A Phase II Trial Assessing the Tolerability of Palbociclib in Combination With Letrozole or Fulvestrant in Patients Aged 70 and Older With Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer
Phase: PHASE2
Conditions: Estrogen Receptor-positive Breast Cancer, HER2/Neu Negative, Stage IV Breast Cancer AJCC v6 and v7
Sponsor: Alliance for Clinical Trials in Oncology

P artici p ati n g N C T N Gr o u p s:  
Allia nce/ Allia nce f or Cli nical Trials i n O nc ol o gy(lea d), E C O G -A C RI N/ E C O G A C RI N Ca ncer Res earc h Gr o u p, 
N R G/ N R G O nc ol o gy, S W O G/ S W O G  
  
1  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
 
 
U p d at e 5  
 
 
 
 
A L LI A N C E F O R C LI NI C A L T RI A L S I N O N C O L O G Y  
A L LI A N C E A 1 7 1 6 0 1  
A  P H A S E II  T RI A L A S S ES S I N G T H E T O L E R A BI LI T Y 
O F P A L B O C I C LI B I N C O M BI N A TI O N W I T H 
L E T R O Z O L E  O R F U L V ES T R A N T I N P A TI E N TS A G E D 7 0  A N D O L D E R 
W I T H E S T R O G E N  R E C E P T O R -
P O S I TI V E , H E R 2 -N E G A TI V E M E T A S T A TI C B R E A S T C A N C E R  
C o m merci al a ge nt( s): P al b ocicli b;  (I N D: exe m pt)  
C li nic al Tri als. g o v I de ntifier: N C T0 3 6 3 3 3 3 1.  
St u d y C hair  
Mi n a S. Se dra k  M D , M S 
Cit y of H o p e Co mpre h e nsi v e Ca n c er Ce nt er  
 
 
 
 
St u d y Co -Ch air  
A mi n a h Jat oi M D  
M a y o Cli nic  
 
 
 
C o m m u nit y O n c ol o g y C o -C h air  
C orr elati v e St u d y C o -C h air  
P h ar m a c o ge n o mics St u d y C o -C h air  
I m a gi n g C o -C h air  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
P h ar m a c o ki n etics St u d y C o -C h air  
Br e ast C o m mitt e e St u d y C o -C h air  
St u d y C o -C h air  
 
 
 
 
 
  
 
 
 
 
 
 
 
Ca n c er i n t h e El derl y C o m mitt e e C o -C h airs  
Br e ast C o m mitt e e C o -C h airs  
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
Dat a M a n a ger  
Pr ot o c ol Co or di nat or  
  
 
 
 
 
 
 
I n m e m ory of Dr. Arti H urri a 
Pri mar y St atisticia n  
Se c o n d ar y St atisticia n  
 
  
   
  
 
 
 

 
Allia nc e A1 7 1 6 0 1  
 
2  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
St u dy Res o u rces:  
Ex pe dit e d A dve rs e Eve nt Re porti n g  
 
Me di dat a R a ve  i Me di dat a port al 
 
O P E N ( O nc ol o g y P ati e nt Enr oll me nt Net wor k)  
 
Bi os pe ci m e n Ma n a ge me nt S yst e m  
 
 
Pr ot oc ol C o ntacts:  
A 1 7 1 6 0 1  N u rsi n g C o nt act  
 
 
 
 
A 1 7 1 6 0 1  P h ar m ac y C o nt act  
  
 
 
 
Alli a n ce  Bi ore posit or y  at Ma y o Cli nic  
  
 
 
 
 
U ni ve rsit y of Pitts b u r g h C a n cer I nstit ute 
 
  
  
 
 
I R O C 
 
 
 
 
   
 
 
 
Pr ot oc ol -rel at e d q u esti o ns m a y be dire ct e d as f ollo ws : 
Q u esti o ns  
C o nt act ( vi a e m ail)  
Q uestio ns r e gar din g patie nt eligibilit y, tr eat me nt, 
a n d d os e m o dific atio n: 
St u d y C hair, N ursin g C o ntact, Pr ot oc ol 
C o or dinat or, a n d ( w her e a p plic a ble) Data Ma na ger 
Q uestio ns r elate d t o data s u b missio n, R A V E or 
patie nt f ollo w -u p: 
Data Ma na ger  
Q uestio ns r e gar din g t he pr ot oc ol d oc u me nt a n d 
m o del inf or me d c o ns e nt:  
Pr ot oc ol C o or dinat or  
Q uestio ns r elate d t o I R B r e vie w  
Allia nc e Re g ulat or y I n b o x  
 
Q uestio ns r e gar din g C T E P -A E R S r e p ortin g:  
Allia nc e P har mac o vigila nc e I n b o x  
 
Q uestio ns r e gar din g s peci me ns/s peci me n 
s u b missio ns: 
A p pr o priate Allia nc e Bior e p osit or y  
Q uestio ns r e gar din g dr u g a d ministr atio n  
P har mac y C o ntact  
 
 

 
Allia nc e A1 7 1 6 0 1  
 
3  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
C A N C E R T RI A L S S U P P O R T U NI T ( C T S U) A D D R E S S A N D C O N T A C T I N F O R M A TI O N  
F or re g ul at or y re q uire me nts:  F or patie nt e n r oll me nts:  
F or dat a s u b missi o n:  
Re g ulat or y d oc u me ntatio n m ust 
be s u b mitt e d t o t he C T S U via 
t he Re g ulat or y S u b missio n 
P ort al.  
( Sig n in at 
 a n d 
s elect t he Re g ulat or y > 
Re g ulat or y S u b missio n.)  
 
I nstit utio ns wit h patie nts 
w aitin g t hat ar e u na ble t o us e 
t he P ort al s h o uld alert t he 
C T S U Re g ulat or y Offic e 
i m m e diat ely at 
 
t o r ec eive f urt her instr uctio n 
a n d s u p p ort.  
 
C o nt act t he C T S U Re g ulat or y 
Help Des k at 
 
f or r e g ulat or y assista nc e. 
Ref er t o t he patie nt e nr oll me nt 
s ectio n of t he pr ot oc ol f or 
instr uctio ns o n usin g t he 
O nc olo g y P atie nt E nr oll me nt 
Net w or k ( O P E N). O P E N is 
ac c ess e d at 
 
 
 
C o ntact t he C T S U Help Des k 
wi t h a n y O P E N-r elate d 
q uestio ns b y p h o ne or e mail  : 
, or 
. 
 
Data c ollectio n f or t his st u d y will 
be d o ne e xclusively t hr o u g h 
Me didata Ra ve. Ref er t o t he data 
s u b missio n s ectio n of t he pr ot oc ol 
f or f urt her instr uctio ns.  
 
 
D o n ot s u b mit st u d y data or f or ms 
t o t he C T S U. D o n ot c o p y t he 
C T S U o n data s u b missio ns.  
T he m ost c urr e nt versio n of t he st u dy pr ot oc ol a n d all s u p porti n g doc u m e nts m ust be d o w nloa de d 
fr o m t he pr ot oc ol-s pecific pa ge loc ate d o n t he C T S U me m bers’ w e bsite 
. Ac c ess 
t o t he C T S U me m bers’ w e bsite is ma na ge d t hr o u g h t he Ca nc er T hera p y a n d E valuatio n Pr o gr a m - 
I de ntit y a n d Ac c ess Ma na ge me nt ( C T E P-I A M) r egistr atio n s yste m a n d r e q uir es lo g in  wit h a C T E P -
I A M us er na me a n d pass w or d.  
P er missio n t o vie w a n d d o w nloa d t his pr ot oc ol a n d its s u p p ortin g d oc u me nts is r estricte d a n d is bas e d 
o n pers o n a n d site r oster assig n me nt h o us e d in t he C T S U Re g ulat or y S u p p ort S yste m ( R S S).   
Instit utio ns will or der t he f ollo win g s u p plies fr o m t he C T S U O per atio ns Offic e: Q uestio n na ir e b o o klets. 
S u p plies c a n be or der e d b y d o w nloa din g a n d c o m pletin g t he C T S U S u p ply Re q uest F or m ( a vaila ble o n 
t he pr ot oc ol-s pecific pa ge o n t he C T S U w e bsite) a n d s u b mittin g it as instr ucte d o n t he f or m.  
F or cli ni c al q u esti o ns (i. e., patie nt eligi bilit y or t re at me nt -rel at e d)  s ee t he Pr ot oc ol C o ntacts, P a ge 2. 
F or n o n -cli nic al q u esti o ns (i.e., u n rel ate d t o patie nt eli gi bilit y, t re at m e nt, or cli nic al dat a 
s u b missi o n) c o ntact t he C T S U Help Des k b y p h o ne or e mail:   
C T S U Ge ner al I nf or matio n Line –  
, or 
. All c alls a n d 
c orr es p o n de nce will be tria ge d t o t he a p pr o priate C T S U r e pr es e ntative.  
 
 
 

 
Allia nc e A1 7 1 6 0 1  
 
4  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
A  P H A S E II  T RI A L A S S ES S I N G T H E T O L E R A BI LI T Y 
O F P A L B O C I C LI B I N C O M BI N A TI O N W I T H 
L E T R O Z O L E  O R F U L V ES T R A N T I N P A TI E N TS A G E D 7 0  A N D O L D E R 
W I T H E S T R O G E N  R E C E P T O R -
P O S I TI V E , H E R 2 -N E G A TI V E M E T A S T A TI C B R E A S T C A N C E R  
 
Eli gi bilit y Crite ri a ( S e e S e cti o n 3. 2 ) 
Estr o g e n  re c ept or p ositi v e  a n d/ or pr o gester o ne re c e pt or ( P R) p ositi ve, 
H E R2 n e g ati v e met astatic bre ast c a nc er Se e 3. 2. 1   
M e as ura ble dis e ase or n o n -me as ura ble dis ease Se e 3. 2. 2  
Pla n ni n g t o b e gi n p al b ocicli b  f or met astatic dis e ase. Patie nts s h o ul d 
h a v e faile d o n e pri or li n e of e n d o cri n e t hera p y.  Se e 3. 2. 3  
N o p ri or t h era p y with a C D K i n hi bit or Se e 3. 2. 4  
Res ol uti o n of all a c ut e t o xic effe cts of pri or t h era p y or s ur gic al 
pr o c e d ures t o C T C A E Gra d e ≤ 1 (e xc e pt al o p e cia) or t o b as eli n e 
t o xicities pri or t o pre vi o us t h erap y or s ur gic al pr o ce d ures. Se e 3. 2. 5  
N o u ntre at e d brai n met astases  Se e 3. 2. 6   
N o k n o w n i nt erstitial l u n g dise ase. Se e 3. 2. 7.  
N o s e c o n d mali g n a n cies ot her t h an n o n -mela n o ma s ki n c a n c ers or 
c er vic al c arci n o ma i n sit u Se e 3. 2. 8.  
N o a cti v e i nfe cti o n re q uiri n g tre at me nt wit h a nti bi otics Se e 3. 2. 9 . 
Patie nts must b e a ble t o s wall o w a n d ret ai n oral me dic ati o n Se e 
3 . 2.1 0 . 
Pa tie nt A g e: ≥ 7 0 y e ars Se e 3. 2. 1 1 . 
E C O G Per f or ma n c e St at us 0, 1 or 2 Se e 3. 2. 1 2 . 
Patie nts must b e a ble t o re a d a n d c o mpre he n d En glis h  or S p a nis h  Se e 
3. 2. 1 3  
Re q ui r e d I niti al La bor at or y V al ues  
A N C  ≥ 1 5 0 0/ m m 3  
Plat elet c o u nt:  ≥ 1 0 0, 0 0 0/ m m 3  
Cre ati ni n e:  ≥ 3 0 ml/ mi n *  
T ot al s er u m 
bilir u bi n  
≤ 1. 5 U L N ( < 3 U L N 
if Gil b ert’s dis e as e) 
A S T a n d/ or 
A L T  
≤ 3 x U L N ( ≤ 5. 0 x 
U L N if li v er 
met ast ases prese nt)  
Al kali n e 
p h os p hatase  
≤ 2. 5 x U L N ( ≤5 x 
U L N if b o n e or 
li v er met ast ases 
pres e nt)  
* Calc ulat e d usi n g t he Co c kcr oft -Ga ult 
f or mula 
 
 
 
 
 
 
S c h e m a  
1 c ycle = 2 8 da ys  
 
 
 
Re gistratio n  
 
Tre at me nt:  
P al b o cicli b 1 2 5 m g a da y ( O nc e daily orally 
o n da ys 1 -2 1 of e a c h 2 8 -da y  c ycle) a n d  
Letr o z ole  o r F ul v e str a nt  
( P er tre atin g in vestigat or dis cretio n) 
D osin g per pa c ket ins ert in e a c h 2 8 -da y  
c ycle  
 
 
 
C o ntin ue  pr ot oc ol tr eat me nt  u ntil u nac c e pta ble t o xicit y or dis eas e pr o gr essio n  
Pl e as e ref er t o t h e f ull pr ot oc ol t e xt f or a c o m plete des cri pti o n of t h e eligi bilit y crit eri a a n d 
t re at m e nt pl a n. 
 
 

 
Allia nc e A1 7 1 6 0 1  
 
5  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
T A B L E O F C O N T E N TS  
1. 0  
B A C K G R O U N D  ............................................................................................................... 7  
1. 1  
Agin g a n d a Decr eas e in P h ysiolo gic Res er ve: Ratio nale f or St u d yin g Ca nc er T her a p y in 
Older Ad ults  .......................................................................................................................... 7  
1. 2  
F act ors Ot her t ha n C hr o n olo gic al Age t hat I mpact Dr u g T oler a nc e  .................................. 7  
1. 3  
P alb ociclib ............................................................................................................... 8  
1. 4  
A Ratio nale f or C o m binin g P alb ociclib a n d E n d o crine T her a p y ....................................... 8  
1. 5  
Meas ur e me nt of S ar c o pe nia .......................................................................................1 1  
1. 6  
Q ualit y of Lif e Q uestio n nair es: E ur o Q ol 5 D 3 L a n d E Q Vis ual Analo g Sc ale ( E Q V A S)  ....1 2  
1. 7  
P R O -C T C A E  ..........................................................................................................1 2  
2. 0  
O B J E C TI V ES .................................................................................................................1 3  
2. 1  
Pri mar y O bjective  ....................................................................................................1 3  
2. 2  
S ec o ndar y o bjectives  ................................................................................................1 3  
2. 3  
C orr elative s cie nc e o bjectives  ....................................................................................1 3  
3. 0  
P A TI E N T S E L E C TI O N .....................................................................................................1 5  
3. 1  
O n -St u dy G uidelines  ................................................................................................1 5  
3. 2  
Eligib ilit y Criteria ....................................................................................................1 6  
4. 0  
P A TI E N T R E GI S T R A TI O N  ...............................................................................................1 7  
4. 1  
I n vestigat or a n d Res earc h Ass ociate Re gistr atio n wit h C T E P .........................................1 7  
4. 2  
C T S U Re gistr atio n Pr oc e d ur es ...................................................................................1 8  
4. 3  
P atie nt Re gistr atio n Re q uir e me nts  ..............................................................................2 0  
4. 4  
P atie nt Re gistr atio n/ Ra n d o mizatio n Pr oc e d ur es  ............................................................2 0  
4. 5  
Re gistr atio n t o C orr elative a n d C o m pa nio n St u dies  .......................................................2 1  
4. 6  
Gr o u pin g F act or  ......................................................................................................2 2  
5. 0  
S T U D Y C A L E N D A R  ........................................................................................................2 3  
6. 0  
D A T A A N D S P E C I M E N S U B MI S S I O N  .................................................................................2 4  
6. 1  
Data C ollectio n a n d S u b missio n .................................................................................2 4  
6. 2  
S peci me n c ollectio n a n d s u b missio n  ...........................................................................2 6  
6. 3  
Digital I ma ge S u b missio n Usin g T RI A D  .....................................................................2 9  
7. 0  
T R E A T M E N T P L A N /IN T E R V E N TI O N  ................................................................................3 1  
7. 1  
P alb ociclib ..............................................................................................................3 1  
7. 2  
Letr oz ole  ................................................................................................................3 2  
7. 3  
F ulvestr a nt ..............................................................................................................3 2  
7. 4  
Ad her e nc e, Geriatric Ass ess me nt, an d P atie nt P ers pective  .............................................3 2  
8. 0  
D O S E A N D T R E A T M E N T M O DI FI C A TI O N S  ........................................................................3 3  
8. 1  
Ancillar y T her a p y, C o nc o mita nt Me dic atio ns, a n d S u p p ortive Car e .................................3 3  
8. 2  
D os e M o dific atio ns  ..................................................................................................3 5  
9. 0  
A D V E R S E E V E N TS .........................................................................................................3 6  
9. 1  
R o utine Ad vers e E ve nt Re p ortin g  ..............................................................................3 6  
9. 2  
C T C A E R o utine Re p ortin g Re q uir e me nts ....................................................................3 7  
9. 3  
E x pe dite d Ad vers e E ve nt Re p ortin g ( C T E P -A E R S)  ......................................................3 7  
9. 4  
C A E P R  ..................................................................................................................4 2  
1 0. 0  
D R U G I N F O R M A TI O N  ....................................................................................................4 5  
1 0. 1  
Ge ner al C o nsider atio ns:  ............................................................................................4 5  

 
Allia nc e A1 7 1 6 0 1  
 
6  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
1 0. 2  
P alb ociclib ..............................................................................................................4 5  
1 0. 3  
F ulvestr a nt ..............................................................................................................4 6  
1 0. 4  
Letr oz ole  ................................................................................................................4 8  
1 1. 0  
M E A S U R E M E N T O F E F F E C T  ...........................................................................................4 9  
1 1. 1  
P atie nt r e p orte d o utc o me meas ur es  .............................................................................4 9  
1 1. 2  
Meas ur e me nt of t u mor r es p o ns e a n d sc he dule of e valuatio ns  ..........................................5 0  
1 1. 3  
Definitio ns of Meas ur a ble a n d N o n -Meas ur a ble Dis eas e ................................................5 1  
1 1. 4  
G uidelines f or E valuatio n of Meas ur a ble Dis eas e  .........................................................5 2  
1 1. 5  
Meas ur e me nt of Tr eat me nt/I nt er ve ntio n Eff ect .............................................................5 3  
1 1. 6  
Definitio ns of Analysis Varia bles  ...............................................................................5 6  
1 2. 0  
E N D O F T R E A T M E N T /IN T E R V E N TI O N  .............................................................................5 6  
1 2. 1  
D ur atio n of Tr eat me nt  ..............................................................................................5 6  
1 2. 2  
F ollo w -u p f or patie nts w h o dis c ontin ue pr otoc ol t her a p y  ...............................................5 6  
1 2. 3  
Ma na gin g ineligible patie nts a n d r e gister e d patie nts w h o ne ver r ec eive pr ot oc ol inter ve ntio n
 
5 7  
1 2. 4  
E xtr a or dinar y Me dic al Cir c u msta nc es  .........................................................................5 7  
1 3. 0  
S T A TI S TI C A L C O N S I D E R A TI O N S  .....................................................................................5 8  
1 3. 1  
Pri mar y E n d p oints:  ..................................................................................................5 8  
1 3. 2  
Pri mar y E n d p oint Analysis: .......................................................................................5 8  
1 3. 3  
S ec o ndar y E n d p oints:  ...............................................................................................5 8  
1 3. 4  
S ec o ndar y E n d p oint Analys es ....................................................................................5 8  
1 3. 5  
S a m ple Size  ............................................................................................................6 0  
1 3. 6  
I nteri m a nalysis a nd st o p pin g r ules: ............................................................................6 0  
1 3. 7  
St u d y  Re p ortin g  ......................................................................................................6 1  
1 3. 8  
I nclusio n of W o me n a n d Min orities  ............................................................................6 2  
1 4. 0  
E X P L O R A T O R Y C O R R E L A TI V E A N D C O M P A NI O N S T U D I ES  ...............................................6 3  
1 4. 1  
C orr elative S cie nc e: Cir c ulatin g mar kers of infla m matio n as p ote ntial mar kers pr e dictive of 
t o xicit y a m o n g elderly patie nts e nr olle d t o Allia nc e A1 7 1 6 0 1 ( Allia nc e A1 7 1 6 0 1-S T 1)  ...................6 3  
1 4. 2  
P har mac o ge n o mics: ( Allia nc e A1 7 1 6 0 1 -S T 2): Ge netic deter mina nts of P alb ociclib Effic ac y 
a n d t o xicit y in t he elderly .......................................................................................................6 7  
1 4. 3  
P har mac o kinetics: ( Allia nc e A1 7 1 6 0 1 -P P 1)  P o p ulatio n P har mac o kinetics of P alb ociclib  ..7 2  
1 5. 0  
G E N E R A L R E G U L A T O R Y C O N S I D E R A TI O N S A N D C R E D E N TI A LI N G  ....................................7 6  
1 5. 1  
Geriatric Ass ess me nt Tr ainin g  ...................................................................................7 6  
1 6. 0  
R E F E R E N C ES ................................................................................................................7 7  
1 7. 0  M O D E L C O N S E N T F O R M  ....................................................................................................8 7  
A P P E N D I X I: P A TI E N T  I N F O R M A TI O N S H E E T S .................................................................. 1 0 0  
A P P E N D I X II: G E R I A T R I C A S S ES S M E N T  ................................................................................... 1 0 4  
A P P E N D I X III  : W
A S I T W
O R T H I T Q U ES TI O N N AI R E  ................................................................. 1 2 4  
A P P E N D I X I V:  O V E R A L L T R E A T M E N T U TI LI T Y  ........................................................................ 1 2 5  
A P P E N D I X V:  E Q -5 D -3 L  H E A L T H Q U ES TI O N N AI R E  .................................................................. 1 2 7  
A P P E N D I X  VI:  P R O -C T C A E  *  -N CI -P R O -C T C A E  T M  I T E M S  ................................................. 1 2 9  
A P P E N DI X  VII:  P A TI E N T M
E DI C A TI O N D I A R Y - P A L B O C I C LI B ................................................. 1 3 6  
A P P E N D I X VIII:  T A B L E O F T A G S N P S F O R A 1 7 1 60 1  S T U D Y  ........................................................ 1 3 8  
A P P E N D I X I X:  P A TI E N T P H A R M A C O KI N E T I C Q U ES TI O N N AI R E.................................................... 1 4 0  
 
 

 
Allia nc e A1 7 1 6 0 1  
 
7  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
1. 0  
B A C K G R O U N D  
T his pr ot oc ol  a d dr ess es a ke y r esear c h priorit y of t he Ca nc er a n d Agin g Res ear c h Gr o u p, Natio nal 
Ca nc er I nstit ute, Natio nal I nstit ute o n Agin g, a n d t he I nstit ute of Me dicin e: t he ass ess me nt of 
c a nc er t her a p y in older a d ults 6 , 7 P alb ociclib is a n o vel dr u g wit h t he p ote ntial t o c ha n ge t he 
tr eat me nt of metastatic br east c a nc er- a pri mar y dis eas e of older a d ults. T he c o m binatio n of 
palb ociclib a n d e n d ocrine t her a p y ( t he ar o mat as e in hibit or , letr oz ole, or f ulvestr a nt) is ass ociated 
wit h a n i m pr o ve me nt in pr o gr essio n -fr ee s ur vival ( P F S) c o m par e d t o e n d ocrine t her a p y alo ne. 1 , 2 
Ho w e ver, a s mall pr o p ortio n of patie nts e nr olle d in t hes e st u dies w er e a ge 7 5 a n d older. T he piv otal 
trial of palb ociclib  r e p orte d in t he pac ka ge ins ert n otes t hat o nly 3 7 patie nts ( 4 4 %) w er e ≥6 5 years 
of a ge a n d 8 patie nts ( 1 0 %) w er e ≥7 5 years of a ge. T he g oal of t his st u d y is t o fill t his ga p in 
k n o wle d ge b y utilizin g a p has e II desig n t o e xa mine t he t oler a bilit y of palb ociclib a n d e n d ocrine 
ther a p y a m o n g older a d ults a ge 7 0  a n d older wit h estr o ge n r ece pt or p ositive, H E R 2 ne gative br east 
t u m ors.  A c o m pr e he nsive c a nc er-s pecific geriatric ass ess me nt w hic h inclu des a n e valuatio n of 
f u nctio nal stat us, ot her me dic al c o n ditio ns, c o g nitive f u nctio n, n utritio nal stat us, s ocial s u p p ort, 
ps yc h olo gic al state, a n d a r e vie w of me dic atio ns will  be inclu de d, as w ell as a n ass ess me nt of 
a d her e nc e.  
1. 1 
A gi n g a n d a De cre as e i n P h ysi ol o gic Res er ve: R ati o n ale f or St u dyi n g C a n cer T h e r a py i n 
Ol de r A d ults  
Agin g brin gs a b o ut a pr o gr essive decr eas e in p h ysiolo gic r es er ve t hat aff ects eac h in divid ual at 
a u niq u e pac e. 8 , 9 T he a ge -r elate d p h ysiolo gic al decline in or ga n s yste ms t y pic ally be gins in t he 
3r d dec a de of lif e a n d is n ot e vide nt at ti mes of r est b ut bec o mes m ost a p par e nt w he n t he b ody 
is str ess e d. 1 0 Bot h  c a nc er a n d c a nc er tr eat me nt c a n be c o nsider e d a p h ysiolo gic al str ess or, and 
a ge-r elate d decr eas es in p h ysiolo gic r es er ve ma y aff ect t oler a nc e t o ca ncer tr eat me nt.  
A n u m ber of a ge -r elate d c ha n ges in dr u g a bs or ptio n, distrib utio n, meta b olis m, a n d e xcr etion 
wit h a gin g ma y c o ntrib ute t o diff er e nc es in tr eat me nt t oler a nc e bet w e e n older a n d y o u n ger 
patie nts. T he a bs or ptio n of dr u gs c a n be aff ecte d b y decr eas e d gastr ointestinal m otilit y, 
decr eas e d s pla nc h nic blo o d flo w, decr eas e d s ecr etio n of digestive e nz y mes, a n d m uc os al 
atr o p h y. 1 1 , 1 2 Wit h  t he incr eas e d us e of or al t her a p y, me dic atio n c o m plia nc e is a n i m p orta nt iss ue 
as w ell. 1 3 As  a pers o n a ges, b o d y c o m p ositio n c ha n ges, wit h a n incr eas e in b o d y f at a n d decr ease 
in lea n b o d y mass a n d t otal b o d y w ater.  T he incr eas e in b o d y f at lea ds t o a ris e in t he v olu me 
of d istrib utio n f or h y dr o p hilic dr u gs. I n t he p o p ulatio n of older a d ults wit h c a nc er, maln utrition 
a n d h y p oalb u mine mia ma y r es ult in a n incr eas e d c o nc e ntr atio n of dr u gs t hat ar e alb u min -
b o u n d. 1 4  
He patic mass a n d blo o d flo w als o decr eas e wit h a ge. 8  T he  i m pact of t he decline in he patic mass 
a n d blo o d flo w o n he patic e nz y me f u nctio n is c o ntr o versial. 1 5 I n a st u d y of 2 2 6 patie nts, t he 
c yt oc hr o me P -45 0 c o nte nt in liver bio ps y s a m ples decr eas e d b y a p pr o xi mately 3 0 % in patie nts 
o ver t he a ge of 7 0. 1 6 Re nal f u nctio n als o declines wit h a ge, a n d r e nal ins ufficie nc y is c o m mon 
in older a d ults.1 7 , 1 8 
A pr o gr essive r e d uctio n in t he f u nctio nal r es er ve of vario us or ga n s yste ms ma y alter t he 
p har mac o kinetics of a nti -c a nc er t her a pies 11 , 19 a n d incr eas e t he s us c e ptibilit y of older in divid uals 
t o c o m plic atio ns of tr eat me nt.1 4 , 2 0-22 N or mal tiss ues ma y be less a ble t o r e pair t he m olec ular 
da ma ge c a us e d b y a ntine o plastic a ge nts d ue t o cellular s e nes c e nce, res ultin g in gr eater p ote ntial 
c ar diot o xicit y, ne ur ot o xicit y, m uc ositis, a n d he ma t olo gic t o xicities.2 3  
1. 2 
F act ors Ot h e r t h a n C h r o n olo gic al A ge t h at I m pact Dr u g Tole r a n ce  
Agin g is a heter o ge ne o us pr oc ess.  W hile c ertain declines in or ga n f u nctio n ar e u nivers al as t he 
h u ma n b o d y a ges, t he r ate of t his decline a n d t he c o ns e q ue nc es of t his decline o n e ver y da y 
f u nctio n pr oc ee ds at a u niq ue pac e in eac h in divid ual.  T her ef or e, c hr o n olo gic al a ge tells us 

 
Allia nc e A1 7 1 6 0 1  
 
8  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
r elatively little a b o ut t he s pecific in divid ual.  A m or e detaile d e valuatio n of a n older a d ult patie nt 
is nee de d in or der t o c a pt ur e f act ors ot her t ha n c hr o n olo gic al a ge t hat pr e dict f or m or bidit y a nd 
m ortalit y.  A c o m pr e he nsive g eriatric ass ess me nt ma y s er ve t his p ur p os e.  T he c o mpr e he nsive 
geriatric ass ess me nt inclu des a n e valuatio n of f u nctio nal stat us, c o -mor bid me dic al c o n ditio ns, 
c o g nitive f u nctio n, n utritio nal stat us, s ocial s u p p ort a n d ps yc h olo gic al state , a n d a r e vie w of 
m e dic atio ns 3 ,4 . C o nclusio ns fr o m s e ver al st u dies ar e e mer gin g r e gar din g t he be nefits of 
perf or min g a c o m pr e he nsive geriatric ass ess me nt f or older patie nts wit h c a nc er.  
1.  
F act ors e valuate d in a c o m pr e he nsive geriatric ass ess me nt pr e dicts s ur vival . 2 4  
2.  
F ac t ors e valuate d in a c o m pr e he nsive geriatric ass ess me nt pr e dicts t o xicit y t o 
c he m ot her a p y . 2 5 
3.  
A c o m pr e he nsive geriatric ass ess me nt u nc o vers pr o ble ms n ot detecte d b y r o utine hist or y 
a n d p h ysic al in initial c o ns ultatio n a n d f ollo w -u p c ar e . 2 6  
4.  
P atie nts u n der g oin g a c o m pr e he nsive geriatric ass ess me nt a n d inter ve ntio n bas e d o n t he 
r es ults ha d i m pr o ve d pain c o ntr ol. 2 7  
5.  
A c o m pr e he nsive geriatric ass ess me nt a n d inter ve ntio n i m pr o ves a n older patie nt’s me ntal 
healt h a n d w ell -bein g. 2 7  
6.  
C o ns e ns us g uidelines r ec o g nize t he be nefits a n d r ec o m me n d t he inclusio n of a geriatric 
ass ess me nt as part of t he e valuatio n of a n older patie nt. 2 8  
1. 3  
P al bocicli b  
P alb ociclib is a r e versible, s elective, c yclin de pe n de nt kinas e ( C D K) 4 /6 in hibit or t hat is a ble t o 
st o p t he n or mal pr oc ess of t he c ell c ycle as t he c ell tr a vels fr o m G 1 p has e t o S p has e 1. I n t he 
a bs e nc e of palb ociclib, t hes e kinas es will p h os p h or ylate t he r etin o blast o ma ( R b) pr otein t o c a use 
a r eleas e of tr a ns criptio n f act ors  w hic h allo w s t he c ell t o m o ve t hr o u g h t he c ell c ycle, t h us 
allo win g t he gr o wt h of c a nc er o us c ells 1 . W he n palb ociclib in hibits C D K4 a n d C D K6, t he 
r etin o blast o ma pr otein is arr este d at t he G 1 p has e, pr o hibitin g “ S-p has e e ntr y a n d c ell gr o wth” 
of t he c a nc er o us c ells 2 9.  
1. 4  
A  R ati o n ale f or C o m bi ni n g P al bocicli b a n d E n docri n e T h e r a py  
P alb ociclib in c o m binatio n wit h e n d ocrine t her a p y c o m par e d t o e n d ocrine t her a p y alo ne 
i m pr o ves pr o gr essio n-fr ee s ur vival.  Data fr o m t he P A L O M A-1 trial de m o nstr ates t he efficac y 
o f palb ociclib wit h letr oz ole in t he first line tr eat me nt of estr o ge n  r ec e pt or p ositive metastatic 
br east c a nc er. 1   I n t his ra n d o mize d o pe n-la bel p has e II st u d y, 1 6 5 w o me n r a n gin g fr o m a ges 54-
7 2 ha d a d va nc e d estr o ge n r ec e pt or p ositive a n d H E R -2 ne gative br east c a nc er. O ne c o h ort of 
w o me n ( mea n a ge 6 5) w as  e nr olle d bec a us e of t heir estr o ge n r ec e pt or p ositive a n d H E R 2 - 
ne g ative br east c a nc er, w her eas a sec o n d c o h ort ( mea n a ge 6 2. 5) was e nr olle d bec a us e t he y als o 
ha d c a nc ers wit h a m plific atio n of C C N D 1  a n d/ or loss of P 1 6. T hes e c o h orts r ec eive d eit her 
letr oz ole alo ne (or ally 2. 5 m g/ da y) or letr oz ole (or ally 2. 5 m g/ da y)  wit h pa lb ociclib (or ally 1 2 5 
m g/ da y f or t hr ee w ee ks o n a n d o ne w ee k off). Eig ht y -f o ur patie nts w er e assig ne d t o t he 
palb ociclib -letr oz ole gr o u p a n d 8 1 t o letr oz ole alo ne. T he me dia n pr o gr essio n-fr ee s ur vival was 
2 0. 2 m o nt hs f or t he palb ociclib a n d letr oz ole ar m, c o m par e d t o 1 0. 2 m o nt hs f or letr oz ole alo ne. 
C o m m o n side eff ects f or palb ociclib wit h letr oz ole c o m par e d t o letr oz ole alo ne  ( T a ble 1) w er e: 
gr a de 3 -4 ne utr o pe nia ( 5 4 % vs. 1 %), le u k o pe nia ( 1 9 % vs. 0 %), a n d f atig ue ( 4 % vs. 1 %). Four 
per c e nt of patie nts r ec ei vin g palb ociclib wit h letr oz ole e x perie nc e d a p ul m o nar y e m b olis m. 
A m o n g patie nts in t he palb ociclib a n d letr oz ole gr o u p, 1 3 % dis c o ntin ue d d ue t o side eff ects 
w her eas o nly 2 % of t he letr oz ole gr o u p dis c o ntin ue d t he st u d y.  

 
Allia nc e A1 7 1 6 0 1  
 
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N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
Ta bl e 1: C o m m o n A dve rs e Re acti o ns w it h a n I n ci de n ce of >  5 % i n P atie nts w h o Re cei ve d 
P al bocicli b pl us Let r oz ole or Let r oz ole Al o ne i n P A L O M A -1 St u dy 1  
 
 
P al bocicli b pl us Let r oz ole ( N = 8 3)  
Let r oz ole ( N = 7 7)  
Gr a de 3  
Gr a de 4  
Gr a de 3  
Gr a de 4  
An y a d vers e e ve nt  
4 9 ( 5 9 %)  
1 4 ( 1 7 %)  
1 6 ( 2 1 %)  
0  
Ne utr o pe nia  
4 0 ( 4 8 %)  
5 ( 6 %)  
1 ( 1 %)  
0  
Le u k o pe nia  
1 6 ( 1 9 %)  
0  
0  
0  
Ane mia  
4 ( 5 %)  
1 ( 1 %)  
1 ( 1 %)  
0  
* Dat a ar e i n n ( %) u nless ot h er wise s p e cifie d  
P A L O M A -2 3 0  - w hic h w as desig ne d t o e x pa n d effic ac y a n d s af et y data f or palb ociclib a n d 
letr oz ole tr eat me nt - ha d a s a m ple size of 6 6 6 p ost me n o pa usal w o m e n wit h E R-p ositive, H E R 2 -
ne gative, br east c a nc er. I n P A L O M A -2, t he me dia n a ge of patie nts r ec eivin g palb ociclib -
letr oz ole w as 6 2 wit h a r a n ge fr o m 3 0-8 9, wit h o nly 3 9. 3 % of participa nts a ge 6 5 a n d o ver with 
n o p u blis he d inf or matio n f or patie nts older t ha n  7 5. A m o n g patie nts r ec eivin g plac e b o a n d 
letr oz ole t he me dia n P F S w as 1 4. 5 m o nt hs ( 9 5 % CI 1 2. 9-1 7. 1). T his effic ac y i m pr o ve d wit h 
palb ociclib -letr oz ole t o 2 4. 8 m o nt hs ( 9 5 % CI 2 2. 1-N ot r eac he d). T he m ost c o m m o n gr ade 3 or 
4 a d vers e e ve nts w er e ne utr o pe nia wit h 6 6. 4 % of patie nts tr eate d wit h palb ociclib -letr oz ole 
e x perie ncin g t his c o m par e d t o 1. 4 % in t he plac e b o -letr oz ole gr o u p. Le u k o pe nia ( 2 4. 8 % vs. 0 %), 
a ne mia ( 5. 4 % vs. 1. 8 %) a n d f atig ue ( 1. 8 % vs. 0. 5 %) w ere als o r e p ort e d.  
F urt her s u p p ort f or use of palb oc iclib in c o nju nctio n wit h h or m o ne t her a p y w as c arrie d o ut in 
t he P A L O M A-3 trial. 2   T his p has e III trial inclu de d 5 2 1 patie nts r a n d o mize d int o 2 gr o u ps:  
palb ociclib a n d f ulvestr a nt ( N = 3 4 7) or f ulvestr a nt alo ne ( N = 1 7 4). P atie nts w ere eligible t o 
participat e in t his st u d y if t he y w er e estr o ge n  r ec e pt or p ositive. P atie nts e nr olle d in t his st u d y 
c o uld ha ve ha d prior e n d ocrine t her a p y ( 3 8. 8 % first line, 2 5. 5 % s ec o n d line, 1 0. 9 % t hir d line 
a n d a b o ve). I n a d ditio n, patie nts w er e allo w e d o ne prior line of c he m ot he r a p y. T he me dia n 
pr o gr essio n -fr ee s ur vival w as 9. 2 m o nt hs f or t he palb ociclib a n d f ulvestr a nt ar m, c o mpar e d t o 
3. 8 m o nt hs f or f ulvestr a nt alo ne. C o m m o n side eff ects f or palb ociclib a n d f ulvestr a nt 
c o m par e d t o f ulvestr a nt alo ne w er e: ne utr o pe nia ( 6 2 % vs. 6 % ), le u k o pe nia ( 2 5. 2 % vs. 0. 6 %), 
a ne mia ( 2. 6 % vs. 1. 7 % ), t hr o m b oc yto pe nia ( 2. 3 % vs. 0 %), f atig ue ( 2. 0 % vs. 1. 2 %), a n d 
f e brile ne utr o pe nia ( 0. 6 % f or b ot h gr o u ps).  A m o n g patie nts in Gr o u p 1, 2. 6 % dis c o ntin ue d 
t he st u d y w hile 1. 7 % of patie nts in Gr o u p 2 dis c ontin ue d d ue t o side eff ects.  
1. 4. 1  A ge S pe cific D at a f r o m P A L O M A -1, P A L O M A -2 a n d P A L O M A -3  
Li mite d e vide nc e e xists t o g uide t her a p y wit h palb ociclib a n d e n d ocrine t her a p y in older 
a d ults.  I n P A L O M A-1, t he mea n a ge of patie nts w as 6 4 wit h a r a n ge fr o m 5 4 -7 2 . I n 
P A L O M A -2, t he me dia n a ge of patie nts r ec eivin g palb ociclib -letr oz ole w as 6 2 wit h a r a nge 
fr o m 3 0-8 9, wit h o nly 3 9. 3 % of participa nts a ge 6 5 a n d o ver wit h n o p u blis he d inf or mation 
f or patie nts older t ha n 7 5. I n P A L O M A-3, t he mea n a ge of patie nts w as 6 4 wit h a r a n ge 
fr o m 2 9 t o 8 8. I n P A L O M A-3, o nly 2 5 % of t he participa nts w er e a ge 6 5 a n d o ver. Re vie w 
of t he data o btaine d fr o m 1 6 5 patie nts in t he P A L O M A -1 trial, as w ell as t he 5 2 1 patie nts 
in t he P A L O M A-3 trial, did n ot s h o w a n y a p par e nt diff er e nces in s yste mic e x p os ur e r elated 
t o a ge. A s u b gr o u p a nalysis of t he effic ac y a n d s af ety of first-line palb ociclib plus letr oz ole 
c o m par e d wit h letr oz ole alo ne in patie nts in t he P A L O M A -1 st u d y e valuate d 1 6 5 
p ost me n o pa us al w o me n. Of t he 7 6 patie nts a ge 6 5 a n d o lder, 3 7 w er e tr eate d wit h 
palb ociclib a n d letr oz ole, a n d t he r e main der r ec eive d letr oz ole alo ne. A m o n g patie nts 
r ec eivin g palb ociclib a n d letr oz ole t he me dia n P F S f or patie nts a ge 6 5 a n d o ver w as 2 6. 6 
m o nt hs ( 9 5 % CI 1 2. 6 -N R) in c o m paris o n t o 7. 7 m o nt hs ( 9 5 % CI 3. 7 -1 0. 9) f or patie nts w ho 

 
Allia nc e A1 7 1 6 0 1  
 
1 0  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
r ec eive d letr oz ole alo ne. Gr a de 3-4 ne utr o pe nia oc c urr e d in 5 6. 8 % of patie nts r ec eivin g 
palb ociclib a n d letr oz ole ( c o m par e d t o 2. 7 % in patie nts wit h letr oz ole alo ne). I n a d ditio n, 
gr a de 3 -4 le u k o pe nia oc c urr e d in 2 9. 7 % of t he patie nts r ec eivin g palb ociclib a n d letr oz ole, 
a n d gr a de 3 -4 f atig ue w as r e p orte d in 1 0. 8 % of patie nts r eceivin g palb ociclib a n d letr oz ole.  
Neit her of t hes e a d vers e e ve nts oc c urre d in a n y patie nts ta kin g letr oz ole alo ne.
3 1  
An ot her s u bs et a nalysis of t he P A L O M A -1 st u d y e valuate d t he ti me t o o ns et of ne utr o pe nia, 
le u k o pe nia, a ne mia, a n d t hr o m b oc yt o pe nia. T he y f o u n d t hat 9 7. 9 % of all a d vers e e ve nts 
oc c urr e d wit hin t he first 6 m o nt hs a n d sta ye d r elatively sta ble or decr eas e d in incide nc e o ver 
ti me. Wit hin t he first 6 m o nt hs, 6 9. 5 % of t he 9 5 participa nts pr es e nte d wit h ne utr o pe nia, 
3 3. 7 % wit h le u k o pe nia, a n d 2 2. 1 % wit h a ne mia. T he me dia n ti me t o o ns et f or ne utr o pe nia 
w as 2 0 da ys, f or le u k o pe nia 
w as 3 6 da ys, f or a ne mia 
w as 1 6 8 da ys , a n d f or 
t hr o m b oc yt o pe nia w as 1 4 0 da ys. T he y did n ot s ee a n y e vide nc e of s pecific c u m ulative or 
late o ns et of t o xicit y wit h tr eat me nt o n  palb ociclib a n d letr oz ole. 3 2   
1. 4. 2  Filli n g a Ga p i n K n o wle dge  
P alb ociclib a n d e n d ocrine t her a p y is e mer gin g as a n o ve l tr eat me nt f or estr o ge n  r ec e ptor 
p ositive metastatic br east c a nc er. A ga p in k n o wle d ge s pecific ally e xists wit h r e gar d t o t he 
t oler a bilit y of t his c o m binatio n in a d ults a ge 70  a n d o ver. T his is a n i m p orta nt r es ear c h ar ea, 
sinc e c a nc er is a dis eas e ass ociate d wit h a gin g. T w e nt y per c e nt of patie nts wit h br east c ancer 
ar e a ge 7 0  a n d older. T his p has e II st u d y will e valuate t he s af et y a n d t oler a bilit y of t he 
c o m binatio n of palb ociclib a n d letr oz ole o r f ulvestr a nt in patie nts a ge 7 0 a n d o ver, as w ell 
as des crib e t he f ull t o xicit y pr ofile, esti mate t he o bjective r es p o ns e r ate a n d clinic al be nefit, 
as w ell as s ur vival. A geriatric ass ess me nt a n d meas ur es of a d her e nc e will be inclu de d 
wit hin t he st u d y.  O ver all o ur g oal is t o clos e t his ga p in k n o wle d ge in older a d ults wit h 
metastatic br east c a nc er w h o ma y derive sig nific a nt be nefit fr o m t his n o vel tr eat me nt 
o ptio n.    
1. 4 . 3 R ati o n ale f or t h e St u dy  
Li mite d e vide nc e e xists t o g uide t her a p y wit h tar gete d a ge nts in t he older a d ult p o p ulatio n 
bec a us e older a d ults ha ve be e n u n der -r e pr es e nte d in clinic al trials. Ad ults a ge 7 0 a n d older 
ma ke u p o nly 2 0 % of s u bjects e nr olle d in F D A r e gistr atio n trials b ut 4 6 % of all patie nts 
wit h c a nc er dia g n os es. D os e -fin din g st u dies s pecific ally in older a d ults ar e n ot r o utinely 
perf or me d.  T his is des pite c ha n ges in dr u g meta b olis m, a bs or ptio n, a n d distrib utio n wit h 
incr easin g a ge. T he c o m binatio n of palb ociclib a n d e n d ocrine t her a p y is a n o vel tr eat me nt 
a p pr oac h f or p ost me n o pa us al w o me n wit h estr o ge n  r ec e pt or p ositive, h u ma n e pider mal 
gr o w t h f act or r ec e pt or 2 ( H E R 2)-ne gative a d va nc e d br east c a nc er. T he c o m binatio n 
sig nific a ntly i m pr o ves pr o gr essio n-fr ee s ur vival c o m par e d t o e n d ocrine t her a p y alo ne. 
Ho w e ver, t hes e st u dies pri marily f oc us e d o n w o me n less t ha n a ge 7 5. F or e xa m ple, t he 
r a n d o mize d p has e II trial ( P A L O M A-1) of palb ociclib a n d letr oz ole c o m par e d t o letr oz ole 
alo ne ( mea n a ge 6 3 a n d 6 4, r es pectively) o nly inclu de d 8 patie nts a ge 7 5 a n d older, a n d t he 
p has e III trial ( P A L O M A -3) of palb ociclib a n d f ulvestr a nt c o m par e d t o f ulvestr a nt al o ne 
( mea n a ge 5 7 a n d 5 6, r es pectively) inclu de d o nly 2 5 % of participa nts a ge 6 5 a n d older, 
w hile n ot r e p ortin g o n participa nts a ge 7 5 a n d older.
1, 2   I n P A L O M A-2, t he me dia n a ge of 
patie nts r ec eivin g palb ociclib -letr oz ole w as 6 2 wit h a r a n ge fr o m 3 0-8 9, wit h o nly 3 9. 3 % 
of participa nts a ge 6 5 a n d o ver wit h n o p u blis he d inf or matio n f or patie nts older t ha n 7 5. I n 
a d ditio n, t he piv otal trial of palb ociclib a n d letr oz ole r e p orte d in t he pac ka ge ins ert n otes 
t hat 3 7 patie nts ( 4 4 %) w er e ≥ 6 5 years of a ge a n d o nly 8 patie nts ( 1 0 %) w er e ≥ 7 5 years of 
a ge.  
T he m ost c o m m o n a d vers e e ve nts of palb ociclib in c o m binatio n wit h e n d ocrine t her a p y are 
ne utr o pe nia, le u k o pe nia, a n d f atig ue. I n partic ular, in P A L O M A -1 patie nts r ec eivin g t he 

 
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c o m binatio n palb ociclib a n d letr oz ole e x p erie nc e d gr a de 3 or 4 ne utr o pe nia ( 5 4 %), 
le u k o pe nia ( 1 9 %), or f atig ue ( 4 %). I n P A L O M A-3, patie nts r ec eivin g palb ociclib a n d 
f ulvestr a nt e x perie nc e d gr a de 3 or 4 ne utr o pe nia ( 6 2 %), le u k o pe nia ( 2 5. 2 %), or f atig ue 
( 2 %). T he pac ka ge ins ert s pecific ally w ar ns of p ote ntial f e brile ne utr o pe nia a n d inf ectio n; 
alt h o u g h, ne utr o pe nic f e ver is ver y r ar e wit h t he c o m binatio n ( P A L O M A -1 wit h 0 %, 
P A L O M A -3 
wit h 0. 6 %). I n a d ditio n, t he 
pac ka ge ins ert inclu des 
w ar nin g of 
t hr o m b oe m b olis m ( P A L O M A-1 wit h 4 %, P A L O M A-3 wit h 0 %). T hes e side eff ects are of 
partic ular c o nc er n in older a d ults. I n partic ular, t her e is a decr eas e in b o ne marr o w r es er ve 
wit h a gin g, he nc e a m plif yin g t he p ote ntial ris k of ne utr o pe nia a n d m yelos u p pr e ssion. 
F urt her m or e, older a d ults ofte n ha ve ot her c o -m or bid  me dic al c o n ditio ns w hic h ma y 
pr e dis p os e t he m t o t hr o m b oe m b olis m t her e b y incr easin g t he ris k. Bec a us e of t his, a 
definitive st u d y in t he older a d ult p o p ulatio n will di minis h a n y r es er vatio ns o nc olo gists may 
ha ve in pr es cribin g palb ociclib wit h letr oz ole or  f ulvestr a nt a n d c a n pr o vide g uida nc e 
r e gar din g t he d osin g a n d t o xicit y ma na ge me nt in older a d ults.  
T his is a n o pe n la bel, sin gle ar m, p has e II st u d y of t he c o m binatio n of palb ociclib a n d 
letr oz ole or f ulvestr a nt in 8 8 patie nts a ge 7 0  or o ver wit h estr o ge n  r ec e pt or p ositive, H E R 2 
ne gative  metastatic br east c a nc er. T he pri mar y g oal of t his st u d y is t o esti mate t he  s af ety 
a n d t oler a bilit y ( a d vers e e ve nt r ate) of t he c o m binatio n of palb ociclib a n d e n d ocrine t her a p y 
in older a d ults wit h es tr o ge n r ec e pt or p ositive, H E R 2 ne gative metastatic br east c a nc er. 
S ec o n dar y ai ms ar e t o des cribe t he f ull t o xicit y pr ofile, des cribe d os e m o dific atio ns, 
e valuate dis eas e r es p o ns e in t his p o p ulatio n , e valuate patie nt a d her e nc e a n d tr eat me nt 
pers pective,  a n d t o e x plor e f act ors ot her t ha n c hr o n olo gic a ge t hat pr e dict t o xicit y usin g a 
c a nc er -s pecific geriatric ass ess me nt. C orr elative st u dies in t his pr o p os al will als o ai m t o  
e valuate cir c ulatin g mar kers of infla m matio n as p ote ntial mar kers pr e dictive of t o xicit y  or  
p h ysic al f u nctio n as ass ess e d b y t he c a nc er -s pecific geriatric ass ess me nt, a n d t o e xa mine 
sin gle n ucle otide p oly m or p his ms ( S N Ps) in c ell c ycle ge nes a n d ge nes t hat meta b olize 
palb ociclib . 
1. 5  
Me as u re m e nt of S arc o pe ni a  
1. 5. 1  B ac k gr o u n d  a n d M et h o ds  
Age -r elate d loss of m us cle mass a n d f u nctio n, ot her wis e k n o w n as s ar c o pe nia, is hig hly 
pr e vale nt in older a d ults a n d ass ociate d wit h f u nctio nal i m pair me nt, dis a bilit y, loss of 
in de pe n de nc e, a n d m ortalit y.3 3 -3 5  L oss es in s keletal m us cle mass a n d str e n gt h ar e a p par e nt 
as early as t he 4t h dec a de of lif e a n d pr o gr ess linearly wit h incr easin g a ge. 3 6  S ar c o pe nia in 
older a d ults wit h c a nc er is a d ditio nally c o m plic ate d b y c a nc er -r elate d c ac he xia a n d 
fr ailt y.3 7, 3 8 T he ele vate d infla m mat or y r es p o ns e a n d alter atio ns in meta b olis m r elate d t o 
c a nc er c ac he xia lea d t o f urt her loss es of m us cle mass 3 9, 40  T her e is a hig h pr e vale nc e of 
s ar c o pe nia in a d ults wit h br east c a nc er, partic ularly in older a d ults ( ~ 6 3 %) .41  S ar c o pe nia 
has bee n ass ociate d wit h incr eas e d gr a de 3/ 4 c he m ot her a p y t o xicit y, h os pitalizatio ns, a n d 
a d vers e e ve nts in a d ults 
wit h 
metastatic br east c a nc er u n der g oin g ta xa ne -bas ed 
c he m ot her a p y 4 2  T he pr es e nc e or a bs e nc e of s ar c o pe nia ma y help e x plain t he inter-
in divid ual varia bilit y in tr eat me nt t oler a bilit y of older a d ults wit h c a nc er a n d c o uld 
ulti mately be us e d t o in divid ualize tr eat me nt pla n nin g.  Alt h o u g h t her e ha ve bee n s e ver al 
st u dies e xa minin g t he ass ociatio n of s ar c o pe nia a n d c he m ot her a p y, t his u niq ue s mall st u dy 
will e x plor e its ass ociatio n wit h tar gete d t her a p y in older a d ults.  T his pr o p os al als o ai ms t o 
e valuate t he i m pact of s ar c o pe nia o n tar gete d t her a p y t o xicit y a n d a d vers e e ve nts in older 
a d ults wit h br east c a nc er u n der g oin g tr eat me nt wit h pa lb ociclib a n d e n d ocrine t her a p y. 
Pr actic al a n d pr ecis e meas ur e me nt a p pr oac hes ha ve bee n de velo pe d t o q ua ntif y b o d y 
c o m p ositio n in patie nts wit h c a nc er usin g C T i ma ges ac q uir e d d urin g r o utine c ar e t hat 

 
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r e q uir e mini mal a d ditio nal r es o ur c e alloc atio n. 4 3  T he L 3 la n d mar k fr o m cr oss -sectio nal 
i ma gin g has bee n ide ntifie d as t he str o n gest pr e dict or of w h ole b o d y f at a n d f at-fr ee mass 
w he n c o m par e d t o d ual -e ner g y x -r a y a bs or ptio metr y ( D X A).4 3  T he a d va nta ge of usin g 
a d va nc e d i ma gin g m o dalities, s uc h as C T i ma gin g, is  t he a bilit y t o pr o vide a d ditio nal 
q ualitative meas ur e me nts of m us cle a n d f at be y o n d p ur ely q ua ntitative meas ur es 4 4  
1. 6  
Q u alit y of Lif e Q u esti o n n aires: E u r o Q ol 5 D 3 L a n d E Q Vis u al A n al o g S c ale ( E Q V A S)  
I n a d ditio n t o t he r e p ortin g of s y m pt o ms, u n dersta n din g h o w q ualit y of lif e ma y be aff ecte d by 
palb ociclib a n d h or m o nal t her a p y  in t he metastatic  s ettin g in older patie nts has n ot bee n 
e valuate d pr e vio usly a n d will a d d i m p orta nt inf or matio n  t o t his st u d y. T he E Q -5 D (Ap pe n dix 
V ) is a meas ur e of healt h stat us f or us e in e valuatin g healt h a n d healt hc ar e. T he E Q-5 D -3 L is 
c o m pris e d of 2 pa ges: t he E Q -5 D des criptive s yste m ( pa ge 1) a n d t he E Q vis ual a nalo g ue s c ale 
( E Q V A S) ( pa ge 2). It pr o vides a si m ple des criptive pr ofile of five f u nctio nal di me nsio ns: 
m o bilit y, s elf -c ar e, us ual activities, pain/ dis c o mf ort, a n d a n xiet y/ de pr essio n. It ge ner ates a 
sin gle in de x value f or healt h stat us o n w hic h f ull healt h is assig ne d a value of 1 a n d deat h a 
value of 0. T h us, t he in de x c a n be us e d t o o b tain a utilit y f or t hes e di me nsio ns f or us e in 
ec o n o mic a nalys es. T he E Q -5 D has bee n s pecially desig ne d t o c o m ple me nt ot her q ualit y of lif e 
m eas ur es s uc h as t he S F -3 6, or c a nc er -s pecific meas ur es. Eac h di me nsio n has t hr ee le vels 
desig nate d si m ply as ' n o pr o ble m', 's o me pr o ble m', or ' e xtr e me pr o ble m', wit h patie nts c hec king 
t he le vel m ost des criptive of t heir c urr e nt le vel of f u nctio n o n eac h di me nsio n. Five di me nsions, 
eac h wit h t hr ee le vels, yield 2 4 3 p ossible distinct healt h states c o m prisin g t he classifi c atio n 
s yste m. T he classific atio n s yste m has bee n assig ne d diff er e nt sta n dar dize d s c or es derive d 
t hr o u g h p o p ulatio n-bas e d s a m ples of r es p o nde nts w ho assig n values t o s u bs ets of t he 2 4 3 states 
usin g t he a nc h orin g la bels n ote d a b o ve. F or e xa m ple, healt h stat e 1 1 2 1 2 r e pr es e nts a patie nt 
w h o in dic ates s o me pr o ble ms o n t he us ual activities a n d a n xiet y/ de pr essio n di me nsio ns.  A s et 
of valuatio n w eig hts has t h us bee n derive d fr o m a U. S. s a m ple.4 5  T he  Age nc y f or Healt hc ar e 
Res ear c h a n d Q ualit y has f u n de d a st u d y t o de velo p definitive w eig hts. E Q -5 D is desig ne d f or 
s elf-c o m pletio n b y patie nts a n d has bee n us e d e xte nsively in maile d s ur ve ys. It is c o g nitively 
si m ple, ta kin g n o m or e t ha n a f e w min utes t o c o m plete.  
1. 7  
P R O -C T C A E  
We will e valuate h o w w ell s y m pt o ms r e p orte d b y patie nts c orrelate/a gr ee wit h t h os e c o mpared 
t o w hat is r e p orte d in clinic usin g tr a ditio nal A E e valuatio ns.   
P atie nt -r e p orte d o utc o mes ( P R O) ar e a n i m p orta nt part of ne w dr u g e valuatio n a n d  ma y pla y a 
r ole in r e g ulat or y a p pr o val of n o vel a ge nts in o nc olo g y 4 6 . P R Os c a n be t he c o ns e q ue nc es of 
dis eas e a n d/ or its tr eat me nt as r e p orte d b y t he patie nt.  P R Os ar e e valuate d t hr o u g h t he us e of 
q uestio n nair es de velo pe d t o ass ess t o pics a patie nt  c a n r e p ort a b o ut his or her o w n healt h a n d 
ar e ofte n c o m plete d electr o nic ally. T his inclu des s y m pt o ms, p h ysic al f u nctio nin g, a n d me ntal 
healt h.  
T he c urr e nt sta n dar d mec ha nis m f or r e p ortin g t o xicities in c a nc er r es ear c h is clinicia n -o nly 
r e p ortin g usin g ite ms fr o m t he Natio nal Ca nc er I nstit ute ( N CI) C T C A Es. I n m ultiple st u dies, 
P R O meas ur es ha ve i m pr o ve d t he pr e dictive ac c ur ac y of clinicia n C T C A E r e p ortin g. I n a 
pr os pective st u d y inclu din g lu n g c a nc er patie nts’  P R O meas ur e me nts of t o xicities better 
r eflected patie nts’ u n derlyin g state a n d f u nctio nal stat us t ha n clinicia n’s e valuatio n  4 7 . Alt h o u gh 
P R Os ha ve bee n w ell validate d  4 8 , 4 9, 5 0, 5 1, t hes e e xa minatio ns ha ve bee n mini mally e valuate d f or 
f easibilit y a n d ac c ur ac y in a n older patie nt gr o u p a n d will mea nin gf ully a d d t o t he data c ollectio n 
o n t his st u d y.   

 
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We will f oc us o ur P R Os o n side eff ects m ost c o m m o nly r e p orte d in prior st u dies wit h 
palb ociclib a n d h or m o nal t her a p y  a n d w hic h of ar e of m ost inter est , inclu din g all s y m pt o ms 
liste d in Ap pe n dix V I. 
All s ur ve ys will be give n t o patie nts o n pa per, a t t he s a me ti me p oints as in-clinic e valuatio ns 
t hr o u g h c ycle 6, u nless patie nts c o me off st u d y prior t o c ycle 6. We will us e t he P R O-C T C A E 
it e ms de velo pe d b y t he Natio nal Ca nc er Instit ute in or der t o allo w patie nts t o s elf -r e p ort t he 
a b o ve s y m pt o matic a d vers e e ve nts. T he pri mar y p ur p ose of t he inclusio n of P R O -C T C A E is to 
e valuate t he perf or ma nc e a n d a gr ee me nt of patie nt -r e p orte d o utc o mes wit h t h os e c ollecte d as 
clinicia n -r e p orte d C T C A Es.   
2. 0  
O B J E C TI V ES  
2. 1  
Pri m ar y O bje cti ve  
T o esti mate t he s af et y a n d t oler a bilit y ( a d vers e e ve nt r ate) of t he c o m binatio n of palb ociclib a n d 
letr oz ole or  f ulvestr a nt in a d ults a ge 7 0 or older wit h estr o ge n  rec e ptor-p ositive, H E R 2 -ne gative 
m etastatic br east c a nc er.  
2. 2  
S e c o n dar y o bje cti ves  
2. 2. 1  T o des cribe t he f ull t o xic it y pr ofile inclu din g all gr a de 2 a n d hig her a d vers e e ve nts ( per N CI 
C T C A E v. 5 . 0), s pecific ally esti mat in g t he r ate of gr a de 2 a n d hig her m yelos u p pr ession 
(ne utr o pe nia, le u k o pe nia, t hr o m b oc yt o pe nia, a n d a ne mia), ne utr o pe nic f e ver , GI side eff ects 
( na us ea, diarr hea, decr eas e d a p petite, v o mitin g, m uc ositis -or al), f atig ue, ne ur o pat h y, and 
t hr o m b oe m b olis m. 
2. 2. 2  T o des cribe r ates of d os e r e d uctio ns, d ose h olds, a n d h os pitalizatio ns . 
2. 2. 3  T o esti mate m e dia n ti me t o tr eat me nt f ailur e , inclu din g pr o gr essio n fr ee s ur vival a n d o ver all 
s ur vival. 
2. 2. 4  T o esti mate t he r ate of a d her e nc e t o palb ociclib , letr oz ole a n d f ulvestr a nt. 
2. 2. 5  T o e x plor e f act ors ot her t ha n c hr o n olo gic a ge t hat c a n aff ect t o xicit y r ates as ide ntifie d usin g 
a c a nc er -s pecific geriatric ass ess me nt. 
2. 2. 6  T o des cribe t he r es ults of t he 
Was It 
W ort h It ( WI WI) Q uestio n nair e  a n d t he O ver all 
Tr eat me nt Utilit y ( O T U) . 
2. 2. 7  T o deter m ine t he de gr ee of a gr ee me nt bet w ee n patie nt -r e p orte d A Es usin g P R O -C T C A E 
meas ur es a n d t h os e r e p ort e d usin g tr a ditio nal c ollectio ns f or A Es . 
2. 2. 8  T o e xa mine t he ass ociatio n bet w ee n s ar c o pe nia a n d t he de velo p me nt of t o xicit y a n d a d verse 
e ve nts . 
2. 3  
C orrel at i ve s cie n ce o bje cti ves 
2. 3 . 1 T o e x plor e t he ass ociatio n bet w ee n bas eline c hr o nic infla m mat or y me diat or  le vels a n d 
de velo p me nt of a d vers e e ve nts.  
2. 3 . 2 T o e x plor e t he ass ociatio n bet w ee n bas eline c hr o nic infla m mat or y  me diat or  le vels a n d 
tr eat me nt m o dific atio n. 
2. 3. 3  T o e x plor e t he ass ociatio n bet w ee n bas eline c hr o nic infla m mat or y  me diat or  le vels a n d 
bas eline p h ysic al f u nctio n as ass ess e d b y t he c a nc er -s pecific geriatric ass ess me nt. 

 
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2. 3. 4  T o e x plor e t he ass ociatio n bet w ee n bas eline c hr o nic infla m mat or y me diat or  le vels a n d 
decline in p h ysic al f u nctio n as ass esse d b y t he c a ncer -s pecific geriatric ass ess me nt. 
2. 3. 5  T o e x plor e t he c orr elatio n bet w ee n in herite d sin gle n ucle otide p oly m or p his ms  ( S N Ps) in 
c ell c ycle pat h w a y ge nes a n d in ge nes t hat meta b olize palb ociclib a n d tr eat me nt effic ac y 
a n d t o xicit y ( clinic al o utc o mes)  in elderly patie nts u n der g oin g c o m bine d e n d ocrine t her apy 
plus palb ociclib f or estr o ge n r ec e pt or p ositive, H E R 2 ne gative  metastatic br eas t c a nc er.  
2. 3. 6  T o e x plor e w het her  ge nes in C Y P 1 9 A , C Y P 2 A 6 a n d E S R 1  will als o c orr elate wit h tr eat ment 
effic ac y a n d t o xicit y ( clinic al o utc o mes) in elderly patie nts u n der g oin g c o m bine d e n d ocrine 
t her a p y plus palb ociclib f or estr o ge n r ec e pt or p ositive, H E R 2 ne gative  metastatic br east 
c a nc er.  
2. 3. 7  T o r efine a p o p ulatio n p har mac o kinetic m o del usin g N O N M E M f or palb ociclib bas e d on 
t hat of S u n a n d Wa n g ( E S M O P oster Pr es e ntatio n 4 6 2 P 2 0 1 4) ta kin g ac c o u nt of r ele va nt 
intrinsic a n d e xtrinsic f act ors. 
2. 3. 8  T o deter mine t he intr a patie nt a n d inter patie nt varia bilit y of palb ociclib e x p os ur e ( A U C) in 
older br east c a nc er patie nts r eceivin g palb ociclib plus letr oz ole/f ulvestr a nt.  
2. 3. 9  T o e x plor e t he e x p os ur e ( A U C/ C ma x ) t o xicit y ( ne utr o pe nia, t hr o m b oc yt o pe nia) r elatio ns hip 
f or palb ociclib w he n c o m bine d wit h letr oz ole/f ulvestr a nt in older br east c a nc er patie nts.  
 
 

 
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3. 0  
P A TI E N T  S E L E C TI O N  
F or q uestio ns r e gar din g eligibilit y criteria, s ee t he St u d y Res o ur c es pa ge. Ple as e n ot e t h at t he 
St u dy C h air c a n n ot gr a nt wai ve rs t o eligi bilit y re q uire me nts.  
3. 1  
O n -St u dy G ui deli n es  
T his clinic al trial c a n f ulfill its o bjectives o nly if patie nts a p pr o pri ate f or t his trial ar e e nr olle d. 
All r ele va nt me dic al a n d ot her c o nsider atio ns s h o uld be ta ke n int o ac c o u nt w he n decidin g 
w het her t his pr ot oc ol is a p pr o priate f or a partic ular patie nt. P h ysicia ns s h o uld c o nsider t he ris ks 
a n d be nefits of a n y t her a p y, a n d t her ef or e o nly e nr oll patie nts f or w h o m t his tr eat me nt is 
a p pr o priate.  
P h ysicia ns s h o uld c o nsider w het her a n y of t he f ollo win g ma y r e n der t he patie nt ina p pr o priate 
f or t his pr ot oc ol: 
• 
Ps yc hiatric illness w hic h w o uld pr e ve nt t he patie nt fr o m givin g inf or me d c o ns e nt.  
• 
Me dic al c o n ditio n s uc h as u nc o ntr olle d inf ectio n (inclu din g 
HI V), u nc o ntr olle d 
dia betes mellit us or c ar diac dis eas e w hic h, in t he o pinio n of t he tr eatin g p h ysicia n, 
w o uld ma ke t his pr ot oc ol u nr eas o na bly hazar d o us f or t he patie nt.  
• 
C o nc o mita nt me dic atio ns : 
C hr o nic c o nc o mita nt tr eat me nt wit h str o n g in hibit ors of C Y P 3 A is str o n gly dis c o ur a ged 
o n t his st u d y. P atie nts o n str o n g C Y P 3 A in hibit ors m ust dis c o ntin ue t he dr u g prior t o 
r e gistr atio n o n t he st u d y. S ee s ectio n 8. 1. 1 0  f or m ore inf or matio n. 
C hr o nic c o nc o mita nt tr eat me nt wit h str o n g C Y P 3 A in d uc ers is str o n gly dis c o ur a ged. 
P atie nts m ust dis c o ntin ue t he dr u g prior t o t he start of st u d y tr eat me nt. S ee s ection 
8. 1. 1 1  f or m or e inf or matio n. 
C hr o nic c o nc o mita nt tr eat me nt wit h C Y P 2 A6 s u bstr ates is str o n gly dis c o ur a ge d f or 
patie nts w h o ar e  bein g tr eate d wit h letr oz ole.  P atie nts m ust dis c o ntin ue t he dr u g prior 
t o t he start of st ud y tr eat me nt. S ee s ectio n 8. 1. 1 2 f or m or e inf or matio n. 
• 
Lif e e x pecta nc y of less t ha n 6 m o nt hs 
 
 

 
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3. 2  
Eli gi bilit y Crit e ri a  
Us e t he s pac es pr o vide d t o c o nfir m a patie nt’s eligibilit y b y in dic atin g Yes or N o as a p pr o priate. 
It is n ot r e q uir e d t o c o m plete or s u b mit t he f ollo win g pa ge(s).  
W he n c alc ulatin g  da ys of tests a n d meas ur e me nts, t he da y a test or meas ur e me nt is d o ne is 
c o nsider e d Da y 0. T her ef or e, if a test w er e d o ne o n a M o n da y, t he M o n da y o ne w ee k later w o uld 
be c o nsider e d Da y 7.  
_ _ _  
3. 2 . 1 
D oc u m e nt ati o n of Dis e as e:  Est r o ge n  re ce pt or positi ve  a n d/ or pr o gest e ro ne 
re ce pt or ( P R) positi ve , 
H E R 2 
n e g ati ve m et ast atic b re ast c a n ce r. Hist olo gic 
c o nfir matio n is r e q uir e d.  
_ _ _  
3. 2. 2  
Me as u r a ble dis e as e or n o n -me as ur a ble dis e ase (s ee S ecti o n 1 1. 3 ) 
_ _ _  
3. 2. 3  
Pl a n ni n g t o be gi n pal bocicli b f or 
m et ast atic dis e as e.  O n e pri or li n e of 
e n docri n e t h e r a py  a n d/ or c h e m ot h er a py  f or m et ast atic dis e as e is all o we d.  
P atie nts ma y be gin or ha ve alr ea d y be g u n e n d ocrine t her a p y bef or e t he y start palb ociclib 
tr eat me nt, b ut n o m or e t ha n t w o w ee ks prior t o r e gistr atio n.  
_ _ _  
3. 2. 4  
No p ri or t h e r a py wit h a C D K i n hi bit or . 
_ _ _  
3. 2. 5  
Res ol uti o n of all ac ut e t o xic eff ects of pri or t h er a py or s u r gic al pr oce d u res t o 
C T C A E Gr a de ≤ 1 ( e xce pt al o pe ci a) or t o bas eli n e t o xicities pri or t o pre vi o us t h era py 
or s u r g ic al pr oce d u res,  pri or t o re gist r ati o n.  
_ _ _  
3. 2. 6  
No u nt re at e d br ai n m et ast ases.  P atie nts wit h tr eate d br ain metastases m ust have 
c o m plete d tr eat me nt wit h ster oids t o be eligible.   
_ _ _  
3. 2. 7  
No k n o w n i nt e rstiti al l u n g dis e as e.  
_ _ _  
3. 2. 8 . 
No s e c o n d m ali g n a n cies ot h e r t h a n n o n -m ela n o m a s ki n c a n ce rs or ce r vic al 
c arci n o m a i n sit u .  Ho we ve r, patie nts are n ot c o nsi dere d t o h a ve a “c u rre ntl y active ” 
m ali g n a n c y if t h e y h a ve c o m plete d t h er a py a n d are f re e of dis e ase f or ≥ 3 ye ars.  
_ _ _  
3. 2. 9  
No acti ve i nf e cti o n re q uiri n g t re at m e nt wit h a nti bi otics.  
_ _ _  
3. 2. 1 0  P atie nts m ust be a ble t o s wall o w a n d ret ai n or al m e dic ati o n. 
_ _ _  
3. 2. 1 1  P atie nt A ge: ≥ 7 0 ye ars  
_ _ _  
3. 2. 1 2  E C O G Pe rf or m a n ce St at us 0, 1 or 2.  
_ _ _  
3 . 2. 1 3 P atie nts m ust be a ble t o re a d a n d c o m pre h e n d E n glis h  or S pa nis h.  
_ _ _  
3. 2. 1 4  Re q uire d I niti al L a bor at or y V al u es:  
Abs olute ne utr o p hil c o u nt 
( A N C) 
≥ 1 5 0 0/ m m 3  ( 1. 5 x 1 09 / L) 
Platelet c o u nt:  ≥ 1 0 0, 0 0 0/ m m 3 ( 1 0 0 x 1 09/ L) 
Cr eatinine  clear a nc e:  
T otal s er u m bilir u bin  
A S T a n d/ or A L T  
 
≥ 3 0 ml/ min *  
≤ 1. 5 U L N ( < 3 U L N if Gilbert’s dis eas e)  
≤ 3 x U L N ( ≤ 5. 0 x U L N if liver metastas es 
pr es e nt)  
Alkaline p h os p hatas e  ≤ 2. 5 x U L N ( ≤ 5 x U L N if b o ne or liver 
metastas es pr es e nt)  
* Calc ulate d usin g t he C oc kcr oft -Ga ult f or m ula  

 
Allia nc e A1 7 1 6 0 1  
 
1 8  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
• 
Assig n t he Clinic al I n vestigat or ( CI) r ole o n t he Dele gatio n of T as ks L og 
( D T L).  
I n a d ditio n, all in vestigat ors actin g as t he Site-Pr ot oc ol PI (in vestigat or liste d o n t he I R B 
a ppr o val), c o ns e ntin g/tr eatin g/ dr u g s hip me nt in vestigat or in O P E N, or as t he CI o n t he D T L 
m ust be r oster e d at t he e nr ollin g site wit h a participatin g or ga nizatio n.  
Ad ditio nal  
inf or matio n  
is  
loc ate d  
o n  
t he  
C T E P  
w e bsite  
at 
 F or q uestio ns, pleas e c o ntact t he 
R C R  Hel p Des k  b y e mail at 
. 
4. 2  
C T S U Re gist r ati o n Pr oce d u res  
P er missio n t o vie w a n d d o w nloa d t his pr ot oc ol a n d its s u p p ortin g d oc u me nts is r estricte d and is 
bas e d o n pers o n a n d site r oster assig n me nt h o us e d in t he C T S U Re g ulat or y S u p p ort S yste m 
( R S S). 
T his st u d y is s u p p orte d b y t he N CI Ca nc er  Trials S u p p ort Unit ( C T S U).  
I R B A p pr o v al   
F or C T E P a n d Divisio n of Ca nc er Pr e ve ntio n ( D C P) st u dies o pe n to t he Natio nal Clinic al Trials 
Net w or k ( N C T N) a n d N CI C o m mu nit y O nc olo g y Res ear c h Pr o gr a m ( N C O R P) Res ear c h Bases 
after Mar c h 1, 2 0 1 9, all U. S. -bas e d sites m ust be me m bers of t he N CI Ce ntr al I nstit utio nal 
Re vie w Boar d ( N CI CI R B). I n a d ditio n, U. S. -bas e d sites m ust ac c e pt t he N CI CI R B r e vie w t o 
activate ne w st u dies at t he site after Mar c h 1, 2 0 1 9. L oc al I R B r e vie w will c o ntin ue t o be 
ac c e pte d f or st u dies  t hat ar e n ot r e vie w e d b y t he CI R B, or if t he st u d y w as pr e vio usly o pe n at 
t he site u n der t he loc al I R B. I nter natio nal sites s h o uld c o ntin ue t o s u b mit Res ear c h Et hics Boar d 
( R E B) a p pr o val t o t he C T S U Re g ulat or y Offic e f ollo win g c o u ntr y-s pecific r e g ulatio ns .  
Sites participatin g wit h t he N CI CI R B m ust s u b mit t he St u d y S pecific W or ks heet f or L oc al 
C o nte xt ( S S W) t o t he CI R B usin g I R B Ma na ger t o in dic ate t heir inte nt t o o pe n t he st u d y loc ally. 
T he N CI CI R B’s a p pr o val of t he S S W is a ut o matic ally c o m m u nic ate d t o t he C T S U Re g ulat or y 
Offic e, 
b ut 
sites 
ar e 
r e q uir e d t o 
c o ntact t he 
C T S U 
Re g ulat or y 
Offic e 
at 
 t o esta blis h site pr ef er e nc es f or a p plyin g N CI CI R B a p pr o vals 
acr oss t heir Sig nat or y Net w or k. Site pr ef er e nc es c a n be s et at t he net w or k or pr ot oc ol le vel. 
Q uestio ns a b o ut esta blis hin g site pr ef er e nc es c a n be a d dr ess e d t o t he C T S U Re g ulat or y Office 
b y e ma il or c allin g 
 
Sites usin g t heir loc al I R B or R E B, m ust s u b mit t heir a p pr o val t o t he C T S U Re g ulat or y Office 
usin g t he Re g ulat or y S u b missio n P ortal loc ate d in t he Re g ulat or y s ectio n of t he C T S U w e bsite. 
Ac c e pta ble d oc u me ntatio n of loc a l I R B/ R E B a p pr o val inclu des: 
• 
L oc al I R B d oc u me ntatio n;  
• 
I R B-sig ne d C T S U I R B Certific atio n F or m; a n d/ or  
• 
Pr ot oc ol of Hu ma n S u bjects Ass ur a nc e I de ntific atio n/I R B Certific atio n/ Declar atio n of 
E xe m ptio n F or m.  
I n a d ditio n, t he Site-Pr ot oc ol Principal I n vestigat or ( PI) (i. e. t he in vestigat or o n t he I R B/ R E B 
a p pr o val) m ust meet t he f ollo win g criteria in or der f or t he pr oc essin g of t he I R B/ R E B a p pr o val 
r ec or d t o be c o m plete d: 
• 
Holds a n active C T E P stat us;  
• 
R oster e d at t he site o n t he I R B/ R E B a p pr o val ( a p plies t o U S a n d C a n a di an 
sites o nly) a n d o n at least o ne participatin g r oster; 
• 
If usin g N CI CI R B, r oster e d o n t he N CI CI R B Sig nat or y r ec or d; 

 
Allia nc e A1 7 1 6 0 1  
 
1 9  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
• 
I nclu des t he I R B n u m ber of t he I R B pr o vidin g a p pr o val in t he F or m F D A 1 5 72 
in t he R C R pr ofile; a n d 
• 
Holds t he a p pr o priate C T E P r e gistr atio n t y pe f or t he pr ot oc ol.  
A d diti o n al Re q uire m e nts : 
Ad ditio nal r e q uir e me nts t o o btain a n a p pr o ve d site r e gistr atio n stat us inclu de:  
• 
An active F e der al Wide Ass ur a nc e ( F W A) n u m ber;  
• 
An active r oster affiliatio n 
wit h t he Le a d Pr ot oc ol Or ga nizatio n ( L P O) or a 
P articipatin g Or ga nizatio n ( P O); a n d  
• 
C o m plia nc e wit h all pr ot oc ol -s pecific r e q uir e me nts ( P S Rs). 
4. 2. 1  Pr ot oc ol S pe cific Re q uire m e nts f o r A 1 7 1 6 0 1 Sit e Re gistr atio n  
• 
E v ide nc e of Geriatric Ass ess me nt Tr ainin g, as des cribe d in S ectio n 1 5. 0  
I R O C cre de nti ali n g: 
T his is a st u d y wit h a r a diatio n a n d/ or i ma gin g ( R TI) c o m p o ne nt a n d t he e nr ollin g site m ust 
be alig ne d t o a n R TI pr o vider. T o ma na ge pr o vider ass ociatio ns or t o a d d or r e m o ve 
ass ociate d pr o viders, ac c ess t he Pr o vider Ass ociatio n pa ge fr o m t he Re g ulat or y s ectio n o n 
t he C T S U me m bers’ w e bsite at 
. Sites 
m ust be lin ke d t o at least o ne I ma gin g a n d Ra diatio n O nc olo g y C or e (I R O C) pr o vider t o 
participate o n trials wit h a n R TI c o m p o ne nt. E nr ollin g sites ar e r es p o nsible f or e ns urin g t hat 
t he a p pr o priate a gr ee me nts a n d I R B a p pr o vals ar e in plac e wit h t heir R TI pr o vider. An 
in divid ual wit h a pri mar y r ole o n a n y r oster is r e q uir e d t o u p date pr o vider ass ociatio ns, 
t h o u g h all in divid uals at a site ma y vie w pr o vider ass ociatio ns. T o fin d w h o h olds pri mar y 
r oles at y o ur site, vie w t he P ers o n R oster Br o w s er u n der t he R U M S s ectio n o n t he C T S U 
w e bsit e.  
4. 2 .2  D o w nl o a di n g Sit e Re gist r ati o n D oc u me nts  
D o w nloa d t he site r e gistr atio n f or ms fr o m t he pr otoc ol -s pecific pa ge loc ate d o n t he C T S U 
me m bers’ w e bsite. P er missio n t o vie w a n d d o w nloa d t his pr ot oc ol a n d its s u p p orting 
d oc u me nts is r estricte d bas e d o n p ers o n a n d site r oster assig n me nt. T o participate, t he 
instit utio n a n d its ass ociate d in vestigat ors a n d staff m ust be ass ociate d wit h t he L P O or a 
Pr ot oc ol Or ga nizatio n ( P O) o n t he pr ot oc ol. O ne w a y t o s ear c h f or a pr ot oc ol is liste d 
belo w.  
• 
L o g in t o t he C T S U me m bers’ w e bsite 
 usin g y o ur C T E P -I A M 
us er na me a n d pass w or d;  
• 
Clic k o n Pr ot oc ols in t he u p per left of t he s cr ee n 
o  E nter t he pr ot oc ol n u m ber in t he s ear c h field at t he t o p of t he pr ot oc ol tr ee; 
o r 
o  Clic k o n t he By Lea d Or ga nizatio n f older t o e x pa n d, t he n s elect [ Alli a nce], 
a n d pr ot oc ol n u m ber [A 1 7 1 6 0 1 ]. 
• 
Clic k o n D oc u me nts , s elect Site R e gistr ati o n , a n d d o w nloa d a n d c o m plete t he f or ms 
pr o vide d. ( N ote: F or sites u n der t he CI R B, I R B data will loa d a ut o matic ally t o t he 
C T S U.)  
 
 

 
Allia nc e A1 7 1 6 0 1  
 
2 0  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
4. 2. 3  S u b mitti n g Re g ul at or y Re q uire me nts  
S u b mit r e q uir e d f or ms a n d d oc u me nts t o t he C T S U Re g ulat or y Offic e usin g t he Re g ulat or y 
S u b missio n P ortal o n t he C T S U w e bsite.  
T o ac c ess t he Re g ulat or y S u b missio n P ortal lo g in t o t he C T S U me m bers’ w e bsite, go to 
t he Re g ulat or y s ectio n a n d s elect Re g ulat or y S u b missio n. 
I nstit utio ns wit h patie nts w aitin g t hat ar e u na ble t o us e t he Re g ulator y S u b missio n P ortal 
s h o uld alert t he C T S U Re g ulat or y Offic e i m me diately at 
 in or der t o 
r ec eive f urt her instr uctio n a n d s u p p ort. 
4. 2 . 4 C h e c ki n g Y o u r Site’s Re gistr ati o n St at us  
Site r e gistr atio n stat us ma y be verifie d o n t he C T S U me m bers’ w e bsite.  
• 
Clic k o n R e g ul at ory at t he t o p of t he s cr ee n;  
• 
Clic k o n Site R e gistr ati o n; a n d  
• 
E nter t he sites 5 -c har acter C T E P I nstit utio n C o de a n d clic k o n G o.  
o  Ad ditio nal filters ar e a vaila ble t o s ort b y Pr ot oc ol, Re gistr atio n Stat us, 
Pr ot oc ol St at us, a n d/ or I R B  T y pe.  
N ote: T he stat us s h o w n o nly r eflects instit utio nal c o m plia nc e wit h site r e gistr atio n 
r e q uir e me nts as o utline d wit hin t he pr ot oc ol. It d oes n ot r eflect c o m plia nc e wit h pr ot oc ol 
r e q uir e me nts f or in divid uals participatin g o n t he pr ot oc ol or t he e nr ollin g in vestigat or’s 
stat us wit h N CI or t heir affiliate d net w or ks.  
4 .2 . 5 Cre de nti ali n g  
S ee S ectio n 1 5. 0 f or cr e de ntialin g r e q uir e me nts f or Geriatric Ass ess me nt Trainin g.  
4. 3  
P atie nt Re gistr atio n Re q uire me nts  
I nf or m e d c o ns e nt: T he patie nt m ust be a w ar e of t he ne o plastic nat ur e of his/ her dis eas e a n d 
willin gly c o ns e nt after bein g inf or me d of t he pr oc e d ur e t o be f ollo w e d, t he e x peri me ntal nat ure 
of t he t her a p y, alter natives, p ote ntial be nefits, side -eff ects, ris ks, a n d dis c o mf orts. C urr ent 
h u ma n pr otectio n c o m mittee a p pr o val of t his pr ot oc ol a n d a c o ns e nt f or m is r e q uir e d prior t o 
patie nt c o ns e nt a n d r e gistr atio n.  
P atie nt c o m plet e d bo o klets : P atie nt q uestio n nair e b o o klets ar e t o be or der e d prior t o t he 
r e gistr atio n of a n y patie nts. P atie nt c o m plete d b o o klets in E n glis h a n d S pa nis h  c a n be or der ed 
b y d o w nloa din g a n d c o m pletin g t he C T S U s u p ply r e q uest  f or m (loc ate d u n der t he site 
r e gistr atio n s ectio n of t he C T S U pr ot oc ol s pecific w e bsite ) a n d s u b mittin g the f or m t hr o u gh the 
C T S U r e g ulat or y p ortal . S a m ples  of t he b o o klets in E n glis h ar e f o u n d in Ap pe n dic es II-VII  a nd 
electr o nic versio ns of t he b o o klets in S pa nis h ar e a vaila ble o n t he Allia nc e a n d C T S U w e b  sites. 
T hes e  ar e t o be us e d f or r ef ere nce a n d I R B s u b missio n o nly.  T he y ar e n ot t o be use d f or patient 
c o m pletio n.  
Pr ot e ct e d He alt h I nf or m ati o n : W h ole blo o d s a m ples c ollecte d f or t he p har mac o kinetics sub-
st u d y A1 7 1 6 0 1-P P 1 will be s e nt dir ectly t o t he Universit y of Pitts b ur g h Ca nc er Ce nter. T hese 
s a m ples will be la bele d wit h patie nt initials, st u d y I D a n d c ollectio n date/ti me.  
4. 4  
P atie nt Re gistr atio n/ R a n do miz atio n Pr oce d u res  
T he O nc olo g y P atie nt E nr oll me nt Net w or k ( O P E N) is a w e b -bas e d r e gistr atio n s yste m a vaila ble 
o n a 2 4/ 7 basis. O P E N is inte gr ate d wit h C T S U r e g ulat or y a n d r oster data a n d wit h t he L P Os 

 
Allia nc e A1 7 1 6 0 1  
 
2 1  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
r e gistr atio n/r a n d o mizatio n s yste ms or t he T her a de x I nter active We b Res p o n s e S yste m (I W R S) 
f or r etrie val of patie nt r e gistr atio n/r a n d o mizatio n assig n me nt. O P E N will p o p ulate t he patie nt 
e nr oll me nt data in N CI’s clinic al data ma na ge me nt s yste m, Me didata Ra ve.  
Re q uir e me nts f or O P E N ac c ess:   
• 
A valid C T E P -I A M ac c o u nt; 
• 
T o perf or m e n r oll me nts or r e q uest slot r es er vatio ns: M ust b e o n an  L P O r oster, E T C T N 
c orr es p o n din g r oster, or participatin g or ga nizatio n r oster wit h t he r ole of Re gistr ar. 
Re gistr ars m ust h old a mini m u m of a n Ass ociate Plus ( A P ) r e gistr atio n t y pe; 
• 
If a Dele gatio n of T as ks L o g ( D T L) is r e q uir e d f or t he st u d y, t he r e gistr ars m ust h old 
t he O P E N Re gistr ar tas k o n t he D T L f or t he site; a n d 
• 
Ha ve a n a p pr o ve d site r e gistr atio n f or t he pr ot oc ol prior t o patie nt e nr oll me nt.  
T o assig n a n I n vestigat or (I V R) or N o n -P h ysicia n I n vesti gat or ( N PI V R) as t he tr eatin g, 
cr e ditin g, c o ns e ntin g, dr u g s hip me nt (I V R o nly), or r ec eivin g in vestigat or f or a patie nt tr a nsfer 
in O P E N, t he I V R or N PI V R m ust list t he I R B n u m ber us e d o n t he site’s I R B a p pr o val o n t heir 
F or m F D A 1 5 7 2 in R C R. If a D T L is r e q uir e d f or t he st u d y, t he I V R or N PI V R m ust be assig ned 
t he a p pr o priate O P E N-r elate d tas ks o n t he D T L. 
Prior t o ac c essin g O P E N, site staff s h ould verif y t he f ollo win g:  
• 
P atie nt has met all eligibilit y criteria wit hin t he pr ot oc ol state d ti mefr a mes; a n d  
• 
Al l patie nts ha ve sig ne d a n a p pr o priate c o ns e nt f or m a n d HI P A A a ut h orizatio n f or m (if 
a p plic a ble).  
• 
Site staff ha ve c o m plete d t he Geriatric Ass ess me nt tr ainin g des cribe d in S ectio n 1 5. 0.  
N ote:   T he O P E N  s yste m will pr o vide t he site wit h a printa ble c o nfir matio n of r e gistr atio n a n d 
tr eat me nt inf or matio n. Yo u ma y print t his c o nfir matio n f or y o ur r ec or ds.   
Ac c ess O P E N at 
 or fr o m t he O P E N lin k o n t he C T S U me m bers’ w e bsite. 
F urt her instr uctio nal inf or matio n is in t he 
O P E N s ectio n of t he C T S U 
w e bsite at 
 F or a n y a d ditio nal q uestio ns, c o ntact t he C T S U 
Help Des k at 
 
T o r ec eive site r ei m b urs e me nt f or s pecific tests a n d/ or bio -s peci me n s u b missio ns, c o m pletion 
dates m ust be e nter e d in t he O P E N F u n din g s cr ee n p ost r e gistr atio n. Pleas e r ef er t o t he pr ot oc ol -
s pecific f u n din g pa ge o n t he C T S U me m bers’ w e bsite f or a d ditio nal inf or matio n. Ti mely e ntr y 
of c o m pletio n dates is r ec o m m e n de d as t his will trig ger site r ei m b urs e me nt.  
4. 5  
Re gist r ati o n t o C orrel ati ve  a n d C o m pa ni o n St u dies  
4. 5 . 1 Re gist r ati o n t o S u b st u di es  descri be d i n S e cti o n 1 4. 0  
T her e  ar e 3  s u b st u dies wit hin Allia nc e A 1 7 1 6 0 1 . T hes e st u dies m ust  be off er e d t o all 
patie nts e nr olle d o n Allia nc e A 1 7 1 6 0 1  (alt h o u g h patie nts ma y o pt t o n ot participate). T hese 
s u b st udies  d o n ot r e q uir e s e par ate I R B a p pr o val. T he s u b st u dies inclu de d wit hin Allia nc e 
A 1 7 1 6 0 1 ar e: 
• 
Cir c ulatin g mar kers of infla m matio n as p ote ntial mar kers pr e dictive of t o xicit y a m o ng 
elderly pat ie nts e nr olle d t o Allia nc e A1 7 1 6 0 1: Allia nc e A 1 7 1 6 0 1 -S T 1 ( S ectio n 1 4. 1 ) 
• 
Ge netic deter mina nts of P alb ociclib Effic ac y a n d t o xicit y in t he elderly:  Al lia nc e 
A1 7 1 6 0 1 -S T 2 (S ectio n 1 4. 2 ) 
• 
P o p ulatio n P har mac o kinetics of P alb ociclib:  Allia nc e A1 7 1 6 0 1 -P P 1  (S ectio n 1 4. 3 ) 

 
Allia nc e A1 7 1 6 0 1  
 
2 2  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
If a patie nt a ns w ers “ yes ” t o “I a gr ee t o ha ve m y s peci me n c ollecte d a n d I a gr ee t hat m y 
s peci me n s a m ple(s) a n d r elate d inf or matio n ma y be us e d f o r t he la b or at or y st u dies des cribed 
a b o ve. , ” Q uestio n # 1 in t he m o del c o ns e nt,  t he y ha ve c o ns e nte d t o participate in t he s ub 
st u dies des cribe d in S ectio n 1 4. 1 , S ectio n 1 4. 2  a n d S ectio n 1 4. 3 .  T he patie nt s h o uld be 
r e gister e d t o Allia nc e A1 7 1 6 0 1  -S T 1 , A1 7 1 6 0 1 -S T 2  a n d A1 7 1 6 0 1 -P P 1 at t he s a m e ti me 
t he y ar e r e gister e d t o t he tr eat me nt trial ( A1 7 1 6 0 1 ). S a m ples s h o uld be s u b mitt e d per 
S ectio n 6. 2 .   
4. 6  
Gr o u pi n g  F act or  
4. 6. 1  A ge 7 0 -7 4  vs.  ≥7 5  
 

 
Allia nc e A1 7 1 6 0 1  
 
2 3  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
5. 0  
S T U D Y C A L E N D A R  
T he pr e -st u d y testin g inter vals ar e g uidelines o nly. La b or at or y a n d clinic al par a meters d urin g 
tr eat me nt ar e t o be f ollo w e d usin g in divid ual instit utio nal g uidelines a n d t he best clinic al ju d g me nt 
of t he r es p o nsible p h ysicia n. It is e x pecte d t hat patie nts o n t his st u d y will be c ar e d f or b y p h ysicia ns 
e x perie nc e d in t he tr eat me nt a n d s u p p ortive c ar e of patie nts o n t his trial.  
Pre -St u dy Testi n g I nt er v als:  
To be c o m plet e d ≤ 1 4 D A Y S bef ore re gist r ati o n : All la b or at or y st u dies, hist or y a n d p h ysic al, 
c o nc o mita nt  me dic atio ns a n d bas eline a d vers e e ve nt ass ess me nt . 
To be c o m plet e d ≤ 4 2  D A Y S bef ore re gistr ati o n:  C T  a n d b o ne s ca n, or P E T s ca n  
*  
+/ - 2  da ys.  1  c y cle  =  2 8  da ys.  ( All Da y  1  baseli n e  assess m e nt s m a y  be  c o m plet e d a n y  ti m e aft er  r e gistr ati o n b ut  bef or e  
tr e at m e nt. H & P  n e e d  n ot  be  r e p e at e d f or Da y  1  if d o n e  wit hi n  a  3 0  da y  wi n d o w  pri or  t o Da y  1  of  C y cle  1.)  
* *  Ne e d  n ot  be  r e p e at e d if d o n e  wit hi n  t h e last 7  da ys   
* * *  C M P  i n cl u des ele ctr ol yt es (s o di u m, p ot assi u m,  c hl ori de,  bic ar b o n at e),  r e n al f u n cti o n ( bl o o d ur e a  nitr o ge n  a n d cr e ati ni n e)  li v er 
f u n cti o n t est s ( A S T, A L T,  al k.  p h os.,  t ot al bilir u bi n,  dir e ct  bilir u bi n  o nl y  if cli nic all y  i n dic at e d), t ot al pr ot ei n,  al b u mi n,  a n d c alci u m  
†  
At  t h e e n d of  pr ot o c ol tr e at m e nt p atie nts will c o m plet e t h e Geriatric Assess m e nt a n d t h e e n d of tr e at m e nt b o o klet. P atie nts will 
t h e n be f oll o we d e v er y y e ar f or s ur vi v al o nl y, u p  t o 5  y e ars  
1  
P R O -C T C A E  a n d E Q -5 L -3 D  r e q uir e d o nl y  f or t h e first 6  c y cles of  pr ot o c ol  t h er a p y d uri n g  t h e first y e ar  of  tr e at m e nt 
2  
D o es  n ot  n e e d  t o be  r e p e at e d if d o n e  wit hi n  t h e last 3 0  da ys.  
3  
Ra di o n ucli de  b o n e  sc a n is n ot  r e q uir e d if baseli n e  P E T  sc a n was  d o n e.   B o n e  sc a n aft er  baseli n e  is r e q uir e d o nl y  if i n dic ati v e 
of  m et ast ases  at  baseli n e  or  if si g ns or  s y m pt o ms s u g gesti v e of  m et ast ases  de v el o p m e nt.  
A  
E n d  of  c y cle  1  a n d 2  
B  
Da y  1,  C y cle  4  o nl y  
C  
C y cle  1  o nl y   
D  
Da y  1  of  C y cle  4  ( +/- 2  we e ks),  t h e n e v er y  1 2  we e ks  ( +/- 2  we e ks)  u ntil  e n d o f tr e at m e nt. Res p o nse  assess m e nt  s h o ul d i n cl u de 
assess m e nt  of  all sit es of  dise ase  a n d use  t h e sa m e i m a gi n g m et h o d  as was  use d  at  baseli n e.   Se e  Se cti o n  6. 3  f or i nstr ucti o ns o n  
s u b missi o n of  i m a ges. 
 
P ri o r t o 
r e gi st r ati
o n  
C y cl e s 1 a n d 2  
D a y 1 of e ve r y c y cl e st arti n g 
wit h C y cl e 3 f o r y e a r 1 of 
t r e at m e nt* 
Eve r y 3 mt h s f r o m 
y e a r 2 u ntil e n d of 
t r e at m e nt( +/-8 d a ys)  
At e n d of 
pr ot o c ol 
t r e at m e nt† 
Da y 1 *  
Da y 1 5 *  
Tests a n d O bs e r vati o ns  
 
 
 
 
 
 
Hist or y a n d P h ysic al  
X  
X  
 
X  
X  
 
A d h ere nc e e v al uati o n  
 
A  
 
B  
X  
 
A d v erse Ev e nt Re p orti n g  
 
X  
X  
X  
X  
X  
P R O -C T C A E  
 
X  
X  
X( 1)  
 
X( 2)  
Co n c o mit a nt me dic ati o ns  
 
X  
X  
X  
X  
 
Geriatric As sess me nt  
 
C  
 
B  
 
X( 2)  
E Q -5 D -3 L 
 
X  
 
X( 1)  
 
X( 2)  
W as It W ort h It a n d O v erall 
Tre at me nt Utilit y  
 
 
 
 
 
X  
La bor at or y St u di es  
 
 
 
 
 
 
C B C, Differe ntial, Plat elets  
X  
X * *  
X  
X  
X  
 
C M P * * *  
X  
X * *  
X  
X  
X  
 
St a gi n g  
 
 
 
 
 
 
C T c h est/a b d +/ - p el vis or P E T  
X  
 
 
D  
X  
 
Bo n e Sc a n, W h ole Bo d y  
X( 3)  
 
 
D  
X  
 
 
C or r el ati ve st u di es f or pati e nts wh o c o ns e nt t o parti ci pate  
T o b e c oll e ct ed at t h e ti me p oi nts d escri bed i n S ecti o n 6. 2  
W h ole Bl o o d a n d Plas ma  

 
Allia nc e A1 7 1 6 0 1  
 
2 4  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
6. 0  
D A T A A N D  S P E C I M E N S U B MI S S I O N  
6. 1  
D at a C olle cti o n a n d S u b missi o n  
6. 1. 1  D at a s u b missi o n sc h e d ule : 
A S c he d ule of F or ms is a vaila ble o n t he Allia nc e st u d y w e b pa ge, wit hin t he Cas e Re p ort 
F or ms s ectio n.  T he S c he d ule of F or ms is als o a vaila ble o n t he C T S U site wit hin  t he Cas e 
Re p ort F or ms ta b . 
6. 1. 2  Me di dat a R a ve  
Me didata Ra ve is a clinic al data ma na ge me nt s yste m bein g us e d f or data c ollectio n f or this 
trial/st u d y. Ac c ess t o t he trial in Ra ve is c o ntr olle d t hr o u g h t he C T E P -I A M s yste m a n d 
r ole assig n me nts.  
Re q ui r e me nts t o ac c ess Ra ve via i Me didata: 
• 
A valid C T E P -I A M ac c o u nt; a n d  
• 
Assig ne d a Ra ve r ole o n t he L P O or P O r oster at t he e nr ollin g site of: Ra ve C R A, Ra ve 
Rea d O nly, Ra ve C R A ( La b Ad min), Ra ve S L A, or Ra ve I n vestigat or.  
Ra ve r ole r e q uir e me nts:  
o  Ra ve C R A or Ra ve C R A ( La b Ad min) r ole m ust ha ve a mini m u m of a n Ass ociate 
Plus ( A P) r e gistr atio n t y pe;  
o  Ra ve I n vestigat or r ole m ust be r e gister e d as a n N o n -P h ysicia n I n vestigat or 
( N PI V R) or I n vestigat or (I V R); a n d 
o  Ra ve Rea d O nly r ole m ust ha ve at a mini m u m a n Ass ociate s ( A) r e gistr atio n t y pe. 
Ref er t o
 f or r e gistr atio n t y pes 
a n d d oc u me ntatio n r e q uir e d.  
Up o n initial site r e gistr atio n a p pr o val  f or t he st u d y in Re g ulat or y S u p p ort S yste m ( R S S), 
all pers o ns wit h Ra ve r oles assig ne d o n t he a p pr o priate r oster will be s e nt a st u d y in vitatio n 
e-mail fr o m i Me didata.  T o ac c e pt t he in vitatio n, site staff m ust lo g in t o t he S elect L o gin 
 usin g t heir C T E P-I A M us er na me a n d pass w or d 
a n d clic k o n t he acce pt  lin k in t he u p per rig ht-c or ner of t he i Me didata pa ge.  Site staff will 
n ot be a ble t o ac c ess t he st u d y in Ra ve u ntil all r e q uir e d Me didata a n d st u d y s pecific 
tr ainin gs ar e c o m plete d. Tr ainin gs will be in t he f or m of electr o nic lear nin gs ( e Lear nin gs) 
a n d c an be ac c esse d b y clic kin g o n t he lin k in t he u p per rig ht pa ne of t he i Me didata s cr een. 
If a n e Lear nin g is r e q uir e d a n d has n ot yet bee n ta ke n, t he lin k t o t he e Lear nin g will a p pear 
u n der t he st u d y na me in i Me didata instea d of t he R av e E D C  lin k; o nc e t he s uc c essf ul 
c o m pletio n of t he e Lear nin g has bee n r ec or de d, ac c ess t o t he st u d y in Ra ve will be gr a nte d, 
a n d a R av e E D C  lin k will dis pla y u n der t he st u d y na me.  
Site staff t hat ha ve n ot pr e vio usly activate d t heir i Me didata/ Ra ve ac c o u nt at t he ti me of 
initial site r e gistr atio n a p pr o val f or t he st u d y in R S S will r ec eive a s e par ate in vitatio n fr o m 
i Me didata t o activate t heir ac c o u nt. Ac c o unt activatio n instr uctio ns ar e loc ate d o n t he 
C T S U w e bsite in t he Data 
Ma na ge me nt s ectio n u n der t he Ra ve r es o ur c e materials 
( Medidata Ac c o u nt Activatio n a n d St u d y I n vitatio n Ac c e pta nc e). Ad ditio nal inf or matio n 
o n i Me didata/ Ra ve is a vaila ble o n t he C T S U me m bers’ w e bsite in t he Data Ma na ge me nt 
>  Ra ve s ectio n at 
or b y c o nta ctin g t he C T S U Help Des k at 
 

 
Allia nc e A1 7 1 6 0 1  
 
2 5  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
• 
P atie nt -c o m plete d q u estio n n aire bo o klets  f or t his st u d y ar e t o be or der e d prior t o t he 
r e gistr atio n of a n y patie nts (s ee S ectio n 4. 3 ).  S a m ples of t he b o o klets in E n glis h ar e 
f o u n d in Ap pe n dic es II-VII a n d electr o nic versio ns of t he b o o klets in S pa nis h ar e 
a vaila ble o n t he Allia nc e a n d C T S U w e b sites, f or r ef er e nc e a n d I R B s u b missio n o nly. 
T he y ar e n ot t o be us e d f or patie nt c o m pletio n. Bo o klets m ust be give n t o patie nts t o 
c o m plete a n d patie nts s h o uld be instr ucte d t o r et ur n t he b o o klets t o site staff eit her in 
pers o n or b y mail a n d site staff will e nter patie nt a n d c ar e giver r es p o ns es int o Ra ve.  
6. 1. 3  D at a Q u alit y P ort al:  
T he Data Q ualit y P ortal ( D Q P) pr o vides a c e ntr al loc atio n f or site staff t o ma na ge 
u na ns w er e d q ueries a n d f or m delin q ue ncies, m o nit or data q ualit y a n d ti meliness, ge ner ate 
r e p orts, a n d r e vie w metrics.  
T he D Q P is loc ate d o n t he C T S U m e m bers’ w e bsite u n der Data Ma na ge me nt. T he Ra ve 
Ho me s ectio n dis pla ys a ta ble pr o vidin g s u m mar y c o u nts of T otal Delin q ue ncies a n d T otal 
Q ueries. D Q P Q ueries, D Q P Delin q ue nt F or ms a n d t he D Q P Re p orts m o d ules ar e a vaila ble 
t o ac c ess details a n d r e p orts of u na ns w er e d q ueries, delin q ue nt f or ms, a n d ti meliness 
r e p orts. Re vie w t he D Q P m o d ules o n a r e g ular basis t o ma na ge s pecifie d q ueries a n d 
delin q ue nt f or ms.  
T he D Q P is ac c essible b y site staff t hat ar e r oster e d t o a site a n d ha ve ac c ess t o t he C T S U 
w e bsite. Sta ff t hat ha ve Ra ve st u d y ac c ess c a n ac c ess t he Ra ve st u d y data usin g a dir ect 
lin k o n t he D Q P. 
T o lear n m or e a b o ut D Q P us e a n d ac c ess, clic k o n t he Help ic o n dis pla ye d o n t he Ra ve 
Ho me, D Q P Q ueries, a n d D Q P Delin q ue nt F or ms m o d ules.  
N ote: S o me Ra ve pr ot oc ols ma y n ot ha ve delin q ue nt f or m details or r e p orts s pecifie d o n 
t he D Q P. A pr ot oc ol m ust ha ve t he Cale n dar f u nctio nalit y i m ple me nte d in Ra ve b y t he 
Lea d Pr ot oc ol Or ga nizatio n f or delin q ue nt f or m details a n d r e p orts t o be a vaila ble o n t he 
D Q P.  Site s taff s h o uld c o ntact t he L P O Data 
Ma na ger f or t heir pr ot oc ol r e gar din g 
q uestio ns a b o ut Ra ve Cale n darin g f u nctio nalit y.  
6. 1. 4  S u p porti n g doc u m e nt ati o n  
T his st u d y r e q uir es s u p p ortin g d oc u me ntatio n f or dia g n osis, r es p o ns e, pr o gr essio n a n d 
s ur vival. S u p p ortin g d oc u me ntatio n will inclu de pat h olo g y a n d i ma gin g r e p orts a n d m ust 
be s u b mitte d at t he f ollo win g ti me p oints:  
B as eli n e: F or patie nts wit h meas ura ble dis eas e o nly, pat h olo g y a n d i ma gin g r e p orts.  
At Pr o gressi o n a n d res po ns e : I ma gin g r e p orts a n d/ or clinic n otes, bas e d o n sta n dar d 
R E CI S T criteria.   
All s u p p ortin g d oc u me ntatio n s h o uld be de -ide ntifie d ac c or din g t o instit utio nal sta n dar ds 
prior t o u ploa d int o R A V E.  

 
Allia nc e A1 7 1 6 0 1  
 
2 6  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
6. 2  
S pe ci m e n c olle cti o n a n d s u b missi o n  
F or patie nts r e gister e d t o s u bst u d y A 1 7 1 6 0 1 -S T 1, A 1 7 1 6 0 1 -S T 2  a n d A1 7 1 6 0 1 -P P 1 : All 
participatin g instit utio ns m ust as k patie nts f or t heir c o ns e nt t o participate in t he c orr elative 
s u bst u dies pla n ne d f or Allia nc e 
A1 7 1 6 0 1 -S T 1,  A 1 7 1 6 0 1 -S T 2  a n d A1 7 1 6 0 1 -P P 1,  alt h o u g h 
patie nt parti cipatio n is o ptio nal. Bio mar ke r, p har mac o ge netics  st u dies a n d p har mac o kinetic 
st u dies will be perf or me d. Ratio nale a n d met h o ds f or t he s cie ntific c o m p o ne nts of t hese st u dies 
ar e des cribe d in S ectio n 1 4. 0 . F or patie nts w h o c o ns e nt t o participate, plas ma a n d w h ole blo o d 
will be c ollecte d at t he f ollo win g ti me p oints f or t hes e st u dies: C ollectio n of plas ma f or t o xicity 
bio mar ker c orr elative st u dies will c oincide wit h t he Geriatric ass ess me nt o n c ycle 1 da y 1, a nd 
prior t o c ycle 4 . 
1  W h ole blo o d f or Plas ma  t o be us e d f or bio mar ker a nalys es des cribe d in S ectio n 1 4. 1 . 
2  W h ole blo o d t o be us e d f or p har mac o ge n o mic a n alys es des cribe d in S ectio n 1 4. 2 . 
3  P har mac o kinetic a nalys es des cribe d in S ectio n 1 4. 3 . P atie nts will be as ke d t o c o m plete a 
p har mac o kinetics q uestio n nai r e (Ap pe n dix I X) t hes e visits  ( Bas eline, C ycles 1 & 2 Da y 
1 5, prior t o tr eat me nt) . T he q uestio n nair e c a n be c o m plete d bef or e or after t he blo o d 
dr a w. A c o p y of t he q uestio n nair e will be s e nt b y site staff alo n g wit h t he s a m ples t o t he 
Universit y of Pitts b ur g h. Q uestio n nair e r es p o ns es ar e t o be e nter e d int o Ra ve b y site 
staff. 
Not e: S a m ples f or A 1 7 1 6 0 1 - P P 1 s u bst u dy are o nl y re q uire d f or patie nts w h o are 
re gist e re d (a n d c o ns e nt t o partici pat e i n t h e s u bst u dies ) aft er U p dat e 1. P atie nts e n r olle d 
pri or t o t h e rele ase of U p dat e 1 will n ot be as k e d t o pr o vi de a d diti o n al s a m ples.  
6. 2. 1  S pe ci m e n S u b missi o n U si n g t h e Alli a nce Bi os pe ci me n Ma n a ge me nt S yst e m  
U S E O F T H E A L LI A N C E 
BI O S P E CI M E N 
M A N A G E M E N T S Y S T E M ( Bio M S) I S 
M A N D A T O R Y A N D A L L S P E CI M E N S M U S T B E L O G G E D A N D S HI P P E D VI A T HI S 
S Y S T E M.  
Bio M S is a w e b -bas e d s yste m f or lo g gin g a n d tr ac kin g all bios peci me ns c ollect e d o n 
Allia nc e trials. 
Aut h orize d in divid uals  ma y ac c ess Bio M S at t he f ollo win g 
U R L:  
 usin g 
m ost sta n dar d w e b br o w sers 
( S af ari, Fir ef o x, I nter net E x plor er). F or inf or matio n o n usin g t he Bio M S s yste m, pleas e r efer 
t o t he ‘ Help’ lin ks o n t he Bio M S w eb pa ge t o ac c ess t he o n -line us er ma n ual, F A Qs, a n d 
F or all patie nts re gist ere d t o A 1 7 1 6 0 1 S T1,  A 1 7 1 6 0 1 - S T2 a n d A 1 7 1 6 0 1 -P P 1 , s u b mit t h e f oll o wi n g:  
 
Pri or t o 
Tre at m e nt  
C ycles 1 & 2  
D a y 1 5 ( Pri or t o 
t re at m e nt) 
Pri or t o C ycle 4  
St or a ge/ S hi p pi n g 
c o n diti o ns  
S u b mit t o:  
W h ol e Bl o o d
1  
( E D T A/la ve n der 
t o p) 
1 0  m L  
 
 
1 0  m L  
 
C o ol pac k /s hip o ver 
nig ht  
Ma y o B A P  
Fr eezer  
W h ol e Bl o o d
2  
( E D T A/la ve n der 
t o p) 
1 0 m L  
 
 
C o ol pac k/s hip o ver 
nig ht  
Ma y o B A P  
Fr eezer   
Pl as m a f r o m 
W h ol e Bl o o d
3  
( E D T A/la ve n der 
t o p) 
5 m L  
 
5 m L  
 
Dr y ic e/ s hip o ver 
nig ht  
Universit y 
of 
Pitts b ur g h  

 
Allia nc e A1 7 1 6 0 1  
 
2 7  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
tr ainin g vide os.  T o r e p ort tec h nic al pr o ble ms, s uc h as lo gin iss ues or a p plic atio n err ors, 
pleas e c o ntact: 
. F or assista nc e in usin g 
t he a p plic atio n or q uestio ns or pr o ble ms r elate d t o s pecific s peci me n lo g gin g, pleas e 
c o ntact: 
. 
After lo g gin g c ollecte d s peci me ns in Bio M S, t he s yste m will cr eate a s hip pin g ma nif est.  
T his s hip pin g ma nif est m ust be printe d a n d plac e d in t he s hip me nt c o ntainer wit h t he 
s peci me ns. 
All s u b mitte d s peci me ns m ust be la bele d wit h t he pr ot oc ol n u m ber ( A 1 7 1 6 0 1 ), Allia nc e 
patie nt n u m ber, patie nt’s initials, date a n d t y pe of s peci me n c ollecte d ( e. g., s er u m , w h ole 
blo o d).  
W he n s peci me ns ar e ti me -s e nsitive, a n d/ or ar e r e q uir e d f or c o m m u nic atio n of test r es ults 
bac k t o instit utio ns a n d patie nts, t he y s h o uld be la bele d wit h patie nt initials a n d date of 
pr oc ur e me nt, in a d ditio n t o pr ot oc ol n u m ber, Allia nc e patie nt n u m ber a n d s peci me n t y pe. 
S peci me ns t hat ar e n ot ti me -s e nsitive, a n d/ or ar e n ot s u b mitte d f or t he p ur p os e of 
perf or min g a n inte gr al test t hat will be r e p orte d bac k t o patie nts, s h o uld n ot inclu de patie nt 
initials or date of pr oc ur e me nt.  
A c o p y of t he S hip me nt P ac kin g Slip pr o d uc e d b y Bio M S m ust be printe d a n d plac e d in t he 
s hip me nt wit h t he s peci me ns.  
I nstr uctio ns f or t he c ollectio n of s a mples ar e inclu de d belo w. Pleas e be s ure t o use a method 
of s hip pin g t hat is s ec ur e a n d tr ac ea ble. E xtr e me heat pr ec a utio ns s h o uld be ta ke n w hen 
nec ess ar y.  
S peci me ns f or t he A1 7 1 6 0 1 - S T 1 a n d A1 7 1 6 0 1 -S T 2 s u b -st u dies s h o uld be s hip pe d M o n da y 
t hr o u g h Frida y mar ke d f or S at ur da y deliver y. S hip pin g b y o ver nig ht s er vic e t o ass ure 
r ec eipt is e nc o ur a ge d.  D o n ot s hip s peci me ns on S at ur da ys . 
S pe ci m e ns f or t h e A 1 7 1 6 01 -P P 1 s u bst u dy s h o ul d be s e nt t o t h e f oll o wi n g a d dress:  
  
  
  
  
  
  
 
 
 
All ot h e r s pe ci m e ns s h o ul d be s e nt t o t h e f oll o wi n g a d dress: 
 
 
 
 
  
6. 2. 2  W h ole Bl o o d s a m ple s u b missi o n f or pl as m a ( A 17 1 6 0 1-S T1)  
F or patie nts w h o c o ns e nt t o participate, w h ole blo o d c ollecte d f or plas ma s a m ples will be 
us e d f or t he bio mar ker a nalys es des cribe d in S ectio n 1 4. 1 .  
F or E D T A plas ma, c ollect 1 0 m L of w h ole blo o d b y sta n dar d ve n o us p hle b ot o m y int o t he 
E D T A t u be , prior t o tr eat me nt a n d prior t o c ycle 4.  T he t u be s h o uld be in verte d s e ver al 

 
Allia nc e A1 7 1 6 0 1  
 
2 8  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
ti mes t o mix t he E D T A a n d r efriger ate d u ntil s hip pe d o n c o ol pac k b y o ver nig ht mail t o t he 
Allia nc e Bior e p osit or y ( M a y o B A P). T he s a m ples s h o uld be s hip pe d t he s a me da y t hat t he 
blo o d is dr a w n per  S ectio n 6. 2. 1 . 
La bel s a m ples wit h t he f ollo win g ide ntific atio n:  
1)  
Pr oc ur e me nt date/ti me of c ollectio n  
2)  
Allia nc e patie nt n u m ber  
3)  
P atie nt initi als  
4)  
Allia nc e st u d y n u m ber (i. e., A 1 7 1 6 0 1 -S T 1 ) 
5)  
S peci me n t y pe  
T he 1 0 ml of blo o d c a n be c ollecte d in o ne 1 0 ml t u be, or t w o 5 ml t u bes or t hr ee 3 ml t u bes, 
as lo n g as t he final v olu me is ~ 1 0 ml.  
6. 2. 3  W h ole b l o o d s u b missi o n f or p h ar m ac o ge n o mic st u dies ( A1 71 6 0 1 -S T2)  
F or patie nts w h o c o ns e nt t o participate, w h ole blo o d s a m ples will be us e d f or t he 
p har mac o ge n o mic s t u dies des cribe d in S ectio n 1 4. 2 . T his s a m ple s h o uld be c ollecte d prior 
t o t he initiatio n of pr ot oc ol tr eat me nt. 
T he f ollo win g bio s peci me ns  will be c ollecte d at bas eline :  
C ollect 1 0 m L  of w h ole blo o d b y sta n dar d ve n o us p hle b ot o m y int o t he E D T A t u be.  T he 
t u be s h o uld be in verte d s e ver al ti mes t o mix t he E D T A a n d r efriger ate d u ntil s hip pe d o n 
c o ol pac k b y o ver nig ht s hip pin g t o t he Allia nc e Bior e p osit or y ( Ma y o B A P). T he s a m ples 
s h o uld be s hip pe d t he s a m e da y t hat t he blo o d is dr a w n per  S ectio n 6. 2. 1.  
La bel s a m ples wit h t he f ollo win g ide ntific atio n:  
1)  Pr oc ur e me nt date/ti me of c ollectio n  
2)  Allia nc e patie nt n u m ber  
3)  P atie nt initials  
4)  Allia nc e st u d y n u m ber (i. e., A 1 7 1 6 0 1 -S T 2 ) 
5)  S peci me n t y pe  
T h e 1 0 ml of blo o d c a n be c ollecte d  in o ne 1 0 ml t u be, or t w o 5 ml t u bes or t hr ee 3 ml t u bes, 
as lo n g as t he final v olu me is ~ 1 0 ml.  
6. 2. 4  Pl as m a s u b missi o n f or p h ar m ac o ki netic st u dies  ( A 1 7 16 0 1-P P 1)  
F or patie nts w h o c o nse nt t o participate, blo o d s a m ples will be us e d f or t he p har mac o kinetic 
a nalys es des cribe d in S ectio n 1 4. 3.   
Pl as m a f r o m W h ole Bl o o d i n E D T A L a ve n de r To p T u be:   
Prior t o r ec eivin g pr ot oc ol t her a p y o n C ycle 1 da y 1 , C ycle 1 Da y 1 5, a n d C ycle 2 Da y 1 5, 
patie nts c o ns e nte d t o t he A1 7 1 6 0 1 -P P 1 s u bst u d y will be as ke d t o c o m plete a P atie nt 
P har mac o kinetics F or m (s ee Ap pe n dix I X) w hic h will pr o vide inf or matio n a b o ut t he 
pr e vio us 4 8 -h o urs of palb ociclib d osin g (i. e. details o n d os e a n d ti me). After c o m pletio n, 
t he f or m s h o uld be c ollecte d, a n d t he data s h o uld be r e p orte d in Ra ve o n t he S peci me n 
S u b missio n F or m f or A1 7 1 6 0 1 -P P 1. C oll ect 1 x 5 m L of perip her al ve n o us blo o d in a 
la ve n der t o p ( E D T A) t u be prior t o t he patie nt r ec eivin g t he daily d os a ge of palb ociclib o n 
C ycle 1  Da y 1 a n d  Da y 1 5, a n d C ycle 2 Da y 1 5. I n vert t he t u bes a p pr o xi mately 8 -1 0 ti mes 
t o mix t he E D T A, a n d t he n c e ntrif u ge at r o o m te m per at ur e f or 10  min utes at 1 5 0 0 g. Aliq u ots 
of plas ma will t he n be plac e d in la belle d p oly pr o p yle ne t u bes ( 1 m L in eac h of t w o t u bes) 
a n d st or e d at -7 0 t o - 8 0 o C u ntil s hip pe d o n dr y ic e . 

 
Allia nc e A1 7 1 6 0 1  
 
2 9  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
La bel all plas ma s a m ples wit h t he f ollo win g ide ntifi c atio n inf or matio n:  
1)  Date of C ollectio n  
2)  Ti me of C ollectio n (i. e. act ual ti me t he blo o d s a m ple w as o btaine d)  
3)  Allia nc e P atie nt I D N u m ber  
4)  P atie nt I nitials  
5)  Allia nc e St u d y N u m ber (i. e. A1 7 1 6 0 1 -P P 1)  
6)  S a m ple T y pe ( e. g. Plas ma)  
If la bels ar e us e d, pleas e e ns ur e la bels ar e c ar ef ully attac he d t o t he t u bes a n d ar e n ot likely 
t o f all off w he n fr oze n or d urin g s hip pin g. 
S hip s peci me ns  a n d c o pies of t he c o m plete d P har mac o kinetics q uestio n nair es  t o t he 
Allia nc e La b or at or y at t he Universit y of Pitts b ur g h ( S ee S ectio n 6. 2. 1 ) wit h Priorit y 
O ver nig ht o n M o n da y t hr o u g h T h urs da y f or ne xt da y deliver y. D o n ot s hip s peci me ns t he 
da y bef or e a h olida y. T he Universit y of Pitts b ur g h  d oes n ot ac c e pt S at ur da y deliveries.   
6. 3  
Di git al I m a ge  S u b missi o n Usi n g T RI A D  
Tr a nsf er of I ma ges a n d Data ( T RI A D) is t he A meric a n C olle ge of Ra diolo g y’s ( A C R) i ma ge 
e xc ha n ge a p plic atio n. T RI A D pr o vides sites participatin g in clinic al trials a s ec ur e met h o d t o 
tr a ns mit i ma ges. T RI A D a n o n y mizes a n d validates t he i ma ges as t he y ar e tr a nsf err e d. 
6. 3. 1  T RI A D Access Re q uire m e nts  
• 
A  valid C T E P -I A M ac c o u nt.  
• 
Re gistr atio n a n d Cr e de ntial Re p osit or y ( R C R)  r e gistr atio n t y pe of: Ass ociate  ( A), 
Ass ociate Plus  ( A P), N o n-P h ysicia n I n vestigat or  ( N PI V R), or I n vestigat or (I V R) 
r e gistr atio n t y pe. Ref er t o t he C T E P  Re gistr atio n Pr oc e d ur es s e ctio n f or instr uctions on 
h o w t o r e q uest a C T E P -I A M ac c o u nt a n d c o mplete r e gistr atio n in R C R. 
• 
T RI A D Site Us er r ole o n a n N C T N or E T C T N r oster.  
All in divid uals o n t he I ma gin g a n d Ra diatio n O nc olo g y C or e pr o vider r oster ha ve access to 
T RI A D a n d ma y s u b mit i m a ges f or cr e de ntialin g p ur p os es, or f or e nr oll me nts t o w hic h the 
pr o vider is lin ke d in O P E N.  
6. 3. 2  T RI A D I nst all atio ns  
T o s u b mit i ma ges, t he in divid ual h oldin g t he T RI A D Site Us er r ole will nee d t o install t he 
T RI A D a p plic atio n o n t heir w or kstatio n. T RI A D installatio n d oc u me ntatio n is a vaila ble at 
 
T his pr oc ess c a n be d o ne in par allel t o o btainin g y o ur C T E P -I A M ac c o u nt a n d R C R 
r e gistr atio n. 
F or q uestio ns, c o n tact T RI A D T ec h nic al S u p p ort staff via e mail 
 
 
6. 3. 3  Pr oce d u res f or D at a S u b missi o n vi a T RI A D  
C ollectio n of C T/ P E T -C T a n d Bo ne i ma ges is r e q uir e d. I ma ges will be c ollecte d digitally 
f or ar c hival a n d r etr os pective p ur p os es at t he f ollo win g ti me p oints: 
• 
B as eli n e ( wit hin 2 8 da ys prior t o patie nt r e gistr atio n ) 

 
Allia nc e A1 7 1 6 0 1  
 
3 0  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
• 
Rest a gi n g (Da y 1 of C ycle 4 ( ± 2 wee ks) t he n e ver y 1 2 w ee ks u ntil e n d of tr eat me nt ) 
T he c o m plete C T / P E T-C T  an d Bo ne  s c a n i ma gin g data in digital DI C O M  f or mat will be 
s u b mitte d ele ct r o nic all y  t o t he I ma gin g a n d Ra diatio n O nc olo g y C or e at O hio (I R O C O hio) 
wit hi n n o m ore t h a n 3 b usi n ess da ys  u p o n patie nt e nr oll me nt ( at bas eline) or u p o n t he 
i ma ge ac q uisitio n c o m plet e ness ( at f ollo w-u ps). B M P files, J P G files, or har d c o pies (fil ms) 
ar e n ot ac c e pta ble.  
I ma gin g data s h o uld be s u b mitte d electr o nic ally  t o I R O C O hio via T RI A D . T he sta n dar d 
T RI A D bas e d d ata tr a nsf er a p pr oac h will be pr o vide d s e par ately t hr o u g h I R O C eff orts via 
t he s pecific trial e-mail 
 per t he r e q uest b y participatin g 
sites bef or e t heir first data s u b mission.  
If T RI A D a p pr oac h is n ot ac hie va ble at site, alter natively s ite nee ds t o de-ide ntif y t he patie nt 
data usin g instit utio nal pr oc e d ur es t o r e m o ve patie nt na me a n d me dic al r ec or d n u m ber w hile 
pr es er vin g t he Allia nc e patie nt I D n u m ber ( e. g., 1 1 2 1 3 6) a n d pr ot oc ol n u m ber ( e. g., 
A1 7 1 6 0 1 ), a n d us e t he f ollo win g electr o nic a p pr oac hes f or data s u b missio n:  
1 ) We b Tr a nsf e r 
 
An y P Cs wit h inter net ac c ess a n d w e b br o ws er ( e. g., I nter net E x plor er, M oz illa Fir ef o x) c an 
be us e d t o w e b tr a nsf er DI C O M i ma ges a n d ot her r e q uir e d files t o I R O C O hio. T he sta n dar d 
We b Tr a nsf er inf or matio n will be pr o vide d s e par ately t hr o u g h t he s pecific trial e -mail 
, per t he r e q uest b y participatin g sites bef or e t heir first data 
s u b missio n.  
2) F T P Tr a nsf e r  
An y F T P s oft w ar e c a n be us e d t o initiate ac c ess t o t he s ec ur e F T P S er ver of I R O C O hio. 
T he sta n dar d F T P ac c ess inf or matio n will be pr o vide d s e par ately t hr o u g h t he s pecific trial 
e-mail 
, per t he r e q uest b y participatin g sites bef or e t heir 
first data s u b missio n.  
Mail/ C D S hi p m e nt  
O nly if electr o nic data tr a nsf er a p pr oac hes c a n not be ac hie ve d, t he de-ide ntifie d i ma ges in 
digital DI C O M f or mat c a n be b ur ne d t o a C D a n d maile d t o I R O C O hio. S u b mit o nly o ne 
patie nt’s i ma ges per C D, wit h t he patie nt’s Allia nc e I D n u m ber, st u d y t y pe, date of s c a ns, 
a n d na me of s u b mittin g instit utio n.  S u b mit t hes e data t o:  
 
 
 
 
 
 
 
 
 
O nc e t he i ma gin g data s u b missio n is d o ne, s e n d a n e -mail t o I R O C O hio at t he s pecific trial 
e mail 
 t o inf or m t hat t he st u d y has bee n s u b mitte d fr o m t he 
instit utio n. Pleas e inclu de t he basic inf or matio n of s u b mitte d data s ets as f ollo w s: 
1)  
Allia nc e patie nt I D n u m ber  
2)  
S c a n ti me p oint (i. e., bas eline)  
3)  
Date of s c a ns  

 
Allia nc e A1 7 1 6 0 1  
 
3 1  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
4)  
I nstit utio n na me  
I R O C O hio will n otif y sit e wit hin 2 b usi n ess da ys  of t he data r ec eipt, a n d t he n, wit hin 3 
b usi n ess da ys  f ollo win g t he data r ec eipt, of t he q ualit y c hec k r e p ort.  
An y q uestio ns or pr o ble ms a b o ut t he data s u b missio n t o I R O C O hio, c all I R O C O hio at 
 f or help 
7. 0  
T R E A T M E N T  P L A N /IN T E R V E N TI O N  
Pr ot oc ol tr eat me nt is t o be gin wit h i n 1 4  da ys  o f re gist r ati o n .  
F or q uestio ns r e gar din g tr eat me nt, pleas e s ee t he pr ot oc ol c o ntacts o n pa ge  2 .  
It is ac c e pta ble f or pr ot oc ol tr eat me nt  t o be deliver e d wit hin  a 2 4-h o ur ( b usiness da y) win do w 
bef or e a n d after t he pr ot oc ol -define d date f or Da y 1 of a ne w c ycl e. F or e xa m ple, if t he tr eat me nt 
d ue date is a Frida y, t he win d o w f or tr eat me nt inclu des t he pr ec e din g T h urs da y t hr o u g h t he 
f ollo win g M o n da y. I n a d ditio n, patie nts ar e per mitte d t o ha ve a ne w c ycle of  pr ot oc ol tr eat me nt 
dela ye d u p t o 7 da ys f or major lif e e ve nts ( e. g., s erio us illness in a f a mily me m ber, major h olida y, 
vac atio n t hat c a n n ot be r es c he d ule d) wit h o ut t his bein g c o nsider e d a pr ot oc ol violatio n. 
D oc u me ntatio n t o justif y t his dela y s h o uld be pr o vide d.  
T he st u d y will be a n o pe n la bel, sin gle ar m, p has e II s af et y a n d t oler a bilit y st u d y of t he c o m binatio n 
of palb ociclib a n d letr oz ole or f ulvestr a nt in patie nts a ge 7 0 or o ver wit h h or m o ne -r ec e pt or p ositive, 
H E R 2 -ne gative metastatic br east c a nc er. All patie nts w h o be gin st u d y tr eat me nt will be inclu de d 
in t he a nalysis of all clinic al e n d p oints. 
A ge nt  
St arti n g 
D os e  
R o ut e of 
A d mi nist r ati o n  
Fre q u e n c y of A d mi nist r ati o n  
P al boci cli b  
1 2 5 m g/ da y  
Or ally  
O nc e daily o n Da ys 1 -2 1 of eac h 2 8 -da y 
c ycle 
Let r oz ol e  
2. 5 m g  
Or ally  
O nc e daily o n Da y s 1 -2 8 of eac h 2 8 da y 
c ycle 
O R  
P al boci cli b  
1 2 5 m g/ da y  
Or ally  
O nc e daily o n Da ys 1 -2 1 of eac h 2 8 -da y 
c ycle 
F ul vest r a nt  
5 0 0 m g  
I M injectio n 
Da y 1 a n d Da y 1 5 of C ycle 1, t he n Da y 1 
of e ver y s u bs e q ue nt c ycle   
T r eat me nt will c o ntin ue u ntil dis eas e pr o gr essio n or u nac c e pta ble t o xicit y.  
7. 1  
P al bocicli b  
A c ycle will be f o ur w ee ks  ( 2 8 da ys) in d ur atio n. Tr eat me nt will be a d minister e d in a n o ut patie nt 
s ettin g.  P alb ociclib will be a d minister e d per t he f ollo win g s c he d ule: 
1.  2 1 c o ns ec utive da ys of 1 2 5 m g palb ociclib, ta ke n or ally wit h f o o d a n d ta ke n at 
a p pr o xi mately t he s a me ti me eac h da y . 
2.  F ollo win g t he 2 1 c o ns ec utive da ys, t her e will be 7 da ys off tr eat me nt t o c o m pris e a 
c o m plete c ycle of 2 8 da ys . 

 
Allia nc e A1 7 1 6 0 1  
 
3 2  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
If a patie nt v o mits or miss es a d os e, a n a d ditio nal d os e s h o uld n ot be ta ke n t hat da y. T he ne xt 
pr es cribe d d os e s h o uld be ta ke n at t he us ual ti me. Miss e d d os es will n ot be ma de u p a n d c ycle 
le n gt h sta ys t he s a me. P alb ociclib c a ps ules s h o uld be s w allo w e d w h ole a n d s h o uld be ta ke n in 
c o m binatio n wit h e n d ocrine t her a p y (if ta kin g letr oz ole). 
7. 2  
Let r oz ole   
Letr oz ole  will be pr es cribe d a n d a d minister e d per M D dis cr etio n a n d d osin g s h o uld f ollo w t he  
pac ka ge ins ert g uidelines . T he r ec o m me n de d d os e is 2. 5 m g daily . D os es miss e d f or t o xicit y 
will n ot be ma de u p. D osin g interr u ptio n a n d/ or d os e r e d uctio ns ar e r ec o m me n de d bas e d o n 
in divid ual s af et y a n d t oler a bilit y.  
7. 3  
F ul vest r a nt  
F ulvestr a nt will be pr es cribe d a n d a d minister e d per M D dis cr etio n a n d d osin g s h o uld f ollo w the 
pac ka ge ins ert g uidelines.  T he r ec o m me n de d d os e is 5 0 0 m g give n I M o n Da ys 1 a n d 1 5 of 
C ycle 1, a n d t he n give n e ver y 2 8 da ys.  D os es miss e d f or t o xicit y will n ot be ma de u p. D osin g 
interr u ptio n a n d/ or d os e r e d uctio ns ar e r ec o m me n de d bas e d o n in divid ual s af et y a n d t oler a bilit y.   
7. 4  
A d h e re n ce , Ge ri atric Ass ess m e nt , a n d P atie nt Pe rs pe cti ve 
Pill di aries will be c ollecte d at t he e n d of c ycles 1 -3 of tr eat me nt t o as c ertain d os e deliver e d 
a d her e nc e t o palb ociclib. Ad her e nc e t o  palb ociclib will be meas ur e d  b y patie nt s elf -r e p ort in 
de dic ate d patie nt diaries at t he e n d of t he first 3 c ycles.  
A c a nc er s pecific geri atric assess me nt  will be c a pt ur e d pr e -tr eat me nt, after 3 c ycles, a n d at the 
e n d of tr eat me nt.  S ee  S ectio n 1 1. 0.  
T o f urt her ass ess t he patie nt’s per c e ptio n of tr eat me nt effic ac y of palb ociclib in a d ditio n t o 
e n d ocrine t her a p y, w e will as k o ur participa nts t o c o m plete t he f ollo win g q uestio n nair es  at t he 
e n d of tr eat me nt : Was It W ort h It  (Ap pe n dix III) a n d O ver all Tr eat me nt Utilit y  (Ap pe n dix I V ), 
t he E Q -5 D -3 L  (Ap pe n dix 
V ) a n d P R O-C T C A E q uestio n nair e ( Ap pe n dix 
V I). T hese 
q uestio n n air es will pr o vide a better u n dersta n din g of t he patie nt’s pers pectives r e gar din g t he 
be nefits a n d side eff ects of tr eat me nt, in c o m binatio n wit h a n ass ess me nt of tr eat me nt efficac y 
a n d t o xicit y.  S ee S ectio n 1 1. 0.  
 
 

 
Allia nc e A1 7 1 6 0 1  
 
3 3  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
8. 0  
D O S E  A N D  T R E A T M E N T  M O DI FI C A TI O N S   
8. 1  
A n cill ar y T h e r a py, C o n c o mit a nt M e dic ati o ns, a n d S u p porti ve C are  
8. 1. 1  P atie nts s h o ul d n ot re cei ve a n y ot h er a ge nt w hic h wo ul d be c o nsi de re d t re at me nt f or 
t h e pri m ar y n e o pl as m or i m pact t h e pri m ar y e n d poi nt. 
8. 1. 2  P atie nts s h o ul d a v oi d i m m u niz ati o ns wit h li ve vir us v acci nes.  
8. 1. 3  P atie nts s h o ul d re cei ve f ull s u p porti ve c are w hile o n t his st u dy.  T his inclu des blo o d 
pr o d uct s u p p ort, a ntibiotic tr eat me nt, a n d tr eat me nt of ot her ne wly dia g n os e d or c onc urrent 
me dic al c o n ditio ns.  All blo o d pr o d ucts a n d c o nc o mita nt me dic atio ns s uc h as a ntidiarr heals, 
a nalgesics, a n d/ or a ntie metics r ec eive d fr o m t he first da y of st u d y tr eat me nt a d ministr ation 
u ntil 3 0 da ys after t he fin al d os e will be r ec or de d in t he me dic al r ec or ds . 
8. 1. 4  Tre at m e nt wit h h or m o n es  f or bre ast c a n ce r t re at m e nt or ot h e r c h e m ot h er a pe utic 
a ge nts ma y n ot be a d minister e d .  
8. 1. 5  A ntie m etics ma y be us e d at t he dis cr etio n of t he atte n din g p h ysicia n, wit h t he e xc e p tion of 
ster oids a b o ve. 
8. 1. 6  Di arr h e a m a n a ge m e nt is per t he dis cr etio n of t he tr eatin g p h ysicia n. Diarr hea c o uld be 
ma na ge d c o ns er vatively wit h me dic atio ns s uc h as lo per a mide.  
P atie nts wit h s e ver e diarr hea s h o uld be ass ess e d  f or intr a ve n o us h y dr atio n a n d c orr ection of 
electr olyte i m bala nc es.  
8. 1. 7  P alli ati ve r a di ati o n t h er a py m a y n ot  be a d mi nist ere d . 
P atie nts w h o r e q uir e r a diatio n t her a p y d urin g pr ot oc ol tr eat me nt will be r e m o ve d fr o m 
pr ot oc ol t her a p y d ue t o dis eas e pr o gr essi o n.  
8. 1. 8  Alli a n ce P olic y C o n ce r ni n g t he Us e of Gr o wt h F act ors  
Blo o d pr o d ucts a n d gr o wt h f act ors s h o uld be utilize d as clinic ally w arr a nte d a n d f ollo win g 
instit utio nal p olicies a n d r ec o m me n datio ns. 
T he us e of c olo n y sti m ulatin g f act ors, filgr asti m ( G -C S F),  pe gfilgr asti m a n d s ar gr a m osti m 
( G M-C S F) is dis c o ur a ge d b ut ma y be us e d in patie nts w h o ha ve pr o g n ostic f actors t hat are 
pr e dictive of clinic al 
deterior atio n s uc h as p ne u m o nia, h y p ote nsio n, 
m ulti -or ga n 
d ysf u nctio n (s e psis s y n dr o me) or f u n gal inf ectio n, as per A S C O g uidelines . I n vestigat ors 
s h o uld us e t heir o w n dis cr etio n in usin g t he C S Fs in t his s ettin g w hic h m ust be d oc u me nted 
a n d r e p orte d o n f or ms.5 3 
8. 1. 9  Hy pe rs e nsiti vit y/i nf usi o n re actio ns  
Tr eat h y pers e nsitivit y a n d inf usio n r eactio ns t o ( dr u g[s]) as per instit utio nal sta n dar ds.  
8. 1. 1 0  C Y P 3 A  I n hi bit ors 
C hr o nic c o nc o mita nt tr eat me nt wit h str o n g in hibit ors of C Y P 3 A  is str o n gly dis c o ur a ged 
w hile o n t his trial. T he f ollo win g dr u gs ar e E X A M P L E S of str o n g in hibit ors of C Y P 3 A  a n d 
ar e n ot  allo w e d d urin g tr eat m e nt wit h p alb ociclib.  
• 
I n dina vir 
• 
Clarit hr o m ycin  
• 
Ket oc o naz ole  
• 
Gr a pefr uit juic e  

 
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Bec a us e lists of t hes e a ge nts ar e c o nsta ntly c ha n gin g, pleas e c o ns ult a n d r e vie w a n y dr u gs 
f or t heir p ote ntial t o in hibit C Y P 3 A. E xa m ples of r es o ur c es t hat ma y be utilize d inclu de t he 
pr o d uct inf or matio n f or t he in divid ual c o nc o mita nt dr u g in q uestio n, me dic al r ef er e nc e te xts 
s uc h as t he P h ysicia ns’ Des k Ref er e nc e, t he F D A w e bsite, or y o ur loc al instit utio n’s 
p har macist.  
8. 1. 1 1  C Y P 3 A  I n d u ce rs 
C hr o nic c o nc o mita nt tr e at me nt wit h str o n g in d uc ers of C Y P 3 A is str o n gly dis c o ur a ged 
w hile o n t his trial. T he f ollo win g dr u gs ar e E X A M P L E S of str o n g in d uc ers of C Y P 3 A a n d 
ar e n ot allo w e d d urin g tr eat me nt wit h palb ociclib . 
• 
Rif a m pin  
• 
Car ba maze pine  
Bec a us e lists of t hes e a ge nts a r e c o nsta ntly c ha n gin g, pleas e c o ns ult a n d r e vie w a n y dr u gs 
f or t heir p ote ntial t o in d uc e C Y P 3 A. E xa m ples of r es o ur c es t hat ma y be utilize d inclu de t he 
pr o d uct inf or matio n f or t he in divid ual c o nc o mita nt dr u g in q uestio n, me dic al r ef er e nc e te xts 
s uc h as t he P h ysicia ns’ Des k Ref er e nc e, t he F D A w e bsite, or y o ur loc al instit utio n’s 
p har macist.  
8. 1. 1 2  C Y P 2 A 6 S u bst r at es  
C hr o nic c o nc o mita nt tr eat me nt wit h s u bstr ates of C Y P 2 A6 is str o n gly dis c o ur a ge d w hile 
o n t his trial. T he f ollo win g dr u gs ar e E X A M P L E S of C Y P 2 A6 s u bstr ates a n d ar e n ot 
allo w e d d urin g tr eat me nt wit h letr oz ole.  
• 
De x me det o midine  
• 
T e gaf ur  
Bec a us e lists of t hes e a ge nts ar e c o nsta ntly c ha n gin g, pleas e c o ns ult a n d r e vie w a n y dr u gs 
f or t heir p ote ntial t o in d uc e C Y P 2 A6. E xa m ples of r es o ur c es t hat ma y be utilize d inclu de 
t he pr o d uct inf or matio n f or t he in divid ual c o nc o mita nt dr u g in q uestio n, me dic al r ef er e nce 
te xts s uc h as t he P h ysicia ns’ Des k Ref er e nc e, t he F D A w e bsite, or y o ur loc al instit utio n’s 
p har macist.  
 
 

 
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8. 2  
D os e Mo dific ati o ns  
P alb ociclib c ycle le n gt h w ill r e main 2 8 da ys ( ± 2 da ys) (des pite a dela y in initiatin g a ne w c ycle 
of palb ociclib ); e n d ocrine t her a p y ma y c o ntin ue t o be a d minister e d per t he pr e pla n ne d s c he d ule. 
• 
D os e h olds/r e d uctio ns of letr oz ole or f ulvestr a nt will oc c ur per t he pac ka ge ins ert an d t he 
tr eatin g in vestigat or’s dis cr etio n. 
• 
D os e es c alatio n will n ot be per mitte d in t his st u d y.  
• 
P alb ociclib d os es miss e d f or t o xicit y will n ot be ma de u p.  
• 
T he initiatio n of a ne w c ycle ma y be dela ye d f or u p t o 7 da ys  
C T E P –  A E R S r e p ortin g ma y be r e q uir e d f or s o me a d vers e e ve nts. S ee S ectio n 9. 0. P R O -
C T C A E data s h o uld n ot be us e d f or d os e m o dific atio ns.  
8. 2. 1  D os e Le vels  
D os e Le vel  
P al bocicli b D os e  
Startin g D os e  
1 2 5 m g/ da y  
-1  
1 0 0 m g/ da y  
-2  
7 5 m g/ da y  
8. 2. 2  He m at ol o gic a dve rs e e ve nts  ( e xce pt l y m p h o pe ni a, u nless ass oci at e d wit h cli nic al 
e ve nts, e. g., o p port u nistic i nfe cti o ns ): 
M o nit or c o m plete blo o d c o u nts prior t o t he start of palb ociclib t her a p y a n d at t he be gin nin g 
of eac h c ycle, as w ell as o n Da y 1 5 of t he first 2 c ycles, a n d as clinic ally in dic ate d.  
F or patie nts w h o e x perie nc e a ma xi m u m of Gr a de 1 or 2 ne utr o pe nia in t he first 6 c ycles, 
m o nit or c o m plete blo o d c o u nts  f or s u bs e q ue nt c ycles e ver y 3 m o nt hs, prior t o t he be gin nin g 
of a c ycle a n d as clinic ally in dic ate d.  
F or gr a de 3 e ve nts:   
D a y 1 of c ycle:  
O mit  palb ociclib , r e peat c o m plete blo o d c o u nt m o nit orin g wit hin 1 w ee k. Up o n r ec over y  to 
Gr a de ≤2, start t he ne xt c yc le at t he s a me ( pr e vio us) d os e.  
D a y 1 5 of first 2 c ycles:  
• 
If Gr a de 3 o n Da y 1 5, c o ntin ue palb ociclib  at c urr e nt d os e t o c o m plete c ycle a n d 
r e peat c o m plete blo o d c o u nt o n Da y 2 2. 
• 
If Gr a de 4 o n Da y 2 2, s ee Gr a de 4 d os e m o dific atio n g uidelines belo w.  
• 
C o nsider  d os e r e d uctio n in c as es of pr olo n ge d ( > 1 w ee k) r ec o ver y fr o m Gr a de 3 
ne utr o pe nia or r ec urr e nt Gr a de 3 ne utr o pe nia o n Da y 1 of s u bs e q ue nt c ycles.  
F or gr a de 3 n e ut r o pe ni a wit h f e ver ≥3 8. 5 º C a n d/ o r i nfe cti o n, a n d Gr a de 4 e v e nts:  
• 
O mit  palb ociclib  u ntil r ec o v er y t o Gr a de ≤2.  
• 
Res u me at t he ne xt lo w er d os e.  

 
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8. 2. 3  No n He m at ol o gic a dve rs e e ve nts:  
F or all g r a de 3 a n d hi g h e r e ve nts  rel ate d t o pal bocicli b, o mit palb ocicli b  u ntil r ec o ver y 
t o Gr a de ≤ 1 , or Gr a de ≤2 (if n ot c o nsider e d a s af et y ris k f or t he patie nt) . 
• 
R es u me p alb ociclib  at t he ne xt lo w er d os e at t he dis cr etio n of t he tr eatin g p h ysicia n.  
• 
P er ma ne ntly dis c o ntin uin g palb ociclib is r ec o m me n de d in  patie nts e x perie ncin g 
s e ver e I nterstitial L u n g D is eas e/ p ne u m o nitis. 
9. 0  
A D V E R S E  E V E N TS  
T he pr o m pt r e p o rtin g of a d vers e e ve nts is t he r es p o nsibilit y of eac h in vestigat or e n ga ge d in clinic al 
r es ear c h, as r e q uir e d b y F e der al Re g ulatio ns. Ad vers e e ve nts m ust be des cribe d a n d gr a de d usin g 
t he ter min olo g y a n d gr a din g c ate g ories define d in t he N CI’s C o m m o n T er minolo g y Criteria f or 
Ad vers e  
E ve nts  
( C T C A E),  
Versio n 
5 . 0. 
T he  
C T C A E  
is  
a vaila ble  
at 
 Attrib utio n t o pr ot oc ol 
tr eat me nt f or eac h a d vers e e ve nt m ust be deter mine d b y t he in vestigat or a n d r e p orte d o n t he 
r e q uir e d f or ms. Pleas e r ef er t he N CI G uidelines: Ad vers e E ve nt Re p ortin g Re q uir e me nts f or f ur t her 
det ails o n A E r e p ortin g pr oc e d ur es.  
T o c o m ple me nt C T C A E r e p ortin g, patie nts will s elf -r e p ort t heir side eff ects usin g t he P R O-
C T C A E. T he s pecific P R O -C T C A E ite ms f or t his pr ot oc ol c a n be f o u n d in Ap pe n dix V I. P R O -
C T C A E s h o uld n ot be us e d f or deter minin g attrib utio n or r e p ortin g of s erio us a d vers e e ve nts.  
9. 1  
R o uti n e A dve rs e E ve nt R e porti n g  
Ad vers e e ve nt data c ollectio n a n d r e p ortin g, w hic h ar e r e q uir e d as part of e ver y clinic al trial ar e 
d o ne t o e ns ur e t he s af et y of patie nts e nr olle d in t he st u dies as w ell as t h os e w h o will e nr oll in 
f ut ur e st u dies usin g si milar a ge nts. Ad vers e e ve nts ar e r ep orte d in a r o utine ma n ner at s c he d uled 
ti mes ac c or din g t o t he st u d y c ale n dar in S ectio n 5. 0 . F or t his trial, t he Ad vers e E ve nt S olicite d 
f or m is us e d f or r o utine A E r e p ortin g in Ra ve. 
S olicite d Ad vers e E ve nts: T he f ollo win g a d ver s e e ve nts ar e c o nsider e d "e x pecte d" a n d t heir 
pr es e nc e/a bs e nce s h o uld be s olicite d, a n d s e verit y gr a de d, at bas eline a n d f or eac h c ycle of 
tr eat me nt b y C T C A E, P R O-C T C A E,  or b ot h.  
C T C A E v. 5 . 0 Te r m 
P R O -C T C A E v. 1. 0 
Te r m  
C T C A E v. 5 . 0 S yst e m Or g a n 
Cl ass ( S O C)  
Ne utr o p hil c o u nt decr eas e d  
 
I n vestigatio ns 
Platelet c o u nt decr eas e d  
 
I n vestigatio ns 
W hite Blo o d c ell c o u nt 
decr eas e d  
 
I n vestigatio ns 
Ane mia  
 
Blo o d a n d ly m p hatic s yste m 
dis or ders  
F e brile Ne utr o pe nia  
 
Blo o d a n d ly m p hatic s yste m 
dis or ders  
Na us ea  
Na us ea  
Gastr ointestinal Dis or ders  
An or e xia  
Decr eas e d Ap petite  
Meta b olis m a n d N utritio nal 
Dis or ders  
Diarr hea  
Diarr hea  
Gastr ointestinal dis or ders  

 
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Vo mitin g  
Vo mitin g  
Gastr ointestinal dis or ders  
M uc ositis or al 
M o ut h/t hr oat s or es  
Gastr ointestinal dis or ders  
F atig ue  
F atig ue  
Ge ner al dis or ders  
P erip her al S e ns or y 
Ne ur o pat h y   
N u m b ness a n d Tin glin g  
Ge ner al dis or ders  
T hr o m b oe m b oli c e ve nt   
 
Vas c ular dis or ders  
Up per Res pir at or y I nf ectio n  
 
I nf ectio ns a n d I nf estatio ns  
Urinar y Tr act I nf ectio n  
 
I nf ectio ns a n d I nf estatio ns  
 
9. 2  
C T C A E R o uti n e Re porti ng Re q uire me nts  
I n a d ditio n t o t he s olicite d a d vers e e ve nts liste d in S ectio n 9. 1, t he f ollo win g ta ble o utlines t he 
c o m binatio ns of ti me p oints, gr a des a n d attrib utio ns of A Es t hat r e q uir e r o utine r e p ortin g t o t he 
Allia nc e Statistics a n d Data Ce nter. Q uestio ns a b o ut r o utine r e p ortin g s h o uld be dir ecte d t o t he 
Data 
Ma na ger.  P R O -C T C A E data s h o uld n ot be us e d f or deter minin g attrib utio n, d ose 
m o dific atio ns, or r e p ortin g of s erio us a d vers e e ve nts.  
• 
C o m binatio ns of C T C A E 
Gr a de & Attrib utio n 
Re q uir e d f or R o utine 
A E 
Data 
S u b missio n o n Cas e Re p ort F or ms ( C R Fs)  
Att ri b uti o n  
Gr a de 1  
Gr a de 2  
Gr a de 3  
Gr a de 4  
Gr a de 5  
Unr elat e d  
 
a 
a 
a 
a 
Unlikely  
 
a 
a 
a 
a 
P ossible  
 
a 
a, b 
a, b 
a, b 
Pr o ba ble  
 
a 
a, b 
a, b 
a, b 
Definit e  
 
a 
a, b 
a, b 
a, b 
• 
a)  
Ad vers e E ve nts: Ot her C R F - Ap plies t o A Es oc c urrin g bet w ee n r e gistr atio n a nd 
wit hin 3 0 da ys of t he patie nt’s last tr eat me nt date, or as part of t he Clinic al F ollo w-Up 
P has e.  
• 
b)  
Ad vers e E ve nts: Late C R F - Ap plies t o A Es oc c urrin g gr eater t ha n 3 0 da ys after 
t he patie nt’s last tr eat me nt date. 
9. 3  
Ex pe dit e d A dve rs e Eve nt Re porti n g ( C T E P -A E R S)  
I n vestigat ors ar e r e q uir e d b y F e der al Re g ulatio ns t o r e p ort s erio us a d vers e e ve nts as define d in 
t he ta ble belo w. Allia nc e in vestigat ors ar e r e q uir e d t o n otif y t he Allia nc e Ce ntr al Pr ot oc ol 
O per atio ns Pr o gr a m, t he St u d y C hair, a n d t heir I nstit utio nal Re vie w Boar d if a patie nt has a 
r e p orta ble s erio us a d vers e e ve nt. T he des criptio ns a n d gr a din g s c ales f o u n d in t he N CI C o m m on 
T er min olo g y Criteria f or Ad vers e E ve nts ( C T C A E) versio n 5  will be utilize d f or A E r e p ortin g.  
T he  
C T C A E  
is  
ide ntifie d  
a n d  
loc ate d  
o n  
t he  
C T E P  
w e bsite  
at:  
 
All  
a p pr o priate 
tr eat me nt ar eas s ho uld ha ve ac c ess t o a c o p y of t he C T C A E. All r eactio ns deter mine d t o be 
“r e p orta ble” in a n e x pe dite d ma n ner m ust be r e p orte d usin g t he Ca nc er T her a p y E valuatio n 
Pr o gr a m Ad vers e E ve nt Re p ortin g S yste m ( C T E P -A E R S).  

 
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F or f urt her inf or matio n o n t he N CI r e q uir e m e nts f or S A E r e p ortin g, pleas e r ef er t o t he ‘ N CI 
G uidelines f or I n vestigat ors: Ad vers e E ve nt Re p ortin g Re q uir e me nts’ d oc u me nt p u blis he d b y 
t he N CI.  
N ote:  All deat hs o n st u d y r e q uir e b ot h r o utine a n d e x pe dite d r e p ortin g r e gar dless of c a us alit y.  
Attrib uti o n t o tr eat me nt or ot her c a us e s h o uld be pr o vide d.  
 
 

 
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9. 3. 2  Ex pe dit e d  A E re porti n g ti m eli n es defi n e d  
 “ 2 4 h o urs; 5 c ale n dar da ys ” –  T he in vestigat or m ust initially r e p ort t he A E via C T E P -A E R S 
≤ 2 4 h o urs of lear nin g of t he e ve nt f ollo w e d b y a c o m plete C T E P -A E R S r e p ort ≤ 5 cale n dar 
da ys of t he initial 2 4 -h o ur r e p ort.  
 “ 1 0 c ale n dar da ys ” - A c o m plete C T E P -A E R S r e p ort o n t he A E m ust be s u b mitte d ≤ 1 0 
c ale n dar da ys of t he in vestigat or lear nin g of t he e ve nt.  
An y me dic al e ve nt e q uivale nt t o C T C A E gr a de 3, 4, or 5 t hat pr ecipitates h os pitalizatio n 
( or pr olo n gatio n of e xistin g h os pitalizatio n) m ust be r e p orte d r e gar dless of attrib utio n a n d 
desig natio n as e x pecte d or u ne x pecte d wit h t he e xc e ptio n of a n y e ve nt s ide ntifie d as 
pr ot oc ol-s pecific e x pe dite d a d vers e e ve nt r e p ortin g e xclusio ns (see belo w).  
Us e t he N CI pr ot oc ol n u m ber a n d t he pr ot oc ol -s pecific patie nt I D pr o vide d d urin g trial 
r e gistr atio n o n all r e p orts. 
9. 3. 3  A d diti o n al I nst r u cti o ns or 
Excl usi o n t o 
C T E P -A E R S 
Ex pe dit e d 
Re porti ng 
Re q uire m e nts  
• 
All a d vers e e ve nts r e p orte d via C T E P -A E R S (i. e., s erio us a d vers e e ve nts) s h o uld 
als o be f or w ar de d t o y o ur loc al I R B.  
• 
Gr a de 3/ 4 he mat os u p pr essio n a n d h os pitalizatio n r es ultin g fr o m s uc h d o n ot 
r e q uir e C T E P-A E R S, b ut s h o uld be s u b mitte d as part of st u d y r es ults. All ot her gr a de 
3, 4, or 5 a d vers e e ve nts t hat pr ecipitate h os pitalizatio n or pr olo n g a n e xistin g 
h os pitalizatio n m ust be r e p orte d via C T E P -A E R S . 
• 
Re p ortin g of c as es of s ec o n dar y A M L/ M D S is t o be d o ne usin g t he N CI/ C T EP 
S ec o n dar y A M L/ M D S Re p ort F or m. Ne w pri mar y malig na ncies s h o uld be r e p orte d in 
Ra ve . 
• 
Deat h d ue t o pr o gr essive dis eas e s h o uld be r e p orte d as Gr a de 5 “ Dis eas e 
pr o gr essio n” in t he s yste m or ga n class ( S O C) “ Ge ner al dis or ders a n d a d ministr atio n site 
c o n ditio ns. ” E vide nc e t hat t he deat h w as a ma nif estatio n of u n derlyin g dis eas e ( e. g., 
r a diolo gic al c ha n ges s u g gestin g t u m or gr o wt h or pr o gr essio n: clinic al deterior atio n 
ass ociate d wit h a d is eas e pr oc ess) s h o uld be s u b mitte d. 
• 
An y deat h oc c urrin g wit hin 3 0 da ys of the last d os e, r e gar dless of attrib utio n to the 
in vestigatio nal a ge nt/inter ve ntio n r e q uir es e x pe dite d r e p ortin g wit hin 2 4 h o urs.  
• 
An y deat h oc c urrin g gr eater t ha n 3 0 da ys after t he last d os e of t he in vestigatio nal 
a ge nt/inter ve ntio n r e q uir es e x pe dite d r e p ortin g wit hin 2 4 h o urs o nly if it is p ossibly, 
pr o ba bly, or definitely r elate d t o t he in vestigatio nal a ge nt/inter ve ntio n.  
• 
All ne w malig na ncies m ust be r e p orte d via C T E P -A E R S w h et her or n ot t he y ar e 
t h o u g ht t o be r elate d t o eit her pr e vio us or c urr e nt tr eat me nt. All ne w malig na ncies 
s h o uld be r e p orte d, i. e. s olid t u m ors (inclu din g n o n -mela n o ma s kin malig na ncies), 
he mat olo gic malig na ncies, m yelo d ys plastic s y n dr o me/ac ute m yelo ge n o us  le u ke mia, 
a n d in sit u t u m ors. I n CT C A E versio n 5 . 0, t he ne w malig na ncies ( b ot h s ec o n d a nd 
s ec o n dar y) ma y be r e p orte d as o ne of t he f ollo win g: ( 1) Le u ke mia s ec o n dar y t o 
o nc olo g y c he m ot her a p y, ( 2) 
M yelo d ys plastic s y n dr o me, ( 3) Tr eat me nt -r elated 
s ec o n dar y malig na nc y, or ( 4) Ne o plas ms be nig n, malig na nt a n d u ns pecifie d-ot her. 
W he ne ver p ossible, t he C T E P -A E R S r e p orts f or ne w malig na ncies s h o uld inclu de 
t u m or pat h olo g y, hist or y or prior t u m ors, prior tr eat me nt/c urr e nt tr eat me nt inclu din g 
d ur atio n, a n y ass ociate d ris k f act ors or e vide nc e r e gar din g h o w lo n g t he ne w 
malig na nc y ma y ha ve bee n pr es e nt, w he n a n d h o w t he ne w malig na nc y w as detected, 

 
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m olec ular c har acterizatio n or c yt o ge netics of t he original t u m or (if a vaila ble) a n d of 
a n y ne w t u m or, a n d ne w malig na nc y tr e at me nt a n d o utc o me, if a vaila ble.  
• 
Tr eat me nt e x pect e d a d vers e e ve nts inclu de t h os e liste d in S ectio n 1 0. 0 a n d in t he 
pac ka ge ins ert.  
• 
Gr a de 1 -3 na us ea or v o mitin g a n d h os pitalizatio n r es ultin g fr o m s uc h d o n ot r e q uir e 
A E R S r e p ortin g, b ut s h o uld be r e p orte d  via r o utine A E r e p ortin g  
• 
Gr a de 3 or 4 na us ea or v o mitin g d oes n ot r e q uir e A E R S r e p ortin g, b ut s h o uld be 
r e p orte d via r o utine A E r e p ortin g.  
• 
Gr a de 1 -3 f atig ue a n d h os pitalizatio n r es ultin g fr o m s uc h d o n ot r e q uir e A E R S 
r e p ortin g, b ut s h o uld be r e p orte d via r o utine A E r e p ortin g. 
• 
Gr a de 3 or 4 f atig ue d oes n ot r e q uir e A E R S r e p ortin g, b ut s h o uld be r e p orte d via 
r o utine A E r e p ortin g 
• 
Gr a de 1 -3 diarr hea d oes n ot r e q uir e A E R S r e p ortin g, b ut s h o uld be r e p orte d via 
r o utine A E r e p ortin g 
• 
Gr a de 3 or 4 diarr hea a n d h os pi talizatio n r es ultin g fr o m s uc h d o n ot r e q uir e A E R S 
r e p ortin g, b ut s h o uld be r e p orte d via r o utine A E r e p ortin g.  
• 
Gr a de 3 ne utr o pe nic f e ver a n d h os pitalizatio n r es ultin g fr o m s uc h d o n ot r e q uir e 
A E R S r e p ortin g, b ut s h o uld be r e p orte d via r o utine A E r e p ortin g.  
• 
C T E P -A E R S r e p orts s h o uld be s u b mitte d electr o nic ally.  
 
 

 
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H E P A T O BI LI A R Y DI S O R D E R S  - He p atic fail ure; He p at o biliar y dis or ders - Ot h er ( bile d u ct o bstr u cti o n); 
He p at o biliar y dis or ders - Ot h er (ja u n dic e)  
I M M U N E S YS T E M DI S O R DE R S  - Aller gic re a cti o n  
I N J U R Y, P OI S O NI N G A N D P R O C E D U R A L C O M P LI C A TI O N S  - Fall; Fra ct ure  
I N V ES TI G A TI O N S  - Al kali n e p h os p hat ase i n cre ase d; Bl o o d bilir u bi n i n cre ased; C P K i n cre as e d; Cre ati ni n e 
i n cre as e d; Eje cti o n fra cti o n d ecre ase d; G G T i n cre as e d; I N R i n cre ase d; W ei g ht l os s  
M E T A B O LI S M A N D N U T RI TI O N DI S O R D E R S  - De h y drati o n; H y percalc e mia; H y per gl y c e mia; 
H y p er kale mia; H y p er ma g nese mia; H y p er uric e mia; H y p oal b u mi n e mia; H y p o calc e mia; H y p o kale mia; 
H y p o n atre mia; H y p o p h os p hate mia; M eta b olis m a n d n utriti o n dis or ders - O t h er (fail ure t o t hri v e) 
M US C U L O S K E L E T A L A N D C O N N E C TI V E TI S S U E DI S O R D E R S
 - Art hral gia; Ba c k p ai n; Fla n k p ai n; 
Ge n eralize d mus cle we a k n ess; M uscle cra mp; M uscul os keletal a n d c o n necti v e tiss u e dis or d er - Ot h er 
( ost e o my elitis); M yal gia; Ne c k p ai n; Ost eo necr osis; Pai n i n e xtre mit y 
N E O P L A S M S B E NI G N, M A LI G N A N T A N D U N S P E CI FI E D (I N C L. C YS T S A N D P O L Y P S)  - Tre at me nt 
relat e d s e c o n dar y mali g n a nc y 
N E R V O US S YS T E M DI S O R D E R S  - Dizzi n es s; D ys est h esia; D ys p hasia; I ntra cra nial h e morr h a ge; Ner v o us 
s yste m dis or ders - Ot h er ( p er i p h eral n e ur o pat h y)5; S y nc o pe 
P S Y C HI A T RI C DI S O R D E R S  - Co nf usi o n; I ns o mnia; Ps ychiatric dis or d ers - Ot h er (alt ere d me nt al st at us)  
R E N A L A N D U RI N A R Y DI S O R D E R S  - A c ut e ki d n ey i nj ur y; He mat uria  
R E S PI R A T O R Y, T H O R A CI C A N D M E DI A S TI N A L DI S O R D E R S  - Co u g h; D ys p ne a; H y p o xia; 
Or o p h ar y n ge al p ai n; Ple ural eff usi o n; P ost nasal dri p; P ul mo n ar y e d e ma; P ul mo nar y h y pert ensi o n  
S KI N A N D S U B C U T A N E O US TI S S U E DI S O R D E R S  - H y p er hi dr osis; Pr urit us  
V A S C U L A R DI S O R D E R S  - H y p ert e nsi o n; H y p ote nsi o n 
 
 
N ote : Pal b o cicli b ( P D-0 3 3 2 9 9 1) i n c o mbi n ati o n wit h ot her a g ents c o ul d c a use a n e xa c er b ati o n of a n y a d verse e ve nt 
c urre ntl y k n o w n t o b e c a use d b y t h e ot her a g ent, or t h e c o mbi n ati o n ma y res ult i n e v e nts n e ver pre vi o usl y 
as s o ciat ed wit h eit h er a g e nt. 
 
 
 
 

 
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1 0. 0  
D R U G I N F O R M A TI O N  
1 0. 1  Ge n e r al C o nsi de r ati o ns:  
All st u d y a ge nts ar e t o be a d minister e d at t he r e gisterin g instit utio n.   
1 0. 2  P al bocicli b  
I N D E xe m pt: P alb ociclib  is I N D e xe m pt as us e d in t his trial. T his e xe m ptio n has bee n 
deter mine d b y attestatio n t hat neit her t he in vestigat or n or s p o ns or inte n ds t o s ee k a ne w 
in dic atio n f or us e or t o s u p p ort a n y ot her sig nific a nt c ha n ge in t he la belin g or pr o d uct a d vertising 
f or P alb ociclib ; t his in vestigatio n will us e a n a p pr o ve d r o ute of a d ministr atio n a n d d os a ge of 
P alb ociclib  a n d has n o f act ors t hat incr eas e t he ris k of t he pr o d uct; t his in vestigatio n will be in 
c o m plia nc e wit h 2 1 C F R parts 5 6, 5 0, a n d 3 1 2. 7; a n d neit her t he i n vestigat or n or s p o ns or will 
pr o m ote or r e pr es e nt t hat P alb ociclib  is s af e or eff ective f or t he c o nte xt t hat is u n der 
in vestigatio n in t his st u d y. 
Pr oc ure me nt  
P alb ociclib is a c o m mer cially a vaila ble a ge nt a n d fille d wit h pr es criptio n.  
F or m ul ati o n  
P alb ocicl ib is s u p plie d as a 1 2 5 m g, 1 0 0 m g, or 7 5 m g ta blet. P alb ociclib is a yello w t o or a n ge 
p o w der a n d t he 1 2 5 m g ca ps ule is a n o pa q ue har d gelatin, size 0 c a ps ules wit h a c ara mel c ap and 
b o d y , printe d wit h w hite in k “ Pfizer ” o n t he c a p, a n d “ P B C 1 2 5 ” o n t he b o d y.  T he 1 0 0 m g 
c a ps ules ar e o pa q ue har d gelatin c a ps ules, size 1, wit h c ar a mel c a p a n d lig ht or a n ge b o d y, 
printe d wit h w hite in k “ Pfizer ” o n t he c a p a n d “ P B C 1 0 0” o n t he b o d y.  T he 7 5 m g ca ps ules are 
o pa q ue har d gelatin c a ps ules, size 2, wit h lig ht or a n ge c a p a n d b o d y, printe d wit h w hite in k 
“ Pfizer ” o n t he c a p a n d “ P B C 7 5” o n t he b o d y.  
I nactive in gr e die nts pr es e nt in t he c a ps ule inclu de: 
Micr ocr ystalline c ellulos e, lact ose 
m o n o h y dr ate, s o diu m star c h glyc olate, c olloidal silic o n dio xide, ma g nesiu m stear ate , a n d har d 
gelatin c a ps ule s hells  
T he lig ht or a n ge, lig ht or a n ge/ c ar a mel a n d c ar a mel o pa q ue c a ps ule s hells c o ntain gelatin, r e d 
ir o n o xide, yello w ir o n o xide, a n d tita niu m dio xide; a n d t he printin g in k c o ntains s hellac, 
tita niu m dio xide, a m m o niu m h y dr o xide, pr o p yle ne glyc ol a n d si met hic o ne 
St or a ge a n d St a bility  
T he intact b ottles s h o uld be st or e d at 2 0 0 C t o 2 5 o C ( 6 8 o F t o 7 7 o F); e xc ursio ns per mitte d bet ween 
1 5 t o 3 0 o C ( 5 9 t o 8 6 o F)  
A d mi nistr ati o n  
D os e: 1 2 5 m g of palb ociclib a d minister e d or ally o nc e a da y ar o u n d t he s a me ti me e ver y da y f or 
2 1 c o ns ec utive da ys f ollo w e d b y 7 da ys off t o c o m pris e a c ycle of 2 8 da ys.  
R o ute of Ad ministr atio n: Or ally wit h meals a n d patie nts s h o uld be e nc o ur a ge d t o ta ke t h eir d ose 
at a p pr o xi mately t he s a me ti me eac h da y. If a patie nt v o mits or miss es a d os e, a n a d ditio nal d ose 
s h o uld n ot be ta ke n t hat da y. I nstea d t he ne xt pr es cribe d d os e s h o uld be ta ke n at t he us ual ti me. 
P alb ociclib c a ps ules s h o uld be s w allo w e d w h ole ( d o n ot c he w, cr us h, or o pe n t he m prior t o 
s w allo win g). N o c a ps ule s h o uld be in geste d if it is br o ke n, cr ac ke d, or ot her wis e n ot intact.  
P atie nts s h o uld a v oid c o ns u m ptio n of gr a pefr uit or gr a pefr uit juic e.  

 
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Dr u g I nter acti o ns  
P alb ociclib is pri marily 
meta b olize d b y C Y P 3 A a n d s ulf otr a nsf er as e ( S U L T) e nz y me 
S U L T 2 A1.  P alb ociclib inter acts wit h C Y P 3 A in hibit ors a n d C Y P 3 A in d uc ers. Av oid 
c o nc urr e nt use of palb ociclib wit h str o n g C Y P 3 A in hibit ors or in d uc ers.  
A dv erse E v e nts  
T he f ollo win g ar e c o m m o n  (≥ 1 0 %)  ad vers e e v e nts oc c urrin g  in at least o ne patie nt w ho 
r ec eive d palb ociclib plus letr oz ole in clinic al trials. 
I nf ectio ns a n d I nf estatio ns: Up per Res pir at or y I nf ectio n 
Blo o d a n d L y m p hatic S yste m Dis or ders:  Ne utr o pe nia, Le u k o pe nia, Ane mia, T hr o m b oc yt o pe nia  
Meta b olis m a n d N utritio n Dis or ders : Decr eas e d Ap petite  
Ner v o us S yste m Dis or ders:   P erip her al Ne ur o pat h y  
Res pir at or y, T h or acic, a n d Me diastinal Dis or ders:  E pista xis  
Gastr ointestinal Dis or ders : St o matitis, Na us ea, Diarr hea, Vo mitin g 
S kin a n d S u bc uta ne o us Ti ss ue Dis or ders : Alo pecia 
Ge ner al Dis or ders a n d Ad ministr atio n Site C o n ditio ns:   F atig ue, Ast he nia  
N ursi n g G ui deli nes  
1.  Age nt s h o uld be a d minister e d wit h f o o d. D o n ot cr us h, br ea k or o pe n c a ps ules prior to 
a d ministr atio n.  
2.  M o nit or C B C w/ diff as c yt o pe nias ar e c o m m o n a n d r e q uir e d os e r e d uctio ns.   I nstr uct 
patie nts t o r e p ort sig ns or s y m pt o ms of inf ectio n a n d/ or a n y u n us ual br uisin g or 
blee din g t o t he st u d y tea m.  
3.  GI s y m pt o ms ar e c o m m o n, inclu din g na us ea/ v o mi tin g, st o matitis a n d diarr hea. Tr eat 
s y m pt o matic ally a n d m o nit or f or eff ective ness. S o me side eff ects ma y r e q uir e d ose 
r e d uctio ns. 
4.  P atie nts s h o uld a v oid gr a pefr uit a n d gr a pefr uit juic e, d ue t o p ossible incr eas e in t he 
s er u m c o nc e ntratio n of palb ociclib.  
5.  T her e ar e dr u g t o dr u g inter a ctio ns wit h C Y P 3 A4 s u bstr ates .  O btain a c o m plete list of 
patie nt me dic atio ns inclu din g O T C a n d her bal pr o d ucts. I nstr uct patie nts t o r e p ort any 
ne w me diatio ns t o t he st u d y tea m i m me diately.  
6.  War n patie nt of ris k of t hr o m b oe m b olic e ve nts, s pecific ally p ul m o nar y e m b olis m.  
7.  War n patie nts of p ossibilit y of alo pecia.  
8.  P atie nts ma y e x perie nc e u p per r es pir at or y inf ectio n. I nstr uct patie nts t o r e p ort U RI 
s y m pt o ms t o st u d y tea m.  
9.  Rar ely patie nts ma y e x perie nc e perip her al ne ur o pat h y. M o nit or patie nts clos ely w ho 
ma y ha ve pr ee xistin g CI P N fr o m pr e vi o us t her a p y.  
1 0. 3  F ul vest r a nt  
Pleas e r ef er t o t he F D A -a p pr o ve d pac ka ge ins ert f or f ulvestr a nt f or pr o d uct inf or matio n, 
e xte nsive pr e par atio n instr uctio ns a n d a c o m pr e he nsive list of a d vers e e ve nts.  
Ot her na mes: F aslo de x  

 
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Classific atio n: Estr o ge n r ec e pt or a nta g o nist 
M olec ular F or m ula: C
3 2 H 4 7 F 5 O 3 S  
 
M. W.: 6 0 6. 7 7  
Ap pr o xi mate S olu bilit y: Eac h injectio n c o ntains as inactive in gr e die nts alc o h ol, U S P, be nz yl 
alc o h ol, N F, a n d be nz yl be nz oate, U S P as c o -s olve nts a n d c ast or oil, U S P as a c o-s olve nt a nd 
r eleas e r ate m o difier. 
T he s olutio n is a clear, c olorless t o yello w, vis c o us liq uid.  
Pr oc ure me nt  
F ulvestr a nt  is a c o m mer cially a vaila ble a ge nt a n d fille d wit h pr es criptio n . 
St or a ge:   
T he s yrin ges of f ulvestr a nt f or all c ycles of tr eat me nt s h o uld be st or e d in t he original c o ntainer 
a n d r efriger ate d at 2° - 8° C ( 3 6° - 4 6° F).  
A d mi n istr ati o n: 
R o utes of Ad ministr atio n: I M I njectio n  
Met h o d of Ad ministr atio n: Re m o ve glass s yrin ge barr el fr o m tr a y a n d c hec k t hat it is n ot 
da ma ge d. P eel o pe n t he s af et y nee dle ( S af et y Glide ™) o uter pac ka gin g. Br ea k t he s eal of t he 
w hite plastic c o ver o n t he s yrin ge luer c o n nect or t o r e m o ve t he c o ver wit h t he attac he d r u b ber 
tip c a p. T wist t o loc k t he nee dle t o t he luer c o n nect or. Re m o ve nee dle s heat h. Re m o ve e xc ess 
air fr o m t he s yrin ge ( a s mall gas b u b ble ma y r e main).  
F or t his st u d y, f ulvestr a nt will be a d minister e d at a d os e of 5 0 0 m g ( 2 X 2 5 0 m g injectio ns) I M 
or as in dic ate d per t he pac ka ge ins ert o n Da y 1 a n d Da y 1 5 of C ycle 1 a n d t he n o n Da y 1 of 
eac h c ycle in eac h s u bs e q ue nt  c ycle. Ad minister intr a m us c ularly slo wly in t he b utt oc k. ( N O T E: 
5 0 0 m g d os e will r e q uir e o ne 2 5 0 m g injectio n in eac h b utt oc k.) I m me diately activate nee dle 
pr otectio n de vic e u p o n wit h dr a w al fr o m patie nt b y p us hin g le ver ar m c o m pletely f or w ar d u ntil 
nee dle  tip is f ully c o ver e d. Vis ually c o nfir m t hat t he le ver ar m has f ully a d va nc e d a n d t he nee dle 
tip is c o ver e d. If u na ble t o activate, dis c ar d i m me diately int o a n a p pr o ve d s har ps c o ntainer. 
T oxicity:  
T he m ost c o m m o n t o xicities r e p orte d in trials of f ulvestr a nt t o date inclu de gastr ointestinal 
s y m pt o ms, me n o pa usal s y m pt o ms a n d injectio n site r eactio ns. Na us ea a n d v o mitin g ha ve bee n 
t he pri mar y GI s y m pt o ms, occ urrin g in a p pr o xi mately 5 0 % of patie nts in p has e III trials. T hey 
w er e ge ner ally of mild t o m o der ate s e verit y. Hot flas hes w er e r e p orte d in a p pr o xi mately 2 0 % 
of patie nts. I njectio n site r eactio ns inclu de pain, he m orr ha ge a n d infla m matio n. S uc h r eactions 
m a y be m or e fr e q ue nt w he n f ulvestr a nt is a d minister e d as 2 injectio ns of 2. 5 ml ( 1 2 5 m g) eac h, 
as c o m par e d wit h 1 injectio n of 5 ml ( 2 5 0 m g).  
P ote ntial Dr u g I nter actio ns: I n i n vitr o  st u dies usin g h u ma n he pat oc ytes, f ulvestr a nt w as 
m eta b olize d pr e d o mina ntly b y c o nju gatio n. T he meta b olites t h us f or me d ar e t h o u g ht t o p ossess 
n o estr o ge nic activit y a n d mini mal a nti-estr o ge nic activit y. I n st u dies usin g h u ma n liver 
micr os o mes, f ulvestr a nt in hibite d t he activit y of C Y P 1 A2, 2 C 9 a n d 3 A4 mini mally. C Y P 3 A4 
did meta b olize f ulvestr a nt in t hes e st u dies, b ut t he h u ma n he pat oc yte st u dies n ote d a b o ve 
in dic ate c o nju gatio n is a m or e i m p orta nt meta b olic pat h w a y. I n a d ditio n, st u dies in healt h y 
v olu nteers in dic ate t hat f ulvestr a nt meta b olis m is n ot sig nific a ntly aff ecte d b y in d uc ers or 
in hibit ors of C Y P 3 A4, n or d oes f ulvestr a nt aff ect t he meta b olis m of 3 A4 s u bstr ates. T hus, 
f ulvestr a nt is n ot e x pecte d t o be in v olve d in sig nific a nt dr u g inter actio ns me diate d b y C Y P 3 A4.  
N ursi n g g ui deli nes  

 
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1  Rar ely a blo o d -tin ge d va ginal dis c har ge has bee n r e p orte d infr e q ue ntly d urin g t her a p y.  
Ad vis e patie nts t hat t his is a p ossibilit y a n d t hat st u dies ha ve s h o w n n o eff ects o n va gina 
or e n d o metriu m.   
2  M o nit or L F T’s bas e d o n pr ot oc ol r e q uir e me nts. Re p ort increas e d L F T’s t o tr eatin g 
p h ysicia n.  
3  Hot pac kin g t he injectio n site f or a s h ort w hile after injectio n ma y pr e ve nt t he p ossible 
br uisin g, te n de r ness, a n d/ or er yt he ma at t he I M injectio n site.  
4  I nstr uct patie nt t o r e p ort a n y sig ns or s y m pt o ms of blo o d clots. P atie nts wit h c alf 
te n der ness or b ur nin g, a n d/ or c hest pain ( p ul m o nar y e m b olus) s h o uld be e valuate d b y a 
p h ysicia n i m me diately.  
5  War n patie nt of p ossible h ot flas hes. Ass ess s e verit y a n d dis c uss n o n -h or m o nal 
tr eat me nts wit h tr eatin g p h ysicia n. Ass ess tr eat me nt f or efficac y.  
6  Ma y c a us e mild GI s y m pt o ms ( na us ea, a n ore xia, v o mitin g, c o nstipatio n). Treat  
s y m pt o matic ally a n d m o nit or f or eff ective ness of inter ve ntio n. 
1 0. 4  L et r oz ole  
Pleas e r ef er t o t he F D A -a p pr o ve d pac ka ge ins ert f or letr oz ole f or pr o d uct inf or matio n, a n d a 
c o m pr e he nsive list of a d vers e e ve nts.  
Ot her na me: F e mar a ®  
Classific atio n : Ar o matas e in hibit or  
M olec ular f or m ula:   C 1 7 H 1 1 N 5  
Pr oc ure me nt   
Letr oz ole is  c o m mer cially a vaila ble a n d fille d wit h pr es criptio n.  
F or m ul ati o n:  
Letr oz ole is s u p plie d as 2. 5 m g, dar k yello w, fil m -c oate d ta blets in b ottles of 3 0 ta blets.  
St or a ge a n d St a bility  
I ntact b ottles of letr oz ole s h o uld be st or e d at 2 5 °C ( 7 7 °F), e xc ursio n s per mitte d t o 1 5 t o 3 0 °C 
( 5 9 t o 8 6°F)  
A d mi nistr ati o n  
Letr oz ole will be ta ke n or ally, at a d os e of 2. 5 m g o nc e daily wit h o ut r e gar d t o meals.  
T oxicities  
T he m ost c o m m o n a d vers e e ve nts r e p orte d inclu de art hr algia, flus hin g, ast he nia, e de ma, 
hea dac he, dizziness, h y per c h olester ole mia, b o ne pain . Of c o nc er n, pri marily wit h lo n g -ter m use 
of ar o matas e in hibit ors inclu din g letr oz ole, ar e eff ects o n lipid meta b oli s m wit h s u bs e q uent 
c ar dio vas c ular e ve nts a n d o n b o ne r es or ptio n. Ot her less fr e q ue nt a d vers e e ve nts inclu de b o ne 
a n d m us cle pain.  
N ursi n g g ui deli nes   
1  Ma na ge h ot flas hes wit h n o n -h or m o nal inter ve ntio ns (ie:  ve nlaf a xine X R 7 5 m g daily).  
2  Ma na ge pain ( art hr algias).  I nstr uct patie nt t o r e p ort u nr elie ve d pain.  
3  Ma y ta ke wit h f o o d if nee de d f or na us ea.  I nstr uct patie nt t o r e p ort u nr elie ve d na us ea or 
v o mitin g.  

 
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4  Ass ess f or c ha n ges in b o w el patter ns.  Ma na ge diarr hea or c o nstipatio n wit h n o n -
pr es criptio n dr u gs.  T ell patie nts t o r e p ort u nr elie ve d diarr hea or c o nstipatio n.  
5  If patie nt e x perie nc es diffic ult y br eat hin g or s u d de n o ns et c hest pain, instr uct t he m t o 
s ee k e mer ge nc y me dic al atte ntio n i m me diately.  
6  M o nit or f or sig ns of e de ma, instr uct patie nt t o r e p ort a n y s wellin g in le gs, f eet, or ha n ds.  
1 1. 0  
M E A S U R E M E N T  O F  E F F E C T  
1 1. 1  P atie nt re port e d o ut c o m e m e as u res  
1 1. 1. 1  Ge ri at ric ass ess me nt  
A c a nc er -s pecific c o m pre he nsive geriatric ass ess me nt will be give n at bas eline, t he first 
r esta gin g (i. e., after 3 c ycles of tr eat me nt a n d prior t o c ycle 4 ), a n d at t he e n d of tr eat me nt 
(s ee Ap pe n dix II f or Geriatric Ass ess me nt S ur ve y). T he c a nc er-s pecific c o m pr e he nsive 
geriatric ass ess me nt inclu des a n e valuatio n of f u nctio nal stat us, c o -m or bidit y, c o g n ition, 
ps yc h olo gic al stat us, s ocial f u nctio nin g a n d s u p p ort, a n d n utritio nal stat us. 3  T his ass ess ment 
has be e n pilote d in t he Allia nc e ( in le gac y Ca nc er a n d Le u ke mia Gr o u p B [C A L G B ]). 
C A L G B 3 6 0 4 0 1 e valuate d t he f easibilit y of inc or p or atin g t he Geriatric Ass ess me nt T o ol 
int o o nc olo g y c o o per ative gro u p trials. 5 2  P atie nts w er e eligible t o participate if t he y w ere 
age ≥ 6 5 a n d ha d sig ne d c o ns e nt f or a c o o per ative gr o u p tr eat me nt trial. T he Geriatric 
Ass ess me nt T o ol w as c o m plete d prior t o initiatio n of t he pr ot oc ol -s pecifie d tr eat me nt. 
Ninet y -t hr ee patie nts e nr olle d in t his st u d y. T he me dia n ti me t o c o m plete t he ass ess ment 
w as 2 2 min utes, 8 8 % of patie nts c o m plete d t he patie nt p ortio n wit h o ut assista nc e, 88 % 
s atisfie d wit h t he ass ess me nt le n gt h, 9 8 % r e p orte d t her e wer e n o u ps ettin g ite ms, a n d 95 % 
s aid t he ass ess me nt w as eas y t o c o m pr e he n d. T he Geriatric Ass ess me nt T o ol met t he 
pr ot oc ol s pecifie d f easibilit y criteria f or inc or p or atio n in o nc olo g y c o o per ative gr o up 
trials.5 2  
S e ver al st u dies ar e e mer gin g r e gar din g t he be nefits of perf or min g a c o m pr e he nsive geriatric 
ass ess me nt f or older patie nts wit h c a nc er. F act ors e valuat e d in a c o m pr e he nsive geriatric 
ass ess me nt c a n pr e dict s ur vival, pr e dict t o xicit y t o c he m ot her a p y, a n d u nc o ver pr o ble ms 
n ot detecte d b y a r o utine hist or y a n d p h ysic al in initial c o ns ultatio n a n d f ollo w -u p c ar e. 53, 
5 4, 5 5  C o ns e ns us g uidelines r ec o g nize t he be nefits a n d r ec o m me n d t he inclusio n of a geriatric 
ass ess me nt as part of t he e valuatio n of a n older patie nt. 5 6  
1 1. 1. 2  O ve r all t re at me nt utilit y  
We will be inclu din g a meas ur e of O ver all Tr eat me nt Utilit y ( O T U) t o ass ess t he “ o bjective 
a n d s u bjective meas u r es of t oler a bilit y a n d ac c e pta bilit y”. T his is ac c o m plis he d wit h a n 
a nalysis of clinic al be nefits in c o nju nctio n wit h a n a nalysis of w het her t o xicit y a n d s erio us 
a d vers e e ve nts aff ect o ne’s daily f u nctio ns. T his pr o vides a wa y t o q ua ntif y a d va nta ges and 
d is a d va nta ges fr o m r ec eivin g tr eat me nt in t his st u d y, as w ell as a n u n dersta n din g of h o w 
patie nts ma y r es p o n d t o tr eat me nt. O T U is us ef ul in a ns w erin g t he f ollo win g h y p ot hetic al 
q uestio n fr o m t he patie nt’s pers pective: “ Wit h t he be nefit of hin dsig ht, ar e y o u gla d y o u 
r ec eive d tr eat me nt?” By inclu din g t he O T U in t his st u d y, r es ear c hers a n d o nc olo gists will 
be a ble t o better u n dersta n d t he patie nt’s pers pectives r e gar din g t he be nefits a n d side effects 
of tr eat me nt, in c o m binatio n wit h a n ass ess me nt of tr eat me nt effic ac y a n d t o xicit y.  
O T U is  a n o vel c o m p osite e n d p oint de velo pe d b y in vestigat ors of t he F O C U S 2 trial t o 
ass ess t he o utc o me of palliative c he m ot her a p y 5 7 . T he inter pr etatio n of clinic al trials, 
es pecially in t he palliative s ettin g, ofte n r e q uir es s u bjective s y nt hesis of o bject data. 
Meas ur es of effic ac y ar e w eig hte d a gainst t he t o xic eff ects, c o n ve nie nc e, a n d ot her varia bles 
bef or e decidin g w hic h tr eat me nt is best. O T U helps inte gr ate t hes e meas ur es int o a sin gle 

 
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c o m p osite e n d p oint. O T U c o m bines clinic al effic ac y ( “Is m y patie nt alive  wit h o ut dis eas e 
pr o gr essio n?”), clinic al t oler a bilit y ( “ Did w e a v oid c a usin g major har m”), a n d patie nt 
o pinio n ( “ Was m y tr eat me nt w ort h w hile a n d ac c e pta ble?”). I n t he original st u d y usin g O T U, 
t he c o m p osite e n d p oint w as f o u n d t o be partic ularly us ef ul w hen c o n ve ntio nal o utc o mes 
w er e diver ge nt ( O xaliplatin i m pr o ve d r es p o ns e r ates a n d pr o gr essio n fr ee s ur vival, yet 
r es ulte d in incr eas e d t o xicit y), a n d helpe d c o nfir m t he be nefit of O xaliplatin 5 7 . 
We will 
meas ur e O T U b y ass essin g clinic al be nefit a n d t oler a bil it y/ac c e pta bilit y at t he e n d of 
tr eat me nt. ( S ee St u d y c ale ndar S ectio n 5. 0  a n d Ap pe n dix I V ). O T U is s c or e d as Go o d O T U  
( clinic al or r a dio gr a p hic e vide nc e or dis eas e pr o gr essio n, n o major negative tr eat me nt 
eff ects in ter ms of t o xicit y or patie nt ac c e pta bilit y), I nt e r m e di at e O T U ( eit her clinic al 
deterior atio n b ut n o ne gative tr eat me nt eff ect, or a sig nific a nt ne gative tr eat me nt eff ect but 
n o clinic al deterior atio n), or P o or O T U  ( b ot h clinic al deterior atio n a n d a major ne gative 
tr eat me nt eff ect, or deat h). 
1 1. 1. 3  W as it wort h it q u esti o n n aire  
T he Was It W ort h It instr u me nt (Ap pe n dix III) w as de velo pe d t o lear n m or e a b o ut t he 
e x perie nc e of patie nts participatin g in clinic al trials.  It is c o m pris e d of f our brief q uestions, 
a n d it has als o bee n c alle d t he “ Trial S atisf actio n” s ur ve y. 5 8  Alt h o u g h f or mal validit y a n d 
r elia bilit y data f or t his instr u me nt ar e n ot yet a vaila ble, m ultiple c o o per ative gr o u p st u dies 
ha ve us e d it t o meas ur e h o w s atisfie d patie nts e n d u p wit h t heir decisio n t o e nr oll o n a 
clinic al trial. 5 9 -6 3  
1 1. 1. 4 .  Q u alit y of lif e  
All participa nts  will be as ke d t o fill o ut a s h ort Q O L s ur ve y a n d o n pa per at eac h pr o vider 
ass ess me nt visit at bas eline t hr o u g h t he start of c ycle 6 ( u nless patie nts c o me off st u dy 
tr eat me nt bef or e t hat ti me). Ap pe n dix V  has t he r e q uir e d E Q -5 D -3 L s ur ve y. )  
1 1. 1. 5  A d h e re n ce e v al u atio n  
Pill diaries will be c ollecte d at t he e n d of eac h c ycle of tr eat me nt t o as certain d os e deliver ed 
a d her e nc e t o palb ociclib  f or a ma xi m u m of t hr ee c ycles fr o m initiatio n of pr ot oc ol 
tr eat me nt. Ad her e nc e t o palb ociclib will be meas ur e d b y patie nt s elf-r e p ort in de dic ate d 
patie nt diaries. ( Ap pe n dix V II). P atie nts will be as ke d t o brin g t heir pill diaries t o e ver y 
clinic visit.   
1 1. 2  Me as u re m e nt of t u m or res po nse a n d s c h e d ule of e v al u ati o ns  
Res p o ns e a n d pr o gr essio n will be e valuate d in t his st u d y usin g t he ne w inter natio nal criteria 
pr o p os e d b y t he r e vis e d Res p o ns e E valuatio n Criteria in S olid T u m ors ( R E CI S T) g uidelines 
( versio n 1. 1).  
P er t he ne w R E CI S T criteria, as dis eas e r es p o ns e is n ot t he pri mar y e n d p oint of t his trial, 
c o nfir mat or y s c a ns f ollo win g d oc u me n tatio n of pr o gr essio n or r es p o ns e will n ot be r e q uir e d. 
Rat her, pr o gr essio n/r es po ns e will be deter mine d bas e d o n r es ults of t he sin gle s c a n.  
C ha n ges in t he lar gest dia meter ( u nidi me nsio nal meas ur e me nt) of t he t u m or lesio ns a n d t he 
s h ort a xis meas ur e me nts in t he c as e of ly m p h n o des ar e us e d in t he R E CI S T g uideline. 6 4  
S c h e d ule of Ev al u ati o ns  
F or t he p ur p os es of t his st u d y, patie nts s h o uld be r ee valuate d f or t u m or r es p o ns e e ver y  1 2  w eeks.   
W hile o n st u d y, a C T of t he c hest, a b d o me n,  wit h or wit h o ut pelvis ( or  P E T -C T as a b o ve) will 
be perf or me d e ver y 1 2 w ee ks ( ± 2  w ee k s). A b o ne s c a n will be d o ne at r esta gin g ti me p oints if 
clinic ally in dic ate d ( or t o  c o nfir m a c o m plete r es p o ns e).  

 
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To xicit y Ev al u ati o n  
T o xicit y e valuatio ns will be perf or me d Da ys 1 ( ± 2 da ys), 8  ( ±2 da ys), a n d 1 5  ( ± 2 da ys) of C ycles 
1 a n d 2. F or s u bse q ue nt c ycles, t o xicit y e valuatio ns will be d o ne o n Da y 1 ( ± 2 da ys). Ad ditio nal 
a d vers e e ve nts c a pt ur e d in -bet w ee n will als o be r ec or de d. ( Pleas e s ee st u d y c ale n dar S ection 
5. 0 ) 
All t o xicit y r elate d d os e interr u ptio ns or r e d uctio ns, h os pitalizatio ns, a n d a d vers e e ve nts will be 
n ote d. P atie nts  will be f ollo w e d f or t o xicit y o utc o mes f or a n a d ditio nal 3 0 da ys after st o p ping 
t he dr u g a n d u ntil r es olutio n of all gr a de > 2 t o xicities. An y t o xicities will be r ec or de d in t he 
patie nt’s me dic al r ec or d a n d hig hest gr a de of t hat t o xicit y will be r e p orte d o n t he c as e r e p ort 
f or ms. 
1 1. 3  Defi niti o ns of Me as ur a ble a n d No n -Me as u r a ble Dise ase  
1 1. 3. 1  Me as u r a ble Dis e ase  
Meas ur a ble lesio ns  ar e define d as t h os e t hat c a n be ac c ur ately meas ur e d in at least o ne 
di me nsio n (lo n gest dia meter t o be r ec or de d) as > 1 0 m m wit h c o n ve ntio nal tec h niq ue s (C T, 
or  c aliper meas ur e me nt). L y m p h n o des gr eater t ha n 1 5 m m o n s h ort a xis ar e c o nsider ed 
meas ur a ble as w ell. All t u m or meas ur e me nts m ust be r ec or de d in milli meters  ( or deci mal 
fr actio ns of c e nti meters).   
T u m or lesio ns in a pr e vio usly irr a diate d ar ea ar e n ot c o nsider e d meas ur a ble dis eas e.   
1 1. 3. 2  No n -Me as u r a ble Dis e ase  
All 
ot her lesio ns ( or sites of dis eas e ), ar e c o nsider e d n o n-meas ur a ble dis eas e.  
Or ga n o me galy, le pt o me nin geal dis eas e, as cites, ple ur al/ peric ar dial eff usio ns, ly m p ha n gitis 
c utis/ p ul m o nis, infla m mat or y br east dis eas e, a n d a b d o minal mass es ( n ot f ollo w e d b y C T 
ar e all n o n -meas ur a ble.  
T ar get lesio ns :  All meas ur a ble lesio ns u p t o a ma xi m u m of 2 lesio ns per or ga n a n d 5 lesio ns 
in t otal, r e pr es e ntative of all in v olve d or ga ns, s h o uld be ide ntifie d as t ar get lesi o ns a nd 
r ec or de d a n d meas ur e d at bas eline. L y m p h n o des less t ha n 1 5 m m in t he s h ort a xis c a n n ot 
be us e d as tar get lesio ns.  T ar get lesio ns s h o uld be s electe d o n t he basis of t heir size (lesions 
wit h t he lo n gest dia meter) a n d t heir s uita bilit y f or ac c ur ate r e peate d meas ur e me nts ( eit her 
b y i ma gin g tec h niq ues or clinic ally).  A s u m of t he lo n gest di a meter ( L D) f or all tar get 
lesio ns will be c alc ulate d a n d r e p orte d as t he bas eline s u m L D.  T he bas eline s u m L D will 
be us e d as r ef er e nc e b y w hic h t o c har acterize t he o bjective t u m or r es p o ns e.  
N o n -tar get lesio ns:  All ot her lesio ns ( or sites of dis eas e) inclu din g a n y meas ur a ble lesio ns 
o ver a n d a b o ve t he 5  tar get lesio ns s h o uld be ide ntifie d as n o n -t ar get lesi o ns a n d s h o uld 
als o be r ec or de d at bas eline.  Meas ur e me nts of t hes e lesio ns ar e n ot r e q uir e d, b ut t he 
pr es e nc e or a bs e nc e of eac h s h o uld be n ote d t hr o u g h o ut f ollo w -u p.  
All ot her lesio ns ( or sites of dis eas e) ar e c o nsider e d n o n -meas ur a ble dis eas e, inclu din g 
pat h olo gic al n o des (t h os e wit h a s h ort a xis ≥ 1. 0 t o < 1. 5 c m).  Bo ne lesio ns, le pt o me nin geal 
dis eas e, as cites, ple ur al/ peric ar dial eff usio ns, ly m p h a n gitis c utis/ p ul m o nis, infla m mat or y 
br east dis eas e, a n d a b d o minal mass es ( n ot f ollo w e d b y C T), ar e c o nsider e d as n o n -
meas ur a ble as w ell.  
N ote: ‘ C ystic lesio ns’ t h o u g ht t o r e pr es e nt c ystic metastas es c a n be c o nsider e d as 
meas ur a ble lesio ns, if t he y meet t h e definitio n of meas ur a bilit y des cribe d a b o ve. Ho w e ver, 
if n o n-c ystic lesio ns ar e pr es e nt in t he s a me patie nt, t hes e ar e pr ef err e d f or s electio n as tar get 
lesio ns.  I n a d ditio n, ly m p h n o des t hat ha ve a s h ort a xis < 1. 0 c m ar e c o nsider e d n o n-
pat h olo gic al (i . e., n or mal) a n d s h o uld n ot be r ec or de d or f ollo w e d. 

 
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1 1. 4  G ui deli n es f or Ev al u ati o n of Me as u r a ble Dis e ase  
1 1. 4 . 1 Me as u re m e nt Met h o ds  
All 
meas ur e me nts s h o uld be r ec or de d in 
metric n otatio n (i. e., deci mal fr actio ns of 
c e nti meters) usin g a r uler or c alipers.  
T he s a me met h o d of ass ess me nt a n d t he s a me tec h niq ue m ust be us e d t o c har acterize eac h 
ide ntifie d a n d r e p orte d lesio n at bas eline a n d d urin g f ollo w-u p. F or patie nts ha vin g o nly 
lesio ns meas urin g at least 1 c m t o less t ha n 2 c m m ust us e C T i ma gin g f or b ot h pr e- a n d 
p ost -tr eat me nt t u m or assess me nts.   
I ma gin g-bas e d e valuatio n is pr ef err e d t o e valuatio n b y clinic al e xa minatio n w he n b ot h 
met h o ds ha ve bee n us e d at t he s a me e valuatio n t o ass ess t he a ntit u m or eff ect of a tr eat ment.  
1 1. 4 . 2 Acce pt a ble Mo d alities f or Me as u r a ble Dis e ase  
• 
C o n ve nti o n al C T:   T his g uideline has define d meas ur a bilit y of lesio ns o n C T s can 
bas e d o n t he ass u m ptio n t hat C T slic e t hic k ness is 5 m m or less. If C T s c a ns ha ve slice 
t hic k ness gr eater t ha n 5 m m, t he mini m u m size f or a meas ur a ble lesio n s h o uld be t wice 
t he slic e t hic k ness. 
• 
P E T -C T:   If t he site’s pr ot oc ol is t o us e a P E T-C T, t he n a P E T -C T wit h or wit h o ut I V 
a n d or al c o ntr ast, c a n be us e d inter c ha n gea bly wit h c o n ve ntio nal C T in ac c ur ately 
meas urin g c a nc er lesio ns o ver ti me .  
• 
P h ysic al Ex a mi n ati o n:   F or s u perficial n o n -n o dal lesio ns, p h ysic al e xa minatio n is 
ac c e pta ble, b ut i ma gin g is pr ef er a ble, if b ot h c a n be d o ne. I n t he c as e of s kin lesio ns, 
d oc u me ntatio n b y c olor p h ot o gra p h y, inclu din g a r uler t o esti mate t he size of t he lesion, 
is r ec o m me n de d. 
• 
F D G -P E T:   F D G -P E T s c a n nin g is allo w e d t o c o m ple me nt C T s c a n nin g in ass ess ment 
of pr o gr essive dis eas e [ P D] a n d partic ularly p ossible ' ne w' dis eas e.  A ‘ p ositive’ F D G -
P E T s c a n ne d lesio n is define d as o ne w hic h is F D G a vid wit h a n u p date gr eater t ha n 
t wic e t hat of t he s urr o u n din g tiss ue o n t he atte n uatio n c orr ecte d i ma ge; ot her wis e, an 
F D G -P E T s c a n ne d lesio n is c o nsider e d ‘ ne gative.’  Ne w lesio ns o n t he basis of F D G -
P E T i ma gin g c a n be ide ntifie d ac c or din g t o t he f ollo win g alg orit h m:  
• 
Ne gative F D G -P E T at bas el ine wit h a p ositive F D G-P E T at f ollo w -u p is a sig n of 
P D bas e d o n a ne w lesio n.  
• 
N o F D G -P E T at bas eline a n d a p ositive F D G -P E T at f ollo w -u p:   
• 
If t he p ositive F D G-P E T at f ollo w -u p c orr es p o n ds t o a ne w site of dis eas e 
c o nfir me d b y C T, t his is P D.   
• 
If t he p ositive F D G-P E T at f ollo w -u p is n ot c o nfir me d as a ne w site of dis eas e on 
C T at t he s a me e valuatio n, a d ditio nal f ollo w -u p C T s c a ns (i. e., a d ditio nal f ollo w -
u p s c a ns at least 4 wee ks later) are nee de d t o deter mine if t her e is tr uly pr o gr ession 
oc c urrin g at t hat site. I n t his sit uatio n, t he date of P D will be t he date of t he initial 
a b n or mal P D G -P E T s c a n.   
• 
If t he p ositive F D G-P E T at f ollo w -u p c orr es p o n ds t o a pr e -e xistin g site of dis ease 
o n C T t hat is n ot pr o gr essin g o n t he basis of t he a nat o mic i ma ges, it is  n ot classifie d 
as P D.  

 
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1 1. 4 . 3 Me as u re m e nt at F oll o w -u p Ev al u ati o n:   
T he c yt olo gic al c o nfir matio n of t he ne o plastic origin of a n y eff usio n t hat a p pears or w orsens 
d urin g tr eat me nt w he n t he meas ur a ble t u m or has met criteria f or r es p o ns e or sta ble dis ease 
is ma n dat or y t o diff er e ntiate bet w ee n r es p o ns e or sta ble dis eas e ( a n eff usio n ma y be a side 
eff ect of t he tr eat me nt) a n d pr o gr essive dis eas e.  
C yt olo gic a n d hist olo gic tec h niq ues c a n be us e d t o diff er e ntiate bet w ee n P R a n d C R in r are 
c as es ( e. g., r esid ual les io ns in t u m or t y pes s uc h as ger m c ell t u m ors, w her e k n o w n r esid ual 
be nig n t u m ors c a n r e main.)  
1 1. 5  Me as u re m e nt of Tre at m e nt/I nter ve nti o n Eff e ct  
1 1. 5 . 1 Tar get Lesi o ns & Tar get L y m p h No des  
Meas ur a ble lesio ns ( as define d in S ect io n 1 1. 3 . 1) u p t o a ma xi m u m of 5 lesio ns in t otal, 
r e pr es e ntative of all in v olve d or ga ns, s h o uld be ide ntifie d as “ T ar get Lesio ns ” a n d r ec or ded 
a n d meas ur e d at bas eline.  T hes e lesio ns c a n be n o n -n o dal or n o dal ( as define d in 1 1. 3 . 1), 
w her e n o m or e t ha n 2 lesio ns ar e fr o m t he s a me or ga n a n d n o m or e t ha n 2 malig na nt n o dal 
lesio ns ar e s electe d.  
Not e : If f e w er t ha n 3  tar get lesio ns a n d tar get ly m p h n o des ar e ide ntifie d ( as t her e oft e n will 
be), t her e is n o r eas o n t o perf or m a d ditio nal s t u dies be y o n d t h os e s pecifie d in t he pr ot oc ol 
t o dis c o ver ne w lesio ns.   
T ar get lesio ns a n d tar get ly m p h n o des s h o uld be s electe d o n t he basis of t heir size, be 
r e pr es e ntative of all in v olve d sites of dis eas e, b ut in a d ditio n s h o uld be t h os e t hat le n d 
t he ms elves t o r e pr o d ucible r e peate d meas ur e me nts.  It ma y be t he c as e t hat, o n oc c asion, 
t he lar gest lesio n ( or malig na nt ly m p h n o de) d oes n ot le n d its elf t o r e pr o d ucible 
meas ur e me nts in w hic h cir c u msta nce t he ne xt lar gest lesio n ( or malig na nt ly m p h n o de) 
w hic h c a n be meas ur e d r e pr o d ucibly s h o uld be s electe d.   
Bas eline S u m of Di me nsio ns ( B S D):  A s u m of t he lo n gest dia meter f or all tar get lesio ns 
plus t he s u m of t he s h ort a xis of all t he tar get ly m p h n o des will be c alc ulate d a n d r e p orted 
as t he bas eline s u m of  di me nsio ns ( B S D).  T he B S D will be us e d as r ef er e nc e t o f urt her 
c har acterize a n y o bjective t u m or r es p o ns e in t he meas ur a ble di me nsio n of t he dis eas e.   
P ost -Bas eline S u m of t he Di me nsio ns ( P B S D):  A s u m of t he lo n gest dia meter f or all tar get 
lesio ns plus t he s u m of t he s h ort a xis of all t he tar get ly m p h n o des will be c alc ulate d a n d 
r e p orte d as t he p ost-bas eline s u m of di me nsio ns ( P B S D).  If t he r a diolo gist is a ble t o pr o vide 
a n act ual meas ur e f or t he tar get lesio n ( or tar get ly m p h n o de), t hat s h o uld be r ec or de d, even 
if it is belo w 0. 5 c m.  If t he tar get lesio n ( or tar get ly m p h n o de) is belie ve d t o be pr es e nt and 
is f aintly s ee n b ut t o o s mall t o meas ur e, a def a ult value of 0. 5 c m s h o uld be assig ne d.  If it 
is t he o pinio n of t he r a diolo gist t hat t he tar get lesio n or tar get ly m p h n o de has likely 
dis a p pear e d, t he meas ur e me nt s h o uld be r ec or de d as 0 c m.  
T he mini m u m s u m of t he di me nsio ns ( M S D) is t he mini m u m of t he B S D a n d t he P B S D.  
1 1. 5 . 2 No n -Tar get Lesi o ns & No n -Tar get L y m p h No des  
N o n -meas ur a ble sites of dis eas e ( S ectio n 1 1. 3 . 2) ar e classifie d as n o n- tar get lesio ns or n o n-
tar get ly m p h n o des a n d s h o uld als o be r ec or de d at baseline.  T hes e lesio ns a n d ly m p h n odes 
s h o uld be f ollo w e d in ac c or d wit h 1 1. 5 . 3. 

 
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1 1. 5 . 3 Res po ns e Crit eri a  
All tar get lesio ns a n d tar get ly m p h n o des f ollo w e d b y C T/ P E T -C T / p h ysic al e xa minatio n 
m ust be 
meas ur e d o n r e -e valuatio n at e valuatio n ti mes s pecifie d in S ectio n 1 1. 2.  
S pecific ally, a c ha n ge in o bjective stat us t o eit her a P R or C R c a n n ot be d o ne wit h o ut r e -
meas urin g tar get lesio ns a n d tar get ly m p h n o des.  
Not e:  N o n -tar get lesio ns a n d n o n-tar get ly m p h n o des s h o uld be e valuate d at eac h 
ass ess me nt, es pecially in t he c as e of first r es p o nse or c onfir matio n of res p o nse.  I n selected 
cir c u msta nces, c ertain n o n -tar get or ga ns ma y be e valuate d less fr e q ue ntly.  F or e xa m ple, 
b o ne s c a ns ma y nee d t o be r e peate d o nly w he n c o m plete r es p o ns e is ide ntifie d in tar get 
dis eas e or w he n pr o gr essio n in b o ne is s us pecte d.  
Ev al u ati o n of Tar get Lesi o ns  
• 
C o m plete Res p o ns e ( C R): All of t he f ollo win g m ust be tr ue:  
▪ 
Dis a p pear a nc e of all tar get lesio ns.  
▪ 
Eac h tar get ly m p h n o de m ust ha ve r e d uctio n in s h ort a xis t o < 1. 0 c m.  
• 
P artial Res p o ns e ( P R): At least a 3 0 % decr eas e in P B S D (s u m of t he lo n gest dia meter 
f or all tar get lesio ns plus t he s u m of t he s h ort a xis of all t he tar get ly m p h n o des at c urr ent 
e valuatio n) ta kin g as r ef er e nc e t he B S D (s ee S ectio n 1 1. 5 . 1). 
• 
Pr o gr essio n ( P D): At least o ne of t he f ollo win g m ust be tr ue:  
▪ 
At least o ne ne w malig na nt lesio n, w hic h als o inclu des a n y ly m p h n o de t hat was 
n or mal at bas eline ( < 1. 0 c m s h ort a xis) a n d incr eas e d t o ≥ 1. 0 c m s h ort a xis d urin g 
f ollo w-u p.  
▪ 
At least a 2 0 % incr eas e  in P B S D (s u m of t he lo n gest dia meter f or all tar get lesio ns 
plus t he s u m of t he s h ort a xis of all t he tar get ly m p h n o des at c urr e nt e valuatio n) 
ta kin g as r ef er e nc e t he M S D (S ectio n 1 1. 5 . 1). I n a d ditio n, t he P B S D m ust als o 
de m o ns tr ate a n a bs olute incr eas e of at least 0. 5 c m fr o m t he M S D.  
▪ 
S ee S ectio n 1 1. 4 . 2 f or details in r e gar ds t o t he r e q uir e me nts f or P D via F D G-P E T 
i ma gin g. 
• 
Sta ble Dis eas e ( S D): Neit her s ufficie nt s hrin ka ge t o q ualif y f or P R, n or s ufficie nt 
incr eas e t o q ualif y f or P D ta kin g as r ef er e nc e t he M S D. 
Ev al u ati o n of No n -Tar get Lesi o ns & No n -t ar get L y m p h No des 
• 
C o m plete Res p o ns e ( C R): All of t he f ollo win g m ust be tr ue:  
▪ 
Dis a p pear a nc e of all n o n -tar get lesio ns.  
▪ 
Eac h n o n -tar get ly m p h n o de must ha ve a r e d uctio n in s h ort a xis t o < 1. 0 c m.  
• 
N o n -C R/ N o n -P D: P ersiste nc e of o ne or m or e n o n -tar get lesio ns or n o n-tar get ly m p h 
n o des  
• 
Pr o gr essio n ( P D): At least o ne of t he f ollo win g m ust be tr ue:  
▪ 
At least o ne ne w malig na nt lesio n, w hic h als o inclu des a n y ly m p h n o de t hat was 
n or mal at bas eline ( < 1. 0 c m s h ort a xis) a n d incr eas e d t o ≥ 1. 0 c m s h ort a xis d urin g 
f ollo w-u p.   
▪ 
Une q uiv oc al pr o gr essio n of e xistin g n o n -tar get lesio ns a n d n o n-tar get ly m p h 
n o d es.  ( N O T E:  Une q uiv oc al pr o gr essio n s h o uld n ot n or mally tr u m p tar get lesion 

 
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1 2. 2 . 3 Ot h e r re as o ns f or dis c o nti n uati o n of pr ot oc ol t h er a py  
P atie nts w h o dis c o ntin ue tr eat me nt f or a n y ot her r eas o n t ha n pr o gr essio n or u nac c e pta ble 
t o xicit y s h o uld c o ntin ue t o be f ollo w e d f or pr o gr essio n. F ollo win g pr o gr essio n, patie nts will 
be f ollo w e d e ver y year f or s ur vival. T he r eas o n f or dis c o ntin uatio n of pr ot oc ol tr eat me nt 
m ust be d oc u me nte d o n t he “ Off tr eat me nt” f or m. 
1 2. 2. 4  Dis c o nti n u ati o n of Ge ri at ric Ass ess me nt a n d S pe ci m e n S u b missi o n  
Ge ri at ric Ass ess me nt: P atie nts will c o m plete t he geriatric ass ess me nt at t he e n d of 
tr eat me nt.  If e n d of tr eat me nt oc c urs prior t o t he e n d of C ycle 3, t he e n d of c ycle 3 
ass ess me nt nee d n ot be s u b mitte d.   ( T hat is, patie nts w h o dis c o ntin ue pr ot oc ol tr eat me nt 
prior t o t he e n d of c ycle 3 will ha ve c o m plete d a geriatric ass ess me nt at bas eline a n d at t he 
e n d of tr eat me nt.) 
S pe ci m e n S u b missi o n:  P atie nts w h o dis c o ntin ue pr ot oc ol tr eat me nt prior t o t he e n d of 
C ycle 3  m ust still be as ke d t o s u b mit a n e n d of tr eat me nt blo o d s a m ple r at her t ha n t he prior 
t o C ycle 4 blo o d s a m ple liste d in S e ctio n 6. 2 .  
1 2. 3  Ma n a gi n g i n eli gi ble patie nts a n d re giste re d patie nts w h o n e ver re cei ve pr ot oc ol 
i nt e r ve nti o n  
Defi niti o n of i n eligi ble patie nt  
A st u d y participa nt w h o is r e gister e d t o t he trial b ut d oes n ot meet all of t he eligibilit y criteria 
is dee me d to be ineligible.  
F oll o w -u p f or i n eli gi ble patie nts w h o c o nti n ue wit h pr ot oc ol t re at me nt  
P atie nts w h o ar e dee me d ineligible after r e gisterin g ma y c o ntin ue pr ot oc ol tr eat me nt, pr o vided 
t he tr eatin g p h ysicia n, st u d y c hair, a n d e xec utive offic er a gr ee t her e ar e n o s af et y c o nc er ns if 
t he patie nt c o ntin ues pr ot oc ol tr eat me nt. All s c a ns, tests, a n d data s u b missio n ar e t o c o ntinue as 
if t he patie nt w er e eligible. N otific atio n of t he loc al I R B ma y be nec ess ar y per loc al I R B 
p olicies.  
F oll o w -u p f or i n eli gi ble  patie nts w h o dis c o nti n u e pr ot oc ol t re at m e nt  
F or patie nts w h o ar e dee me d ineligible after r e gisterin g t o t he trial, w h o start tr eat me nt, b ut then 
dis c o ntin ue st u d y tr eat me nt, t he s a me data s u b missio n r e q uir e me nts ar e t o be f ollo w e d as f or 
t h os e patie nts w h o ar e eligible a n d w h o dis c o ntin ue st u d y tr eat me nt.  
F oll o w -u p f or patie nts w h o are re gistere d, b ut w h o n e ver st art st u dy t re at m e nt  
F or all st u d y participa nts w h o ar e re gister e d t o the trial b ut w h o ne ver r eceive st u d y inter ve ntion 
(r e gar dless of eligibilit y), t he f ollo w -u p r e q uir e me nts ar e s pecifie d belo w.  
Bas eline a n d off -tr eat me nt n otic e data s u b missio n r e q uir e d. S ee t he Data S u b missio n S c he d ule 
ac c o m pa n yin g t he All F or ms P ac ket.  
1 2. 4  Ext r a or di n ar y Me dic al Circ u mst a n ces  
If, at a n y ti me t he c o nstr aints of t his pr ot oc ol ar e detri me ntal t o t he patie nt's healt h a n d/ or t he 
patie nt n o lo n ger wis hes t o c o ntin ue pr ot oc ol t her a p y, pr ot oc ol t her a p y s hall be dis c o ntin ued. I n 
t his e ve nt: 
• 
D oc u me nt t he r eas o n(s) f or dis c o ntin uatio n of t her a p y o n data f or ms . 
• 
F ollo w t he patie nt f or pr ot oc ol e n d p oints as r e q uir e d b y t he St u d y Cale n dar.  

 
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1 3. 0  
S T A TI S TI C A L  C O N S I D E R A TI O N S  
1 3. 1  Pri m ar y E n d poi nts : 
T he pri mar y e n d p oint is t he a d vers e e ve nt  r ate at 6 m o nt hs, define d as the pr o p ortio n of patients 
wit h d oc u me ntat io n of gr a de 3 - 5 t o xicit y (r e gar dless of attrib utio n usin g t h e N CI  C T C A E v. 5 . 0 
criteria).    
1 3. 2  Pri m ar y E n d poi nt A n al ysis : 
A 9 5 % bin o mial c o nfide nc e inter val f or sin gle pr o p ortio ns will be c o nstr ucte d f or t he s e vere 
t o xicit y r ate oc c urrin g t he first 6 m o nt hs of  tr eat me nt. Univariate r elatio ns hips bet w ee n t he 
pri mar y e n d p oint a n d vario us pr e -tr eat me nt patie nt c har acteristics s uc h as a ne mia, s elf-assessed 
f u nctio nal stat us, or s ocial s u p p ort will be des cribe d via cr oss -ta b ulatio n a n d Fis her’s e xact 
t esting.  E x plor at or y lo gistic r e gr essio n m o delin g, wit h li mite d ge ner aliza bilit y d ue t o t he 
m o dest s a m ple size, will be us e d t o ass ess t he r elative c o ntrib utio ns of t hes e varia bles i m pact 
t he likelih o o d of de velo pin g a s e ver e t o xicit y d urin g tr eat me nt. T he str en gt h of t his ass ociation 
will be e x pr ess e d in ter ms of a n o d ds r atio a n d its ass ociate d 9 5 % c o nfide nc e inter val.  As a 
s ec o n dar y a nalysis f or t his e n d p oint, w e will als o lo o k at gr a de 3 -5 t o xicities  oc c urrin g wit hin 
t he first 6 m o nt hs of tr eat me nt t hat ar e at least p ossibly r elate d t o palb ociclib. T his a nalysis will 
be c o n d ucte d in a si milar f as hio n as t he pri mar y e n d p oint.  T o e x plor e t he r elatio ns hip bet w een 
t he s e ver e t o xicit y r ate oc c urrin g wit hin t he first 6 m o nt hs of tr eat me nt  in t his p o p ulatio n a n d 
t he t y pe of e n d ocrine t her a p y us e d (letr oz ole vs. f ulvestr a nt), w e will c o n d uct a c hi-s q uar e test 
or Fis her’s e xact test as a p pr o priate.  
1 3. 3  S e c o n dar y E n d poi nts : 
• 
All t o xicities ass ociate d wit h t he c o m binatio ns as meas ur e d b y N CI  C T C A E v. 5 . 0 
• 
D os e r e d uctio ns,  d os e h olds, a n d h os pitalizatio ns  
• 
Ti me t o tr eat me nt f ailur e ( a n d r eas o n f or c o min g off st u d y –  t o xicit y, patie nt 
pr ef er e nc e, pr o gr essio n)  
• 
T he per c e nta ge of d os es of palb ociclib ta ke n eac h c ycle f or t he first 3 c ycles  
• 
Res ults of t he geriatric ass ess me nt, Wa s It W ort h It ( WI WI) Q uestio n nair e, a n d 
O ver all Tr eat me nt Utilit y ( O T U)  
1 3. 4  S e c o n dar y E n d poi nt A n al ys es  
1 3. 4. 1  P al bocicli b Tole r a bilit y  
C o nclusio ns c o nc er nin g t he t oler a bilit y of t his r e gi me n in elderly patie nts will ta ke int o 
ac c o u nt t he per c e nta ge of patie nts w h o de velo p gr a de 2 a n d hig her t o xicities inclu din g 
f e brile ne utr o pe nia, le u k o pe nia, t hr o m b oc yt o pe nia, a n d a ne mia, GI side eff ects  ( na us ea, 
diarr hea, 
decr eas e d 
a p petite, 
v o mitin g, 
st o matitis), 
f atig ue, 
ne ur o pat h y, 
a n d 
t hr o m b oe m b olis m , t he per c e nta ge of patie nts w h o r e q uir e d os e m o dific atio ns a n d t he 
per c e nta ge of patie nts w h o r ef us e t o c o ntin ue o n st u d y tr eat me nt f or a n y r eas o n. 
1 3. 4. 2  Re as o ns f or D os e Re d u cti o n, D os e Hol ds, a n d Hos pit aliz ati o ns  
S u m maries of r eas o ns f or d os e r e d uctio ns, d ose h olds, a n d h os pitalizatio ns will be pr e par e d.  
An y d os e r e d uctio n will be c o nsider e d a n d r eas o n f or d os e r e d uctio n will be n ote d. Sinc e 
palb ociclib is give n in c o m binatio n wit h e n d ocrine t her a p y as per sta n dar d of c ar e, w e are 
e valuatin g clinic al e n d p oints bas e d o n t oler a bilit y of t he c o m binatio n. I n t he c as e r e p ort 
f or ms, w e will c a pt ur e w het her t he t o xicit y is d ue t o t he e n d ocrine t her a p y or t he palb ociclib.  

 
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1 3. 4. 3  Ti m e t o Tre at m e nt F ail u re  
Distrib utio ns ti me t o tr eat me nt f ailur e will be esti mate d usin g Ka pla n -Meier met h o d olo g y.  
Tr eat me nt f ailur e is define d as a s e ver e a d vers e e ve nt, dis eas e pr o gr essio n or patie nt r ef usal 
t o c o ntin ue assig ne d tr eat me nt. We w o uld inclu de a n y r eas o n t hat tr eat me nt is dis c ontin ued 
t o ti me t o tr eat me nt f ailur e a n d n ot c e ns or patie nts. T he r eas o n f or tr eat me nt dis c o ntin uation 
will be c a pt ur e d.  
1 3. 4. 4  A d h e re n ce t o P al bocicli b  
P atie nts t o be inclu de d in t he a nalysis c o h ort will be t h os e patie nts w h o ha ve ta ke n o ne or 
m or e d os es of t he st u d y tr eat me nt . T h os e patie nts will be c o nsider e d a d her e nt  t o st u dy 
tr eat me nt. F or eac h of t he first 3 c ycles, a n esti mate of t he pr o p ortio n of patie nts w h o mee t 
t he criteria f or a d her e nc e a n d its c orr es p o n din g 9 5 % c o nfide nce inter val will be deter mine d. 
1 3. 4. 5  Res po ns e R at e as Det er mi n e d by R E CI S T  
T he r es p o ns e r ate is define d as t he pr o p ortio n of patie nts w h os e dis ease stat us met R E CI S T 
criteria f or c o m plete r es p o ns e ( C R) or partial r es p o ns e ( P R) o n 2 c o nsec utive e valuatio ns at 
least 8 w ee ks a part. A 9 5 % bin o mial c o nfide nc e inter val f or t he r es p o ns e r ate will be 
c o nstr ucte d.  
1 3. 4. 6  Pr o gressi o n Fre e S ur vi v al ( P F S) a n d O ve r all S u r vi v al ( O S)  
Distrib utio ns of P F S a n d  O S ti mes will be esti mate d usin g Ka pla n -Meier met h o d olo g y.  
Pr o gr essio n fr ee s ur vival is define d as f ollo w s: “t he ti me fr o m start of tr eat me nt t o t he first 
of  t he f ollo win g dis eas e e ve nts: loc al/r e gio nal/ dista nt r ec urr e nc e, in vasive c o ntr alater al 
br east dis eas e, s ec o n d pri mar y or deat h d ue t o a n y c a us e”. 
1 3. 4. 7  Ge ri at ric Ass ess m e nt, WI WI Q u esti o n n aire, a n d O T U  
Des criptive statistics will be pr o vide d f or r es p o ns es fr o m t he WI WI Q uestio n nair e a n d t he 
O T U.  Ge ner al linear m o dels a n d gr a p hic al met h o ds will be u s e d t o e x plor e f act ors as 
ide ntifie d b y a c a nc er-s pecific geriatric ass ess me nt t hat ma y be pr e dictive of t o xicit y/ d ose 
r e d uctio n, d os e h olds, or h os pitalizatio ns. Re peate d meas ur es m o dels a n d gr a p hic al met h o ds 
will als o be utilize d in a n e x plor at or y f as hio n t o ass ess t he i m pact of t he le n gt h of tr eat ment 
o n t he r es ults of t he geriatric ass ess me nt.  
1 3. 4. 8  S arc o pe ni a a n al ysis  
Ab d o minal or t h or acic C T i ma ges perf or me d as part of r o utine c ar e f or sta gin g a n d dis ease 
m o nit orin g d urin g t he trial, ( w hic h is e ver y 1 2 w ee ks -See St u d y cale n dar S ectio n 5. 0)   will 
be ac q uir e d fr o m st u d y sites. Usin g t he tr a ns vers e s ectio n at t he L 3 le vel f or a b d o minal 
i ma gin g ( as m ost hig hly c orr elate d wit h t otal b o d y m us cle mass [r 2 = 0. 8 6]6 5) or at L 1 le vel 
f or t h or acic i ma gin g ( as most hig hly c orr elate d wit h L 3), 66 s keletal m us cle ar ea ( S M A) will 
be q ua ntifie d wit hin a Ho u nsfield u nit ( H U) r a n ge of -2 9 t o + 1 5 0 H U usin g Slic e -O -Matic 
s oft w ar e ( v. 4. 3; T o m ovisio n, M o ntr eal, Q ue bec, Ca na da). A S keletal M us cle I n de x ( S MI) 
will t he n be c alc ulate d usin g t he f ollo win g f or m ula: S MI = S M A ( c m 2) / patie nt heig ht 
( m 2). Esti mate d L B M will als o be c alc ulate d usin g t he f ollo win g f or m ula: [ L B M ( k g) = 
0. 3 0 × [ S M A ( c m 2)] + 6. 0 6]. 1 5 Mea n s keletal m us cle de nsit y ( S M D) will be derive d b y 
a ver a gin g H U of s k eletal m us cle. S keletal m us cle ga u ge ( S M G) will t he n be c alc ulate d b y 
m ultiplyin g S MI x S M D. S u bc uta ne o us a dip os e tiss ue ( S A T) ar ea will als o be c alc ulate d 
fr o m e xtr a-m us c ular tiss ue wit h de nsit y bet w ee n −1 9 0 a n d -3 0 H U, a n d vis c er al a dip os e 
tiss ue ( V A T) fr o m n o n-s u bc uta ne o us tiss ue wit h de nsit y bet w ee n -1 5 0 a n d -5 0 H U. T he 
pri mar y meas ur e of s keletal m us cle mass will be S MI, a n d ot her meas ur es will be ass essed 
s ec o n darily. 

 
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Des criptive statistics will be pr o vide d f or b o d y c o m p ositio n varia bles inclu din g S MI , S M D, 
S M G, a n d L B M. S ar c o pe nia will be tr eate d as a binar y varia ble ( bas e d o n c ut -p oints of S MI 
fr o m prior liter at ur e ; S MI < 4 1c m 2/ m 2 = s ar c o pe nic 7 0 ) a n d diff er e nc es in gr a des  6 7 -69  
c he m ot her a p y t o xicit y a n d a d vers e e ve nts will be a nalyze d usin g t w o gr o u p t -tests a n d 
Fis her’s e xact test. De pe n din g o n t he n u m ber of a b d o minal vers us t h or acic s c a ns t hat are 
utilize d, a nalys es ma y be str atifie d b y loc atio n of S M A meas ur e me nt ( L 3 vers us L 1). 
Relative ris ks ( R R) a n d 9 5 % C o nfide nc e I nter val ( CI) will be r e p orte d f or ass ociatio ns 
bet w ee n s ar c o pe nia a n d gr a de 3 -5 t o xicit y a n d h os pitalizatio n, a n d s ec o n darily f or S M D 
a n d S M G ( bas e d o n liter at ur e bas e d c ut -p oints). 7 0, 7 1 Bot h u na djuste d a n d a djus te d R R will 
be c alc ulate d usin g P oiss o n r e gr essio n m o dels wit h r o b ust varia nc e. 7 2  C o variates in t he 
m o del inclu de a ge, a n d r ac e/et h nicit y. Rec eiver o per atin g c har acteristic ( R O C) c ur ves will 
be ge ner ate d, as w ell as t he ar ea u n der t he c ur ve ( A U C), t o e valu ate t he pr e dictive a bilit y 
of eac h b o d y c o m p ositio n meas ur e wit h gr a des 3 -5 t o xicit y. De pe n din g o n t he a vaila bilit y 
of s u bs e q ue nt f ollo w u p i ma gin g after 3 tr eat me nt c ycles, we will des cribe c ha n ges in b ody 
c o m p ositio n fr o m bas eline t o start of c ycle 4. We  will e xa mine varia bles ass ociate d wit h 
s keletal m us cle loss d urin g tr eat me nt a n d w het her s keletal m us cle loss d urin g tr eat me nt is 
ass ociate d wit h t he pr es e nc e of gr a de 3 -5 t o xicit y a n d a d vers e e ve nts.  
1 3. 4. 9  E u r o Q ol 5 D 3 L q u esti o n n aire:  
T he E Q -5 D -3 L will be s c or e d a n d t he r es ults will be e valuate d des criptively a n d gr a p hic ally.  
1 3. 4. 1 0  P R O -C T C A E:  
We will e valuate f easibilit y of P R O -C T C A E r e p ortin g in t his p o p ulatio n b y lo o kin g at t he 
c o m plia nc e r ates of t he P R O -C T C A E. T he P R O -C T C A E will be c o nsider e d f easible if 7 5 % 
of t he patie nts c o m plete d 7 5 % of t he P R O -C T C A E q uestio n nair es. We will als o c o m pare 
s y m pt o ms r e p orte d b y patie nts o n t heir P R O-C T A E in p uts c o m par e d t o w hat is r e p orte d in 
clinic usin g tr a ditio nal 
A E e valuatio ns. P R O -C T C A E r es ults  will be s u m marize d a n d 
pr es e nte d des criptively.  
1 3. 5  S a m ple Size  
T he s a m ple size w as deter mine d bas e d o n T ur ner et al .’s fin din g t hat t he s e ver e t o xicit y r ate in 
patie nts a ge 2 9 –  8 8 ( a p pr o xi mately 2 5 % a ge ≥ 7 0 ) w as 7 0 %.2   T he s a m ple size is 8 8  patie nts 
w hic h will ta ke int o ac c o u nt p ote ntial dr o p o ut w hic h will allo w f or 8 0  e valua ble patie nts. Give n 
a s a m ple of 8 0  patie nts, t he widest half -widt h of t he 9 5 % c o nfide nce li mits f or t he r ate of se vere 
t o xicities will be less t ha n or e q ual t o 0. 1. Ass u min g a r ate of s e ver e t o xicities of 7 0 %, o ur 95 % 
c o nfide nc e inter val will r a n ge fr o m 0. 6  t o 0. 8. 
Ad ditio nally, t o e ns ur e w e ha ve s ufficie nt patie nts w h o ar e a ge d 7 5 + t o esti mate t he s e ve re 
t o xicit y r ate a n d s af et y of palb ociclib, w e will ac cr ue patie nts u ntil w e ha ve 4 0  patie nts w h o are 
7 5 or older. Give n a s a m ple of 4 0  patie nts, t he widest half -widt h of t he 9 5 % c o nfide nc e li mits 
f or t he r ate of s e ver e t o xicities will be less t ha n or e q ual t o 0. 1 4 2 . Ass u min g a r ate of s e vere 
t o xicities of 7 0 %, o ur 9 5 % c o nfide nce inter val will r a n ge fr o m 0. 55 8  t o 0. 84 2 . 
1 3. 6  I nt e ri m a n al ysis a n d st o p pi n g r ules:  
After  a p pr o xi mately  2 0  patie nts  ha ve  c o m plete d  o ne  f ull c ycle,  t he st u d y tea m will  r e vie w t he 
data  (inclu din g t he t o xicit y  pr ofile,  r ates of  d os e  r e d uctio n, h olds  a n d h os pitalizatio ns)  a n d 
ass ess  if t he d os e  bein g  st u die d is t o o hig h,  t hat is if m or e  t ha n 5 0 %  of  patie nts  e x perie nc e a 
d os e  r e d uctio n. If s o, a r e d uctio n of  t he d os e  will  be  c o nsider e d,  ot her wis e  t he st u d y wi ll 
c o ntin ue t o c o m pletio n  at  t he pla n ne d  d os e.   

 
Allia nc e A1 7 1 6 0 1  
 
6 1  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
P er  c orr es p o n de nce  wit h  N CI,  w e  inclu de a s e par ate st o p pin g r ule f or patie nts  wit h  a 
perf or ma nc e  stat us of  3  or  4  t o m o dif y  eligibilit y  criteria if t her e is e vide nc e t hat patie nts  wit h  
P S  3  or  4  d o  n ot  s ee m to  t oler ate t he r e gi me n. If, in t he r e vie w des cribe d  a b o ve of  t he first 2 0  
patie nts,  m or e  t ha n 5 0 %  of  t he patie nts  wit h  perf or ma nc e  stat us 3  or  4  e x perie nc e a n a d verse 
e ve nt,  w e  will  c o nsider  c ha n gin g  t he eligibilit y  r e q uir e me nts t o pr eclu de  patie nts  wit h  P S  3or  4  
fr o m participatin g  in t he st u d y. 
Wit h  Up date  2  t o t he st u d y, w e  ha ve  r e vis e d eligibilit y  criteria t o r estrict st u d y participatio n  to 
patie nts  wit h  E C O G  perf or ma nc e  stat us 0 -2.   ( S ee S ectio n  3. 2. 1 1 )  
1 3. 7  St u dy  Re porti n g  
T his st u d y will be m o nit or e d b y t he st u d y tea m (inclu din g t he St u d y C hair, C o m mittee C hair, 
st u d y statisticia ns, pr ot oc ol c o or dinat or, a n d Allia nc e E xec utive Offic er) o n a m o nt hly basis, to 
ass ess s e ver e a d vers e e ve nts.  Re p orts c o ntainin g a s u m m ar y of a d vers e e ve nts will be r e vie w ed 
o n t hes e c alls. T he st u d y tea m will als o m o nit or t he ac cr ual r ate . 
 
 

 
Allia nc e A1 7 1 6 0 1  
 
6 3  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
1 4. 0  
E X P L O R A T O R Y C O R R E L A TI V E  A N D  C O M P A NI O N  S T U DI ES   
T her e will b e 3  s u b st u dies a n d all patie nts ar e e nc o ur a ge d t o participate.  
1 4. 1  C orrel ati ve S cie n c e:  Circ ul ati n g m ar k ers of i nfl a m m ati o n as pot e nti al m ar k ers 
pre dicti ve of t o xicit y a m o n g el de rl y patie nts e n r olle d t o Alli a n ce A 1 7 1 6 0 1 ( Alli a nce 
A 1 7 1 6 0 1 -S T1 )  
Allia nc e A1 7 1 6 0 1 -S T 1 will e valuate  cir c ulatin g mar kers of infla m matio n as p ote ntial m ar kers 
pr e dictive of t o xicit y a m o n g older patie nts wit h Estr o ge n  r ec e pt or p ositive, H E R 2 ne gative 
m etastatic br east c a nc er.  
1 4. 1 . 1 B ac k gr o u n d  
T her e is gr eat heter o ge neit y in t he a bilit y of older a d ults t o t oler ate c a nc er tr eat me nt.  So me 
older patie nts t oler ate tr eat me n t w ell a n d derive as m uc h be nefit fr o m tr eat me nt as y o u nger 
patie nts, w hile ot hers ha ve incr eas e d r ates of t o xicit y r es ultin g in tr eat me nt r e d uctions 
a n d/ or c ess atio n of tr eat me nt. T he best -st u die d t o ols t o pr e dict t o xicit y ar e c o m pr e he nsive 
geriatric ass e ss me nts, w hic h r e q uir e ti me a n d r es o ur c es t hat li mit t heir us e in r o utine 
o nc olo g y pr actic e.  A meas ur e of cir c ulatin g bio mar kers t o pr e dict t o xicit y w o uld be a n 
e xtr e mely valua ble  t o ol t o c o m ple me nt t he c a nc er -s pecific geriatric assess me nt t o g uide the 
clinicia n in ma kin g tr eat me nt decisio ns a n d a v oid e xc essive t o xicit y in t his p o p ulatio n.  T his 
pr o p os al ai ms t o e valuate cir c ulatin g mar kers of infla m matio n as p ote ntial 
m ar kers 
pr e dictive of t o xicit y a m o n g older  w o me n wit h metastatic br east c a nc er .  T his class of 
mar kers w as c h os e n bas e d o n t heir c orr elatio n wit h p h ysic al f u nctio n, f u nctio nal decline, 
a n d m ortalit y in t he ge ner al geriatric p o p ulatio n , as w ell as e mer gin g e vide nc e of t heir 
s ecr etio n b y s e nes c e nt c ells ass ociate d wit h t he a gin g pr oc ess.  I n a d ditio n t o t o xicit y, t his 
st u d y will als o ass ess f or a c orr elatio n bet w ee n bas eline mar kers of c hr o nic infla m matio n 
a n d ot her i m p orta nt o utc o mes s uc h as f u nctio nal decline, a n d tr eat me nt m o dific atio n. 
Le vels of cir c ulatin g pr o -infla m mat or y me diat ors s uc h as I L -6 a n d T N F -alp ha, D -di mer, 
a n d plas min o ge n activat or in hibit or ( P AI) -1, incr eas e wit h a ge. 7 3 -7 5  T hes e mar kers ar e 
pr o p os e d t o ac c eler ate t he a gin g pr oc ess a n d e xac er bate m ultiple a ge -r elate d dis eas es.76-78  
T her e is a c o -sti m ulat or y aff ect bet w ee n mar kers of infla m matio n a n d pr o -t hr o m b otic 
f act ors. C yt o kines s uc h as T N F-α a n d I L -6 sti m ulate pr o d uctio n of pr o -t hr o m b otic f actors 
s uc h as P AI-1 a n d fibrin o ge n. 7 9  I n t ur n, D-di mer, a mar ker of t he clottin g pr ocess, has been 
s h o w n t o in d uc e s y nthesis a n d r eleas e of c yt o kines I L -1 B, I L -6, a n d P AI -1. 8 0  Like wis e, 
w he n vas c ular c ell a d hesio n m olec ule ( V C A M) is e x p os e d t o infla m mat or y mar kers T N F -
α a n d I L -1 B, it is clea ve d t o s olu ble (s) -V C A M, w hic h is ele vate d in patie nts wit h a ge -
r elate d dis eas es.8 1  T h us, w e r ef er t o mar kers of infla m matio n a n d c oa g ulatio n dis c uss e d in 
t his pr o p os al c ollectively as ‘infla m mat or y me diat ors’. 
S e ver al st u dies ha ve s h o w n t hat infla m mat or y me diat ors c orr elate wit h meas ur es of p h ysical 
f u nctio n, a n d ar e ele vate d t o a gr eater de gr ee in fr ail patie nts t ha n in a ge -matc he d, n o n -fr ail 
c o ntr ols. 1 0-1 6 A st u d y of 1 1 0 patie nts > 7 5 years de m o nstr ate d t hat a c o m binatio n of 
infla m mat or y mar kers ( T N F-α, I L -6, C R P) a n d lo w alb u min c orr elate d wit h lo w er p h ysical 
f u nctio n s c or es, in de pe n de nt of a ge, s e x, b o d y mass in de x ( B MI), s m o kin g stat us, n u m ber 
of c o -m or biditie s a n d n u m ber of me dic atio ns 8 2   
I n t he ge ner al geriatric p o p ulatio n, ele vate d c hr o nic infla m mat or y a n d pr o -c oa g ula nt 
mar kers pr e dict f u nctio nal decline.
8 3 -9 0  An a nalysis of dis a ble d w o me n ≥ 6 5 years s h o wed 
hig her I L -6 le vels at bas eline w er e ass ociate d wit h  hig her le vels of f u nctio nal decline 
inclu din g decr eas e d m o bilit y, activities of daily livin g deficits, incr eas e d w alkin g 
li mitatio ns a n d decr eas e d w alkin g s pee d, c o m pare d t o w o me n wit h lo w I L-6 le vels. 8 7  T hese 

 
Allia nc e A1 7 1 6 0 1  
 
6 4  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
mar kers als o c orr elate wit h f u nctio nal decline after h os pitalizatio n a n d p ost o per ative 
c o m plic atio ns fr o m o nc olo gic s ur ger y. 85, 91  
Mar kers of c hr o nic infla m matio n a n d c oa g ulatio n ar e als o ass ociate d wit h all -c a us e 
m ortalit y ris k in t he elderly
8 3, 8 4, 8 8, 9 0  I n a p o p ulatio n of c o m m u nit y dw ellin g a d ults ( mea n a ge 
7 8), s olu ble (s) -V C A M w as in de pe n de ntly c orr elate d wit h p o or er f u nctio nal stat us at 
bas eline ( H R 1. 2, p = 0. 0 0 2). 8 8  After a djustin g f or f u nctio nal stat us, de m o gr a p hic f actors 
a n d c o m or bidities, hig her plas ma s -V C A M, 
D -di mer, a n d I L -6 c o nc e ntr atio ns w ere 
in de pe n de ntly r elate d t o m ortalit y wit hin 4 years. I nfla m mat or y me diat ors c a n ha ve gr eater 
pr e dictive a bilit y a m o n g patie nts wit h o ut bas eline f u nctio nal i m pair me nts, s u g gestin g t hey 
ma y ide ntif y pr e -fr ail patie nts t hat ma y n ot ot her wis e ha ve bee n ide ntifie d wit h o ut e xte nsive 
geriatric ass ess me nt testin g 8 3, 9 0, a n d 9 2 
Pr e vio us st u dies ha ve de m o nstr ate d t he utilit y of infla m mat or y mar ker meas ur e m e nt in 
c a nc er patie nts. I n a st u d y e valuatin g gait s pee d of 3 2 9 older participa nts wit hin t w o 
p h ysic al activit y inter ve ntio n st u dies, t h os e wit h a n incr easin g n u m ber of ele vate d 
infla m mat or y mar kers (I L-6, T N F R 2, a n d D -di mer) ha d lo w er gait s pee ds ( linear tr e n d 
p < 0. 0 0 0 1; T a ble 1).  T his eff ect w as m or e pr o n o unce d a m o n g t he 6 % of patie nts t hat w er e 
c a nc er s ur viv ors (linear tr e n d p = 0. 0 0 9).  T he patie nts wit h a c a nc er dia g n osis a n d t w o 
ele vate d bio mar kers ha d a gait s pee d of 0. 8 8 meters/s ec o nd ( +/ -0. 3 7), w hic h is w ell belo w 
t he n or mal gait s pee d of 1. 0 m/s ec.  T he gr o u p of c a nc er s ur viv ors als o ha d a clinic ally 
mea nin gf ul slo w er gait s pee d c o m par e d t o t he gr o u p wit h o ut a c a nc er dia g n osis a n d t hr ee 
ele vate d bio mar kers ( -0. 2 0 m/s ec).  
T his st u d y in dic ates cir c ulatin g 
mar kers of 
infla m matio n c a n ide ntif y c a nc er patie nts in nee d of tar gete d inter ve ntio ns t o pr e ve nt f urt her 
f u nctio nal decline.9 3  
I n vestigat ors o utside of t he Unite d States ha ve r ec o g nize d t hat s yste mic infla m matio n pla ys 
a major r ole in t he decline of c a nc er patie nts, es pecially in ter ms of n utritio n a n d p h ysic al 
f u nctio n.  T he s yste mic inflam matio n -bas e d Glas g o w Pr o g n ostic S c or e ( G P S), bas ed on 
le vels of C-r eactive pr otein ( C R P) a n d h y p oalb u mine mia, w as derive d as a s urr o gate of 
s yste mic infla m mat or y stat us.  Data fr o m 8, 3 3 3 patie nts fr o m 2 8 st u dies in patie nts wit h 
o per a ble c a nc er de m o nstr at e t he G P S w as a n in de pe n de nt pr e dict or of s ur vival ( H R r a n ge 
1. 5 –  5. 1). 9 4  F o urtee n of t hes e st u dies in v olve d patie nts wit h c olor ectal c a nc er a n d t he 
pr o g n ostic sig nific a nc e of t he G P S w as in de pe n de nt of sta ge, pat h olo gic al f eat ur es, a nd 
c o m or bidit y.  Si milar pr o g n ostic a bilit y of t he G P S w as s ee n in 1 1 st u dies in v olvin g 1, 5 04 
patie nts wit h metastatic c a nc er.  I n a st u d y of 5 6 patie nts wit h a d va nc e d -sta ge c olor ectal 
c a nc er, t he G P S n ot o nly pr e dicte d s ur vival, b ut it als o pr e dicte d t o xicit y t o c he m other apy 95  
A hig her G P S s c or e c orr elate d wit h hig her gr a de 2/ 3 diarr hea a n d hig her incide nc e of grade 
2/ 3 t o xicit y c o m par e d t o t h os e wit h lo w er s c or es ( p = 0. 0 23 a n d 0. 0 1 5 r es pectively).  Ot her 
c yt o kines inclu din g I L-1 β, I L -6, I L -2, I L -1 2, I L -8, T N F -α, MI P -1 α, a n d MI P -1 β c orr elated 
wit h clinic al o utc o mes.   
E mer gin g da ta s u g gest c ellular s e nes c e nc e is a n u n derlyin g pr oc ess c o ntrib utin g t o t he 
incr eas e in cir c ulatin g infla m mat or y a n d pr o-t hr o m b otic f act ors ass ociate d wit h f u nctio nal 
decline a n d m ortalit y in t he elder ly.1 8, 2 9  S e nes c e nt c ells ac c u m ulate wit h a ge as a r eactio n 
t o lif e-lo n g c ellular str ess. Alt h o u g h s e nes c e nt c ells ar e n ot mit otic ally active, t he y ac q uir e 
a s e nes c e nc e-ass ociate d s ecr etor y p he n ot y pe ( S A S P), wit h incr ease d pr o ductio n of pr oteins 
in v olve d in c hr o nic infla m matio n a n d c oa g ulatio n, ver y si milar t o t he mar kers ass ociated 
wit h p o or er p h ysic al f u nctio n a n d m ortalit y in t he elderl y. 9 6 -9 7  T her ef or e, t his pr o p os al 
inclu des s o me mar kers of c hr o nic infla m matio n t hat ar e part of t he S A S P t o e valuate if t hey 
ar e ele vate d in patie nts w h o e x perie nc e d a d vers e o utc o mes wit h c a ncer tr eat me nt.  

 
Allia nc e A1 7 1 6 0 1  
 
6 5  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
Alt h o u g h c hr o nic infla m mat or y me diat ors ha ve n ot bee n esta blis he d as tr ue a gin g 
bio mar kers, t he f act t hat t he y c orrelate wit h meas ur es of p h ysic al stat us, f u nctio nal decline, 
a n d m ortalit y in t he older a d ult p o p ulatio n s u g gests t he y ma y r eflect u n derlyin g biolo gic 
pr oc ess es t hat c o uld pr e dict a patie nt’s ris k of t o xicit y fr o m ca ncer treat me nt a n d t her ef ore, 
t heir a bilit y t o t oler ate it.  T he le vels of infla m mat or y me diat ors c a n be meas ur e d wit h 
E LI S A ass a ys o n plas ma s a m ples c ollecte d d urin g blo o d dr a w s r o utinely d o ne f or c a ncer 
ma na ge me nt.  T her ef ore, t he meas ure me nt of t hes e le vels c o uld bec o me a n efficie nt way of 
pr o vidin g t he o nc olo gist insig ht int o p ote ntial t oler a nc e of c a nc er  t her a p y a n d pr o vide 
g uida nc e as t o t he m ost a p pr o priate r e gi me ns a n d d os es t o pre ve nt e xcessive t o xicit y f or the 
older patie nt.  
1 4. 1. 2  O bje cti ves  
• 
T o e x plor e t he ass ociatio n bet w ee n bas eline c hr o nic infla m mat or y me diat or  le vels 
a n d de velo p me nt of a d vers e e ve nts.  
• 
T o e x plor e t he ass ociatio n bet w ee n bas eline c hr o nic infla m mat or y me diat or  le vels 
a n d tr eat me nt m o dific atio n.  
• 
T o e x plor e t he ass ociatio n bet w ee n bas eline c hr o nic infla m mat or y me diat or  le vels 
a n d bas eline p h ysic al f u nctio n as ass ess e d b y t he c a nc er -s pecific geriatric 
ass ess me nt.  
• 
T o e x plor e t he ass ociatio n bet w ee n bas eline c hr o nic infla m mat or y me diat or  le vels 
a n d decline in p h ysic al f u nctio n as ass ess e d b y t he c a nc er -s pecific geriatric 
ass ess me nt.   
1 4. 1 . 3 Met h o ds  
V -Ple x pa nels ar e 1 0 -s p ot 9 6-w ell plates. I n divid ual pa nels meas ur e 1 0 c yt o kines i m p ortant 
in infla m mat or y r es p o ns es a n d i m m u ne s yste m r e g ulatio n, a n d w e a nticipate r u n nin g t hr ee 
V -ple x pa nels f or a t otal of 3 0 a nalytes teste d. T hes e 1 0 -s p ot ass a ys c a n detect s ecr eted 
bio mar kers a n d ass ess c yt o kines i m p orta nt in c har acterizin g T H1 a n d T H2 s u bs ets of T c ells 
i m p orta nt in s e ver al infla m mat or y dis or ders. We will als o r u n n o n 1 0-s p ot pa nels f or T N F R-
1, T N F R -2, a n d D -di mer.  
T he 
Mes o S c ale Dis c o ver y ( M S D) platf or m  will be utilize d f or testin g ( Mes o S c ale 
Dis c o ver y R oc k ville, Mar yla n d).  O ur pr o p os e d st u dies r e q uir e 1 0 0 u L of s a m ple per 1 0 
a nalytes teste d o n t he V-Ple x 1 0 -s p ot platf or m. Sinc e w e pla n t o us e 3 s e par ate V-Ple x 
pa nels, w e a nticipate usin g a p pr o xi mately 3 0 0 u L of s a m ple t o c har acterize e x pr essio n of 
3 0 c yt o kines. Ad ditio nal mar kers bein g teste d in s e par ate kits inclu de T N F R -1 a n d T N F R -
2, as w ell as D -di mer, w hic h will a d d a n ot her 2 0 0 u L of s a m ple r e q uir e me nt. T her ef ore, the 
t otal mini m u m s a m ple r e q uir e me nt is 5 0 0 u L of plas ma. Ad ditio nal s a m ple w o uld be 
f a v or e d, sinc e at least 2 0 % a d ditio nal s a m ple ma y be r e q uir e d f or err or a n d or pipettin g 
loss es.  T he V-Ple x kits ar e desig ne d f or t he a nalysis of all or a n y c o m binatio n of t hes e 
c yt o kine bio mar kers in c ell c ult ur e s u per nata nts, s er u m, plas ma, a n d urine.  
P las ma s a m ples ar e r e q uir e d f or all testin g , w hic h will be r u n in d u plic ate usin g  t he 
f ollo win g kits: 
 
 

 
Allia nc e A1 7 1 6 0 1  
 
6 6  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
 
KI T# 1:  
I F N-g a m m a, I L -1 bet a, I L -2, I L -4, I L -6, I L -8, I L -1 0, I L -1 2 p7 0, I L -1 3, T N F -al p h a  
Le vel of det e ctio n : 
I F N-γ: 0. 0 4 p g/ m L  
I L-2: 0. 2 2 p g/ m L  
I L-4: 0. 1 4 p g/ m L  
I L-5: 0. 0 7 p g/ m L  
I L-6: 0. 6 1 p g/ m L  
K C/ G R O: 0. 2 4 p g/ m L  
I L-1 0: 0. 9 5 p g/ m L  
I L-1 2 p 7 0: 9. 9 5 p g/ m L  
T N F -α: 0. 1 3 p g/ m L  
KI T# 2:  
Eot a xi n, MI P -1 bet a, Eot a xi n -3, T A R C, I P -1 0, MI P -1 al p h a, I L -8, M C P -1, 
M D C, 
M C P -4  
Le vel of det e ctio n:  
E ota xin: 3. 2 6 p g/ m L  
MI P -1 β: 0. 3 7 p g/ m L  
E ota xin -3: 1. 7 7 p g/ m L  
T A R C: 0. 2 2 p g/ m L  
I P-1 0: 0. 3 7 p g/ m L  
MI P -1 α: 3. 0 2 p g/ m L  
I L-8( H A): 9 5. 6 p g/ m L  
M C P -1: 0. 0 9 p g/ m L  
M D C: 1. 2 2 p g/ m L  
M C P -4: 1. 6 9 p g/ m L  
KI T# 3:  
C R P, I C A M -1, S A A, V C A M -1  
Le vel of det e ctio n:  
S A A: 1 0. 9 p g/ m L  
C R P: 1. 3 3 p g/ m L  
V C A M -1: 6. 0 0 p g/ m L  
I C A M-1: 1. 0 3 p g/ m L  
KI T# 4:  
T N F R 1 a n d T N F R 2  
T N F -R 1:  I ntr a-ass a y C. V.'s ar e 6. 9 %, 3. 1 %, a n d 4. 2 % at 6 1. 0 1, 4 4 2 6. 3, a n d 
3 8 4 1. 2 p g/ m L r es pectively.  
T N F -R 2 : I ntr a-ass a y C. V.'s ar e 2. 6 %, 3. 6 %, a n d 3. 4 % at 1 2 6. 6, 7 1 5 8. 6, a n d 
6 1 2 0. 5 p g/ m L r es pectively.  

 
Allia nc e A1 7 1 6 0 1  
 
6 7  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
KI T# 5:  D -di m e r  
Le vel of det e ctio n:  
1 1 0 - 2, 0 0 0 n g/ m L  
T he I m m u n oc he mic al C or e La b or at or y at Ma y o Clinic.  T he I C L is c ertifie d by 
b ot h t he C olle ge of A meric a n P at h olo gists  ( C A P # 1 8 0 8 2 0 1, A U I D # 1 1 8 3 8 32) 
a n d t he De part me nt of Healt h a n d Hu ma n S er vic es  ( C LI A I D # 2 4 D 0 8 6 1 2 6 5). 
Re g ulat or y r e q uir e me nts inclu de t h or o u g h test validatio n, d oc u me ntation, 
sta n dar dize d test pr oc e d ur es a n d r e vie w of q ualit y c o ntr ol mar kers.   
1 4. 1. 4  A n al ys es  
Bas eline 
c hr o nic infla m mat or y 
me diat or le vels  will be s u m marize d a n d pr es e nted 
des criptively f or all patie nts. T he ass ociatio n bet w ee n  bas eline c hr o nic infla m mat or y 
me diat or le vels a n d t he r ate of a d vers e e ve nts a n d tr eat me nt m o dific atio ns will be ass essed 
gr a p hic ally. L o gistic r e gr essio n m o dels will als o be utilize d in a n e x plor at or y f as hio n t o 
ass ess t hes e ass ociatio ns. T o e xa mine t he ass ociatio n bet w ee n bas eline c hr o nic 
infla m mat or y me diat or le vels a n d t he bas eline geriatric ass ess me nt s c or es, w e will us e 
gr a p hic al mea ns a n d S pear ma n’s c orr elatio n c oefficie nt. E x plor at or y linear r e gr ession 
m o dels will als o be utilize d f or t his ai m. T he  ass ociatio n bet w ee n bas eline c hr o nic 
infla m mat or y me diat or le vels a n d t he c ha n ge in t he geriatric ass ess me nt t hr o u g h ti me will 
be a nalyze d gr a p hic ally a n d wit h e x plor at or y r e peate d meas ur es m o dels.  
1 4. 2  P h ar m ac o ge n o mics : ( Alli a n ce A1 7 1 6 0 1 -S T2 ): Ge n etic de t er mi n a nts of P al bocicli b 
Effic ac y a n d t o xicit y i n t h e el derl y  
Allia nc e A1 7 1 6 0 1 -S T 2  will e valuate ge netic deter mina nts of palb ociclib effic ac y a n d t o xicit y 
in elderly patie nts wit h estr o ge n  r ec e pt or p ositive, H E R 2 ne gative metastatic br east c a ncer 
1 4. 2 . 1 B ac k gr o u n d  
M ultiple e n d ocrine t her a p y o ptio ns e xist f or tr eat me nt a n d pr e ve ntio n of br east c a nc er in 
p ost -me n o pa us al w o me n wit h estr o ge n r ec e pt or p ositive br east (H R p ositive) c a nc ers. 98-
1 0 0 Ar o matas e in hibit ors ( AI) s uc h as letr oz ole, a nastr oz ole a n d e xe mesta ne w hic h f u nction 
b y in hibitin g t he ar o matas e e nz y me ( C Y P 1 9), ha ve i m pr o ve d t he r ec urr e nc e r ates of br east 
c a nc er after 5 years of ta m o xif e n tr eat me nt c o m par e d t o plac e b o. 1 0 0  Ho w e ver, sid e eff ects 
n ota bly m us c ulos keletal s y m pt o ms, fr o m AI t her a p y ha ve le d t o int oler a nc e a n d s u bse q uent 
dis c o ntin uatio n of tr eat me nt. 1 0 1-10 2 Data ac c u mulate d o ver t he perio d n o w s u g gests t hat the 
be nefits ass ociate d wit h pr olo n ge d e n d ocrine t her a p y s h o uld be ba la nc e d wit h tr eat me nt 
t oler a bilit y a n d fr act ur e ris ks1 03 
P ost -me n o pa us al w o me n wit h metastatic  H R p ositive  br east c a nc ers ar e tr eate d wit h 
fulvestr a nt w hic h acts diff er e ntly fr o m t he AIs b y tar getin g t he estr o ge n r ec e pt or. As a n 
a nta g o nist, f ulvestr a nt bin ds t o estr o ge n r ec e ptors c o mpetitively o n t u m ors a n d ot her tiss ue 
tar gets, pr o d ucin g a n uclear c o m ple x t hat c a us es a d os e-r elate d d o w n-r e g ulatio n of estr o gen 
r ec e pt ors a n d in hibits t u m or gr o wt h. 10 4  F or a d va nc e d metastatic br east c a nc ers e x hibitin g 
b ot h H R -p ositive a n d h u ma n e pider mal gr o wt h f act or r ec e pt or 2 ( H E R 2) -ne gative 
c har acteristics, i m pr o ve d pr o gr essio n fr ee s ur vival has bee n ass ociate d wit h tr eat me nt 
o ptio ns t hat inclu de a n AI or f ulvestr a nt t o get her wit h a c yclin -de pe n de nt kinas e ( C D K) 4/6  
in hibit or s uc h as p alb ociclib. 1 0 5 -10 7  
P alb ociclib  has bee n s h o w n t o s pecific ally in hibit C D K 4/ 6  b y bloc kin g t he pr o gr essio n of 
c ells fr o m G 1 int o S p has e of t he c ell c ycle a n d r es ultin g in r e d uc e d c ellular pr olif er atio n of 
E R -p ositive br east c a nc er c ell lines 1 0 8, 1 0 9 .  Re p orts in dic ate t hat palb ociclib e n ha nc es t he 

 
Allia nc e A1 7 1 6 0 1  
 
6 8  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
effic ac y of c yt ostatic a ge nts, s uc h as e n d ocrine t her a p y or H E R 2 -tar gete d t her a p y, b ut 
decr eas es t he effic ac y of c ytot o xic c he m ot hera p y s uc h as wit h c ar bo platin a n d  d o x or u bicin 
1 1 0 -1 1 2. Clinic al trials ha ve s h o w n sig nific a nt be nefit in pr o gr essio n fr ee s ur vival f or w o men 
wit h metastatic br east c a nc er o n palb ociclib wit h or wit h o ut prior AI (letr oz ole) or 
f ulvestr a nt tr eat me nt.  T he variatio n in me dia n P F S a m o n g t he patie nts ha ve r a n ge d fr o m 
1 0. 2 m o nt hs ( 9 5 % CI, 5. 7 – 1 2. 6) f or t he letr oz ole gr o u p t o 2 0. 2 m o nt hs ( 9 5 % CI, 1 3. 8 –
2 7. 5) f or t he palb ociclib -letr oz ole gr o u p s u g gestin g t hat ot her f act ors ass ociate d wit h 
palb ociclib c o uld be c o ntrib utin g t o t he clinic al o utc o mes.
10 5 Si milar P F S tr e n ds w er e s een 
in t he st u d y of palb ociclib wit h/ wit h o ut f ulvestr a nt 1 06, 107 . T ur ner et al.1 0 6 r e p orte d a me dian 
P F S of 9. 2 m o nt hs ( 9 5 % CI, 7. 5 – n ot esti ma ble) f or palb ociclib -f ulvestr a nt gr o u p a n d 3. 8 
m o nt hs ( 9 5 % CI, 3. 5 – 5. 5) f or t he  plac e b o -f ulvestr a nt gr o u p,1 0 6, w hile Crist of a nilli et 
al1 0 7 r e p orte d a me dia n P F S of 9 .5 m o nt hs ( 9 5 % CI, 9 .2 – 1 1.0) in t he palb ociclib -f ulvestr a nt 
gr o u p a n d 4 .6 m o nt hs ( 9 5 % CI, 3 .5– 5 .6) in t he plac e b o -f ulvestr a nt gr o u p. 
All of t hes e trials ha ve s h o w n variat io ns in t he clinic al o utc o mes 1 0 5-1 07. O ne f act or t hat c o uld 
in part e x plain s o me of t hes e variatio ns mig ht be t he r ole of in herite d ge netic varia nts w h ose 
pr oteins ma y be r es p o nsible f or t he biotr a nsf or matio n of t he AIs, f ulvestr a nt a n d palb ociclib.  
S e ver al r e p orts o n c a n didate ge nes a n d ge n o me wide ass ociatio n st u dies ( G W A S) ha ve 
c orr elate d sin gle n ucle otide p oly m or p his ms ( S N P) in t he estr o ge n meta b olis m r elate d 
pat h w a y ge nes wit h r es p o ns e t o e n d ocrine t her a p y f or br east c a ncer. 1 14 -1 18  T o date, t here is 
n o st u d y t hat has lo o ke d at ge netic varia nts ass ociate d wit h palb ociclib biotr a nsf or mation 
pat h w a y ge nes wit h r es p o nse t o t he treat me nt in metastatic br east ca ncer, let alo ne elucidate 
h o w t hes e p oly m or p his ms ar e ass ociate d wit h t oler a bilit y a n d r es p o ns e t o palb ociclib 
t her a p y in t he elderly, s pecific ally w o me n a ge d 7 0 years a n d o ver. T his pr o p os al pla ns t o 
elucidate t he ge netic deter mina nts of palb ociclib effic ac y in p ost -me n o pa us al w o me n with 
metastatic  H R p ositive , H E R 2 ne gative br east c a nc ers u n der g oin g tr eat me nt in t he par e nt 
st u d y.  
P al bocicli b m et a bolis m, cell c ycle pr ot ei ns, ge n es a n d ge n etic v ari a nts : P alb ociclib is 
pri marily meta b olize d b y C Y P 3 A e nz y me a n d u n der g oes s ulf o natio n b y S U L T 2 A1 e nz y me 
a n d u n der g oes ac ylatio n a n d gluc ur o nidatio n as min or meta b olic pat he w a ys. 1 0 9, 1 1 9 -121. 
P a lb ociclib is als o a hig hly s elective in hibit or of C D K4 a n d C D K6 kinas es a n d in lo w 
na n o m olar c o nc e ntr atio ns bloc ks r etin o blast o ma ( R b) ge ne pr otein pr o d uct p R b. 108   
C yclin -de pe n de nt kinas es ( C D Ks) ar e s erine/t hr e o nine kinas es t hat pla y a ke y r ole in 
r e g ulatin g c ell c ycle pr o gr essio n b y ass ociatin g wit h c yclins. T he c ell c ycle is a tig htly 
r e g ulate d pr oc ess of five distinct p has es: G 0 ( q uies c e nc e) f ollo w e d b y G 1 ( pr e-D N A 
s y nt hesis), S ( D N A s y nt hesis), G 2 ( pr e-divisio n) a n d M ( c ell divisio n) wit h t he G 1  t o S 
p has e bein g t he ke y c hec k p oint in pr otectin g t he c ell fr o m a b n or mal r e plic atio n. 1 0 8  C D K4 
a n d C D K6 inter act wit h c yclin D 1 early in t his c hec k p oint p has e r es ultin g in t he 
p h os p h or ylatio n of p R b a n d allo win g t he r eleas e of tr a ns criptio n f act or E 2 F w hic h lea ds to 
tr a ns criptio n of ot her tar get ge nes t o allo w pr o gr essio n t o t he S p has e. 1 0 8   C D K activit y is 
t h us tig htly r e g ulate d at s e ver al le vels b y C yclin D a n d r etin o blast o ma pr oteins a n d b y C D K 
in hibit or y pr oteins t he I N K4 f a mily ( p 1 6, p 1 5, p 1 8, p 1 9) a n d CI P/ KI P f a mily ( p 2 1, p 2 7, 
p 5 7). 1 2 2 -124  T h us w he n t he c ell c ycle r e g ulat or y mec ha nis m is alter e d, u nc o ntr olle d c ell 
pr olif er atio n oc c urs w hic h is a distinctive f eat ur e of h u ma n c a nc ers. 1 25  
Cell c ycle ge n es, pol y m or p his ms a n d c a n ce r : Ma n y of t he ge nes e nc o d in g t he c ell c ycle 
pr oteins ar e fr e q ue ntly m ut ate d in h u ma n c a nc ers a n d t his lea ds t o u nc o ntr olle d c ell divisio n 
a n d t u m or gr o wt h as w ell. 1 2 6  F or insta nc e, in br east c a nc er, alter atio ns in c ell c ycle 
r e g ulat ors ha ve bee n r e p orte d t o inclu de a m plific atio n of c yclin D 1 ge ne ( 1 5-2 0 % c a ncers) 
a n d o ver e x pr essio n of its pr otein pr o d uct w hic h has bee n ass ociate d wit h p o or clinic al 
o utc o mes, t o in d ole nt estr o ge n r ec e pt or p ositive p he n ot y pe a n d t o ta m o xif e n r esista nce 

 
Allia nc e A1 7 1 6 0 1  
 
6 9  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
c yclin D pr otein. 1 0 8,  1 2 7-13 2 F u rt her m or e, st u dies ha ve bee n r e p orte d t hat s h o w t hat in hibitin g 
C D K4 a n d C D K6 kinas es in d uc e G 1 arr est in s e nsitive c ell lines a n d pri mar y b o ne marr o w 
c ells a n d pr e ve nt t u m or gr o wt h in h u ma n m yelo ma xe n o gr afts. 1 33-1 37  
T he ge nes e nc o din g t he pr oteins in v olve d in t he G 1 -S p has e inclu de C C N D 1 [ c yclin D 1], 
C C N D 2  [ c yclin D 2], C C N D 3  [ c yclin D 3], C C N E 1  [ c yclin E] (t he c yclin f a mily w hic h 
r e g ulate c yclin-de pe n de nt kinas es); C D K 2  [ p 3 3], C D K 4 , a n d C D K 6  ( c yclin-de pe n de nt 
kinas es f or t he G 1 / S tr a nsitio n); C D K N 1 A  [ p 2 1, Cip 1], C D K N 1 B  [ p 2 7, Kip 1] ( CI P/ KI P 
f a mily c yclin-de pe n de nt kinas e in hibit ors); C D K N 2 A  [ p 1 6], C D K N 2 B  [ p 1 5], C D K N 2 C  
[ p 1 8], a n d C D K N 2 D  [ p 1 9] (I N K4 f a mily c yclin-de pe n de nt kinas e in hibit ors) a n d R B 1  
r etin o blast o ma ge ne. St u dies r elatin g t o ge netic p oly m or p his ms in c ell c ycle ge nes a n d ris k 
of s o me c a nc ers inclu din g lu n g, bla d der, pr ostate, br east, o varia n, e n d o metrial, pa ncr eas, 
a n d c olor ectal 1 3 8 -1 45  ha ve bee n p u blis he d alt h o u g h n o ne ha ve ta ke n int o c o nsider atio n t he 
eff ects t hes e in herite d ge netic varia tio ns ma y ha ve o n t he effic ac y of palb ociclib w hic h 
s pecific ally in hibits t he C D K4/ 6 c hec k p oint.  
I n br east c a nc er st u dies, p oly m or p his ms s uc h as C D K N 1 B  rs 2 0 6 6 8 2 7 has bee n ass ociated 
wit h s h orte ne d dis eas e -fr ee s ur vival in patie nts wit h infiltr atin g 
metastasis-fr ee br east 
c a nc er 1 4 6 w hile C C N D 3  rs 2 4 7 9 7 1 7 has bee n ass ociate d wit h a n incr eas e d ris k of deat h. 147  
Ot her S N Ps inclu din g 
C C N E 1 rs 9 9 7 6 6 9, C D K N 1 A rs 3 1 7 6 3 3 6, C D K N 1 B  rs 3 4 3 30, 
C D K N 2 B  rs 3 2 1 8 0 0 5 a n d C D K N 2 A rs 3 7 3 1 2 3 9 ha ve bee n ass ociate d wit h br east c a nc er as 
w ell. 1 4 8  C C N D 1  rs 9 3 4 4 (C C N D 1 -0 2  A8 7 0 G or C C N D 1  G 8 7 0 A) t he m ost st u die d S N P in 
C C N D 1  a n d pr e vio usly r ef err e d t o as C C N D 1 rs 6 0 3 9 6 5 has bee n s h o w n t o be ass ociated 
wit h br east c a nc er s ur vival in C hines e s u bjects,
1 4 9 a n d has als o bee n ass ociate d wit h  br east 
c a nc er ris k a n d p o or er br east c a nc er s pecific s ur vival in patie nts wit h metastatic br east 
c a nc er .1 5-15 2 P oly m or p his ms in C Y P 3 A 4 1 5 3, 1 54 a n d in S U L T 2 A 1 1 5 5, 15 6 ha ve als o bee n 
ass ociate d wit h br east a n d ot her c a ncers.  
T hes e ass ociatio ns of t he c ell c yc le ge ne S N Ps wit h br east c a nc er ma y be influe nc e d b y 
palb ociclib’s  actio n of in hibitin g C D K4/ 6 in t he G 1 -S tr a nsitio n p oint t her e b y m o dif yin g 
clinic al r es p o ns e a n d t o xicit y o utc o mes. T his st u d y is ideal t o elucidate t he ass ociatio ns of 
c ell c ycle S N Ps in t he pr es e nc e of palb ociclib o n br east c a nc er in t he elderly. We n ote t hat 
p oly m or p his ms in ar o matas e C Y P 1 9 A , C Y P 2 A 6  a n d estr o ge n r ec e pt or E R S 1 ge nes 1 5 7-160, 
t he tar gets f or AI in hibit ors a n d fulvestr a nt r es pectively, ha ve als o bee n ass ociate d with 
br east c a nc er.  T her ef or e S N Ps in t hes e 2 ge nes u n der t he influe nc e of t heir s pecific 
in hibit ors c o m bine d wit h palb ociclib in t he tr eat me nt ( c h oic e of AI or f ulvestr a nt ma de at 
t he dis cr etio n of t he tr eatin g in vestigat or) will be st u die d f or ass ociatio ns w it h clinic al 
r es p o ns e a n d t o xicit y t o palb ociclib. F urt her m ore, t he ge netic varia nts in palb ociclib r elate d 
ge nes will be c or r elate d wit h t he pri mar y o bjective of t he st u d y w hic h inclu des t oler a bilit y 
(a d vers e e ve nts ); a n d wit h t he s ec o n dar y o bjectives w hic h inclu de t o xicit y, r es p o ns e t o 
tr eat me nt, a n d o ver all s ur vival.  
We h y p ot hesize t hat in herite d ge netic p oly m or p his ms in c ell c ycle pat h w a y ge nes a n d in 
ge nes t hat meta b olize palb ociclib will c orr elate wit h clinic al o utc o mes in elderly patie nts 
u n der g oin g  palb ociclib tr eat me nt f or estr o ge n r ec e pt or p ositive, H E R 2 ne gative metastatic 
br east c a nc er. We f urt her h y p ot hesize t hat ge nes in C Y P 1 9 A1 , C Y P 2 A6 a n d E S R 1 will als o 
c orr elate will t o xicit y o utc o mes in t his st u d y.  
We pr o p os e t o ac hie ve t his h y p ot hesis b y ge n ot y pin g patie nt D N A s a m ples f or S N Ps in t he 
c ell c ycle ge nes inclu din g C C N D 1, C C N D 2, C C N D 3 , C C N E1 , C D K2 , C D K4 , C D K6 , 
C D K N1 A , C D K N1 B , C D K N2 A , C D K N2 B, 
C D K N2 C , C D K N2 D , C Y P 3 A 4, 
C Y P 1 9 A 1, C Y P 2 A 6,  E S R 1  R B 1  a n d S U L T 2 A 1  a n d c orr elate t hes e S N Ps  t o effic ac y a n d 
t o xicit y of palb ociclib. 

 
Allia nc e A1 7 1 6 0 1  
 
7 1  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
 
Ge n ot y pin g   
T he Age na i P L E X ( pr e vio usly c alle d s e q ue n o m) ge n ot y pin g pr ot oc ol in v olves P C R 
a m plific atio n of D N A usin g S N P s pecific pri mers, f ollo w e d b y a bas e e xte nsio n r eactio n 
usin g t he i P L E X G old c he mistr y ( Age na Bios cie nc es, S a n Die g o, C A).  T he pr ot oc ol has 
bee n us e d f or years a n d will briefly be des cribe d her e.  S N P -s pecific P C R a n d e xte nsio n 
pri mers w er e desig ne d a n d or ga nize d int o p o ols wit h t he Ass a y Desig n S uite ( Age na). All 
pri mers w er e p ur c hase d fr o m I nte gr ate d D N A T ec h n olo gies ( C or alville, I A). A Q C r u n was 
perf or me d wit h C oriell a n d C E P H c o ntr ols, a n d r es ults w er e teste d f or 
Me n delia n 
inc o nsiste ncies. Hot Star T a q P oly mer as e ( Qia ge n) w as us e d f or all P C Rs. 1 5 n g of D N A 
w as a d de d t o eac h 5 -ul P C R r eactio n mixt ur e in a 3 8 4 -w ell micr otiter plate. T he P C R 
c o n ditio n w as 9 4° C f or 1 5 min f or h ot start, f ollo w e d b y 4 5 c ycles of de nat urin g at 9 4° C 
f or 2 0 s ec, a n nealin g at 5 6° C f or 30 s ec, e xte nsio n at 7 2° C f or 1 min f or 4 5 c ycles, a n d final 
inc u batio n at 7 2° C f or 3 min. T he P C R pr o d ucts w er e t he n tr eate d wit h S A P (s hri mp 
alkaline p h os p hatas e, Age na) f or 4 0 min at 3 7° C t he n r a m pe d t o 8 5° C f or 5 min t o r e m o ve 
e xc ess d N T Ps. T he final ba s e e xte nsio n pr o d ucts wer e dilute d in d o u ble distille d w ater a nd 
t he n tr eate d wit h 6 m g of S pectr o C L E A N ( Age na) r esin per w ell t o r e m o ve c o nta minatin g 
s alts. 1 0-1 8 nl of tr eate d e xte nsio n pr o d uct was s p otte d t o the a p pr o priate loc atio n o n a 3 8 4 -
pa d S pectr o C HI P II ( Age na) usin g a R S 1 0 0 0 Na n o dis pe ns er  ( Age na, S a n Die g o, C A).  A 
Mass A R R A Y Analyzer C o m pact M A L DI -T O F M S ( Age na) w as us e d f or data ac q uisitions 
fr o m t he S pectr o C HI P. All r es ulta nt ge n ot y pin g c alls w er e perf or me d in r eal ti me b y t he 
Mass A R R A Y T y per A nalyzer v 4. 0. 2 6. 7 3 ( Age na)  
1 4. 2. 4  A n al ys es  
S N P a nalysis : Res ults fr o m ge n ot y pin g will be s e nt t o t he bioinf or matics/statisticia ns f or 
a nalys es t o c orr elate t he S N Ps wit h t he pri mar y o bjective of t he st u d y  w hic h is a d verse 
e ve nts . T he S N Ps will als o be c orr elate d t o  t he s ec o n dar y o bjectives w hic h inclu de t o xicity, 
r es p o ns e t o tr eat me nt a n d o ver all s ur vival.  
1 4. 2. 5  Hy pot h es es  
1.  P atie nts wit h hig her bio mar ker le vels ha ve a n incr eas e d incide nc e of gr a de 3 + a d verse 
e ve nts.  
2.  P atie nts wit h hig her bio mar ker le vels ha ve hig her r ates of tr eat me nt m o dific atio n 
d urin g a dju va n t t her a p y. 
3.  P atie nts wit h hig her bio mar ker le vels ha ve p o or er bas eline perf or ma nc e stat us and 
hig her r ates of perf or ma nce stat us decline d urin g a dju va nt t her a p y.  
1 4. 2. 6  St atistic al a n al yses  
Tr eat me nt m o dific atio n is define d as a n y d os e r e d uctio n or o missio n  d urin g t he c o urs e of 
t he st u d y. Bio mar ker le vels will be c o m par e d t o gr a de 3 + a d vers e e ve nt incide nc e ( as 
meas ur e d b y t he C T C A E versio n 5 . 0), rate of treat me nt m o dific atio n, baseline perf or mance 
stat us a n d perf or ma nc e stat us t hr o u g h o ut t he c o urs e of t he s t u d y des criptively a n d 
gr a p hic ally. An y testin g d o ne will be d o ne in a n e x plor at or y ma n ner.  
 
 

 
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1 4. 3  P h ar m ac o ki n etics : ( Alli a nce A 1 7 1 60 1-P P 1)  P o p ul ati o n P h ar m ac o ki n etics of P al bocicli b  
Allia n c e A1 7 1 6 0 1 - P P 1 will e valuate if palb ociclib e x p os ur e ( A U C/ C ma x ) is r elate d t o c ha n ge 
fr o m bas eline in ne utr o p hil n u m bers i. e. ne utr o pe nia. 
1 4. 3. 1  B ac k gr o u n d a n d Hy pot h es es  
P alb ociclib is a s elective in hibit or of c yclin -de pe n de nt kinas es 4 a n d 6 ( C D K4 a n d C D K6).  
T he F D A a p pr o ve d r e gi me n is a 1 2 5 m g c a ps ule of palb ocicl ib ta ke n or ally o nc e daily f or 
2 1 c o ns ec utive da ys f ollo w e d b y 7 da ys off tr eat me nt c o m bine d wit h letr oz ole 2. 5 m g P O 
daily, o n 2 8 -da y  c ycles.  
P alb ociclib is slo wly a bs or be d wit h a T ma x of 6 -1 2 h f ollo win g a n or al 1 2 5 m g d os e, with a  
mea n C ma x  of  1 3 3 ( +/ -S D 1 8. 6) n g/ m L.. T he ter minal eli minatio n half -lif e is mea n 2 9 +/- 5 
h, a n d stea d y state c o nc e ntr atio ns ar e us ually r eac he d in 8 da ys.  T he palb o ciclib is 8 5 % 
b o u n d t o plas ma pr oteins a n d its ge o metric mea n a p par e nt v olu me of distrib utio n ( Vz/ F) 
w as 2 5 8 3 L wit h a c oefficie nt of variatio n ( C V) of 2 6 %. T he ge o metric mea n a p par e nt or al 
clear a nc e ( C L/ F) of palb ociclib w as 6 3. 1 L/ hr ( 2 9 % C V).    I n 6 healt h y male s u bjects given 
a sin gle or al d os e of 1 4 C - palb ociclib, a me dia n of 9 1. 6 % of t he t otal a d minister e d 
r a dioactive d os e w as r ec o ver e d in 1 5 da ys; f ec es ( 7 4. 1 % of d os e) w as t he major r o ute of 
e xcr etio n, wit h 1 7. 5 % of t he d os e r ec o ver e d in urine.  T he majorit y of t he material w as 
e xcr ete d as meta b olites.  
P alb ociclib a bs or ptio n a n d e x p os ur e w ere ver y lo w in a p pr o xi mately 1 3 % of t he p o pulation 
u n der t he f aste d c o n ditio n. F o o d inta ke incr eas e d t he palb ociclib e x p os ur e in t his s mall 
s u bs et of t he p o p ulation, b ut did n ot alter palb ociclib e x p os ur e in t he r est of t he p o p ulatio n 
t o a clinic ally r ele va nt e xte nt. T her ef or e, f o o d inta ke r e d uc e d t he inters u bject varia bilit y of 
palb ociclib e x p os ur e, w hic h s u p p orts a d ministr atio n of palb ociclib wit h f o o d. C o m par ed t o 
palb ociclib  give n u n der o ver nig ht f aste d c o n ditio ns, t he p o p ulatio n a ver a ge ar ea u n der t he 
c o nc e ntr atio n -ti me c ur ve fr o m zer o t o infinit y ( A U C(i nf)) a n d Cma x of palb ociclib incr eas ed 
b y 2 1 % a n d 3 8 %, r es pectively, w he n give n wit h hig h -f at, hig h-c alorie f o o d ( a p pr o xi mately 
8 0 0 t o 1 0 0 0 c alories wit h 1 5 0, 2 5 0, a n d 5 0 0 t o 6 0 0 calories fr o m pr otein, car b o h y drate, and 
f at, r es pectively), b y 1 2 % a n d 2 7 %, r es pectively, w he n give n wit h lo w -f at, lo w-c alorie f o od 
( a p pr o xi mately 4 0 0 t o 5 0 0 c alories wit h 1 2 0, 2 5 0, a n d 2 8 t o 3 5 c alories fr o m pr otein, 
c ar b o h y dr ate, a n d f at, res pectively), a n d b y 1 3 % a n d 2 4 %, r es pectively, w he n m o der ate -fat, 
sta n dar d c alorie f o o d ( a p pr o xi mately 5 0 0 t o 7 0 0 calories wit h 7 5 t o 1 0 5, 2 5 0 t o 35 0 a nd 175 
t o 2 4 5 c alories fr o m pr otein, c ar b o h y dr ate, a n d f at, r es pectively) w as give n 1 h o ur bef ore 
a n d 2 h o urs after palb ociclib  d osin g.  
I n vitr o a n d in viv o st u dies in dic ate t hat palb ociclib u n der g oes he patic meta b olis m in 
h u ma ns. F ollo win g or al a d ministr at io n of a sin gle 1 2 5 m g d os e of 1 4 C palb ociclib  t o 
h u ma ns, t he pri mar y 
meta b olic pat h w a ys f or palb ociclib in v olve d o xidatio n a n d 
s ulf o natio n, wit h ac ylatio n a n d gluc ur o nidatio n c o ntrib utin g as min or pat h w a ys. P alb ociclib 
w as t he major cir c ulatin g dr u g -derive d e ntit y in plas ma ( 2 3 %). T he major cir c ulati n g 
meta b olite w as a gluc ur o nide c o nju gate of palb ociclib, alt h o u g h it o nly r e pr es e nte d 1. 5 % of 
t he a d minister e d d os e in t he e xcr eta. P alb ociclib 
w as e xte nsively 
meta b olize d 
wit h 
u nc ha n ge d dr u g ac c o u ntin g f or 2. 3 % a n d 6. 9 % of r a dioactivit y in f ec es a n d urin e, 
r es pectively. I n f ec es, t he s ulf a mic acid c o nju gate of palb ociclib w as t he major dr u g -r elated 
c o m p o ne nt, ac c o u ntin g f or 2 6 % of t he a d minister e d d os e. Data fr o m a clinic al trial in 
patie nts wit h br east c a nc er s h o w e d t hat t her e w as n o dr u g inter actio n bet w ee n palb ociclib 
a n d letr oz ole w he n t he 2 dr u gs w er e c oa d minister e d.  
I n vitr o st u dies wit h h u ma n he pat oc ytes, liver c yt os olic a n d S 9 fr actio ns, a n d r ec o m binant 
S U L T e nz y mes in dic ate d t hat C Y P 3 A a n d S U L T 2 A1 ar e 
mainly in v olve d in t he 

 
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meta b olis m of palb ocicl ib. I n viv o, palb ociclib e x p os ur e w as incr eas e d b y 1. 9-f old w he n it 
w as c oa d minister e d wit h itr ac o naz ole (str o n g C Y P 3 A4 in hibit or), a n d c o -a d ministr atio n of 
str o n g C Y P 3 A4 in hibit ors s h o uld be a v oide d. If c o -a d ministr atio n wit h a str o n g C Y P 3 A 
in hibit or c a n not be a v oide d, t he daily palb ociclib d os e s h o uld be r e d uc e d t o 7 5 m g. I n vivo, 
palb ociclib e x p os ur e w as decr eas e d b y 8 5 % w he n it w as c oa d minister e d wit h rif a m pin 
(str o n g C Y P 3 A in d uc er), a n d c o-a d ministr atio n of str o n g C Y P 3 A in d uc ers s h o uld be 
a v oide d. T he eff ect of m o der ate C Y P 3 A in d uc ers o n palb ociclib e x p os ur e is n ot k n o w n, 
a n d c o -a d ministr atio n of m o der ate C Y P 3 A4 in d uc ers s h o uld be a v oide d. C o -a d ministr ation 
of palb ociclib wit h m ultiple d os es of r a be pr az ole ( pr ot o n p u m p in hibit or) u n der f e d 
c o n ditio ns did n ot ha ve a clinic ally sig nific a nt eff ect o n palb ociclib e x p os ur e. I n vitr o, 
palb ociclib c a us e d ti me -de pe n de nt in hibitio n of C Y P 3 A4.  P alb ociclib incr eas e d t he 
midaz ola m ( C Y P 3 A s u bstr ate) A U C b y 6 1 % in healt h y s u bjects, a n d t her ef or e c o -
a d ministr atio n of s ensitive C Y P 3 A s u bstr ates wit h narr o w t her a pe utic in dic es s h o uld be 
a v oide d.  
Bas e d o n prior p o p ulatio n p har mac o kinetic a nalysis fr o m male a n d f e male patie nts tr eate d 
wit h palb ociclib, neit her ge n der, a ge n or b o d y w eig ht ha d a clinic ally i m p orta nt eff ect o n 
palb ociclib e x p os ur e.  F urt her m or e, n o d os e r e d uctio n is nee de d in patie nts wit h mild or 
m o der ate r e nal i m pair me nt, or mild he patic i m pair me nt. N o clinic ally sig nific a nt c ha n ge in 
t he Q T c inter val w as detecte d w he n palb ociclib w as a d minister e d t o stea d y state.  Definitive 
c o nclusio ns r e gar din g a n e x p os ur e -r es p o nse r elatio ns hip f or pr o gr essio n fr ee s ur vival ( P F S)  
c o uld n ot be ma de bas e d o n t he li mite d data at a fixe d d os e of 1 2 5 m g fr o m prior clinic al 
st u dies.  Ho w e ver, a gr eater r e d uctio n in a bs olute ne ut r o p hil c o u nt is s u g geste d t o be 
ass ociate d wit h incr eas e d palb ociclib e x p os ur e. T hes e e x p os ur e eff ect r elatio ns hips f or 
older patie nts ( o ver 7 0 a n d o ver 7 5 years of a ge) ha ve  n ot bee n define d.   
T he pri mar y h y p ot hesis of t his p o p ulatio n -p har mac o kinetic nest e d st u d y is  
( 1) T hat palb ociclib e x p os ur e ( A U C/ C ma x ) is r elate d t o c ha n ge fr o m bas eline in ne utr o p hil 
n u m bers i. e. ne utr o pe nia.   
S ec o n dar y e x plor at or y h y p ot hes es ar e t hat palb ociclib e x p os ur e is ass ociate d wit h (i) de gr ee 
of t hr o m b oc yt o pe nia in older patie nts (ii) p r o gr essio n fr ee s ur vival in older patie nts (iii) 
t hes e r elatio ns hips will be str e n gt he ne d b y c o nsider atio n of k n o w n p oly m or p his ms in 
palb ociclib dr u g meta b olizin g e nz y m es ( es p ecially  C Y P 3 A a n d S U L T -2 A1) a n d dr u g 
tr a ns p orters.  
1 4. 3. 2  O bje cti ves:  
• 
T o r efine a p o p ulatio n p har mac o kinetic m o del ( of S u n a n d Wa n g) usin g 
N O N M E M f or palb ociclib  ta kin g ac c o u nt of r ele va nt intrinsic a n d e xtrinsic 
f act ors.  
• 
T o deter mine t he intr a patie nt a n d inter patie nt varia bilit y of palb ociclib ( A U C) in 
older br east c a nc er patie nts r eceivin g palb ociclib plus letr oz ole  
• 
T o e x plor e t he e x p os ur e ( A U C/ Cma x ) t o xicit y (ne utr o pe nia, t hr o m b oc yt o pe nia) 
r elatio ns hip f or palb ociclib w he n  c o m bine d wit h letr oz ole in older br east c a ncer 
patie nts  
1 4. 3. 3  Met h o ds  
F or patie nts in t he st u d y w h o ar e r ec eivin g palb ociclib  plus letr oz ole  or f ulvestr a nt , ve n ous 
blo o d s a m ples f or palb ocic lib c o nc e ntr atio ns will be o btaine d at bas eline, a n d at t he 
s c he d ule d f ollo w -u p clinic visit s o n  da y 1 5 of c ycle 1 a n d c ycle 2, w hile still r ec eivin g st u dy 
dr u g t her a p y. T hes e s a m ples will ha ve t he ti me of da y t he y w er e o btaine d d oc u me nte d.  At 

 
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t hes e f ollow u p visits a P atie nt P ha r mac o kinetic Q uestio n naire (s ee Ap pe n dix I X ) will be 
fille d in w hic h will r e q uest inf or matio n a b o ut t he prior 4 8 h d osin g of palb ociclib  a n d t he 
c o nc o mita nt me dic atio ns .  T his will detail t he ti me of da y t he last t w o d os es of st u d y dr ug 
w er e ta ke n, a n d r elatio ns hip of w he n t he d os es w er e ta ke n in r elatio n t o meals.  
P alb ociclib plas ma  c o nc e ntr atio ns will be meas ur e d usin g a n L C -M S -M S ass a y validate d 
in t he Allia nc e P har mac olo g y/ P har mac o kinetic c or e la b at t he Univ. of Pitts b ur g h usin g a 
m o dific atio n of t he validate d a n d p u blis he d ass a y b y P a ul et al Bio me d C hr o mat o gr. 2 0 18 
Dec 1 3:e 4 4 6 9.   
P har mac o kinetic p o p ulatio n data m o delin g of t he C mi n  (tr o u g h) dr u g c o nce ntratio ns will be 
perf or me d  usin g N O N M E M t o derive palb ociclib s pecific A U Cs a n d t he intr a a n d inter -
patie nt varia bilit y (s ee belo w f or details).  
1 4. 3. 4  St atistic al desig n:  
T he pri mar y s cie ntific h y p ot hesis is that palb ociclib e x p os ur e ( A U C/ C ma x ) is r elate d t o 
c ha n ge fr o m bas eline in ne utr o p hil n u m bers i. e. de gr ee of ne utr o pe nia.   
P o p ul ati o n 
P h ar m ac oki netic 
M o deli n g : 
We 
will 
de velo p 
par a metric p o p ulatio n 
p har mac o kinetics m o dels f or t he e x p os ur e of palb ociclib . T o c a pt ur e b ot h bet w ee n a n d 
wit hin -s u bject varia bilities in palb ociclib  ex p os ur es, a n o n -linear mixe d eff ects m o del will 
be us e d.  I n partic ular, w e will c o nsider m o dels of t he f or m  
𝑦𝑖 [𝑡] =  𝛹 [𝑡,𝜃,𝜂𝑖;𝐷,𝑥] +  𝜀𝑖 [𝑡]   
w her e de n otes yi [t] t he o bs er ve d plas ma c o nc e ntr atio n at ti me t, t (t 1, …, t k), o btaine d 
t hr o u g h spars e s a m plin g as pr e vio usly des cribe d, f or t he i -t h in divid ual a n d  de n otes t he 
vect or of p o p ulatio n par a meters of size p. T he q ua ntit y D de n otes t he d os e le vel a n d x is a 
vect or of a d ditio nal c o variates. T he r a n d o m vect ors i a n d  = (i[t 1], …, i[t k]) ac c o u nt f or the 
bet w ee n a n d wit hin s u bject varia bilities r es pectively.  If p ossible, n o n -linearities wit h 
r es pect t o ti me will be e x plor e d. T he m o del will be fitte d usin g first-or der c o n ditio nal 
ma xi m u m likelih o o d esti matio n in t he N O N M E M pr o gr a m ( versio n 5)
1 61 .  F or t his p ur pose 
it will be ass u me d t hat t he r a n d o m eff ects i.... n ar e in de pe n de nt q-variate mea n -zer o n or mal 
r a n d o m varia bles wit h c o m m o n varia nc e i w her e q is at m ost e q ual t o p (t he di me nsio n of 
t he p o p ulatio n par a meter vect or 𝜃). It is als o ass u me d t hat t he meas ur e me nt err ors 1, …, n 
ar e in de pe n de nt k -variate mea n -zer o n or mal vect ors wit h c o m m o n c o varia nc e matrix. 
I n divid ual p har mac o kinetic par a meter esti mates will be o btaine d fr o m t he esti mate d 
p o p ulatio n P K m o del f or palb ociclib .   
C o variate testin g will be perf or me d t o ide ntif y s o ur c es of varia bilit y in e x p os ur e t o 
palb ociclib  a m o n g in divid uals. 
C o variates t hat will be teste d inclu de: de m o gr a p hic 
c har acteristics, or ga n f u nctio n mar kers, dis eas e s e verit y, ge netic mar kers, a n d c o n c o mitant 
me dic atio ns a n d ti me r elatio ns hip t o in gestio n of t he pr e vio us meal. 
 All derive d P K 
par a meters will be s u m marize d usin g sta n dar d n u meric al a n d gr a p hic al dis pla ys . 
P h ar m ac o m et ric A n al yses:  
P atie nts  wit h p har mac o kinetic, ke y t o xicit y a n d effic ac y data will be inclu de d in t he 
p har mac o metric a nalys es.  First a p o p ulatio n p har mac o kinetic a p pr oac h will be e m plo ye d 
t o a nalyze t he plas ma c o nc e ntr atio n data f or palb ociclib. Rele va nt de m o gr a p hic a n d 
intrinsic /e xtrinsic f act ors will be e x plor e d f or c o variate r elatio ns hip.  Diff er e nt e m piric al 
Ba yesia n P K par a meters will be c orr elate d initially 
wit h t o xicit y a n d later wit h effic ac y 
e n d p oints s uc h as t he o ver all s ur vival. P har mac o kinetic -bio mar ker r elatio ns hips usin g ke y 
mar kers will als o be c o n d ucte d.  

 
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P o p ul ati o n P K s a m pli n g s c h e d ule  
P atie nts ar e s c he d ule d t o be r e vie w e d in t he clinic o n Da y 1 5 of c ycle 1 a n d 2. Ve n o us blo o d 
( 5 ml) will be o btaine d at t he ti me of t hes e clinic visits a n d me dic al e valuatio ns.  P atients 
M U S T 
be instr ucte d N O T  t o ta ke t heir palb ociclib d os e o n t he da y of t he s e visits bef ore 
bein g s ee n a n d ha vin g t his blo o d s a m ple o btaine d.  Blo o d will be c ollecte d int o p otassiu m  
E D T A (la ve n der t o p)  t u bes, a n d plas ma s e par ate d b y c e ntrif u gatio n at 1 5 0 0 g f or 1 0 
min utes. Aliq u ots of plas m a will t he n be plac e d in la belle d p oly pr o p yle ne t u bes ( 1 m L in 
eac h of t w o t u bes) a n d st or e d at -7 0 t o - 8 0 o C u ntil s hip pe d o n dr y ic e t o t he Allia nc e 
P har mac olo g y/ P har mac o kinetic c or e as in dic ate d in S ectio n 6. 2 . 1.  
                                                                                                              

 
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1 5. 0  
G E N E R A L  R E G U L A T O R Y  C O N S I D E R A TI O N S  A N D  C R E D E N TI A LI N G  
1 5. 1  Ge ri at ric Ass ess m e nt Tr ai ni n g  
At eac h participatin g site, a r es ear c h n urs e or  clinic al r es ear c h pr of essio nal ( C R P)  (pers on w ho 
inte n ds t o a d minister t he geriatric ass ess me nt) will r ec eive tr ainin g o n a d ministr atio n of t he 
geriatric ass ess me nt usin g t he o nline vide o tr ainin g m o d ule t hr o u g h t he Alli a nc e w e bsite, 
h y perlin k belo w:  
 
T o lo gin, s elect “ Me m ber L o gin” o n t he Allia nc e h o me pa ge a n d e nter t he C T E P -I A M ac c o unt 
us er na me a n d pass w or d. After lo g gin g in, t he tr ainin g m o d ule c a n be f o u n d u n der e d uc atio n a n d 
tr ainin g > o nline tr ainin g a n d u n der “ F or Site Staff. ” O nc e t he tr ainin g is c o m plete, print a c opy 
of t he c o m pletio n c ertific ate t o kee p in t he st u d y r ec or ds  a n d s u b mit it t o C T S U ac c or din g to 
S ectio n 4. 2 . 3. Tr ainin g c o m plete d wit hin t he past t w o years is ac c e pta b le, as it is n ot st u dy 
s pecific .  
An y f urt her q uestio ns or c o nc er ns r e gar din g a d ministerin g  t he geriatric ass ess me nt ma y be 
dir ecte d t o t he st u d y c hair.  
 
 

 
Allia nc e A1 7 1 6 0 1  
 
7 7  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
1 6. 0  
R E F E R E N C ES  
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P MI D: 1 8 2 9 8 5 6 6.  
1 2 6  
Ca na ves e M, S a nt o L, Raje N. C yclin de pe n de nt kinas es in c a nc er: p ote ntial f or t her a pe utic 
int er ve ntio n. Ca nc er Biol T her. 2 0 1 2 Ma y; 1 3( 7):4 5 1-7. d oi:1 0. 4 1 6 1/c bt. 1 9 5 8 9. Re vie w. P u b Med 
P MI D: 2 2 3 6 1 7 3 4.  
1 2 7  
Bart k o va J, L u kas J, M uller H, L utz h oft D, Str a uss M, Barte k J: C yclin D 1 pr otein e x pr essio n a nd 
f u nctio n in h u ma n br east c a nc er. I nt J C a ncer 1 9 9 4, 5 7:3 5 3 -3 6 1.  
1 2 8  
Gillett C, F a ntl V, S mit h R, Fis her C, Barte k J, Dic ks o n C, Bar nes D, P eters G: A m plific atio n a n d 
o ver e x pr essio n  of c yclin D 1 in br east c a nc er detecte d b y i m m u n o hist oc he mic al stainin g. C a ncer 
R es 1 9 9 4, 5 4:1 8 1 2 -1 8 1 7.  
1 2 9  
Ke n n y F S, Hui R, M us gr o ve E A, Gee J M, Bla me y R W, Nic h ols o n RI, S ut herla n d R L, R o berts on 
J F: O ver e x pr essio n of c yclin D 1 mess e n ger R N A pr e dicts f or p o or pr o g n osis in estr o ge n r ece ptor -
p ositive br east c a nc er. Cli n C a ncer R es 1 9 9 9,  5:2 0 6 9 -2 0 7 6.  
1 3 0  
H w a n g T S, Ha n H S, Ho n g Y C, Lee HJ, P aik N S: Pr o g n ostic value of c o m bine d a nalysis of c yclin 
D 1 a n d estr o ge n r ec e pt or stat us in br east c a ncer patie nts. P at h ol I nt 2 0 0 3, 5 3:7 4 -8 0.  
1 3 1  
R u das M, Le h nert M, Hu y n h A, J a kes z R, Sin ger C, La x S, et al:  C yclin D 1 e x pr essio n in br east 
c a nc er patie nts r ec eiv in g a dju va nt ta m o xif e n-bas e d t her a p y. Cli n C a ncer R es 2 0 0 8, 1 4:1 7 6 7 -1 774.  
1 3 2  
Jirstr o m K, Ste n da hl M, R y de n L, Kr o n bla d A, Be n da hl P O, Stal O, La n d ber g G: Ad vers e eff ect 
of a dju va nt ta m o xif e n in pr e me n o pa us al  br east c a nc er wit h c yclin D 1 ge ne a m plific atio n. C a ncer  
R es 2 0 0 5, 6 5:8 0 0 9 -8 0 1 6.  
1 3 3  
Fr y D W, Har ve y PJ, Keller P R, Elliott W L, Mea de M, Tr ac het E, et al: S pecific  in hibitio n of c yclin-
de pe n de nt kinas e 4/ 6 b y P D 0 3 3 2 9 9 1  a n d ass ociate d a ntit u m or activit y in h u ma n t u m or xe n o gr afts.  
M ol C a ncer T her 2 0 0 4, 3:1 4 2 7 -1 4 3 8.  
1 3 4  
T o o g o o d P L, Har ve y PJ, Re pine J T, S hee ha n DJ, Va n der Wel S N, et al: Dis c o ver y of a p ote nt a nd 
s elective in hibit or of c yclin-de pe n de nt kinas e 4/ 6. J M e d C he m 2 0 0 5, 4 8:2 3 8 8 -2 4 0 6.   
1 3 5  
Mar zec M, Kas pr z yc ka 
M, Lai R, Gla d de n A B, et al: 
Ma ntle  c ell ly m p h o ma c ells e x pr ess 
pr e d o mina ntly  c yclin D 1a is of or m a n d ar e hig hly s e nsitive t o s elective in hibitio n of C D K4 kinas e 
activit y. Bl o o d 2 0 0 6, 1 0 8:1 7 4 4 -1 7 5 0.   
1 3 6  
S aa b R, Bills J L, Mic eli A P, An ders o n C M, et al: P har mac olo gic in hibitio n of  c yclin -de p e n de nt 
kinas e 4/ 6 activit y arr ests pr olif er atio n in  m y o blasts a n d r ha b d o m y os ar c o ma -derive d c ells. M ol 
C a ncer T her 2 0 0 6, 5:1 2 9 9 -1 3 0 8.  
1 3 7  
Ba u g h n L B, Di Libert o M, W u K, T o o g o o d P L, L o uie T, G otts c halk R, et al: A n o vel  or ally active 
s m all m olec ule p ote ntly in d uc es G 1 arr est in pri mar y m yelo ma c ells a n d pr e ve nts t u m or gr o wth by 
s pecific  in hibitio n of c yclin-de pe n de nt kinas e 4/ 6. C a ncer R es 2 0 0 6, 6 6:7 6 6 1 -7 6 6 7.  
1 3 8  
De n g Q, G u o H, Dai J, Ya n g L, W u C, Wa n g Q, Hu Z, et al: I m p utatio n -bas e d ass ociatio n a nalyses 
ide ntif y ne w lu n g c a nc er s us c e ptibilit y varia nts in C D K6 a n d S H3 R F 1 a n d t heir inter actio ns with 
s m o kin g 
in  
C hines e 
p o p ulatio ns. 
Car cin o ge nesis. 
2 0 1 3 
S e p; 3 4( 9):2 0 1 0 -6. 
d oi: 
1 0. 1 0 9 3/c ar cin/ b gt 1 4 5. P u b Me d P MI D: 2 3 6 4 4 7 4 4.  
1 3 9  
Ye Y, Ya n g H, Gr oss ma n H B , Din ne y C, W u X, G u J. Ge netic varia nts in c ell c ycle c o ntr ol 
pat h w a y c o nf er s us c e ptibilit y t o bla d der c a nc er. Ca nc er. 2 0 0 8 J u n; 1 1 2( 1 1):2 4 6 7 -7 4. d oi: 
1 0. 1 0 0 2/c ncr. 23 4 7 2. P u b Me d P MI D: 1 8 3 6 1 4 2 7.  
1 4 0.  
Kibel A S, Ah n J, Isik ba y M, Kli m A, W u W S, Ha yes R B, Is aacs W B , Da w E W. Ge netic varia nts 
in c ell c ycle c o ntr ol pat h w a y c o nfer s usce ptibilit y t o a g gr essive pr ostate c arcin o ma. Pr ostate. 2016 
Apr; 7 6( 5):4 7 9 -9 0. d oi:1 0. 1 0 0 2/ pr os. 2 31 3 9. P u b Me d P MI D: 2 6 7 0 8 9 9 3  
1 4 1.  
Driver K E, S o n g H, Les ue ur F, Ah me d S, Bar b os a -M or ais N L, T yr er J P, et al: St u dies in 
E pide miolo g y a n d Ris ks of Ca nc er Her e dit y ( S E A R C H) T ea m.. Ass ociatio n of sin gle -n ucle otide 
p oly m or p his ms in t he c ell c ycle ge nes wit h br east ca ncer in t he Britis h p o p ulatio n. Car cin o ge nesis. 
2 0 0 8 F e b; 2 9( 2):3 3 3 -4 1. d oi: 1 0. 1 0 9 3/c ar cin/ b g m 2 8 4. P u b Me d P MI D: 1 8 1 7 4 2 4 3; P u b Me d  Ce ntr al 
P M CI D: P M C 2 3 4 6 5 4 6.  

 
Allia nc e A1 7 1 6 0 1  
 
8 5  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
1 4 2.  
G o o de E L, Fridle y B L, Vier ka nt R A, C u n nin g ha m J M, et al: Ca n didate ge ne a nalysis usin g 
i m p ute d ge n ot y pes: c ell c ycle sin gle-n ucle otide p oly m or p his ms a n d o varia n c a nc er ris k. Ca nc er 
E pide miol  Bio mar kers Pr e v. 2 0 0 9 
Mar; 1 8( 3):9 3 5 -4 4. d oi: 1 0. 1 1 5 8/ 1 0 5 5 -9 9 6 5. E PI -0 8-0 860. 
P u b Me d P MI D: 1 9 2 5 8 4 7 7; P u b Me d Ce ntr al P M CI D: P M C 2 7 4 3 1 8 4.  
1 4 3.  
Cai H, Xia n g Y B, Q u S, L o n g J, Cai Q, Ga o J, Z he n g 
W, S h u X O. Ass ociatio n of ge netic 
p oly m or p his ms in c ell -c ycle c o ntr ol g e nes a n d s usce ptibilit y t o e n d o metrial c a nc er a m o n g C hinese 
w o m e n. A m J E pide miol. 2 0 1 1 J u n 1; 1 7 3( 1 1):1 2 6 3 -7 1. d oi: 1 0. 1 0 9 3/aje/ k wr 0 0 2. P u b Me d P MI D: 
2 1 4 5 4 8 2 6; P u b Me d Ce ntr al P M CI D: P M C 3 1 0 1 0 6 6.  
1 4 4.  
Ca m pa D, P ast or e M, Ge ntilu o m o M, T alar -W ojnar o w s ka R, et al:. F u nctio nal sin gle n ucle otide 
p oly m or p his ms wit hin t he c yclin -de pe n de nt kinas e in hibit or 2 A/ 2 B r e gio n aff ect pa ncr eatic cancer 
ris k. O nc otar get. 2 0 1 6 Au g 3 0; 7( 3 5):5 7 0 1 1-5 7 0 2 0. d oi:1 0. 1 8 6 3 2/ o nc otar get. 1 0 9 3 5. P u b Me d 
P MI D: 2 7 4 8 6 9 7 9; P u b Me d Ce ntr al P M CI D: P M C 5 3 0 2 9 6 9.  
1 4 5.  
Cacina C, Ya yli m -Er alta n I, Arika n S, S a gla m E K, Ze y be k U, Is bir T. Ass ociatio n bet w een 
C D K N 1 A S er 3 1 Ar g a n d C 2 0 T ge ne p oly m or p his ms a n d c olor ectal c a nc er ris k a n d pr o g n osis. I n 
Viv o. 2 0 1 0 Mar -Apr; 2 4( 2):1 7 9 -8 3. P u b Me d P MI D:2 0 3 6 3 9 9 1.  
1 4 6.  
S c h o n d orf T, Eis e le L, G o hrin g UJ, Valter M M, et al : T he V1 0 9 G p oly m or p his m of t he p 2 7 ge ne 
C D K N 1 B in dic ates a w ors e o utc o me in n o de -ne gative br east c a nc er patie nts. T u mo ur Biol. 2 0 0 4, 
2 5: 3 0 6 -3 1 2. 1 0. 1 1 5 9/ 0 0 0 0 8 13 9 6.  P ub Me d P MI D: 1 5 6 2 7 8 9 6.  
1 4 7.  
Azzat o E M, Driver K E, Les ue ur F,  S ha h M, et al : Eff ects of c o m m o n ger mline ge netic variatio n 
in c ell c ycle c o ntr ol ge nes o n breast ca ncer s ur vival: r es ults fr o m a p o p ulatio n-bas e d c o h ort. Br east 
Ca nc er Res. 2 0 0 8; 1 0( 3): R 4 7. d oi: 1 0. 1 1 8 6/ bcr 2 1 0 0. P u b Me d P MI D: 1 8 5 0 7 8 3 7; P u b Me d Ce ntr al 
P M CI D: P M C 2 4 8 1 4 9 6.  
1 4 8.  
Driver K E, S o n g H, Les ue ur F, Ah me d S, Bar b os a -M or ais N L, T yr er J P, P o n der B A, East o n D F, 
P har oa h P D, D u n nin g A M; St u dies in E pide miolo g y a n d Ris ks of Ca nc er Her e dit y ( S E A R C H) 
T ea m.. Ass ociatio n of sin gle -n ucle otide p oly m or p his ms in t he c ell  c ycle ge nes wit h br east c a ncer 
in t he Britis h p o p ulatio n. Car cin o ge nesis. 2 0 0 8 F e b; 2 9( 2):3 3 3-4 1. d oi: 1 0. 1 0 9 3/c ar cin/ b g m 284. 
P u b Me d P MI D:1 8 1 7 4 2 4 3; P u b Me d Ce ntr al P M CI D: P M C 2 3 4 6 5 4 6.    
1 4 9.  
S h u X O, M o or e D B, Cai Q, C he n g J, We n W, Pier c e L, Cai H, Ga o Y T, Z he n g  W: Ass ociatio n of 
c yclin D 1 ge n ot y pe wit h br east c a nc er ris k a n d s ur vival. Ca nc er E pide miol Bio mar kers Pr e v. 2 0 05, 
1 4: 9 1 -9 7.  P u b Me d P MI D: 1 5 6 6 8 4 8 1.  
1 5 0.  
S olei ma ni Z, Kheir k ha h D, S harif M R, S harif A, Kari mia n M, Afta bi Y. Ass ociatio n of C C N D 1 
Ge ne c. 8 7 0 G > A P oly m or p his m wit h Br east Ca nc er Ris k: A Cas e -C o ntr ol St u d y a n d a Meta -
Analysis. P at h ol O nc ol Res. 2 0 1 6 Dec 2 1. d oi:1 0. 1 0 0 7/s 1 2 2 5 3 -0 1 6 -0 16 5 -3. [ E p u b a hea d of print] 
P u b Me d P MI D: 2 8 0 0 4 3 5 3.  
1 5 1.  
Ya yli m -Er alta n I, Er ge n A, G ör m üs U, Arika n S, Küç üc ü k S, S a h in O, Yigit N, Yildiz Y, Is bir T. 
Br east c a nc er a n d c yclin D 1 ge ne p oly m or p his m in T ur kis h w o me n. I n Viv o. 2 0 0 9 S e p -
Oct; 2 3( 5):7 6 7 -7 2. P u b Me d P MI D: 1 9 7 7 9 1 1 3.  
1 5 2.  
Be wic k M A, C o nlo n M S, Lafr e nie R M. P oly m or p his ms in X R C C 1, X R C C 3, a n d C C N D 1 a n d 
s ur vival after tr eat me nt f or metastatic br east c a nc er. J Clin O nc ol. 2 0 0 6 Dec 2 0; 2 4( 3 6):5 6 4 5-51. 
P u b Me d P MI D: 1 7 1 1 6 9 4 3.  
1 5 3.  
Z h o u L P, Ya o F, L ua n H, Wa n g Y L, D o n g X H, Z h o u W W, Wa n g Q H. C Y P 3 A4 * 1 Bp oly m or p his m 
a n d c a nc er ris k: a Hu G E r e vie w a n d meta -a nalysis. T u m o ur Biol. 2 0 1 3 Apr; 3 4( 2):6 4 9 -6 0. d oi: 
1 0. 1 0 0 7/s 1 3 2 7 7 -0 1 2-0 5 9 2 -z. Re vie w. P ub Me d P MI D: 2 3 1 7 9 4 0 2.  
1 5 4.  
J o h ns o n N, D u d brid ge F, Orr N, Gibs o n L, J o nes M E, S c h oe ma ker MJ, et al. Ge netic variatio n at 
C Y P 3 A is ass ociate d wit h a ge at me nar c he a n d br east c a nc er ris k: a c as e -c o ntr ol st u d y . Br east 
Ca nc er Res. 2 0 1 4 Ma y 2 6; 1 6( 3): R 5 1. d oi: 1 0. 1 1 8 6/ bcr 36 6 2. P u b Me d P MI D: 2 4 8 8 7 5 1 5; P u b Med 
Ce ntr al P M CI D: P M C 4 5 2 2 5 9 4.  

 
Allia nc e A1 7 1 6 0 1  
 
8 6  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
1 5 5.  
Wilb or n T W, La n g N P, S mit h M, Melet h S, F ala n y C N. Ass ociatio n of S U L T 2 A1 allelic varia nts 
wit h plas ma a dr e nal a n dr o ge ns a n d pr ostat e c a nc er in Afric a n -A meric a n me n. J Ster oid Bioc he m 
M ol Biol. 2 0 0 6 J u n; 9 9( 4 -5):2 0 9 -1 4. P u b Me d P MI D: 1 6 6 1 7 0 1 4.  
1 5 6.  
K w o n E M, Holt S K, F u R, Kolb S, Willia ms G, Sta nf or d J L, Ostr a n der E A. An dr o ge n 
m et a b olis m a n d J A K/ S T A T pat h w a y ge nes a n d pr ostate c a ncer ris k. Ca nc er E pide miol. 2 0 1 2 
Au g; 3 6( 4):3 4 7 -5 3. d oi: 1 0. 1 0 1 6/j. c a ne p. 2 0 1 2. 0 4. 0 0 2. P u b Me d P MI D: 2 2 5 4 2 9 4 9; P u b Me d 
Ce ntr al P M CI D: P M C 3 3 9 2 4 0 9.  
1 5 7.  
Oest err eic h S, He nr y N L, Kid w ell K M, Va n P oz na k C H, et al: Ass ociatio ns bet w ee n ge netic 
varia nts a n d t he eff ect of letr oz ole a n d e xe mesta ne o n b o ne mass a n d b o ne t ur n o ver. Br east 
Ca nc er Res Tr eat. 2 0 1 5 N o v; 1 5 4( 2):2 6 3 -7 3. d oi: 1 0. 1 0 0 7/s 1 05 4 9 -0 15 -3 6 0 8-8. P u b Me d P MI D:  
2 6 5 3 6 8 7 0; P u b Me d Ce ntr al P M CI D: P M C 4 8 0 7 6 1 0.  
1 5 8.  
Le yla n d -J o nes B, Gr a y K P, Abr a m o vitz M, Bo uz y k M, Yo u n g B, et al; BI G 1 -9 8 C olla b or ative 
Gr o u p.. E S R 1 a n d E S R 2 p oly m or p his ms in t he BI G 1 -9 8 trial c o m parin g a dju va nt letr oz ole 
vers us ta m o xif e n or t heir s e q ue nc e f or early br east c a ncer. Br east Ca nc er Res Treat. 2 0 1 5 
Dec; 1 5 4( 3):5 4 3 -5 5. d oi:1 0. 1 0 0 7/s 10 5 4 9 -0 1 5 -3 63 4 -6. P u b Me d P MI D:  2 6 5 9 0 8 1 3; P u b Me d 
Ce ntr al P M CI D: P M C 4 7 3 0 9 4 9.  
1 5 9.  
Artigal Ã¡s O, Va n ni T, Hutz M H, As ht o n -Pr olla P, S c h w artz I V. I nflue nce of C Y P 1 9 A1 
p oly m or p his ms o n t he tr eat me nt of br east c a ncer wit h ar o matas e in hibit ors: a s yste matic r e vie w 
a n d meta-a nalysis. B M C Me d. 2 0 1 5 J u n 1 1; 1 3:1 3 9. d oi: 1 0. 1 1 8 6/s 1 2 9 1 6-0 1 5 -0 3 7 3 -9. P u b Me d 
P MI D: 2 6 0 6 7 7 2 1; P u b Me d Ce ntr al P M CI D: P M C 4 4 7 5 2 9 4  
1 6 0.  
Ra u nio  H, etal  Br J Clin P har mac ol . 2 0 0 1  Oct;  5 2( 4): 3 5 7 – 3 6 3  
1 6 1.     Beal, S. a n d L. S heiner, N O N M E M Us ers G uide. 1 9 9 2, N O N M E M Pr oject Gr o u p, Universit y of  
C alif or nia at S a n Fr a ncis c o: S a n Fr a ncis c o  
 
 
 

 
Allia nc e A1 7 1 6 0 1  
 
8 7  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
1 7. 0  M O D E L C O N S E N T F O R M  
St u d y Title f or St u d y P articipa nts:  
 
Testi n g t he effects of p al b o cicli b a n d f ul vestra nt o r letro z ole f o r p atie nts 
7 0 ye ars of a ge  a n d ol der  wit h met ast atic bre ast c a ncer  
 
Official St u d y Title f or I nter net Searc h o n htt p:// w w w. Clinical Trials. go v :  
Alli a nce A 1 7 1 6 0 1: A P h ase II Tri al Assessi n g t he t olera bilit y of P al b o cicli b i n 
c o m bi n ati o n wit h letro z ole o r f ul vestra nt i n p atie nts a ge d 7 0 a n d ol der wit h 
estro ge n  rece pt o r p ositi ve, H E R -2 ne g ati ve met ast atic bre ast c a ncer  
 
T his st u d y is c o n d ucte d b y t he Allia nc e f or Clin ic al Trials in O nc olo g y, a natio nal clinic al 
res e arc h gr o u p s u p p orte d b y t he N atio nal Ca nc er I nstit ute T his st u d y has p u blic f u n din g fr o m t he 
N atio nal Ca nc er I nstit ute ( N CI), part of t he N atio nal I nstit utes of H e alt h ( NI H) in t he U nite d 
States D e part me nt o f H e alt h a n d H u ma n Ser vic es. T he Allia nc e is ma de u p of c a nc er d oct ors, 
he alt h pr ofessio nals, a n d la b orat or y res e arc hers, w h os e g oal is t o de velo p better tre at me nts f or 
c a nc er, t o pre ve nt c a nc er, t o re d uc e side effe cts fr o m c a nc er, a n d t o i m pr o ve t he q uali t y of life of 
c a nc er patie nts.   
 
 
W h at is t he us u al a p pro ac h t o m y bre ast c a ncer ?  
We are as kin g y o u t o ta ke part in t his st u d y be c a us e y o u 
are 7 0 ye ars old or o ver a n d ha ve be e n 
re c e ntly dia g n os e d wit h estr o ge n re c e pt or p ositive, H E R 2 ne gative metastatic bre ast c a nc er. 
P atie nts wit h t his metastatic bre ast c a nc er are us ually tre ate d wit h a dr u g c alle d palb ociclib alo n g 
wit h a h or m o nal a ge nt, eit her f ulvestra nt or letr oz ole, as de ter mine d b y y o ur  d oct or.  P alb ocic lib 
a n d letr oz ole are give n b y m o ut h a n d f ulvestra nt is a n inje ctio n. T his st u d y f ollo ws t he us ual 
F o o d a n d Dr u g A d ministratio n ( F D A ) a p pr o ve d tre at me nt, b ut w e are c o n d uctin g t his st u d y 
be c a us e  w e d o n’t k n o w if older patie nts ha ve m ore side effe cts t ha n y o u n ger patie nts.  
 
 
W h at are m y ot her c h oices if I d o n ot t a ke p art i n t his st u d y ?  
If y o u de cide n ot t o ta ke part in t his st u d y, y o u ha ve ot her c h oic es. F or e xa m ple: 
•  Y o u ma y c h o os e t o ha ve t he us ual a p pr oa c h des cribe d a b o ve  wit h o ut bein g in a 
st u d y. 
•  Y o u ma y c h o os e t o ta ke part in a differe nt st u d y, if o ne is a vaila ble.  
•  Y o u ma y c h o os e n ot t o be tre ate d f or c a nc er a n d ma y w a nt t o re c eive c o mf ort c are t o 
relie ve s y m pt o ms. 
 
 
W h y is t his st u d y bei n g d o ne ?  
T he p ur p os e of t his st u d y is t o fin d o ut t he side effe cts t hat t he sta n dar d, F D A -a p pr o ve d 
c o m binatio n tre at me nt of letr oz ole or f ulvestra nt a n d palb ocicli b has o n patie nts 7 0 ye ars old a n d 
o ver.  P alb oci clib give n alo n g wit h letr oz ole or fulvestra nt inste a d of letr oz ole or f ulvestra nt 

 
Allia nc e A1 7 1 6 0 1  
 
8 8  
N CI Versi o n D at e: 5/ 2 9 / 2 0 2 0 
U p d ate 5   
alo ne s e e ms t o pre ve nt t he c a nc er fr o m gettin g w ors e. H o w e ver, fe w patie nts a ge d  7 5  a n d older 
participate d in pre vio us  st u dies. T here will be a b o ut  8 8  pe o ple ta kin g part in t his st u d y.  
 
 
W h at are t he st u d y gro u ps ? 
I n t his st u d y, all st u d y participa nts will get t he s a me tre at me nt. Y o u will ta ke o ne c a ps ule  of 
palb ocicli b o nc e a da y  wit h f o o d f or  2 1 da ys. Y o u will n ot ta ke palb ocicli b f or t he ne xt 7 da ys. 
T his 2 8 da y perio d is c alle d a c ycle. Y o u  s h o uld tr y t o ta ke t he palb ociclib c a ps ules at a b o ut t he 
s a me ti me e a c h da y. Y o u s h o uld n ot ha ve gra pefr uit or gra pefr uit juic e w hile o n t his st u d y. Y o u 
s h o uld also c he c k wit h y o ur d oct or or p har ma cist bef ore usin g a n y ne w me dicines, inclu din g 
o ver -t he-c o u nter dr u gs be c a us e of p ossible dr u g intera ctio ns.  
 
D urin g t his perio d, y o u will als o be give n eit her letr oz ole or f ulvestra nt bas e d o n w hat y o ur 
d oct or de cides. If  y o ur d oct or pres cribes letr oz ole, y o u will ta ke o ne pill daily f or 2 8 da ys. If 
y o ur d oct or pres cribes f ulvestra nt y o u will re c eive inje ctio ns o n t he first da y a n d fifte e nt h da y of 
t he first c ycle a n d t he n o n t he first da y of e ver y c ycle after t hat. Y o u wi ll c o ntin ue o n t his 
tre at me nt pla n  u ntil y o ur c a nc er pr o gress es or if y o u ha ve side effe cts t hat ma y pre ve nt y o u fr o m 
c o ntin uin g t o ta ke t he tre at me nt.  
 
E ac h c ycle is  2 8 d a ys  ( 4 we e ks) 
 
P al b o cicli b pl us  Letr o z ole  
 
We e k 1  
We e k 2  
We e k 3  
We e k 4  
We e k 5 +  
P al b o cicli b  
1 c a ps ule 
e ver y da y 
1 c a ps ule 
e ver y da y 
1 c a ps ule 
e ver y da y 
N o c a ps ule  
1 c a ps ule e ver y da y f or 
2 1 da ys, t he n 7 da ys n o 
c a ps ules  
Letr o z ole  
1 pill e ver y 
da y  
1 pill 
e ver y da y 
1 pill e ver y 
da y  
1 pill e ver y 
da y  
1 pill e ver y da y f or 2 8 
da ys  
 
If y o u f or get t o ta ke a c a ps ule of palb ocicli b or letr oz ole, d o n ot ma ke u p t he miss e d d os e. S kip 
t hat d os e a n d ta ke t he dr u g o n t he ne xt da y.  
 
O r  
 
P al b o cicli b pl us  F ul v e str a nt  
 
We e k 1  
We e k 2  
We e k 3  
We e k 4  
We e ks 5 +  
P al b o cicli b  
1 c a ps ule 
e ver y da y 
1 c a ps ule 
e ver y da y 
1 c a ps ule 
e ver y da y 
N o c a ps ule  
1 c a ps ule e ver y da y f or 
2 1 da ys, t he n 7 da ys n o 
c a ps ules  
F ul v e str a nt  
I nje ctio n 
o n D a y 1  
N o 
inje ctio n 
I nje ctio n o n 
D a y 1 5  
N o 
inje ctio n 
I nje ctio n o n D a y 1 of 
e ver y 2 8 -da y c ycle  
 
If y o u f or get t o ta ke a c a ps ule of palb ocicli b, d o n ot ma ke u p t he miss e d d os e. S kip t hat d os e a n d 
ta ke t he c a ps ule o n t he ne xt da y. 

 
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H o w l o n g will I be i n t his st u d y ?  
Y o u will re c eive t he  st u d y tre at me nt f or as lo n g as y o u d o n ot ha ve s e vere side effe cts a n d y o ur 
c a nc er d oes n ot get w ors e.  If y o u  de velo p s e vere side effe cts or y o ur c a nc er gets w ors e , y o ur 
d oct or ma y de cide t o re m o ve y o u fr o m t he st u d y tre at me nt. After y o u st o p t he st u d y tre at me nt, 
y o ur  d oct or will c o ntin ue t o f ollo w y o ur pr o gress e ver y ye ar f or u p t o five ye ars. 
 
 
W h at e xtra tests, a n d pro ce d ures will I h a ve if I t a ke p art  i n t his st u d y ? 
M ost of t he e xa ms, tests, a n d pr oc e d ures y o u will ha ve are part of t he us ual a p pr oa c h f or y o ur 
c a nc er. H o w e ver, t here are s o me e xtra q uestio n naires t hat y o u will ne e d t o c o m plete if y o u ta ke 
part in t his st u d y . 
 
Y o u will be as ke d t o c o m plete  fo ur  q uestio n naires a n d perf or m s o me tas ks as part of t his st u d y.  
T he q uestio n naires will be us e d in t his st u d y in or der t o fin d o ut m ore a b o ut h o w y o u fe el d urin g 
c a nc er tre at me nt a n d w hat t he effe ct of t he tre at me nt ma y be.  
 
T he q uestio n naires will be c o m plete d at t he f ollo win g ti me p oints: 
 
Ge ri atric A s s ess me nt: Y o u will be as ke d t o c o m plete t he  geriatric ass ess me nt bef ore y o u be gin 
tre at me nt, prior t o c ycle 4, a n d at t he e n d of y o ur tre at me nt perio d. It will ta ke a b o ut 3 0 min utes 
t o c o m plete. T he geriatric ass ess me nt in v olves a q uestio n naire, a n inter vie w a n d a t as k. S o me 
q uestio ns will be as ke d b y a me m ber of t he he alt h c are te a m. Y o u will c o m plete ot her q uestio ns 
o n y o ur o w n. If y o u ha ve diffic ult y c o m pletin g a n y of t he q uestio ns or tas ks, a me m ber of t he 
te a m will help y o u. Y o u ma y s kip a n y q uestio ns y o u d o n ot  wis h t o a ns w er. T he w alkin g tas k 
in v olves mini mal risk.  It will in v olve y o u gettin g u p fr o m a c hair, w alkin g 1 0 fe et, a n d ret ur nin g 
t o t he c hair. P ossible ris ks inclu de fe elin g tire d, dizziness, incre as e d he art rate, a n d fallin g. T o 
mini mize t his ris k y o u  will be clos ely m o nit ore d b y a me m ber of t he he alt h c are te a m d urin g t his 
tas k. If y o u are u nc o mf orta ble wit h w alkin g, y o u ma y s kip t his tas k. 
 
Y o u will be as ke d t o c o m plete t hre e ot her q uestio n naires, t w o of w hic h will be re q uire d at t he 
be gin nin g of e ver y c ycle f or  t he first 6 c ycles of tre at me nt, a n d at t he e n d of y o ur tre at me nt 
perio d. T hes e q uestio n naires will in v olve q uestio ns a b o ut t he side e ffe cts y o u are e x perie ncin g 
fr o m y o ur tre at me nt a n d a b o ut y o ur ge neral q ualit y of life . T he y will ta ke a b o ut fifte e n t o t w e nt y 
min utes t o c o m plete.  T he ot her q uestio n naire  will o nly ne e d t o be c o m plete d at t he e n d of y o ur 
tre at me nt. It will as k q uestio ns re gar din g h o w t he st u d y helpe d y o u. It will ta ke a b o ut five 
min utes t o c o m plete.  
 
 
 
 

 
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Pill Di ar y  
Y o u will als o be c o m pletin g a pill diar y e ver y da y , f or t he first t hre e c ycles. Y o u will be as ke d t o 
brin g t he c o m plete d pill diar y at t he e n d of e ver y c ycle, t o ma ke s ure y o u are ta kin g t he c orre ct 
d os e a n d n ot m ore t ha n t he sta n dar d d os e.  
 
Y o u will re c eive r o utine s c a ns e ve r y 1 2 w e e ks t o s e e if y o ur c a nc er is gettin g w ors e or bet ter, as 
part of y o ur c a nc er c are. Y o ur d oct or will s e n d c o pies of t hes e s c a ns t o t he Allia nc e, s o t hat 
res e arc hers c a n e valuate w het her t he tre at me nt y o u are re c eivin g ma y c a us e loss of m us cle 
tiss ue.  
 
W h at p ossi ble ris ks c a n I e x pect fro m t a ki n g p art i n t his st u d y ? 
If y o u c h o os e t o ta ke part in t his st u d y, t here is a ris k t hat: 
•  Y o u ma y s pe n d m ore ti me in t he h os pital or d oct or’s offic e t ha n us ual  
•  Y o u ma y be as ke d s e nsitive or private q uestio ns w hic h y o u n or mally d o n ot dis c uss  
 
T he dr u gs us e d in t his s t u d y ma y affe ct h o w differe nt parts of y o ur b o d y w or k s uc h as y o ur liver, 
kid ne ys, he art, a n d blo o d. T he st u d y d oct or will test y o ur blo o d a n d let y o u k n o w if c ha n ges 
oc c ur t hat ma y affe ct y o ur he alt h.  
 
T here is als o a ris k t hat y o u c o uld ha ve side effe cts  fr o m t he st u d y dr u gs. 
 
H ere are i m p orta nt p oints a b o ut side effe cts:  
•  T he st u d y d oct ors d o n ot k n o w w h o will or will n ot ha ve side effe cts.  
•  S o me side effe cts ma y g o a w a y s o o n, s o me ma y last a lo n g ti me, or s o me ma y ne ver g o 
a w a y.  
•  S o me side effe cts ma y be s erio us a n d ma y e ve n res ult in de at h.  
 
Y o u c a n as k t he st u d y d oct or q uestio ns a b o ut side effe cts at a n y ti me. H ere are i m p orta nt p oints 
a b o ut h o w y o u a n d t he st u d y d oct or c a n ma ke side effe cts less of a pr o ble m:  
•  Tell t he st u d y d oct or if y o u n otic e or fe el a n yt hin g differe nt, s o t he y c a n s e e if y o u are 
ha vin g a side effe ct.  
•  T he st u d y d oct or ma y be a ble t o tre at s o me side effe cts.  
•  T he st u d y d oct or ma y a djust t he st u d y dr u gs t o tr y t o re d uc e side effe cts.  
 
T he ta bles belo w s h o w t he m ost c o m m o n a n d t he m ost s eri o us side effe cts t hat res e arc hers k n o w 
a b o ut. K e e p in min d t hat t here mig ht be ot her side effe cts t hat res e arc hers d o n ot yet k n o w a b o ut. 
If i m p orta nt ne w side effe cts are f o u n d, t he st u d y d oct or will dis c uss t hes e wit h y o u.  
 
 
P ossible side effe cts of P alb ociclib, Letr oz ole a n d F ulvestra nt : 
 
 

 
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P os si ble Si de Effe cts fo r P al b o cicli b ( P D -0 3 3 2 9 9 1)  
 
C O M M O N, S O M E M A Y B E S E RI O U S   
I n 1 0 0 pe o ple r ec eivin g P alb ociclib ( P D -0 3 3 2 9 9 1) , m ore t ha n 2 0 a n d u p t o 1 0 0 ma y ha ve: 
• 
Ane mia w hic h ma y r e q uir e blo o d tr a nsf usio n 
• 
Na us ea   
• 
Tir e d ness  
 
• 
I nf ectio n, es pecially w he n w hite blo o d c ell c o u nt is lo w   
 
O C C A SI O N A L, S O M E M A Y B E S E RI O U S   
I n 1 0 0 pe o ple r ec eivin g P alb ociclib ( P D -0 3 3 2 9 9 1) , fr o m 4 t o 2 0 ma y ha ve: 
• 
Blurr e d visio n, w aterin g e yes  
 
• 
Dr y e ye  , s kin 
• 
C o nstipatio n, diarr hea, v o mitin g   
• 
S or es in t he m o ut h w hic h ma y c a us e diffic ult y s w allo win g  
• 
F e ver   
• 
Br uisin g, blee din g  
 
• 
L oss of a p petite   
• 
C ha n ges in taste  
 
• 
Hea dac he  
 
• 
N os e blee d  
 
• 
Hair loss, r as h   
 
 
 
 
R A R E, A N D S E RI O U S  
I n 1 0 0 pe o ple r ec eivin g P alb ociclib ( P D -0 3 3 2 9 9 1) , 3 or f e wer ma y ha ve: 
• 
Da ma ge t o t he lu n gs w hic h ma y c a us e s h ortness of br eat h  
 
 
P os si ble Si de Effe cts of F ul v e str a nt  
C O M M O N, S O M E M A Y B E S E RI O U S  
I n 1 0 0 pe o ple re c eivin g F ulvestra nt, m ore t ha n 2 0 a n d u p t o 1 0 0 ma y ha ve: 
•  P ain  
•  Tire d ness  
•  I ncre as e d s w e atin g 
•  H ot flas hes, flus hin g  
•  S w ellin g a n d re d ness at t he site of t he me dic atio n inje ctio n  
 
O C C A SI O N A L, S O M E M A Y B E S E RI O U S  
I n 1 0 0 pe o ple re c eivin g F ulvestra nt, fr o m 4 t o 2 0 ma y ha ve: 
•  C o nstipatio n, diarr he a, na us e a, v o mitin g, loss of a p petite, he art b ur n  
•  S w ellin g of t he b o d y  
•  L oss of b o ne tiss ue, br o ke n b o ne, or de cre as e d heig ht  
•  Dizziness, he a da c he  

 
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O C C A SI O N A L, S O M E M A Y B E S E RI O U S  
I n 1 0 0 pe o ple re c eivin g F ulvestra nt, fr o m 4 t o 2 0 ma y ha ve: 
•  Diffic ult y sle e pin g  
•  Fluid ar o u n d lu n gs  
•  S w ellin g of t he liver w hic h ma y c a us e belly pain  
•  W orr y, de pressio n, m o o d s win gs  
•  H air  t hin nin g 
•  C o u g h  
 
R A R E, A N D S E RI O U S  
I n 1 0 0 pe o ple re c eivin g F ulvestra nt, 3 or fe w er ma y ha ve: 
•  Aller gic re a ctio n w hic h ma y c a us e ras h, lo w blo o d press ure, w he e zin g, s h ort ness of 
bre at h, s w ellin g of t he fa c e or t hr oat  
•  Liver da ma ge w hic h ma y c a us e yello w e yes a n d s kin  
•  V a ginal ble e din g  
•  Blo o d clot w hic h ma y c a us e s w ellin g, pain, s h ort ness of bre at h  
•  H e art atta c k or he art failure w hic h ma y res ult in c hest pain, s h ort ness of bre at h, s w ellin g 
of a n kles, a n d tire d ness  
•  Str o ke w hic h ma y c a us e w e a k ness, paralysis  
 
P os si ble Si de Effe cts of Letr o z ole  
C O M M O N, S O M E M A Y B E S E RI O U S  
I n 1 0 0 pe o ple re c eivin g Letr oz ole, m ore t ha n 2 0 a n d u p t o 1 0 0 ma y ha ve: 
•  P ain  
•  Tire d ness  
•  I ncre as e d s w e atin g 
•  H ot flas hes, flus hin g  
 
O C C A SI O N A L, S O M E M A Y B E S E RI O U S  
I n 1 0 0 pe o ple re c eivin g Letr oz ole, fr o m 4 t o 2 0 ma y ha ve:  
•  C o nstipatio n, diarr he a, na us e a, v o mitin g, loss of a p petite, he art b ur n  
•  S w ellin g of t he b o d y  
•  L oss of b o ne tiss ue, br o ke n b o ne, or de cre as e d heig ht  
•  Dizziness, he a da c he  
•  Diffic ult y sle e pin g  
•  Fluid ar o u n d lu n gs  
•  S w ellin g of t he liver w hic h ma y c a us e belly pain  
•  W orr y, de pressio n, m o o d s win gs  
•  H air t hin nin g  
 

 
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R A R E, A N D S E RI O U S  
I n 1 0 0 pe o ple re c eivin g Letr oz ole, 3 or fe w er ma y ha ve: 
•  Aller gic re a ctio n w hic h ma y c a us e ras h, lo w blo o d press ure, w he e zin g, s h ort ness of 
bre at h, s w ellin g of t he fa c e or t hr oat  
•  Liver da ma ge w hic h ma y c a us e yello w e yes a n d s kin  
•  V a ginal ble e din g  
•  Blo o d clot w hic h ma y c a us e s w ellin g, pain, s h ort ness of bre at h  
•  H e art atta c k or he art failure w hic h ma y c a us e s h ort ness of bre at h, s w ellin g of a n kles, a n d 
tire d ness 
•  Str o ke w hic h ma y c a us e w e a k ness, paralysis  
 
 
Ris ks fr o m q ue sti o n n aire s  
Y o u ma y be c o me tire d fr o m t he a m o u nt of ti me ne e de d t o fill o ut t he q uestio n naires a n d d o  t he 
ot her e valuatio ns. T he q uestio n naire will f oc us o n life iss ues t hat c o uld c a us e y o u t o be c o me 
e m otio nall y u ps et.   If y o u be c o me distress e d a me m ber of t he st u d y te a m will talk wit h y o u.  If 
ne e de d, y o u c a n be referre d t o y o ur d oct or t o deter mine h o w best t o ha n dle y o ur c o nc er ns .  
 
Ris ks fr o m wal ki n g t as k  
As part of t he geriatric ass ess me nt, y o u will be as ke d t o c o m plete a w alkin g tas k. Y o u ma y fe el 
tire d, dizz y, ha ve a n incre as e d he art rate or fall d urin g t he w alkin g tas k.  T o mini mize t his ris k, 
y o u will be clos ely m o nit ore d b y a me m ber of t he he alt h c are te a m d urin g t his tas k. If y o u are 
u nc o mf orta ble wit h w alkin g, y o u ma y s kip t his tas k.  
 
 
W h at p ossi ble be nefits c a n I e x pect fro m t a ki n g p art i n t his st u d y ?  
T his st u d y ma y or ma y n ot help y o u. H o w e ver, t his st u d y ma y help us u n dersta n d h o w t his st u d y 
dr u g w or ks  in older a d ults, a n d ma y help res e arc hers le ar n t hin gs t hat ma y help ot her older 
pe o ple in t he f u t ure. 
 
 
C a n I st o p t a ki n g p art i n t his st u d y ?  
Y es. Y o u c a n de cide t o st o p at a n y ti me. If y o u de cide t o st o p f or a n y re as o n, it is i m p orta nt t o let 
t he st u d y d oct or k n o w as s o o n as p ossible s o y o u c a n st o p s afely. If y o u st o p, y o u c a n de cide 
w het her or n ot t o let t he st u d y d oct or c o ntin ue t o pr o vide y o ur me dic al inf or matio n t o t he 
or ga nizatio n r u n nin g t he st u d y.  
 
T he st u d y d oct or will tell y o u a b o ut ne w inf or matio n or c ha n ges in t he st u d y t hat ma y affe ct 
y o ur he alt h or y o ur willin g ness t o c o ntin ue in t he  st u d y. 
 
I n t ur n, t he st u d y d oct or ma y re m o ve y o u fr o m t he st u d y, if: 
•  Y o ur he alt h c ha n ges a n d t he st u d y is n o lo n ger in y o ur best interest  
•  N e w inf or matio n be c o mes a vaila ble  
•  Y o u d o n ot f ollo w t he st u d y r ules  
•  T he st u d y is st o p pe d b y t he s p o ns or, I nstit utio na l Re vie w B oar d (I R B) or F D A.  

 
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W h at are m y ri g hts i n t his st u d y ?  
Ta kin g part in t his st u d y is y o ur c h oic e. N o matter w hat de cisio n y o u ma ke, a n d e ve n if y o ur 
de cisio n c ha n ges, t here will be n o pe nalt y t o y o u. Y o u will n ot los e me dic al c are or a n y le gal 
rig hts. 
 
F or q uestio ns a b o ut y o ur rig hts w hile in t his st u d y, c all t he _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (i ns ert 
n a me of c e nter) I nstit utio nal Re vie w B oar d at _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (i ns ert tele p h o n e n u mb er).  
 
 
W h at are t he c osts of t a ki n g p art i n t his st u d y ?  
Y o ur P ote ntia l C osts: 
Y o u a n d/ or y o ur he alt h pla n/ins ura nc e c o m pa n y will ne e d t o pa y f or all of t he c osts of tre atin g 
y o ur c a nc er w hile in t his st u d y, inclu din g t he c ost of tests, pr oc e d ures, or me dicines t o ma na ge 
a n y side effe cts, u nless y o u are t old t hat c ertain tests are s u p plie d at n o c har ge. Bef ore y o u 
de cide t o be in t he st u d y, y o u s h o uld c he c k wit h y o ur he alt h pl a n or ins ura nc e c o m pa n y t o fin d 
o ut e xa ctly w hat t he y will pa y f or.  
Y o u a n d/ or y o ur he alt h pla n/ins ura nc e c o m pa n y will be res p o nsible f or:  
•  P alb ociclib, letr oz ole or f ulvestra nt  a n d all pre me dic atio ns, fluids a n d pr oc e d ures.  
•  E xa ms, tests, a n d pr oc e d ures t h at ma y be ne e de d t o ma na ge side effe cts a n d t o m o nit or 
y o ur s afet y.  
 
 
C osts P aid b y t he St u d y  
E xa ms, tests, a n d pr oc e d ures d o ne f or res e arc h p ur p os es o nly will n ot be bille d t o y o u or y o ur 
ins ura nc e pla n. T hes e inclu de b lo o d c olle ctio ns f or t he o ptio nal st u dies a n d s u b missio n of 
i ma ges t o t he Allia nc e f or e valuatin g w het her t he tre at me nt y o u are rec eivin g ma y c a us e loss of 
m us cle tiss ue.   
 
Y o u will n ot be paid f or ta kin g part in t his st u d y . 
 
 
W h at h a p pe ns if I a m i nj ure d bec a use I t o o k p art i n t his st u d y ?  
If y o u are injure d as a res ult of ta kin g part in t his st u d y a n d ne e d me dic al tre at me nt, ple as e tell 
y o ur st u d y d oct or. T he st u d y s p o ns ors will n ot  offer t o pa y f or me dic al tre at me nt f or injur y. Y o ur 
ins ura nc e c o m pa n y ma y n ot be willin g t o pa y f or st u d y-relate d injur y. If y o u ha ve n o ins ura nc e, 
y o u w o uld be res p o nsible f or a n y c osts.  
 
If y o u fe el t his injur y w as a res ult of me dic al err or, y o u ha ve le gal rig hts t o re c eive pa y me nt f or 
t his injur y e ve n t h o u g h y o u are in a st u d y. 
 
 
W h o will see m y me dic al i nf o r m ati o n ?  
Y o ur priva c y is ver y i m p orta nt t o us a n d t he res e arc hers will ma ke e ver y eff ort t o pr ote ct it.   T he 
st u d y d oct ors ha ve a priva c y per mit t o help pr ote ct y o ur re c or ds if t here is a c o urt c as e. 

 
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H o w e ver, y o ur inf or matio n ma y be give n o ut if re q uire d b y la w. F or e xa m ple, c ertain states 
re q uire d oct ors t o re p ort t o he alt h b oar ds if t he y fin d a dis e as e like t u berc ulosis. H o w e ver, t he 
res e arc hers will d o t heir best t o ma ke s ure t hat a n y inf or matio n t hat is rele as e d will n ot ide ntif y 
y o u. S o me of y o ur he alt h inf or matio n a n d inf or matio n a b o ut y o ur s pe ci me n fr o m t his st u d y will 
be ke pt in a c e ntral data bas e f or res e arc h. Y o ur na me or c o nta ct inf or matio n will n ot be p ut in 
t he data bas e. 
 
T here are or ga nizatio ns t hat ma y lo o k at or re c eive c o pies of s o me of  t he inf or matio n in y o ur 
st u d y re c or ds.  Y o ur he alt h inf or matio n in t he data bas e ma y als o be s hare d wit h t hes e 
or ga nizatio ns. T he y are re q uire d t o ma ke s ure y o ur inf or matio n is ke pt private, u nless re q uire d 
b y la w t o pr o vide inf or matio n. S o me of t hes e or ga nizatio ns are: 
•  T he Allia nc e f or Clinic al Trials in O nc olo g y 
•  T he N CI Ce ntral I R B  is a gr o u p of pe o ple w h o re vie w t he res e arc h wit h t he g oal of 
pr ote ctin g t he pe o ple w h o ta ke part in t he st u d y.  
•  T he F o o d a n d Dr u g A d ministratio n a n d t he N atio nal Ca nc er I nstit u te in t he U. S., a n d 
si milar o nes if ot her c o u ntries are in v olve d in t he st u d y.  
 
I n a d ditio n t o st orin g data in t he st u d y data bas e, data fr o m st u dies t hat are p u blicly  f u n de d ma y 
als o be s hare d br oa dly f or f ut ure res e arc h wit h pr ote ctio ns f or y o ur priva c y. T he g oal of t his data 
s harin g is t o ma ke m ore res e arc h p ossible t hat ma y i m pr o ve pe o ple’s he alt h. Y o ur st u d y re c or ds 
ma y be st ore d a n d s hare d f or f ut ure us e in p u blic data bas es .  H o w e ver, y o ur na me a n d ot her 
pers o nal inf or matio n will n ot be us e d.   
 
 
S o me t y pes of f ut ure res e arc h ma y inclu de lo o kin g at y o ur inf or matio n a n d inf or matio n fr o m 
ot her patie nts t o s e e w h o ha d side effe cts a cr oss ma n y st u dies or c o m parin g ne w st u d y data wit h 
older st u d y data.  H o w e ver, rig ht n o w w e d o n’t k n o w w hat res e arc h ma y be d o ne in t he f ut ure 
usin g y o ur inf or matio n.  T his me a ns t hat:  
 
• 
Y o u will n ot be as ke d if y o u a gre e t o ta ke part in t he s pe cific f ut ure res e arc h st u dies 
usin g y o ur he alt h inf or matio n.   
• 
Y o u a n d y o ur st u d y d oct or will n ot be t old w he n or w hat t y pe of res e arc h will be d o ne.  
• 
Y o u will n ot get re p orts or ot her inf or matio n a b o ut a n y res e arc h t hat is d o ne usin g y o ur 
inf or matio n.  
 
 
W here c a n I get m o re i nf o r m ati o n ?  
Y o u ma y visit t he N CI w e b site at htt p://c a nc er. g o v/  f or m ore inf or matio n a b o ut st u dies or 
ge neral inf or matio n a b o ut c a nc er. Y o u ma y als o c all t he N CI Ca nc er I nf or matio n Ser vic e t o get 
t he s a me inf or matio n at: 1-8 0 0 -4 -C A N C E R ( 1 -8 0 0 -4 2 2 -6 2 3 7).  
 
A des criptio n of t his clinic al trial will be a vaila ble o n htt p:// w w w. Clinic al Trials. g o v , as re q uire d 
b y U. S. la w. O nc e t he st u d y is o ver, t he site ma y inclu de a s u m mar y of t he res ults. T his 
s u m mar y will n ot inclu de a n y inf or matio n t hat c a n ide ntif y y o u.  

 
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W h o c a n a ns wer m y q uesti o ns a b o ut t his st u d y ?  
Y o u c a n talk t o t he st u d y d oct or a b o ut a n y q u estio ns or c o nc er ns y o u ha ve a b o ut t his st u d y or t o 
re p ort side effe cts or injuries. Co nta ct t he st u d y d oct or _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (i ns ert n a me of 
st u d y d o ct or[s]) at _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (i ns ert tele p h o n e n u mb er). 
 
 
A d diti o n al St u dies Secti o n:  
T his secti o n is a b o ut o pti o n al st u dies y o u c a n c h o ose t o t a ke p art i n  
 
T his part of t he c o ns e nt f or m is a b o ut o ptio nal st u dies t hat y o u c a n c h o os e t o ta ke part in. T he y 
are s e parate fr o m t he main st u d y des cribe d a b o ve. T hes e o p tio nal st u dies will n ot be nefit y o ur 
he alt h. T he res e arc hers le a din g t hes e o ptio nal st u dies h o pe t he res ults will help ot her pe o ple wit h 
c a nc er in t he f ut ure.  
 
T he res ults  will n ot be a d de d t o y o ur me dic al re c or ds a n d y o u or y o ur st u d y d oct or will n ot k n o w 
t he res ults. 
 
N eit her y o u n or y o ur ins ura nc e will be bille d f or t hes e o ptio nal st u dies. Y o u c a n still ta ke part in 
t he main st u d y e ve n if y o u s a y “ n o” t o a n y or all of t hes e st u dies. If y o u sig n u p f or b ut c a n n ot 
c o m plete a n y of t he o ptio nal st u dies f or a n y re as o n, y o u c a n still ta ke part in t he main st u d y.  
 
Circle y o ur c h oic e of “ yes ” or “ n o” f or e a c h of t he f ollo win g st u dies.  
 
O pti o n al s a m ple c ollecti o ns f o r l a b o rat ory st u dies a n d  bi o b a n ki n g f o r p ossi ble 
f ut ure st u dies 
Res e arc hers are tr yin g t o le ar n m ore a b o ut c a nc er a n d ot her he alt h pr o ble ms usin g s a m ples fr o m 
pe o ple’s tiss ue, blo o d, urine, or ot her fluids. B y c o n d uctin g res e arc h o n t hes e s a m ples, 
res e arc hers h o pe t o fin d ne w w a ys t o pre ve nt, dete ct, tre at, or c ure he alt h pr o ble ms.  
 
S o me of t he s e st u dies ma y be a b o ut h o w ge nes affe ct he alt h a n d dis e as e a n d h o w pe o ple res p o n d 
t o tre at me nt. Ge nes c arr y inf or matio n a b o ut fe at ures t hat are f o u n d in y o u a n d y o ur fa mily, fr o m 
t he c olor of y o ur e yes t o he alt h c o n ditio ns f or w hic h y o u ma y be at ris k. Res e arc h t hat st u dies 
y o ur ge nes is k n o w n as ge n o mics or ge netics.  
 
If y o u c h o os e t o ta ke part in t hes e o ptio nal st u dies , t he st u d y d oct or f or t he main st u d y w o uld 
like t o c olle ct blo o d  f or res e arc h o n  w h y patie nts ha ve differe nt side effe cts fr o m t he tre at m e nt.  
 
I n a d ditio n, t he res e arc hers as k y o ur per missio n t o st ore a n d us e y o ur s a m ples a n d relate d he alt h 
inf or matio n (f or e xa m ple, y o ur res p o ns e t o c a nc er tre at me nt, res ults of st u d y tests a n d me dicines 
y o u are give n) f or me dic al res e arc h. T he a d ditio nal r es e arc h t hat ma y be d o ne is u n k n o w n at t his 
ti me. St orin g s a m ples f or f ut ure st u dies is c alle d “ bio ba n kin g”. T he Bio ba n k is bein g r u n b y t he 
Allia nc e a n d s u p p orte d b y t he N atio nal Ca nc er I nstit ute.  
 

 
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W h at is i n v ol ve d ?  
If y o u a gre e t o ta ke part, here is w hat will ha p pe n ne xt:  
1)  A b o ut  6  te as p o o ns  of blo o d will be c olle cte d fr o m a vein in y o ur ar m. F o ur  te as p o o ns 
of blo o d will be dra w n bef ore y o u be gin tre at me nt, a n d t w o te as p o o ns will be dra w n 
after y o u ha ve ta ke n t hre e c ycles of tre at me nt.  
2)  I n a d ditio n, o ne te as p o o n of blo o d will be c olle cte d bef ore y o u start st u d y tre at me nt, 
at y o ur c ycle 1 da y 1 a n d da y 1 5 clinic visits, a n d c ycle 2 da y 1 5 clinic visit, f or 
res e arc h o n h o w t he st u d y dr u g c ha n ges in y o ur b o d y o ver ti me a n d if t hat c a n c ha n ge 
y o ur side effe cts. Y o u will als o c o m plete a f or m at t hes e visits w he n blo o d is 
c olle cte d f or t his res e arc h. It will ta ke less t ha n five min utes t o c o m plete t his f or m. 
F or t his st u d y, y o ur blo o d will be s e nt t o res e arc hers at t he U niversit y of Pitts b ur g h 
Ca nc er Ce nter wit h y o ur initials a n d c olle ctio n date  a n d ti me  o n it.  
3)  Y o ur bas eline blo o d s a m ple a n d s o me relate d he alt h inf or matio n will be s e nt t o a 
res e arc her f or us e in t he st u d y des cribe d a b o ve. Re mainin g bas eline blo o d s a m ples 
ma y be st ore d in t he Bio ba n k, alo n g wit h s a m ples fr o m ot her pe o ple w h o ta ke part. 
T he s a m ples will be ke pt u ntil t he y are us e d u p.  
4)  O nly q ualifie d res e arc hers c a n re c eive s a m ple s fr o m t he bio ba n k. T here will be  
s cie ntific a n d et hics re vie ws t o e ns ure t hat t he res e arc h is ne c ess ar y a n d pr o per. 
Res e arc hers will n ot be give n y o ur na me or a n y ot her inf or matio n t hat c o uld dire ctly 
ide ntif y y o u.  
5)  N eit her y o u n or y o ur st u d y d oct or will be n otifie d w he n res e arc h will be c o n d ucte d. 
Y o u will n ot re c eive re p orts or ot her inf or matio n a b o ut a n y res e arc h t hat is d o ne 
usin g y o ur s a m ples.  
6)  S o me of y o ur ge netic a n d he alt h inf or matio n 
ma y be pla c e d in c e ntral data bas es t hat 
will be a vaila ble t o  q ualifie d res e arc hers. I nf or matio n t hat c o uld dire ctly ide ntif y y o u 
will n ot be inclu de d.  
 
 
W h at are t he p ossi ble ris ks ?  
1)  T he m ost c o m m o n ris ks relate d t o dra win g blo o d fr o m y o ur ar m are brief pain a n d 
ma y be a br uis e.  
2)  E ve n wit h o ut y o ur na me or ot her ide ntifiers, y o ur ge netic inf or matio n is u niq ue t o 
y o u. T here is a ris k t hat s o me o ne o utside of t he res e arc h c o uld get a c c ess t o y o ur 
pers o nal inf or matio n in y o ur me dic al re c or ds or tra c e inf or matio n in a data bas e ba c k 
t o y ou. T he res e arc hers belie ve t he c ha nc e t hat s o me o ne c o uld re -ide ntif y y o u is ver y 
s mall, b ut t he ris k ma y c ha n ge in t he f ut ure as pe o ple c o me u p wit h ne w w a ys of 
tra cin g inf or matio n.  
3)  I n s o me c as es, t his inf or matio n c o uld be us e d t o ma ke it har der f or y o u to get or ke e p 
a jo b or ins ura nc e. T here are la ws a gainst t he mis us e of ge netic inf or matio n, b ut t he y 
ma y n ot give f ull pr ote ctio n. T here c a n als o be a ris k in k n o win g ge netic inf or matio n. 
N e w he alt h inf or matio n a b o ut in herite d traits t hat mig ht affe ct y o u or y o ur blo o d 
relatives c o uld be f o u n d d urin g a st u d y. T he res e arc hers belie ve t he c ha nc e t hes e 
t hin gs will ha p pe n is ver y s mall, b ut c a n n ot pr o mis e t hat t he y will n ot oc c ur. 
 

 
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H o w will i nf o r m ati o n a b o ut me be ke pt pri v ate ?  
Y o ur priva c y is ver y i m p orta nt t o t he res e arc hers a n d t he y will ma ke e ver y eff ort t o pr ote ct it. 
H ere are just a fe w of t he ste ps t he y will ta ke:  
1)  W he n y o ur s a m ple s are s e nt b y t he bio ba n k t o t he q ualifie d res e arc hers, n o 
inf or matio n ide ntif yin g y o u (s uc h as y o ur na me) will be s e nt. Sa m ples will be 
ide ntifie d b y a u niq ue c o de o nly.   
2)  T he list t hat lin ks t he u niq ue c o de t o y o ur na me will be ke pt s e parate fr o m y o ur 
s a m ple a n d he alt h inf or matio n. A n y bio ba n k a n d Allia nc e  staff wit h a c c ess t o t he list 
m ust sig n a n a gre e me nt t o ke e p y o ur ide nti t y c o nfide ntial. 
3)  Y o ur blo o d  s a m ple c olle cte d f or o ne of t he a d ditio nal st u dies  will be s e nt t o 
res e arc hers at t he U niversit y of Pitts b ur g h Ca nc er Ce nter wit h y o ur initials a n d 
c olle ctio n date a n d ti me o n it . 
4)  Res e arc hers t o w h o m t he Allia nc e se n ds y o ur s a m ple a n d inf or matio n will n ot k n o w 
w h o y o u are. T he y m ust als o sig n a n a gre e me nt  t hat t he y will n ot tr y t o fin d o ut w h o 
y o u are.  
5)  I nf or matio n t hat ide ntifies y o u will n ot be give n t o a n y o ne, u nless re q uire d b y la w.  
6)  If res e arc h res ults are p u blis he d, y o ur na me a n d ot her pers o nal inf or matio n will n ot 
be us e d.  
 
 
W h at are t he p ossi ble be nefits ?  
Y o u will n ot be nefit fr o m ta kin g part.  T he res e arc hers, usin g t he s a m ples fr o m y o u a n d ot hers, 
mig ht ma ke dis c o veries t hat c o uld help pe o ple in t he f ut ure.  
 
 
Are t here a n y c osts o r p a y me nts ?  
T here are n o c osts t o y o u or y o ur ins ura nc e. Y o u will n ot be paid f or ta kin g part. If a n y of t he 
res e arc h le a ds t o ne w tests, dr u gs, or ot her c o m mercial pr o d ucts, y o u will n ot s hare in a n y 
pr ofits.  
 
 
W h at if I c h a n ge m y mi n d ?  
If y o u de cide y o u n o lo n ger w a nt y o ur s a m ples t o be us e d, y o u c a n c all t he st u d y d oct or,  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _,  (i ns ert n a me of st u d y d o ct or f or mai n tri al) at 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  (i ns ert tele p h o ne n u mb er of st u d y d o ct or f or mai n tri al) w h o will 
let t he res e arc hers k n o w. T he n, a n y s a m ple t hat re mains in t he bio ba n k will n o lo n ger be us e d 
a n d relate d he alt h inf or matio n will n o lo n ger be c olle cte d. T his will n ot a p ply t o t h os e s a m ples 
or relate d inf or matio n t hat ha ve alre a d y be e n give n t o or us e d b y q ualifie d res e arc hers.  
 
 

 
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W h at if I h a ve q uesti o ns ?  
If y o u ha ve q uestio ns a b o ut t he us e of y o ur s a m ples f or res e arc h, c o nta ct t he st u d y d oct or, 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _,  (i ns ert n a me of st u d y d oct or f or mai n tri al), at _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
(i ns ert tele p h o n e n u mb er of st u d y d oct or f or mai n tri al). 
 
 
Ple as e circle y o ur a ns w er t o s h o w w het her or n ot y o u w o uld like t o ta ke part in e a c h o ptio n: 
 
 
S a m ples f o r t he l a b o rat o ry st u dies:  
1.  I a gre e t o ha ve m y s pe ci me n c olle cte d a n d I a gre e t hat m y s pe ci me n s a m ple(s) a n d 
relate d inf or matio n ma y be us e d f or t he la b orat or y st u dies des cribe d a b o ve.  
 
 
Y E S  
 
N O  
 
S a m ples f o r f ut ure rese arc h st u dies:  
2.  M y s a m ples a n d relate d inf or matio n ma y be ke pt in a bio ba n k f or us e in f ut ure he alt h 
res e arc h. 
 
 
Y E S  
 
N O  
 
3.  I a gre e t hat m y st u d y d oct or, or t heir re pres e ntative, ma y c o nta ct me or m y p h ysicia n t o 
s e e if I wis h t o participate in ot her res e arc h in t he f ut ure.  
 
 
Y E S  
 
N O  
 
T his is t he e n d of t he s e ctio n a b o ut o ptio nal st u dies.  
 
 
M y si g n at ure a greei n g t o t a ke p art i n t he m ai n st u d y  
 
I ha ve re a d t his c o ns e nt f or m or ha d it re a d t o me. I ha ve dis c uss e d it wit h t he st u d y d oct or a n d 
m y q uestio ns ha ve be e n a ns w ere d. I will be give n a sig ne d c o p y of t his f or m. I a gre e t o ta ke part 
in t he main st u d y a n d a n y a d ditio nal st u dies w here I circle d ‘ yes’.   
 
P articipa nt’s sig nat ure _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
D ate of sig nat ure _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
Sig nat ure of pers o n(s) c o n d uctin g t he inf or me d c o ns e nt 
dis c ussio n _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
D ate of sig nat ure _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 

 
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A P P E N DI X I: P A TI E N T  I N F O R M A TI O N S H E E T S  
P atie nt C o m plet e d B o o klet A : C ycle 1 a n d 4, D a y 1 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _  
 
Y o u h a ve be e n gi ve n a bo o klet t o c o m plet e f o r t his st u dy.  T his bo o klet c o nt ai ns s o m e q u esti o ns a bo ut 
y o u r ‘ q u alit y -of -life’ as a patie nt re cei vi n g t re at me nt f or c a n cer.  Y o u r a ns we rs will h el p us t o better 
u n de rst a n d h o w t h e t re at me nt y o u are receivi n g is aff ecti n g t he wa y y o u f e el.  
 
1.  Yo u ar e bei n g as ke d t o c o m plete a q uestio n nair e b o o klet f or t his st u d y. T his b o o klet m ust be 
c o m plete d o n Da y 1 of C ycle  1  a n d 4 of y o ur st u d y tr eat me nt. It c o ntains t he f ollo win g 
q uestio n nair es:  
 
• 
Geriatric Ass ess me nt  
• 
E Q -5 D 3 L  
• 
P R O -C T C A E q uestio n nair e  Da y 1  
• 
Geriatric Ass ess me nt: Healt hc ar e Pr of essio nal Q uestio n nair e  
-Not e: T his f or m is t o be c o m plet e d by t h e h e alt h c are pr of essio n al, n ot t he 
patie nt.  
 
2.  Dir ectio ns o n h o w t o c o m plete eac h s et of q uestio ns ar e writte n o n t he t o p of eac h s et.  
 
3.  It is ver y i m p orta nt t hat y o u r et ur n t he b o o klets t o us, w het her y o u finis h t he st u d y or n ot. 
 
4.  Yo u will be give n t he n urs e’s or st u d y c o or dinat or’s na me a n d tele p h o ne n u m ber. Yo u c a n c all 
a n yti me wit h a n y c o nc er ns or q uestio ns.  
 
5.  Aft er c o m pletin g t his b o o klet, p leas e r et ur n it t o y o ur n urs e or p h ysicia n. 
 
 
 
T ha n k y o u f or t a ki ng t he ti me t o hel p us.  
 
 
 

 
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P A TI E N T I N F O R M A TI O N S H E E T  
P atie nt C o m plet e d B o o klet B : C ycles 1 a n d 2, D a y 1 5  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _  
 
Y o u h a ve be e n gi ve n a bo o klet t o c o m plet e f or t his st u dy.  T his bo o klet c o nt ai ns s o m e q u esti o ns a bo ut 
y o u r ‘ q u alit y -of -life’ as a patie nt re cei vi n g t re at me nt f or c a n cer.  Y o u r a ns we rs will h el p us t o better 
u n de rst a n d h o w t h e t re at me nt y o u are receivi n g is aff ecti n g t he wa y y o u f e el.  
 
1.  Y o u are bein g as ke d t o c o m plete a q uestio n naire b o o klet f or t his st u d y. T his b o o klet m ust 
be c o m plete d o n D a y 1 5 of C ycle s 1  a n d 2 of y o ur st u d y tre at me nt. It c o ntains t he 
f ollo win g q uestio n naires: 
 
• 
P R O -C T C A E q uestio n naire D a y 1 5  
 
2.  Dir ectio ns o n h o w t o c o m plete eac h s et of q uestio ns ar e writte n o n t he t o p of eac h s et.  
 
3.  It is ver y i m p orta nt t hat y o u r et ur n t he b o o klets t o us, w het her y o u finis h t he st u d y or n ot.  
 
4.  Yo u will be give n t he n urs e’s or st u d y c o or dinat or’s na me a n d tele p h o ne n u m ber. Yo u c a n c all 
a n yti me wit h a n y c o nc er ns or q uestio ns.  
 
5.  Aft er c o m pletin g t his b o o klet, pleas e r et ur n it t o y o ur n urs e or p h ysicia n.  
 
 
 
T ha n k y o u f or t a ki ng t he ti me t o hel p us.  
 
 

 
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P A TI E N T I N F O R M A TI O N S H E E T  
P atie nt C o m plet e d B o o klet C : C ycle 2, D a y 1, a n d C ycles 3, 5, a n d 6  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _  
 
Y o u h a ve be e n gi ve n a bo o klet t o c o m plet e f or t his st u dy.  T his bo o klet c o nt ai ns s o m e q u esti o ns a bo ut 
y o u r ‘ q u alit y-of -life’ as a patie nt re cei vi n g t re at me nt f or c a n cer.  Y o u r a ns we rs will h el p us t o better 
u n de rst a n d h o w t h e t re at me nt y o u are receivi n g is aff ecti n g t he wa y y o u f e el.  
 
1.  Yo u ar e bein g as ke d t o c o m plete a q uestio n nair e b o o klet f or t his st u d y. T h is b oo klet m ust be 
c o m plete d o n Da y 1 of C ycle 2 , a n d C ycles 3, 5, a n d 6 of y o ur st u d y tr eat me nt. It c o ntains t he 
f ollo win g q uestio n nair es: 
• 
E Q -5 D 3 L  
• 
P R O -C T C A E q uestio n nair e  Da y 1  
 
2.  Dir ectio ns o n h o w t o c o m plete eac h s et of q uestio ns ar e writte n o n t he t o p of eac h s et.  
 
3.  It is ver y i m p orta nt t hat y o u r et ur n t he b o o klets t o us, w het her y o u finis h t he st u d y or n ot.  
 
4.  Yo u will be give n t he n urs e’s or st u d y c o or dinat or’s na me a n d tele p h o ne n u m ber. Yo u c a n c all 
a n yti me wit h a n y c o nc er ns or q uestio ns.  
 
5.  Aft er c o m pletin g t his b o o klet, pleas e r et ur n it t o y o ur n urs e or p h ysicia n.  
 
 
 
T ha n k y o u f or t a ki ng t he ti me t o hel p us.  
 

 
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P A TI E N T I N F O R M A TI O N S H E E T  
P atie nt C o m plet e d B o o klet D: E N D O F T R E A T M E N T  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _  
 
Y o u h a ve be e n gi ve n a bo o klet t o c o m plet e f or t his st u dy.  T his bo o klet c o nt ai ns s o m e q u esti o ns a bo ut 
y o u r ‘ q u alit y -of -life’ as a patie nt re cei vi n g t re at me nt f or c a n cer.  Y o u r a ns we rs will h el p us t o better 
u n de rst a n d h o w t h e t re at me nt y o u are receivi n g is aff ecti n g t he wa y y o u f e el. 
 
 
1.  Yo u ar e bein g as ke d t o c o m plete a q uestio n nair e b o o klet f or t his st u d y. T his b o o klet m ust be 
c o m plete d at t he e n d of y o ur tr eat me nt. It c o ntains t he f ollo win g q uestio n nair es:  
• 
Geriatric Ass ess m e nt  
• 
P R O -C T C A E q uestio n nair e  
• 
E Q -5 D 3 L  
• 
Was it W ort h It Q uestio n nair e  
• 
Geriatric Ass ess me nt: Healt hc ar e Pr of essio nal Q uestio n nair e  
-Not e: T his f or m is t o be c o m plet e d by t h e h e alt h c are pr of essio n al, n ot t he 
patie nt.  
 
2.  Dir ectio ns o n h o w t o c o m plete eac h s et of q uestio ns ar e writte n o n t he t o p of eac h s et.  
 
3.  It is ver y i m p orta nt t hat y o u r et ur n t he b o o klets t o us, w het her y o u finis h t he st u d y or n ot.  
 
4.  Yo u will be give n t he n urs e’s or st u d y c o or dinat or’s na me a n d tele p h o ne n u m ber. Yo u c a n c all 
a n yti me wit h a n y c o nc er ns or q uestio ns.  
 
5.  Aft er c o m pletin g t his b o o klet, pleas e r et ur n it t o y o ur n urs e or p h ysicia n.  
 
 
 
T ha n k y o u f or t a ki ng t he ti me t o hel p us.  
 
 
 
 

 
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A P P E N DI X II: G E RI A T RI C A S S ES S M E N T 
G E RI A T RI C A S S ES S M E N T S U R V E Y  
T o b e c o mpl et e d b y Ph y si ci a n, N ur s e, or C R A:  
R e s p o n si bl e p er s o n n a me ( P h y si ci a n, N ur s e, or C R A ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
A s s e s s me nt Peri o d ( a s a p pli c a bl e t o t hi s st u d y)  □ Pr e -tr e at me nt   □□ Cy cl e #    □ En d of Tr e at me nt  
 
 
P A TI E N T Q U ES TI O N N AI R E  
 
P ati e nt I n str u cti o n s:   If y o u ar e u n a bl e t o c o mpl et e t h e q u e sti o n n air e, a me mb er of y o ur h e alt h c ar e t e a m will a s si st 
y o u. Pl e a s e d o n ot h a v e a f a mil y me mb er c o mpl et e t h e q u e sti o n n air e f or y o u.  
□ M ar k b o x wit h a n “ X ”, if f or m w a s n ot c o m pl et e d at s p e cifi e d ti m e p oi nt a n d s p e cif y r e a s o n:  
   ( M ar k o n e wit h a n X.) 
□ Pati e nt r ef u s e d  
□ Pati e nt wit h dr e w  c o n s e nt  
□ N ot d o n e  
 
 
 
□ Ot h er, s p e cif y _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
 
 
 
( For a ss e ss m e nt d at e, r e c or d a p pr o xi m at e d at e f or m w a s t o b e c o m pl et e d.)  
A.  B A C K G R O U N D I N F O R M A TI O N  
 
1.  
W h at i s t h e hi g h e st gr a d e y o u fi ni s h e d i n s c h o ol ? 
( M ar k o n e wit h a n X.) 
□ 8t h gr a d e or l e s s  
□ V o c ati o n al/ t e c h ni c al s c h o ol  
 
□ 9 -1 1 t h gr a d e  
□ B a c h el or’ s d e gr e e  
□ Hi g h s c h o ol gr a d u at e/ G E D  
□ A d va n c e d d e gr e e  
 
□ A s s o ci at e d e gr e e/ s o m e 
c oll e g e  
□ I pr ef er n ot t o a n s w er  
 
2.  
W h at i s y o ur marit al st at u s ? ( M ar k o n e wit h a n X.) 
□ M arri e d  
□ Di v or c e d  
□ I pr ef er n ot t o a ns w er 
□ D o m e sti c p art n er s hi p  
□ S e p ar at e d  
 
□ Wi d o w e d  
□ N e v er marri e d  
 
 
 
3.  
Wit h w h o m d o y o u li v e ? ( M ar k all t h at a p pl y wit h a n X.) 
□ S p o u s e / p art n er  
 
 
□ Par e nt( s)/ p ar e nt( s) -i n-l a w 
□ Girlfri e n d / b o yfri e n d  
 
 
□ Li v e al o n e  
□ C hil dr e n a g e d 1 8 y e ar s or y o u n g er  
□ Ot h er s, s p e cif y: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
□ C hil dr e n a g e d 1 9 y e ar s or ol d er   
□ Ot h er r el ati v e, s p e cif y: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 

 
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4.  
W h at i s y o ur c urr e nt e mpl o y me nt st at u s ?  ( M ar k o n e wit h a n X.) 
□ E mpl o y e d 3 2 h o ur s or mor e p er w e e k  
 
□ U n e mpl o y e d  
□ E mpl o y e d l e s s t h a n 3 2 h o ur s p er w e e k  
 
□ R etir e d  
□ H o me ma k er  
 
 
 
 
□ F ull -ti me st u d e nt 
□ Di s a bl e d  
 
 
 
 
□ Part -ti me st u d e nt  
□ O n me di c al l e a v e  
 
 
 
□ Ot h er, s p e cif y: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
B. D AI L Y A C TI VI TI E S*  
 
P A TI E N T I N S T R U C TI O N S:  I n di c at e y o ur r e s p o n s e b y mar ki n g a n X i n o n e b o x p er q u e sti o n. 
 
1.  
C a n y o u u s e t h e t el e p h o n e …  
□ wit h o ut h el p, i n cl u di n g l o o ki n g u p a n d di ali n g;  
□ wit h s o me h el p ( c a n a n s w er p h o n e or di al o p er at or i n a n e mer g e n c y, b ut n e e d a s p e ci al p h o n e or h el p i n 
g etti n g t h e p h o n e n u mb er or di ali n g); or  
□ ar e y o u c o mpl et el y u n a bl e t o u s e t h e t el e p h o n e ?  
 
2.  
C a n y o u g et t o pl a c e s o ut of w al ki n g di st a n c e …  
□ wit h o ut h el p ( c a n tr a v el al o n e o n b u s s e s, t a xi s, or dri v e y o ur o w n c ar);  
□ wit h s o me h el p ( n e e d s o me o n e t o h el p y o u or g o wit h y o u w h e n tr a v eli n g); or  
□ ar e y o u u n a bl e t o tr a v el u nl e s s e mer g e n c y arr a n g e me nt s ar e ma d e f or a s p e ci ali z e d v e hi cl e li k e a n 
a mb ul a n c e ?  
 
 

 
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3.  
C a n y o u g o s h o p pi n g f or gr o c eri e s or cl ot h e s ( a s s u mi n g y o u h a v e tr a n s p ort ati o n) …  
□ wit h o ut h el p (t a ki n g c ar e o f all s h o p pi n g n e e d s y o ur s elf, a s s u mi n g y o u h a v e tr a n s p ort ati o n); 
□ wit h s o me h el p ( n e e d s o me o n e t o g o wit h y o u o n all s h o p pi n g tri p s); or  
□ ar e y o u c o mpl et el y u n a bl e t o d o a n y s h o p pi n g ?  
 
4.  
C a n y o u pr e p ar e y o ur o w n me al s …  
□ wit h o ut h el p ( pl a n a n d c o o k f ull m e al s y o ur s elf);  
□ wit h s o me h el p ( c a n pr e p ar e s o me t hi n g s b ut u n a bl e t o c o o k f ull me al s y o ur s elf); or  
□ ar e y o u c o mpl et el y u n a bl e t o pr e p ar e a n y me al s ?  
 
5.  
C a n y o u d o y o ur h o u s e w or k …  
□ wit h o ut h el p ( c a n cl e a n fl o or s, et c);  
□ wit h s o me h el p ( c a n d o li g ht h o u s e w or k b ut n e e d h el p wit h h e a v y w or k); or  
□ ar e y o u c o mpl et el y u n a bl e t o d o a n y h o u s e w or k ?  
 
6.  
C a n y o u t a k e y o ur o w n me di ci n e s …  
□ wit h o ut h el p (i n t h e ri g ht d o s e s at t h e ri g ht ti me);  
□ wit h s o me h el p ( a bl e t o t a k e me di ci n e if s o me o n e pr e p ar e s it f or y o u a n d/ or r e mi n d s y o u t o t a k e it); or  
□ ar e y o u c o mpl et el y u n a bl e t o t a k e y o ur me di ci n e s ?  
 
7.  
C a n y o u h a n dl e y o ur o w n mo n e y …  
□ wit h o ut h el p ( w rit e c h e c k s, p a y bill s, et c.);  
□ wit h s o me h el p ( ma n a g e d a y -t o-d a y b u yi n g b ut n e e d h el p wit h ma n a gi n g y o ur c h e c k b o o k a n d  p a yi n g y o ur 
bill s); or  
□ ar e y o u c o mpl et el y u n a bl e t o h a n dl e mo n e y ?  
 
* O A R S I A D L
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C. P H Y SI C A L A C TI VI TI E S*  
 
1.  
T h e f oll o wi n g it e ms ar e a cti viti e s y o u mi g ht d o d uri n g a t y pi c al d a y. D o e s y o ur h e alt h li mit y o u  i n t h e s e a cti viti e s ?  
(M a r k a n X i n t h e b o x o n e a c h li n e t h at b e st r efl e ct s y o ur sit u ati o n. ) 
 
 
A cti viti e s  
Li mit e d  
a l ot  
Li mit e d  
a littl e  
N ot li mit e d  
at all  
a.  
Vi g or o u s a cti viti e s  s u c h a s: r u n ni n g, lifti n g h e a v y o bj e ct s, 
p arti ci p ati n g i n str e n u o u s s p ort s  
□ 
□ 
□ 
b.  
Mo d er at e a cti viti e s  s u c h a s: mo vi n g a t a bl e, p u s hi n g a v a c u u m 
cl e a n er, b o wli n g, or pl a yi n g g olf  
□ 
□ 
□ 
c.  
Lifti n g or c arr yi n g gr o c eri e s  
□ 
□ 
□ 
d.  
Cli mbi n g 
s e v er al  fli g ht s of st air s 
□ 
□ 
□ 
e.  
Cli mbi n g 
o n e  fli g ht of st air s 
□ 
□ 
□ 
f. 
B e n di n g, k n e eli n g, or st o o pi n g  
□ 
□ 
□ 
g.  
W al ki n g 
mor e t h a n a mil e 
□ 
□ 
□ 
h.  
W al ki n g 
s e v er al bl o c k s  
□ 
□ 
□ 
i. 
W al ki n g 
o n e bl o c k  
□ 
□ 
□ 
j. 
B at hi n g or dr e s si n g y o ur s elf  
 
□ 
□ 
□ 
 
 
* M O S, P h y si c al F u n cti o ni n g S c al e
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D. C U R R E N T H E A L T H R A TI N G*  
 
  W hi c h o n e of t h e f oll o wi n g p hr a s e s b e st d e s cri b e s y o u at t hi s ti me ? 
( M ar k o n e wit h a n X.) 
□ N or mal, n o c o mpl ai nt s, n o s y mpt o ms of di s e a s e  
□ A bl e t o c arr y o n n or mal a cti vit y, mi n or s y mpt o ms of di s e a s e  
□ N or mal a cti vit y wit h eff ort, s o me s y mpt o ms of di s e a s e  
□ C ar e f or s elf, u n a bl e t o c arr y o n n or mal a cti vit y or d o a cti v e w or k  
□ R e q uir e o c c a si o n al a s si st a n c e b ut a bl e t o c ar e f or mo st of p er s o n al n e e d s  
□ R e q uir e c o n si d er a bl e a s si st a n c e f or p er s o n al c ar e  
□ Di s a bl e d, r e q uir e s p e ci al c ar e a n d a s si st a n c e  
□ S e v er el y di s a bl e d, r e q uir e c o nti n u o u s n ur si n g c ar e  
 
* P ati e nt K P S
3 5 
 
 
E. F A L L S  
H o w  ma n y ti me s h a v e y o u f all e n i n t h e l a st 6 mo nt h s ?  □□□ 
 
 
F. Y O U R H E A L T H  
1.  
Y o ur G e n e r al H e alt h*  
P ati e nt I n str u cti o n s:  D o y o u h a v e a n y of t h e f oll o wi n g ill n e s s e s at t h e pr e s e nt ti me, a n d if s o, h o w  mu c h d o e s it 
i nt erf er e wit h y o ur a cti viti e s: N ot at all, S o m e w h at or A Gr e at D e al ?  ( M ar k a n X i n t h e b o x t h at b e st r efl e ct s y o ur 
a n s w er.)  
 
 
 
If y o u h a v e t hi s ill n e s s:  
H o w m u c h d o e s it i nt e rf e r e wit h y o ur a cti viti e s ?  
Ill n e s s 
N o  
Y e s  
 
N ot  
at all  
A littl e  
A gr e at 
d e al  
a.  
Ot h er c a n c er s or l e u k e mi a  
□ 
□ 
→ 
□ 
□ 
□ 
b.  
Art hriti s or r h e u mati s m  
□ 
□ 
→ 
□ 
□ 
□ 

 
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If y o u h a v e t hi s ill n e s s:  
H o w m u c h d o e s it i nt e rf e r e wit h y o ur a cti viti e s ?  
Ill n e s s 
N o  
Y e s  
 
N ot  
at all  
A littl e  
A gr e at 
d e al  
c.  
Gl a u c o ma  
□ 
□ 
→ 
□ 
□ 
□ 
d.  
E mp h y s e ma or c hr o ni c br o n c hiti s  
□ 
□ 
→ 
□ 
□ 
□ 
e.  
Hi g h bl o o d pr e s s ur e  
□ 
□ 
→ 
□ 
□ 
□ 
f. 
H e art di s e a s e  
□ 
□ 
→ 
□ 
□ 
□ 
g.  
Cir c ul ati o n tr o u bl e i n ar ms or l e g s  
□ 
□ 
→ 
□ 
□ 
□ 
h.  
Di a b et e s  
□ 
□ 
→ 
□ 
□ 
□ 
i. 
St o ma c h or i nt e sti n al di s or d er s  
□ 
□ 
→ 
□ 
□ 
□ 
j. 
Ost e o p or o si s  
□ 
□ 
→ 
□ 
□ 
□ 
k.  
Li v er di s e a s e  
□ 
□ 
→ 
□ 
□ 
□ 
l. 
Ki d n e y di s e a s e  
□ 
□ 
→ 
□ 
□ 
□ 
m.  Str o k e  
□ 
□ 
→ 
□ 
□ 
□ 
n.  
D e pr e s si o n  
□ 
□ 
→ 
□ 
□ 
□ 
 
 
* O A R S I A D L
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2.  
H o w  i s y o ur e y e si g ht ( wit h gl a s s e s or c o nt a ct s) ?  ( M ar k o n e wit h a n X.) 
□ Ex c ell e nt  
 
□ G o o d  
 
□ F air  
 
 
□ Po or  
 
 
□ T ot all y bl i n d 
 
3.  
H o w  i s y o ur h e ari n g ( wit h a h e ari n g ai d, if n e e d e d) ? ( M ar k o n e wit h a n X.) 
□ Ex c ell e nt  
 
□ G o o d  
 
□ F air  
 
 
□ Po or  
 
 
□ T ot all y d e af  
 
4.  
D o y o u h a v e a n y ot h er p h y si c al pr o bl e ms or ill n e s s e s ( ot h er t h a n li st e d i n q u e sti o n s 1 -4) at t h e pr e s e nt ti me t h at 
s eri o u sl y aff e ct y o ur h e alt h ?  
□ N o  
 
□ Y e s, s p e cif y:  
 
If y e s, h o w  mu c h d o e s t hi s i nt erf er e wit h y o ur a cti viti e s ?  ( M ar k o n e wit h a n X.) 
 
 
□ N ot at all  
 
□ S o me w h at  
 
□ A gr e at d e al  
  
 
 
* O A R S I A D L
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G. N U T RI TI O N A L 
S T A T U S  
1.  H a v e y o u l o st w ei g ht i n v ol u nt aril y o v er t h e p a st 6 mo nt h s ?   
 
□ N o  
 
□ Y e s  
 
 
 
If y e s, h o w  mu c h ?  
 
 
□□□ p o u n d s  
2.  W h at i s y o ur w ei g ht n o w ?  
  
 
 □□□ p o u n d s  
3.  
W h at w a s y o ur w ei g ht 6 mo nt h s a g o ?  
  □□□ p o u n d s  
H. H E A L T H 
Q U E S TI O N N AI R E * 
I N S T R U C TI O N S: T h e s e q u e sti on s ar e a b o ut h o w y o u h a v e b e e n f e eli n g wit hi n t h e p a st m o nt h. Pl e a s e m ar k 
a n “ X ” i n t h e b o x o n e a c h li n e t h at b e st r efl e ct s y o ur sit u ati o n.  
 
 
H o w m u c h of t h e ti m e d uri n g t h e p a st 
m o nt h : 
All  
of t h e 
Ti m e  
M o st  
of t h e 
Ti m e  
A G o o d 
Bit of 
t h e Ti m e  
S o m e  
of t h e 
Ti m e  
A Littl e  
of t h e 
Ti m e  
N o n e  
of t h e 
Ti m e  
1.  
h a s y o ur d ail y lif e b e e n f ull of t hi n g s 
t h at w er e i nt er e sti n g t o y o u ? 
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2.  
di d y o u f e el d e pr e s s e d ?  
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h a v e y o u f elt l o v e d a n d w a nt e d ?  
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4.  
h a v e y o u b e e n a v er y n er v o u s 
p er s o n ?  
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5.  
h a v e y o u b e e n i n fir m c o ntr ol of y o ur 
b e h a vi or, t h o u g ht s, e moti o n s, 
f e eli n g s ? 
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6.  
h a v e y o u f elt t e n s e or hi g h -str u n g ?  
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h a v e y o u f elt c al m a n d p e a c ef ul ?  
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8.  
h a v e y o u f elt e moti o n all y st a bl e ?  
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9.  
h a v e y o u f elt d o w n h e art e d a n d bl u e ?  
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1 0.  h a v e y o u f elt r e stl e s s, fi d g et y, or 
i mp ati e nt ? 
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1 1.  h a v e y o u b e e n mo o d y, or br o o d e d 
a b o ut t hi n g s ?  
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1 2.  h a v e y o u f elt c h e erf ul, li g ht -h e art e d ?  
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1 3.  h a v e y o u b e e n i n l o w  or v er y l o w  
s pirit s ?  
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1 4.  w er e y o u a h a p p y p er s o n ?  
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1 5.  di d y o u f e el y o u h a d n ot hi n g t o l o o k 
f or w ar d t o ? 
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1 6.  h a v e y o u f elt s o d o w n i n t h e d u mp s 
t h at n ot hi n g c o ul d c h e er y o u u p ? 
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1 7.  h a v e y o u b e e n a n xi o u s or w orri e d ?  
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* M HI -1 7
3 4 - St e w art, A. L. a n d W ar e, J. E., 1 9 9 2  
 
 
 
 

 
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I. S O CI A L A C TI VI TI E S* 
 
1.  
D uri n g t h e p a st 4 w e e k s , h o w  mu c h ti me h a s y o ur p h y si c al h e alt h  or e moti o n al pr o bl e ms  i nt erf er e d wit h y o ur 
s o ci al a cti viti e s (li k e vi siti n g wit h fri e n d s, r el ati v e s, et c.) ? ( M ar k o n e wit h a n X.) 
 
□ All of t h e ti me  
□ Mo st of t h e ti me  
□ S o me of t h e ti me  
□ A littl e of t h e ti me  
□ N o n e of t h e ti me  
 
2.  
C o mp ar e d t o y o ur u s u al l e v el of s o ci al a cti vit y , h a s y o ur s o ci al a cti vit y d uri n g t h e p a st 6 mo nt h s  d e cr e a s e d, 
st a y e d t h e s a me, or i n cr e a s e d b e c a u s e of a c h a n g e i n y o ur p h y si c al or e moti o n al c o n diti o n ?  ( M ar k o n e wit h a n 
X.)  
 □ Mu c h l e s s s o ci all y a cti v e t h a n b ef or e  
□ S o me w h at l e s s s o ci all y a cti v e t h a n b ef or e  
□ A b o ut a s s o ci all y a cti v e a s b ef or e  
□ S o me w h at mor e s o ci all y a cti v e a s b ef or e  
□ Mu c h mor e s o ci all y a cti v e t h a n b ef or e  
 
3.  
C o mp ar e d t o ot h er s y o ur a g e, ar e y o ur s o ci al a cti viti e s mor e or l e s s li mit e d b e c a u s e of y o ur p h y si c al h e alt h  or 
e moti o n al pr o bl e ms ? ( M ar k o n e wit h a n X.) 
 □ Mu c h mor e li mit e d t h a n ot h er s  
□ S o me w h at mor e li mit e d t h a n ot h er s  
□ A b o ut t h e s a me a s ot h er s  
□ S o me w h at l e s s li mit e d t h a n ot h er s  
□ Mu c h l e s s li mit e d t h a n ot h er s  
 
 
 
* M O S, S o ci al A cti viti es
3 4 
 

 
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J. S O CI A L S U P P O R T * 
 
I N S T R U C TI O N S: 
P e o pl e s o m eti m e s l o o k t o ot h e r s f or c o m p a ni o n s hi p, a s si st a n c e or ot h e r t y p e s of s u p p ort. 
H o w oft e n i s e a c h of t h e f oll o wi n g ki n d s of s u p p ort a v ail a bl e t o y o u if y o u n e e d it ? ( M a r k a n X i n t h e b o x o n 
e a c h li n e t h at b e st r efl e ct s y o ur sit u ati o n. ) 
 
 
N o n e  
of t h e 
Ti m e  
A Littl e 
of t h e 
Ti m e  
S o m e  
of t h e 
Ti m e  
M o st  
of t h e 
Ti m e  
All  
of t h e 
Ti m e  
1.  
S o me o n e t o h el p y o u if y o u w er e c o nfi n e d t o b e d.  
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S o me o n e y o u c a n c o u nt o n t o li st e n t o y o u w h e n 
y o u n e e d t o t al k.  
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S o me o n e t o gi v e y o u g o o d a d vi c e a b o ut a cri si s.  
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S o me o n e t o t a k e y o u t o t h e d o ct or if n e e d e d.  
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S o me o n e t o gi v e y o u i nf or mati o n t o h el p y o u 
u n d er st a n d a sit u ati o n.  
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6.  
S o me o n e t o c o nfi d e i n or t al k t o a b o ut y o ur s elf or 
y o ur pr o bl e m.  
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7.  
S o me o n e t o pr e p ar e y o ur me al s if y o u w er e u n a bl e 
t o d o it y o ur s elf. 
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8.  
S o me o n e w h o s e a d vi c e y o u r e all y w a nt.  
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9.  
S o me o n e t o h el p y o u wit h d ail y c h or e s if y o u w er e 
si c k.  
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1 0.  S o me o n e t o s h ar e y o ur mo st pri v at e w orri e s a n d 
f e ar s wit h. 
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1 1.  S o me o n e t o t ur n t o f or s u g g e sti o n s a b o ut h o w  t o 
d e al wit h a p er s o n al pr o bl e m.  
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1 2.  S o me o n e w h o u n d er st a n d s y o ur pr o bl e ms.  
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* M O S S o ci al S u p p ort S ur v e y 
3 6 
 

 
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K.  S PI RI T U A LI T Y/ R E LI GI O N*  
 
Dir e cti o n s: Pl e a s e a n s w e r t h e f oll o wi n g q u e sti o n s a b o ut y o ur r eli gi o u s b eli ef s a n d/ or i n v ol v e m e nt. ( Pl e a s e 
m ar k a n “ X ” i n t h e b o x o n e a c h li n e t h at b e st r efl e ct s y o ur sit u ati o n.)  
 
1.  
H o w  oft e n d o y o u att e n d c h ur c h, s y n a g o g u e, or ot h er r eli gi o u s me eti n g s ? 
( M ar k o n e wit h a n X.) 
 □ Mor e t h a n o n c e p er w e e k  
□ O n c e a w e e k  
□ A f e w  ti me s a mo nt h  
□ A f e w  ti me s a y e ar  
□ O n c e a y e ar or l e s s  
□  N e v er  
 
2.  
H o w  oft e n d o y o u s p e n d ti me i n pri v at e r eli gi o u s a cti viti e s, s u c h a s pr a y er, me dit ati o n, or Bi bl e st u d y ? ( M ar k o n e 
wit h a n X.)  
 □ Mor e t h a n o n c e a d a y  
□ D ail y  
□ T w o or mor e ti me s p er w e e k  
□ O n c e a w e e k  
□ A f e w  ti me s a mo nt h  
□  R ar el y or n e v er  
 
T h e f oll o wi n g s e cti o n c o nt ai n s 3 st at e m e nt s a b o ut r eli gi o u s b eli ef or e x p eri e n c e. Pl e a s e m ar k t h e e xt e nt t o w hi c h 
e a c h st at e m e nt i s tr u e or n ot tr u e f or y o u.  
 
3.  I n my lif e, I e x p eri e n c e t h e pr e s e n c e of t h e Di vi n e (i. e., G o d). ( M ar k o n e wit h a n X.) 
 
□ D efi nit el y tr u e of me  
□ T e n d s t o b e tr u e  
□ U n s ur e  
□ T e n d s n ot  t o b e tr u e 
□ D efi nit el y n ot  tr u e 
 
4.    My r eli gi o u s b eli ef s ar e w h at r e all y li e b e hi n d my w h ol e a p pr o a c h t o lif e. ( M ar k o n e wit h a n X.) 
 
□ D efi nit el y tr u e of me  
□ T e n d s t o b e tr u e  
□ U n s ur e  
□ T e n d s n ot  t o b e tr u e 
□ D efi nit el y n ot  tr u e 

 
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5 .   I tri e d h ar d t o c arr y my r eli gi o n o v er i nt o all ot h er d e ali n g s i n my lif e. ( M ar k o n e wit h a n X.) 
 
□ D efi nit el y tr u e of me  
□ T e n d s t o b e tr u e  
□ U n s ur e  
□ T e n d s n ot  t o b e tr u e 
□ D efi nit el y n ot  tr u e 
 
* D U R E L: D u k e U ni v er sit y R eli gi o nI n d e x
3 7–  K o e ni g et al., 1 9 9 7  
 
L.  Y O U R F E E LI N G S*  
1.  D o y o u oft e n f e el s a d or d e pr e s s e d ? ( M ar k o n e wit h a n X.)  
□ N o  
□ Y e s  
 
2.  H o w  w o ul d y o u d e s cri b e y o ur l e v el of a n xi et y, o n a v er a g e ? Pl e a s e cir cl e t h e n u mb er ( 0 -1 0) b e st r efl e cti n g y o ur  
 
r e s p o n s e t o t h e f oll o wi n g t h at d e s cri b e s y o ur f e eli n g s d uri n g t h e p a st w e e k, i n cl u di n g t o d a y . 
 
0  
1  
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5  
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8  
9  
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N o a n xi et y  
 
 
 
 
 
 
 
 
A n xi et y a s b a d a s  
It c a n b e 
* M a h o n e y et al., 1 9 9 4; L A S A
3 8 
 
M.  Q U E S TI O N S 
C O N C E R NI N G T H E Q U E S TI O N N AI R E  
 
1.  
W er e t h er e a n y q u e sti o n s diffi c ult t o u n d er st a n d ? 
 
□ N o     □ Y e s  
If Y e s, w hi c h q u e sti o n s w er e t h e y ? 
 
 
 
 
2.  
W a s t h e ti me it t o o k t o a n s w er all t h e q u e sti o n s t o o l o n g, j u st ri g ht or t o o s h ort ?  
□ T o o s h ort  →
  H o w  l o n g w o ul d y o u h a v e li k e d t h e q u e sti o n n air e t o b e ?   □□ mi n ut e s  
□ J u st ri g ht  
□ T o o l o n g →
  H o w  l o n g w o ul d y o u h a v e li k e d t h e q u e sti o n n air e t o b e ?   □□ mi n ut e s  
 
 
W hi c h it e ms w o ul d y o u r e mo v e ?  
 

 
Allia nc e A1 7 1 6 0 1  
 
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3.  
Di d y o u fi n d a n y of t h e q u e sti o n s u p s etti n g ?  
 
□ N o     □ Y e s  
 
If Y e s, w hi c h q u e sti o n s w er e t h e y ? 
 
 
 
 
 
C o ul d y o u t ell me w h y t h e y w er e u p s etti n g ?  
 
 
 
 
 
4.  
D o y o u t hi n k t h e q u e sti o n n air e l eft o ut a n y q u e sti o n s t h at w er e i mp ort a nt t o a s k ?  
 
 
 
 
 
T h a n k y o u f or y o ur p arti ci p ati o n.  
 
 

 
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B.  Ti me d “ U p a n d G o”*  
 
I N S T R U C TI O N S: T h e ti me d “ U p a n d G o” me a s ur e s, i n s e c o n d s, t h e ti me it t a k e s f or a n i n di vi d u al t o  st a n d u p 
fr o m a st a n d ar d ar m c h air ( a p pr o xi mate s e at h ei g ht of 4 6 c m [ a p pr o xi mat el y 1. 5 ft]), w al k a di st a n c e of 3 met er s 
( a p pr o xi mat el y 1 0 f e et), t ur n, w al k b a c k t o t h e c h air, a n d sit d o w n a g ai n. T h e s u bj e ct w e ar s hi s/ h er r e g ul ar 
f o ot w e ar a n d u s e s t h eir c u st o mar y w al ki n g ai d ( n o n e, c a n e, w al k er, et c.) N o p h y si c al a s si st a n c e i s gi v e n. T h e 
s u bj e ct st art s wit h hi s b a c k a g ai n st t h e c h air, hi s ar m r e sti n g o n t h e c h air’ s ar m, a n d hi s w al ki n g ai d i n h a n d.  H e 
i s i n str u ct e d t h at o n t h e w or d “ g o”, h e i s t o g et u p a n d w al k at a c o mf ort a bl e a n d s af e p a c e t o a lin e o n t h e fl o or 3 
met er s ( a p pr o xi mat el y 1 0 f e et) a w a y, t ur n, a n d r et ur n t o t h e c h air a n d sit d o w n a g ai n. T h e s u bj e ct w al k s t hr o u g h 
t h e t e st o n c e b ef or e b ei n g ti me d i n or d er t o b e c o me f a mili ar wit h t h e t e st. Eit h er a w ri st w at c h wit h a s e c o n d 
h a n d or a st o p -w at c h c a n b e u s e d t o ti me t h e p erf or ma n c e.  
 
 
Ti me t o p erf or m “ U p a n d G o”  □□. □ s e c o n d s  
 
* Ti m e d “ U p a n d G o”
4 0  
 
 
 
III.  C O G NI TI O N 
T hi s s e cti o n i s o nl y c o m pl et e d Pr etr e at m e n t a n d at t h e e n d of tr e at m e nt 
 
6 -I T E M O RI E N T A TI O N-M E M O R Y -C O N C E N T R A TI O N T E S T**  
 
P ati e nt’ s 
R e s p o n s e  
M a xi m u m 
e r r or s  
                                         Fi n al  
S c or e          W ei g ht          s c or e  
1.  
W h at y e ar  i s it n o w ? 
[ wit h o ut l o o ki n g at a c al e n d ar]  
□□□□ 
1  
□□  x               4        =      □□ 
2.  
W h at mo nt h  i s it n o w ? 
[ wit h o ut l o o ki n g at a c al e n d ar] 
□□ 
1  
□□   x               3        =      □□ 
M e m or y P hr a s e:  
R e p e at t hi s p hr a s e aft er me:  
‘ J o h n Br o w n, 4 2 Mar k et Str e et, 
C hi c a g o’  
 
 
 
3.  
A b o ut w h at ti me i s it ? 
[ wit hi n 1 h o ur –  wit h o ut l o o ki n g at 
y o ur w at c h]  
□□: □□ 
1  
□□   x               3        =      □□ 
4.  
C o u nt  b a c k w ar d s 2 0 t o 1.  
 
2  
□□   x               2         =      □□ 
5.  
S a y t h e mo nt h s i n r e v er s e or d er.  
 
2  
□□   x               2        =      □□ 
6.  
R e p e at t h e Me mor y Phr a s e.  
 
5  
□□   x               2        =      □□ 
 
 
 
 
                  T O T A L S C O R E:     □□ 
 

 
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S c ori n g : F or it e ms 1 t o 3, t h e r e s p o n s e i s eit h er c orr e ct ( s c or e 0) or i n c orr e ct ( s c or e 1). F or it e ms 4 t o 6, a d d o n e 
p oi nt f or e a c h err or (it e m 4 a n d 5 ma xi mu m err or i s 2; f or it e m 6, ma xi mu m err or i s 5); t ot al all s c or e s i n “ Fi n al S c or e” 
c ol u mn. D at a fr o m p arti ci p a nt s f o u n d t o h a v e gr o s s c o g niti v e i mp air me nt a s d et er mi n e d b y t h e Ori e nt ati o n -Me mor y -
C o n c e ntr ati o n S c or e ≥1 1 will b e e x cl u d e d fr o m t h e a n al y si s. Ma xi mu m s c or e = 2 8.  
 
** O M C –  K at z ma n, R., et al., 1 9 8 3; K a w a s, C., et al., 1 9 9 5  
 
 

 
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I V.  S C O RI N G T hi s s e cti o n i s o nl y a p pli c a bl e if O M C -T e st i s c o m pl et e d Pr etr e at m e nt a n d P o st tr e at m e nt  
 
Di d t h e p a ti e nt s c or e ≥1 1 o n t h e 6-It e m Ori e nt ati o n-Me m or y -C o n c e ntr ati o n T e st ?  
 
□ N o  
□ Y e s ( If y e s, n otif y t h e p ati e nt’ s tr e ati n g p h y si ci a n.) 
 
T hi s q u e sti o n i s o nl y a p pli c a bl e t o q u e sti o n # 1 i n “ S e cti o n K. Y o ur F e eli n g s” fr o m t h e P ati e nt 
Q u e sti o n n air e.  
 
1.  H o w di d t h e p ati e nt a n s w er t h e q u e sti o n “ D o y o u oft e n f e el s a d or d e pr e s s e d ?” i n t h e P ati e nt 
 
Q u e sti o n n air e ( S e cti o n K)?  
 N o  
 Y e s (If y e s, n otif y t h e p ati e nt’ s tr e ati n g p h y si ci a n.) 
 
 
 
V. N U T RI TI O N  
 
W h at i s t h e p ati e nt’ s h ei g ht ? ( fr o m p ati e nt’ s c h art)    □□□ c m 
 
W h at i s t h e p ati e nt’ s c urr e nt w ei g ht ? ( fr o m p ati e nt’ s c h art)    □□□ k g  
 
W h at w a s t h e p ati e nt’ s w ei g ht a p pr o xi mat el y 6 mo nt h s a g o ? 
(fr o m p ati e nt’ s c h art or p ati e nt s s elf r e p ort)  □□□ k g  
 
C al c ul at e d B o d y Ma s s I n d e x: □□.□ 
 
Per c e nt U ni nt e nti o n al 
W ei g ht L o s s:  □□.□%  
 
 
 
VI. Q U E S TI O N S 
R E G A R DI N G T H E Q U E S TI O N N AI R E S  
 
A.  W er e a n y of t h e q u e sti o n n air e s i n t h e “ G eri atri c A s s e s s me nt –  H e alt h c ar e Pr of e s si o n al Q u e sti o n n air e” diffi c ult 
f or y o u t o a d mi ni st er ? 
 
□Y e s     □N o  

 
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If n o, pl e a s e pr o c e e d t o t h e n e xt q u e sti o n. 
If y e s, pl e a s e i n di c at e w hi c h q u e sti o n n air e w a s diffi c ult t o a d mi ni st er ? ( M ar k all t h at a p pl y wit h a n X.) 
□ K P S H e alt h c ar e Pr of e s si o n al R at e d ( p a g e 1)  
□ Ti me d U p a n d G o ( p a g e 2)  
□ 6 -It e m Ori e nt ati o n-Me mor y -C o n c e ntr ati o n T e st ( p a g e 2)  
□ Ot h er: Pl e a s e s p e cif y _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
B.  W er e a n y of t h e q u e sti o n n air e s i n t h e “ G eri atri c A s s e s s me nt –  Pati e nt Q u e sti o n n air e” diffi c ult f or t h e p ati e nt t o 
c o mpl et e ?  
 
□Y e s     □N o  
 
B.    If n o, pl e a s e pr o c e e d t o t h e n e xt q u e sti o n. If y e s, pl e a s e i n di c at e w hi c h  q u e sti o n n air e( s) w a s diffi c ult f or t h e 
p ati e nt t o c o mpl et e ? ( M ar k all t h at a p pl y wit h a n X.) 
 
□ B a c k gr o u n d I nf or mati o n ( p a g e 1)  
□ D ail y A cti viti e s ( p a g e 2 -3)  
□ Ph y si c al A cti viti e s ( p a g e 3)  
□ C urr e nt H e alt h R ati n g ( p a g e 4)  
□ F all s ( p a g e 4)  
□ Y o ur H e alt h ( p a g e 4 -5)  
□ N utriti o n al St at u s ( p a g e 7-8)  
□ H e alt h Q u e sti o n n air e  ( p a g e 9) 
□ S o ci al A cti viti e s ( p a g e 1 0) 
□ S o ci al S u p p ort ( p a g e 1 1 ) 
□ S pirit u alit y or r eli gi o n ( p a g e 1 2 ) 
□ Y o ur F e eli n g s ( p a g e 1 3 ) 
 
C.  W a s t h e p ati e nt a bl e t o c o mpl et e 
“ G eri atri c A s s e s s me nt –  Pati e nt Q u e sti o n n air e” o n hi s/ h er o w n ?  
 
□Y e s     □N o  
 
If n o, w h y ? ( M ar k all t h at a p pl y wit h a n X.) 
□ N ot lit er at e ( d o e s n ot r e a d or w rit e)  
□ Vi s u al pr o bl e m  
□ F ati g u e  

 
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□ Q u e sti o n s t o o diffi c ult ( a b o v e t h e p ati e nt’ s r e a di n g a bilit y)  
□ Ot h er: s p e cif y _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
D.  L e n gt h of ti me t o c o mpl et e b ot h t h e Pati e nt a n d H e alt h c ar e Pr of e s si o n al Q u e sti o n n air e s  
 
L e n gt h of ti me t o c o mpl et e h e alt h c ar e pr of e s si o n al q u e sti o n n air e  
□□□ mi n ut e s  
 
L e n gt h of ti me  t o c o mpl et e p ati e nt q u e sti o n n air e 
 
 
□□□ mi n ut e s  
 
T ot al l e n gt h of ti me t o c o mpl et e b ot h q u e sti o n n air e s  
 
 
□□□ mi n ut e s  
 
 
C o mpl et e d b y: _
_ _  
D at e f or m c o mpl et e d: □□ / □□ / □□□□ 
 
( L a st n a m e, Fir st n a m e) 
 
 
 
        M M         D  D         Y   Y   Y  Y  
 
 
 
 
 
 
 

 
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A P P E N DI X III  : W
A S I T W
O R T H I T Q U ES TI O N N AI R E  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _  
T o be c o m plete d b y P h ysicia n, N urs e, or C R A:  
P atie nt Na m e: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _                 Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _                
P atie nt N u m ber: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ _ _ __ _ _ _ _ ___  
P arti ci pati n g i n a cli nic al t ri al / res e arc h st u dy is a pe rs o n al c h oice a n d a n i n di vi d u al e x pe rie nce. 
We wo ul d li k e t o get y o u r f ee d bac k o n y o u r e x pe rie n ce i n t his res e ar c h st u dy.  
Di re cti o ns : Pleas e a ns w er eac h q uestio n b y cir clin g Y (f or yes), N (f or n o), or U (f or u nc ertain).  
 
1. Was it w ort h w hile f or y o u t o participate in t his r es ear c h st u d y ? 
 
Y            N            U  
2. If y o u ha d t o d o it o ver, w o uld y o u participa te in t his r es ear c h st u d y a gain?       Y            N            U 
3. W o uld y o u r ec o m me n d participatin g in t his r es ear c h st u d y t o ot hers ?   
Y            N            U  
4. O ver all, did y o ur q ualit y of lif e c ha n ge b y participatin g in t his r es ear c h st u d y ? ( circle o ne res p o nse) 
 
It i m pr o ve d 
 
It sta ye d t he s a me 
 
It g ot w ors e 
5. O ver all h o w w as y o ur e x perie nc e participatin g in t his r es ear c h st u d y ? ( circle o ne res p o nse) 
 
Bett er t ha n I e x pecte d   
T he s a me as I e x pecte d   
W ors e t ha n I e x pecte d  
6. If t her e w as o ne t hin g t hat c o uld ha ve bee n d o ne t o i m pr o ve y o ur e x perie nc e in t his r es ear c h st u d y, 
w hat w o uld it be?  
 
 
7. W o uld y o u like t o talk t o s o me o ne a b o ut y o ur c o nc er ns? 
Yes                      N o  
( circl e o ne res p o nse)  
 
 

 
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A P P E N DI X IV : O V E R A L L T R E A T M E N T U TI LI T Y  
 
O T U is a n o vel clinic al o utc o me meas ur e inc or p oratin g o bjective a n d s u bjective meas ur es of a ntic a nc er 
effic ac y, t oler a bilit y, a n d ac c e pta bilit y, ass ess e d at t he e n d of tr eat me nt a n d c o n de nse d int o a si m ple 3 
p oint s c or e.  
O T U m a y be r e gar de d as as kin g t he clinicia n: “ Wit h t he be nefit of hin dsig ht, ar e y o u gla d y o u ga ve t his 
tr eat m e nt ?” a n d as kin g t he patie nt: “ Wit h t he be nefit of hin dsig ht, ar e y o u gla d y o u r ec eive d it?”. O T U is 
s c or e d as g o o d, inter me diate or p o or, c orr es p o n din g  t o “ yes ”, “ u ncertain” or “ n o” r e plies t o t hes e 
q uestio ns.  
T o s c or e t he O T U, t he patie nt is ass ess e d at t he e n d of tr eat me nt , usin g t he f ollo win g criteria: 
1)  Cli nic al be n efit ?  Cate g orize d as:  
a.  Bot h  r a diolo gic ally pr o gr essio n- fr ee ( R E CI S T r es p o nse or sta ble dis eas e) a n d n o clinic al 
deterior atio n as ass ess e d b y tr eatin g c o ns ulta nt  
b.  Eit her  r a diolo gic ally pr o gr essio n- fr ee ( R E CI S T pr o gr essive dis eas e) or clinic al 
deterior atio n as ass ess e d b y tr eatin g c o ns ulta nt  
2)  Tol e r a ble a n d acce pt a ble ?  Cate g orize d as:  
a.  All of t he f ollo win g: 
• N o S A E or S U S A R attrib ute d t o tr eat me nt  
• N o e pis o des of gr a de ≥3 n o n -he mat olo gic al t o xicit y  
• P atie nt r es p o ns e t o “ W hic h o ne of t he f ollo win g p hr as es best des cribes y o u at 
t his ti me?” in s ectio n D of t he Geriatric Ass ess me nt at t he e n d of tr eat me nt is n ot 
“ Re q uir e c o nsider a ble assista nc e f or pers o nal c ar e”, “ Dis a ble d, r e q uir e s pecial 
c ar e a n d assista nc e” or “ S e ver ely dis a ble d, r e q uir e c o ntin u o us n ursin g c ar e. ”  
• P atie nt r es p o ns e t o “ Was  it w ort h w hile f or y o u t o u n der g o t his c a nc er 
tr eat me nt?” fr o m t he Was It W ort h It q uestio n nair e is “ Y” 
b.  An y of t he f ollo win g : 
• An S A E or S U S A R (s us pecte d u ne x pecte d s erio us a d verse r eactio n) attrib ute d t o 
tr eat me nt 
• An e pis o de of gr a de ≥3 n o n -he mat olo gic al t o xicit y  
• P atie nt r es p o ns e t o “W hic h o ne of t he f ollo win g p hr as es best des cribes y o u at 
t his ti me?” in s ectio n D of t he Geriatric Ass ess me nt at t he e n d of tr eat me nt is 
“ Re q uir e c o nsider a ble assista nc e f or pers o nal c ar e”, “ Dis a ble d, r e q uir e s pecial 
c ar e a n d assista nc e” or “ S e ver ely dis a ble d, r e q uir e c o ntin u o us n ursin g c ar e. ”  

 
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• P atie nt r es p o ns e t o  “Was it w ort h w hile f or y o u t o u n der g o t his c a nc er 
tr eat me nt?” fr o m t he Was I t W ort h It q uestio n nair e is n ot “ Y” 
S c ori n g :  
 
G o o d O T U: P atie nt is alive a n d s c or es 1a/ 2a  
 
I nt er me diate O T U: P atie nt is alive a n d s c or es 1a/ 2 b or 1 b/ 2a 
 
P o or O T U: P atie nt is alive a n d s c or es 1 b/ 2 b, or patie nt is dea d  
 
 

 
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A P P E N DI X V : E Q -5 D -3 L  H E A L T H Q U ES TI O N N AI R E  
 
E Q -5 D -3 L  
 
Un der eac h hea din g, pleas e c hec k t he O N E b o x t hat best des cribes y o ur healt h T O D A Y.  
M O BI LI T Y  
 
I ha ve n o pr o ble ms w alkin g 
❑ 
I ha ve m o der ate pr o ble ms w alkin g 
❑ 
I a m c o nfine d t o be d 
❑ 
 
 
S E L F -C A R E  
 
I ha ve n o pr o ble ms w as hin g or dr essin g m ys elf  
❑ 
I ha ve m o der ate pr o ble ms w as hin g or dr essin g m ys elf 
❑ 
I a m u na ble t o w as h or dr ess m ys elf 
❑ 
 
 
U S U A L A C TI VI TI E S ( e. g. w ork, st u dy, h o use w ork, f a mily or leis ure 
acti viti es)  
 
I ha ve n o pr o ble ms d oin g m y us ual activities 
❑ 
I ha ve m o der ate pr o ble ms d oin g m y us ual activities  
❑ 
I a m u na ble t o d o m y us ual activities 
❑ 
 
 
P AI N / DI S C O M F O R T  
 
I ha ve n o pain or dis c o mf ort 
❑ 
I ha ve m o der ate pain or dis c o mf ort 
❑ 
I ha ve e xtr e me pain or dis c o mf ort 
❑ 
 
 
A N XI E T Y / D E P R E S SI O N  
 
I a m n ot a n xio us or de pr ess e d  
❑ 
I a m m o der ately a n xio us or de pr ess e d 
❑ 
I a m e xtr e mely a n xio us or de pr ess e d 
❑ 
 
 
 

 
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•  We w o uld like t o k n o w h o w g o o d or ba d y o ur he alt h is T O D A Y.  
•  T his s c ale is n u m bere d fr o m 0 t o 1 0 0.  
•  1 0 0 me a ns t he best  he alt h y o u c a n i ma gine.  
 0 me a ns t he w orst  he alt h y o u c a n i ma gine.  
•  Mar k a n X o n t he s c ale t o in dic ate h o w y o ur he alt h is T O D A Y.  
•  N o w, ple as e write t he n u m ber y o u mar ke d o n t he s c ale in t he b o x belo w.  
 
 
 
 
 
 
1 0  
0  
2 0  
3 0  
4 0  
5 0  
6 0  
8 0  
7 0  
9 0  
1 0 0  
5  
1 5  
2 5  
3 5  
4 5  
5 5  
7 5  
6 5  
8 5  
9 5  
Y O U R H E A L T H T O D A Y  =  

 
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A P P E N DI X  V II: P A TI E N T M E DI C A TI O N D I A R Y - P A L B O C I C LI B  
To da y’s dat e  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _  
 
P ati e nt Na m e _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ (initials ac c e pta ble)  
P atie nt St u dy I D  _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
I N S T R U C TI O N S T O T H E P A TI E N T: 
1.  C o m plete t his f or m w hile y o u ta ke  palb ociclib  a n d if y o u are ta kin g letr oz ole .  T his f or m 
is a 28  da y diar y. Y o u d o n’t ne e d t o c o m plete t he letr oz ole c olu m n if y o u are n ot ta kin g 
it. Y o u ma y ne e d t o c o m plete m ore t ha n o ne f or m bet w e e n clinic visits.  
2.  Y o u will ta ke y o ur d os e of palb ocicli b daily f or 2 1 da ys.  Y o u will als o ta ke y o ur d os e 
of letr oz ole daily f or 2 8 da ys.  
3.   P alb ociclib  intera cts wit h ot her me dic atio ns. D o n ot start a n y ne w pres criptio n or o ver 
t he c o u nter me dic atio ns wit h o ut dis c ussin g wit h y o ur d oct or or p har ma cist.  
4  
Ta ke t he palb ociclib c a ps ule wit h f o o d  at a b o ut t he s a me ti me e ver y da y . Letr oz ole c a n 
be ta ke n o nc e daily wit h o ut re gar d t o f o o d.  
5 . Re c or d t he date, a n d w he n y o u t o o k t he c a ps ule  a n d pill. Re c or d d os es as s o o n as y o u 
ta ke t he m; d o n ot  batc h e ntries t o get her at a later ti me.  
6 . If y o u v o mit or miss a d os e , d o n ot ma ke u p t hat d os e; res u me d osin g wit h t he ne xt 
s c he d ule d d os e at t he us ual ti me.  
7 . S w allo w c a ps ule w h ole, d o n ot cr us h or c he w.  It s h o uld be ta ke n in c o m binatio n wit h 
e n d ocrine t hera p y (if ta kin g Letr oz ole) . T he c o m binatio n t hat y o u are bein g tre ate d wit h 
ma y be  palb ociclib alo n g wit h  letr oz ole pill or f ulvestra nt inje ctio n. D o n ot ta ke 
gra pefr uit or gra pefr uit juic e w he n y o u are ta kin g t his dr u g. 
8 . If y o u ha ve a n y c o m me nts or n otic e a n y side effe cts, ple as e re c or d t he m in t he 
C o m me nts c olu m n. If y o u ma ke a mista ke w hile y o u write, ple as e cr oss it o ut wit h o ne 
line, p ut y o ur initials ne xt t o it, a n d t he n write t he c orre cte d inf or matio n ne xt t o y o ur 
initials.  E xa m ple: 1 0:3 0 a m S B 9:3 0 a m  
9 . If y o u d o n’t ta ke y o ur palb ociclib d os e f or a n y re as o n, c o nta ct y o ur p h ysicia n.  
1 0 . Ple as e ret ur n t his f or m t o y o ur p h ysicia n at y o ur ne xt a p p oint me nt. Y o u ma y ne e d t o 
ret ur n m ore t ha n o ne f or m per clinic visit.  
 
 
 
 
 

 
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D a y  
D ate  
Ti me of d ail y 
d os e - 
P al b o cicli b ( 2 1 
d a ys)  
Ti me of d ail y 
d os e - 
Letr o z ole( 2 8 
d a ys ) 
If y o u mis s e d a 
d os e,  
R e as o n fo r n ot 
t a ki n g t he c a ps ule  
C o m me nts  
1  
 
 
 
 
 
2  
 
 
 
 
 
3  
 
 
 
 
 
4  
 
 
 
 
 
5  
 
 
 
 
 
6  
 
 
 
 
 
7  
 
 
 
 
 
8  
 
 
 
 
 
9  
 
 
 
 
 
1 0  
 
 
 
 
 
1 1  
 
 
 
 
 
1 2  
 
 
 
 
 
1 3  
 
 
 
 
 
1 4  
 
 
 
 
 
1 5  
 
 
 
 
 
1 6  
 
 
 
 
 
1 7  
 
 
 
 
 
1 8  
 
 
 
 
 
1 9  
 
 
 
 
 
2 0  
 
 
 
 
 
2 1  
 
 
 
 
 
2 2  
 
N o c a ps ule  
 
 
 
2 3  
 
N o c a ps ule  
 
 
 
2 4  
 
N o c a ps ule  
 
 
 
2 5  
 
N o c a ps ule  
 
 
 
2 6  
 
N o c a ps ule  
 
 
 
2 7  
 
N o c a ps ule  
 
 
 
2 8  
 
N o c a ps ule  
 
 
 
P atie nt’s sig nat ure  
 
 
D ate  
 
 
Ad ditio nal s pac e f or C o m me nts:  

 
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A P P E N DI X I X: P A TI E N T P H A R M A C O KI N E T I C Q U ES TI O N N AI R E 
N ot e: T his f or m is r e q uir e d t o be c o m plete d at all blo o d dr a w ti me p oints ass ociate d wit h t he 
p har m ac o kinetic s u bst u d y ( A1 7 1 6 0 1 -P P 1).  
O n pr e -st u d y tr eat me nt visit ( bas eline), C ycle 1 Da y 1 5 a n d C ycle 2 Da y 1 5, t his f or m is t o be 
a d minist er e d b y a n urs e/ C R P , c o m plete d b y t he patie nt, a n d e nter e d int o Ra ve b y site staff. 
F or bas eli n e visit: T h e patie nt m ay i n dic at e N/ A f or t h e q u esti o ns t hat are n ot a p plic a ble.  
Not e: st u dy m e dic ati o n s ho ul d O N L Y be t a k e n o n t h e da y of t h e cli nic visit after pr o vi di n g t h e P K 
bl o o d s a m ple . 
 
P atie nt I nitials: _ _ _ _ _ _ _ _ _ _ _  
P atie nt I D #: _ _ _ _ _ _ _ _ _ _ _ _ _  
St u d y #: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C ycle #: _ _ _ _ _ _ _  
Da y #: _ _ _ _ _ _ _ _ _  
Dat e: _ _ _ _ _ _ _ _ _ _  
T he f ollo win g q uestio n r ef ers t o t he da y bef or e yester da y ( 2 da ys a g o):  
W hat ti m e did y o u ta ke y o ur or al st u d y me dic atio n ( palb ociclib) ? _ _ _ _:_ _ _ _ A M / P M 
W hat d os e of or al st u d y me dic atio n ( palb ociclib) did y o u ta ke o n t he da y bef or e yester da y                               
------    m g  
 
T he f ollo win g q uestio n r ef ers t o yester da y ( 1 da y a g o):  
W hat ti m e did y o u ta ke y o ur or al st u d y me dic atio n ( palb ociclib) ? _ _ _ _:_ _ _ _ A M / P M  
W hat d os e of or al st u d y me dic atio n ( palb ociclib) did y o u ta ke yester da y  ------    m g  
 
T he f ollo win g q uestio n r ef ers t o t o da y ( T HI S O N L Y A P P LI E S I F Y O U H A V E T A K E N Y O U R  
S T U D Y M E DI C A T I O N B E F O R E B EI N G S E E N I N T H E C LI NI C T O D A Y): 
W hat ti m e did y o u ta ke y o ur st u d y me dic atio n ( palb ociclib) ? _ _ _ _:_ _ _ _ A M / P M  
W hat d os e of or al st u d y me dic atio n ( palb ociclib) did y o u ta ke t o da y?    -------- m g  
 
List c o n c o mit a nt m e dic ati o ns patie nt is t a ki n g  at bas eli ne st u dy visit O N L Y: