel y l o w t u m or p urit y (e. g., ha vi n g hi g h mi ni m u m  de pt h of c o vera ge acr oss all 
re gi o ns of i nterest)
C o m pre he nsi ve se q ue nci n g a p pr oac hes s uc h as w h ole e x o me se q ue nci n g or w h ole 
ge n o me se q ue nci n g ma y be perf or me d i n lie u of a tar gete d a p pr oac h. A fi nal decisi o n o n 
t he best se q ue nci n g m o dalit y will be ma de bef ore t he pla n ne d a nal ysis. 
Of i m p orta nce, s o matic m utati o ns i de ntifie d w hile pr ofili n g t u m or sa m ples c o ul d als o be 
prese nt i n t he patie nt’s D N A a n d c o ul d be passe d t o s u bse q ue nt ge nerati o ns. T o t he 
prese nt date, t here is n o c o nse ns us o n t he t y pe of fi n di n gs o n a t u m or-se q ue nci n g assa y 
t hat w o ul d i m pl y t he prese nce-a bse nce of m utati o n. Se q ue nci n g of ger mli ne D N A ma y 
be nee de d t o all o w t he a p pr o priate i nter pretati o n of s o matic e ve nts. 
T u m or a n d/ or ger mli ne fi n di n gs will be c o m m u nicate d t o t he treati n g cli nicia n wit h 
a d vice t o c o nsi der ger mli ne testi n g if cli nical a n d/ or fa mil y hist or y is c o nsiste nt wit h t he 
prese nce of s uc h a b n or malit y. 
R N A e xtracte d fr o m c ore bi o psies will be pr ofile d usi n g R N A- Se q tec h n ol o g y

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
6 1
I n a d diti o n, we will use deter mi ne t he S E T 2, 3 I n de x usi n g t he M D A n ders o n platf or m 
o n researc h bi o ps y sa m ples a n d t he F F P E sli des. T his will be use d t o e val uate sa m ples 
f or fact ors t hat ma y pre dict patie nts w h o are better ca n di dates f or ne oa dj u va nt e n d ocri ne-
base d treat me nt. T his a nal ysis will be perf or me d at M D A n ders o n.
9. 2. 2
Pri oritizati o n of m olec ular assa ys
D N A- a n d R N A- base d assa ys will be perf or me d after a de q uate t u m or tiss ue is sec ure d 
f or t he c o- pri mar y e n d p oi nts of t he st u d y. R N A- base d assa ys will be perf or me d usi n g 
fr oze n t u m or bi o psies. 
9. 2. 3
Li q ui d bi o psies
Cell-free Circ ulati n g D N A ma y be a s o urce of t u m or D N A w here ge netic a nal ysis ca n be 
d o ne.  T he c urre nt pr ot oc ol will i n vesti gate w het her m olec ular alterati o ns f o u n d i n t u m or 
bi o psies are detecta ble i n peri p heral circ ulati o n. T he fiel d of “li q ui d bi o psies” is e v ol vi n g 
q uic kl y a n d we e x pect t o use t he m ost u p date d se q ue nci n g a p pr oac h t o st u d y t he 
c ollecte d sa m ples. We e x pect t o use a m ulti- ge ne tar gete d se q ue nci n g a p pr oac h or w h ole 
e x o me se q ue nci n g f or t he a nal ysis of cell free t u m or D N A. Pr ofili n g will be perf or me d at 
t he Br oa d I nstit ute of MI T wit h a nal ysis at Da na- Far ber Ca ncer I nstit ute. 
1 0. S T U D Y C A L E N D A R
All s u bjects m ust si g n a n i nf or me d c o nse nt d oc u me nt pri or t o i nitiati o n of a n y st u d y relate d 
pr oce d ures.
Baseli ne e val uati o ns (la b orat or y tests a n d ot her n o n-la b orat or y tests) m ust be perf or me d wit hi n 2 8 
da ys of st u d y e ntr y wit h t he e xce pti o n of t he f oll o wi n g tests: D oc u me ntati o n of 
M RI, 
ma m m o gra m, or ultras o u n d (i ncl u di n g D CI S a n d i n vasi ve ca ncer) of t he disease d breast perf or me d 
wit hi n 4 2 da ys pri or t o re gistrati o n. Ma m m o gra m f or t he u naffecte d c o ntralateral breast is re q uire d 
wit hi n 1 2 m o nt hs pri or t o re gistrati o n. Ser u m or uri ne pre g na nc y test m ust be ne gati ve i n w o me n 
j u d ge d pre me n o pa usal wit hi n 7 da ys of ra n d o mizati o n, or i n w o me n wit h a me n orr hea of less t ha n 
1 2 m o nt hs at ti me of ra n d o mizati o n. 
All assess me nts m ust be perf or me d pri or t o a d mi nistrati o n of a n y st u d y me dicati o n. Da y 1 5 
st u d y assess me nts s h o ul d be perf or me d wit hi n + 3 da ys of t he pr ot oc ol-s pecifie d date, u nless 
ot her wise n ote d. T here is a  +/- 3 da y wi n d o w f or da y 1 of C ycles 1- 6 o n t he treat me nt p hase. 
Scree ni n g P hase (f or wi n d o w p hase a n d treat me nt p hase): All scree ni n g e val uati o ns m ust be 
c o m plete d a n d re vie we d t o c o nfir m t hat patie nts meet all i ncl usi o n criteria a n d d o n ot meet a n y of 
t he e xcl usi o n criteria bef ore ra n d o mizati o n. If scree ni n g assess me nts occ ur wit hi n 7 d a ys bef ore 
Wi n d o w or Tre at me nt D a y 1, t he n t he y m a y ser ve as t he 
Wi n d o w or Tre at me nt D a y 1 
assess me nts als o a n d d o n ot nee d t o be re pe ate d.  Partici pa nts ra n d o mize d t o recei ve Pal b ocicli b 
m ust meet la b eli gi bilit y criteria f or Treat me nt Da y 1. S u bse q ue nt c ycles wit h Pal b ocicli b m ust 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
6 2
meet retreat me nt criteria o utli ne d i n Secti o n 6. 3. 2.
Wi n d o w P hase: It is str o n gl y rec o m me n de d t o sc he d ule t he 2- wee k i ma ge- g ui de researc h bi o ps y 
pri or t o treat me nt i nitiati o n. I ma ge- g ui de d researc h bi o ps y m ust be perf or me d wit hi n +/- 3 da ys 
after t he 2- wee k wi n d o w peri o d.  A 
mi ni m u m of 1 4 da ys of letr oz ole or ta m o xife n is 
rec o m me n de d. Treat me nt s h o ul d n ot be i nterr u pte d u ntil t he researc h bi o ps y is perf or me d (i.e. 
patie nts s h o ul d be o n treat me nt at t he ti me of researc h bi o ps y). 
Treat me nt p hase: s h o ul d start wit hi n 7 da ys + 2 da ys after t he wi n d o w p hase researc h c ore bi o ps y. 
T here is a +/- 3- da y wi n d o w f or da y 1 of C ycles 1- 6 o n t he treat me nt p hase. Patie nts assi g ne d t o 
Ar m C (recei vi n g pal b ocicli b) will ha ve safet y la b orat or y testi n g perf or me d at C 1 D 1 5 a n d C 2 D 1 5.  
T his la b orat or y testi n g ca n be perf or me d at a l ocal la b orat or y or at t he researc h ce nter, b ut res ults 
nee d t o be a vaila ble a n d re vie we d b y t he researc h tea m bef ore treat me nt ca n c o nti n ue. 
F oll o w- u p: P ost-s ur ger y f oll o w- u p i nf or mati o n will be c ollecte d at assess me nts a n n uall y u ntil 1 0 
years after s ur ger y. N o tests or pr oce d ures are re q uire d d uri n g f oll o w- u p b ut cli nical data will be 
c ollecte d o n C R Fs. T hese data s h o ul d be base d o n e xa ms, tests, or pr oce d ures d o ne at t he 
re gisteri n g i nstit uti o n or at a l ocal facilit y. Data t o be c ollecte d fr o m all patie nts i ncl u de a dj u va nt 
c yt ot o xic ( +/- tar gete d) treat me nt, a dj u va nt e n d ocri ne ( +/- tar gete d) treat me nt, date a n d site of all 
rec urre nces, date a n d ca use of deat hs as well as date a n d dia g n osis of sec o n dar y mali g na ncies.
T a ble 8. Sc he d ule of assess me nt f or p atie nts e nr olle d i n t he wi n d o w p h ase of t he st u d y
Tre at me nt P h ase
( C ycle 2 8 d a ys)
P ar a meter
Scree ni n g
Wi n d o w P h ase
( 1 4 d a ys)
C ycle 1 a n d 2 
C ycles 
3 t o 6
Pre-
S ur ger y  a
P ost 
S ur ger y b
Da y
- 2 8 t o 0
Wi n d o w 
D 1
Wi n d o w 
D 1 5
D 1
D 1 5
D 1
 wit hi n 4 2 
da ys of 
last c ycle 
Wit hi n 
4 2 da ys 
after 
s ur ger y
Ti me Wi n d o w
+/- 3
+/- 3 
da ys
+/- 3
+/- 3 
da ys
 - 2 da ys
I nf or me d c o nse nt
X
C o m plete me dical 
hist or y
X
P h ysical e xa m/
Vital si g ns
X
X
X
X
X
Perf or ma nce stat us 
( E C O G)
X
X
A d verse E ve nt 
e val uati o n
X
X
X
X
X
X
C o nc o mita nt me ds
X
He mat ol o g y c
X 
X h
X h, i
X h
X h
C he mistr y  d
X 
X h
X h
X h
Pre g na nc y test e
X
Breast I ma gi n g f
X
X
A xillar y e val uati o n g
X
Tiss ue c ollecti o n
( Secti o n 5. 8)
X
X
X j
X
Researc h bl o o d 
X
X

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6 3
c ollecti o n ( Secti o n 5. 9)
Ca n di date f or breast 
c o nser vati o n 
e val uati o n
X
X
a)
Pre-s ur gical i ma gi n g m ust occ ur wit hi n 4 2 da ys of c o m pleti o n of treat me nt ( wit h a - 2 da y wi n d o w). 
b)
F oll o w- u p i nf or mati o n will be c ollecte d yearl y u ntil 1 0 years after s ur ger y. N o tests or pr oce d ures are 
re q uire d d uri n g f oll o w- u p b ut cli nical data will be c ollecte d o n C R Fs. T hese data s h o ul d be base d o n e xa ms, 
tests, or pr oce d ures d o ne at t he re gisteri n g i nstit uti o n or at a l ocal facilit y. Data t o be c ollecte d fr o m all 
patie nts i ncl u de a dj u va nt c yt ot o xic ( +/- tar gete d) treat me nt, a dj u va nt e n d ocri ne ( +/- tar gete d) treat me nt, 
date a n d site of all rec urre nces, date a n d ca use of deat hs as well as date a n d dia g n osis of sec o n dar y 
mali g na ncies.
c)
He mat ol o g y i ncl u des he m o gl o bi n, w hite bl o o d cell c o u nt ( W B C), a bs ol ute ne utr o p hils, a n d platelet c o u nt. 
d)
C he mistr y i ncl u des A S T ( S G O T)/ A L T ( S G P T), al kali ne p h os p hatase, s o di u m, p otassi u m, t otal calci u m, t otal 
bilir u bi n, ser u m creati ni ne, t otal pr otei n a n d al b u mi n. 
e)
Ser u m or uri ne pre g na nc y test f or w o me n of c hil d beari n g p ote ntial ( ≤ 7 da ys pri or ra n d o mizati o n). 
f)
Baseli ne i ma gi n g wit hi n 4 2 da ys pri or t o e nr oll me nt; M RI is str o n gl y rec o m me n de d, alt h o u g h ot her i ma gi n g 
m o dalities ( ma m m o gra m, ultras o u n d) are per mitte d if practical or fi na ncial c o nsi derati o ns precl u de M RI, as 
l o n g as t he tar get lesi o n ca n be a de q uatel y meas ure d. T his sa me i ma gi n g m o dalit y s h o ul d be perf or me d a gai n 
pri or t o s ur ger y. Ma m m o gra m of t he u naffecte d c o ntralateral breast is re q uire d wit hi n 1 2 m o nt hs pri or t o 
re gistrati o n.
g)
F or w o me n wit h cli nicall y s us pici o us l y m p h n o des, pre o perati ve a xillar y ultras o u n d wit h fi ne nee dle 
as pirati o n or c ore bi o ps y of s us pici o us s h o ul d be perf or me d. F or s u bjects wit h a cli nicall y ne gati ve a xilla, a 
se nti nel l y m p h n o de bi o ps y s h o ul d be perf or me d eit her bef ore or after pre o perati ve t hera p y at t he discreti o n 
of t he s u bject’s p h ysicia ns.  A xillar y e val uati o n m ust be d o ne wit hi n 4 2 da ys pri or t o e nr oll me nt. 
h)
He mat ol o g y a n d c he mistr y are n ot re q uire d f or Ar m D patie nts at t he s pecifie d ti me p oi nts.
i)
Ar m C patie nts o nl y. Testi n g ca n be perf or me d at a l ocal la b orat or y or at t he researc h ce nter.
j)
It is str o n gl y rec o m me n de d t o sc he d ule t he i ma ge- g ui de researc h bi o ps y at wi n d o w p hase D 1 5 pri or t o 
wi n d o w p hase treat me nt i nitiati o n. See Secti o n 5. 8 f or details.
T a ble 9. Sc he d ule of assess me nt f or p atie nts e nr olle d directl y i nt o t he tre at me nt p h ase of 
t he st u d y
Tre at me nt P h ase
P ar a meter
Scree ni n g
C ycle 1 a n d 2 
C ycles 
3 t o 6
Pre-
S ur ger y  a
P ost 
s ur ger y b
Da y
- 2 8 t o 0
D 1
D 1 5
D 1
Wit hi n 4 2 
da ys of last 
c ycle 
Wit hi n 4 2 
da ys after 
s ur ger y
Ti me Wi n d o w
+/- 3 
da ys
+/- 3 
da ys
+/- 3 
da ys
- 2 da ys
I nf or me d c o nse nt
X
C o m plete me dical hist or y
X
I ncl usi o n/ E xcl usi o n
X
P h ysical e xa m/ Vital si g ns
X
X
X
X
Perf or ma nce stat us ( E C O G)
X
A d verse E ve nt e val uati o n
X
X
X
X
X
C o nc o mita nt me ds
X
He mat ol o g y  c
X
X h
X h, i
X h
X h
C he mistr y  d
X
X h
X h
X h
Pre g na nc y test e
X
Breast I ma gi n g f
X
X
A xillar y e val uati o n g
X

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6 4
Tiss ue C ollecti o n
( Secti o n 5. 8)
X
X
C 1 D 1 5 
o nl y
X  j
C 1 D 1 5 
o nl y
X
Researc h Bl o o d c ollecti o n
( Secti o n 5. 9)
X
X
Ca n di date f or breast 
c o nser vati o n e val uati o n
X
X
 
a)
Pre-s ur gical i ma gi n g m ust occ ur wit hi n 4 2 da ys of c o m pleti o n of treat me nt ( wit h a - 2 da y wi n d o w). 
b)
F oll o w- u p i nf or mati o n will be c ollecte d yearl y u ntil 1 0 years after s ur ger y. N o tests or pr oce d ures are 
re q uire d d uri n g f oll o w- u p b ut cli nical data will be c ollecte d o n C R Fs. T hese data s h o ul d be base d o n e xa ms, 
tests, or pr oce d ures d o ne at t he re gisteri n g i nstit uti o n or at a l ocal facilit y. Data t o be c ollecte d fr o m all 
patie nts i ncl u de a dj u va nt c yt ot o xic ( +/- tar gete d) treat me nt, a dj u va nt e n d ocri ne ( +/- tar gete d) treat me nt, 
date a n d site of all rec urre nces, date a n d ca use of deat hs as well as date a n d dia g n osis of sec o n dar y 
mali g na ncies.
c)
He mat ol o g y i ncl u des he m o gl o bi n, w hite bl o o d cell c o u nt ( W B C), a bs ol ute ne utr o p hils, a n d platelet c o u nt. 
d)
Bl o o d c he mistr y i ncl u des A S T ( S G O T)/ A L T ( S G P T), al kali ne p h os p hatase, s o di u m, p otassi u m, t otal 
calci u m, t otal bilir u bi n, ser u m creati ni ne, t otal pr otei n a n d al b u mi n. 
e)
Ser u m or uri ne pre g na nc y test f or w o me n of c hil d beari n g p ote ntial ( ≤ 7 da ys pri or ra n d o mizati o n). 
f)
Baseli ne i ma gi n g wit hi n 4 2 da ys pri or t o e nr oll me nt; M RI is str o n gl y rec o m me n de d, alt h o u g h ot her i ma gi n g 
m o dalities ( ma m m o gra m, ultras o u n d) are per mitte d if practical or fi na ncial c o nsi derati o ns precl u de M RI, as 
l o n g as t he tar get lesi o n ca n be a de q uatel y meas ure d. T his sa me i ma gi n g m o dalit y s h o ul d be perf or me d a gai n 
pri or t o s ur ger y. Ma m m o gra m of t he u naffecte d c o ntralateral breast is re q uire d wit hi n 1 2 m o nt hs pri or t o 
re gistrati o n
g)
F or w o me n wit h cli nicall y s us pici o us l y m p h n o des, pre o perati ve a xillar y ultras o u n d wit h fi ne nee dle 
as pirati o n or c ore bi o ps y of s us pici o us s h o ul d be perf or me d. F or s u bjects wit h a cli nicall y ne gati ve a xilla, a 
se nti nel l y m p h n o de bi o ps y s h o ul d be perf or me d eit her bef ore or after pre o perati ve t hera p y at t he discreti o n 
of t he s u bject’s p h ysicia ns.  A xillar y e val uati o n m ust be d o ne wit hi n 4 2 da ys pri or t o e nr oll me nt. 
h)
He mat ol o g y a n d Bl o o d c he mistr y are n ot rec o m me n de d f or Ar m D at t he s pecifie d ti me p oi nts.
i)
Ar m C patie nts o nl y.  Testi n g ca n be perf or me d at a l ocal la b orat or y or at t he researc h ce nter
j)
It is str o n gl y rec o m me n de d t o sc he d ule t he i ma ge- g ui de researc h bi o ps y at C 1 D 1 5 pri or t o treat me nt 
i nitiati o n.  See Secti o n 5. 8 f or details.
T a ble 1 0. Re q uire d Rese arc h S peci me n S u b missi o ns
Ti me P oi nt
Wi n d o w P h ase 
a
Tre at me nt P h ase  b
S peci me n T y pe
Scree ni n g
D 1
D 1 5
C 1 D 1
C 1 D 1 5
Pre- 
S ur ger y
P ost 
S ur ger y
S hi p pi n g 
C o n diti o n
Bl oc k or 
U nstai ne d F F P E 
sli des
X
X
A m bie nt 
2 0 m L w h ole 
bl o o d i n la ve n der 
t o p ( E D T A) t u be
X
X
A m bie nt 
T w o 1 0 m L Strec k 
t u bes of w h ole 
bl o o d
X
X
X
A m bie nt 
T hree 1 0 m L C P T 
t u be f or P B M Cs
X
X
A m bie nt 
C ore bi o psies i n 
f or mali n
X
X
X
X
A m bie nt 

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C ore bi o psies i n 
O C T
X
X
X
X
Fr oze n,
Dr y ice
a.  
O nl y f or pts w h o e nr oll i n t he wi n d o w p hase first ( Ar m A a n d B patie nts)
b.  
O nl y f or pts w h o e nr oll i n treat me nt p hase directl y.
Refer t o pr ot oc ol secti o n 5. 8 f or details a b o ut tiss ue a n d bi o ps y c ollecti o n, pr ocessi n g, a n d 
s hi p pi n g details.  Refer t o pr ot oc ol secti o n 5. 9 f or bl o o d sa m ple c ollecti o n, pr ocessi n g, a n d 
s hi p pi n g details.
1 1.
M E A S U R E M E N T O F E F F E C T
1 1. 1  
A ntit u m or Effect – S oli d T u m ors
A baseli ne a n d pres ur gical ra di o gra p hic st u d y of t he breast is re q uire d; M RI is rec o m me n de d. 
T he sa me ra di o gra p hic m o dalit y s h o ul d be use d c o nsiste ntl y. T he baseli ne sca n m ust be o btai ne d 
wit hi n 4 2 da ys pri or t o e nr oll me nt. T he pres ur gical sca n s h o ul d occ ur 2- 6 wee ks ( Da y 1 4- 4 2) 
after t he last c ycle e n ds. If t he partici pa nt cli nicall y pr o gresses, re peat i ma gi n g is re q uire d. If 
t here is disc or da nce (cli nical pr o gressi o n, b ut ra di o gra p hic sta ble disease or res p o nse), c o ntact 
t he st u d y c hair.
1 1. 2  
R a di o gr a p hic assess me nt
Eac h partici pa nt will ha ve pre- a n d p ost-t hera p y ra di o gra p hic t u m or meas ure me nts, prefera bl y 
b y M RI, h o we ver if l o gistic or practical iss ues precl u de M RI use, ma m m o gra m or ultras o u n d 
ma y be s u bstit ute d. I n t he e ve nt of m ultif ocal or m ultice ntric disease i n t he breast, t he 
i n vesti gat or m ust deter mi ne w hic h will re prese nt t he tar get lesi o n(s). T his s h o ul d re mai n 
c o nsiste nt t hr o u g h o ut t he st u d y. T he tar get lesi o n(s) s h o ul d be selecte d o n t he basis of its size 
a n d s uita bilit y f or acc urate re petiti ve meas ure me nts f oll o wi n g R E CI S T 1. 1 rec o m me n dati o ns. 
Res p o nse criteria are base d o n t he R E CI S T 1. 1 criteria:
R a di o gr a p hic C o m plete Res p o nse ( C R): C o m plete disa p peara nce of t he tar get lesi o n
R a di o gr a p hic P arti al Res p o nse ( P R): Greater t ha n or e q ual t o 3 0 % decrease i n t he
l o n gest dia meter ( L D) of t he tar get lesi o n ta ki n g as refere nce t he baseli ne L D
R a di o gr a p hic Pr o gressi ve Dise ase ( P D): Greater t ha n or e q ual t o 2 0 % i ncrease i n t he
L D of tar get lesi o n ta ki n g as refere nce t he baseli ne L D or t he a p peara nce of o ne or m ore ne w 
lesi o ns
R a di o gr a p hic St a ble Dise ase ( S D): Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R
n or s ufficie nt i ncrease t o q ualif y f or P D ta ki n g as refere nce t he baseli ne L D
1 1. 3  
Cli nic al assess me nts
B ot h tar get a n d, i n t he e ve nt of m ultif ocal or m ultice ntric i n vasi ve ca ncer, n o ntar get lesi o ns 

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Versi o n D ate: J uly 6, 2 0 2 2
6 6
s h o ul d be f oll o we d cli nicall y. If t he partici pa nt de m o nstrates cli nical pr o gressi o n at a n y ti me, 
re peat i ma gi n g is re q uire d. If t here is disc or da nce (cli nical pr o gressi o n, b ut ra di o gra p hic sta ble 
disease or res p o nse), st u d y PI s h o ul d be c o ntacte d t o s ol ve disc or da nce.
1 1. 4 
P at h ol o gic Res p o nse
Pat h ol o gic res p o nse will be re p orte d usi n g t he Resi d ual Ca ncer B ur de n calc ulat or [ 6 2]  M. D 
A n ders o n htt p:// w w w. m da n ders o n. or g/ breastca ncer _ R C B . 
T he f oll o wi n g para meters are re q uire d fr o m pat h ol o gic e xa mi nati o n i n or der t o calc ulate 
Resi d ual Ca ncer B ur de n ( R C B) after ne oa dj u va nt treat me nt:

T he lar gest t w o di me nsi o ns ( m ms) of t he resi d ual t u m or be d i n t he breast (lar gest t u m or 
be d if m ultice ntric disease)

Hist ol o gic assess me nt of t he perce nta ge of t he t u m or be d area t hat c o ntai ns carci n o ma 
(all carci n o ma, i.e. i n vasi ve a n d i n sit u), select o ne of t he f oll o wi n g: 0 %, 1 %, 5 %, 1 0 %, 
2 0 %, 3 0 %, 4 0 %, 5 0 %, 6 0 %, 7 0 %, 8 0 %, 9 0 %

T o assess cell ularit y it is hel pf ul t o sca n acr oss t he secti o ns of t u m or be d a n d t he n 
esti mate t he a vera ge cell ularit y fr o m t he differe nt micr osc o pic fiel ds.

W he n esti mati n g perce nta ge ca ncer cell ularit y i n a n y micr osc o pic fiel d, c o m pare t he 
i n v ol ve d area wit h o b vi o us sta n dar ds, e. g. m ore or less t ha n half, o ne q uarter, o ne fift h, 
o ne te nt h, o ne t we ntiet h, etc.

E x pect t here t o be varia ble cell ularit y wit hi n t he cr oss secti o n of a n y t u m or be d, b ut 
esti mate t he o verall cell ularit y fr o m t he a vera ge of t he esti mates i n differe nt micr osc o pic 
fiel ds of t he t u m or be d. E. g., if cell ularit y i n differe nt fiel ds of t he t u m or be d were 
esti mate d as 2 0 %, 1 0 %, 2 0 %, 0 %, 2 0 %, 3 0 %, t he n a n a vera ge esti mate of o verall 
cell ularit y w o ul d be 2 0 %.

Hist ol o gic esti mate of t he perce nta ge of t he carci n o ma i n t he t u m or be d t hat is i n sit u, 
select o ne of t he f oll o wi n g: 0 %, 1 %, 5 %, 1 0 %, 2 0 %, 3 0 %, 4 0 %, 5 0 %, 6 0 %, 7 0 %, 8 0 %, 
9 0 %, 1 0 0 %

T he n u m ber of p ositi ve ( metastatic) l y m p h n o des

T he lar gest dia meter ( m m) of t he lar gest n o dal metastasis
1 2. D A T A R E P O R TI N G / R E G U L A T O R Y R E Q UI R E M E N T S
A d verse e ve nt lists, g ui deli nes, a n d i nstr ucti o ns f or A E re p orti n g ca n be f o u n d i n Secti o n 7. 0 
( A d verse E ve nts: List a n d Re p orti n g Re q uire me nts).
1 2. 1  
D at a Re p orti n g
1 2. 1. 1
Met h o d
T he O D Q/ C T RI O will c ollect, ma na ge, a n d perf or m q ualit y c hec ks o n t he data f or t his 
st u d y.

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Versi o n D ate: J uly 6, 2 0 2 2
6 7
1 2. 1. 2
Res p o nsi bilit y f or Data S u b missi o n
I n vesti gati ve sites are res p o nsi ble f or s u b mitti n g data a n d/ or data f or ms t o t he 
O D Q/ C T RI O acc or di n g t o t he sc he d ule set b y t he O D Q/ C T RI O  .
1 2. 2  
D at a S afet y M o nit ori n g
T he D F/ H C C Data a n d Safet y M o nit ori n g B oar d ( D S M B) will re vie w a n d m o nit or st u d y 
pr o gress, t o xicit y, safet y a n d ot her data fr o m t his st u d y. T he b oar d is c haire d b y a me dical 
o nc ol o gist fr o m o utsi de of D F/ H C C a n d has e xter nal a n d i nter nal re prese ntati o n. I nf or mati o n 
t hat raises a n y q uesti o ns a b o ut partici pa nt safet y or pr ot oc ol perf or ma nce will be a d dresse d b y 
t he O verall PI, statisticia n a n d st u d y tea m. S h o ul d a n y maj or c o ncer ns arise, t he D S M B will 
offer rec o m me n dati o ns re gar di n g w het her or n ot t o s us pe n d t he st u d y.
T he D S M B will meet t wice a year t o re vie w accr ual, t o xicit y, res p o nse a n d re p orti n g 
i nf or mati o n. I nf or mati o n t o be pr o vi de d t o t he D S M B ma y i ncl u de: partici pa nt accr ual; 
treat me nt re gi me n i nf or mati o n; a d verse e ve nts a n d seri o us a d verse e ve nts re p orte d b y cate g or y; 
s u m mar y of a n y deat hs o n st u d y; a u dit res ults; a n d a s u m mar y pr o vi de d b y t he st u d y tea m. Ot her 
i nf or mati o n (e. g. sca ns, la b orat or y val ues) will be pr o vi de d u p o n re q uest. 
1 2. 3  
M ultice nter G ui deli nes
T his pr ot oc ol will a d here t o t he p olicies a n d re q uire me nts of t he D F/ H C C M ulti- Ce nter Data a n d 
Safet y M o nit ori n g Pla n.  T he s pecific res p o nsi bilities of t he O verall PI, C o or di nati n g Ce nter, a n d 
Partici pati n g I nstit uti o ns a n d t he pr oce d ures f or a u diti n g are prese nte d i n A p pe n di x E.

T he O verall PI/ C o or di nati n g Ce nter is res p o nsi ble f or distri b uti n g all I N D Acti o n Letters 
or Safet y Re p orts t o all partici pati n g i nstit uti o ns f or s u b missi o n t o t heir i n di vi d ual I R Bs 
f or acti o n as re q uire d.

Mec ha nis ms will be i n place t o e ns ure q ualit y ass ura nce, pr ot oc ol c o m plia nce, a n d 
a d verse e ve nt re p orti n g at eac h site.

E xce pt i n ver y u n us ual circ u msta nces, eac h partici pati n g i nstit uti o n will or der t he st u d y 
a ge nt(s) directl y fr o m s u p plier.  A partici pati n g site ma y or der t he a ge nt(s) o nl y after t he 
i nitial I R B a p pr o val f or t he site has bee n f or war de d t o t he C o or di nati n g Ce nter.
1 2. 4
C oll a b or ati ve Rese arc h a n d F ut ure Use of D at a a n d Bi os peci me ns
Tiss ue, bl o o d, b o dil y fl ui ds, a n d ot her materials deri ve d fr o m t hese will be c ollecte d i n t his st u d y 
t o a nal yze ge nes, D N A, R N A, pr otei ns a n d cells f or t he st u d y’s c orrelati ve e n d p oi nts a n d p ote ntial 
f ut ure researc h, utilizi n g ne w t y pes of bi o mar ker testi n g as it bec o mes a vaila ble. 
T hese sa m ples a n d a n y data ge nerate d as a part of t hese cli nical trials ma y be use d f or f ut ure 
researc h st u dies a n d ma y be pr o vi de d t o c olla b orati n g i n vesti gat ors b ot h wit hi n a n d o utsi de of t he 
D F/ H C C f or eit her c orrelati ve e n d p oi nts or sec o n dar y use. Sa m ples a n d data ma y be s hare d wit h 
o utsi de n o n- pr ofit aca de mic i n vesti gat ors, as well as wit h f or- pr ofit p har mace utical i n vesti gat ors 

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Versi o n D ate: J uly 6, 2 0 2 2
6 8
or c o m mercial e ntities, wit h w h o m we c olla b orate. W he n sa m ples or data are se nt t o c olla b orat ors 
a n d w he n a n y researc h is perf or me d o n t he m, all i nf or mati o n will be i de ntifie d wit h a c o de, a n d 
will n ot c o ntai n a n y P HI, s uc h as na me, birt h da y, or M R Ns. 
I n or der t o all o w t he greatest a m o u nt of researc h t o be perf or me d o n t he s peci me ns a n d 
i nf or mati o n ge nerate d as a part of t his trial, researc hers i n t his st u d y ma y s hare res ults of ge netic 
se q ue nci n g wit h ot her scie ntists. De-i de ntifie d s peci me n or ge netic data ma y be place d i nt o o ne 
of m ore p u blicl y-accessi ble scie ntific data bases, s uc h as t he Nati o nal I nstit utes of Healt h’s 
Data base f or Ge n ot y pes a n d P he n ot y pes ( d b Ga P). T he res ults fr o m t he c orrelati ve researc h o n 
t his st u d y will be s hare d wit h t hese p u blic data bases. T hr o u g h s uc h data bases, researc hers fr o m 
a n y w here will ha ve access t o de-i de ntifie d sa m ples or data f or f ut ure researc h. M ore detaile d 
i nf or mati o n, be y o n d t he p u blic data base, ma y o nl y be accesse d b y scie ntists at ot her researc h 
ce nters w h o ha ve recei ve d s pecial per missi o n t o re vie w de-i de ntifie d data.
1 3. S T A TI S TI C A L C O N SI D E R A TI O N S
1 3. 1 
St u d y Desi g n/ E n d p oi nts
T his is a n o pe n la bel p hase II ne oa dj u va nt cli nical trial of Pal b ocicli b i n c o m bi nati o n wit h 
e n d ocri ne t hera p y f or E R + earl y-sta ge breast ca ncer. T he pla n ne d sa m ple size is u p t o 1 9 5 
partici pa nts. T he st u d y i ncl u des a “ wi n d o w of treat me nt” p hase f oll o we d b y a treat me nt p hase. 
Patie nts will be ra n d o mize d t o treat me nt assi g n me nt t o eac h p hase u p o n e nr oll me nt.
I n t he wi n d o w p hase, patie nts will be ra n d o mize d i n a 1: 1 rati o t o recei ve a t w o- wee k c o urse of 
ta m o xife n or letr oz ole. A researc h bi o ps y will be o btai ne d bef ore a n d after c o m pleti o n of t w o-
wee k c o urse of e n d ocri ne t hera p y.  I n t he treat me nt p hase partici pa nts will be ra n d o mize d i n a 
2: 1 rati o t o recei ve e n d ocri ne t hera p y i n c o m bi nati o n wit h pal b ocicli b or e n d ocri ne t hera p y 
m o n ot hera p y f or a t otal d urati o n of 2 4 wee ks. Patie nts will be ra n d o mize d wit h strata defi ne d b y 
hist ol o g y, i nitial l y m p h n o de stat us ( p ositi ve vs. ne gati ve) a n d pre-treat me nt t u m or size ( T 1- 2 vs. 
T 3). 
St u d y e nr oll me nt will be perf or me d as f oll o ws: P ost me n o pa usal w o me n dia g n ose d wit h eit her 
i n vasi ve l o b ular carci n o ma ( n = 6 0) or i n vasi ve d uctal carci n o ma ( n = 6 0) will be eli gi ble t o e nr oll 
i n t he wi n d o w p hase of t he st u d y as s pecifie d a b o ve a n d w o ul d c o nti n ue o n st u d y i nt o t he 
treat me nt p hase. Pre me n o pa usal patie nts will be eli gi ble t o e nr oll directl y i nt o t he treat me nt 
p hase of t he st u d y.  U p o n c o m pleti o n of e nr oll me nt of eit her t he i n vasi ve l o b ular carci n o ma or 
i n vasi ve d uctal carci n o ma s u bsets i n t he wi n d o w p hase, t he st u d y will be a me n de d s uc h t hat 
s u bse q ue nt p ost me n o pa usal patie nts will be eli gi ble t o e nr oll directl y i nt o t he treat me nt p hase of 
t he st u d y. A t otal of 7 5 patie nts will be e nr olle d directl y i nt o t he treat me nt p hase of t he st u d y.
T he st u d y has t w o c o- pri mar y o bjecti ves. I n t he wi n d o w p hase, t he pri mar y o bjecti ve is t o 
e val uate t he differe nce i n a nti- pr oliferati ve acti vit y of letr oz ole vers us ta m o xife n wit hi n c o h orts 
of E R + breast ca ncer f or patie nts wit h i n vasi ve l o b ular a n d i n vasi ve d uctal carci n o ma.  T he 
e n d p oi nt f or a nti- pr oliferati ve acti vit y will be f ol d-c ha n ge i n perce nt Ki 6 7 stai ni n g fr o m baseli ne 
t o da y 1 5. I n t he treat me nt p hase of t he st u d y t he pri mar y o bjecti ve is t o c o m pare t he pat h ol o gic 

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Versi o n D ate: J uly 6, 2 0 2 2
6 9
res p o nse of e n d ocri ne t hera p y + pal b ocicli b vers us e n d ocri ne t hera p y al o ne i n breast ca ncer 
patie nts dia g n ose d wit h h or m o ne rece pt or p ositi ve i n vasi ve breast ca ncer, as deter mi ne d b y t he 
Resi d ual Ca ncer B ur de n ( R C B). Sec o n dar y cli nical e n d p oi nts i ncl u de cli nical res p o nse, safet y 
a n d t olera bilit y defi ne d u n der C T C A E versi o n 4. 0
 
1 3. 2 
S a m ple Size, Accr u al R ate a n d St u d y D ur ati o n
T he sa m ple size of t he st u d y was selecte d t o ha ve a de q uate p o wer i n t he wi n d o w p hase t o 
differe ntiate t he differe nce i n a nti- pr oliferati ve acti vit y of letr oz ole vers us ta m o xife n i n s u b gr o u ps 
of patie nts wit h i n vasi ve l o b ular a n d d uctal carci n o ma. Sa m ple size was e x pa n de d i n t he treat me nt 
p hase i n or der t o c o m pare pat h ol o gic res p o nse i n all patie nts treate d wit h letr oz ole wit h pal b occili b 
vers us letr oz ole m o n ot hera p y.  
Wit h 6 0 patie nts per hist ol o gic s u bt y pe ra n d o mize d 1: 1 t o ta m o xife n or letr oz ole, a n d ass u mi n g 
1 0 % of paire d sa m ples will n ot be e val ua ble f or Ki 6 7, n = 2 7 patie nts per gr o u p will pr o vi de > 9 0 % 
p o wer f or eac h c o m paris o n t o detect a differe nce of 1 sta n dar dize d u nit w he n usi n g a t w o-si de d 
Wilc o x o n-ra n k s u m test wit h al p ha = 0. 0 5. I n e val uati n g s h ort –ter m c ha n ges of Ki 6 7 d uri n g 
ne oa dj u va nt treat me nt of pri mar y breast ca ncer, D o wsett et al. ( 2 0 0 5) re p orte d a - 5 9. 5 % c ha n ge 
wit h ta m o xife n ( 9 5 % CI - 6 8. 5 t o - 4 7. 9). Usi n g t hese res ults t o esti mate t he sta n dar d de viati o n 
( ~ 5. 4 %) i n meas ure d c ha n ges i n Ki 6 7 i n t he ge neral p o p ulati o n, t his tar get differe nce i n t his st u d y 
w o ul d c orres p o n d t o a n i ncrease i n a nti- pr oliferati ve acti vit y t o a – 6 5. 2 % c ha n ge wit h letr oz ole.
N o restricti o n f or hist ol o gical s u bt y pe (i.e. i n vasi ve l o b ular or i n vasi ve d uctal) is i m p ose d f or t he 
treat me nt p hase patie nts. T he e n d p oi nt f or pat h ol o gic res p o nse will be deter mi ne d b y t he R C B 
i n de x, meas ure d o n a c o nti n u o us scale, at t he ti me of s ur ger y. Wit h 6 5 patie nts o n treat me nt wit h 
e n d ocri ne t hera p y a n d 1 3 0 patie nts o n treat me nt wit h e n d ocri ne t hera p y pl us pal b ocicli b, t here 
will be a n 8 0 % p o wer f or detecti n g a differe nce of 0. 4 4 sta n dar dize d u nits usi n g a t w o-si de d 
Wilc o x o n-ra n k s u m test wit h al p ha = 0. 0 5. T his ass u mes 

Sta n dar d de viati o n of R C B i n de x is 1 i n b ot h treat me nt gr o u ps ( base d o n res ults i n 
S y m ma ns et al ( 2 0 0 7)

Me dia n R C B i n de x i n patie nts o n e n d ocri ne t hera p y is 3. 3 6, w hic h u n der a n ass u m pti o n 
of n or malit y c orres p o n ds t o 2. 3 % patie nts ha vi n g R C B i n de x ≤1. 3 6 t hat c orres p o n ds t o 
pat h ol o gic c o m plete res p o nse.

Me dia n R C B i n de x i n patie nts o n e n d ocri ne t hera p y + pal b ocicli b is 2. 9 2, w hic h u n der a n 
ass u m pti o n of n or malit y c orres p o n ds t o 5. 9 % patie nts ha vi n g R C B i n de x ≤1. 3 6 t hat 
c orres p o n ds t o pat h ol o gic c o m plete res p o nse.
It is e x pecte d t hat it w o ul d ta ke a p pr o xi matel y 4 2 m o nt hs t o c o m plete accr ual.  A n a d diti o nal 6 
m o nt hs of f oll o w- u p will be re q uire d o n t he last partici pa nt accr ue d t o c o ver t he ti me fr o m i nitial 
e nr oll me nt t o t he p ost- o perati ve, off-st u d y visit.
1 3. 3 
I nteri m M o nit ori n g Pl a n
N o i nteri m a nal ysis will be c o n d ucte d f or t he pri mar y e n d p oi nts of t he wi n d o w a n d treat me nt 
p hases of t his st u d y. T he D F/ H C C D S M B will m o nit or t o xicit y.

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7 0
1 3. 4  
A n al ysis of Pri m ar y E n d p oi nts
Wi n d o w P hase
Descri pti ve statistics will be use d t o s u m marize t he perce nta ge of Ki 6 7 stai ni n g meas ure d at
baseli ne a n d at da y 1 5. T he e val uati o n of c ha n ge i n Ki 6 7 will be perf or me d o n t he l o g-scale. F or 
t he pri mar y o bjecti ve, we will e val uate t he effects of e n d ocri ne t hera p y wit hi n eac h hist ol o g y 
s u bt y pe. A Wilc o x o n-ra n k s u m test wit h t w o-si de d al p ha = 0. 0 5 will be use d t o c o m pare t he 
c ha n ges i n Ki 6 7 i n patie nts treate d wit h letr oz ole vers us ta m o xife n a n d test t he n ull h y p ot hesis of 
n o differe nce. 
Treat me nt P hase 
F or t he pri mar y o bjecti ve, we will e val uate t he effect of i ncl u di n g pal b ocicli b wit h e n d ocri ne 
t hera p y c o m pare d t o e n d ocri ne t hera p y al o ne o n pat h ol o gic res p o nse a m o n g all patie nts. T he 
differe nce R C B i n de x bet wee n patie nts recei vi n g e n d ocri ne t hera p y a n d patie nts recei vi n g 
e n d ocri ne t hera p y pl us pal b ocicli b will be c o m pare d usi n g a Wilc o x o n-ra n k s u m test wit h t w o-
si de d al p ha = 0. 0 5. 
1 3. 5  
A n al ysis of Sec o n d ar y E n d p oi nts
Wi n d o w P hase
I n sec o n dar y a nal yses we will esti mate t he relati ve effect of letr oz ole vs ta m o xife n i n patie nts wit h 
d uctal hist ol o g y s u bt y pe c o m pare d t o l o b ular s u bt y pe. T he h y p ot hesis is t hat t he i m pr o ve me nt i n 
a nti- pr oliferati ve acti vit y a n d ac hie ve me nt of cell-c ycle arrest is str o n ger i n patie nts wit h l o b ular 
hist ol o g y c o m pare d t o d uctal hist ol o g y. T his will be assesse d usi n g a l o gistic re gressi o n m o del 
wit h o utc o me bei n g ac hie vi n g cell c ycle arrest at e n d of wi n d o w p hase. Cell c ycle arrest is defi ne d 
t o be perce nta ge of Ki 6 7 < 2. 7. T he m o del will i ncl u de mai n effects f or treat me nt a n d hist ol o g y a n d 
a n i nteracti o n bet wee n treat me nt a n d hist ol o g y, a dj usti n g f or baseli ne Ki 6 7. If t he i nteracti o n ter m 
is statisticall y si g nifica nt, we will c o ncl u de t hat t he effect of letr oz ole vs ta m o xife n is differe nt i n 
patie nts wit h d uctal a n d l o b ular hist ol o gies.
Treat me nt P hase 
I n sec o n dar y a nal yses, we will use li near m o dels ( or n o nli near m o dels if necessar y) t o u n dersta n d 
t he effect of treat me nt o n R C B i n de x, a dj usti n g f or t u m or size, n o dal stat us a n d me n o pa usal stat us 
at baseli ne. A n a d diti o nal sec o n dar y a nal ysis will c o nsi der t he bi nar y o utc o me of R C B 0/II 
(c o nti n u o us R C B i n de x ≤1. 3 6) t o meas ure pat h ol o gic c o m plete res p o nse. We will c o m pare t he 
treat me nt ar ms usi n g a Fis her’s e xact test. We will als o use a C oc hra n- Ma ntel- Hae nszel test t o 
e val uate treat me nt effect stratifie d b y e n d ocri ne bac k b o ne ( or e q ui vale ntl y, me n o pa usal stat us) 
a n d a d diti o nal fact ors s uc h hist ol o g y, l y m p h n o de stat us a n d t u m or size if t he n u m ber of res p o nses 
wit hi n s u b gr o u ps all o ws f or as y m pt otic ass u m pti o ns t o be reas o na ble. I n a d diti o n, we will i ncl u de 
patie nts w h o were e xcl u de d fr o m t he pri mar y a nal ysis of R C B i n de x beca use t he y d o n ot ha ve a n 
R C B sc ore d ue t o recei vi n g c he m ot hera p y pri or t o s ur ger y. T hese patie nts will be treate d as ha vi n g 
n o pat h ol o gic c o m plete res p o nse.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
7 1
T he ce ntral m o difie d Pre o perati ve E n d ocri ne T hera p y Pr o g n ostic I n de x ( m P E PI) will be defi ne d 
as 0 ( g o o d pr o g n osis), 1 – 3 (i nter me diate) a n d 4 + ( p o or pr o g n osis). 
We will descri be t he 
distri b uti o n of t he cate g orical P E PI sc ore i n patie nts recei vi n g e n d ocri ne t hera p y al o ne vers us 
e n d ocri ne t hera p y + pal b ocicli b. We will use e xact tests t o c o m pare t he distri b uti o n of P E PI sc ores 
i n eac h treat me nt gr o u p.
We will esti mate t he cli nical res p o nse rate, defi ne d as t he n u m ber of partial a n d c o m plete 
res p o nses, after pre o perati ve e n d ocri ne t hera p y + pal b ocicli b a n d e n d ocri ne t hera p y al o ne a n d 
ass ociate d 9 5 % Wils o n sc ore c o nfi de nce i nter vals.
Partici pa nts will be e val uate d f or t o xicit y fr o m t he ti me of t heir first treat me nt, a n d rates of a d verse 
e ve nts a n d treat me nt m o dificati o n or disc o nti n uati o n will be re p orte d wit h 9 5 % Wils o n sc ore 
c o nfi de nce i nter vals. 
A m o n g all patie nts t hat e ntere d t he trial d uri n g t he treat me nt p hase, we will ha ve a researc h bi o ps y 
at baseli ne ( pre-treat me nt), t w o wee ks after starti n g treat me nt a n d t he n s peci me n c ollecti o n at 
s ur ger y. We will first c o m pare c ha n ge i n Ki 6 7 at s ur ger y c o m pare d t o baseli ne, stratifie d b y t he 
e n d ocri ne bac k b o ne ( or e q ui vale ntl y, me n o pa usal stat us) i n all patie nts. We will t he n f oc us o n t he 
pre- me n o pa usal w o me n recr uite d i nt o t he treat me nt p hase a n d first c o m pare t he c ha n ge i n Ki 6 7 
fr o m baseli ne t o t w o wee ks.  
T he ass ociati o n of c orrelati ve bi o mar kers t o hist ol o gical s u bt y pes a n d cli nical o utc o mes i n t he 
treat me nt p hase will be e x pl orat or y a n d h y p ot hesis ge nerati n g, a n d will n ot a dj ust f or m ulti ple 
c o m paris o ns i n a n y statistical i nfere nces.
Sec o n dar y o bjecti ves will use t w o-si de d al p ha = 0. 0 5 f or all i nfere ntial tests
1 3. 6  
C orrel ati ve Scie nce O bjecti ves 
F or t he 7 5 patie nts w h o e nr oll directl y o n t he treat me nt p hase of t he st u d y, a pre-treat me nt a n d 2-
wee k is re q uire d t o assess t he c orrelati o n of R b p h os p h or ylati o n a n d % c ha n ge i n Ki 6 7. T he 
a nal ysis pla n t o assess t he c orrelati o n of c ha n ges fr o m baseli ne will be as f oll o ws: if Ga ussia n 
ass u m pti o ns are s h o w n t o h ol d u n der B o x- C o x tra nsf or mati o n of Ki 6 7 a n d R b, we will re p ort t he 
Pears o n pr o d uct m o me nt c orrelati o n c oefficie nt a n d 9 5 % c o nfi de nce i nter val, a n d use t he Fis her 
Z tra nsf or mati o n t o test w het her t he c orrelati o n is greater t ha n a n ull val ue of 0. 8. If Ga ussia n 
ass u m pti o ns fail t o h ol d, we will re p ort t he S pear me n c orrelati o n c oefficie nt wit h a n e m pirical 
9 5 % c o nfi de nce i nter val dra w n fr o m t he B C A b o otstra p met h o d t o assess w het her t he n ull val ue 
is e xcl u de d.  Ass u mi n g t hat 8 0 % of patie nts pr o vi de pairs of s peci me n e val ua ble f or eac h 
bi o mar ker, 6 0 patie nts will pr o vi de 8 2. 6 % p o wer t o reject t he n ull if t he tr ue r h o = 0. 9 1.  
1 3. 7 
E x pl or at or y A xill ar y L y m p h N o de S ur ger y O bjecti ves
T he l y m p h n o de s ur ger y o bjecti ves will utilize i nf or mati o n alrea d y necessar y a n d 
c ollecte d f or t he pri mar y a n d sec o n dar y e n d p oi nt a nal yses (f or e xa m ple R C B, m P E PI, a n d 
cli nical res p o nse rates). N o dal res p o nse will be c o m pare d bet wee n treat me nt ar ms. O verall n o dal 
res p o nse will be meas ure d i n ter ms of 1) cli nical n o dal d o w nsta gi n g (i.e. c N 1 t o c N 0, or c N 2 t o 

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Versi o n D ate: J uly 6, 2 0 2 2
7 2
c N 1/ 0) a n d 2) hist ol o gic n o dal res p o nse. We will meas ure t he f oll o wi n g hist ol o gic feat ures of 
t he l y m p h n o des wit hi n eac h treat me nt ar m t o deter mi ne hist ol o gic n o dal res p o nse: 1) lar gest 
size of l y m p h n o de metastasis (is olate d t u m or cells, micr o metastases, or macr o metastases); 2) 
prese nce ( yes/ n o) a n d t y pe of str o mal fi br osis ( de nse vs l o ose); 3) perce nt t u m or cell ularit y of 
t he l y m p h n o de metastasis; a n d 4) prese nce of e xtra n o dal e xte nsi o n. We will st u d y t he 
ass ociati o n bet wee n i n- breast Ki 6 7 stai ni n g res p o nse t o ne oa dj u va nt e n d ocri ne t hera p y ( o ne-ti me 
Ki 6 7 le vels o btai ne d o n t he 2- wee k researc h bi o ps y as well as t he delta fr o m baseli ne t o 2- wee k 
bi o ps y, alrea d y c ollecte d f or t he sec o n dar y e n d p oi nt a nal ysis) a n d n o dal res p o nse after 2 4 wee ks 
of ne oa dj u va nt e n d ocri ne t hera p y. We will esti mate s u m mar y statistics a n d gra p hicall y e xa mi ne, 
via b o x pl ots, t he bi o mar ker le vels at 2 wee ks a n d c ha n ge i n bi o mar ker le vels f or patie nts t hat di d 
a n d di d n ot ha ve a n o dal res p o nse, f or eac h treat me nt gr o u p. 
We will deter mi ne t he rates of vari o us a xillar y s ur geries ( n o a xillar y s ur ger y, se nti nel 
l y m p h n o de bi o ps y al o ne, se nti nel l y m p h n o de bi o ps y f oll o we d b y a xillar y l y m p h n o de 
dissecti o n, a n d u pfr o nt a xillar y l y m p h n o de dissecti o n) a m o n g c N 0 a n d c N 1 patie nt p o p ulati o ns. 
We will use t w o- wa y c o nti n ge nc y ta bles t o c haracterize t he n o dal stat us pre- a n d p ost-e n d ocri ne 
t hera p y f or eac h treat me nt ar m (t he perce nta ge of patie nts t hat are c N 0 pre-e n d ocri ne t hera p y b ut 
p N + p ost-e n d ocri ne t hera p y a n d t hat are c N + pre-e n d ocri ne t hera p y a n d ha ve persiste nt p N + 
disease p ost-e n d ocri ne t hera p y), stratifie d b y hist ol o gic s u bt y pe ( d uctal/l o b ular). A m o n g t he 
se nti nel l y m p h n o de bi o ps y al o ne a n d se nti nel l y m p h n o de bi o ps y f oll o we d b y a xillar y l y m p h 
n o de dissecti o n gr o u ps, we will descri be t he n u m ber of p ositi ve n o des a n d size of lar gest n o dal 
metastasis (is olate d t u m or cells, micr o metastases 0. 2 m m - 2 m m, a n d macr o metastasis > 2 m m).
A critical varia ble i n t he c haracterizati o n of a xillar y s ur gical ma na ge me nt after 
pre o perati ve t hera p y is t he s ur ge o n’s decisi o n ma ki n g. We will c o n d uct a mi xe d- met h o ds st u d y 
of t he a xillar y s ur geries i n P E L O P S via se mi-str uct ure d i nter vie ws a m o n g t he s ur ge o ns w h o 
treate d patie nts o n t his trial t o e x pl ore t heir rati o nale f or c h oice of a xillar y s ur ger y f oll o wi n g 
ne oa dj u va nt e n d ocri ne t hera p y. P h o ne c o nse nt f or se mi-str uct ure d i nter vie ws will be o btai ne d 
wit h o ut a waiti n g peri o d, pri or t o be gi n ni n g t he i nter vie w.  T he pla n ne d i nter vie w g ui de is base d 
o n t he c o m pre he nsi ve, i nte grate d c hec klist of deter mi na nts of practice 6 8. I n part ners hi p wit h 
D F CI’s S ur ve y a n d Data Ma na ge me nt C ore, t he i nter vie w g ui de ( A P P E N DI X G) will be refi ne d 
t hr o u g h iterati ve re vie w a n d pil ot teste d f or vali dit y. I nter vie ws will be c o n d ucte d u ntil 
sat urati o n of t he me is reac he d, t he y will be tra nscri be d ver bati m, a n d t he n c o de d usi n g a 
gr o u n de d t he or y a p pr oac h 6 9. P o wer is n ot a p plica ble beca use sa m ple sizes are fi xe d. It is 
esti mate d t hat 2 0- 2 4 s ur ge o ns will be s ur ve ye d i n t otal, fr o m a mi x of aca de mic, pri vate, a n d 
c o m m u nit y practices.
Lastl y, we will esti mate 3- year a xillar y rec urre nce rates i n t he P E L O P S trial base d o n 
a xillar y s ur ger y (se nti nel l y m p h n o de bi o ps y or a xillar y l y m p h n o de dissecti o n), c o m pare d b y 
treat me nt ar m a n d c o ntr olli n g f or cli nical c haracteristics i ncl u di n g b ut n ot li mite d t o a dj u va nt 
ra diati o n t hera p y recei ve d, a ge, hist ol o g y ( d uctal, l o b ular, mi xe d), hist ol o gic gra de, m ultice ntric 
disease, l y m p h o vasc ular i n vasi o n, cli nical T cate g or y, cli nical N cate g or y, breast s ur ger y 
perf or me d. We are e x pecti n g rec urre nce rates of less t ha n 2 % at 3 years, base d o n t he rec urre nce 
rates o bser ve d i n pri or a xillar y treat me nt trials a m o n g patie nts u n der g oi n g u pfr o nt s ur ger y7 0, 7 1.
1 3. 8  
Re p orti n g a n d E xcl usi o ns
1 3. 8. 1
E val uati o n of T o xicit y

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
7 3
All partici pa nts will be e val ua ble f or t o xicit y fr o m t he ti me of t heir first treat me nt.  
Partici pa nts w h o ne ver start pr ot oc ol t hera p y will be c o nsi dere d u ne val ua ble.  
1 3. 8. 2
E val uati o n of t he Pri mar y Efficac y E n d p oi nt
All patie nts w h o recei ve at least o ne d ose of st u d y dr u g i n t he treat me nt p hase will be 
e val ua ble f or efficac y e n d p oi nts. Partici pa nts w h o ne ver start pr ot oc ol t hera p y as part of 
t he treat me nt p hase will be c o nsi dere d i n val ua ble.  T he pri mar y a nal ysis of t he wi n d o w 
a n d treat me nt p hase will be c o n d ucte d u n der i nte nti o n-t o-treat pri nci ples wit h gr o u ps 
defi ne d b y ra n d o mize d treat me nt assi g n me nt. Bi o mar ker a nal yses will be c o n d ucte d i n 
all patie nts wit h e val ua ble bi os peci me n wit hi n ar m t hat is defi ne d b y t he treat me nt 
recei ve d ( per pr ot oc ol).
1 4. P U B LI C A TI O N P L A N
T he res ults s h o ul d be ma de p u blic wit hi n a p pr o xi matel y 6 m o nt hs of t he e n d of data c ollecti o n. 
T he res ults of t he wi n d o w p hase of t he st u d y ma y be prese nte d pri or t o t he c o m pleti o n of t he 
treat me nt p hase of t he st u d y. T he e n d of t he st u d y is t he ti me p oi nt at w hic h t he last data ite ms are 
t o be re p orte d, or after t he o utc o me data are s ufficie ntl y mat ure f or a nal ysis, as defi ne d i n t he 
secti o n o n Sa m ple Size, Accr ual Rate a n d St u d y D urati o n. If a re p ort is pla n ne d t o be p u blis he d i n 
a peer-re vie we d j o ur nal, t he n t hat i nitial release ma y be a n a bstract t hat meets t he re q uire me nts of 
t he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors. A f ull re p ort of t he o utc o mes s h o ul d be 
ma de p u blic n o later t ha n t hree ( 3) years after t he e n d of t he st u d y.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
7 4
1 5. R E F E R E N C E S
1.  
Ar pi n o, G., et al., I nfiltr ati n g l o b ul ar c arci n o m a of t he bre ast: t u m or c h ar acteristics a n d 
cli nic al o utc o me.  Breast Ca ncer Res, 2 0 0 4. 6 ( 3): p. R 1 4 9- 5 6.
2. 
La m o vec, J. a n d M. Brac k o, Met ast atic p atter n of i nfiltr ati n g l o b ul ar c arci n o m a of t he 
bre ast: a n a ut o psy st u dy.  J S ur g O nc ol, 1 9 9 1. 4 8 ( 1): p. 2 8- 3 3.
3. 
Crist ofa nilli, M., et al., I nv asive l o b ul ar c arci n o m a cl assic ty pe: res p o nse t o pri m ary 
c he m ot her a py a n d s urviv al o utc o mes.  J Cli n O nc ol, 2 0 0 5. 2 3 ( 1): p. 4 1- 8.
4. 
Ra k ha, E. A. a n d I. O. Ellis, L o b ul ar bre ast c arci n o m a a n d its v ari a nts.  Se mi nars i n 
Dia g n ostic Pat h ol o g y, 2 0 1 0. 2 7 ( 1): p. 4 9- 6 1.
5. 
S herr, C.J. a n d J. M. R o berts, C D K i n hi bit ors: p ositive a n d ne g ative re g ul at ors of G 1-
p h ase pr o gressi o n.  Ge nes De v, 1 9 9 9. 1 3 ( 1 2): p. 1 5 0 1- 1 2.
6. 
va n de n He u vel, S. a n d E. Harl o w, Disti nct r oles f or cycli n- de pe n de nt ki n ases i n cell 
cycle c o ntr ol.  Scie nce, 1 9 9 3. 2 6 2 ( 5 1 4 2): p. 2 0 5 0- 4.
7.  
Wei n ber g, R. A., T he reti n o bl ast o m a pr otei n a n d cell cycle c o ntr ol.  Cell, 1 9 9 5. 8 1 ( 3): p. 
3 2 3- 3 0.
8.  
Har per, J. W., et al., T he p 2 1 C dk-i nter acti n g pr otei n Ci p 1 is a p ote nt i n hi bit or of G 1 
cycli n- de pe n de nt ki n ases.  Cell, 1 9 9 3. 7 5 ( 4): p. 8 0 5- 1 6.
9.  
K off, A., et al., Ne g ative re g ul ati o n of G 1 i n m a m m ali a n cells: i n hi biti o n of cycli n E-
de pe n de nt ki n ase by T G F- bet a.  Scie nce, 1 9 9 3. 2 6 0 ( 5 1 0 7): p. 5 3 6- 9.
1 0. 
P ol ya k, K., et al., p 2 7 Ki p 1, a cycli n- C dk i n hi bit or, li nks tr a nsf or mi n g gr o wt h f act or- bet a 
a n d c o nt act i n hi biti o n t o cell cycle arrest.  Ge nes De v, 1 9 9 4. 8 ( 1): p. 9- 2 2.
1 1. 
S herr, C.J., D-ty pe cycli ns.  Tre n ds Bi oc he m Sci, 1 9 9 5. 2 0 ( 5): p. 1 8 7- 9 0.
1 2. 
T o y os hi ma, H. a n d T. H u nter, p 2 7, a n ovel i n hi bit or of G 1 cycli n- C dk pr otei n ki n ase 
activity, is rel ate d t o p 2 1.  Cell, 1 9 9 4. 7 8 ( 1): p. 6 7- 7 4.
1 3. 
L u kas, J., et al., Reti n o bl ast o m a- pr otei n- de pe n de nt cell-cycle i n hi biti o n by t he t u m o ur 
s u p press or p 1 6. Nat ure, 1 9 9 5. 3 7 5 ( 6 5 3 1): p. 5 0 3- 6.
1 4.  
Me de ma, R. H., et al., Gr o wt h s u p pressi o n by p 1 6i nk 4 re q uires f u ncti o n al reti n o bl ast o m a 
pr otei n.  Pr oc Natl Aca d Sci U S A, 1 9 9 5. 9 2 ( 1 4): p. 6 2 8 9- 9 3.
1 5. 
B utt, A.J., et al., D o w nstre a m t ar gets of gr o wt h f act or a n d oestr o ge n si g n alli n g a n d 
e n d ocri ne resist a nce: t he p ote nti al r oles of c- Myc, cycli n D 1 a n d cycli n E.  E n d ocr Relat 
Ca ncer, 2 0 0 5. 1 2 S u p pl 1 : p. S 4 7- 5 9.
1 6.  
Alt ucci, L., et al., Estr o ge n i n d uces e arly a n d ti me d activ ati o n of cycli n- de pe n de nt 
ki n ases 4, 5, a n d 6 a n d i ncre ases cycli n messe n ger ri b o n ucleic aci d ex pressi o n i n r at 
uter us.  E n d ocri n ol o g y, 1 9 9 7. 1 3 8 ( 3): p. 9 7 8- 8 4.
1 7.  
Ge u m, D., et al., Estr o ge n-i n d uce d cycli n D 1 a n d D 3 ge ne ex pressi o ns d uri n g m o use 
uteri ne cell pr olifer ati o n i n viv o: differe nti al i n d ucti o n mec h a nis m of cycli n D 1 a n d D 3.  
M ol Re pr o d De v, 1 9 9 7. 4 6 ( 4): p. 4 5 0- 8.
1 8.  
Watts, C. K., et al., A ntiestr o ge n i n hi biti o n of cell cycle pr o gressi o n i n bre ast c a ncer cells 
i n ass oci ate d wit h i n hi biti o n of cycli n- de pe n de nt ki n ase activity a n d decre ase d 
reti n o bl ast o m a pr otei n p h os p h oryl ati o n. M ol E n d ocri n ol, 1 9 9 5. 9 ( 1 2): p. 1 8 0 4- 1 3.
1 9. 
T ha n ga vel, C., et al., T her a pe utic ally activ ati n g R B: reest a blis hi n g cell cycle c o ntr ol i n 
e n d ocri ne t her a py-resist a nt bre ast c a ncer.  E n d ocr Relat Ca ncer, 2 0 1 1. 1 8 ( 3): p. 3 3 3- 4 5.
2 0.  
Y u, Q., et al., Re q uire me nt f or C D K 4 ki n ase f u ncti o n i n bre ast c a ncer.  Ca ncer Cell, 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
7 5
2 0 0 6. 9 ( 1): p. 2 3- 3 2.
2 1.  
K o nec n y, G. E., et al., Ex pressi o n of p 1 6 a n d reti n o bl ast o m a deter mi nes res p o nse t o 
C D K 4/ 6 i n hi biti o n i n ov ari a n c a ncer.  Cli n Ca ncer Res, 2 0 1 1. 1 7 ( 6): p. 1 5 9 1- 6 0 2.
2 2. 
Fr y, D. W., et al., S pecific i n hi biti o n of cycli n- de pe n de nt ki n ase 4/ 6 by P D 0 3 3 2 9 9 1 a n d 
ass oci ate d a ntit u m or activity i n h u m a n t u m or xe n o gr afts.  M ol Ca ncer T her, 2 0 0 4. 3 ( 1 1): 
p. 1 4 2 7- 3 8.
2 3. 
Ce n, L., et al., p 1 6- C dk 4- R b axis c o ntr ols se nsitivity t o a cycli n- de pe n de nt ki n ase 
i n hi bit or P D 0 3 3 2 9 9 1 i n gli o bl ast o m a xe n o gr aft cells. Ne ur o O nc ol, 2 0 1 2. 1 4 ( 7): p. 8 7 0-
8 1.
2 4. 
Fi n n, R. S., et al., P D 0 3 3 2 9 9 1, a selective cycli n D ki n ase 4/ 6 i n hi bit or, prefere nti ally 
i n hi bits pr olifer ati o n of l u mi n al estr o ge n rece pt or- p ositive h u m a n bre ast c a ncer cell li nes 
i n vitr o. Breast Ca ncer Res, 2 0 0 9. 1 1 ( 5): p. R 7 7.
2 5. 
Fi n n, R. S., et al., T he cycli n- de pe n de nt ki n ase 4/ 6 i n hi bit or p al b ocicli b i n c o m bi n ati o n 
wit h letr oz ole vers us letr oz ole al o ne as first-li ne tre at me nt of oestr o ge n rece pt or- p ositive, 
H E R 2- ne g ative, a dv a nce d bre ast c a ncer ( P A L O M A- 1/ T RI O- 1 8): a r a n d o mise d p h ase 2 
st u dy. La ncet O nc ol, 2 0 1 5. 1 6 ( 1): p. 2 5- 3 5.
2 6.  
Metz ger, O., et al., Rel ative effective ness of letr oz ole c o m p are d wit h t a m oxife n f or 
p atie nts wit h l o b ul ar c arci n o m a i n t he BI G 1- 9 8 tri al.  Ca ncer Res 7 2: S 1- 1, 2 0, 2 0 1 2.
2 7. 
Carr oll, J. S., et al., Ge n o me- wi de a n alysis of estr o ge n rece pt or bi n di n g sites.  Nat Ge net, 
2 0 0 6. 3 8 ( 1 1): p. 1 2 8 9- 9 7.
2 8.  
H urta d o, A., et al., F O X A 1 is a key deter mi n a nt of estr o ge n rece pt or f u ncti o n a n d 
e n d ocri ne res p o nse.  Nat Ge net, 2 0 1 1. 4 3 ( 1): p. 2 7- 3 3.
2 9. 
L u pie n, M., et al., F ox A 1 tr a nsl ates e pi ge netic si g n at ures i nt o e n h a ncer- drive n li ne a ge-
s pecific tr a nscri pti o n. Cell, 2 0 0 8. 1 3 2 ( 6): p. 9 5 8- 7 0.
3 0. 
L u pie n, M., et al., Gr o wt h f act or sti m ul ati o n i n d uces a disti nct E R( al p h a) cistr o me 
u n derlyi n g bre ast c a ncer e n d ocri ne resist a nce.  Ge nes De v, 2 0 1 0. 2 4 ( 1 9): p. 2 2 1 9- 2 7.
3 1. 
R oss-I n nes, C. S., et al., Differe nti al oestr o ge n rece pt or bi n di n g is ass oci ate d wit h 
cli nic al o utc o me i n bre ast c a ncer.  Nat ure, 2 0 1 2. 4 8 1 ( 7 3 8 1): p. 3 8 9- 9 3.
3 2.  
Vaz- L uis, I., et al., Cli nic o p at h ol o gic al fe at ures a m o n g p atie nts wit h a dv a nce d h u m a n 
e pi der m al gr o wt h f act or- 2- p ositive bre ast c a ncer wit h pr ol o n ge d cli nic al be nefit t o first-
li ne tr ast uz u m a b- b ase d t her a py: a retr os pective c o h ort st u dy. Cli n Breast Ca ncer, 2 0 1 3. 
1 3 ( 4): p. 2 5 4- 6 3.
3 3. 
Par ker, J. S., et al., S u pervise d risk pre dict or of bre ast c a ncer b ase d o n i ntri nsic s u bty pes.  
J Cli n O nc ol, 2 0 0 9. 2 7 ( 8): p. 1 1 6 0- 7.
3 4. 
S ha h, S. P., et al., M ut ati o n al ev ol uti o n i n a l o b ul ar bre ast t u m o ur pr ofile d at si n gle 
n ucle oti de res ol uti o n.  Nat ure, 2 0 0 9. 4 6 1 ( 7 2 6 5): p. 8 0 9- 1 3.
3 5.
C o m pre he nsive m olec ul ar p ortr aits of h u m a n bre ast t u m o urs.  Nat ure, 2 0 1 2. 4 9 0 ( 7 4 1 8): 
p. 6 1- 7 0.
3 6. 
Ciriell o, G., et al., C o m pre he nsive M olec ul ar P ortr aits of I nv asive L o b ul ar Bre ast 
C a ncer.  Cell, 2 0 1 5. 1 6 3 ( 2): p. 5 0 6- 1 9.
3 7. 
S para n o, J. A., et al., A dj uv a nt C he m ot her a py G ui de d by a 2 1- Ge ne Ex pressi o n Ass ay i n 
Bre ast C a ncer.  N E n gl J Me d, 2 0 1 8. 3 7 9 ( 2): p. 1 1 1- 1 2 1.
3 8. 
Pai k, S., et al., Ge ne ex pressi o n a n d be nefit of c he m ot her a py i n w o me n wit h n o de-
ne g ative, estr o ge n rece pt or- p ositive bre ast c a ncer.  J Cli n O nc ol, 2 0 0 6. 2 4 ( 2 3): p. 3 7 2 6-
3 4.
3 9. 
Car d os o, F., et al., 7 0- Ge ne Si g n at ure as a n Ai d t o Tre at me nt Decisi o ns i n E arly- St a ge 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
7 6
Bre ast C a ncer.  N E n gl J Me d, 2 0 1 6. 3 7 5 ( 8): p. 7 1 7- 2 9.
4 0.  
Al bai n, K. S., et al., Pr o g n ostic a n d pre dictive v al ue of t he 2 1- ge ne rec urre nce sc ore 
ass ay i n p ost me n o p a us al w o me n wit h n o de- p ositive, oestr o ge n-rece pt or- p ositive bre ast 
c a ncer o n c he m ot her a py: a retr os pective a n alysis of a r a n d o mise d tri al.  La ncet O nc ol, 
2 0 1 0. 1 1 ( 1): p. 5 5- 6 5.
4 1.  
G o n g, Y., et al., Deter mi n ati o n of oestr o ge n-rece pt or st at us a n d E R B B 2 st at us of bre ast 
c arci n o m a: a ge ne-ex pressi o n pr ofili n g st u dy.  La ncet O nc ol, 2 0 0 7. 8 ( 3): p. 2 0 3- 1 1.
4 2.  
Kar n, T., et al., D at a- drive n deriv ati o n of c ut offs fr o m a p o ol of 3, 0 3 0 Affy metrix arr ays 
t o str atify disti nct cli nic al ty pes of bre ast c a ncer. Breast Ca ncer Res Treat, 2 0 1 0. 1 2 0 ( 3): 
p. 5 6 7- 7 9.
4 3.  
Ki m, C., et al., Estr o ge n rece pt or ( E S R 1) m R N A ex pressi o n a n d be nefit fr o m t a m oxife n i n 
t he tre at me nt a n d preve nti o n of estr o ge n rece pt or- p ositive bre ast c a ncer. J Cli n O nc ol, 
2 0 1 1. 2 9 ( 3 1): p. 4 1 6 0- 7.
4 4. 
Si n n, B. V., et al., S E T E R/ P R: a r o b ust 1 8- ge ne pre dict or f or se nsitivity t o e n d ocri ne 
t her a py f or met ast atic bre ast c a ncer. N PJ Breast Ca ncer, 2 0 1 9. 5 : p. 1 6.
4 5.  
Hai be- Kai ns, B., et al., A T hree- Ge ne M o del t o R o b ustly I de ntify Bre ast C a ncer 
M olec ul ar S u bty pes.  J Natl Ca ncer I nst, 2 0 1 2.
4 6. 
C uzic k, J., et al., Pr o g n ostic v al ue of a n R N A ex pressi o n si g n at ure derive d fr o m cell 
cycle pr olifer ati o n ge nes i n p atie nts wit h pr ost ate c a ncer: a retr os pective st u dy.  La ncet 
O nc ol, 2 0 1 1. 1 2 ( 3): p. 2 4 5- 5 5.
4 7. 
S y m ma ns, W. F., et al., Ge n o mic i n dex of se nsitivity t o e n d ocri ne t her a py f or bre ast 
c a ncer. J Cli n O nc ol, 2 0 1 0. 2 8 ( 2 7): p. 4 1 1 1- 9.
4 8.  
Gra dis har, W.J., et al., Bre ast C a ncer, Versi o n 3. 2 0 2 0, N C C N Cli nic al Pr actice 
G ui deli nes i n O nc ol o gy.  J Natl C o m pr Ca nc Net w, 2 0 2 0. 1 8 ( 4): p. 4 5 2- 4 7 8.
4 9. 
S para n o, J. A., et al., Cli nic al a n d Ge n o mic Risk t o G ui de t he Use of A dj uv a nt T her a py 
f or Bre ast C a ncer. N E n gl J Me d, 2 0 1 9. 3 8 0 ( 2 5): p. 2 3 9 5- 2 4 0 5.
5 0.  
Ue n o, T., et al., Ev al u ati n g t he 2 1- ge ne ass ay Rec urre nce Sc ore( R) as a pre dict or of 
cli nic al res p o nse t o 2 4 weeks of ne o a dj uv a nt exe mest a ne i n estr o ge n rece pt or- p ositive 
bre ast c a ncer.  I nt J Cli n O nc ol, 2 0 1 4. 1 9 ( 4): p. 6 0 7- 1 3.
5 1.  
A kas hi- Ta na ka, S., et al., 2 1- Ge ne ex pressi o n pr ofile ass ay o n c ore nee dle bi o psies 
pre dicts res p o nses t o ne o a dj uv a nt e n d ocri ne t her a py i n bre ast c a ncer p atie nts.  Breast, 
2 0 0 9. 1 8 ( 3): p. 1 7 1- 4.
5 2. 
I wata, H., et al., V ali d ati o n of t he 2 1- ge ne test as a pre dict or of cli nic al res p o nse t o 
ne o a dj uv a nt h or m o n al t her a py f or E R +, H E R 2- ne g ative bre ast c a ncer: t he Tr a ns N E O S 
st u dy. Breast Ca ncer Res Treat, 2 0 1 9. 1 7 3 ( 1): p. 1 2 3- 1 3 3.
5 3.  
Gia n ni, L., et al., Ge ne ex pressi o n pr ofiles i n p ar affi n-e m be d de d c ore bi o psy tiss ue 
pre dict res p o nse t o c he m ot her a py i n w o me n wit h l oc ally a dv a nce d bre ast c a ncer.  J Cli n 
O nc ol, 2 0 0 5. 2 3 ( 2 9): p. 7 2 6 5- 7 7.
5 4.  
Yar dle y, D. A., et al., A p h ase II tri al of ix a be pil o ne a n d cycl o p h os p h a mi de as 
ne o a dj uv a nt t her a py f or p atie nts wit h H E R 2- ne g ative bre ast c a ncer: c orrel ati o n of 
p at h ol o gic c o m plete res p o nse wit h t he 2 1- ge ne rec urre nce sc ore.  Breast Ca ncer Res 
Treat, 2 0 1 5. 1 5 4 ( 2): p. 2 9 9- 3 0 8.
5 5. 
S ora n, A., et al., T he i m p act of O nc oty pe D X( R) rec urre nce sc ore of p ar affi n-e m be d de d 
c ore bi o psy tiss ues i n pre dicti n g res p o nse t o ne o a dj uv a nt c he m ot her a py i n w o me n wit h 
bre ast c a ncer.  Breast Dis, 2 0 1 6. 3 6 ( 2- 3): p. 6 5- 7 1.
5 6.  
De Mic hele, A., et al., A p h ase II tri al of a n or al C D K 4/ 6 i n hi bit or, P D 0 3 3 2 9 9 1, i n 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
7 7
a dv a nce d bre ast c a ncer.  J Cli n O nc ol, 2 0 1 3. 3 1 s u p pl : p. a bstr 5 1 9.
5 7. 
Fi n n, R. S., et al., Preli mi n ary res ults of a r a n d o mize d p h ase 2 st u dy of P D 0 3 3 2 9 9 1, a 
cycli n- de pe n de nt ki n ase ( C D K) 4/ 6 i n hi bit or, i n c o m bi n ati o n wit h letr oz ole f or first-li ne 
tre at me nt of p atie nts ( pts) wit h p ost- me n o p a us al, E R +, H E R 2- ne g ative ( H E R-) a dv a nce d 
bre ast c a ncer.  Ca ncer Res, 2 0 1 1. 7 1 ( 2 4s): p. P 1- 1 7- 0 5.
5 8. 
Sla m o n, D.J., et al., P h ase I st u dy of P D 0 3 3 2 9 9 1, cycli n- D ki n ase ( C D K) 4/ 6 i n hi bit or i n 
c o m bi n ati o n wit h letr oz ole f or first-li ne tre at me nt of p atie nts wit h E R- p ositive, H E R 2-
ne g ative bre ast c a ncer.  J Cli n O nc ol, 2 0 1 0. 2 8 ( 1 5s s u p pl): p. a bstr 3 0 6 0.
5 9.  
D o wsett, M., et al., Assess me nt of Ki 6 7 i n bre ast c a ncer: rec o m me n d ati o ns fr o m t he 
I nter n ati o n al Ki 6 7 i n Bre ast C a ncer w orki n g gr o u p. J Natl Ca ncer I nst, 2 0 1 1. 1 0 3 ( 2 2): p. 
1 6 5 6- 6 4.
6 0.  
Ha m m o n d, M. E., et al., A meric a n S ociety of Cli nic al O nc ol o gy/ C olle ge of A meric a n 
P at h ol o gists G ui deli ne Rec o m me n d ati o ns f or I m m u n o hist oc he mic al Testi n g of Estr o ge n 
a n d Pr o gester o ne Rece pt ors i n Bre ast C a ncer.  J Cli n O nc ol, 2 0 1 0.
6 1.  
Da b bs, D.J., R. B har ga va, a n d M. C hi v u k ula, L o b ul ar vers us d uct al bre ast ne o pl as ms: 
t he di a g n ostic utility of p 1 2 0 c ate ni n. A m J S ur g Pat h ol, 2 0 0 7. 3 1 ( 3): p. 4 2 7- 3 7.
6 2. 
S y m ma ns, W. F., et al., Me as ure me nt of resi d u al bre ast c a ncer b ur de n t o pre dict s urviv al 
after ne o a dj uv a nt c he m ot her a py.  J Cli n O nc ol, 2 0 0 7. 2 5 ( 2 8): p. 4 4 1 4- 2 2.
6 3.  
Par k K U, Gre g or y M, Baza n J, et al. Ne oa dj u va nt e n d ocri ne t hera p y use i n earl y sta ge 
breast ca ncer d uri n g t he c o vi d- 1 9 pa n de mic. Bre ast C a ncer Res Tre at . Mar 2 2 0 2 1: 1- 1 0.
6 4.  
Gi ulia n o A E, Ha wes D, Ball ma n K V, et al. Ass ociati o n of occ ult metastases i n se nti nel 
l y m p h n o des a n d b o ne marr o w wit h s ur vi val a m o n g w o me n wit h earl y-sta ge i n vasi ve 
breast ca ncer. J a m a. J ul 2 7 2 0 1 1; 3 0 6( 4): 3 8 5- 9 3.
6 5.  
Ka nt or O, W o n g S, Weiss A, Metz ger O, Mitte n d orf B A, Ki n g T A. Pr o g n ostic 
si g nifica nce of resi d ual n o dal disease after ne oa dj u va nt e n d ocri ne t hera p y f or h or m o ne 
rece pt or- p ositi ve breast ca ncer. n pj Bre ast . 2 0 2 0; A u g 1 3; 6: 3 5.
6 6.  
Ka nt or O, Wa ke ma n M, Weiss A, et al. A xillar y Ma na ge me nt After Ne oa dj u va nt 
E n d ocri ne T hera p y f or H or m o ne Rece pt or- P ositi ve Breast Ca ncer. A n n S ur g O nc ol . A u g 
3 1 2 0 2 0.
6 7.  
Gi ulia n o A E, H u nt K K, Ball ma n K V, et al. A xillar y dissecti o n vs n o a xillar y dissecti o n 
i n w o me n wit h i n vasi ve breast ca ncer a n d se nti nel n o de metastasis: a ra n d o mize d cli nical 
trial. J A M A. Fe b 9 2 0 1 1; 3 0 5( 6): 5 6 9- 7 5.
6 8. 
Fl ott or p S A, O x ma n A D, Kra use J, et al. A c hec klist f or i de ntif yi n g deter mi na nts of 
practice: a s yste matic re vie w a n d s y nt hesis of fra me w or ks a n d ta x o n o mies of fact ors t hat 
pre ve nt or e na ble i m pr o ve me nts i n healt hcare pr ofessi o nal practice. I m ple me nt Sci. Mar 
2 3 2 0 1 3; 8: 3 5.
6 9.  
Wal ker D, M yric k F. Gr o u n de d t he or y: a n e x pl orati o n of pr ocess a n d pr oce d ure. Q u al 
He alt h Res . A pr 2 0 0 6; 1 6( 4): 5 4 7- 5 9.
7 0.  
Gi ulia n o A E, H u nt K K, Ball ma n K V, et al. A xillar y dissecti o n vs n o a xillar y dissecti o n 
i n w o me n wit h i n vasi ve breast ca ncer a n d se nti nel n o de metastasis: a ra n d o mize d cli nical 
trial. J A M A. Fe b 9 2 0 1 1; 3 0 5( 6): 5 6 9- 7 5.
7 1.  
D o n ker M, va n Tie n h o ve n G, Stra ver M E, et al. Ra di ot hera p y or s ur ger y of t he a xilla 
after a p ositi ve se nti nel n o de i n breast ca ncer ( E O R T C 1 0 9 8 1- 2 2 0 2 3 A M A R O S): a 
ra n d o mise d, m ultice ntre, o pe n-la bel, p hase 3 n o n-i nferi orit y trial. L a ncet O nc ol . N o v 
2 0 1 4; 1 5( 1 2): 1 3 0 3- 1 0.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
7 8

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
7 9
A P P E N DI X A 
P E R F O R M A N C E S T A T U S C RI T E RI A
E C O G Perf or m a nce St at us Sc ale
K ar n ofs k y Perf or m a nce Sc ale
Gra de
Descri pti o ns
Perce nt
Descri pti o n
1 0 0
N or mal, n o c o m plai nts, n o e vi de nce 
of disease.
0
N or mal acti vit y.  F ull y acti ve, a ble 
t o carr y o n all pre- disease 
perf or ma nce wit h o ut restricti o n.
9 0
A ble t o carr y o n n or mal acti vit y; 
mi n or si g ns or s y m pt o ms of disease.
8 0
N or mal acti vit y wit h eff ort; s o me 
si g ns or s y m pt o ms of disease.
1
S y m pt o ms, b ut a m b ulat or y.  
Restricte d i n p h ysicall y stre n u o us 
acti vit y, b ut a m b ulat or y a n d a ble 
t o carr y o ut w or k of a li g ht or 
se de ntar y nat ure (e. g., li g ht 
h o use w or k, office w or k).
7 0
Cares f or self, u na ble t o carr y o n 
n or mal acti vit y or t o d o acti ve w or k.
6 0
Re q uires occasi o nal assista nce, b ut 
is a ble t o care f or m ost of his/ her 
nee ds.
2
I n be d < 5 0 % of t he ti me.  
A m b ulat or y a n d ca pa ble of all 
self-care, b ut u na ble t o carr y o ut 
a n y w or k acti vities.  U p a n d a b o ut 
m ore t ha n 5 0 % of wa ki n g h o urs.
5 0
Re q uires c o nsi dera ble assista nce a n d 
fre q ue nt me dical care.
4 0
Disa ble d, re q uires s pecial care a n d 
assista nce.
3
I n be d > 5 0 % of t he ti me.  Ca pa ble 
of o nl y li mite d self-care, c o nfi ne d 
t o be d or c hair m ore t ha n 5 0 % of 
wa ki n g h o urs.
3 0
Se verel y disa ble d, h os pitalizati o n 
i n dicate d.  Deat h n ot i m mi ne nt.
2 0
Ver y sic k, h os pitalizati o n i n dicate d. 
Deat h n ot i m mi ne nt.
4
1 0 0 % be dri d de n.  C o m pletel y 
disa ble d.  Ca n n ot carr y o n a n y 
self-care.  T otall y c o nfi ne d t o be d 
or c hair.
1 0
M ori b u n d, fatal pr ocesses 
pr o gressi n g ra pi dl y.
5
Dea d.
0
Dea d.

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
8 1

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
8 2
A P P E N DI X C 
S T U D Y P A R TI CI P A N T D R U G DI A R Y- WI N D O W
 
P A TI E N T I N S T R U C TI O N S: 
Ta ke y o ur me dicati o ns e xactl y as prescri be d b y y o ur d oct or.  See t he ne xt pa ge f or s pecific d oses f or eac h 
me dicati o n t hat y o u are ta ki n g o n t his st u d y. 
C o nti n ue ta ki n g y o ur me dicati o n u ntil t he date of y o ur bi o ps y pr oce d ure. If y o u ta ke m ore t ha n 1 4 da ys of 
me dicati o n, rec or d t he a d diti o nal da ys o n t he e xtra li nes o n t he diar y o n t he ne xt pa ge. T hese are s ha de d i n gra y. 
T hese li nes are o nl y t o be c o m plete d if y o u ta ke m ore t ha n 1 4 da ys of me dicati o n lea di n g u p t o y o ur bi o ps y. 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
8 3
S T U D Y P A R TI CI P A N T S E L F- A D MI NI S T E R E D DI A R Y:  E N D O C RI N E T H E R A P Y
Partici pa nt Na me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                         C ycle #: _ _ _ _ _ _
S T U D Y D R U G I N S T R U C TI O N S: Ta ke o ne _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ o n Da ys 1 – 1 4. Rec or d t he d ose of eac h 
me dicati o n o n t he c hart t o t he ri g ht after ta ki n g eac h da y.
D ate
Ti me
N u m ber of Pills 
T a ke n
C o m me nts
E x:
6/ 1/ 2 0 0 9
      8 : 1 5    
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1
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Da y 2
 
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Da y 3
 
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Da y 4
 
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Da y 5
 
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Da y 6
 
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Da y 7
 
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Da y 8
 
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Da y 9
 
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Da y 1 0
 
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Da y 1 1
 
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Da y 1 2
 
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Da y 1 3
 
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Da y 1 4
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Da y 1 5
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Da y 1 6
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Da y 1 7
         :          
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Patie nt Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   Date: _ _ _ _ _/ _ _ _/ _ _ _ _ _

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
8 4
A P P E N DI X D  
S T U D Y P A R TI CI P A N T A D MI NI S T E R E D D R U G DI A R Y- T R E A T M E N T
 
P A TI E N T I N S T R U C TI O N S: 
Ta ke y o ur me dicati o ns e xactl y as prescri be d b y y o ur d oct or.  See t he ne xt pa ge f or s pecific d oses f or eac h me dicati o n t hat 
y o u are ta ki n g o n t his st u d y. 

Kee p Pal b ocicli b ca ps ules i n t he b ottle(s) pr o vi de d a n d d o n ot tra nsfer t he m t o a n y ot her c o ntai ner. St ore at r o o m 
te m perat ure.
Pal b ocicli b s h o ul d b e t a k e n b y m o ut h o n c e p er d a y at a p pr o xi matel y t he sa me ti me eac h da y t o get her wit h f o o d.  T here is 
n o ti mefra me s pecifie d i n w hic h partici pa nts s h o ul d eat w he n ta ki n g pal b ocicli b.

D uri n g C ycles 1 a n d 2 y o u will ha ve bl o o d w or k d o ne o n Da y 1 5. Please d o n ot ta ke t he ne xt da y’s dr u g ( Da y 1 6) 
u ntil a pr o vi der calls y o u t o disc uss t he res ults.

Ca ps ules m ust be s wall o we d w h ole. D o n ot s oa k ca ps ules or e m pt y c o nte nts i nt o a n y f o o d or dri n k. 

If y o u v o mit aft er t a ki n g P al b o ci cli b, d o N O T t a k e a n ot h er d os e. Pl e as e n ot e a n y v o miti n g i n t h e C o m m e nts  
s e cti o n of t h e di ar y o n t h e n e xt p a g e. 

If a d os e is miss e d a n d it is l ess t h a n 6 h o urs fr o m us u al ti m e of d osi n g, t h e n y o u m a y t a k e t h at d os e. 
Ot h er wis e  t h at d os e s h o ul d b e s ki p p e d a n d N O T t a k e n. Y o u s h o ul d r es u m e r e g ul ar d osi n g t h e f oll o wi n g d a y.  
If y o u miss a d os e, r e c or d “ 0 ” f or N u m b er T a k e n o n t h e n e xt p a g e. 

If y o u a c ci d e nt all y t a k e a n e xtr a d os e d uri n g a d a y s ki p t h e n e xt d a y’s d os e a n d r e c or d t h e e xtr a d os e o n t h e 
n e xt p a g e.  
T he  use of t he f oll o wi n g c o m p o u n ds is 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 d ucers, i ncl u di n g 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.

Str o n g C Y P 3 A i n hi bit ors, i ncl u di n g, b oce pre vir, clarit hr o m yci n, c o ni va pta n, dela vir 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 pefr uit.

M o derate C Y P 3 A i n hi bit ors i ncl u di n g a m pre na vir, ataza na vir, diltiaze m, er yt hr o m yci n, f osa m pre na vir, 
vera pa mil.

M o derate C Y P 3 A i n d ucers i ncl u di n g fel ba mate, ne vira pi ne, p he n o bar bital, rifa b uti n.
F O R C LI NI C U S E O N L Y: 
Staff I nitials:
 
Date Dis pe nse d:
 
Date Ret ur ne d:
 
# Pal b ocicli b ca ps ules 
dis pe nse d: 
#  Pal b ocicli b ca ps ules 
ret ur ne d:
#  Pal b ocicli b ca ps ules t hat s h o ul d ha ve bee n ta ke n:
 

Gi ve patie nt all 4 pa ges of Dr u g Diar y 
sta ple d t o get her.  Pr o vi de o ne diar y per 
c ycle ( 2 8 da ys).

C o m plete patie nt i de ntifiers a n d me dical 
tea m c o ntact i nf or mati o n o n pa ges 2- 5. 

C o m plete date of last Pal b ocicli b d ose n 
pa ge 2 a n d t he na me of e n d ocri ne 
t hera p y o n pa ge 4. 

W he n patie nt ret ur ns pill b ottles a n d 
diar y perf or m a Pal b ocicli b pill c o u nt 
a n d rec or d a d here nce i nf or mati o n i n t he 
b o x t o t he ri g ht O R i n t he p atie nt 
rec or d . 
Discre pa nc y N otes:
 
 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
8 5
S T U D Y P A R TI CI P A N T S E L F- A D MI NI S T E R E D DI A R Y: P A L B O CI C LI B ( C ycles 1- 2)
Partici pa nt Na me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                         C ycle #: _ _ _ _ _ _
Y o ur D oct or _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _    P h o ne _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Y o ur N urse _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   P h o ne _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
S T U D Y D R U G I N S T R U C TI O N S: Ta ke o ne Pal b ocicli b ca ps ule o n Da ys 1 – 2 1. Rec or d t he d ose of eac h me dicati o n o n 
t he c hart t o t he ri g ht after ta ki n g eac h da y.
D ate
Ti me
N u m ber of 
P al b ocicli b 
C a ps ules T a ke n
C o m me nts
E x:
6/ 1/ 2 0 0 9
      8 : 1 5    
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1
V o mite d 1 h o ur later
Da y 1
 
         :         
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Da y 2
 
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Da y 3
 
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Da y 4
 
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Da y 5
 
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Da y 6
 
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Da y 7
 
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Da y 8
 
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Da y 9
 
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Da y 1 0
 
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Da y 1 1
 
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Da y 1 2
 
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Da y 1 3
 
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Da y 1 4
 
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Da y 1 5
 
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D uri n g Cycles 1 a n d 2: Re me m ber t o h ave y o ur l a b w ork d o ne o n D ay 1 5.  M ake s ure y o u s pe ak wit h y o ur pr ovi der 
bef ore t aki n g t he c a ps ule o n D ay 1 6.
Da y 1 6
 
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Da y 1 7
 
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Da y 1 8
 
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Da y 1 9
 
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Da y 2 0
 
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Da y 2 1
 
         :         
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D o n ot t a ke a n y P al b ocicli b after:  _ _ _ _ _/ _ _ _ _ _/ _ _ _ _ _ _ _ _ _  
Patie nt Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   Date: _ _ _ _ _/ _ _ _ _ _/ _ _ _ _ _ _ _ _ _

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
8 6
S T U D Y P A R TI CI P A N T S E L F- A D MI NI S T E R E D DI A R Y: P A L B O CI C LI B ( C ycle 3- 6)
Partici pa nt Na me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                         C ycle #: _ _ _ _ _ _
Y o ur D oct or _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _    P h o ne _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Y o ur N urse _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   P h o ne _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
S T U D Y D R U G I N S T R U C TI O N S: Ta ke o ne Pal b ocicli b ca ps ule o n Da ys 1 – 2 1. Rec or d t he d ose of eac h me dicati o n o n 
t he c hart t o t he ri g ht after ta ki n g eac h da y.
D ate
Ti me
N u m ber of 
P al b ocicli b 
C a ps ules T a ke n
C o m me nts
E x:
6/ 1/ 2 0 0 9
      8 : 1 5    
 A M    
 P M
1
V o mite d 1 h o ur later
Da y 1
 
         :         
 A M    
 P M
 
 
Da y 2
 
         :         
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Da y 3
 
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Da y 4
 
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Da y 5
 
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Da y 6
 
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Da y 7
 
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Da y 8
 
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Da y 9
 
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Da y 1 0
 
         :         
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Da y 1 1
 
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Da y 1 2
 
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Da y 1 3
 
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Da y 1 4
 
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Da y 1 5
 
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Da y 1 6
 
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Da y 1 7
 
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Da y 1 8
 
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Da y 1 9
 
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Da y 2 0
 
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Da y 2 1
 
         :         
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D o n ot t a ke a n y P al b ocicli b after:  _ _ _ _ _/ _ _ _ _ _/ _ _ _ _ _ _ _ _ _  
Patie nt Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   Date: _ _ _ _ _/ _ _ _ _ _/ _ _ _ _ _ _ _ _ _

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
8 7
S T U D Y P A R TI CI P A N T S E L F- A D MI NI S T E R E D DI A R Y:  E N D O C RI N E T H E R A P Y
Partici pa nt Na me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                         C ycle #: _ _ _ _ _ _
S T U D Y D R U G I N S T R U C TI O N S: Ta ke o ne _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ o n Da ys 1 – 2 8. Rec or d t he 
d ose of eac h me dicati o n o n t he c hart t o t he ri g ht after ta ki n g eac h da y.
D ate
Ti me
N u m ber of Pills 
T a ke n
C o m me nts
E x:
6/ 1/ 2 0 0 9
      8 : 1 5    
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1
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Patie nt Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   Date: _ _ _ _ _/ _ _ _/ _ _ _ _ _

Pr ot oc ol #: 1 6- 0 5 2
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A P P E N DI X E 
D F/ H C C M U L TI- C E N T E R D S M P
D F CI I R B Pr ot oc ol #: 1 6- 0 5 2
A P P E N DI X E
D a n a- F ar ber/ H ar v ar d C a ncer Ce nter
M ulti- Ce nter D at a a n d S afet y M o nit ori n g Pl a n

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
8 9
T A B L E O F C O N T E N T S
S C H E M A......................................................................................................................................... 2
1.  
O BJ E C TI V E S...................................................................................................................... 7
1. 1 
St u d y Desi g n............................................................................................................ 7
1. 2 
Pri mar y O bjecti ve.................................................................................................... 7
1. 3 
Sec o n dar y O bjecti ves............................................................................................... 8
1. 4 
C orrelati ve Scie nce O bjecti ves................................................................................ 8
2. 
B A C K G R O U N D................................................................................................................. 9
2. 1 
St u d y Disease(s)....................................................................................................... 9
2. 2 
Rati o nale................................................................................................................ 1 4
2. 3 
Rati o nale - C orrelati ve St u dies.............................................................................. 1 6
3. 
P A R TI CI P A N T S E L E C TI O N........................................................................................... 2 1
3. 1 
Eli gi bilit y Criteria.................................................................................................. 2 1
3. 2 
E xcl usi o n Criteria.................................................................................................. 2 3
3. 3 
I ncl usi o n of W o me n a n d Mi n orities...................................................................... 2 4
4. 
R E GI S T R A TI O N P R O C E D U R E S ................................................................................... 2 4
4. 1  
Ge neral G ui deli nes f or D F/ H C C a n d D F/ P C C I nstit uti o ns................................... 2 5
4. 2 
Re gistrati o n Pr ocess f or D F/ H C C a n d D F/ P C C I nstit uti o ns................................. 2 5
4. 3  
Ge neral G ui deli nes f or Ot her I n vesti gati ve Sites.................................................. 2 5
4. 4 
Re gistrati o n Pr ocess f or Ot her I n vesti gati ve Sites................................................. 2 5
5. 
S T U D Y P R O C E D U R E S................................................................................................... 2 6
5. 1 
Pr oce d ures f or assi g ni n g patie nts i nt o t he st u d y.................................................... 2 6
5. 2  
Me dical Hist or y a n d De m o gra p hic Data............................................................... 2 7
5. 3 
P h ysical E xa mi nati o ns........................................................................................... 2 7
5. 4  
Vital si g ns.............................................................................................................. 2 7
5. 5 
La b orat or y assess me nts ......................................................................................... 2 7
5. 6 
T u m or Sta gi n g ....................................................................................................... 2 8
5. 7 
S ur gical Assess me nt.............................................................................................. 2 8
5. 8 
T u m or Tiss ue C ollecti o n........................................................................................ 2 8
T u m or bl oc ks a n d sli des will be ke pt f or f ut ure researc h at D F/ H C C; 
h o we ver, if a t u m or bl oc k or sli des are nee de d f or cli nical care 
p ur p oses, t he partici pati n g site s h o ul d c o ntact t he c o or di nati n g 
ce nter st u d y c o or di nat or t o re q uest t hat t he a p plica ble tiss ue be 
ret ur ne d...................................................................................................... 3 0
5. 9 
Researc h Bl o o d Sa m ple C ollecti o n ....................................................................... 3 1
5. 1 0  
A ge nt A d mi nistrati o n............................................................................................. 3 3
5. 1 1  
Ge neral C o nc o mita nt Me dicati o n a n d S u p p orti ve Care G ui deli nes...................... 3 6
5. 1 2  
Defi niti ve Breast S ur ger y ...................................................................................... 3 8
5. 1 3 
P ost- o perati ve Ra di ot hera p y.................................................................................. 3 8

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5. 1 4 
P ost- o perati ve A dj u va nt T hera p y.......................................................................... 3 8
5. 1 5 
Criteria f or Ta ki n g a Partici pa nt off Pr ot oc ol T hera p y.......................................... 3 9
5. 1 6  
D urati o n of F oll o w U p........................................................................................... 3 9
5. 1 7 
Criteria f or Ta ki n g a Partici pa nt off St u d y............................................................ 4 0
6. 
E X P E C T E D T O XI CI TI E S A N D D O SI N G D E L A Y S/ D O S E M O DI FI C A TI O N S ......... 4 1
6. 1 
E n d ocri ne T hera p y................................................................................................. 4 1
6. 2 
Pal b ocicli b.............................................................................................................. 4 2
6. 3  
D ose M o dificati o n G ui deli nes............................................................................... 4 4
7.  
A D V E R S E E V E N T S:  LI S T A N D R E P O R TI N G R E Q UI R E M E N T S............................ 4 9
7. 1  
M o nit ori n g of A d verse E ve nts a n d Peri o d of O bser vati o n.................................... 4 9
7. 2 
E x pecte d T o xicities................................................................................................ 5 0
7. 3  
A d verse E ve nt C haracteristics............................................................................... 5 1
7. 4 
E x pe dite d A d verse E ve nt Re p orti n g...................................................................... 5 1
7. 5 
E x pe dite d Re p orti n g t o  
............................................................................... 5 2
7. 6 
E x pe dite d Re p orti n g t o H os pital Ris k Ma na ge me nt ............................................. 5 4
7. 7 
R o uti ne A d verse E ve nt Re p orti n g......................................................................... 5 4
8. 
P H A R M A C E U TI C A L I N F O R M A TI O N.......................................................................... 5 4
8. 1 
Ta m o xife n.............................................................................................................. 5 4
8. 2 
Letr oz ole................................................................................................................ 5 5
8. 3 
Pal b ocicli b.............................................................................................................. 5 6
9. 
BI O M A R K E R, C O R R E L A TI V E, A N D S P E CI A L S T U DI E S ........................................ 5 8
9. 1 
Bi o mar ker li n ke d t o st u d y pri mar y o bjecti ve........................................................ 5 8
9. 2 
Bi o mar kers li n ke d t o c orrelati ve st u dies................................................................ 5 9
1 0. 
S T U D Y C A L E N D A R ....................................................................................................... 6 0
1 1.  
M E A S U R E M E N T O F E F F E C T ....................................................................................... 6 3
1 1. 1  
A ntit u m or Effect – S oli d T u m ors.......................................................................... 6 3
1 1. 2 
Ra di o gra p hic assess me nt....................................................................................... 6 4
1 1. 3 
Cli nical assess me nts............................................................................................... 6 4
1 1. 4 
Pat h ol o gic Res p o nse.............................................................................................. 6 4
1 2.  
D A T A R E P O R TI N G / R E G U L A T O R Y R E Q UI R E M E N T S........................................... 6 5
1 2. 1  
Data Re p orti n g....................................................................................................... 6 5
1 2. 2  
Data Safet y M o nit ori n g.......................................................................................... 6 5
1 2. 3  
M ultice nter G ui deli nes........................................................................................... 6 6
1 2. 4 
C olla b orati ve Researc h a n d F ut ure Use of Data a n d Bi os peci me ns...................... 6 6
1 3. 
S T A TI S TI C A L C O N SI D E R A TI O N S............................................................................... 6 7
1 3. 1 
St u d y Desi g n/ E n d p oi nts ........................................................................................ 6 7
1 3. 2 
Sa m ple Size, Accr ual Rate a n d St u d y D urati o n.................................................... 6 7
1 3. 3 
I nteri m M o nit ori n g Pla n ........................................................................................ 6 8
1 3. 4  
A nal ysis of Pri mar y E n d p oi nts.............................................................................. 6 8

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1 3. 5  
A nal ysis of Sec o n dar y E n d p oi nts.......................................................................... 6 9
1 3. 6 
C orrelati ve Scie nce O bjecti ves.............................................................................. 7 0
1 3. 7 
E x pl orat or y A xillar y L y m p h N o de S ur ger y O bjecti ves........................................ 7 0
1 3. 8 
Re p orti n g a n d E xcl usi o ns...................................................................................... 7 1
1 4. 
P U B LI C A TI O N P L A N ..................................................................................................... 7 1
1 5. 
R E F E R E N C E S .................................................................................................................. 7 3
A P P E N DI X A 
P E R F O R M A N C E S T A T U S C RI T E RI A .................................................. 7 8
A P P E N DI X B 
S P E CI M E N R E Q UI SI TI O N F O R M......................................................... 7 9
A P P E N DI X C  
S T U D Y P A R TI CI P A N T D R U G DI A R Y- WI N D O W............................. 8 1
A P P E N DI X D  
S T U D Y P A R TI CI P A N T A D MI NI S T E R E D D R U G DI A R Y- 
T R E A T M E N T................................................................................................................... 8 3
A P P E N DI X E  
D F/ H C C M U L TI- C E N T E R D S M P........................................................... 8 7
1. 
I N T R O D U C TI O N............................................................................................................. 9 2
1. 1 
P ur p ose................................................................................................................... 9 2
1. 2  
M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n Defi niti o ns.................................. 9 2
2.  
G E N E R A L R O L E S A N D R E S P O N SI BI LI TI E S ............................................................. 9 3
2. 1  
D F/ H C C S p o ns or................................................................................................... 9 3
2. 2 
C o or di nati n g Ce nter............................................................................................... 9 4
2. 3 
Partici pati n g I nstit uti o n.......................................................................................... 9 4
3.  
D F/ H C C R E Q UI R E M E N T S F O R M U L TI- C E N T E R P R O T O C O L S ............................. 9 5
3. 1 
Pr ot oc ol Distri b uti o n.............................................................................................. 9 5
3. 2 
Pr ot oc ol Re visi o ns a n d Cl os ures ........................................................................... 9 5
3. 3 
I nf or me d C o nse nt Re q uire me nts........................................................................... 9 5
3. 4 
I R B D oc u me ntati o n............................................................................................... 9 6
3. 5 
I R B Re- A p pr o val................................................................................................... 9 6
3. 6 
Partici pa nt C o nfi de ntialit y a n d A ut h orizati o n State me nt...................................... 9 6
3. 7  
D F/ H C C M ulti- Ce nter Pr ot oc ol Re gistrati o n P olic y............................................. 9 7
3. 8  
D F/ H C C Pr ot oc ol Case N u m ber............................................................................ 9 7
3. 9 
Pr ot oc ol De viati o ns, E xce pti o ns a n d Vi olati o ns ................................................... 9 7
3. 1 0 
Safet y Assess me nts a n d T o xicit y M o nit ori n g....................................................... 9 8
3. 1 1  
Data Ma na ge me nt.................................................................................................. 9 9
4. 
R E Q UI SI TI O NI N G I N V E S TI G A TI O N A L D R U G........................................................ 1 0 0
5.  
M O NI T O RI N G: Q U A LI T Y C O N T R O L........................................................................ 1 0 0
5. 1  
O n g oi n g M o nit ori n g of Pr ot oc ol C o m plia nce..................................................... 1 0 0
5. 2  
M o nit ori n g Re p orts.............................................................................................. 1 0 1

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Versi o n D ate: J uly 6, 2 0 2 2
9 2
5. 3  
Accr ual M o nit ori n g.............................................................................................. 1 0 1
6.  
A U DI TI N G: Q U A LI T Y A S S U R A N C E......................................................................... 1 0 1
6. 1  
A u dit Pla n: D F/ H C C S p o ns ore d Trials ............................................................... 1 0 2
6. 2  
A u dit N otificati o n................................................................................................ 1 0 2
6. 3  
A u dit Re p orts....................................................................................................... 1 0 2
6. 4 
Partici pati n g I nstit uti o n Perf or ma nce.................................................................. 1 0 2
A P P E N DI X F  
Re p orta ble E ve nt C o ver S heet................................................................. 1 0 2
A P P E N DI X G  
A xillar y Ma na ge me nt after Ne oa dj u va nt E n d ocri ne T hera p y f or H or m o ne-
P ositi ve Breast Ca ncer ( S ur ge o n I nter vie w G ui de)......................................................... 1 0 5

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
9 3
1.
I N T R O D U C TI O N
T he Da na- Far ber/ Har var d Ca ncer Ce nter M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n ( D F/ H C C 
D S M P) o utli nes t he pr oce d ures f or c o n d ucti n g a D F/ H C C M ulti- Ce nter researc h pr ot oc ol. T he 
D F/ H C C D S M P s h o ul d ser ve as a refere nce f or a n y sites e xter nal t o D F/ H C C t hat will be 
partici pati n g i n t he researc h pr ot oc ol.
1. 1 
P ur p ose
T o esta blis h sta n dar ds t hat will e ns ure t hat a Da na- Far ber/ Har var d Ca ncer Ce nter M ulti-
Ce nter pr ot oc ol will c o m pl y wit h Fe deral Re g ulati o ns, Healt h I ns ura nce P orta bilit y a n d 
Acc o u nta bilit y Act ( HI P A A) re q uire me nts a n d a p plica ble D F/ H C C Sta n dar d O perati n g 
Pr oce d ures. .       
1. 2  
M ulti- Ce nter D at a a n d S afet y M o nit ori n g Pl a n Defi niti o ns
D F/ H C C M ulti- Ce nter Pr ot oc ol :  A researc h pr ot oc ol i n w hic h o ne  or m ore o utsi de 
i nstit uti o ns are c olla b orati n g wit h Da na- Far ber/ Har var d Ca ncer Ce nter w here  a D F/ H C C 
i n vesti gat or is t he s p o ns or. D F/ H C C i ncl u des Da na- Far ber/ Part ners Ca ncer Care ( D F/ P C C) 
Net w or k Cli nical Trial Affiliates. 
Le a d I nstit uti o n:  O ne of t he  Da na- Far ber/ Har var d Ca ncer Ce nter c o ns orti u m me m bers 
( Da na- Far ber Ca ncer I nstit ute ( D F CI), Massac h usetts Ge neral H os pital ( M G H), Bet h Israel 
Deac o ness Me dical Ce nter ( BI D M C), B ost o n C hil dre n’s H os pital ( B C H), Bri g ha m a n d 
W o me n’s H os pital ( B W H)) res p o nsi ble f or t he c o or di nati o n, de vel o p me nt, s u b missi o n, a n d 
a p pr o val of a pr ot oc ol as well as its s u bse q ue nt a me n d me nts per t he D F CI I R B a n d 
a p plica ble re g ulat or y g ui deli nes ( F o o d a n d Dr u g A d mi nistrati o n ( F D A), etc.).  T he Lea d 
I nstit uti o n is t y picall y t he h o me of t he D F/ H C C S p o ns or. T he Lea d I nstit uti o n als o t y picall y 
ser ves as t he C o or di nati n g Ce nter f or t he D F/ H C C M ulti- Ce nter Pr ot oc ol.  
D F/ H C C S p o ns or:  T he  pers o n s p o ns ori n g t he s u b mitte d M ulti- Ce nter pr ot oc ol.  Wit hi n 
D F/ H C C, t his pers o n is t he O verall Pri nci pal I n vesti gat or w h o ta kes res p o nsi bilit y f or 
i nitiati o n, ma na ge me nt a n d c o n d uct of t he pr ot oc ol at all researc h l ocati o ns. I n a p plica ble 
pr ot oc ols, t he D F/ H C C S p o ns or will ser ve as t he si n gle liais o n wit h a n y re g ulat or y a ge ncies 
(i.e. F D A). T he D F/ H C C S p o ns or has ulti mate a ut h orit y o ver t he pr ot oc ol a n d is res p o nsi ble 
f or t he c o n d uct of t he st u d y at D F/ H C C a n d all Partici pati n g I nstit uti o ns. I n m ost cases t he 
D F/ H C C S p o ns or is t he sa me pers o n as t he D F/ H C C O verall Pri nci pal I n vesti gat or; 
h o we ver, b ot h r oles ca n be fille d b y t w o differe nt pe o ple. 
P artici p ati n g I nstit uti o n:  A n i nstit uti o n t hat is o utsi de t he D F/ H C C a n d D F/ P C C 
c o ns orti u m t hat is c olla b orati n g wit h D F/ H C C o n a pr ot oc ol w here t he s p o ns or is a D F/ H C C 
I n vesti gat or.  T he Partici pati n g I nstit uti o n ac k n o wle d ges t he D F/ H C C S p o ns or as ha vi n g 
t he ulti mate a ut h orit y a n d res p o nsi bilit y f or t he o verall c o n d uct of t he st u d y.   
C o or di n ati n g Ce nter: T he e ntit y (i.e. Lea d I nstit uti o n, 
Me dical 
M o nit or, C o ntract 
Researc h Or ga nizati o n ( C R O), etc) t hat pr o vi des a d mi nistrati ve s u p p ort t o t he D F/ H C C 
S p o ns or i n or der t hat he/s he ma y f ulfill t he res p o nsi bilities o utli ne d i n t he pr ot oc ol 

Pr ot oc ol #: 1 6- 0 5 2
Versi o n D ate: J uly 6, 2 0 2 2
9 4
d oc u me nt a n d D S M P, a n d as s pecifie d i n a p plica ble re g ulat or y g ui deli nes (i.e. C T E P M ulti-
Ce nter G ui deli nes). I n ge neral, t he Lea d I nstit uti o n is t he C o or di nati n g Ce nter f or t he 
D F/ H C C M ulti- Ce nter Pr ot oc ol. S h o ul d t he D F/ H C C S p o ns or deci de t o use a C R O, t he 
C R O will be dee me d t he C o or di nati n g Ce nter.  
D F/ H C C Office of D at a Q u alit y ( O D Q), f or merl y Q u alit y Ass ur a nce Office f or 
Cli nic al Tri als ( Q A C T): A gr o u p wit hi n D F/ H C C res p o nsi ble f or re gisteri n g h u ma n 
s u bjects f or trials, e ns uri n g hi g h- q ualit y sta n dar ds are use d f or data c ollecti o n a n d t he 
o n g oi n g ma na ge me nt of cli nical trials, a u diti n g, a n d data a n d safet y m o nit ori n g. O D Q als o 
c o or di nates q ualit y ass ura nce eff orts relate d t o m ulti-ce nter cli nical researc h.
2.
G E N E R A L R O L E S A N D R E S P O N SI BI LI TI E S
F or D F/ H C C M ulti- Ce nter Pr ot oc ols, t he D F/ H C C S p o ns or, t he C o or di nati n g Ce nter, a n d t he 
Partici pati n g I nstit uti o ns are e x pecte d t o a d here t o t he f oll o wi n g ge neral res p o nsi bilities: 
2. 1  
D F/ H C C S p o ns or
T he D F/ H C C S p o ns or, Ott o Metz ger, M D, will acce pt res p o nsi bilit y f or all as pects of c o n d ucti n g 
a D F/ H C C M ulti- Ce nter pr ot oc ol w hic h i ncl u des b ut is n ot li mite d t o: 

O versee t he c o or di nati o n, de vel o p me nt, s u b missi o n, a n d a p pr o val of t he pr ot oc ol as well 
as s u bse q ue nt a me n d me nts.  

E ns ure t hat t he i n vesti gat ors, st u d y tea m me m bers, a n d Partici pati n g I nstit uti o ns are 
q ualifie d a n d a p pr o priatel y res o urce d t o c o n d uct t he pr ot oc ol. 

I ncl u de t he M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n as a n a p pe n di x t o t he pr ot oc ol.

E ns ure all Partici pati n g I nstit uti o ns are usi n g t he c orrect versi o n of t he pr ot oc ol.

E ns ure t hat eac h partici pati n g i n vesti gat or a n d st u d y tea m me m ber recei ves a de q uate 
pr ot oc ol trai ni n g a n d/ or a Site I nitiati o n Visit pri or t o e nr olli n g partici pa nts a n d t hr o u g h o ut 
trial’s c o n d uct as nee de d.

E ns ure t he pr ot oc ol will be pr o vi de d t o eac h partici pati n g site i n a la n g ua ge u n dersta n da ble 
t o all a p plica ble site pers o n nel w he n E n glis h is n ot t he pri mar y la n g ua ge. 

M o nit or pr o gress a n d o verall c o n d uct of t he st u d y at all Partici pati n g I nstit uti o ns. 

E ns ure all D F CI I nstit uti o nal Re vie w B oar d (I R B), D F/ H C C a n d ot her a p plica ble (i.e. 
F D A) re p orti n g re q uire me nts are met. 

Re vie w data a n d mai ntai n ti mel y s u b missi o n of data f or st u d y a nal ysis. 

Act as t he si n gle liais o n wit h F D A as a p plica ble.

E ns ure c o m plia nce wit h all re q uire me nts as set f ort h i n t he C o de of Fe deral Re g ulati o ns, 
a p plica ble D F/ H C C re q uire me nts, HI P A A re q uire me nts, a n d t he a p pr o ve d pr ot oc ol.

C o m mit t o t he pr o visi o n t hat t he pr ot oc ol will n ot be re writte n or m o difie d b y a n y o ne ot her 
t ha n t he D F/ H C C S p o ns or.

I de ntif y a n d q ualif y Partici pati n g I nstit uti o ns a n d o btai n accr ual c o m mit me nts pri or t o 
e xte n di n g t he pr ot oc ol t o t hat site.

M o nit or accr ual a n d a d dress Partici pati n g I nstit uti o ns t hat are n ot meeti n g t heir accr ual 
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2. 2  
C o or di n ati n g Ce nter 
T he ge neral res p o nsi bilities of t he C o or di nati n g Ce nter ma y i ncl u de b ut are n ot li mite d t o:

Assist i n pr ot oc ol de vel o p me nt 

Mai ntai n F D A c orres p o n de nce, as a p plica ble.

Re vie w re gistrati o n materials f or eli gi bilit y a n d re gister partici pa nts fr o m Partici pati n g 
I nstit uti o ns wit h D F/ H C C O D Q/ Q A C T.

Distri b ute pr ot oc ol a n d i nf or me d c o nse nt d oc u me nt u p dates t o Partici pati n g I nstit uti o ns as 
nee de d.

O versee t he data c ollecti o n pr ocess fr o m Partici pati n g I nstit uti o ns.

Mai ntai n d oc u me ntati o n of Seri o us A d verse E ve nt ( S A E) re p orts a n d 
de viati o ns/ vi olati o n s u b mitte d b y Partici pati n g I nstit uti o ns a n d pr o vi de t o t he D F/ H C C 
S p o ns or f or ti mel y re vie w.  

Distri b ute seri o us a d verse e ve nts re p orte d t o t he D F/ H C C S p o ns or t hat fall u n der t he D F CI 
I R B A d verse E ve nt Re p orti n g P olic y t o all Partici pati n g I nstit uti o ns.

Pr o vi de Partici pati n g I nstit uti o ns wit h i nf or mati o n re gar di n g D F/ H C C re q uire me nts t hat 
t he y will be e x pecte d t o c o m pl y wit h.

Carr y o ut pla n t o m o nit or Partici pati n g I nstit uti o ns eit her b y o n-site or re m ote m o nit ori n g. 

Mai ntai n Re g ulat or y d oc u me nts of all Partici pati n g I nstit uti o ns w hic h i ncl u des b ut is n ot 
li mite d t o t he f oll o wi n g: l ocal I R B a p pr o vals/ n otificati o ns fr o m all Partici pati n g 
I nstit uti o ns, c o nfir mati o n of Fe deral wi de Ass ura nces ( F W As) f or all sites,  all S A E 
s u b missi o ns, Scree ni n g L o gs f or all sites, I R B a p pr o ve d c o nse nts f or all sites

C o n d uct re g ular c o m m u nicati o ns wit h all Partici pati n g I nstit uti o ns (c o nfere nce calls, 
e mails, etc) a n d mai ntai n d oc u me ntati o n all rele va nt c o m m u nicati o ns.
2. 3 
P artici p ati n g I nstit uti o n
Eac h Partici pati n g I nstit uti o n is e x pecte d t o c o m pl y wit h all a p plica ble fe deral re g ulati o ns a n d 
D F/ H C C re q uire me nts, t he pr ot oc ol a n d HI P A A re q uire me nts. 
T he ge neral res p o nsi bilities f or eac h Partici pati n g I nstit uti o n ma y i ncl u de b ut are n ot li mite d t o:

D oc u me nt t he dele gati o n of researc h s pecific acti vities t o st u d y pers o n nel.

C o m mit t o t he accr ual of partici pa nts t o t he pr ot oc ol.

S u b mit pr ot oc ol a n d/ or a me n d me nts t o t heir l ocal I R B.

Mai ntai n re g ulat or y files as per s p o ns or re q uire me nts.

Pr o vi de t he C o or di nati n g Ce nter wit h re g ulat or y d oc u me nts or s o urce d oc u me nts as 
re q ueste d.

Partici pate i n pr ot oc ol trai ni n g pri or t o e nr olli n g partici pa nts a n d t hr o u g h o ut t he trial as 
re q uire d (i.e. telec o nfere nces).

U p date C o or di nati n g Ce nter wit h researc h staff c ha n ges o n a ti mel y basis.

Re gister partici pa nts t hr o u g h t he C o or di nati n g Ce nter pri or t o be gi n ni n g researc h relate d 
acti vities. 

S u b mit Seri o us A d verse E ve nt ( S A E) re p orts t o l ocal I R B per l ocal re q uire me nts a n d t o 
t he C o or di nati n g Ce nter, i n acc or da nce wit h D F/ H C C re q uire me nts. 

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
S u b mit pr ot oc ol de viati o ns a n d vi olati o ns t o l ocal I R B per l ocal re q uire me nts a n d t o t he 
D F/ H C C S p o ns or i n acc or da nce wit h D F/ H C C re q uire me nts.

Or der, st ore a n d dis pe nse i n vesti gati o nal a ge nts a n d/ or ot her pr ot oc ol ma n date d dr u gs per 
fe deral g ui deli nes a n d pr ot oc ol re q uire me nts.

Ha ve office s pace, office e q ui p me nt, a n d i nter net access t hat meet HI P A A sta n dar ds.

Partici pate i n a n y q ualit y ass ura nce acti vities a n d meet wit h m o nit ors or a u dit ors at t he 
c o ncl usi o n of a visit t o re vie w fi n di n gs.

Pr o m ptl y pr o vi de f oll o w- u p a n d/ or c orrecti ve acti o n pla ns f or a n y m o nit ori n g q ueries or 
a u dit fi n di n gs.
3.
D F/ H C C R E Q UI R E M E N T S F O R M U L TI- C E N T E R P R O T O C O L S
T he f oll o wi n g secti o n will clarif y D F/ H C C Re q uire me nts a n d f urt her detail t he e x pectati o ns f or 
partici pati n g i n a D F/ H C C M ulti- Ce nter pr ot oc ol. 
3. 1 
Pr ot oc ol Distri b uti o n
T he C o or di nati n g Ce nter will distri b ute t he fi nal D F CI I R B a p pr o ve d pr ot oc ol a n d a n y s u bse q ue nt 
a me n de d pr ot oc ols t o all Partici pati n g I nstit uti o ns.   
3. 2 
Pr ot oc ol Re visi o ns a n d Cl os ures
T he Partici pati n g I nstit uti o ns will recei ve n otificati o n of pr ot oc ol re visi o ns a n d cl os ures fr o m t he 
C o or di nati n g Ce nter.  It is t he i n di vi d ual Partici pati n g I nstit uti o n’s res p o nsi bilit y t o n otif y its I R B 
of t hese re visi o ns.

N o n life-t hre ate ni n g re visi o ns:  Partici pati n g I nstit uti o ns will recei ve writte n n otificati o n 
of pr ot oc ol re visi o ns re gar di n g n o n life-t hreate ni n g e ve nts fr o m t he C o or di nati n g Ce nter. 
N o n-life-t hreate ni n g pr ot oc ol re visi o ns m ust be I R B a p pr o ve d a n d i m ple me nte d wit hi n 9 0 
da ys fr o m recei pt of t he n otificati o n.

Re visi o ns f or life-t hre ate ni n g c a uses:  Partici pati n g I nstit uti o ns will recei ve i m me diate 
n otificati o n fr o m t he C o or di nati n g Ce nter c o ncer ni n g pr ot oc ol re visi o ns re q uire d t o pr otect 
li ves wit h f oll o w- u p b y fa x, mail, e- mail, etc.  Life-t hreate ni n g pr ot oc ol re visi o ns will be 
i m ple me nte d i m me diatel y f oll o we d b y I R B re q uest f or a p pr o val.

Pr ot oc ol cl os ures a n d te m p or ar y h ol ds:  Partici pati n g I nstit uti o ns 
will recei ve 
n otificati o n of pr ot oc ol cl os ures a n d te m p orar y h ol ds fr o m t he C o or di nati n g Ce nter. 
Cl os ures a n d h ol ds will be effecti ve i m me diatel y.  I n a d diti o n, t he C o or di nati n g Ce nter, 
will u p date t he Partici pati n g I nstit uti o ns o n a n o n g oi n g basis a b o ut pr ot oc ol accr ual data 
s o t hat t he y will be a ware of i m mi ne nt pr ot oc ol cl os ures.
3. 3 
I nf or me d C o nse nt Re q uire me nts
T he D F/ H C C a p pr o ve d i nf or me d c o nse nt d oc u me nt will ser ve as a te m plate f or t he i nf or me d 
c o nse nt f or Partici pati n g I nstit uti o ns. T he Partici pati n g I nstit uti o n c o nse nt f or m m ust f oll o w t he 
c o nse nt te m plate as cl osel y as p ossi ble a n d s h o ul d a d here t o s pecificati o ns o utli ne d i n t he D F/ H C C 

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G ui da nce D oc u me nt o n M o del C o nse nt La n g ua ge f or PI-I nitiate d M ulti- Ce nter Pr ot oc ols.  T his 
d oc u me nt will be pr o vi de d se paratel y t o eac h Partici pati n g I nstit uti o n.
Partici pati n g I nstit uti o ns are t o se n d t heir versi o n of t he i nf or me d c o nse nt d oc u me nt a n d HI P A A 
a ut h orizati o n, if a se parate d oc u me nt, t o t he C o or di nati n g Ce nter f or re vie w a n d a p pr o val pri or t o 
s u b missi o n t o t heir l ocal I R B. T he a p pr o ve d c o nse nt f or m m ust als o be s u b mitte d t o t he 
C o or di nati n g Ce nter after a p pr o val b y t he l ocal I R B f or all c o nse nt versi o ns.
T he Pri nci pal I n vesti gat or ( PI) at eac h Partici pati n g I nstit uti o n will i de ntif y t he p h ysicia n me m bers 
of t he st u d y tea m w h o will be o btai ni n g c o nse nt a n d si g ni n g t he c o nse nt f or m f or t hera pe utic 
pr ot oc ols. Partici pati n g i nstit uti o ns m ust f oll o w t he D F/ H C C re q uire me nt t hat o nl y atte n di n g 
p h ysicia ns o btai n i nf or me d c o nse nt a n d re-c o nse nt t o i nter ve nti o nal trials (i.e. dr u g a n d/ or de vice 
trials).  
3. 4 
I R B D oc u me nt ati o n
T he f oll o wi n g m ust be o n file wit h t he C o or di nati n g Ce nter:

I nitial a p pr o val letter of t he Partici pati n g I nstit uti o n's I R B. 

C o p y of t he I nf or me d C o nse nt F or m(s) a p pr o ve d b y t he Partici pati n g I nstit uti o n’s 
I R B. 

Partici pati n g I nstit uti o n’s I R B a p pr o val f or all a me n d me nts.

A n n ual a p pr o val letters b y t he Partici pati n g I nstit uti o n's I R B.
3. 5 
I R B Re- A p pr o v al
Verificati o n of I R B re-a p pr o val fr o m t he Partici pati n g I nstit uti o ns is re q uire d i n or der t o c o nti n ue 
researc h acti vities.  T here is n o grace peri o d f or c o nti n ui n g a p pr o vals.
T he C o or di nati n g Ce nter will n ot re gister partici pa nts if a re-a p pr o val letter is n ot recei ve d fr o m 
t he Partici pati n g I nstit uti o n o n or bef ore t he a n ni versar y of t he pre vi o us a p pr o val date.  
3. 6 
P artici p a nt C o nfi de nti alit y a n d A ut h oriz ati o n St ate me nt
I n 1 9 9 6, c o n gress passe d t he first fe deral la w c o veri n g t he pri vac y of healt h i nf or mati o n k n o w n as 
t he Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P P A). A n y i nf or mati o n, relate d t o t he 
p h ysical or me ntal healt h of a n i n di vi d ual is calle d Pr otecte d Healt h I nf or mati o n ( P HI). HI P A A 
o utli nes h o w a n d u n der w hat circ u msta nces P HI ca n be use d or discl ose d. 
I n or der f or c o vere d e ntities t o use or discl ose pr otecte d healt h i nf or mati o n d uri n g t he c o urse of a 
st u d y, t he st u d y partici pa nt m ust si g n a n a ut h orizati o n state me nt.  T his a ut h orizati o n state me nt 
ma y or ma y n ot be se parate fr o m t he i nf or me d c o nse nt d oc u me nt.  T he C o or di nati n g Ce nter, wit h 
t he a p pr o val fr o m t he D F CI I R B, will pr o vi de a c o nse nt te m plate, wit h i nf or mati o n re gar di n g 
a ut h orizati o n f or t he discl os ure of pr otecte d healt h i nf or mati o n. 
T he D F/ H C C S p o ns or will use all eff orts t o li mit its use of pr otecte d healt h i nf or mati o n i n its trials. 
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c ollecte d. D F/ H C C has c h ose n t o use a ut h orizati o ns, si g ne d b y t he partici pa nt i n t he trial, rat her 
t ha n li mite d data sets wit h data use a gree me nts.
3. 6. 1  D F/ H C C M ulti- Ce nter Pr ot oc ol C o nfi de ntialit y
All d oc u me nts, i n vesti gati ve re p orts, or i nf or mati o n relati n g t o t he partici pa nt are strictl y 
c o nfi de ntial. 
W he ne ver reas o na bl y feasi ble, a n y partici pa nt s pecific re p orts (i.e. Pat h ol o g y 
Re p orts, M RI Re p orts, O perati ve Re p orts, etc.) s u b mitte d t o t he C o or di nati n g Ce nter s h o ul d be 
de-i de ntifie d. It is rec o m me n de d t hat t he assi g ne d D F/ H C C case n u m ber (as descri be d bel o w) be 
use d f or all partici pa nt s pecific d oc u me nts. Partici pa nt i nitials ma y be i ncl u de d or retai ne d f or 
cr oss verificati o n of i de ntificati o n. 
3. 7
D F/ H C C M ulti- Ce nter Pr ot oc ol Re gistrati o n P olic y
3. 7. 1  Partici pa nt Re gistrati o n a n d Ra n d o mizati o n 
Please refer t o pr ot oc ol Secti o n 4 f or partici pa nt re gistrati o n a n d treat me nt assi g n me nt i nf or mati o n. 
Treat me nt ma y n ot be gi n wit h o ut c o nfir mati o n fr o m t he C o or di nati n g Ce nter t hat t he partici pa nt has 
bee n re gistere d. 
3. 7. 2  I nitiati o n of T hera p y
Partici pa nts m ust be re gistere d wit h t he D F/ H C C O D Q bef ore recei vi n g treat me nt.  Treat me nt 
ma y n ot be i nitiate d u ntil t he Partici pati n g I nstit uti o n recei ves c o nfir mati o n of t he partici pa nt’s 
re gistrati o n fr o m t he C o or di nati n g Ce nter. T he D F/ H C C S p o ns or a n d D F CI I R B m ust be n otifie d 
of a n y vi olati o ns t o t his p olic y.
3. 7. 3  Eli gi bilit y E xce pti o ns
T he D F/ H C C O D Q will ma ke n o e xce pti o ns t o t he eli gi bilit y re q uire me nts f or a pr ot oc ol wit h o ut 
D F CI I R B a p pr o val. T he D F/ H C C O D Q re q uires eac h i nstit uti o n t o f ull y c o m pl y wit h t his 
re q uire me nt.
3. 8  
D F/ H C C Pr ot oc ol C ase N u m ber
At t he ti me of re gistrati o n, O D Q re q uires t he f oll o wi n g i de ntifiers f or all s u bjects: i nitials, date of 
birt h, ge n der, race a n d et h nicit y. O nce eli gi bilit y has bee n esta blis he d a n d t he partici pa nt 
s uccessf ull y re gistere d, t he partici pa nt is assi g ne d a u ni q ue pr ot oc ol case n u m ber.  Partici pati n g 
I nstit uti o ns s h o ul d s u b mit all de-i de ntifie d s u bse q ue nt c o m m u nicati o n a n d d oc u me nts t o t he 
C o or di nati n g Ce nter, usi n g t his case n u m ber t o i de ntif y t he s u bject.  
3. 9 
Pr ot oc ol De vi ati o ns, E xce pti o ns a n d Vi ol ati o ns
Fe deral Re g ulati o ns re q uire a n I R B t o re vie w pr o p ose d c ha n ges i n a researc h acti vit y t o e ns ure 
t hat researc hers d o n ot i nitiate c ha n ges i n a p pr o ve d researc h wit h o ut I R B re vie w a n d a p pr o val, 
e xce pt w he n necessar y t o eli mi nate a p pare nt i m me diate hazar ds t o t he partici pa nt. D F/ H C C 
re q uires all de part ures fr o m t he defi ne d pr oce d ures set f ort h i n t he I R B a p pr o ve d pr ot oc ol t o be 
re p orte d t o t he D F/ H C C S p o ns or, w h o i n t ur n is res p o nsi ble f or re p orti n g t o t he D F CI I R B.

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F or re p orti n g p ur p oses, D F/ H C C uses t he ter ms “ vi olati o n”, “ de viati o n” a n d “e xce pti o n” t o 
descri be de part ures fr o m a pr ot oc ol. 
All Partici pati n g I nstit uti o ns 
m ust a d here t o t hese 
re q uire me nts f or re p orti n g t o t he D F/ H C C S p o ns or a n d will f oll o w t heir i nstit uti o nal p olic y f or 
re p orti n g t o t heir l ocal I R B.
3. 9. 1  Defi niti o ns
Pr ot oc ol De viati o n: A n y de part ure fr o m t he defi ne d pr oce d ures set f ort h i n t he I R B-
a p pr o ve d pr ot oc ol w hic h is pr os pectively a p pr ove d  pri or t o its i m ple me ntati o n.
Pr ot oc ol E xce pti o n:  A n y pr ot oc ol de viati o n t hat relates t o t he eli gi bilit y criteria, e. g.
e nr oll me nt of a partici pa nt w h o d oes n ot meet all i ncl usi o n/e xcl usi o n criteria.
Pr ot oc ol Vi olati o n: A n y pr ot oc ol de viati o n t hat was n ot pr os pectively a p pr ove d  b y 
t he I R B pri or t o its i nitiati o n or i m ple me ntati o n. 
3. 9. 2  Re p orti n g Pr oce d ures
D F/ H C C S p o ns or: is res p o nsi ble f or e ns uri n g t hat clear d oc u me ntati o n is a vaila ble i n t he me dical 
rec or d a n d/ or re g ulat or y d oc u me nts t o descri be all pr ot oc ol e xce pti o ns, de viati o ns a n d vi olati o ns. 
T he D F/ H C C S p o ns or will als o be res p o nsi ble f or e ns uri n g t hat all pr ot oc ol vi olati o ns/ de viati o ns 
are pr o m ptl y re p orte d per D F CI I R B g ui deli nes. 
Partici pati n g I nstit uti o ns: Pr ot oc ol de viati o ns re q uire pr os pecti ve a p pr o val fr o m t he D F CI I R B. 
T he Partici pati n g I nstit uti o n m ust s u b mit t he de viati o n re q uest t o t he C o or di nati n g Ce nter w h o 
will t he n s u b mit t he de viati o n re q uest t o t he D F CI I R B. U p o n D F CI I R B a p pr o val t he de viati o n is 
s u b mitte d t o t he Partici pati n g I nstit uti o n I R B, per i nstit uti o nal p olic y. A c o p y of t he Partici pati n g 
I nstit uti o n’s I R B re p ort a n d deter mi nati o n will be f or war de d t o t he C o or di nati n g Ce nter wit hi n 1 0 
b usi ness da ys after t he ori gi nal s u b missi o n. 
All pr ot oc ol vi olati o ns m ust be se nt t o t he C o or di nati n g Ce nter i n a ti mel y ma n ner. 
C o or di nati n g Ce nter:  U p o n recei pt of t he vi olati o n/ de viati o n re p ort fr o m t he Partici pati n g 
I nstit uti o n, t he C o or di nati n g Ce nter will s u b mit t he re p ort t o t he D F/ H C C S p o ns or f or re vie w. 
S u bse q ue ntl y, t he Partici pati n g I nstit uti o n’s I R B vi olati o n/ de viati o n re p ort will be s u b mitte d t o 
t he D F CI I R B f or re vie w per D F CI I R B re p orti n g g ui deli nes. 
3. 1 0 
S afet y Assess me nts a n d T o xicit y M o nit ori n g
T he st u d y tea ms at all partici pati n g i nstit uti o ns are res p o nsi ble f or pr otecti n g t he safet y, ri g hts a n d 
well- bei n g of st u d y partici pa nts. Rec or di n g a n d re p orti n g of a d verse e ve nts t hat occ ur d uri n g t he 
c o urse of a st u d y hel p e ns ure t he c o nti n ui n g safet y of st u d y partici pa nts. 
All partici pa nts recei vi n g i n vesti gati o nal a ge nts a n d/ or ot her pr ot oc ol ma n date d treat me nt will be 
e val uate d f or safet y. T he safet y para meters i ncl u de all la b orat or y tests a n d he mat ol o gical 
a b n or malities, p h ysical e xa mi nati o n fi n di n gs, a n d s p o nta ne o us re p orts of a d verse e ve nts re p orte d 

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b y partici pa nts.  All t o xicities e nc o u ntere d d uri n g t he st u d y will be e val uate d acc or di n g t o t he 
N CI criteria s pecifie d i n t he pr ot oc ol. Life-t hreate ni n g t o xicities m ust be re p orte d i m me diatel y t o 
t he D F/ H C C S p o ns or via t he C o or di nati n g Ce nter. 
A d diti o nal safet y assess me nts a n d t o xicit y m o nit ori n g will be o utli ne d i n t he pr ot oc ol.
3. 1 0. 1 G ui deli nes f or Re p orti n g Seri o us A d verse E ve nts 
G ui deli nes f or re p orti n g A d verse E ve nts ( A Es) a n d Seri o us A d verse E ve nts ( S A Es) are detaile d 
i n pr ot oc ol secti o n 7. 
Partici pati n g I nstit uti o ns m ust re p ort t he S A Es t o t he D F/ H C C S p o ns or a n d t he C o or di nati n g 
Ce nter f oll o wi n g t he D F CI I R B A d verse E ve nt Re p orti n g P olic y . 
T he C o or di nati n g Ce nter will mai ntai n d oc u me ntati o n of all Partici pati n g I nstit uti o n A d verse 
E ve nt re p orts a n d be res p o nsi ble f or c o m m u nicati n g t o all partici pati n g i n vesti gat ors, a n y 
o bser vati o ns re p orta ble u n der t he D F CI I R B Re p orti n g Re q uire me nts.  Partici pati n g I nstit uti o ns 
will re vie w a n d s u b mit t o t heir I R B acc or di n g t o t heir i nstit uti o nal p olicies a n d pr oce d ures
3. 1 0. 2 G ui deli nes f or Pr ocessi n g I N D Safet y Re p orts 
T he D F/ H C C S p o ns or will re vie w all I N D Safet y Re p orts a n d e ns ure t hat all I N D Safet y Re p orts 
are distri b ute d t o t he Partici pati n g I nstit uti o ns. Partici pati n g I nstit uti o ns will re vie w a n d s u b mit 
t o t heir I R B acc or di n g t o t heir i nstit uti o nal p olicies a n d pr oce d ures.
3. 1 1  
D at a M a n a ge me nt
T he D F/ H C C O D Q de vel o ps case re p ort f or ms ( C R F/e C R Fs), f or use wit h t he pr ot oc ol.  T hese 
f or ms are desi g ne d t o c ollect data f or eac h st u d y. T he D F/ H C C O D Q pr o vi des a we b base d trai ni n g 
f or e C R F users.
  
3. 1 1. 1 Data F or ms Re vie w
Data s u b missi o ns are m o nit ore d f or ti meli ness a n d c o m plete ness of s u b missi o n. Partici pati n g 
I nstit uti o ns are n otifie d of t heir data s u b missi o n deli n q ue ncies i n acc or da nce wit h t he f oll o wi n g:
I nc o m plete or Q uesti o na ble Data
If st u d y f or ms are recei ve d wit h missi n g or q uesti o na ble data, t he s u b mitti n g i nstit uti o n will 
recei ve a writte n or electr o nic q uer y fr o m t he D F/ H C C O D Q Data A nal yst, C o or di nati n g Ce nter 
or desi g nee.  Res p o nses t o all q ueries s h o ul d be c o m plete d a n d s u b mitte d wit hi n 1 4 cale n dar da ys.  
Res p o nses ma y be ret ur ne d o n t he writte n q uer y or o n a n a me n de d pa per case re p ort f or m, or i n 
t he case of electr o nic q ueries, wit hi n t he electr o nic data ca pt ure (e D C) s yste m. I n t he case of a 
writte n q uer y f or data s u b mitte d o n a pa per case re p ort f or m, t he q uer y m ust be attac he d t o t he 
s pecific data bei n g re-s u b mitte d i n res p o nse.  
Missi n g F or ms

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If st u d y f or ms are n ot s u b mitte d o n sc he d ule, t he Partici pati n g I nstit uti o n will recei ve a Missi n g 
F or m Re p ort fr o m t he C o or di nati n g Ce nter n oti n g t he missi n g f or ms.  T hese re p orts are c o m pile d 
b y t he D F/ H C C O D Q a n d distri b ute d o n a m o nt hl y basis. 
4.
R E Q UI SI TI O NI N G I N V E S TI G A TI O N A L D R U G
T he or deri n g of i n vesti gati o nal a ge nt is s pecifie d i n t he pr ot oc ol secti o n 8. 
Partici pati n g I nstit uti o ns s h o ul d or der t heir o w n a ge nt re gar dless of t he s u p plier. 
If t he a ge nt is c o m merciall y a vaila ble, c hec k wit h t he l ocal Direct or of P har mac y a n d/ or t he 
Researc h P har mac y t o e ns ure t hat t he a ge nt is i n st oc k. If t he a ge nt is n ot st oc ke d, e ns ure t hat t he 
a ge nt ca n be or dere d o nce t he pr ot oc ol is a p pr o ve d b y t he l ocal I R B. 
If t he a ge nt is i n vesti gati o nal, e ns ure t hat t he p har mac y will be a ble t o recei ve a n d st ore t he a ge nt 
acc or di n g t o state a n d fe deral re q uire me nts. T he l ocal I R B s h o ul d be ke pt i nf or me d of w h o will 
s u p pl y t he a ge nt (i.e., N CI or a p har mace utical c o m pa n y) s o t hat a n y re g ulat or y res p o nsi bilities 
ca n be met i n a ti mel y fas hi o n. 
5.
M O NI T O RI N G: Q U A LI T Y C O N T R O L
T he q ualit y c o ntr ol pr ocess f or a cli nical trial re q uires verificati o n of pr ot oc ol c o m plia nce a n d data 
acc urac y. T he C o or di nati n g Ce nter, wit h t he ai d of t he O D Q pr o vi des q ualit y c o ntr ol o versi g ht f or 
t he pr ot oc ol.
5. 1  
O n g oi n g M o nit ori n g of Pr ot oc ol C o m pli a nce
T he Partici pati n g I nstit uti o ns ma y be re q uire d t o s u b mit partici pa nt s o urce d oc u me nts t o t he 
C o or di nati n g Ce nter f or m o nit ori n g. Partici pati n g I nstit uti o n ma y als o be s u bject t o o n-site 
m o nit ori n g c o n d ucte d b y t he C o or di nati n g Ce nter. 
At a mi ni m u m, t he C o or di nati n g Ce nter will m o nit or eac h partici pati n g site t wice a year w hile 
partici pa nts are recei vi n g treat me nt wit h a c o m bi nati o n of o n-site a n d virt ual m o nit ori n g. S h o ul d 
a Partici pati n g I nstit uti o n be m o nit ore d o nce a n d t he n n ot accr ue a n y a d diti o nal patie nts, t he n 
f ut ure m o nit ori n g visits ma y n ot be necessar y. T he first o n site m o nit ori n g visit will be tri g gere d 
b y pr ot oc ol e nr oll me nt of t hree patie nts. 
T he C o or di nati n g Ce nter will i m ple me nt o n g oi n g m o nit ori n g acti vities t o e ns ure t hat Partici pati n g 
I nstit uti o ns are c o m pl yi n g wit h re g ulat or y a n d pr ot oc ol re q uire me nts, data q ualit y, a n d partici pa nt 
safet y. M o nit ori n g will occ ur bef ore t he cli nical p hase of t he pr ot oc ol be gi ns, c o nti n ue d uri n g 
pr ot oc ol perf or ma nce a n d t hr o u g h st u d y c o m pleti o n. A d diti o nal m o nit ori n g practices ma y i ncl u de 
b ut are n ot li mite d t o; s o urce verificati o n, re vie w a n d a nal ysis of t he f oll o wi n g: eli gi bilit y 
re q uire me nts of all partici pa nts, i nf or me d c o nse nt pr oce d ures, a d verse e ve nts a n d all ass ociate d 
d oc u me ntati o n, st u d y dr u g a d mi nistrati o n/treat me nt, re g ulat or y files, pr ot oc ol de part ures, 
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A d diti o nall y, re g ular a n d o n g oi n g c o m m u nicati o n wit h Partici pati n g I nstit uti o ns will be 
acc o m plis he d b y h ol di n g all site bi- wee kl y telec o nfere nces. T he C o or di nati n g Ce nter will kee p 
i n cl ose t o uc h wit h t he Partici pati n g I nstit uti o ns via e mail a n d p h o ne.
O n- Site 
M o nit ori n g:  O n-site 
m o nit ori n g will occ ur o n a n as- nee de d basis. Partici pati n g 
I nstit uti o ns will be re q uire d t o pr o vi de access t o partici pa nt’s c o m plete me dical rec or d a n d s o urce 
d oc u me nts f or s o urce d oc u me ntati o n verificati o n ( S D V) d uri n g t he o n-site visit. I n a d diti o n, u p o n 
re q uest fr o m a m o nit or or a u dit or, Partici pati n g I nstit uti o ns s h o ul d pr o vi de access t o re g ulat or y 
d oc u me nts, p har mac y rec or ds, l ocal p olicies relate d t o t he c o n d uct of researc h, a n d a n y ot her trial-
relate d d oc u me ntati o n mai ntai ne d b y t he partici pati n g site. If t here are c o ncer ns f or pr ot oc ol 
c o m plia nce, iss ues t hat i m pact s u bject safet y or t he i nte grit y of t he st u d y are f o u n d, or tre n ds 
i de ntifie d base d o n areas of nee d, a d diti o nal m o nit ori n g visits ma y be sc he d ule d. O n site 
m o nit ori n g visits ca n be s u p ple me nte d wit h virt ual m o nit ori n g assess me nts, pr o vi de d t hat t he 
mi ni m u m m o nit ori n g fre q ue ncies are a d here d t o.
Virt u al 
M o nit ori n g:  T he 
C o or di nati n g 
Ce nter 
will re q uest s o urce d oc u me ntati o n fr o m 
Partici pati n g I nstit uti o ns as nee de d t o c o m plete m o nit ori n g acti vities. Partici pati n g I nstit uti o ns 
will be re q uire d t o f or war d de-i de ntifie d c o pies of partici pa nts’ me dical rec or d a n d s o urce 
d oc u me nts t o t he C o or di nati n g Ce nter t o ai d i n s o urce d oc u me ntati o n verificati o n.
5. 2  
M o nit ori n g Re p orts
T he D F/ H C C S p o ns or will re vie w all m o nit ori n g re p orts f or o n-site a n d re m ote m o nit ori n g of 
Partici pati n g I nstit uti o ns t o e ns ure pr ot oc ol c o m plia nce. T he D F/ H C C S p o ns or ma y i ncrease t he 
m o nit ori n g acti vities at Partici pati n g I nstit uti o ns t hat are u na ble t o c o m pl y wit h t he pr ot oc ol, 
D F/ H C C S p o ns or re q uire me nts or fe deral a n d l ocal re g ulati o ns. Partici pati n g I nstit uti o ns ma y als o 
be s u bject t o a n a u dit as deter mi ne d b y t he D F/ H C C S p o ns or. All q ueries fr o m m o nit ori n g visits 
m ust be res ol ve d wit hi n 3 0 da ys of t he re p ort bei n g se nt.
5. 3  
Accr u al M o nit ori n g
Pri or t o e xte n di n g a pr ot oc ol t o a n e xter nal site, t he D F/ H C C S p o ns or will esta blis h accr ual 
re q uire me nts f or eac h partici pati n g i nstit uti o n. Accr ual will be m o nit ore d f or eac h partici pati n g 
i nstit uti o n b y t he D F/ H C C S p o ns or or desi g nee. Sites t hat are n ot meeti n g t heir accr ual 
e x pectati o ns ma y be s u bject t o ter mi nati o n. Sites are e x pecte d t o accr ue at least 3 patie nts per 
year.
6.
A U DI TI N G: Q U A LI T Y A S S U R A N C E
A u diti n g is a met h o d of Q ualit y Ass ura nce. Its mai n f oc us is t o meas ure w het her sta n dar ds a n d 
pr oce d ures were f oll o we d. A u diti n g is t he s yste matic a n d i n de pe n de nt e xa mi nati o n of all trial 
relate d acti vities a n d d oc u me nts.  A u dits deter mi ne if e val uate d acti vities were a p pr o priatel y 
c o n d ucte d a n d w het her data was ge nerate d, rec or de d a n d a nal yze d, a n d acc uratel y re p orte d per t he 
pr ot oc ol, Sta n dar d O perati n g Pr oce d ures ( S O Ps), a n d t he C o de of Fe deral Re g ulati o ns ( C F R).

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6. 1  
A u dit Pl a n: D F/ H C C S p o ns ore d Tri als
O ne o n-site a u dit will be sc he d ule d b y t he O D Q, ass u mi n g at least t hree partici pa nts ha ve bee n 
treate d o n pr ot oc ol at t he site. If si g nifica nt iss ues wit h n o n-c o m plia nce or vi olati o ns are f o u n d 
t hat i m pact partici pa nt safet y or t he i nte grit y of t he st u d y are n ote d at partici pati n g sites, t he 
D F/ H C C S p o ns or will tri g ger a u dit of a d diti o nal partici pa nt rec or ds. 
6. 2  
A u dit N otific ati o n
It is t he Partici pati n g I nstit uti o n’s res p o nsi bilit y t o n otif y t he C o or di nati n g Ce nter of all sc he d ule d 
a u dit dates (i nter nal or N CI) a n d re-a u dit dates (if a p plica ble), w hic h i n v ol ve t his pr ot oc ol. All 
i nstit uti o ns will f or war d a c o p y of fi nal a u dit a n d/ or re-a u dit re p orts a n d c orrecti ve acti o n pla ns (if 
a p plica ble) t o t he C o or di nati n g Ce nter, wit hi n 1 2 wee ks after t he a u dit date. 
6. 3  
A u dit Re p orts 
T he D F/ H C C S p o ns or will re vie w all fi nal a u dit re p orts a n d c orrecti ve acti o n pla ns if a p plica ble. 
T he C o or di nati n g Ce nter, m ust f or war d t hese re p orts t o t he D F/ H C C O D Q per D F/ H C C p olic y 
f or re vie w b y t he D F/ H C C A u dit C o m mittee. Base d u p o n t he a u dit assess me nts t he D F/ H C C A u dit 
C o m mittee c o ul d acce pt or c o n diti o nall y acce pt t he a u dit rati n g a n d fi nal re p ort. C o n diti o nal 
a p pr o val c o ul d re q uire t he D F/ H C C S p o ns or t o i m ple me nt rec o m me n dati o ns or re q uire f urt her 
f oll o w- u p.  F or u nacce pta ble a u dits, t he D F/ H C C A u dit C o m mittee w o ul d f or war d t he fi nal a u dit 
re p ort a n d c orrecti ve acti o n pla n t o t he D F CI I R B as a p plica ble.
6. 4 
P artici p ati n g I nstit uti o n Perf or m a nce
T he D F/ H C C S p o ns or a n d D F CI I R B are c har ge d wit h c o nsi deri n g t he t otalit y of a n i nstit uti o n’s 
perf or ma nce i n c o nsi deri n g i nstit uti o nal partici pati o n i n t he pr ot oc ol.
6. 4. 1 C orrecti ve Acti o ns
Partici pati n g I nstit uti o ns t hat fail t o meet t he perf or ma nce g oals of accr ual, s u b missi o n of ti mel y 
a n d acc urate data, a d here nce t o pr ot oc ol re q uire me nts, a n d c o m plia nce wit h state a n d fe deral 
re g ulati o ns, ma y be rec o m me n de d f or a si x- m o nt h pr o bati o n peri o d. S uc h i nstit uti o ns m ust 
res p o n d wit h a c orrecti ve acti o n pla n a n d m ust de m o nstrate d uri n g t he pr o bati o n peri o d t hat 
deficie ncies ha ve bee n c orrecte d, as e vi de nce d b y t he i m pr o ve d perf or ma nce 
meas ures. 
Partici pati n g I nstit uti o ns t hat fail t o de m o nstrate si g nifica nt i m pr o ve me nt will be c o nsi dere d b y 
t he D F/ H C C S p o ns or f or re v ocati o n of partici pati o n. A D F/ H C C S p o ns or a n d/ or t he D F CI I R B 
ma y ter mi nate a site’s partici pati o n if it is deter mi ne d t hat a site is n ot f ulfilli n g its res p o nsi bilities 
as descri be d a b o ve.
A P P E N DI X F  
R E P O R T A B L E E V E N T C O V E R S H E E T

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C o nfi de nti alit y N otice:   T he d oc u me nts acc o m pa n yi n g t his telec o p y tra ns missi o n c o ntai n 
i nf or mati o n bel o n gi n g t o  
w hic h is i nte n de d o nl y f or t he use of t he a d dressee.  If y o u are 
n ot t he i nte n de d reci pie nt, y o u are here b y n otifie d t hat a n y discl os ure, c o p yi n g, distri b uti o n, or 
t he ta ki n g of a n y acti o n i n relia nce o n t he c o nte nts of t his telec o pie d i nf or mati o n is strictl y 
pr o hi bite d.  If y o u ha ve recei ve d t his telec o p y i n err or, please i m me diatel y n otif y us b y 
tele p h o ne t o arra n ge f or t he ret ur n of t he ori gi nal d oc u me nts t o us.  T ha n k y o u.
P FI Z E R 
R E F E R E N C E 
N U M B E R
E X T E R N A L 
R E F E R E N C E 
N U M B E R
S T U D Y TI T L E
Ne oa dj u va nt e n d ocri ne t hera p y wit h pal b ocicli b f or E R- p ositi ve i n vasi ve l o b ular a n d i n vasi ve d uctal 
carci n o ma
P A TI E N T 
N U M B E R
I N V E S TI G A T O R
Ott o Metz ger, M D

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A P P E N DI X G  
A XI L L A R Y M A N A G E M E N T A F T E R N E O A D J U V A N T 
E N D O C RI N E T H E R A P Y F O R H O R M O N E- P O SI TI V E B R E A S T C A N C E R 
( S U R G E O N I N T E R VI E W G UI D E)
I ntr o d ucti o n
Hi, m y na me is ” N A M E” a n d I’ m calli n g fr o m t he Da na Far ber/ Bri g ha m a n d 
W o me n’s Ca ncer Ce nter. T ha n k y o u f or ta ki n g t he ti me t o s pea k wit h me t o da y. We are 
s pea ki n g wit h s ur ge o ns t o better u n dersta n d t heir pers pecti ves o n a xillar y s ur ger y after 
ne oa dj u va nt e n d ocri ne t hera p y.  O ur disc ussi o n t o da y will hel p i nf or m a s ur ve y t hat will e x pl ore 
iss ues a n d attit u des t o war ds t he p ossi ble o missi o n of a xillar y l y m p h n o de dissecti o n i n w o me n 
wit h h or m o ne- p ositi ve breast ca ncer treate d wit h ne oa dj u va nt e n d ocri ne t hera p y. It ma y als o 
i nf or m t he desi g n of a f ut ure cli nical trial testi n g t he o missi o n of a xillar y l y m p h n o de dissecti o n 
i n t his p o p ulati o n. T here are n o ri g ht or wr o n g a ns wers i n o ur disc ussi o n t o da y, as we are here t o 
better u n dersta n d y o ur e x perie nce a n d pers pecti ves o n t he t o pic at ha n d. 
T his i nter vie w will be rec or de d a n d ta kes, o n a vera ge, t we nt y mi n utes.  Rec or di n gs will n ot be 
s hare d wit h y o ur c ollea g ues, patie nts or fa milies, or wit h a n y o ne else o utsi de t he researc h tea m.   
I wa nt t o be s ure t hat y o u u n dersta n d t hat bei n g part of t his i nter vie w is v ol u ntar y, y o u ca n o pt t o 
n ot a ns wer q uesti o ns or e n d t he c o n versati o n at a n y ti me. We a p preciate y o ur partici pati o n i n 
t his st u d y. O bt ai n i nf or me d c o nse nt
D o y o u ha ve a n y q uesti o ns bef ore we be gi n t he i nter vie w? Be gi n rec or di n g
I.  De m o gr a p hic I nf or m ati o n
First off, c o ul d I get s o me baseli ne i nf or mati o n a b o ut y o u?
1) H o w ma n y years ha ve y o u bee n i n practice?
2)  H o w w o ul d y o u descri be y o ur practice wit h re gar ds t o bei n g aca de mic or c o m m u nit y- base d 
or a h y bri d m o del?
3)  I n w hat fiel d/s pecialt y, if a n y, are y o u b oar d certifie d?
4) W hat fell o ws hi p trai ni n g d o y o u ha ve, if a n y? 
5)  W hat is t he sc o pe of y o ur s ur gical practice?
a) W hat perce nta ge of y o ur practice is breast s ur ger y?
b) H o w ma n y ne w breast ca ncer patie nts d o y o u see per m o nt h?
c) A p pr o xi matel y h o w ma n y w o me n d o y o u see a m o nt h w h o ha ve h or m o ne- p ositi ve 
breast ca ncer a n d are treate d wit h ne oa dj u va nt e n d ocri ne t hera p y?
d) H o w d o y o u us uall y cli nicall y e val uate t he a xilla i n t hese w o me n (i.e. p h ysical e xa m 
a n d/ or U/ S?) - If s ur ge o n r o uti nely uses U/ S, ask h o w t hey defi ne bei n g “cli nic ally n o de-
ne g ative ”
e) H o w d o y o u us uall y s ur gicall y sta ge t he a xilla i n t hese w o me n (i.e. A L N D or S L N B)? 
-If s ur ge o n us u ally perf or ms A L N D, ask f or f urt her ex pl a n ati o n
F or t he ne xt set of q uesti o ns, I a m as ki n g y o u t o f oc us s pecificall y o n t he ma na ge me nt of 
patie nts wit h cli nicall y n o de- ne gati ve, h or m o ne- p ositi ve breast ca ncer, treate d wit h ne oa dj u va nt 
e n d ocri ne t hera p y.  
II.  C U R R E N T P R A C TI C E
     A)   G ui deli ne f act ors
6)  D o y o u k n o w of a n y pre-e xisti n g g ui deli nes f or t he s ur gical ma na ge me nt of t he a xilla i n t his 

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patie nt p o p ulati o n?
-If yes, h o w d o t he y i nfl ue nce y o ur practice?
-If n o, d o y o u t hi n k t hat g ui deli nes f or a xillar y ma na ge me nt i n t his patie nt p o p ulati o n 
w o ul d be usef ul?
7) Are y o u a ware of a n y data e val uati n g a xillar y ma na ge me nt after ne oa dj u va nt e n d ocri ne 
t hera p y?
B) I n di vi d u al He alt h Pr ofessi o n al F act ors: Pr ofessi o n al Be h a vi or
8) H o w d o y o u us uall y a p pr oac h t he decisi o n t o e val uate t he a xillar y i n t his patie nt p o p ulati o n?  
- W hat cli nical a n d disease fact ors pla y a r ole i n y o ur decisi o n t o e val uate t he a xillar y?
- Wit h t his patie nt p o p ulati o n, h o w ofte n, if e ver, d o y o u c o nsi der t he o missi o n of t he 
a xillar y e val uati o n?  I n w hat perce nta ge of patie nts d o y o u act uall y o mit it?
- H o w has y o ur a p pr oac h c ha n ge d o ver ti me?
9) If a cli nicall y n o de- ne gati ve patie nt is f o u n d t o ha ve p ositi ve pat h ol o gic n o dal disease, h o w d o 
y o u a p pr oac h t he decisi o n t o perf or m a n a xillar y l y m p h n o de dissecti o n?
- W hat cli nical a n d disease fact ors pla y a r ole i n y o ur decisi o n t o e val uate t he a xillar y?
- Wit h t his patie nt p o p ulati o n, h o w ofte n, if e ver, d o y o u c o nsi der t he o missi o n of t he 
a xillar y l y m p h n o de dissecti o n?  I n w hat perce nta ge of patie nts d o y o u act uall y o mit it?
- H o w has y o ur a p pr oac h c ha n ge d o ver ti me?
     C)    I n di vi d u al He alt h Pr ofessi o n al F act ors: K n o wle d ge/ C o g niti o ns
If s ur ge o n d oes o mit axill ary n o de dissecti o n: 
1 0) W hat d o y o u see as t he pr os a n d t he c o ns of o mitti n g a xillar y n o de dissecti o ns?
- F or e xa m ple, w hat p ote ntial c o nse q ue nces mi g ht kee p y o u fr o m o mitti n g a xillar y 
e val uati o n?
1 1) W hat are y o ur disc ussi o ns wit h patie nts li ke ar o u n d a xillar y dissecti o n/ o missi o n?
- F or e xa m ple, t o w hat e xte nt d o y o u c o u nsel patie nts a b o ut w het her or n ot t o p urs ue 
a xillar y e val uati o n?
1 2) Ca n y o u descri be a n y sit uati o ns i n w hic h y o ur patie nt has preferre d t o pr ocee d wit h t he 
a xillar y dissecti o n e ve n t h o u g h y o u offer t o o mit it? 
- H o w ofte n d oes t his ha p pe n?
If s ur ge o n never o mits axill ary dissecti o n:  
1 3) O verall, h o w d o y o u feel a b o ut t he p ote ntial o missi o n of a xillar y dissecti o n i n t his 
p o p ulati o n?
1 4) Ha ve y o u c o me acr oss a n y data/st u dies t hat e x pl ore o missi o n of a xillar y dissecti o n i n t his 
p o p ulati o n?  If s o, w hat d o y o u t hi n k of t hese data?
     D)    P atie nt F act ors:
1 5) Fr o m y o ur pers pecti ve, w hat d o patie nts t hi n k a b o ut o mitti n g A L N D?  Is it a n o verall 
p ositi ve or ne gati ve f or t he patie nt?
1 6) W hat i m pact d o y o u t hi n k t his practice has o n patie nt o utc o mes? [ pr o be o n reas o ns be hi n d 
t he i m pact]
P ossi ble pr o be: - D o y o u t ur n t o a n y partic ular p u blis he d data t hat g ui de y o ur o pi ni o ns?
1 7) W hat patie nt fact ors, if a n y, w o ul d i nfl ue nce y o ur decisi o n t o perf or m A L N D?
- D oes t he patie nt’s breast s ur ger y (i.e. l u m pect o m y or mastect o m y) i nfl ue nce y o ur 
decisi o n?

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     E)    Pr ofessi o n al I nter acti o ns
1 8) D o y o u t hi n k t hat y o ur s ur ger y c ollea g ues o mit A L N D? - D o y o ur s ur ger y c ollea g ues 
i nfl ue nce y o ur decisi o n t o o mit/ perf or m A L N D?
1 9) D o y o u r o uti nel y disc uss t hese patie nts at a m ulti- disci pli nar y t u m or b oar d?
2 0) Are y o u i nfl ue nce d i n y o ur a xillar y s ur ger y rec o m me n dati o ns b y ot her s pecialists (i.e. 
me dical o nc ol o g y or ra diati o n o nc ol o g y)? -If y o u o mit A L N D, d o y o u feel t he patie nt s h o ul d 
recei ve ra diati o n?
     F)    S oci al, P olitic al, a n d Le g al F act ors
2 1) Are t here a n y e xter nal fact ors (li ke fi na ncial press ure or i nce nti ve, or re g ulati o ns) t hat 
i nfl ue nce y o ur a p pr oac h t o a xillar y s ur ger y? P ossi ble pr o bes: - D o fi na ncial i nce nti ves or 
disi nce nti ves pla y a r ole?  
- Or i nstit uti o nal press ures or re g ulati o ns? 
- W hat a b o ut mal practice e n vir o n me nt? 
III.  I N T H E O R Y
     A)    I n di vi d u al He alt h Pr ofessi o n al F act ors:  C o g niti o ns
2 2) Ca n y o u descri be a n y fact ors or reas o ns t hat mi g ht kee p y o u fr o m o mitti n g a xillar y 
dissecti o n i n t his p o p ulati o n?
P ossi ble pr o bes: - W hat d o y o u t hi n k of t he q ualit y of e vi de nce s u p p orti n g t his practice?  [ pr o be 
o n c o ncer ns, if a ny]
- D o y o u feel t hat u pfr o nt s ur ger y trial res ults ca n be c o nsi dere d i n t his p o p ulati o n? 
[ pr o be o n c o ncer ns, if a ny]
     B)    Pr ofessi o n al I nter acti o ns:  C o m m u nic ati o n a n d I nfl ue nce
2 3) H o w w o ul d y o u descri be t he c o m m u nicati o n y o u ha ve, if a n y, re gar di n g a xillar y 
ma na ge me nt i n t his p o p ulati o n of patie nts wit h y o ur me dical o nc ol o g y or ra diati o n o nc ol o g y 
c ollea g ues? [ pr o be o n s pecifics as nee de d]
2 4) Fr o m y o ur e x perie nce, h o w d o y o ur me dical or ra diati o n o nc ol o g y vie w o missi o n of a xillar y 
dissecti o n i n t his p o p ulati o n? [ pr o be o n h o w t his is si mil ar or differe nt fr o m s ur gic al vie w]
2 5)  W h o is us uall y part of t he decisi o n- ma ki n g pr ocess ar o u n d a xillar y ma na ge me nt?
- F or e xa m ple, d o y o u t hi n k y o ur me dical or ra diati o n o nc ol o g y c ollea g ues w o ul d li ke t o 
wei g h i n o n t his decisi o n?
2 6) H o w, if at all, w o ul d decisi o ns ar o u n d a dj u va nt treat me nt c ha n ge wit h t he o missi o n of 
a xillar y dissecti o n? [r a di ati o n, syste mic t her a py]
     C)    I nce nti ves a n d Res o urces: M o nit ori n g a n d Fee d b ac k Mec h a nis ms
2 7) D o y o u trac k o utc o mes a m o n g y o ur gr o u p or practice?
-I n w hat f or mat d o y o u d o s o?
- Are t he o utc o mes s hare d p u blicl y?
2 8) D o y o u ha ve a relati o ns hi p wit h patie nt a d v ocates or a patie nt a d v ocate gr o u p at y o ur 
i nstit uti o n?
-If yes, h o w d o y o u i nc or p orate t heir fee d bac k i nt o y o ur practice?
2 9) W o ul d y o u feel c o mf orta ble recr uiti n g t o a cli nical trial t hat pla ns t o o mit A L N D f or patie nts 
wit h s mall v ol u me n o dal metastases w h o ha ve bee n treate d wit h ne oa dj u va nt e n d ocri ne t hera p y?

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     D)    C a p acit y f or Or g a niz ati o n al C h a n ge
3 0) H o w w o ul d y o u i m ple me nt t his c ha n ge i n y o ur i nstit uti o n?
- W h o are t he sta ke h ol ders i n v ol ve d i n ma ki n g c ha n ges li ke t his at y o ur i nstit uti o n?
- Are t here a n y percei ve d barriers t o s