Clinical trial NCT03312738
Conditions: Advanced Breast Cancer
Keywords: everolimus exemestane advanced Breast Cancer non-steroidal aromatase inhibitors breast carcinoma breast cancer breast lump HER2 negative breast cancer progression
Sponsor: Novartis Pharmaceuticals
Start date: 2017-09-15; Completion date: 2022-04-25
Enrollment: 159 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aimed at evaluating the safety and efficacy of everolimus plus exemestane in Chinese postmenopausal women with ER+ HER2- locally advanced, recurrent, or metastatic breast cancer after recurrence or progression on letrozole or anastrozole.

Detailed description:
This was a multicenter, double-blind, randomized, placebo-controlled, phase II study evaluating treatment with everolimus (10 mg daily) in combination with exemestane (25 mg daily) vs placebo in combination with exemestane (25 mg daily) in Chinese postmenopausal women with locally advanced, recurrent or metastatic ER+ HER2- breast cancer refractory to non-steroidal aromatase inhibitors.

Randomized participants started the study treatment at Cycle 1 Day 1, and were treated continuously until disease progression (assessed by RECIST 1.1), unacceptable toxicity, death or discontinuation from treatment for any other reason.

After end of treatment, all participants were followed up for safety up to 30 days after last dose of study treatment (exemestane and/or everolimus/placebo). All participants were followed for survival status at least every 3 months after treatment discontinuation unless they discontinued due to death, consent withdrawal or lost to follow-up

If a participants permanently discontinued study treatment for reasons other than disease progression, death, lost to follow-up, or withdrawal of consent to efficacy follow-up then they entered the post-treatment efficacy follow-up period until disease progression, death, lost to follow-up or withdrawal of consent for efficacy follow-up.

Arms: arm 1: Participants received everolimus as a continuous oral daily dose of 10 mg and exemestane as a continuous oral daily dose of 25 mg arm 2: Participants received placebo as a continuous oral daily dose and exemestane as a continuous oral daily dose of 25 mg
Interventions: intervention 1: Everolimus intervention 2: Exemestane intervention 3: Everolimus Placebo
Intervention descriptions: intervention 1: Everolimus was formulated as tablets of 5 mg strength and was packaged into blister packs . Everolimus (two 5 mg tablets daily) was administered in a blinded manner by continuous oral daily dosing. intervention 2: Commercially available exemestane was supplied as 25 mg tablets. Exemestane was administered as continuous oral daily dose of 25 mg tablets. intervention 3: Placebo was formulated to be indistinguishable from the everolimus tablets. Matching placebo (two tablets daily) was administered in a blinded manner by continuous oral daily dosing.

Protocol documents:
Prot_000.pdf: 
Cli ni c al D e v el o p m e nt
R A D 0 0 1 ( e v er oli m u s)
O n c ol o g y Cli ni c al Pr ot o c ol C R A D 0 0 1 Y 2 2 0 2  / N C T 0 3 3 1 2 7 3 8
A r a n d o mi z e d, d o u bl e -bli n d, pl a c e b o  c o ntr oll e d , p h a s e II 
st u d y  of E v er oli m u s i n c o m bi n ati o n w it h E x e m e st a n e i n t h e 
tr e at m e nt of C hi n e s e p o st m e n o p a u s al wo m e n w it h 
e str o g e n r e c e pt or p o siti v e, H E R -2 n e g ati v e, l o c all y  
a d v a n c e d, r e c urr e nt, or m et a st ati c br e a st c a n c er af t er 
r e c urr e n c e or pr o gr e s si o n o n pri or l etr o z ol e or a n a str o z ol e
A ut h or s
 
D o c u m e nt t y p e 
A m e n d e d Pr ot o c ol V er si o n
E U D R A C T n u m b er
N ot a p pli c a bl e
V er si o n n u m b er
0 1 (Cl e a n )
D e v el o p m e nt p h a s e
II
D o c u m e nt st at u s
Fi n al
R el e a s e d at e
2 3 -M a y -2 0 1 7
Pr o p ert y of N o v arti s
C o nfi d e nti al
M a y n ot b e u s e d, di v ul g e d, p u bli s h e d or ot h er wi s e di s cl o s e d
wit h o ut t h e c o n s e nt of N o v arti s


N o v arti s
C o nfi d e nti al
P a g e 2
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a bl e of c o nt e nt s
Ta ble of c o nte nts .................................................................................................................2
List of fi g ures ......................................................................................................................5
List of ta bles ........................................................................................................................5
List of a b bre viati o ns ............................................................................................................7
Gl ossar y  of ter ms...............................................................................................................1 1
Pr ot oc ol s u m mar y ..............................................................................................................1 2
A me n d me nt 1 ( 2 3 -M a y - 2 0 1 7)...........................................................................................1 9
1
Bac k gr o u n d ........................................................................................................................2 3
1. 1
O ver vie w of disease pat h o ge nesis, e pi de mi ol o g y a n d c urre nt treat me nt ..............2 3
1. 1. 1
E pi de mi ol o g y  of breast ca ncer..............................................................2 3
1. 1. 2
Treat me nt o pti o ns f or h or m o ne rece pt or p ositi ve a d va nce d breast
ca ncer ....................................................................................................2 3
1. 1. 3
R ole of ma m malia n tar get of ra pa m yci n i n E R + A B C .........................2 4
1. 2 
I ntr o d ucti o n t o i n vesti gati o nal treat me nt(s) a n d ot her st u d y  treat me nt(s).............2 5
1. 2. 1
O ver vie w of e ver oli m us ........................................................................2 6
1. 2. 2
O ver vie w of exe mesta ne .......................................................................3 3
2
Rati o nale ............................................................................................................................3 4
2. 1
St u d y  rati o nale a n d p ur p ose...................................................................................3 4
2. 2
Rati o nale f or t he st u d y desi g n ...............................................................................3 6
2. 3
Rati o nale f or d ose a n d re gi me n selecti o n ..............................................................3 6
2. 4 
Rati o nale f or c h oice of c o m bi nati o n dr u gs............................................................ 3 6
2. 5
Ris ks a n d be nefits ..................................................................................................3 7
3
O bjecti ves a n d e n d p oi nts ...................................................................................................3 8
4
St u d y  desi g n ......................................................................................................................3 9
4. 1
Descri pti o n of st u d y desi g n ...................................................................................3 9
4. 2
Ti mi n g of i nteri m a nal ys es a n d desi g n a da ptati o ns ...............................................4 3
4. 3
Defi niti o n of e n d of st u d y ......................................................................................4 3
4. 4
Earl y st u d y ter mi nati o n ..........................................................................................4 3
5
P o p ulati o n ..........................................................................................................................4 3
5. 1
Patie nt p o p ulati o n ..................................................................................................4 3
5. 2
I ncl usi o n criteria ....................................................................................................4 4
5. 3
E xcl usi o n criteria ...................................................................................................4 5
6
Treat me nt ...........................................................................................................................4 7
6. 1
St u d y  treat me nt......................................................................................................4 7
6. 1. 1
D osi n g re gi me n .....................................................................................4 7


N o v arti s
C o nfi d e nti al
P a g e 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
6. 1. 2
A ncillar y  treat me nts..............................................................................4 7
6. 1. 3 
Resc ue me dicati o n ................................................................................ 4 7
6. 1. 4
G ui deli nes f or c o nti n uati o n of treat me nt ..............................................4 7
6. 1. 5
Treat me nt d urati o n ................................................................................4 8
6. 2
D ose escalati o n g ui deli nes .....................................................................................4 8
6. 3
D ose m o dificati o ns ................................................................................................4 8
6. 3. 1
D ose m o dificati o n a n d d ose dela y ........................................................4 8
6. 3. 2  
A d diti o nal ma na ge me nt a n d f oll o w- u p f or selecte d t o xicities .............5 1
6. 3. 3
E xe mesta ne ...........................................................................................5 7
6. 3. 4
F oll o w -u p f or t o xicities .........................................................................5 8
6. 4 
C o nc o mita nt me dicati o ns ...................................................................................... 5 8
6. 4. 1
Pr o hi bite d c o nc o mita nt t hera p y............................................................ 5 8
6. 4. 2
Use of bis p h os p h o nates .........................................................................5 9
6. 4. 3
Ot her c o nc o mita nt me dicati o ns .............................................................5 9
6. 5
Patie nt n u m beri n g, treat me nt assi g n me nt or ra n d o mizati o n .................................6 1
6. 5. 1 
Patie nt n u m beri n g ................................................................................. 6 1
6. 5. 2 
Treat me nt assi g n me nt or ra n d o mizati o n............................................... 6 2
6. 5. 3
Treat me nt bli n di n g ................................................................................6 2
6. 6
St u d y  treat me nt pre parati o n a n d dis pe nsati o n .......................................................6 3
6. 6. 1
St u d y  treat me nt pac ka gi n g a n d la beli n g...............................................6 3
6. 6. 2
Dr u g s u p pl y  a n d st ora ge........................................................................6 3
6. 6. 3
St u d y  treat me nt c o m plia nce a n d acc o u nta bilit y ...................................6 4
6. 6. 4
Dis p osal a n d destr ucti o n .......................................................................6 4
7  
Visit sc he d ule a n d assess me nts......................................................................................... 6 4
7. 1
St u d y  fl o w a n d visit sc he d ule................................................................................6 4
7. 1. 1
M olec ular pre -scree ni n g........................................................................6 8
7. 1. 2
Scree ni n g ...............................................................................................6 8
7. 1. 3
Treat me nt peri o d ...................................................................................7 0
7. 1. 4
Disc o nti n uati o n of st u d y  treat me nt.......................................................7 0
7. 1. 5
Wit h dra wal of c o nse nt
..........................................................................7 1
7. 1. 6
F oll o w -u p peri o d ...................................................................................7 1
7. 1. 7
L ost t o f oll o w - u p...................................................................................7 2
7. 2
Assess me nt t y pes ...................................................................................................7 2
7. 2. 1
Efficac y  assess me nts.............................................................................7 2
7. 2. 2
Safet y  a n d t olera bilit y assess me nts.......................................................7 5
7. 2. 3
P har mac o ki netics ..................................................................................7 8


N o v arti s
C o nfi d e nti al
P a g e 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
7. 2. 4
Bi o mar kers ............................................................................................8 1
7. 2. 5
Res o urce utilizati o n ...............................................................................8 1
7. 2. 6
Patie nt re p orte d o utc o mes .....................................................................8 1
8
Safet y  m o nit ori n g a n d re p orti n g........................................................................................8 1
8. 1
A d verse e ve nts .......................................................................................................8 1
8. 1. 1  
Defi niti o ns a n d re p orti n g ...................................................................... 8 1
8. 1. 2
La b orat or y  test a b n or malities................................................................8 2
8. 2
Seri o us a d verse e ve nts ...........................................................................................8 3
8. 2. 1  
Defi niti o ns............................................................................................. 8 3
8. 2. 2 
Re p orti n g............................................................................................... 8 3
8. 3
E mer ge nc y  u n bli n di n g of treat me nt assi g n me nt ...................................................8 4
8. 4
Pre g na ncies ............................................................................................................8 5
8. 5
War ni n gs a n d preca uti o ns ......................................................................................8 5
8. 6
Data M o nit ori n g C o m mittee ..................................................................................8 5
8. 7
Steeri n g C o m mittee ...............................................................................................8 5
9
Data c ollecti o n a n d ma na ge me nt .......................................................................................8 5
9. 1
Data c o nfi de ntialit y ...............................................................................................8 5
9. 2
Site m o nit ori n g ......................................................................................................8 6
9. 3  
Data c ollecti o n....................................................................................................... 8 6
9. 4
Data base ma na ge me nt a n d q ualit y  c o ntr ol............................................................8 7
1 0
Statistical met h o ds a n d data a nal ys is ................................................................................8 7
1 0. 1
A nal y sis sets ..........................................................................................................8 8
1 0. 1. 1
F ull A nal ys is Set ...................................................................................8 8
1 0. 1. 2
Safet y  set...............................................................................................8 8
1 0. 1. 3 
P har mac o ki netic set ( P A S) ................................................................... 8 8
1 0. 2
Patie nt de m o gra p hics/ ot her baseli ne c haracteristics .............................................8 8
1 0. 3
Treat me nts (st u d y treat me nt, c o nc o mita nt t hera pies, c o m plia nce) .......................8 8
1 0. 4
Pri mar y  o bjecti ve...................................................................................................8 9
1 0. 4. 1
Varia ble .................................................................................................8 9
1 0. 4. 2
Statistical h y p ot hesis, m o del, a n d met h o d of a nal y sis ..........................8 9
1 0. 4. 3
Ha n dli n g of missi n g val ues/ce ns ori n g/ disc o nti n uati o ns .......................8 9
1 0. 4. 4
S u p p orti ve a n d se nsiti vit y a nal ys es ......................................................9 0
1 0. 5
Sec o n dar y  o bjecti ves .............................................................................................9 0
1 0. 5. 1 
S ec o n dar y efficac y o bjecti ves...............................................................9 0
1 0. 5. 2
Safet y  o bjecti ves ...................................................................................9 1
1 0. 5. 3
P har mac o ki netics ..................................................................................9 3


N o v arti s
C o nfi d e nti al
P a g e 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
1 0. 6 
Sa m ple size calc ulati o n.......................................................................................... 9 4
1 0. 7
P o wer f or a nal ys is of ke y sec o n dar y varia bles......................................................9 4
1 1
Et hical c o nsi derati o ns a n d a d mi nistrati ve pr oce d ures ......................................................9 5
1 1. 1
Re g ulat or y a n d et hical c o m plia nce ........................................................................9 5
1 1. 2
Res p o nsi bilities of t he i n vesti gat or a n d I R B/ I E C/ R E B.........................................9 5
1 1. 3
I nf or me d c o nse nt pr oce d ures.................................................................................9 5
1 1. 4
Disc o nti n uati o n of t he st u d y ..................................................................................9 5
1 1. 5
P u blicati o n of st u d y  pr ot oc ol a n d res ults...............................................................9 5
1 1. 6
St u d y  d oc u me ntati o n, rec or d kee pi n g a n d rete nti o n of d oc u me nts.......................9 6
1 1. 7
C o nfi de ntialit y  of st u d y d oc u me nts a n d patie nt rec or ds .......................................9 7
1 1. 8  
A u dits a n d i ns pecti o ns........................................................................................... 9 7
1 1. 9
Fi na ncial discl os ures ..............................................................................................9 7
1 2
Pr ot oc ol a d here nce ............................................................................................................9 7
1 2. 1
A me n d me nts t o t he pr ot oc ol ..................................................................................9 7
1 3
Refere nces (a vaila ble u p o n re q uest) ..................................................................................9 8
1 4
A p pe n dices ......................................................................................................................1 0 1
1 4. 1
A p pe n di x 1: G ui deli nes f or Res p o nse, D urati o n of O verall Res p o nse, T T F, 
T T P, Pr o gressi o n -Free S ur vi val a n d O verall S ur vi val ( versi o n 3. 2, base d o n 
R E CI S T 1. 1) ........................................................................................................1 0 1
1 4. 1. 1
I ntr o d ucti o n .........................................................................................1 0 2
1 4. 1. 2
Efficac y  assess me nts...........................................................................1 0 2
1 4. 1. 3
Efficac y  defi niti o ns.............................................................................1 1 1
1 4. 1. 4
Data ha n dli n g a n d pr o gra m mi n g r ules ................................................1 2 2
1 4. 1. 5
Refere nces (a vaila ble u p o n re q uest) ...................................................1 2 5
Li st of fi g ur e s
Fi g ure 1 - 1 
C he mical str uct ure of e ver oli m us .........................................................2 6
Fi g ure 4 - 1
St u d y  desi g n..........................................................................................4 2
Li st of t a bl e s
Ta ble 1 - 1
E ver oli m us - dr u g s u bsta nce .................................................................2 6
Ta ble 1 - 2
B O L E R O -2 St u d y : m ost c o m m o nl y re p orte d a d verse e ve nts ( >/ = 
1 0 % of patie nts treate d wit h e ver oli m us + e xe mesta ne)....................... 3 2
Ta ble 1 - 3
A n y -gra de a d verse e ve nts wit h >/ + 1 0 % i nci de nce i n Asia n A B C 
patie nts treate d wit h e ver oli m us + e xe mesta ne..................................... 3 3
Ta ble 3 - 1
O bjecti ves a n d relate d e n d p oi nts ..........................................................3 8


N o v arti s
C o nfi d e nti al
P a g e 6
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Ta ble 6 - 1
D ose a n d treat me nt sc he d ule................................................................. 4 7
Ta ble 6 - 2
Rec o m me n dati o n of e ver oli m us d ose re d ucti o ns ................................. 4 8
Ta ble 6 - 3
Criteria f o r i nterr u pti o n a n d re-i nitiati o n of e ver oli m us/ place b o 
treat me nt................................................................................................4 9
Ta ble 6 - 4
Ma na ge me nt of n o n -i nfecti o us p ne u m o nitis.........................................5 3
Ta ble 6 - 5
Acti o n t o be ta ke n base d o n he patitis B scree ni n g res ults ....................5 5
Ta ble 6 - 6
G ui deli nes f or mana ge me nt of he patitis B ............................................5 5
Ta ble 6 - 7
G ui deli nes f or ma na ge me nt of he patitis C flare ...................................5 6
Ta ble 6 - 8
Cli nicall y  rele va nt dr u g i nteracti o ns: i n d ucers, a n d i n hi bit ors of
is oe nz yme C Y P 3 A ................................................................................6 0
Ta ble 6 - 9
Cli nicall y  rele va nt dr u g i nteracti o ns: s u bstrates, i n d ucers,
i n hi bit ors of P g P a n d P g P/ C Y P 3 A d ual i n hi bit ors ...............................6 1
Ta ble 6 - 1 0 
Pac ka gi n g a n d la beli n g .........................................................................6 3
Ta ble 6 - 1 1
S u p pl y  a n d st ora ge of st u d y treat me nts ................................................6 3
Ta ble 7 - 1
Visit e val uati o n sc he d ule ......................................................................6 5
Ta ble 7 - 2
I ma gi n g assess me nt c ollecti o n pla n......................................................7 3
Ta ble 7 - 3
E C O G Perf or ma nce Stat us Scale ..........................................................7 6
Ta ble 7 - 4
L ocal cli nical la b orat or y  para meters c ollectio n pla n ............................7 7
Ta ble 7 - 5
P K bl o o d c ollecti o n sc he d ule ................................................................8 0
Ta ble 1 0 - 1
9 0 % CI s f or vari o us o bser ve d hazar d rati os .........................................9 4
Ta ble 1 4 - 1
Res p o nse criteria f or tar get lesi o ns .....................................................1 0 7
Ta ble 1 4 - 2
Res p o nse criteria f or n o n -tar get lesi o ns..............................................1 0 9
Ta ble 1 4 - 3
O verall lesi o n res p o nse at eac h assess me nt ........................................1 1 1
Ta ble 1 4 - 4
O verall lesi o n res p o nse at eac h assess me nt: patie nts wit h n o n -
tar get disease o nly............................................................................... 1 1 8
Ta ble 1 4 - 5
O pti o ns f or e ve nt dates use d i n P F S, T T P, d urati o n of res p o nse ........1 2 0


N o v arti s
C o nfi d e nti al
P a g e 7
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Li st of a b br e vi ati o n s
A B C
A d v a n c e d Br e a st C a n c er
A D M E
A b s or pti o n Di stri b uti o n M et a b oli s m a n d E x cr eti o n
A E
A d v er s e E v e nt
A K T
Pr ot ei n Ki n a s e B
A L P
Al k ali n e p h o s p h at a s e
A L T
Al a ni n e a mi n otr a n sf er a s e/ gl ut a mi c p yr u vi c tr a n s a mi n a s e/ G P T
A N C
A b s ol ut el y N e utr o p hil C o u nt
A S C O
A m eri c a n S o ci et y of Cli ni c al O n c ol o g y
A S T
A s p art at e a mi n otr a n sf er a s e/ gl ut a mi c o x al o a c eti c tr a n s a mi n a s e/ G O T
A U C 0- 2 4 h
Ar e a U n d er t h e C ur v e 0- 2 4 h
B A L
Br o n c h o al v e ol ar l a v a g e
B C
Br e a st C a n c er
B RI C
Bli n d e d i n d e p e n d e nt r e vi e w c o m mitt e e
B S A
B o d y S urf a c e Ar e a
B U N
Bl o o d Ur e a Nitr o g e n
C B C
C ell s Bl o o d C o u nt
C B R
Cli ni c al B e n efit R at e
C C G
C a s e R e p ort/ R e c or d F or m ( C R F) C o m pl eti o n G ui d eli n e s
C E R T
C e nt er f or E d u c ati o n a n d R e s e ar c h o n T h er a p e uti c s
CI
C o nfi d e n c e I nt er v al
CI S H
C hr o m o g e ni c i n sit u h y bri di z ati o n
C L
Cl e ar a n c e
C m a x
M a xi m u m C o n c e ntr ati o n
C M V
C yt o m e g al o vir u s
C M O & P S
C hi ef M e di c al Offi c e a n d P ati e nt S af et y
C N S
C e ntr al N er v o u s S y st e m
C P K
Cr e ati n e P h o s p h o ki n a s e
C R
C o m pl et e R e s p o n s e
C R F
C a s e R e p ort/ R e c or d F or m; t h e t er m C R F c a n b e a p pli e d t o eit h er E D C or P a p er
C R O
C o ntr a ct R e s e ar c h Or g a ni z ati o n
C S R
Cli ni c al st u d y r e p ort
C T
C o m p ut e d T o m o gr a p h y
C T C A E
C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s
C Y P
C yt o c hr o m e P
D H E A
D e h y dr o e pi a n dr o st er o n e
DI LI
Dr u g- i n d u c e d li v er i nj ur y
D L C O
C ar b o n m o n o x y d e diff u si n g c a p a cit y
D L T
D o s e li miti n g t o xi cit y
D M C
D at a M o nit ori n g C o m mitt e e
D N A
D e o x yri b o n u cl ei c A ci d
D O R
D ur ati o n of R e s p o n s e
D S M-
I V
Di a g n o sti c a n d St ati sti c al M a n u al of M e nt al Di s or d er s, 4 t h E diti o n
E B V
E p st ei n - B arr vir u s
E C
Et hi c C o m mitt e e
E C G
El e ctr o c ar di o gr a m


N o v arti s
C o nfi d e nti al
P a g e 8
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
E C H O
E c h o c ar di o gr a m
E C O G
E a st er n C o o p er ati v e O n c ol o g y Gr o u p
E crf
El e ctr o ni c C a s e R e p ort/ R e c or d F or m
E D C
El e ctr o ni c D at a C a pt ur e
E G F
E pi d er m al gr o wt h f a ct or
E G F R
E pi d er m al gr o wt h f a ct or r e c e pt or
EI A E D
E n z y m e- i n d u ci n g a nti-e pil e pti c dr u g
E O T
E n d of Tr e at m e nt
E R
E str o g e n r e c e pt or
E U
E ur o p e a n U ni o n F
F A S
F ull A n al y si s S et
F D G -P E T
Fl u or o d e o x y gl u c o s e- P o sitr o n E mi s si o n T o m o gr a p h y
F F P E
F or m ali n- fi x e d p ar affi n e m b e d d e d
F G F
Fi br o bl a st gr o wt h f a ct or
FI S H
Fl u or e s c e n c e i n sit u H y bri di z ati o n
F m
T h e r el ati v e m et a b oli c c o ntri b uti o n
F P G
F a sti n g pl a s m a gl u c o s e
F S H
F olli cl e- sti m ul ati n g h or m o n e
G A B A
G a m m a a mi n o- b ut yri c a ci d
G A D - 7
G e n er al A n xi et y Di s or d er A s s e s s m e nt
G C P
G o o d Cli ni c al Pr a cti c e
G- C S F
gr a n ul o c yt e c ol o n y sti m ul ati n g f a ct or
G G T
G a m m a -gl ut a m yltr a n s p e pti d a s e
GI
G a str oi nt e sti n al
G L P
G o o d L a b or at or y Pr a cti c e
G M -C S F
Gr a n ul o c yt e m a cr o p h a g e c ol o n y -sti m ul ati n g f a ct or
H A V
H e p atiti s A Vir u s
H b A 1 c
Gl y c o s yl at e d H e m o gl o bi n
H B s A g
H e p atiti s B s urf a c e A nti g e n
H B V
H e p atiti s B Vir u s
H C V
H e p atiti s C Vir u s
h C G
h u m a n c h ori o ni c g o n a d otr o p hi n
H D L
Hi g h d e n sit y li p o pr ot ei n
H D P E
Hi g h D e n sit y P ol y et h yl e n e
H E R 2
H u m a n e pi d er m al gr o wt h f a ct or r e c e pt or 2
H E R 2-
H u m a n e pi d er m al gr o wt h f a ct or r e c e pt or 2 n e g ati v e
H E R 2 +
H u m a n e pi d er m al gr o wt h f a ct or r e c e pt or 2 p o siti v e
HI V
H u m a n i m m u n o d efi ci e n c y vir u s
H L G T
Hi g h L e v el Gr o u p T er m
H R
H or m o n e R e c e pt or
H R
H e art R at e
H R +
H or m o n e s e n siti v e
H S V
H er p e s Si m pl e x Vir u s
i. m.
I ntra- m u s c ul arl y
i. v.
i ntr a v e n o u s(l y)
I B
I n v e sti g at or s Br o c h ur e
I C5 0
H alf m a xi m al I n hi bit or y C o n c e ntr ati o n


N o v arti s
C o nfi d e nti al
P a g e 9
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
I C F
I nf or m e d C o n s e nt F or m
I C H
I nt er n ati o n al C o nf er e n c e o n H ar m o ni z ati o n
I E C
I n d e p e n d e nt Et hi c s C o m mitt e e
I G F- 1
I n s ulin- li k e gr o wt h f a ct or 1
I gG
I m m u n o gl o b uli n G
I gM
I m m u n o gl o b uli n M
I H C
I m m u n o hi st o c h e mi str y
I N R
I nt er n ati o n al N or m ali z e d R ati o
I R B
I n stit uti o n al R e vi e w B o ar d
I R T
I nt er a cti v e R e s p o n s e T e c h n ol o g y
L C- M S/ M S
Li q ui d c hr o m at o gr a p h y t a n d e m m a s s s p e ctr o m etr y
L D H
L a ct at e d e h y dr o g e n a s e
L D L
L o w d e n sit y li p o pr ot ei n
L F T
Li v er F u n cti o n T e st s
L M W H
L o w m ol e c ul ar w ei g ht h e p ari n
L V E F
L eft V e ntri c ul ar Ej e cti o n Fr a cti o n
M B C
M et a st ati c br e a st c a n c er
M e d D R A
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s
M G M T
T h e O - 6-m et h yl g u a ni n e- D N A m et h yltr a n sf er a s e
M RI
M a g n eti c R e s o n a n c e I m a gi n g
M T D
M a xi m u m T ol er at e d D o s e
m T O R
M a m m ali a n t ar g et of r a p a m y ci n
M U G A
M ulti pl e G at e d a c q ui siti o n s c a n
N
S a m pl e si z e
N C C N
N ati o n al C o m pr e h e n si v e C a n c er N et w or k
N CI C T C
N ati o n al C a n c er I n stit ut e C o m m o n T er mi n ol o g y Crit eri a
N E C
N ot el s e w h er e cl a s sifi e d
N TI
N arr o w T h er a p e uti c I n d e x
O C
Or al c o ntr a c e pti o n
O R R
O bj e cti v e R e s p o n s e R at e
O S
O v er all s ur vi v al
P D
Pr o gr e s si v e di s e a s e
P D
P h ar m a c o d y n a mi c s
P F S
Pr o gr e s si o n- fr e e s ur vi v al
P- g R
Pr o g e st er o n e R e c e pt or
P HI
Pr ot e ct e d h e alt h i nf or m ati o n
P K
P h ar m a c o ki n eti c s
P L T
Pl at el et s
p N E T
P a n cr e ati c N e ur o e n d o cri n e T u m or
P o C
Pr o of of C o n c e pt
P P S
P er Pr ot o c ol S et
P R
P arti al R e s p o n s e
P T
Pr ot hr o m bi n ti m e
P T E N
P h o s p h at a s e a n d t e n si n h o m ol o g
Q T c F
Q- T i nt er v al i n t h e E C G ( c orr e ct e d a c c or di n g t o t h e f or m ul a of Fri d eri ci a)
R A P
R e p ort A n al y si s Pl a n
R B C
R o u n d Bl o o d C ell s


N o v arti s
C o nfi d e nti al
P a g e 1 0
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
R C C
R e n al c ell c ar ci n o m a
R E B
R e s e ar c h Et hi c s B o ar d
R E CI S T
R e s p o n s e E v al u ati o n Crit eri a I n S oli d T u m or s
R P 2 D
R e c o m m e n d e d P h a s e II d o s e
S A E
S eri o u s A d v er s e E v e nt
S C
St e eri n g C o m mitt e e
S D
St a bl e di s e a s e
S o C
St a n d ar d of C ar e Tr e at m e nt
T B L
T ot al bilir u bi n
T d P
T or s a d e s d e P oi nt e s
T m a x
T h e ti m e at w hi c h t h e m a xi m u m o b s er v e d c o n c e ntr ati o n ( C m a x) o c c ur s
T N B C
Tri pl e N e g ati v e Br e a st C a n c er
T S H
T h yr oi d sti m ul ati n g h or m o n e
T T P
Ti m e t o Pr o gr e s si o n
U D P G A
Uri di n e 5' -di p h o s p h o- gl u c ur o ni c a ci d
U G T 1 A 4
U D P - gl u c ur o n o s yltr a n sf er a s e 1 f a mil y, p ol y p e pti d e A 4
U N K
U n k n o w n
U L N
U p p er Li mit of N or m al
V E G F
V a s c ul ar e n d ot h eli al gr o wt h f a ct or
V s s
V ol u m e of di stri b uti o n at st e a d y st at e
W B C
W h it e Bl o o d C ell
W H O
W o rl d H e alt h Or g a ni z ati o n


N o v arti s
C o nfi d e nti al
P a g e 1 1
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Gl o s s ar y  of t er m s
A s s e s s m e nt
A pr o c e d ur e u s e d t o g e n er at e d at a r e q uir e d b y t h e st u d y
Bi ol o gi c S a m pl e s
A bi ol o gi c al s p e ci m e n i n cl u di n g, f or e x a m pl e, bl o o d
( pl a sm a, s er u m), s ali v a, 
ti s s u e, uri n e, st o ol, et c. t a k e n fr o m a st u d y s u bj e ct or st u d y p ati e nt
C o ntr ol dr u g
A st u d y tr e at m e nt u s e d a s a c o m p ar at or t o r e d u c e a s s e s s m e nt bi a s, pr e s er v e 
bli n di n g of i n v e sti g ati o n al dr u g, a s s e s s i nt er n al st u d y v ali dit y, a n d/ or e v al u at e 
c o m p ar ati v e eff e ct s of t h e i n v e sti g ati o n al dr u g
C y cl e s
N u m b er a n d ti mi n g or r e c o m m e n d e d r e p etiti o n s of t h er a p y ar e u s u all y 
e x pr e s s e d a s n u m b er of d a y s ( e. g.: q 2 8 d a y s)
D o s e l e v el
T h e d o s e of dr u g gi v e n t o t h e p ati e nt ( t ot al d ail y or w e e kl y et c.)
E nr oll m e nt
P oi nt/ti m e of p ati e nt e ntr y i nt o t h e st u d y; t h e p oi nt at w hi c h i nf or m e d c o n s e nt 
m u st b e o bt ai n e d (i. e. pri or t o st arti n g a n y of t h e pr o c e d ur e s d e s cri b e d i n t h e 
pr ot o c ol)
I n v e sti g ati o n al dr u g
T h e st u d y tr e at m e nt w h o s e pr o p erti e s ar e b ei n g t e st e d i n t h e st u d y; t hi s 
d efi niti o n i s c o n si st e nt wit h U S C F R 2 1 S e cti o n 3 1 2. 3 a n d i s s y n o n y m o u s wit h 
“i n v e sti g ati o n al n e w dr u g.”
I n v e sti g ati o n al tr e at m e nt
Dr u g w h o s e pr o p erti e s ar e b ei n g t e st e d i n t h e st u d y a s w ell a s t h eir 
a s s o ci at e d pl a c e b o a n d a cti v e tr e at m e nt c o ntr ol s ( w h e n a p pli c a bl e). T hi s al s o 
i n cl u d e s a p pr o v e d dr u g s u s e d o ut si d e of t h eir i n di c ati o n/ a p pr o v e d d o s a g e, or 
t h at ar e t e st e d i n a fi x e d c o m bi n ati o n. I n v e sti g ati o n al tr e at m e nt g e n er all y d o e s 
n ot i n cl u d e ot h er st u d y tr e at m e nt s a d mi ni st er e d a s c o n c o mit a nt b a c k gr o u n d 
t h er a p y r e q uir e d or all o w e d b y t h e pr ot o c ol w h e n u s e d i n wit hi n a p pr o v e d 
i n di c ati o n/ d o s a g e
M e di c ati o n n u m b er
A u ni q u e i d e ntifi er o n t h e l a b el of e a c h st u d y tr e at m e nt p a c k a g e w hi c h i s 
li n k e d t o o n e of th e tr e at m e nt gr o u p s of a st u d y
Ot h er st u d y tr e at m e nt
A n y dr u g a d mi ni st er e d t o t h e p ati e nt a s p art of t h e r e q uir e d st u d y pr o c e d ur e s 
t h at w a s n ot i n cl u d e d i n t h e i n v e sti g ati o n al tr e at m e nt
S u bj e ct N u m b er
A u ni q u e i d e ntif yi n g n u m b er a s si g n e d t o e a c h p ati e nt/ s u bj e ct/ h e alt h y 
v ol u nt e er w h o e nr oll s i n t h e st u d y
R a n d o mi z ati o n n u m b er
A u ni q u e tr e at m e nt i d e ntifi c ati o n c o d e a s si g n e d t o e a c h r a n d o mi z e d p ati e nt, 
c orr e s p o n di n g t o a s p e cifi c tr e at m e nt ar m a s si g n m e nt
St a g e r el at e d t o st u d y ti m eli n e
A m aj or s u b di vi si o n o f t h e st u d y ti m eli n e; b e gi n s a n d e n d s wit h m aj or st u d y 
mil e st o n e s s u c h a s e nr oll m e nt, r a n d o mi z ati o n, c o m pl eti o n of tr e at m e nt, et c.
St a g e i n c a n c er
T h e e xt e nt of a c a n c er i n t h e b o d y. St a gi n g i s u s u all y b a s e d o n t h e si z e of t h e 
t u m or, w h et h er l y m p h n o d e s c o nt ai n c a n c er, a n d w h et h er t h e c a n c er h a s 
s pr e a d fr o m t h e ori gi n al sit e t o ot h er p art s of t h e b o d y
St o p st u d y p arti ci p ati o n
P oi nt/ti m e at w hi c h t h e p ati e nt c a m e i n f or a fi n al e v al u ati o n vi sit or w h e n 
st u d y tr e at m e nt w a s di s c o nti n u e d w hi c h e v er i s l at er
St u d y tr e at m e nt
I n cl u d e s a n y dr u g or c o m bi n ati o n of dr u g s i n a n y st u d y ar m a d mi ni st er e d t o 
t h e p ati e nt ( s u bj e ct) a s p art of t h e r e q uir e d st u d y pr o c e d ur e s, i n cl u di n g 
pl a c e b o a n d a cti v e dr u g r u n -i n s.
I n s p e cifi c e x a m pl e s, it i s i m p ort a nt t o j u d g e i n v e sti g atio n al tr e at m e nt 
c o m p o n e nt r el ati o n s hi p r el ati v e t o a st u d y tr e at m e nt c o m bi n ati o n; st u d y 
tr e at m e nt i n t hi s c a s e r ef er s t o t h e i n v e sti g ati o n al a n d n o n-i n v e sti g ati o n al 
tr e at m e nt s i n c o m bi n ati o n.
St u d y tr e at m e nt di s c o nti n u ati o n
P oi nt/ti m e w h e n p ati e nt p er m a n e n tl y st o p s t a ki n g st u d y tr e at m e nt f or a n y 
r e a s o n
V ari a bl e
I d e ntifi er u s e d i n t h e d at a a n al y si s; d eri v e d dir e ctl y or i n dir e ctl y fr o m d at a 
c oll e ct e d u si n g s p e cifi e d a s s e s s m e nt s at s p e cifi e d ti m e p oi nt s
Wi t h dr a w al of c on s e nt
Wi t h dr a w al of c on s e nt o c c ur s o nl y w h e n a p ati e nt d o e s n ot w a nt t o p arti c ip at e 
i n t h e st u d y a n y l o n g er, an d d o e s n ot w a nt a n y f urt h er vi sit s or a s s e s s m e n ts, 
a n d d o e s n o t wa nt a n y f urt h er st u d y r el at e d c o nt a c t


N o v arti s
C o nfi d e nti al
P a g e 1 2
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Pr ot o c ol s u m m ar y
Titl e
A r a n d o mi z e d, d o u bl e -bli n d, pl a c e b o c o ntr oll e d , p h a s e II st u d y of E v er oli m u s i n 
c o m bi n ati o n w it h E x e m e st a n e i n t h e tr e at m e nt of C hi n e s e p o st m e n o p a u s al w o m e n 
wit h e str o g e n r e c e pt or p o siti v e, H E R -2 n e g ati v e, l o c all y a d v a n c e d, r e c urr e nt, or 
m et a st ati c
br e a st c a n c er aft er r e c urr e n c e or pr o gr e s si o n o n pri or l etr o z ol e or 
a n a str o z ol e
Bri ef titl e
A st u d y of e v er oli m u s pl u s e x e m e st a n e i n C hi n e s e p o st m e n o p a u s al w o m e n wit h 
e str o g e n r e c e pt or p o siti v e, l o c all y a d v a n c e d, r e c urr e nt, or m et a st ati c br e a st c a n c er 
aft er r e c urr e n c e or pr o gr e s si o n o n n o n -st er oi d al ar o m at a s e i n hi bit o r
S p o n s or a n d Cli ni c al 
P h a s e
N o v arti s
P h a s e II
I n v e sti g ati o n t yp e
Dr u g
St u d y  t yp e
I nt er v e nti o n al
P ur p o s e a n d r ati o n al e
T hi s st u d y ai m s at e v al u ati n g t h e s af et y a n d effi c a c y of e v er oli m u s pl u s e x e m e st a n e 
i n C hi n e s e p o st m e n o p a u s al w o m e n wit h E R + H E R 2- A B C aft er r e c urr e n c e or 
pr o gr e s si o n o n l etr o z ol e or a n a str o z ol e.
T h e r ati o n al e of t hi s st u d y i s b a s e d o n t h e f oll o wi n g:

Pr o v e n e v er oli m u s a cti vit y i n br e a st c a n c er i n c o m bi n ati o n wit h e x e m e st a n e

Effi c a c y a n d m a n a g e a bl e s af et y pr ofil e of e v er oli m u s i n c o m bi n ati o n wit h 
e x e m e st a n e i n t h e A si a n s u b p o p ul ati o n of B O L E R O - 2
Pri m ar y  O bj e cti v e
T o a s s e s s t h e pr o gr e s si o n-fr e e s ur vi v al ( P F S) a s d et er mi n e d b y i n v e sti g at or 
a s s e s s m e nt of e v er oli m u s a n d e x e m e st a n e a n d of e x e m e st a n e a n d pl a c e b o
S e c o n d ar y  O bj e cti v e s

T o a s s e s s P F S i n t h e t w o tr e at m e nt ar m s a s d et er mi n e d b y a Bli n d e d 
I n d e p e n d e nt R e vi e w C o m mitt e e ( BI R C).

T o a s s e s s o v er all s ur vi v al ( O S) i n t h e t w o tr e at m e nt ar m s

T o a s s e s s t h e f oll o wi n g effi c a c y e n d p oi nt s i n t h e t w o tr e at m e nt ar m s b a s e d o n
b ot h l o c al i n v e sti g at or’s a s s e s s m e nt a n d BI R C

O v er all r e s p o n s e r at e ( O R R)

Cli ni c al b e n efit r at e ( C B R)

T i m e t o r e s p o n s e a n d d ur ati o n of r e s p o n s e

T o a s s e s s ti m e t o d et eri or ati o n of E C O G P erf or m a n c e St at u s

T o c h ar a ct eri z e t h e s af et y a n d t ol er a bilit y of e v er oli m u s a n d e x e m e st a n e 
v er s u s pl a c e b o a n d e x e m e st a n e

C h ar a ct eri z e t h e p h ar m a c o ki n eti c s of e v er oli m u s ( C mi n , C2 h ) w h e n a d mi ni st er e d 
i n c o m bi n ati o n wit h e x e m e st a n e

C o m p ar e t h e t w o tr e at m e nt ar m s wit h r e s p e ct t o pr e -d o s e c o n c e ntr ati o n ( C mi n ) 
a n d c o n c e ntr ati o n at 2 h o ur s p o st d o s e ( C 2 h ) of e x e m e st a n e a n d t o c o m p ar e 
t h e t w o tr e at m e nt ar m s wit h r e s p e ct t o e str a di ol ( E 2) c h a n g e s fr o m b a s eli n e.
St u d y  d e si g n
R ef er t o S e cti o n 4 .
T hi s i s a m ulti c e nt er, d o u bl e -bli n d, r a n d o mi z e d, pl a c e b o- c o ntr oll e d, p h a s e II st u d y 
e v al u ati n g tr e at m e nt wit h e v er oli m u s ( 1 0 m g d ail y) v er s u s pl a c e b o i n c o m bi n ati o n 
wit h e x e m e st a n e ( 2 5 m g d ail y) i n C hi n e s e p o st m e n o p a u s al w o m e n wit h l o c all y 
a d v a n c e d, r e c urr e nt or m et a st ati c , E R p o siti v e , H E R-2 n e g ati v e br e a st c a n c er 
r efr a ct or y t o n o n-st er oi d al ar o m at a s e i n hi bit or s.
A p pr o xi m at el y 1 6 0 p at ie nt s will b e r a n d o mi z e d i n 1 : 1 r ati o t o r e c ei v e eit h er 
e v er oli m u s or m at c hi n g pl a c e b o i n a bli n d e d m a n n er i n a d diti o n t o o p e n l a b el 
e x e m e st a n e).
S cr e e n i n g p h a s e:
Wr itt e n i nf or m e d c o n s e nt m u st b e o bt ai n e d b ef or e a n y st u d y s p e cifi c m e di c al 
pr o c e d ur e s ar e p erf or m e d. T h e i n v e sti g at or or hi s /h er a ut h ori z e d d e si g n e e will 
a s si g n a u ni q u e n u m b er t o p ati e nt s b ei n g c o n si d er e d f or t h e st u d y.
Aft er t h e p ati e nt si g n s t h e i nf or m e d c o n s e nt a n d pri or t o t h e fir st d o s e of st u d y 


N o v arti s
C o nfi d e nti al
P a g e 1 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
tr e at m e nt, p ati e nt s will b e s cr e e n e d i n I R T. A ll i n cl u si o n/ e x cl u si o n crit eri a m u st b e
v erifi e d . P ati e nt s w h o d o n ot m e et t h e eli gi bilit y crit eri a will n ot r e c ei v e st u d y 
tr e at m e nt.
All s cr e e ni n g a s s e s s m e nt s t o c o nfir m eli gi bilit y m u st b e p erf or m e d wit hi n m a xi m u m 
2 1 d a y s pri or t o t h e fir st d o s e of st u d y tr e at m e nt ( T a bl e 7 - 1 a n d S e cti o n 7. 1 ).
R a n d o mi z e d t r e at m e nt p h as e :
A ll eli gi bl e p ati e nt s will r e c ei v e st u d y tr e at m e nt o n C y cl e 1 D a y 1 . T h e s e p ati e nt s 
m u st b e r a n d o mi z e d
i nt o o n e of t h e t w o tr e at m e nt ar m s (e v er oli m u s pl u s 
e x e m e st a n e ar m or pl a c e b o pl u s e x e m e st a n e ar m ) wit hi n 7 d a y s b ef or e C y cl e 1 
D a y 1 . R a n d o mi z ati o n will b e str atifi e d a c c or di n g t o t h e pr e s e n c e of vi s c er al 
di s e a s e a n d s e n siti vit y t o pri or h or m o n al t h er a p y st at u s. Vi s c er al r ef er s t o l u n g, 
li v er, br ai n, pl e ur al a n d p erit o n e al i n v ol v e m e nt. S e n siti vit y t o pri or h or m o n al t h er a p y 
i s d efi n e d as eit h er ( 1) d o c u m e nt e d cli ni c al b e n efit ( c o m pl et e r e s p o n s e, p arti al 
r e s p o n s e, st a bl e di s e a s e ≥2 4 w e e k s) t o at l e a st o n e pri or h or m o n al t h er a p y i n t h e 
a d v a n c e d s etti n g or ( 2) at l e a st 2 4 m o nt h s of a dj u v a nt h or m o n al t h er a p y pri or t o 
r e c urr e n c e.
R a n d o mi z e d p ati e nt s will st art t h e st u d y tr e at m e nt at C y cl e 1 D a y 1 . P ati e nt s will 
r e c ei v e e v er oli m u s/ pl a c e b o ( 1 0 m g d ail y or al t a bl et s) i n a d diti o n t o e x e m e st a n e ( 2 5 
m g d ail y or al t a bl et s)
c o nti n u o u sl y . D o s e a dj u st m e nt (r e d u cti o n, i nt err u pti o n) 
a c c or di n g t o s af et y f i n di n g s will b e a ll o w e d.
P ati e nt s will r e c ei v e tr e at m e nt u ntil di s e a s e pr o gr e s si o n ( a s s e s s e d b y R E CI S T 1. 1), 
u n a c c e pt a bl e t o xi cit y, d e at h or di s c o nti n u ati o n fr o m tr e at m e nt f or a n y ot h er r e a s o n.
T u m or a s s e s s m e nt s will b e p erf or m e d e v er y 8 w e e k s aft er r a n d o m i z ati o n d at e u ntil 
r a di ol o gi c al pr o gr e s si o n p er l o c al a s s e s s m e nt . T h e fr e q u e n c y of t u m or a s s e s s m e nt 
will b e c h a n g e d t o e v er y 1 2 w e e k s aft er pri m ar y a n al y si s d at a c ut -off a n d a s 
cli ni c all y i n di c at e d, u ntil di s e a s e pr o gr e s si o n.
P o st -tr e at m e nt f oll o w-u p p h a s e :
Aft er e n d of tr e at m e nt vi sit, all p ati e nt s will b e f oll o w e d u p f or s af et y u p t o 3 0 d a y s 
aft er l a st d o s e of st u d y tr e at m e nt ( e x e m e st a n e a n d/ or e v er oli m u s / pl a c e b o).
All p ati e nt s w h o di s c o nti n u e fr o m st u d y tr e at m e nt d u e t o di s e a s e pr o gr e s si o n m u st 
h a v e t h ei r pr o gr e s si o n cl e arl y d o c u m e nt e d a c c or di n g t o t h e crit eri a s p e cifi e d i n 
R E CI S T 1. 1.
If a p ati e nt p er m a n e ntl y di s c o nti n u e s st u d y tr e at m e nt f or r e a s o n s ot h er t h a n
di s e a s e pr o gr e s si o n, d e at h, l o st t o f oll o w -u p, or wit h dr a w al of c o n s e nt t o effi c a c y 
f oll o w- u p t h e n t u m or a s s e s s m e nt s s h o ul d c o nti n u e t o b e p erf or m e d p er a s s e s s m e nt 
s c h e d ul e u ntil di s e a s e pr o gr e s si o n, d e at h, l o st t o f oll o w- u p or wit h dr a w al of c o n s e nt 
f or effi c a c y f oll o w-u p.
A nti n e o pl a sti c t h er a p y r e gi m e n r e c ei v e d b et w e e n E O T a n d pr o gr e s si o n will al s o b e 
c oll e ct e d a s w ell a s t h e fir st r e gi m e n r e c ei v e d aft er pr o gr e s si o n.
S ur vi v al f oll o w -u p p h a s e
All p ati e nt s will b e f oll o w e d f or s ur vi v al st at u s at l e a st e v er y 3 m o nt h s aft er 
r a n d o mi z e d tr e at m e nt p h a s e or p o st-tr e at m e nt f oll o w-u p p h a s e u nl e s s t h e y 
di s c o nti n u e d d u e t o d e at h, c o n s e nt wit h dr a w al or l o st t o f oll o w -u p . S ur vi v al 
i nf or m ati o n c a n b e o bt ai n e d vi a p h o n e a n d i nf or m ati o n will b e d o c u m e nt e d i n t h e 
s o ur c e d o c u m e nt s a n d e C R F. A d diti o n al s ur vi v al a s s e s s m e nt s m a y b e p erf or m e d 
m or e fr e q u e ntl y if a s ur vi v al u p d at e i s r e q uir e d f or r e p orti n g t h e r e s ult s or t o m e et 
s af et y or r e g ul at or y n e e d s .
P o p ul ati o n
R ef er t o S e cti o n 5. 1 .
C hi n e s e P o st m e n o p a u s al w o m e n wit h E R + H E R 2 - l o c all y a d v a n c e d, r e c urr e nt, or 
m et a st ati c br e a st c a n c er aft er r e c urr e n c e or pr o gr e s si o n o n pri or l etr o z ol e or 
a n a str o z ol e.
R e c urr e n c e or pr o gr e s si o n o n pri or N S AI i s d efi n e d a s:

R e c urr e n c e w hil e o n, or wit hi n o n e y e ar ( 1 2 m o nt h s) of e n d of a dj u v a nt
tr e atm e nt wit h l etr o zol e or a n a s tr oz ol e

Pr o gr e s si o n w hil e o n or wit hi n o n e m o nt h
( 3 0 d a y s) of t h e e n d of pri or
tr e atm e nt wit h l etr o z ol e or a n a str o z ol e
E x c e pt f or pri or u s e of e x e m e st a n e , m T O R i n hi bit or s, PI 3 K i n hi bit or s, A K T


N o v arti s
C o nfi d e nti al
P a g e 1 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
i n hi bit or s, t h er e ar e n o r e stri cti o n s a s t o t h e l a st a nti c a n c er tr e at m e nt pri or t o 
r a n d o mi z ati o n. P ati e nt s m u st h a v e a d o c u m e nt e d e vi d e n c e of r e c urr e n c e or 
pr o gr e s si o n o n l a st t h er a p y pri or t o r a n d o mi z ati o n. N o m or e t h a n o n e li n e of pr i or 
c h e m ot h er a p y f or a d v a n c e d di s e a s e i s all o w e d.
I n cl u si o n crit eri a
R ef er t o S e cti o n 5. 2 .
P ati e nt s eli gi bl e f or i n cl u si o n i n t hi s st u d y h a v e t o m e et all of t h e f oll o wi n g crit eri a:
1.
W o m e n ( 1 8 y e ar s or ol d er) of A si a n et h ni cit y wit h l o c all y a d v a n c e d, r e cu rr e nt,
or
m et a st ati c br e a st c a n c er. L o c all y a d v a n c e d br e a st c a n c er m u st n ot b e
a m e n a bl e t o c ur ati v e tr e atm e nt b y s ur g er y or r a di ot h er a p y.
2.
Hi st ol o gi c al or c yt o l o gic a l c o n firm a ti o n of e str o g e n -r ec e pt or p o siti v e ( ER + )
br e a st c a n c er
3.
P o st m e n o p a u s al w o m e n. P o st m e n o p a u s al st at u s i s d efi n e d eit h er b y:

Pri or bil at er al o o p h or e ct o m y

Or a g e ≥6 0

Or a g e < 6 0 a n d a m e n orr h e a f or 1 2 or m or e m o nt h s (i n t h e a b s e n c e of
c h e m ot h er a p y , t a m o xif e n, t or e mif e n, or ov ari a n s u p pr e s si o n), a n d F S H 
a n d e str a di ol i n t h e p o st m e n o p a u s al r a n g e ( s er u m F S H > 4 0 mI U/ m L a n d 
e str a di ol < 2 0 p g/ m L or a c c or di n g t o t h e p o st m e n o p a u s al r a n g e d e fi n e d b y 
l o c al l a b or at ory).
F or w o m e n wit h t h er a p y -i n d u c e d a m e n orr h e a, o o p h or e ct om y or s eri al 
m e a s ur e m e nt s of
F S H a n d/ or e str a di ol ar e n e e d e d t o e n s ur e 
p o st m e n o p a u s al st at u s.
N ot e : O v ari a n r a di ati o n or tr e at m e nt wit h a l ut ei ni zi n g h or m o n e- r el e a si n g 
h or m o n e ( L H- R H) a g o ni st ( g o s er eli n a c et at e or l e u pr oli d e a c et at e) i s n ot 
p er mitt e d f or i n d u cti o n of o v ari a n s u p pr e s si o n.
4.
R e c urr e n c e or pr o gr e s si o n o n pri or N S AI i s d efi n e d a s:

R e c urr e n c e w hil e o n, or wit hi n o n e y e ar ( 1 2 m o nt h s) of e n d of a dj u v a nt
tr e atm e nt wit h l etr o zol e or a n a s tr oz ol e
O R

Pr o gr e s si o n w hil e o n or wit hi n o n e m o nt h
( 3 0 d a y s) of t h e e n d of pri or
tr e atm e nt wit h l etr o z ol e or a n a str o z ol e
N ot e s:

L etr o z ol e or a n a str o z ol e d o n ot h a v e t o b e t h e l a st tr e at m e nt pri o r t o t he
e nr oll m e n t i n t h e st u d y
5.
P ati e nt s m u st h a v e i m pr o v e d t o gr a d e 1 or b ett er fr o m a n y a d v er s e e v e nt s 
( wit h e x c e pti o n of al o p e ci a) r el at e d t o pr e vi o u s t h er a p y pri or t o e nr oll m e nt
6.
H a v e ra di ol o gi c al or o bj e cti v e e vi d e n c e of r e c urre n c e or pr o gr e s si o n o n or aft e r
t he l a st s y st e m i c t h er a p y pri or t o e nr oll m e nt
7.
P ati e nt m u st h a v e a s p er R E C IS T 1. 1

m e a s ur a bl e di s e a s e
or

n o n -m e a s ur a bl e l yti c or mi x e d (ly ti c + bl a sti c) b o n e l e si o n s i n t h e a b s e n c e 
of m e a s ur a bl e di s e a s e.
N ot e : M e a s ur a bl e l e si o n s i n cl u d e l y ti c or mi x e d
(ly ti c + bl a sti c) b o n e 
l e si o n s, wit h a n i d e ntifi a bl e s oft ti s s u e c o m p o n e nt t h at m e et s t h e 
m e a s ur a bilit y crit eri a p e r R E C IS T 1. 1.
P ati e nt s wit h o nl y n o n- m e a s ur a bl e l e si o n s ( e. g. pl e ur al eff u si o n, a s cit e s) 
a n d n o l y ti c or a mi x of l yti c a n d bl a sti c b o n e l e si o n s ar e n ot eli gi bl e.
8.
P ati e nt i s a bl e t o s w all o w a n d r et ai n or al m e di c ati o n.
9.
P ati e nt m u st m e et t h e f oll o wi n g l a b or at or y v al u e s at t h e s cr e e ni n g vi sit:

A b s ol ut e N e utr o p hil C o u nt ( A N C) ≥1. 5 × 1 0 9 / L

Pl at el et s ≥1 0 0 × 1 0 9 / L

H e m o gl o bi n ( H g b) ≥9 g/ d L

I N R≤2

S er u m cr e ati ni n e ≤1. 5 × U L N


N o v arti s
C o nfi d e nti al
P a g e 1 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

T ot al bilir u bi n ≤1. 5 × U L N ( ≤3 × U L N f or p ati e nt s k n o w n t o h a v e Gil b ert
S y n dr o m e)

A s p art at e tr a n s a mi n a s e ( A S T) ≤2. 5 × U L N, e x c e pt f or p ati e nt s wit h li v er 
m et a st a si s, w h o m a y o nl y b e i n cl u d e d if A S T ≤
5. 0 × U L N

Al a ni n e tr a n s a mi n a s e ( A L T) ≤2. 5 × U L N, e x c e pt f or p ati e nt s wit h li v er 
m et a st a si s, w h o m a y o nl y b e i n cl u d e d if A L T ≤
5. 0 × U L N

F a sti n g s e r u m c h ol e st er ol ≤3 0 0 m g/ dl or 7. 7 5 m m ol/ L a n d f a sti n g tri gl y c eri d e s 
≤2. 5 × U L N. I n c a s e o n e or b ot h of t h e s e t hr e s h ol d s ar e e x c e e d e d, t h e p ati e nt 
c a n o nl y b e i n cl u d e d aft er i niti ati o n of st ati n t h er a p y a n d w h e n t h e a b o v e 
m e nti o n e d v al u e s h a v e b e e n a c hi e v e d
1 0.
P ati e nt h a s a W H O p erf or m a n c e st at u s ≤2
1 1.
Wr itt e n i nf or m e d c o n s e nt m u st b e o bt ai n e d pri or t o a n y s cr e e ni n g pr o c e d ur e s.
E x cl u si o n crit eri a
R ef er t o S e cti o n 5. 3 .
P ati e nt s eli gi bl e f or t hi s st u d y m u st n ot m e et a n y of t h e f oll o wi n g crit eri a:
1.
H E R 2 - o v er e x pr e s si n g p ati e nt s b y l o c al l a b or at or y t e sti n g (I H C 3 + st ai ni n g or i n 
sit u h y bri di z ati o n p o siti v e), b a s e d o n t h e m o st r e c e nt t e st. N ot e: P ati e nt s wit h 
I H C 2 + m u st h a v e a n e g ati v e i n sit u h y bri di z ati o n t e st .
2.
P ati e nt s w h o r e c ei v e d m or e t h a n o n e c h e m ot h er a p y li n e f or A B C
N ot e: A c h e m ot h er a p y li n e i n a d v a n c e d di s e a s e i s a n a nti c a n c er r e gi m e n t h at 
c o nt ai n s at l e a st o n e c h e m ot h er a p y a g e nt a n d i s gi v e n f or 2 1 d a y s or l o n g er. If
a c yt ot o xi c c h e m ot h er a p y r e gi m e n w a s di s c o nti n u e d f or a r e a s o n ot h er t h a n 
di s e a s e pr o gr e s si o n a n d l a st e d l e s s t h a n 2 1 d a y s, t h e n t hi s r e gi m e n d o e s n ot 
c o u nt a s a " pri or li n e of c h e m ot h er a p y". C h e m ot h er a p y r e gi m e n s c o m p o s e d of 
m or e t h a n o n e dr u g ar e c o n si d er e d a s o n e li n e of t h er a p y.
3.
P ati e nt s wit h s y m pt o m ati c vi s c er al di s e a s e a n d c a n di d at e t o c h e m ot h er a p y
4.
P ati e nt s wit h o nl y n o n - me a s ur a bl e l e si o n s ot h er t h a n l yti c or mi x e d (l yti c a n d
bl a sti c) b o n e m e t a st a si s ( e. g. pl e ur al eff u si o n, a s cit e s et c .)
5.
Pr e vi o u s tr e at m e nt wit h e x e m e st a n e, m T O R i n hi bit or s, PI 3 K i n hi bit or s, A K T
i n hi bit or s.
6.
K n o w n h y p er s e n siti vit y t o m T O R i n hi bit or s, e. g. sir oli m u s (r a p a m y ci n)
7.
P ati e nt s w h o h a v e a hi st or y of a n ot h er pri m ar y m ali g n a n c y, wit h t h e e x c e pti o n s 
of n o n - m el a n o m a s ki n c a n c er, an d c ar ci n o m a i n sit u of t h e c er vi x, ut eri, or 
br e a st fr o m w hi c h h a v e b e e n di s e a s e fr e e f or ≥3 y e ar s
8.
R a di ot h er a p y wit hi n f o ur w e e k s pri or t o e nr oll m e nt i n t h e st u d y e x c e pt i n c a s e
of l o c ali z e d p a lliati v e r a diot h er a p y (f or a n al g e si c p ur p o s e) or f or l yti c l esi o n s at
ris k of fr a ct ur e w hi c h w a s c o m pl et e d at l e a st t w o w e e k s pri or t o r e gi str ati o n i n
t h e c urr e nt st u d y. P ati e nt s m u st
h a v e r e c o v er e d fr o m r a di ot h er a p y t o xi citi e s.
9.
C urr e ntl y r e c ei vi n g a n y h or m o n e r e pl a c e m e nt t h er a p y, u nl e s s di s c o nti n u e d 
pri or t o r e gi st r ati o n i n t h e c urr e nt st u d y.
1 0.
P ati e nt s wit h c e ntr al n er v o u s s y st e m ( C N S) i n v ol v e m e nt u nl e s s t h e y m e et A L L 
of t h e f oll o wi n g crit eri a:

At l e a st 4 w e e k s fr o m pri or t h er a p y c o m pl eti o n (i n cl u di n g r a di ati o n a n d/ or 
s ur g er y) t o st arti n g st u d y tr e at m e nt.

Cli ni c all y st a bl e C N S l e si o n s at t h e ti m e of s cr e e ni n g w hi c h ar e u ntr e at e d 
or wit h o ut e vi d e n c e of pr o gr e s si o n f or at l e a st 4 w e e k s aft er tr e at m e nt, a s 
d et er mi n e d b y cli ni c al e x a mi n ati o n a n d br ai n i m a gi n g ( M RI or C T). 
P ati e nt s m u st h a v e n ot b e e n tr e at e d wit h st er oi d s f or br ai n m et a st a s e s 
d uri n g t h e s cr e e ni n g p eri o d
1 1.
P ati e nt s r e c ei vi n g c o n c o mit a nt i m m u n o s u p pr e s si v e a g e nt s or c hr o ni c 
c orti c o st er oi d s u s e at t h e ti m e of st u d y e ntr y e x c e pt t o pi c al a p pli c ati o n s, 
i n h al e d s pr a y s, e y e dr o p s or l o c al i nj e cti o n s.
1 2.
Bil at er al diff u s e l y m p h a n giti c c ar ci n o m at o si s
1 3.
S e v er el y i m p air e d l u n g f u n cti o n a s d efi n e d a s s pir o m etr y a n d D L C O t h at i s 
5 0 % or l e s s of t h e n or m al pr e di ct e d v al u e a n d/ or O 2 s at ur ati o n t h at i s 8 8 % or 
l e s s at r e st o n r o o m air
1 4.
P ati e nt s w h o h a v e s eri o u s li v er di s e a s e s u c h a s cirr h o si s, d e c o m p e n s at e d li v er 


N o v arti s
C o nfi d e nti al
P a g e 1 6
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
di s e a s e, a n d a c ut e or c urr e ntl y a cti v e h e p atiti s (i. e. q u a ntifi a bl e H B V -D N A 
a n d/ or p o siti v e H b s A g, q u a ntifi a bl e H C V -R N A)
1 5.
P ati e nt s wit h a k n o w n hi st or y of HI V s er o p o siti vit y. S cr e e ni n g f or HI V i nf e cti o n 
at b a s eli n e i s n ot r e q uir e d.
1 6.
A cti v e, bl e e di n g di at h e si s, or o n or al a nti- vit a mi n K m e di c ati o n ( e x c e pt l o w 
d o s e w arf ari n, L M W H  a n d a c et yl s ali c yli c a ci d or e q ui v al e nt, a s l o n g a s t h e I N R 
i s ≤2).
1 7.
I m p air m e nt of g a str oi nt e sti n al ( GI) f u n cti o n or GI di s e a s e t h at m a y si g nifi c a ntl y 
alt er t h e a b s or pti o n of or al e v er oli m u s.
1 8.
U n c o ntr oll e d di a b et e s m ellit u s a s d efi n e d b y H b A 1 c > 7 % d e s pit e a d e q u at e 
t h er a p y. P ati e nt s wit h a k n o w n hi st or y of i m p air e d f a sti n g gl u c o s e or di a b et e s 
m ellit u s ( D M) ar e eli gi bl e, h o w e v er bl o o d gl u c o s e a n d a nti di a b eti c tr e at m e nt 
m u st b e m o nit or e d cl o s el y t hr o u g h o ut t h e tri al a n d a dj u st e d a s n e c e s s ar y;
1 9.
A cti v e ul c er ati o n of t h e u p p er g a str oi nt e sti n al tr a ct.
2 0.
A n y s e v er e a n d / or u n c o ntr oll e d m e di c al c o n diti o n s s u c h a s
a.
u n st a bl e a n gi n a p e ct ori s, s y m pt o m ati c c o n g e sti v e h e art f ail ur e, m y o c ar di al 
i nf ar cti o n ≤6 m o nt h s pri or t o r a n d o mi z ati o n, s eri o u s u n c o ntr oll e d c ar di a c 
arr h yt h mi a,
b.
a cti v e or u n c o ntr oll e d s e v er e i nf e cti o n,
2 1.
P ati e nt s b ei n g tr e at e d wit h dr u g s r e c o g ni z e d a s b ei n g str o n g i n hi bit or s or 
i n d u c er s of t h e i s o e n z y m e C Y P 3 A 4 ( Rif a b uti n, Rif a m pi ci n, Cl arit hr o m y ci n, 
K et o c o n a z ol e, Itr a c o n a z ol e, V ori c o n a z ol e, Rit o n a vir, T elit hr o m y ci n) 
c o nti n u o u sl y f or at l e a st 7 d a y s d uri n g a n y ti m e p eri o d i n t h e l a st 2 w e e k s pri or 
t o r e gi str ati o n i n th e c urr e nt st u d y
2 2.
P ati e nt s w h o h a v e r e c ei v e d li v e att e n u at e d v a c ci n e s wit hi n 1 w e e k of st art of 
st u d y dr u g a n d d uri n g t h e st u d y. P ati e nt s h o ul d al s o a v oi d cl o s e c o nt a ct wit h 
ot h er s w h o h a v e r e c ei v e d li v e att e n u at e d v a c ci n e s. E x a m pl e s of li v e att e n u at e d 
v a c c i n e s i n cl u d e i ntr a n a s al i nfl u e n z a, m e a sl e s, m u m p s, r u b ell a, or al p oli o, 
B C G, y ell o w f e v er, v ari c ell a a n d T Y 2 1 a t y p h oi d v a c ci n e s;
2 3.
Hi st or y of n o n c o m pli a n c e t o m e di c al r e gi m e n s
2 4.
P ati e nt s u n willi n g t o or u n a bl e t o c o m pl y wit h t h e pr ot o c ol
2 5.
P ati e nt s w h o ar e c urr e ntl y p art of or h a v e p arti ci p at e d i n a n y cli ni c al 
i n v e sti g ati o n wit h a n i n v e sti g ati o n al dr u g wit hi n 1 m o nt h pri or t o d o si n g;
I n v e sti g ati o n al a n d 
r ef er e n c e t h er a p y
R ef er t o S e cti o n 6. 1 .
St u d y tr e at m e nt i s d efi n e d a s e v er oli m u s + e x e m e st a n e or pl a c e b o + e x e m e st a n e
(1 0 m g/ d a y + 2 5 m g/ d a y )
Effi c a c y  a s s e s s m e nt s
R ef er t o S e cti o n 7. 2 .
I m a gi n g a s s e s s m e nt s a s d e s cri b e d i n T a bl e 7 - 2 s h o ul d b e p erf or m e d at t h e ti m e-
p oi nt s s p e cifi e d u si n g t h e s a m e i m a gi n g m o d alit y u s e d at b a s eli n e, irr e s p e cti v e of 
st u d y tr e at m e nt i nt err u pti o n or a ct u al d o si n g ( s e e T a bl e 7 - 1). I m a gin g a s s e s s m e nt s 
f or r e s p o n s e e v al u ati o n will b e p erf or m e d e v er y 8 w e e k s aft er r a n d o mi z ati o n. 
T u m or a s s e s s m e nt s ar e t o b e p erf or m e d e v er y 1 2 w e e k s aft er pri m ar y a n al y si s 
d at a c ut -off a n d a s cli ni c all y i n di c at e d, u ntil di s e a s e pr o gr e s si o n.
A d diti o n al i m a gi n g a s s e s s m e nt s m a y b e p erf or m e d at a n y ti m e d uri n g t h e st u d y at 
t h e i n v e sti g at or’ s di s cr eti o n t o s u p p ort t h e effi c a c y e v al u ati o n s f or a s u bj e ct, a s 
n e c e s s ar y. Cli ni c al s u s pi ci o n of di s e a s e pr o gr e s si o n at a n y ti m e r e q uir e s a p h y si c al 
e x a mi n ati o n a n d i m a gi n g a s s e s s m e nt s t o b e p erf or m e d pr o m ptl y r at h er t h a n w aiti n g 
f or t h e n e xt s c h e d ul e d i m a gi n g a s s e s s m e nt.
E a c h l e si o n t h at i s m e a s ur e d at b a s eli n e m u st b e m e a s ur e d b y t h e s a m e m et h o d 
( eit h er s a m e i m a gi n g m et h o d or b y p h ot o gr a p h y, i n cl u di n g a m etri c r ul er) a n d w h e n
p o s si bl e, t h e s a m e l o c al r a di ol o gi st/ p h y si ci a n t hr o u g h o ut t h e st u d y s o t h at t h e 
c o m p ari s o n i s c o n si st e nt. If a n off -s c h e d ul e i m a gi n g a s s e s s m e nt i s p erf or m e d 
b e c a u s e pr o gr e s si o n i s s u s p e ct e d, s u b s e q u e nt i m a gi n g a s s e s s m e nt s s h o ul d b e 
p erf or m e d i n a c c or d a n c e wit h t h e ori gi n al i m a gi n g s c h e d ul e.
C o m bi n e d P E T/ C T m a y b e u s e d o nl y if t h e C T i s of si mil ar di a g n o sti c q u alit y a s a 
C T p erf or m e d wit h o ut P E T, i n cl u di n g t h e utili z ati o n of I V c o ntr a st m e di a. At t h e 
di s cr eti o n of t h e I n v e sti g at or s, F D G- P E T s c a n s m a y b e p erf or m e d t o d o c u m e nt 


N o v arti s
C o nfi d e nti al
P a g e 1 7
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
pr o gr e s si v e di s e a s e p er R E CI S T 1. 1 ( A p p e n di x 1 ).
I m a gi n g d at a will b e c e ntr all y c oll e ct e d a n d c h e c k e d f or q u alit y b y a n i m a gi n g 
C o ntr a ct R e s e ar c h Or g a ni z ati o n ( C R O) d e si g n at e d b y N o v arti s .
S af et y  a s s e s s m e nt s
R ef er t o S e cti o n 8 .
S af et y a s s e s s m e nt s will c o n si st of m o nit ori n g a n d r e c or di n g all a d v er s e e v e nt s 
( A E s), i n cl u di n g s eri o u s a d v er s e e v e nt s ( S A E), t h e r e g ul ar m o nit ori n g of 
h e m at ol o g y, s er u m c h e mi str y, r o uti n e m o nit o ri n g of vit al si g n s ( h e art r at e, bl o o d 
pr e s s ur e, a n d b o d y t e m p er at ur e), w ei g ht, E C O G p erf or m a n c e st at u s, c h e st C T 
s c a n s, a n d p h y si c al c o n diti o n. T o xi cit y will b e a s s e s s e d u si n g t h e N CI- C T C 
C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s, v er si o n 4. 0 3 : ( C T C AE v 4 . 03 ).
D at a a n al y si s
R ef er t o S e cti o n 1 0 .
T h e pri m ar y effi c a c y p o p ul ati o n i s d efi n e d a s t h e F ull A n al y si s S et ( F A S), w hi c h 
c o n si st s of all r a n d o mi z e d p ati e nt s. All pri m ar y effi c a c y a n al y s e s will b e e v al u at e d 
b a s e d o n d at a fr o m t hi s p o p ul ati o n o n a n i nt e nt -t o-tr e at (I T T) b a si s a c c or di n g t o t h e 
tr e at m e nt gr o u p a n d str at a t h e y w er e a s si g n e d t o at r a n d o mi z ati o n.
T h e s af et y p o p ul ati o n will c o n si st of all p ati e nt s w h o r e c ei v e d at l e a st o n e d o s e of 
t h e st u dy tr e at m e nt d efi n e d a s eit h er e v er oli m u s + e x e m e st a n e or m at c hi n g 
pl a c e b o + e x e m e st a n e. P ati e nt s will b e a n al y z e d a c c or di n g t o tr e at m e nt a ct u all y 
r e c ei v e d.
D at a a n al y si s f or t h e pri m ar y o bj e cti v e:
T h e pri m ar y o bj e cti v e i n t hi s st u d y i s t o a s s e s s P F S o n t h e c o m bi n ati o n tr e at m e nt of 
e v er oli m u s + e x e m e st a n e a n d pl a c e b o + e x e m e st a n e i n C hi n e s e p o st m e n o p a u s al 
w o m e n wit h e str o g e n r e c e pt or p o siti v e, l o c all y a d v a n c e d, r e c urr e nt, or m et a st ati c 
br e a st c a n c er aft er r e c urr e n c e or pr o gr e s si o n o n pri or l etr o z ol e or a n a str o z ol e.
T h e pri m ar y a n al y si s of P F S will b e p erf or m e d b a s e d o n t h e l o c al i n v e sti g at or’ s 
a s s e s s m e nt. T h e di stri b uti o n of P F S will b e e sti m at e d u si n g t h e K a pl a n -M ei er 
m et h o d. T h e m e di a n P F S al o n g wit h 9 0 % CI will b e pr e s e nt e d b y tr e at m e nt ar m. 
T h e K a pl a n -M ei er c ur v e s will b e di s pl a y e d
a n d t h e n u m b er of p ati e nt s at ri s k at 
c ert ai n ti m e p oi nt s will b e s h o w n o n t h e pl ot. A C o x r e gr e s si o n m o d el str atifi e d b y 
r a n d o mi z ati o n str atifi c ati o n f a ct or s will b e u s e d t o e sti m at e t h e h a z ar d r ati o ( H R) of 
P F S, al o n g wit h 9 0 % CI. T h e pri m ar y a n al y si s f or P F S will b e r e p e at e d b a s e d o n 
c e ntr al r e vi e w d at a a s a s u p p orti v e a n al y si s.
D at a a n al y si s f or t h e s e c o n d ar y o bj e cti v e s:
T h e s e c o n d ar y o bj e cti v e s i n t hi s st u d y ar e t o a s s e s s t h e t w o tr e at m e nt gr o u p s wit h 
r e s p e ct t o P F S d et er mi n e d b y BI R C ( C e ntr al r e vi e w s h o ul d st o p aft er t h e n u m b er of 
e v e nt s i s r e a c h e d f or pri m ar y P F S a n al y si s ), O S, O R R, d et eri or ati o n i n t h e E C O G 
P S, s af et y, a n d C B R. A d diti o n all y, ti m e t o r e s p o n s e ( T T R) a n d d ur ati o n of r e s p o n s e
( D O R) will b e s u m m ari z e d f or b ot h tr e at m e nt gr o u p s.
O v er all s ur vi v al will b e e sti m at e d u si n g t h e K a pl a n -M ei er m et h o d. T h e m e di a n O S 
al o n g wit h 9 0 % c o nfi d e n c e i nt er v al s will b e pr e s e nt e d b y t w o tr e at m e nt gr o u p s, 
al o n g wit h pr o p orti o n of p ati e nt s ali v e at 3, 6, 9 , 1 2 a n d 1 8 m o nt h s a n d t h e 
a s s o ci at e d 9 0 % c o nfi d e n c e i nt er v al s. T h e str atifi e d C o x r e gr e s si o n will b e u s e d t o 
e sti m at e t h e H R of O S, al o n g wit h 9 0 % c o nfi d e n c e i nt er v al.
O R R a n d C B R will b e e sti m at e d a n d t h e e x a ct bi n o mi al 9 0 % CI will b e r e p ort e d b y 
tr e at m ent ar m . T h e a b o v e a n al y s e s will b e p erf or m e d o n l o c al a s s e s s m e nt a n d al s o 
b e r e p e at e d u si n g d at a fr o m c e ntr al r e vi e w a s s u p p orti v e a n al y si s.
T T R a n d D O R will b e s u m m ari z e d u si n g d e s cri pti v e st ati sti c s. T h e a n al y si s will b e 
p erf or m e d b a s e d o n i n v e sti g at or a s s e s s m e nt a n d al s o r e p e at e d u si n g d at a fr o m 
c e ntr al r e vi e w a s s u p p orti v e a n al y s e s.
A n a n al y si s of t h e ti m e t o d efi niti v e d et eri or ati o n of t h e E C O G P S b y o n e c at e g or y 
of t h e s c or e fr o m b a s eli n e will b e p erf or m e d. K a pl a n -M ei er m et h o d will b e u s e d t o 
e sti m at e t h e di stri b uti o n f u n cti o n of ti m e t o d efi niti v e w or s e ni n g. T h e e sti m at e d 
tr e at m e nt-s p e cifi c m e di a n ti m e t o d efi niti v e w or s e ni n g will b e pr e s e nt e d al o n g wit h a 
9 0 % c o nfi d e n c e i nt er v al f or t h e t w o tr e at m e nt ar m s.
T h e a s s e s s m e nt of s af et y will b e b a s e d m ai nl y o n t h e fr e q u e n c y of a d v er s e e v e nt s 
a n d o n t h e n u m b er of l a b or at or y v al u e s t h at f all o ut si d e of pr e- d et er mi n e d r a n g e s. 
Ot h er s af et y d at a ( e. g., el e ctr o c ar di o gr a m, vit al si g n s) wil l b e c o n si d er e d a s 


N o v arti s
C o nfi d e nti al
P a g e 1 8
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
a p pr o pri at e.
K e y w or d s
C hi n e s e p o st m e n o p a u s al w o m a n, A d v a n c e d br e a st c a n c er, E n d o cri n e t h er a p y, 
Ar o m at a s e i n hi bit or s


N o v arti s
C o nfi d e nti al
P a g e 1 9
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
A m e n d m e nt 1 (2 3 -M a y -2 0 1 7 )
E nr oll me nt t o St u d y  CR A D 0 0 1 Y 2 2 0 2 is e x pecte d t o c o m me nce i n J ul y 2 0 1 7. P r ot oc ol
Versi o n 0 0 was pre vi o usl y a p pr o ve d b y p O P R C o n 3 1 A u g ust 2 0 1 6.
A m e n d m e nt r ati o n al e
T h e mai n p ur p oses of t his a me n d me nt are t o:
1.
Re vise t he P K c ollecti o n sc he d ule t o better clarif y ti me p oi nts of P K c ollecti o n d uri n g 
c ycle 1 wee k 4, as well t he defi niti o n of t he stea d y  state relate d t o v o miti n g e ve nt pri or t o 
t he p har mac o ki netic bl o o d sa m plin g.
2.
D M C is n ot a p plica ble f or t his st u d y beca use of t he f oll o wi n g reas o ns:
a.
N o i nteri m a nal ys is is pla n ne d f or t his st u d y. Acc or di n g t o N o vartis i nter nal 
g ui deli nes , data m o nit ori n g c o m mittees are t o be c o nsi dere d f or st u dies wit h at least 
o ne i nteri m a nal y sis of safet y a n d/ or efficac y data
b.
T he s afet y pr ofile of e ver oli m us is well esta blis he d, i ncl u di n g t he p o p ulati o n of 
C hi nese patie nts wit h breast ca ncer . The Steeri n g C o m mittee will re vie w t he bli n de d
p o ole d safet y data a p pr o xi matel y e ver y 6 m o nt hs
c.
T he e ver oli m us P K e x p os ure i n C hi nese patie nts is c o m para ble t o Ca ucasia n patie nts
3.
T o clarif y  t he pr ocess a n d eli gi bilit y f or re-scree ni n g
4.
U p date G ui deli nes f or Res p o nse, D urati o n of O verall Res p o nse, T T F, T T P, Pr o gressi o n -
Free S ur vi val a n d O verall S ur vi val ( b ase d o n R E CI S T 1. 1) t o versi o n 3. 2
5.
T o be c o nsiste nt wit h t he u p date d R A D safet y pr ofile, t he i ncl usi o n/e xcl usi o n criteria 
secti o n is u p date d acc or di n gly.
6.
T o be c o nsiste nt wit h t he u p date d R A D safet y pr ofile , t he d ose m o dificati o n secti o n is 
u p date d acc or di n gl y.
7.
T o u p date vari o us secti o ns of t he pr ot oc ol t o e ns ure c o nsiste nc y wit h t he m ost rece nt 
sta n dar d pr ot oc ol f or o nc ol o g y st u d y. Na mely, t he visit sc he d ule a n d t he defi niti o n of t he 
e n d of treat me nt, e n d of p ost-treat me nt p hase a n d s ur vi val f oll o w- u p were clarifie d. T he 
A E secti o n is n o w i ncl u di n g c ollecti o n of gra de 5 A E’s. Als o t y p o gra p hical err ors were 
c orrecte d t hr o u g h o ut t he pr ot oc ol.
C h a n g e s t o t h e pr ot o c ol
T he c ha n ges bei n g ma de t o t he pr ot oc ol d ue t o t his a me n d me nt are i nc or p orate d i n t he 
f oll o wi n g secti o ns:

A ut h or list: u p date d a ut h ors lists: 
 
.

List of a b bre viati o ns: delete d D S & E a n d a d de d C M O & P S per t he latest pr ot oc ol te m plate.

Pr ot oc ol s u m mar y : re vise d pr ot oc ol s u m mar y acc or di n g t o c ha n ges i n mai n c o nte nts.

Secti o n 1. 1. 2: A d de d “Ri b ocicli b, a n ot her C D K 4/ 6 i n hi bit or, c o m bi ne d wit h letr oz ole als o 
gai ne d F D A a p pr o val i n Marc h 2 0 1 7 as first li ne treat me nt p ost -me n o pa usal f or w o me n 
wit h H R- p ositi ve, H E R 2 - negati ve a d va nce d breast ca ncer.”

Secti o n 2. 1: A d de d “ Breast ca ncer” t o N C C N g ui deli nes


N o v arti s
C o nfi d e nti al
P a g e 2 0
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

Secti o n 4. 1: Patie nt n u m ber was re place d b y S u bject n u m ber

Secti o n 4. 1: S ur vi val f oll o w -u p secti o n was c larifie d: All patie nts will be f oll o we d f or 
s ur vi val stat us at least e ver y 3 m o nt hs after ra n d o mize d treat me nt p hase or p ost -treat me nt 
f oll o w-u p p hase u nless t he y  disc o nti n ue d d ue t o deat h, c o nse nt wit h dra wal or l ost t o 
f oll o w- u p.

Fi g ure 4 -1: St u d y  desi g n fi g ure clarifies t he p ost –treat me nt f oll o w-u p p hase a n d t he 
s ur vi val f oll o w-u p p hase.

Secti o n 4. 3 : delete d “ If t he p ri mar y a nalys is of P F S d oes n ot de m o nstrate treat me nt
be nefit, t he f oll o w u p f or O S will e n d ”

Secti o n 4. 4: I n case of earl y  st u d y ter mi nati o n, t he c o m pleti o n of e n d of p ost treat me nt 
f oll o w u p visit was a d de d

Secti o n 5. 2 i ncl usi o n criteria # 9, I N R ≤2 was a d de d

Secti o n 5. 2 i ncl usi o n criteria # 1 0, c ha n ge d t o Patie nt has a W H O perf or ma nce stat us ≤2;

Secti o n 5. 3:

E xcl usi o n criteria relate d t o patie nts w h o ha ve a hist or y  of a n ot her pri mar y 
mali g na nc y , peri o d of disease free > 5 ye ars t o 3 years.

Criteria of patie nts wit h C N S i n v ol ve me nt were u p date d per t he latest pr ot oc ol 
te m plate.

E xcl usi o n criteria of patie nts wit h u nc o ntr olle d dia betes mellit us was a d de d

E xcl usi o n criteria of patie nt wit h u nc o ntr olle d me dical c o n diti o n was u p date d

E xcl usi o n criteria of patie nts w h o ha ve recei ve d li ve atte n uate d vacci nes wit hi n a 
wee k of st u d y start was a d de d

E xcl usi o n criteria of patie nts ha vi n g partici pate d i n cli nical trials was a d de d

Secti o n 6. 1. 5 : i n t he treat me nt d urati o n secti o n, A d diti o n of e n d of treat me nt reas o ns: 
Pr ot oc ol de viati o n, St u d y  ter mi nati o n b y s p o ns or, Tec h nical pr o ble m

Secti o n 6. 3. 1, Ta ble 6 -3 u p date d :

f or he mat ol o gical t o xicit y, m o dificati o n of g ui da nce f or t hr o m b ocyt o pe nia gra de 2 
a n d detaile d g ui da nce f or fe brile ne utr o pe nia gra de 3 a n d gra de 4

f or ot her t o xicities ( n o n-he mat ol o gical), a d diti o n of detaile d g ui da nce f or gra de 1 t o 
gra de 4

Secti o n 6. 3. 2. 1 : a d diti o n of t he secti o n relate d t o ma na ge me nt of i nfecti o n d uri n g 
treat me nt wit h e ver oli m us

Secti o n 6. 3. 2. 3: A d de d “ es peciall y d uri n g t h e first 8 wee ks of treat me nt ( maj orit y  of 
st o matitis e ve nts occ ur wit hi n first 8 wee ks of treat me nt).”

Secti o n 6. 4. 3:

Ta bles 6 -8 a n d 6 -9 were u p date d

I nstr ucti o ns re gar di n g t he use of vacci nati o n d uri n g t he st u dy has bee n a d de d

Secti o n 6. 5. 1: Patie nt n u m ber was re place d b y  S u bject n u m ber.

Ta ble 7 - 1 Visit e val uati o n sc he d ule:


N o v arti s
C o nfi d e nti al
P a g e 2 1
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

A d diti o n of t he visit na me relate d t o P ost- treat me nt f oll o w-u p p hase a n d s ur vi val 
f oll o w-u p p hase

Rele va nt me dical hist or y/c urre nt me dical c o n diti o ns was re place d b y me dical hist or y

P K bl o o d sa m pli n g visit was a d de d f or c ycle 1.

Re m o ve d “ X” of P K bl o o d sa m pli n g fr o m t he c ol u m n of “E ver y  2 c ycles after C 1 D 1 ”.

Re m o ve d visit 4 i n f o ot n otes 1 a n d 1a, res pecti vel y, as visit n u m ber is n ot a p plica ble 
i n t his pr ot oc ol.

Re m o ve d “ X” f or perf or ma nce stat us d uri n g p ost -treat me nt f oll o w-u p p hase as n ot 
perf or me d d uri n g t he p ost -treat me nt f oll o w-u p p hase

Clarif y  i n t he t u m or e val uati o n, t he fre q ue nc y of t u m or e val uati o n i n t he p ost-
treat me nt f oll o w-u p p hase

Secti o n 7. 1. 1. 1: Pr ocess a n d eli gi bilit y f or re-scree ni n g was i ncl u de d: patie nts, w h o met 
all i ncl usi o n e xcl usi o n criteria, h o we ver were n ot a ble t o be ra n d o mize d wit hi n t he 
scree ni n g wi n d o w d ue t o a d mi nistrati ve iss ues, will be all o we d t o be re -scree ne d f or 
ra n d o mizati o n.

Secti o n 7. 1. 2. 3: u p date of “ H E R stat us” t o “ H E R 2 + stat us”. Re place me nt of “ date of birt h” 
b y  “ year of birt h”.

Secti o n 7. 1. 4 : Re m o ve d “st u d y” i n t he se nte nce “ Patie nts w h o disc o nti n ue st u d y  treat me nt 
s h o ul d u n der g o a n e n d of st u d y treat me nt visit”.

Secti o n 7. 1. 6. 1: Re m o ve d t he se nte nce “t he i n vesti gat or or his/ her desi g nee will c o m plete 
a St u d y E val uati o n C o m pleti o n C R F pa ge”. Re place t he “ St u d y  E val uati o n C o m pleti o n 
e C R F” b y t he “a p pr o priate dis p ositi o n C R F”.

Secti o n 7. 1. 6. 3: A d diti o n of t he para gra p h relate d t o S ur vi val f oll o w - u p “All patie nts w h o 
disc o nti n ue d treat me nt p hase or t he p ost -treat me nt f oll o w- u p p hase f or reas o ns ot her t ha n 
deat h, c o nse nt wit h dra wal, will be f oll o we d f or s ur vi val stat us at least e ver y 3 a n d u ntil 
e n d of st u d y. S ur vi val i nf or mati o n ca n be o btai ne d via p h o ne a n d i nf or mati o n will be 
d oc u me nte d i n t he s o urce d oc u me nts a n d e C R F. A d diti o nal s ur vi val assess me nts ma y be 
perf or me d m ore fre q ue ntl y  if a s ur vi val u p date is re q uire d f or re porti n g t he res ults or t o 
meet safet y or re g ulat or y nee ds ”

Secti o n 7. 2. 1 – Efficac y  assess me nts: N o vartis g ui deli ne versi o n 3. 1 was u p date d t o 3. 2.

Secti o n 7. 2. 1 – Efficac y  assess me nts: A d de d “ Ce ntral re vie w s h o ul d st o p after t he n u m ber 
of e ve nts is reac he d f or Pri mar y P F S a nalys is.”

Secti o n 7. 2. 1: Re m o val of “ if cli nicall y i n dicate d “ f or Brai n C T or M RI a n d W h ole b o d y  
b o ne sca n

Secti o n 7. 2. 2. 4: Perf or ma nce stat us, re m o val of “ e ve n if st u d y treat me nt is bei n g 
i nterr u pte d”

Secti o n 7. 2. 3: i n t he secti o n “ i f t he patie nt v o mits wit hi n t he first 4 h o urs”, “ or t he 2 da y s” 
was re place d b y “ or t he da y bef ore”, a n d re m o val of t he “V o miti n g L o g e C R F”

Secti o n 7. 2. 3. 1 P har mac o ki netic bl o o d sa m ple c ollecti o n a n d ha n dli n g:

V ol u mes of P K bl o o d sa m pli n g were re vise d t o be c o nsiste nt wit h Ta ble 7 - 5

Delete d visit 4 a n d a d de d a n y ti me d uri n g wee k 4


N o v arti s
C o nfi d e nti al
P a g e 2 2
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

Secti o n 7. 2. 2. 5. 3: “ Ne w or w orse ni n g” was re place d b y  “Ne w (i ncl u di n g ne w or 
w orse ne d)”

Ta ble 7 - 5 P K Bl o o d C ollecti o n Sc he d ule :

“Visit ” was c ha n ge d t o “ Visit Na me ”;” ; “ 4” was c ha n ge d t o “C y cle 1/ Wee k 4 ” i n t his 
c ol u m n.

“P K C ollecti o n n u m ber ” was c ha n ge d t o “D ose d Refere nce I D”.”

Secti o n 8. 1. 1 Defi niti o n a n d re p orti n g:

A E SI s were u p date d acc or di n g t o c urre nt Case Retrie val Strate g y

A Es were u p date d per t he latest pr ot oc ol te m plate (i ncl u de c ollecti o n of gra de 5)

“ Acti o n ta ke n wit h res pect t o st u d y  or i n vesti gati o nal treat me nt” was u p date d per t he 
latest o nc ol o g y sta n dar ds.

Secti o n 8. 2. 2 Re p orti n g: D S & E was c ha n ge d t o C hief Me dical Office a n d Patie nt Safet y
per t he pr ot oc ol te m plate.

Secti o n 8. 6: C ha n ge d t o: “ N ot A p plica ble ”.

Secti o n 8. 7: A d de d “T he S C will re vie w bli n de d p o ole d safet y data a p pr o xi matel y e ver y 6 
m o nt hs (after t he first ra n d o mize d patie nt has starte d st u d y  treat me nt) a n d pr o vi de 
rec o m me n dati o ns t o t he s p o ns or re gar di n g t he c o n d ucti o n of t he st u d y. ”

Secti o n 1 0. 1. 2 Safet y  set: “ N ote: t he state me nt t hat a patie nt ha d n o a d verse e ve nts 
c o nstit utes a safet y assess me nt. ” was re m o ve d.

Secti o n 1 0. 2: sec o n d para gra p h, re m o val of t he “ Rele va nt”, i n t he se nte nce “ Rele va n t 
me dical hist or y  ( …) will be s u m marize d”.

Secti o n 1 0. 5. 1 Sec o n dar y efficac y  o bjecti ves: “safet y” was re m o ve d fr o m t he list of 
sec o n dar y efficac y o bjecti ves.

Secti o n 1 0. 5. 1 Sec o n dar y efficac y  o bjecti ves: A d de d “( Ce ntral re vie w s h o ul d st o p after 
t he n u m ber of e ve nts is reac he d f or Pri mar y  P F S a nalys is)”

Secti o n 1 0. 5. 1. 6 E C O G Perf or ma nce Stat us: T he last se nte nce was c ha n ge d t o: “T he 
esti mate d treat me nt -s pecific me dian ti mes t o defi niti ve w orse ni n g will be prese nte d al o n g 
wit h a 9 0 % c o nfi de nce i nter val f or t h e t w o treat me nt ar ms. ”

Secti o n 1 0. 5. 2. 2 A d verse e ve nts: A E SI s were u p date d acc or di n g t o c urre nt Case Retrie val 
Strate g y

Secti o n 1 0. 5. 2. 3 La b orat or y a b n or malities : “ F or la b orat or y tests w here gra des are n ot 
defi ne d b y C T C A E v 4. 0 3, res ults will be cate g orize d as l o w/ n or mal/ hi g h base d o n 
la b orat or y n or mal ra n ges.” was a d de d per t he latest pr ot oc ol te m plate.

Secti o n 1 0. 5. 3 P har mac o ki netics: “( visit 4)” was delete d.

Secti o n 1 0. 5. 3 P har mac o ki netics : t he se nte nce “ n o v o miti n g wit hi n 4 h o urs after a n y of 
t he pre vio us 2 d oses” was re place d b y  “ n o v o miti n g wit hi n 4 h o urs f oll o wi n g st u d y dr u g 
a d mi nistrati o n o n t he da y of or t he da y  bef ore p har mac o ki netic bl o o d sa m pli n g”; a n d t he 
se nte nce “ n o v o miti n g wit hi n 4 h o urs after a ny of t he pre vi o us 2 d oses a n d t he d ose pri or 
t o t he C2 h sa m ple” was re place d by “n o v o miti n g wit hi n 4 h o urs f oll o wi n g st u d y  dr u g 
a d mi nistrati o n o n t he da y of or t he da y  bef ore p har mac o ki netic bl o o d sa m pli n g”

Secti o n 1 4. 1 A p pe n di x 1: N o vartis g ui deli ne versi o n 3. 1 was u p date d t o 3. 2.


N o v arti s
C o nfi d e nti al
P a g e 2 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
1
B a c k gr o u n d
1. 1
O v er vi e w  of di s e a s e p at h o g e n e si s, e pi d e mi ol o g y a n d c urr e nt 
tr e at m e nt
1. 1. 1
E pi d e mi ol o g y  of br e a st c a n c er
Breast ca ncer is t he m ost fre q ue ntl y dia g n ose d ca ncer i n w o me n acc o u nti n g f or 2 3 % ( 1. 3 8
milli o n) of all ne w ca ncer cases a n d is t he lea di n g ca use of ca ncer relate d deat hs i n fe males
w orl d wi de ca usi n g m ore t ha n 4 0 0, 0 0 0 deat hs yearl y . T he i nci de nce rates i n Asia is l o wer t ha n
i n wester n c o u ntries (Je mal et al 2 0 1 1) acc o u nti n g f or 2 1. 6 cases per 1 0 0, 0 0 0 w o ma n i n C hi na
(Gl o b oca n 2 0 0 8 ). It, h o we ver, has i ncrease d dra maticall y  over past 3 0 years a n d t his tre n d is
e x pecte d t o c o nti n ue i n t he ne xt 2 0 ye ars d ue t o s hifts i n t he re pr o d ucti ve a n d lifestyl e ris k
fact ors (Li n os et al 2 0 0 8 ). T he prese nce of h or m o ne rece pt or ( H R) [estr o ge n rece pt or ( E R)
a n d/ or pr o gester o ne rece pt or ( P g R)] is o ne of t he m ost i m p orta nt pr o g n ostic a n d pre dicti ve
fact ors detecte d i n a p pr o xi matel y 7 0 % of all i n vasi ve breast ca ncers. E n d ocri ne t hera p y is t he
c ore treat me nt m o dalit y i n patie nts wit h H R + a d va nce d breast ca ncer ( A B C).
1. 1. 2
Tr e at m e nt o pti o n s f or h or m o n e r e c e pt or p o siti v e a d v a n c e d br e a st
c a n c er
E n d ocri ne t hera p y opti o ns f or p ost me n o pa usal w o me n wit h estr o ge n rece pt or p ositi ve ( E R +),
A B C i ncl u de selecti ve n o nster oi dal ar o matase i n hi bit ors ( N S AI; a nastr oz ole a n d letr oz ole),
ster oi dal ar o matase i n hi bit ors (e xe mesta ne), estr o ge n rece pt or a nta g o nist (f ul vestra nt), a n d
selecti ve estr o ge n rece pt or m o d ulat or ( S E R M; ta m o xife n). Bl oc ki n g of estr o ge nic si g nali n g
wit h ta m o xife n has bee n t he mai n a p pr oac h i n treat me nt f or E R + breast ca ncer f or o ver 3 0
ye ars. Ta m o xife n is i n dicate d f or t he treat me nt acr oss t he w h ole c o nti n u u m of breast ca ncer,
ra n gi n g fr o m ris k re d ucti o n i n w o me n wit h hi g h ris k of de vel o pi n g breast ca ncer t o treat me nt
i n m ulti ple li nes of metastatic disease. Ar o matase i n hi bit ors ( AI) re d uce peri p heral estr o ge n 
s ynt hesis b y  bl oc ki n g t he c o n versi o n of a n dr o ge ns t o estr o ge ns, w hic h is t he pri mar y wa y 
estr o ge ns are pr o d uce d i n p ost me n o pa usal w o me n. Ar o matase i n hi bit ors are ge nerall y 
prescri be d as t he first li ne of t hera py f or t he treat me nt of p ost me n o pa usal w o me n wit h E R + 
breast ca ncer (Beslija 2 0 0 9 , Car d os o 2 0 1 1 , [N C C N 2 0 1 1. 2 ]).
I n hi biti o n of C D K 4/ 6 pre ve nts D N A re plicati o n b y  pr o hi biti n g pr o gressi o n fr o m G 1 t o S 
p hase d uri n g cell di visi o n. Bl oc ki n g t his mec ha nis m pre ve nts t u m or cell pr oliferati o n t hr o u g h 
c o ntr ol of t he cell c ycle. Pal b ocicli b is t he first C D K 4/ 6 i n hi bit or w hic h was a p pr o ve d b y  
F D A i n Fe br uar y  20 1 5, i n c o m bi nati o n wit h letr oz ole as i nitial e n d ocri ne base d t hera p y f or 
t he treat me nt of p ost me n o pa usal w o me n wit h H R -p ositi ve, H E R 2- ne gati ve a d va nce d breast 
ca ncer. O n Fe br uar y  19, 2 0 1 6, t he F D A als o a p pr o ve d pal b ocicli b i n c o m bi nati o n wit h 
f ul vestra nt f or t he treat me nt of w o me n 
wit h 
h or m o ne rece pt or ( H R)-p ositi ve, h u ma n 
e pi der mal gr o wt h fact or rece pt or 2 ( H E R 2)-ne gati ve a d va n ce d or metastatic breast ca ncer 
wit h disease pr o gressi o n f oll o wi n g e n d ocri ne t hera p y. Ri b ocicli b, a n ot her C D K 4/ 6 i n hit or, 
c o m bi ne d wit h letr oz ole als o gai ne d F D A a p pr o val i n Marc h 2 0 1 7 as first li ne treat me nt p ost -
me n o pa usal f or w o me n wit h H R - p ositi ve, H E R 2-ne gati ve a d va nce d breast ca ncer .


N o v arti s
C o nfi d e nti al
P a g e 2 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Des pite a br oa d s pectr u m of a vaila ble o pti o ns of e n d ocri ne t hera p y for t he patie nts wit h E R +
A B C, all patie nts will e ve nt uall y de vel o p resista nce t o i nitial treat me nt. A n e mer gi n g
mec ha nis m of e n d ocri ne resista nce is a ber ra nt si g nali n g via t he p h os p hati d y li n osit ol 3- ki nase
( PI3 K)/ A kt/ ma m malia n tar get of ra pa myci n ( m T O R) si g nali n g pat h wa y  (B urstei n 2 0 1 1 ,
J o h nst o n 2 0 0 6 , Sc hiff 2 0 0 4 ). Als o, h y peracti vati o n of t he PI 3 K/ m T O R pat h wa y  is o bser ve d
i n e n d ocri ne -resista nt breast ca ncer cells, a n d treat me nt wit h m T O R i n hi bit ors, i ncl u di n g
ra pa myci n a nal o gs, re verses t his resistance (e. g. Miller 2 0 1 0 ). I n a d diti o n, gr o wi n g e vi de nce
s u p p orts a cl ose i nteracti o n of t he m T O R pat h wa y  wit h E R si g nali n g. A s u bstrate of m T O R
C o m ple x 1 ( m T O R C 1), S 6 ki nase - 1 ( S 6 K 1), p h os p h or ylates t he ac ti vati o n d o mai n A F - 1 of
t he E R, res p o nsi ble f or li ga n d-i n de pe n de nt rece pt or acti vati o n (Ya m ni k 2 0 0 9 ; Ya m ni k 2 0 1 0 ).
E ver oli m us is a ra pa m yci n deri vati ve t hat i n hi bits m T O R t hr o u g h all osteric bi n di n g t o
m T O R C 1 b ut n ot m T O R C 2 (Efe y a n a n d Sa bati ni 2 0 1 0 ). I n the h u ma n st u d y, e ver oli m us
m o n ot hera p y de m o nstrate d cli nical acti vit y i n patie nts wit h A B C w h o ha d m ostl y  E R + t u m ors
a n d ha d recei ve d pre vi o us e n d ocri ne t hera py (Ellar d et al 2 0 0 9 ). I n this trial, 1 9 of t he 4 9
patie nts e nr olle d were E R -p ositi ve/ h u ma n e pi der mal gr o wt h fact or rece pt or 2 ( H E R 2)-
ne gati ve; Me dia n P F S f or t hese 1 9 patie nts was 3. 5 m o nt hs ( 9 5 % C.I .: 1. 9 – 5. 5 m o nt hs, data 
s o urce: N CI-Ca na da).
M ore 
rece ntl y, t he c o m bi nati o n of e ver oli m us wit h 
e xe mesta ne s h o we d si g nifica nt
i m pr o ve me nt i n efficac y, i n ter ms of P F S, res p o nse rate, a n d c li nical be nefit rate, relati ve t o
e xe mesta ne m o n ot hera p y  (Basel ga et al 2 0 1 1 ). T he me dia n P F S b y  local assess me nt was 7. 8
m o nt hs f or e ver oli m us + e xe mesta ne vers us 3. 2 m o nt hs f or e xe mesta ne ( H R = 0. 4 5; 9 5 % CI :
0. 3 8- 0. 5 4; P <. 0 0 0 1). O verall res p o nse rate ( O R R) ( 1 2. 6 % vs 1. 7 %; P <. 0 0 0 1) a n d C B R 
( 5 1. 3 % vs 2 6. 4 %; P <. 0 0 0 1) were s u peri or i n t he e ver oli m us + e xe mesta ne ar m vers us 
e xe mesta ne + place b o. A nal y ses b y  ce ntral assess me nt s h o we d a me dia n
P F S of 1 1. 0 m o nt hs 
wit h e ver oli m us vers us 4. 1 m o nt hs wit h place b o ( H R = 0. 3 8; 9 5 % CI : 0. 3 1 – 0. 4 8; P <. 0 0 0 1) 
c o nfir mi n g t he res ults of t he pri mar y  PF S a nal ys is (Yar dle y  et al 2 0 1 3 ). At t he ti me of t he 
fi nal O S a nal ysis, t he me dia n d urati o n of O S was 3 0. 9 8 m o nt hs vers us 2 6. 5 5 m o nt hs f or t he 
e ver oli m us + e xe mesta ne ar m a n d t he place b o + e xe mesta ne ar m, res pecti vely [ H R = 
0. 8 9( 9 5 % CI : 0. 7 3 t o 1. 1 0; p = 0. 1 4 2 6)] (Piccart et a l 2 0 1 4 ). T he c o m bi nati o n of e ver oli m us 
a n d e xe mesta ne has recei ve d a mar keti n g a ut h orizati o n i n t he U S A, E U a n d ma n y  ot her 
c o u ntries base d o n t he res ults of t his lar ge ra n d o mize d p hase III st u d y.
1. 1. 3
R ol e of m a m m ali a n t ar g et of r a p a m y ci n i n E R + A B C
T he m T O R, a ke y  pr otei n ki nase, acts as a n utrie nt se ns or a n d m o nit or of t he cell ular
meta b olic state re g ulati n g pr otei n s ynt hesis a n d ulti matel y  cell gr o wt h, pr oliferati o n, a n d
s ur vi val. m T O R ser ves a k e y  role i n n or mal ma m malia n cell p h y si ol o g y, a n d is ce ntrall y
i nv ol ve d i n t u m or-cell p h y si ol o g y, (f or e xa m ple, facilitati n g cell - c ycle pr o gressi o n fr o m G 1 -
S p hase) a n d c o nse q ue ntl y in hi biti o n of t his tar get has recei ve d c o nsi dera ble atte nti o n as a n
a ntica ncer a p pr oac h, as re vie we d b y  (Bj or nsti 2 0 0 4 ; A bra ha m 2 0 0 7 ). m T O R re g ulates gl o bal
m R N A tra nslati o n (Be u vi n k 2 0 0 5 ). I n dee d, d o w nstrea m fr o m m T O R is t he seri ne / t hre o ni ne
ki nase p 7 0 S 6 ki nase ( S 6 K). S 6 K p h os p h or y lates k e y  resi d ues o n t he ri b os o mal pr otei n S 6,
per mitti n g its acti vati o n a n d f ull f u ncti o n as a pr otei n i n v ol ve d i n ri b os o mal bi o ge nesis. T he
m T O R ki nase als o m o d ulates p h os p h or y lati o n of 4 E- bi n di n g pr ote i n 1 ( 4 E-B P 1), releasi n g its


N o v arti s
C o nfi d e nti al
P a g e 2 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
i n hi biti o n of eI F -4 E a n d c o nse q ue ntl y per mitti n g efficie nt ca p - de pe n de nt tra nslati o n (Bj or nsti 
a n d H o u g ht o n 2 0 0 4 ).
Acti vati o n of t he m T O R pat h wa y  is a k e y  ada pti ve c ha n ge dri vi n g e n d ocri ne resista nce.
Researc h i nt o t he mec ha nis ms of resista nce has s h o w n t hat vari o us si g nal tra ns d ucti o n
pat h wa y s are acti vate d t o esca pe t he effect of e n d ocri ne t hera p y. F or e xa m ple, t he PI 3
ki nase/ A kt/ m T O R pat h wa y  is c o nstit uti vel y acti vate d i n a r o matase i n hi bit or resista nt a n d
l o n g-ter m estr o ge n de pri vati o n B C cells (T o k u na ga 2 0 0 6 ; Sa nte n 2 0 0 5 ; Ca m p bell 2 0 0 1 ).
Selecti ve i n hi bit or of m T O R, sir oli m us or ra pa m yci n, de m o nstrate d a si g nifica nt gr o wt h
i n hi biti o n partic ularl y  in l o n g-ter m estr o ge n de pri ve d B C cells (Y ue et al 2 0 0 7 ). Ra pa m yci n
a n d its a nal o g ues partiall y  in hi bit m T O R t hr o u g h all osteric bi n di n g t o m T O R C 1 b ut n ot
m T O R C 2 (Efe y a n a n d Sa bati ni 2 0 1 0 ). H o we ver, pr ol o n ge d e x p os ure t o ra pa myci n als o
res ults i n m T O R C 2 i n hi biti o n (Sar bass o v et al 2 0 0 6 ).
1. 2
I ntr o d u cti o n t o i n v e sti g ati o n al tr e at m e nt( s) a n d ot h er st u d y 
tr e at m e nt( s)
E ver oli m us first e ntere d cli nical de vel o p me nt f or o ne of n u mer o us o nc ol o g y  in dicati o ns i n 
2 0 0 2.
It was a p pr o ve d b y  t he F D A o n 3 0- Mar -2 0 0 9 u n der t he tra de na me Afi nit or ® f or t he 
treat me nt of patie nts wit h a d va nce d re nal cell carci n o ma ( R C C) after fail ure of treat me nt wit h 
s u niti ni b or s orafe ni b. T he E ur o pea n C o m missi o n a p pr o ve d Afi nit or ® o n 0 3- A u g -2 0 0 9 f or 
t he treat me nt of patie nts wit h a d va nce d R C C, w h ose disease has pr o gresse d o n or after 
treat me nt wit h vasc ular e n d ot helial gr o wt h fact or ( V E G F)-tar gete d t hera p y. E ver oli m us has 
bee n a p pr o ve d i n > 1 2 1 c o u ntries w orl d wi de f or t he treat me nt of patie nts wit h a d va nce d R C C.
O n 0 5- M a y - 2 0 1 1, F D A a p pr o ve d Afi nit or ® f or t he treat me nt of pr o gressi ve ne ur oe n d ocri ne 
t u m ors of pa ncreatic ori gi n ( P N E T) i n patie nts wit h u nresecta ble, l ocall y ad va nce d or 
metastatic 
disease. T he E C a p pr o ve d Afi nit or ® o n 2 4- A u g -2 0 1 1 f or t he treat me nt of 
u nr esecta ble or metastatic, 
well - or m o deratel y -differe ntiate d ne ur oe n d ocri ne t u m ors of 
pa ncreatic ori gi n i n a d ults wit h pr o gressi ve disease. E ver oli m us has bee n a p pr o ve d i n > 1 1 5 
c o u ntries w orl d wi de f or t he treat me nt of patie nts wit h a d va nce d p N E T/ N E T.
O n 2 0- J ul- 2 0 1 2, F D A a p pr o ve d Afi nit or ® f or t he treat me nt of p ost me n o pa usal w o me n wit h 
a d va nce d h or m o ne rece pt or-p ositi ve ( H R +), h u ma n e pi der mal gr o wt h fact or rece pt or 2 
ne gati ve ( H E R 2-) breast ca ncer i n c o m bi nati o n wit h e xe mesta ne, after fail ure of treat me nt 
wit h letr oz ole or a nastr oz ole. T he E C a p pr o ve d Afi nit or ® o n 2 3 -J ul-2 0 1 2 f or t he treat me nt of 
H R +, H E R 2-
a d va nce d breast ca ncer, i n c o m bi nati o n wit h e xe mesta ne, i n p ost me n o pa usal 
w o me n wit h o ut s y m pt o matic visceral disease after rec urre nce or pr o gressi o n f oll o w i n g a n o n-
ster oi dal ar o matase i n hi bit or. E ver oli m us has bee n a p pr o ve d i n > 1 1 5 c o u ntries w orl d wi de f or 
t he treat me nt of patie nts wit h a d va nce d H R +, H E R 2- breast ca ncer.
I n Ja n uar y 2 0 1 3, e ver oli m us, u n der t he tra de na me Afi nit or, was a p pr o ve d f or t he treat me nt of
a d va nce d R C C i n C hi na. I n Fe br uar y 2 0 1 4, e ver oli m us (tra de na me: Afi nit or ® ) was a p pr o ve d 
f or t he treat me nt of p N E T a n d T S C -S E G A i n C hi na. Afi nit or is a p pr o ve d i n m ore t ha n 1 0 5 
c o u ntries f or eac h of t he o nc ol o g y  in dicati o ns a n d m ore t ha n 9 5 f or eac h o f t he T S C 
i n dicati o ns. M ost rece ntl y e ver oli m us was a p pr o ve d i n t he U S
o n 2 6- Fe b - 2 0 1 6 f or Afi nit or 
f or t he treat me nt of a d ult patie nts wit h 
pr o gressi ve, 
well -differe ntiate d, 
a d va nce d 


N o v arti s
C o nfi d e nti al
P a g e 2 6
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
n o nf u ncti o nal ne ur oe n d ocri ne t u m ors ( N E T) of gastr oi ntesti nal ( N E Ts of GI ) or l u n g ori gi n 
t hat. A p plicati o ns f or t his ne west o nc ol o g y  in dicati o n are u nresecta ble, l ocall y ad va nce d or 
metastatic pe n di n g w orl d wi de.
T he f oll o wi n g is a brief s u m mar y of t he mai n c haracteristics of e ver oli m us. M ore detaile d
i nf or mati o n ca n be o btai ned fr o m t he e ver oli m us i n vesti gat or’s br oc h ure.
1. 2. 1
O v er vi e w  of e v er oli m u s
M e c h a ni s m of a cti o n
E ver oli m us is a deri vati ve of ra pa m yci n w hic h acts as a si g nal tra ns d ucti o n i n hi bit or ( Ta ble 1 -
1 , Fi g ure 1- 1 ). E ver oli m us selecti vely i n hi bits ma m malia n tar get of ra pa myci n ( m T O R), 
s pecifically tar geti n g t he m T O R -ra pt or si g nal tra ns d ucti o n c o m ple x. m T O R is a k e y  seri ne -
t hre o ni ne ki nase i n t he p h os p h oi n o siti de 3- ki nase/ pr otei n ki nase B
( PI 3 K/ A K T) si g nali ng 
casca de, w hic h is k n o w n t o be d ysre g ulate d i n a wi de s pectr u m of h u ma n ca ncers ( B o ula y  a n d 
La ne 2 0 0 7 ).
E ver oli m us is bei n g i n vesti gate d as a n a ntica n cer a ge nt base d o n its p ote ntial t o act

directl y  o n t he t u m or cells b y i n hi biti n g t u m or cell gr o wt h a n d pr oliferati o n;

i n directl y b y i n hi biti n g a n gi o ge nesis lea di n g t o re d uce d t u m or vasc ularit y ( via p ote nt 
i n hi biti o n of t u m or cell V E G F pr o d ucti o n a n d V E G F -i n d uce d pr oliferati o n of e n d ot helial 
cells).
T a bl e 1 - 1
E v er oli m u s - dr u g s u b st a n c e
C h e mi c al n a m e
( 1 R, 9 S, 1 2 S, 1 5 R, 1 6 E, 1 8 R, 1 9 R, 2 1 R, 2 3 S, 2 4 E, 2 6 E, 2 8 E, 3 0 S, 3 2 S, 3 5 R)-1, 1 8 -di h y dr o x y -1 2 -
{( 1 R)- 2-[( 1 S, 3 R, 4 R)- 4-( 2-h y dr o x y et h o x y) - 3-m et h o x y c y cl o h e x yl] - 1-m et h yl et h yl} - 1 9, 3 0-
di m et h o x y -1 5, 1 7, 2 1, 2 3, 2 9, 3 5 -h e x a m et h yl - 1 1, 3 6-di o x a - 4-a z a -
tri c y cl o[ 3 0. 3. 1. 04, 9 ] h e x atri a c o nt a-1 6, 2 4, 2 6, 2 8 -t etr a e n e-2, 3, 1 0, 1 4, 2 0 -p e nt a o n e
I nt er n ati o n al n o n-
pr o pri et ar y n a m e
E v er oli m u s
Fi g ur e 1 - 1
C h e mi c al str u ct ur e of e v er oli m u s


N o v arti s
C o nfi d e nti al
P a g e 2 7
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
m T O R p at h w a y  a n d c a n c er
At t he cell ular a n d m olec ular le vel, e ver oli m us acts as a si g nal tra ns d ucti o n i n hi bit or. It 
selecti vely i n hi bits m T O R, a ke y pr otei n ki nase w hic h re g ulates cell gr o wt h, pr oliferati o n a n d 
s ur vi val. T he m T O R ki nase is mai nl y  acti vate d via t he PI 3 K pat h wa y  thr o u g h A K T/ P K B a n d 
T S C 1/ 2. M utati o ns i n t hese c o m p o ne nts or i n p h os p hatase a n d te nsi n h o m ol o g ( P T E N), a 
ne gati ve re g ulat or of PI 3 K, ma y  res ult i n t heir d y sre g ulati o n. A b n or mal f u ncti o ni n g of 
vari o us c o m p o ne nts of t he si g nali n g pat h wa y s c o ntri b utes t o t he pat h o p h y si ol o g y of 
n u mer o us h u ma n ca ncers. Vari o us precli nical m o dels ha ve c o nfi r me d t he r ole of t his pat h wa y 
i n t u m or de vel o p me nt (C o he n et al 2 0 0 5 ).
T he mai n k n o w n f u ncti o ns of m T O R i ncl u de t he f oll o wi n g ( Bj or nsti a n d H o u g ht o n 2 0 0 4 ):

m T O R f u ncti o ns as a se ns or of mit o ge ns, gr o wt h fact ors a n d e ner g y  a n d n utrie nt le vels;

Facilitati n g cell -c ycle pr o gressi o n fr o m G 1 -S p hase i n a p pr o priate gr o wt h c o n diti o ns;

T he PI 3 K/ m T O R pat h wa y  itself is fre q ue ntly d ys re g ulate d i n ma n y h u ma n ca ncers, a n d 
o nc o ge nic tra nsf or mati o n ma y  se nsitize t u m or cells t o m T O R i n hi bit ors;

PI 3 K m utati o ns ha ve bee n re p orte d i n t he pri mar y t u m or i n 1 0 -2 0 % of h u ma n c ol orectal 
ca ncers ( Fratti ni 2 0 0 5 , Vel h o 2 0 0 5 );

T he l oss of P T E N pr otei n, eit her t hr o u g h ge ne deleti o n or f u ncti o nal sile nci n g ( pr o m oter 
h y per met h y lati o n), is re p orte d i n a p pr o xi matel y 6 0 % of pri mar y h u ma n c ol orectal ca ncers 
(G oel et al 2 0 0 4 );

T he m T O R pat h wa y  is i n v ol ve d i n t he pr o d ucti o n of pr o-a n gi o ge nic fact ors (i.e., V E G F) 
a n d i n hi biti o n of e n d ot helial cell gr o wt h a n d pr oliferati o n;

T hr o u g h i nacti vati n g e u kar y otic i nitiati o n fact or 4 E bi n di n g pr otei ns a n d acti vati n g t he 
4 0 S ri b os o mal S 6 ki nases (i.e., p 7 0 S 6 K 1), m T O R re g ulates pr otei n tra nslati o n, i ncl u di n g 
t he HI F-1 pr otei ns. I n hi biti o n of m T O R is e x pecte d t o lea d t o decrease d e x pressi o n of 
HI F- 1.
1. 2. 1. 1
N o n -cli ni c al e x p eri e n c e
E ver oli m us i n hi bits t he pr oli ferati o n of a ra n ge of h u ma n t u m or cell li nes i n vitr o i ncl u di n g
li nes ori gi nati n g fr o m l u n g, breast, pr ostate, c ol o n, mela n o ma a n d gli o blast o ma. I n hi bit or y
c o nce ntrati o n at 5 0 % (I C 5 0s) ra n ges fr o m s u b/l o w n M t o μ M. E ver oli m us als o i n hi bits t he
pr oliferati o n of h u ma n u m bilical vei n e n d ot helial cells ( H U V E C S) i n vitr o, wit h partic ular
p ote nc y  agai nst V E G F -i n d uce d pr oliferati o n s u g gesti n g t hat e ver oli m us ma y  als o act as a n
a nti-a n gi o ge nic a ge nt. T he a ntia n gi o ge nic acti vit y of e ver oli m us was c o nfir me d i n vi v o.
E ver oli m us selecti vel y  i n hi bite d V E G F-de pe n de nt a n gi o ge nic res p o nse at well t olerate d d oses.
Mice 
wit h pri mar y  an d metastatic t u m ors treate d wit h e ver oli m us s h o we d a si g nifica nt
re d ucti o n i n bl o o d vessel de nsit y w he n c o m pare d t o c o ntr ols.
T he p ote ntial of e ver oli m us as a n a ntica ncer a ge nt was s h o w n i n r o de nt m o dels. E ver oli m us is 
orall y  bi oa vaila ble, resi di n g l o n ger i n t u m or tiss ue t ha n i n plas ma i n a s u bc uta ne o us m o use
xe n o graft m o del, a n d de m o nstrati n g hi g h t u m or pe netrati o n i n a rat pa ncreatic t u m or m o d el.
T he p har mac o ki netic pr ofile of e ver oli m us i n dicates s ufficie nt t u m or pe netrati o n, a b o ve t hat
nee de d t o i n hi bit t he pr oliferati o n of e n d ot helial cells a n d t u m or cell li nes dee me d se nsiti ve t o
e ver oli m us i n vitr o.


N o v arti s
C o nfi d e nti al
P a g e 2 8
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
E ver oli m us a d mi nistere d orall y dail y was a p ote nt i n hi bit or of t u m or gr o wt h, at well t olerate d
d oses, i n 1 1 differe nt m o use xe n o graft m o dels (i ncl u di n g pa ncreatic, c ol o n, e pi der m oi d, l u n g
a n d mela n o ma) a n d t w o s yn ge neic m o dels (rat pa ncreatic, m o use
ort h ot o pic mela n o ma).
T hese m o dels i ncl u de d t um or li nes c o nsi dere d se nsiti ve a n d “relati vel y resista nt” i n vitr o. I n
ge neral, e ver oli m us was better t olerate d i n m o use xe n o graft m o dels t ha n sta n dar d c yt ot o xic
a ge nts (i.e., d o x or u bici n a n d 5 -fl u or o uracil), w hile p ossessi n g si milar a nti-t u m or acti vit y.
A d diti o nall y , acti vit y in a V E G F -i m pre g nate d s u bc uta ne o us i m pla nt m o del of a n gi o ge nesis 
a n d re d uce d vasc ularit y ( vessel de nsit y ) of e ver oli m us -treate d t u m ors ( m uri ne mela n o ma) 
pr o vi de d e vi de nce of i n viv o effects of a n gi o ge nesis.
It is n ot clear w hic h m olec ular deter mi na nts pre dict res p o nsi ve ness of t u m or cells t o
e ver oli m us. M olec ular a nal ysis has re veale d t hat relati ve se nsiti vit y to e ver oli m us i n vitr o
c orrelates wit h t he de gree of p h os p h or y lati o n (acti vati o n) of t he A K T/ P K B pr otei n ki nase a n d
t he S 6 ri b os o mal pr otei n; i n s o me cases (i.e., gli o blast o ma) t here is als o a c orrelati o n wit h
P h os p hatase a n d Te nsi n H o m ol o g ( P T E N) stat us.
I n vi v o st u dies i n vesti gati n g t he a nti-t u m or acti vit y of e ver oli m us i n e x peri me ntal a ni mal 
t u m or m o dels s h o we d t hat e ver oli m us m o n ot hera p y  t ypicall y re d uce d t u m or cell gr o wt h rates 
rat her t ha n pr o d uce d re gressi o ns. T hese effects occ urre d wit hi n t he d ose ra n ge of 2. 5 m g t o 1 0 
m g/ k g, orall y o nce a da y.
I n precli nical m o dels, t he a d mi nistrati o n of e ver oli m us is ass ociate d wit h re d ucti o n of pr otei n
p h os p h or y lati o n i n tar get pr otei ns d o w nstrea m of m T O R, n ota bl y p h os p h or y late d S 6 ( p -S 6)
a n d p- 4 E- B P 1, a n d occasi o nall y  wit h a n i ncrease i n p h os p h or y late d A K T, a pr otei n u pstrea m
of m T O R si g nali n g pat h wa y .
All si g nifica nt a d verse e ve nts o bser ve d i n t o xic ol o g y st u dies wit h e ver oli m us i n mice, rats,
m o n ke y s a n d mi ni-pi gs were c o nsiste nt wit h its a ntici pate d p har mac ol o gical acti o n as a n a nti-
pr oliferati ve a n d i m m u n os u p pressa nt a n d at least i n part re versi ble after a 2 or 4 - wee k
rec o ver y peri o d wi t h t he e xce pti o n of t he c ha n ges i n male re pr o d ucti ve or ga ns, m ost n ota bl y
testes. F urt her details ca n be f o u n d i n t he e ver oli mus [I n vesti gat or’s Br oc h ure].
1. 2. 1. 2
Cli ni c al e x p eri e n c e
1. 2. 1. 2. 1 E v er oli m u s p h ar m a c o ki n eti c s
E ver oli m us is ra pi dly a bs or be d wit h a me dia n tma x of o ne t o t w o h o urs. T he stea dy- state area
u n der t he c o nce ntrati o n ti me c ur ve A U C 0 -τ is d ose -pr o p orti o nal o ver t he d ose ra n ge bet wee n
5 t o 7 0 m g i n t he wee kl y  re gi me n a n d 5 a n d 1 0 m g i n t he daily re gi me n. Stea d y -state was
ac hie ve d wit hi n t w o wee ks wit h t he dail y  dosi n g re gi me n. C ma x is d ose -pr o p orti o nal bet wee n
5 a n d 1 0 m g f or b ot h t he wee kl y a n d dail y re gi me ns. At d oses of 2 0 m g/ wee k a n d hi g her, t he
i ncrease i n Cma x is less t ha n d ose pr o p orti o nal (a me n de d [ St u d y C 2 1 0 2 C P re p ort]).
I n healt h y  patie nts, hi g h fat meals re d uce d s yste mic e x p os ure t o e ver oli m us 1 0 m g (as
meas ure d b y  AU C) b y  22 % a n d t he pea k plas ma c o nce ntrati o n C ma x b y  54 %. Li g ht fat meals
re d uce d A U C b y  32 % a n d C ma x b y  42 %. F o o d, h o we ver, ha d n o a p pare nt effect o n t he p ost
a bs or pti o n p hase c o nce n trati o n-ti me pr ofile [ St u d y C 2 1 2 0].


N o v arti s
C o nfi d e nti al
P a g e 2 9
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T he bl o o d -t o-plas ma rati o of e ver oli m us, w hic h is c o nce ntrati o n -de pe n de nt o ver t he ra n ge of
5 t o 5, 0 0 0 n g/ m L, is 1 7 % t o 7 3 %. T he a m o u nt of e ver oli m us c o nfi ne d t o t he plas ma is
a p pr o xi matel y 20 % at bl o o d c o nce ntrati o ns o bser ve d i n ca ncer patie nts gi ve n e ver oli m us 1 0
m g/ da y  [ St u d y 30 3- 0 4 4] . Plas ma pr otei n bi n di n g is a p pr o xi matel y 74 % b ot h i n healt h y
patie nts a n d i n patie nts wit h m o derate he patic i m pair me nt [ St u d y A 2 3 0 3].
T he maj or a n d nearl y  excl usi ve e nz yme res p o nsi ble f or t he meta b olis m of e ver oli m us i n ma n
was C Y P 3 A 4 ([ D M P K( U S) 1 9 9 8/ 0 0 5]; [ D M P K( C H) R 9 9 - 2 4 4 8], (K u h n et al 2 0 0 1 )). Ot her
c yt oc hr o me P 4 5 0 ( C Y P) is oe nz ymes eit her d o n ot meta b olize e ver oli m us or d o s o at ver y  lo w
rates. E ver oli m us is als o a m o derate i n hi bit or of P- gl yc o pr otei n -li ke me diate d effl u x s yste ms,
alt h o u g h t he c o m p o u n d has a hi g h i ntri nsic per mea bilit y  whe n P- gl yc o pr otei n is i n hi bite d
(Cr o we 1 9 9 8 , La pla nte 2 0 0 2 , [ D M P K( C H) 1 9 9 7/ 4 1 7] ). F oll o wi n g oral a d mi nistrati o n,
e ver oli m us is t he mai n circ ulati n g c o m p o ne nt i n h u ma n bl o o d a n d is c o nsi dere d t o c o ntri b ute
t he maj orit y of t he o verall p har mac ol o gic acti vit y [ St u d y W 1 0 7].
N o s pecific e xcreti o n st u dies ha ve bee n u n derta ke n i n ca ncer patie nts; h o we ver, data a vaila ble
fr o m t he tra ns pla ntati o n setti n g f o u n d t he dr u g t o be mai nl y eli mi nate d t hr o u g h t he feces.
E ver oli m us at a d ose of 5 m g / da y or 1 0 m g / da y was c o nfir me d P K pr ofile i n 2 4 C hi nese 
patie nts wit h a d va nce d s oli d t u m ors. A bs or pti o n of e ver oli m us after oral a d mi nistrati o n was 
ra pi d t o m o derate wit h me dia n t ma x of 2 t o 3 h o urs. T he C mi n, C ma x, a n d A U C 0 -τ at t he 
d ose of 1 0 m g / da y were a p pr o xi matel y 2-f ol d t h ose at 5 m g / da y an d i ncrease d d ose -
pr o p orti o nall y . After reac hi n g stea dy- state o n Da y  8, mea n ( ± S D) val ues of C L / F were 1 6. 7 
( ± 5. 6) a n d 1 8. 2 ( ± 7. 2) L/ h at d oses of 5 a n d 1 0 m g/ da y , res pecti vely [ St u d y X2 1 0 1]. T he 
mea n ( ± S D) stea d y-state C ma x a n d C L / F va l ues o btai ne d i n t his st u d y po p ulati o n of C hi nese 
patie nts were c o m para ble t o t he val ues o bser ve d i n Ja pa nese patie nts wit h N o n -H o d g ki n’s 
L y m p h o ma after t he res pecti ve dail y d oses [ St u d y C1 1 0 4] , a n d t he val ues o bser ve d i n 
Ca ucasia n patie nts wit h R C C at t he e ver oli m us 1 0 m g/ da y  once -dail y d o se [ St u d y C2 2 4 0], 
w hic h de m o nstrate d t he P K pr ofile of e ver oli m us o bser ve d i n C hi nese patie nts was c o nsiste nt 
wit h pre vi o us e x perie nce i n o nc ol o g y  setti n g.
1. 2. 1. 2. 2 Effi c a c y i n h or m o n e r e c e pt or p o siti v e br e a st c a n c er
Se veral ra n d omize d trials e val uate d e ver oli m us i n H R + breast ca ncer a n d s h o we d e vi de nce of
efficac y of e ver oli m us i n t his patie nt p o p ulati o n.
I n a m ultice nter, ra n d o mize d p hase II st u d y, a dail y d ose of e ver oli m us ( 1 0 m g) was e val uate d
i n patie nts wit h A B C i ncl u di n g pa tie nts wit h H R + disease pre vi o usl y recei ve d e n d ocri ne
t hera py. I n t his trial, 1 9 of t he 4 9 patie nts e nr olle d were E R -p ositi ve/ H E R 2 -ne gati ve; o ne
c o m plete res p o nse, 2 partial res p o nses, 3 sta ble disease f or l o n ger t ha n 6 m o nt hs, a n d 6 sta ble
diseases f or less t ha n 6 m o nt hs were re p orte d i n t his s u b gr o u p. Me dia n P F S i n t his s u bset of
1 9 patie nts was 3. 5 m o nt hs ( 9 5 % C.I .: 1. 9 – 5. 5 m o nt hs, data s o urce: N CI -Ca na da). A n
a d diti o nal partial res p o nse was re p orte d i n a patie nt wit h E R -p ositi ve H E R 2- u n k n o w n t u m or
(Ellar d et al 2 0 0 9 ).
T he c o m bi nati o n of e ver oli m us wit h e n d ocri ne t hera py has bee n assesse d i n differe nt disease
setti n gs. I n ne wl y dia g n ose d patie nts wit h H R + earl y B C, a ne oa dj u va nt ra n d o mize d 2 7 0 -
patie nt p hase II st u d y co m pare d t he c o m bi nati o n of e ver oli m us a n d letr oz ole t o letr oz ole 
al o ne. T he o verall res p o nse rate i n t he e ver oli m us ar m was hi g her t ha n t hat wit h letr oz ole 


N o v arti s
C o nfi d e nti al
P a g e 3 0
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
al o ne ar m ( 6 8 % vs. 5 9 % ( pal pati o n, p = 0. 0 6 2) a n d 5 8 % vs. 4 7 % ( ultras o u n d, p = 0. 0 2 1)
res pecti vely. A d diti o nall y , t here was a greater a nti pr oliferati ve res p o nse, wit h a decrease of 
t he Ki 6 7 pr oliferati o n i n de x t o < 1 i n 5 7 % of patie nts i n t he e ver oli m us ar m a n d i n 3 0 % of 
patie nts i n t he place b o ar m ( P < 0. 0 1). T his re d ucti o n i n Ki 6 7 was o bser ve d o nl y  tw o wee ks 
after i nitiati o n of trial t hera p y (Basel ga et al 2 0 0 9 ).
I n a ra n d o mize d p hase III, d o u ble -bli n d, place b o -c o ntr olle d st u d y (B O L E R O -2), e ver oli m us
i n c o m bi nati o n wit h e xe mesta ne was c o m p are d wit h e xe mesta ne al o ne i n 7 2 4 p ost me n o pa usal
w o me n wit h H R + A B C w h o ha d a rec urre nce or pr o gressi o n o n letr oz ole or a nastr oz ole. T he
c o m bi nati o n of e ver oli m us wit h e xe mesta ne s h o we d si g nifica nt i m pr o ve me nt i n efficac y, i n
ter ms of P F S, res p o nse rate, a n d cli nical be nefit rate, relati ve t o e xe mesta ne m o n ot hera p y
(Basel ga et al 2 0 1 1 ). E ver oli m us pl us e xe mesta ne si g nifica ntly i m pr o ve d P F S vers us
e xe mesta ne m o n ot hera p y  (H R = 0. 4 5; 9 5 % CI , 0. 3 8- 0. 5 4; P < .0 0 0 1) i n t he o verall st u d y
p o p ulati o n (Yar dle y  20 1 3 ). Of 1 4 3 patie nts of Asia n ori gi n e nr olle d i n t his st u d y, 9 8 recei ve d 
e ver oli m us pl us e xe mesta ne a n d 4 5 recei ve d e xe mesta ne pl us place b o. At t he ti me o f data 
c ut-off, 5 5 Asia n patie nts ( 5 6 %) i n t he c o m bi nati o n ar m ha d e x perie nce d disease pr o gressi o n 
c o m pare d wit h 3 4 patie nts ( 7 6 %) i n t he e xe mesta ne pl us place b o ar m. T he
c o m bi nati o n 
t hera py re d uce d t he ris k of disease pr o gressi o n vers us e xe mesta ne al o ne b y 3 8 % a m o n g Asia n 
patie nts ( H R = 0. 6 2; 9 5 % CI , 0. 4 1- 0. 9 4) c orres p o n di n g t o me dia n P F S pr ol o n gati o n fr o m 4. 1 
m o nt hs i n t he place b o pl us e xe mesta ne ar m t o 8. 5 m o nt hs i n t he e ver oli m us pl us e xe mesta ne 
ar m (N o g uc hi et al 2 0 1 3 ).
I n a 1 1 1- patie nt ra n d o mize d p hase II st u d y in p ost me n o pa usal w o me n wit h E R + A B C
pre vi o usl y  pretreate d wit h ar o matase i n hi bit ors, t he c o m bi nati o n of e ver oli m us a n d ta m o xife n
s h o we d a si g nifica nt i m pr o ve me nt i n pr o gressi o n -free s ur vi val ( 8. 6 m o nt hs vs. 4. 5 m o nt hs,
p = 0. 0 0 2 1) a n d o verall s ur vi val ( me dia n n ot reac he d vs. 2 4. 4 m o nt hs, p = 0. 0 1 3 7) relati ve t o
ta m o xife n al o ne ( T A M R A D trial, Bac hel ot et al 2 0 1 2 ).
B ot h e ver oli m us a n d e xe mesta ne a re s u bstrates of C Y P 3 A 4 a n d t here is a p ote ntial D DI 
bet wee n t he t w o dr u gs. I n B O L E R O - 2, avera ge e xe mesta ne pre d ose c o nce ntrati o n ( Cmi n ) a n d 
t w o-h o ur p ost -d ose c o nce ntrati o n ( C2 h) were 4 5 % a n d 6 4 % hi g her, res pecti vely, w he n c o -
a d mi nistere d wit h e ver oli m us. H o we ver, t he i ncrease i n e xe mesta ne le vel is n ot li kel y t o h a v e 
maj or i m pact o n t he efficac y a n d safet y of e xe mesta ne. I n t he e ver oli m us pl us e xe mesta ne 
ar m, e xe mesta ne C mi n or C 2 h val ues were si milar f or Ja pa nese a n d n o n- J apa nese patie nts. I n 
t he place b o pl us e xe mesta ne ar m, e xe mesta ne C mi n
or C 2 h val ues were als o si milar f or 
Ja pa nese a n d n o n- Ja pa nese patie nts. It was de m o nstrate d t hat t he P K e x p os ure is si milar 
bet wee n Ja pa nese a n d n o n- Ja pa nese patie nts.
S af et y  pr ofil e of e v er oli m u s
T he f oll o wi n g a d verse e ve nts are c o nsi dere d t o be t he class -effects of t he m T O R i n hi bit ors:
st o matitis/ oral m uc ositis/ ulcers, i nfecti o ns a n d i nfestati o ns, ras h a n d si milar e ve nts, c yt o pe nia,
he m orr ha ges, n o n- i nfecti o us p ne u m o nitis, h y per gl y ce mia/ ne w -o nset dia betes mellit us, re nal
e ve nts, a n d t hr o m b oe m b olis m. T he m ore c o m m o n meta b olic si de effects re p orte d wit h m T O R
i n hi bit ors res ult fr o m i n hi bit or y effects o n m T O R-re g ulate d li pi d a n d gl uc ose pat h wa ys, w hile
i nfecti o ns ste m fr o m t he i m m u n os u p pressi ve pr o perties of t hese a ge nts . Virt uall y  all of t he
si de effects ass ociate d wit h 
m T O R 
i n hi bit ors ca n be ma na ge d 
effecti vel y wit h 
d ose
m o dificati o n a n d/ or s u p p orti ve i nter ve nti o n.


N o v arti s
C o nfi d e nti al
P a g e 3 1
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T he safet y pr ofile of e ver oli m us o bser ve d i n t he p hase III St u d y  Y2 3 0 1 ( B O L E R O -2) is
c o nsiste nt wit h pri or e x perie nce i n t he o nc ol o g y  setti n g; e ve nts c o nti n ue t o be pre d o mi na ntl y
l o w gra de ( gra de 1 or 2). C o m pare d t o t he c o ntr ol ar m [e xe mesta ne + place b o], a n i ncrease d
ris k of n o n- i nfecti o us p ne u m o nitis, i nfecti o n, a n d st o matitis i n t he e ver oli m us pl us
e xe mest a ne ar m was o bser ve d. T he m ost c o m m o n (i n ≥1 0 % patie nts) a d verse e ve nts ( A Es)
re p orte d i n t he patie nts treate d wit h e ver oli m us pl us e xe mesta ne were st o matitis, ras h, fati g ue,
diarr hea, decrease d a p petite, wei g ht 
decrease d, c o u g h, d y s ge usia, d y s p nea, hea da c he 
art hral gia, peri p heral e de ma, a ne mia, na usea, e pista xis, v o miti n g, p yre xia, p ne u m o nitis, 
c o nsti pati o n, bac k pai n, pr urit us, i ns o m nia, ast he nia, A S T/ A L T/ G G T i ncrease, h y per gl yc e mia, 
dr y  
mo ut h, al o pecia nas o p har y n gitis a n d uri nar y  tract i nfecti o n (Ta ble 1- 1 ). T he m ost 
c o m m o n gra de 3- 4 A Es s us pecte d t o be relate d t o treat me nt wit h a n i nci de nce of ≥2 % were: 
st o matitis, fati g ue, diarr hea, 
wei g ht 
l oss, d ys p nea, 
a ne mia, p ne u m o nitis, 
ast he nia, 
h y per gl y ce mia a n d A S T/ G G T i ncrease.


N o v arti s
C o nfi d e nti al
P a g e 3 2
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a bl e 1- 2
B O L E R O -2 St u d y: m o st c o m m o nl y r e p ort e d a d v er s e e v e nt s ( >/ = 1 0 %
of p ati e nt s tr e at e d wit h e v er oli m u s + e x e m e st a n e)
E V E + E X E
( n = 4 82 ), %
Pl a c e b o + E X E
( n = 2 38 ), %
Gr a d e
Gr a d e
A E ( pr ef e rre d t er m)
All
1 
2 
3 
4
All
1 
2 
3 
4
St o m atiti s
5 9 
2 9 
2 2
8 
0
1 2
9 
2 
1 
0
R a s h
3 9 
2 9
9 
1 
0 
7 
5 
2 
0 
0
F ati g u e
3 7 
1 8 
1 4
4
< 1
2 7 
1 6 
1 0
1 
0
Di arr h e a
3 4 
2 6
6 
2
< 1
1 9 
1 4
4 
1 
0
N a u s e a
3 1 
2 1
9
< 1 
< 1
2 9 
2 1
7 
1 
0
D e cr e a s e d a p p etit e
2 8 
1 9 
1 0
2 
0
1 3
8 
4 
1 
0
W e i ght d e cr e a s e d
2 6 
1 0 
1 6
2 
0 
7 
3 
5 
0 
0
C o u g h
2 2 
2 1
4 
1 
0
1 2
8 
3 
0 
0
D y s g e u si a
2 2 
1 8
4 
0 
0 
6 
6 
0 
0 
0
D y s p n e a
2 3 
1 0
6 
5
< 1
1 1
8 
2 
1
< 1
H e a d a c h e
2 1 
1 7
6
< 1
0
1 5 
1 3
2 
0 
0
Art hr al g i a
2 1 
1 5
5 
1 
0
1 7 
1 1
6
< 1
0
P eri p h er al e d e m a
2 1 
1 4
6 
1 
0 
6 
5 
1
< 1
0
A n e mi a
2 1
4
1 0
7 
1 
5 
2 
2
< 1 
< 1
E pi st a xi s
1 7 
1 6
2 
0 
0 
1 
1 
0 
0 
0
V o miti n g
1 7 
1 1
6 
1
< 1
1 3
9 
3 
1 
0
P yr e xi a
1 6 
1 3
3
< 1
0 
7 
6 
1
< 1
0
P n e u m o niti s
1 6
7 
6 
3 
0 
0 
0 
0 
0 
0
C o n s ti p atio n
1 5 
1 1
3 
1 
0
1 3
8 
5
< 1
0
B a c k p ai n
1 5 
1 0
5
< 1
0
1 1
6 
3 
2 
0
Pr urit u s
1 4 
1 1
3
< 1
0 
7 
5 
2 
0 
0
I n s o m ni a
1 4 
1 0
4
< 1
0 
8 
6 
3 
0 
0
A st h e ni a
1 4
7 
6 
2
< 1
4 
3 
1
< 1
0
A S T i n cr e a s e d
1 4
6 
5 
3
< 1
6 
2 
2 
1 
0
H y p er gl y c e mi a
1 4
4 
5 
5
< 1
2 
1 
1
< 1
0
A L T i n cr e a s e d
1 2
5 
4 
3
< 1
5 
1 
2 
2 
0
Dr y m o ut h
1 1 
1 0
1 
0 
0 
7 
7
< 1
0 
0
Al o p e c i a
1 1
9 
1 
0 
0
1 2 
1 2
0 
0 
0
N a s o p h ar y n g iti s
1 0
9 
1 
0 
0 
9 
7 
2 
0 
0
P ai n i n e xtr e mit y
1 0
6 
3
< 1
0
1 2
5 
5 
2 
0
Uri n ar y tr a c t i nf e cti o n
1 0
3 
7
< 1
0 
2
< 1
2 
0 
0
G G T i ncr e a s e
1 0
2 
2 
5 
2 
9 
1 
1 
5 
2
I n t he a nal ys is of Asia n s u bset ( 1 4 3), c o m m o n ly re p orte d a d verse e ve nts i n t he c om bi nati o n 
ar m were c o nsiste nt wit h t he o verall p o p ulati o n a n d i ncl u de d st om atitis ( 8 0 %), ras h ( 4 9 %), 
a n d d y s ge usia ( 3 1 %). A d verse e ve nts t hat occ urr e d more fre q ue ntly i n t he Asia n s u bset vers us 
Ca ucasia ns i ncl u de d sto m atitis ( 80 % vs 5 4 %) a n d ras h ( 49 % vs 3 7 %), w hereas d y sp nea ( 8 % 
vs 2 4 %) a n d ast he nia ( 1 % vs 1 7 %) occ urre d less fre q ue ntl y in t he Asia n
s u bset vers us 
Ca ucasia ns (N o g uc hi et al 2 0 1 3 ).


N o v arti s
C o nfi d e nti al
P a g e 3 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a bl e 1- 3  
A n y - gr a d e a d v er s e e v e nt s w it h >/ + 1 0 % i n cid e n c e i n A s i a n A B C 
p ati e nt s tr e at e d wit h e v er oli m u s + e x e m e st a n e
E V E + E X E ( n = 4 82)
Pl a c e b o + E X E ( n = 2 38)
A d v er s e E v e nt, n ( %)
N o n -A si a n
( n = 3 8 4)
A s i a n
( n = 9 8)
N o n -A si a n
( n = 1 9 3)
A s i a n
( n = 4 5)
St o m atiti s
2 0 7 ( 5 4)
7 8 ( 8 0)
2 1 ( 1 1)
7 ( 1 6)
R a s h
1 4 0 ( 3 6)
4 9 ( 5 0)
1 2 ( 6)
4 ( 9)
D y s g e u si a
7 6 ( 2 0)
3 0 ( 3 1)
1 1 ( 6)
3 ( 7)
F ati g u e
1 5 4 ( 4 0)
2 4 ( 2 4)
5 7 ( 3 0)
8 ( 1 8)
H e a d a c h e
8 5 ( 2 2)
2 4 ( 2 4)
3 0 ( 1 6)
5 ( 1 1)
Di arr h e a
1 4 2 ( 3 7)
2 3 ( 2 3)
3 8 ( 2 0)
6 ( 1 3)
W e i ght d e cr e a s e d
1 1 0 ( 2 9)
2 3 ( 2 3)
1 4 ( 7)
3 ( 7)
P n e u m o niti s
5 4 ( 1 4)
2 3 ( 2 3)
0
0
N a u s e a
1 2 5 ( 3 3)
2 2 ( 2 2)
5 7 ( 3 0)
1 1 ( 2 4)
N a s o p h ar y n g iti s
2 7 ( 7)
2 2 ( 2 2)
1 2 ( 6)
9 ( 2 0)
N ail d is or d er
1 8 ( 5)
2 2 ( 2 2)
1 ( < 1)
0
C o n s ti p atio n
5 0 ( 1 3)
2 0 ( 2 0)
2 7 ( 1 4)
5 ( 1 1)
C o u g h
1 0 3 ( 2 7)
2 0 ( 2 0)
2 5 ( 1 3)
3 ( 7)
D e cr e a s e d a p p etit e
1 2 9 ( 3 4)
1 9 ( 1 9)
2 7 ( 1 4)
4 ( 9)
A S T i n cr e a s e d
4 9 ( 1 3)
1 8 ( 1 8)
1 2 ( 6)
1 ( 2)
A L T i n cr e a s e d
4 2 ( 1 1)
1 7 ( 1 7)
1 0 ( 5)
1 ( 2)
P yr e xi a
6 1 ( 1 6)
1 6 ( 1 6)
1 2 ( 6)
4 ( 9)
Art hr al g i a
8 3 ( 2 2)
1 6 ( 1 6)
3 6 ( 1 9)
4 ( 9)
E pi st a xi s
6 8 ( 1 8)
1 5 ( 1 5)
2 ( 1)
1 ( 2)
T hr o m b o c yt o p e ni a
4 6 ( 1 2)
1 5 ( 1 5)
1 ( < 1)
0
A n e mi a
8 6 ( 2 2)
1 4 ( 1 4)
1 1 ( 6)
1 ( 2)
L D H i n cr e a s e d
1 5 ( 4)
1 4 ( 1 4)
3 ( 2)
1 ( 2)
V o miti n g
7 1 ( 1 8)
1 3 ( 1 3)
2 8 ( 1 5)
4 ( 9)
I n s o m ni a
5 4 ( 1 4)
1 3 ( 1 3)
1 8 ( 9)
2 ( 4)
I nt er stiti al l un g di s e a s e
5 ( 1)
1 3 ( 1 3)
0
0
Pr urit u s
5 3 ( 1 4)
1 2 ( 1 2)
8 ( 4)
3 ( 7)
B a c k p ai n
6 2 ( 1 6)
1 1 ( 1 1)
2 3 ( 1 2)
2 ( 4)
N o ne w safety c o ncer ns ha ve e mer ge d c o m pare d t o pre vi o us e x perie nce wit h e ver oli m us 
m o n ot hera p y or c o m bi nati o n t hera p y.
1. 2. 2
O v er vi e w  of e x e m e st a n e
E xe mesta ne is a n irre versi ble ster oi dal ar o matase i nacti vat or t hat has de m o nstrate d efficac y  i n 
t he treat me nt of p ost me n o pa usal patie nts wit h A B C. It is i n dicate d f or a dj u va nt treat me nt of 
p ost me n o pa usal w o me n wit h Estr o ge n rece pt or p ositi ve ( E R +) earl y BC w h o ha ve recei ve d 
t w o t o t hree ye ars of ta m o xife n a n d are s witc he d t o e xe mesta ne f or c o m pleti o n of a t otal of 
fi ve c o nsec uti ve ye ars of a dj u va nt e n d ocri ne t hera p y. It is als o i n dicate d f or t he treat me nt of 
a d va nce d breast ca ncer ( A B C) i n p ost me n o pa usal w o me n w h ose disease has pr o gresse d 
f oll o wi n g ta m o xife n t hera p y (i n t he U S A a n d C hi na) or f oll o wi n g a nti -oestr o ge n t hera py (i n 
E ur o pe).


N o v arti s
C o nfi d e nti al
P a g e 3 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
E xe mesta ne is i nitiall y rec o g nize d b y  the ar o matase e nz yme as a false s u bstrate a n d t he n 
tra nsf or me d t hr o u g h a n N A D P H - de pe n de nt mec ha nis m 
t o a n i nter me diate t hat bi n ds 
irre versi bly t o t he e nz y me ca usi n g i nacti vati o n. E xe mesta ne si g nifica ntl y lo wers circ ulati n g 
estr o ge n c o nce ntrati o ns (estra di ol, estr o ne a n d estr o ne s ul fate) b ut has n o detecta ble effect o n 
a dre nal bi os y nt hesis of c ortic oster oi ds or al d oster o ne ( [Ar o masi n prescri bi n g i nf or mati o n PI -
Pfizer -P har macia 2 0 0 5 ]).
T he rec o m me n de d dail y  dose of e xe mesta ne is 2 5 m g via oral a d mi nistrati o n. E xe mesta ne is 
ra pi dl y a bs or be d fr o m t he gastr oi ntesti nal tract. Its bi oa vaila bilit y is li mite d b y  first -pass 
meta b olis m, b ut is i ncrease d w he n ta ke n wit h f o o d. E xe mesta ne is wi del y distri b ute d, a n d is 
e xte nsi vel y bo u n d t o plas ma pr otei ns. It ap pears t o be m ore ra pi dly a bs or be d i n w o me n wit h 
breast ca ncer (t ma x of 1. 2 h o urs) t ha n i n healt h y w o me n (t ma x of 2. 9 h o urs). T he ter mi nal 
halflife f or e xe mesta ne is 1 8-2 4 h o urs. T he ti me nee de d t o reac h ma xi mal E 2 s u p pressi o n is 7 
da y s (De mers 1 9 9 3 , Pl o ur de 1 9 9 5 , B uz dar 2 0 0 3 ). E xe mesta ne is meta b olize d b y  CY P 3 A 4 
a n d al d o ket ore d uctases. It d oes n ot i n hi bit a n y of t he maj or C Y P is oe nz ym es, i ncl u di n g C Y P
1 A 2, 2 C 9, 2 D 6, 2 E 1 a n d 3 A 4. Alt h o u g h n o f or mal dr u g -dr u g i nteracti o n st u dies ha ve bee n 
c o n d ucte d, si g nifica nt effects o n e xe mesta ne cleara nce b y  CY P is oe nzy m e i n hi bit ors a p pear 
u nli kel y  ([Ar o masi n prescri bi n g i nf or mati o n-Pfizer -P har macia 2 0 1 1] , H uts o n 2 0 0 5 , B uz dar 
2 0 0 3 ).
T he m ost fre q ue ntly re p orte d a d verse effects f or e xe mesta ne are gastr oi ntesti nal dist ur ba nces,
h ot fl us hes, art hral g ia, m y al gia, s weati n g, fati g ue, a n d dizzi ness. Ot her re p orte d effects 
i ncl u de hea dac he, i ns o m nia, s o m n ole nce, de pressi o n, s ki n ras hes, al o pecia, ast he nia, a n d 
peri p heral a n d le g e de ma. T hr o m b oc y t o pe nia a n d le uc o pe nia ha ve bee n re p orte d occasi o nally.  
Re d uct i o ns i n b o ne mi neral de nsit y  ca n occ ur wit h l o n g-ter m use of e xe mesta ne. A t otal of
1 0 5 8 patie nts were treate d wit h e xe mesta ne 2 5 m g o nce dail y  in t he cli nical trials pr o gra m. 
E xe mesta ne was ge nerall y  well t olerate d, a n d a d verse e ve nts were us uall y  mil d t o m o derate. 
A d verse e ve nts occ urri n g i n greater t ha n 1 0 % of patie nts i ncl u de h ot fl us hes ( 1 4 %), na usea 
( 1 1. 9 %), i ns o m nia, hea dac he, i ncrease d s weati n g, j oi nt a n d m usc ul os keletal pai n, a n d fati g ue 
( U S PI; Ar o masi n s u m mar y of pr o d uct c haracteristics A u g ust 2 0 0 8 ( U K as refere nce me m ber 
state f or E U m ut ual rec o g niti o n pr oce d ure)). A n dr o ge nic effects were re p orte d i n a li mite d 
n u m ber of patie nts ( 4. 3 %) ( B uz dar et al 2 0 0 3 ).
Refer t o t he pac ka ge i nsert of t he l ocal s u p pl y of e xe mesta ne f or m ore details.
2
R ati o n al e
2. 1
St u d y r ati o n al e a n d p ur p o s e
T his
stu d y aims
at e val uati n g t he efficac y an d safety of e ver olim us
pl us e x e m esta ne i n 
C hi nese p ost m e n o pa usal w o me n wit h
E R + H E R 2- A B C
after rec urre nce or pr o gressi o n o n 
letr oz ole or a nastroz ole.
T he rati o nale of t his st u d y  is base d o n t he f oll o wi n g:

E ver oli m us activ it y i n br east cancer i n c om bi nati o n wit h e n d ocri ne t hera p y (Basel ga 2 0 0 9 ;
Basel ga 2 0 1 1 ; Bac hel ot 2 0 1 2 )


N o v arti s
C o nfi d e nti al
P a g e 3 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

P ositi ve efficac y a n d ma na gea ble safet y pr o file of e ver olim us i n c om bi nati o n wit h 
e xem esta ne i n lar ge P h III ra n d o mize d st ud y  (Basel ga 2 0 1 1 ) a n d i n Asia n patie nt
p o p ulati o n of B O L E R O - 2 (N o g uc hi et al 2 0 1 3 )
I n a P hase II st u d y, 4 9 patie nts w h o recei ve d n o or o ne pri or c he m ot hera p y re gi me n f or 
metastatic breast ca ncer recei ve d e ver oli m us eit her 1 0 m g  dail y or 7 0 m g  wee kl y ( Ellar d e t 
al 2 0 0 9 ). M aj orit y of patie nts i n t he st u d y ha d ha d pri or c he m ot hera p y f or a d va nce d dis ease 
a n d was E R p ositi ve ( 2 9/ 4 9) a n d H E R 2 ne gati ve ( 4 0/ 4 9). 1 9 of t he 4 9 patie nts wit h 
E R +/ H E R 2- e nr olle d were treate d wit h e ver oli m us 1 0 m g dail y ; o ne c o m plete res p o nse, 2 
partial res p o nses, 3 sta ble disease f or l o n ger t ha n 6 m o nt hs, a n d 6 sta ble diseases f or less t ha n
6 m o nt hs were re p orte d i n t his s u b gr o u p. Me dia n P F S i n t his s u bset of 1 9 patie nts was 3. 5 
m o nt hs ( 9 5 % C.I.: 1. 9 – 5. 5 m o nt hs, data s o urce: N CI -Ca na da). A n a d diti o nal partial res p o nse 
was re p orte d i n a patie nt wit h E R -p ositi ve H E R 2 -u n k n o w n t um or. T he st u d y de m o nstrate d 
t hat dail y t hera p y wit h 1 0 m g is w ort h y of f urt her st u d y i n t his patie nt p o p ulati o n (Ellar d et al 
2 0 0 9 ).
A GI N E C O st u d y i n patie nts wit h H R +, h u ma n e pi der mal gr o wt h fact or rec e pt or 2 - metastatic 
breast ca ncer wit h pri or e x p os ure t o ar o matase i n hi bit ors s h o we d t hat 6 -m o nt h C B R was 6 1 % 
( 9 5 % CI , 4 7 t o 7 4) wit h ta m o xife n 2 0 m g/ da y  pl us e ver oli m us 1 0 m g / da y an d 4 2 % ( 9 5 % CI,
2 9 t o 5 6) wit h ta m o xife n al o ne (Bac hel ot et al 2 0 1 2 ). Ti me t o pr o gressi o n i ncrease d fr o m 4. 5 
m o nt hs wit h ta m o xife n al o ne t o 8. 6 m o nt hs wit h ta m o xife n pl us e ver oli m us, c orres p o n di n g t o 
a 4 6 % re d ucti o n i n ris k of pr o gressi o n wit h t he c o m bi nati o n ( hazar d rati o [ H R] , 0. 5 4; 9 5 % CI, 
0. 3 6 t o 0. 8 1). Ris k of deat h was re d uce d b y  55 % wit h ta m o xife n pl us e ver oli m us vers us 
ta m o xife n al o ne ( H R, 0. 4 5; 9 5 % CI, 0. 2 4 t o 0. 8 1) (Bac hel ot et al 2 0 1 2 ).
A ne oa dj u va nt p hase II st u d y i n ne wl y dia g n ose d patie nts wit h E R + earl y BC s h o we d t he 
o verall res p o nse rate i n t he c o m bi nati o n of e ver oli m us a n d letr oz ole was si g nifica ntly hi g her 
t ha n letr oz ole al o ne ( 6 8 % vs. 5 9 % b y  pal pati o n, p = 0. 0 6 2 a n d 5 8 % vs. 4 7 % b y  ultras o u n d, 
p = 0. 0 2 1) ( Basel ga et al 2 0 0 9 ).
I n B O L E R O - 2, t he c o m bi nati o n t hera p y of e ver oli m us a n d e xe mesta ne has s h o w n s u peri orit y 
i n ter ms of P F S c o m pare d t o e xe mesta ne al o ne (Basel ga 2 0 1 1 ; Yar dle y  20 1 3 ). I n t he m ost 
c urre nt re p ort of 5 1 0 P F S e ve nts at a me dia n f oll o w- u p of 1 8 m o nt hs, t he a d diti o n of 
e ver oli m us t o e xe mesta ne si g nifica ntly 
pr ol o n ge d 
me dia n 
P F S 
vers us 
e xe mesta ne
m o n ot hera p y as per l ocal assess me nt ( 7. 8 vs 3. 2 m o, res pecti vely;  HR = 0. 4 5 [ 9 5 % CI , 0. 3 8 -
0. 5 4]; l o g-ra n k p < 0. 0 0 0 1) (Yar dle y  20 1 3 ). F urt her m ore, t hese data were c o nsiste nt wit h 
res ults base d o n ce ntral assess me nt ( 1 1. 0 m o f or e ver oli m us pl us e xe mesta ne vs 4. 1 m o f or 
e xe mesta ne al o ne; H R = 0. 3 8 [ 9 5 % CI , 0. 3 1-0. 4 8]; l o g-ra n k p < 0. 0 0 0 1). Fe wer deat hs were 
re p orte d wit h e ver oli m us pl us e xe mesta ne ( 2 5. 4 %) vs e xe mesta ne ( 3 2. 2 %). I n a d diti o n, P F S 
be nefits wit h 
e ver oli m us pl us e xe mesta ne vers us e xe mesta ne were 
c o nsiste nt i n all 
pr os pecti vel y defi ne d s u b gr o u ps, i ncl u di n g s u bsets of patie nts wit h visceral metastases 
( n = 4 0 6), 3 or m ore sites of metastasis ( n = 2 7 1), a n d Easter n C o o perati ve O nc ol o g y  Gr o u p 
( E C O G) perf or ma nc e stat us 1 or 2 ( n = 2 7 4) ( Yar dle y  20 1 3 ). T he s u b gr o u p a nal ys is i n Asia n 
patie nts i n B O L E R O -2 s h o we d me dia n P F S of 8. 4 8 m o nt hs i n e ver oli m us pl us e xe mesta ne 
ar m c o m pare d t o 4. 1 4 m o nt hs i n place b o pl us e xe mesta ne ar m (N o g uc hi et al 2 0 1 3 ). T he 
c o m bi nati o n t hera py re d uce d t he ris k of disease pr o gressi o n vers us e xe mesta ne al o ne b y  3 8 % 
a m o n g Asia n patie nts ( H R = 0. 6 2 ; 9 5 % CI, 0. 4 1-0. 9 4 ).


N o v arti s
C o nfi d e nti al
P a g e 3 6
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
O n 2 0- J ul- 2 0 1 2, F D A a p pr o ve d Afi nit or ® f or t he treat me nt of p ost me n o pa usal w o me n wit h
a d va nce d h or m o ne rece pt or-p ositi ve, H E R 2- ne gati ve breast ca ncer i n c o m bi nati o n wit h
e xe mesta ne, after fail ure of treat me nt wit h letr oz ole or a nastr oz ole. T he E C a p pr o ve d
Afi nit or ® o n 2 3- J ul- 2 0 1 2 f or t he treat me nt of h or m o ne rece pt or-p ositi ve, H E R 2/ ne u ne gati ve
a d va nce d breast ca ncer, i n c o m bi nati o n wit h e xe mesta ne, i n p ost me n o pa usal w o me n wit h o ut
s ym pt o matic 
visceral disease after rec urre nce or pr o gressi o n f oll o wi n g a n o n- ster oi dal
ar o matase i n hi bit or.
Base d o n t he res ults fr o m t he st u dies af ore me nti o ne d, t he N C C N g ui deli ne f or breast ca ncer
( Versi o n 3. 0,
2 0 1 2) has rec o m me n de d t he use of t he c o m bi nati o n of e ver oli m us a n d 
e xe mesta ne f or p ost me n o pa usal w o me n wit h H R + H E R 2 - A B C after fail ure of N S AI. I n li g ht 
of t he nee d f or t his ne w treat me nt o pti o n f or C hi nese patie nts, it is i m perati ve a n d reas o na ble 
t o c o n d uct a st u d y in C hi nese patie nts t o assess t he efficac y an d safet y of t he c o m bi nati o n of 
e ver oli m us a n d e xe mesta ne i n t his tar get p o p ulati o n. Gi ve n t he a vaila ble str o n g e vi de nce 
pr o vi de d b y  the B O L E R O - 2 st u d y, t he be nefit of e ver oli m us pl us e xe mesta ne i n t he tar get 
p o p ulati o n a n d als o i n t he Asia n s u b gr o u p are o b vi o us a n d ha ve bee n ac k n o wle d ge d. 
T heref ore, it is n ot necessar y t o d o a lar ge sa m ple size ra n d o mize d st u d y in C hi nese patie nts. 
T his p hase II, ra n d o mize d, c o ntr ol st u d y is t o meet C hi na re gistrati o n p ur p ose a n d t o c o nfir m 
t he efficac y a n d safet y of e ver oli m us pl us e xe mesta ne i n C hi nese patie nts.
2. 2
R ati o n al e f or t h e st u d y  d e si g n
T his is a p hase II, d o u ble - bli n d, place b o c o ntr olle d, m ultice nter st u d y co n d ucte d i n C hi na. 
T his 
st u d y 
desi g n 
is well -esta blis he d 
t o 
assess
t he 
efficac y 
a n d 
safety 
of 
e ver oli m us/e xe mesta ne c o m bi nati o n.
2. 3
R ati o n al e f or d o s e a n d r e gi m e n s el e cti o n
T he
selecti o n
of
t he 1 0
m g
c o nti n u o us d a il y d ose
f or e ver oli m us is base d
o n
a 
p har m ac o d y n a mi c m o del ( Ta na ka et al 2 0 0 8 ), w hic h
was
s u p p orte d b y res ults of a cli nical 
p har m ac o d y n a mi c st u d y i n patie nts wit h s oli d t u m ors (Ta ber ner o et al 2 0 0 8 ). T he 1 0 m g dail y 
d ose of e ver oli m us
was
fa v ore d o ver a 5
m g dail y d ose i n St u d y C 2 1 0 8, a P hase I st u d y 
c om bi ni n g e ver oli m us wit h letr ozole i n p ost me n o pa usal patie nts wit h a d va nce d breast ca ncer 
(A wa da et al 2 0 0 8 ). E ver oli m us 1 0
m g/ da y
was effecti vel y use d as m o n ot hera p y i n patie nts 
wit h
rec urre nt/m etastatic breast can cer (Ellar d et al 2 0 0 9 ). T he same
d ose of e ver olim us 
s h o we d p ositi ve efficac y o utc o me s i n c om bi nati o n wit h
letr oz ole as ne oa dj u va nt t hera p y i n 
patie nts wit h E R + earl y breast ca n cer a n d i n c o m bi nati o n wit h ta m o xi fen i n patie nt wit h A B C 
(Basel ga 2 0 0 9 , Bac hel ot 2 0 1 2 ). T his was
f urt her c orr ob or ate d b y resu lts fr o m B O L E R O - 2 
st u d y, w here
a dail y re gime n of 1 0
m g e ver oli m us i n c om bi nati o n wit h e xem esta ne 2 5
m g 
dail y was m ore efficaci o us t ha n e xem esta ne al o ne (Piccart et al 2 0 1 2 ).
T he rec o m me n de d dail y d ose of e xem esta ne is 2 5 m g via oral a dmi nistrati o n.
2. 4
R ati o n al e f or c h oi c e of c o m bi n ati o n dr u g s
Res ults i n B O L E R O - 2 st u d y d e m o nstrate d P F S be n efit of t he c om bi nat i o n of e ver oli m us a n d 
e xem esta ne c om pare d t o e xem esta ne al o ne i n p ost m e n o pa usal w o me n wit h
H R +
H E R 2- , 
A B C w h o has a rec urre nce or pr o gressi o n o n N S AI wit h acce ptabl e safet y pr ofile (Yar dle y et 


N o v arti s
C o nfi d e nti al
P a g e 3 7
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
al 2 0 1 3 ). T he a p pr o ve d d oses i n t he treat me nt of p ost me n o pa usal w o me n wit h H R + H E R 2 -
a n d A B C are 1 0 m g 
dail y  of e ver oli m us pl us 2 5 m g 
dail y of e xe mesta ne via oral 
a d mi nistrati o n.
2. 5
Ri s k s a n d b e n ef it s
T he ris k t o s u bjects i n t his trial ma y  be mi ni mize d b y  co m plia nce wit h t he eli gi bilit y criteria 
a n d st u d y pr oce d ures, cl ose cli nical m o nit ori n g, a n d d ose m o dificati o n, earl y ter mi nati o n 
pr oce d ure . T here ma y  be u nf oresee n ris ks wit h st u d y treat me nt w hich c o ul d be seri o us.


N o v arti s
C o nfi d e nti al
P a g e 3 8
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
3
O bj e cti v e s a n d e n d p oi nt s
T a bl e 3- 1
O bj e cti v e s a n d r el at e d e n d p oi nt s
O bj e cti v e
E n d p oi nt
A n al y si s
Pri m ar y
R ef er t o S e cti o n 1 0. 4 .
T o a s s e s s t h e c o m bi n ati o n 
tr e at m e nt of e v er oli m u s a n d 
e x e m e st a n e t o e x e m e st a n e a n d 
pl a c e b o wit h r e s p e ct t o 
pr o gr e s si o n -fr e e s ur vi v al
P F S , d efi n e d a s t h e ti m e fr o m t h e 
d at e of r a n d o mi z ati o n t o t h e d at e of 
t h e fir st d o c u m e nt e d pr o gr e s si o n 
( a s a s s e s s e d b y l o c al a s s e s s m e nt 
p er R E CI S T 1. 1) or d e at h d u e t o 
a n y c a u s e
S e c o n d ar y
R ef er t o S e cti o n 1 0. 5 .
T o a s s e s s t h e t w o tr e at m e nt ar m s 
wit h r e s p e ct t o P F S a s d et er mi n e d
b y a Bli n d e d I n d e p e n d e nt R e vi e w 
C o m mitt e e ( BI R C).
P F S , d efi n e d a s t h e ti m e fr o m t h e 
d at e of r a n d o mi z ati o n t o t h e d at e of 
t h e fir st d o c u m e nt e d pr o gr e s si o n 
( a s a s s e s s e d b y BI R C a s s e s s m e nt 
p er R E CI S T 1. 1) or d e at h d u e t o 
a n y c a u s e
T o a s s e s s t h e t w o tr e at m e nt ar m s 
wit h r e s p e ct t o o v er all s ur vi v al
O S, d efi n e d a s ti m e fr o m d at e of 
r a n d o mi z ati o n t o d at e of d e at h d u e 
t o a n y c a u s e
T o a s s e s s t h e t w o tr e at m e nt ar m s 
wit h r e s p e ct t o f oll o wi n g b a s e d o n 
l o c al i n v e sti g at or a s s e s s m e nt a n d 
BI R C

O v er all r e s p o n s e r at e ( O R R)

Cli ni c al b e n efit r at e ( C B R)

T o s u m m ari z e ti m e t o r e s p o n s e 
a n d d ur ati o n of r e s p o n s e i n t h e 
t w o tr e at m e nt ar m s
T h e f oll o wi n g e n d p oi nt s will b e 
e v al u at e d b y I n v e sti g at o r a n d BI R C 
a s s e s s m e nt p er R E CI S T 1. 1:

O R R , d efi n e d a s t h e pr o p orti o n 
of p ati e nt s wit h a b e st o v er all 
r e s p o n s e d efi n e d a s c o m pl et e 
r e s p o n s e ( C R) or p arti al 
r e s p o n s e ( P R); ( C R + P R)

C B R , d efi n e d a s t h e pr o p orti o n 
of p ati e nt s wit h b e st o v er all 
r e s p o n s e of c o m pl et e r e s p o n s e 
( C R), p arti al r e s p o n s e ( P R) or 
st a bl e di s e a s e ( S D) wit h 
d ur ati o n of 2 4 w e e k s or l o n g er .

Ti m e t o r e s p o n s e, d efi n e d a s 
t h e ti m e b et w e e n d at e of 
r a n d o mi z ati o n u ntil fir st 
d o c u m e nt e d r e s p o n s e ( C R or 
P R)

D O R, d efi n e d a s t h e ti m e fr o m 
d at e of fir st d o c u m e nt e d C R or 
P R t o d at e of fir st d o c u m e nt e d 
di s e a s e pr o gr e s si o n or d e at h 
d u e t o a n y c a u s e
Ti m e t o d et eri or ati o n of E C O G 
P erf or m a n c e St at u s
E C O G P S c at e g ori e s ar e d efi n e d i n 
S e cti o n 7. 2. 2 .
T o c h ar a ct eri z e t h e s af et y a n d 
t ol er a bilit y of e v er oli m u s a n d 
e x e m e st a n e v er s u s pl a c e b o a n d 
e x e m e st a n e i n all p ati e nt s
A d v er s e e v e nt s ( A E s ), E C G s a n d 
l a b or at or y a b n or m aliti e s


N o v arti s
C o nfi d e nti al
P a g e 3 9
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
O bj e cti v e
E n d p oi nt
A n al y si s
C h ar a ct eri z e t h e p h ar m a c o ki n eti c s 
of e v er oli m u s ( C mi n, C 2 h) w h e n 
a d mi ni st er e d i n c o m bi n ati o n wit h 
e x e m e st a n e
C o m p ar e t h e t w o tr e at m e nt ar m s 
wit h r e s p e ct t o pr e -d o s e 
c o n c e ntr ati o n ( C mi n) a n d 
c o n c e ntr ati o n at 2 h o ur s p o st d o s e 
( C 2 h) of e x e m e st a n e a n d t o 
c o m p ar e t h e t w o tr e at m e nt ar m s 
wit h r e s p e ct t o e str a di ol ( E 2) 
c h a n g e s fr o m b a s eli n e.
4
St u d y  d e si g n
4. 1
D e s cri pti o n of st u d y  d e si g n
T his is a m ultice nter, d o u ble -bli n d, ra n d o mize d, place b o -c o ntr olle d, p hase II st u d y eval uati n g 
treat me nt wit h e ver oli m us ( 1 0 m g dail y ) vers us place b o i n c o m bi nati o n wit h
e xe mesta ne 
( 2 5 m g 
dail y ) i n C hi nese p ost me n o pa usal w o me n wit h l ocall y ad va nce d, rec urre nt or 
metastatic E R p ositi ve H E R 2- ne gati ve breast ca ncer refract or y to n o n- ster oi dal ar o matase 
i n hi bit ors.
A p pr o xi m atel y 1 6 0 pat ie nts will be ra n d o mize d i n 1 : 1 rati o t o recei ve eit her e ver oli m us or 
matc hi n g place b o i n a bli n de d ma n ner i n a d diti o n t o o pe n la bel e xe mesta ne ( 2 5 m g dail y 
ta blets).
Scree ni n g p hase
Wr itte n i nf or me d c o nse nt m ust be o btai ne d bef ore a n y st u d y s pecific medical pr o ce dures ar e 
per f orme d. T he
i n vesti gat or or hi s/her a ut ho rize d desi g n ee will
assi g n a u ni q ue n u m ber
(s u bject n u m ber) t o patie nts bei n g c o nsi dere d f or t he st u d y. O nce
assi g ne d, t he s u bject
n u m bers f or patie nts will n ot be re use d.
T he
st u d y will
use I n teractive
Re s p o nse T e c h n ol o g y (I R T) f or patie nt
screen i n g a n d 
ma na g e ment of e ver oli m us
dr u g s u p pl y. E x e mesta ne will be s u p plie d l ocall y b y N o vartis i n 
acc or dan ce wit h t he c ou ntr y re gu lati o ns.
After t he patie nt si g ns t he i nf or me d c o nse nt a n d pri or t o t he first d ose of st u d y treat me nt, 
patie nts will be scree ne d i n I RT. A ll i ncl usi o n/e xcl usi o n criteria m ust be verifie d . Patie nts 
w h o d o n ot meet t he criteria will n ot be gi ve n t he st u d y treat me nt.
All scree ni n g assess me nts t o c o nfir m eli gi bilit y must be perf or me d wit hi n ma xi m u m 2 1 da y s
pri or t o t he first d ose of st u d y treat me nt (Ta ble 7 - 1 a n d Secti o n 7. 1 ).
Scree ni n g f or he patitis B
D uri n g
t he scree ni n g p hase, all patie nts s h o ul d be teste d f or he patitis B
viral l oa d a n d 
ser ol o gic mar kers of H B V -D N A, H Bs A g, H Bs A b, a n d H B c A b.


N o v arti s
C o nfi d e nti al
P a g e 4 0
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Patie nts wit h p ositi ve he patitis B res ults s h o ul d start pr o p h yl actic a nti viral treatme nt of 1 t o 2
wee ks pri or t o t he first d oses of t he st u d y treatme nt, a n d s h o ul d c o nti n ue f or at least 4 wee ks
after last d ose of st u d y treat me nt.
T he ma na ge me nt g ui deli nes, i n Secti o n 6. 3. 2. 3 , are pr o vi de d acc or di n g t o t he res ults of t he 
baseli ne assess me nt of viral l oa d a n d ser ol o gical mar kers f or he patitis B.
Scree ni n g f or he patitis C
Patie nt s wit h
a n y of t he foll o wi n g ris k f actors f or he patitis C
s h o ul d be teste d usi n g 
q ua ntitati ve R N A -P C R

k n o w n or s us pecte d past he patitis C i nfecti o n (i ncl u di n g patie nts wit h past i nterfer o n
‘c urati ve’ treat me nt),

bl o o d tra nsf usi o ns pri or t o 1 9 9 0,

c urre nt or pri or I V dr u g users,

c urre nt or pri or dial ys is,

h o use h ol d c o ntact of he patitis C i nfecte d patie nt(s),

c urrent or pr i or hi g h-r is k se x ual activ it y,

b o d y pierci n g or tatt o os,
At t he discreti o n of t he i n vestig at or, a d diti o nal patie nts ma y als o b e teste d f or he patitis C. T he
ma na ge me nt g ui deli nes, i n Secti o n 6. 3. 2. 3 , are pr o vi de d acc or di n g t o t he res ults of t he 
baseli ne assess me nt of he patitis C viral l oa d.
R a n d o mi z e d t r e at m e nt p h a s e
A ll eli gi ble patie nts will be ra n d o mize d wit hi n 7 da y s bef ore C ycl e 1 D a y 1 to o ne of t he t w o 
treat me nt ar ms: e ver oli m us
pl us e xe mesta ne ar m or place b o pl us e xe mesta ne ar m. 
Ra n d o mizati o n will be stratifie d acc or di n g t o t he prese nce of visceral disease a n d se nsiti vity 
t o pri or h or m o nal t hera p y stat us. Visceral refers t o l u n g, li ver, brai n, ple ural a n d perit o neal 
i n v ol ve me nt. Se nsiti vit y  to pri or h or m o nal t hera p y is defi ne d as eit her ( 1) d oc u me nte d 
cli nical be nefit (c o m plete res p o nse, par tial res p o nse, sta ble disease ≥2 4 wee ks) t o at least o ne 
pri or h or m o nal t hera py i n t he a d va nce d setti n g or ( 2) at least 2 4 m o nt hs of a dj u va nt h or m o nal 
t hera py pri or t o rec urre nce.
Ra n d o mize d p atie nts will start t he st u d y treat me nt at C y cle 1 Da y  1. Patie nts will recei ve 
e ver oli m us/ place b o ( 1 0 m g dail y  oral ta blets) i n a d diti o n t o e xe mesta ne ( 2 5 m g  dail y oral 
ta blets) c o nti n u o usl y. D ose a dj ust me nt (re d ucti o n, i nterr u pti o n) acc or di n g t o safety fi n di n gs 
will be all o we d (Secti o n 6. 3 ).
Patie nts will 
recei ve treat me nt u ntil disease pr o gressi o n (assesse d b y  
RE CI S T 1. 1), 
u nacce pta ble t o xicit y, deat h or disc o nti n uati o n fr o m treat me nt f or a n y ot her reas o n. T u m or 
assess me nts will 
be perf or me d e ver y 8 wee ks 
after ra n d o mizati o n u ntil ra di ol o gical 
pr o gressi o n per l ocal assess me nt . Tu m or assess me nts are t o be perf or me d e ver y 12 wee ks
after data c ut -off f or pri mar y  a nalys is a n d as cli nicall y i n dicate d, u ntil disease pr o gressi o n.
I ma gi n g data use d f or t u m or assess me nts d uri n g treat me nt p hase a n d f oll o w- u p p hase will be 
ce ntrall y c ollecte d , c hec ke d f or q ualit y  a n d re vie we d b y  a ce ntral ve n d or desi g nate d b y 


N o v arti s
C o nfi d e nti al
P a g e 4 1
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
N o vartis. T he ce ntral re vie w of t he sca ns will be carrie d o ut i n a bli n de d fas hi o n. T he decisi o n 
re gar di n g patie nt ma na ge me nt will re mai n wit h t he l ocal i n vesti gat or.
P o st -tr e at m e nt foll o w -u p p h a s e
After e n d of treat me nt visit, all patie nts will be f oll o we d u p f or safety u p t o 3 0 da y s afte r last 
d ose of st u d y treat me nt (e x e mesta ne a n d/ or e ver oli m us / place b o).
All patie nts w h o disc o nti n ue fr o m st u dy treat me nt d ue t o disease pr o gressi o n m ust ha ve t heir 
pr o gressi o n clear l y d oc u me nte d acc or di n g t o t he criteria s pecifie d i n R E CI S T 1. 1.
If
a patie nt
per ma ne ntl y
disc o nti n ue s st u dy treat me nt f or reas o ns ot her
t ha n disease
pr o gressi o n, deat h, l ost t o f oll ow- u p, or
wit h dra wal
of c o nse nt t o efficac y foll o w- u p t he n
t u m or assess me nts s h o uld c o nti n ue t o be perf or me d per assess me nt sc he d ule u ntil diseas e
pr o gressi o n, deat h, l ost t o f oll ow- u p or wit h dra wal of c o nse nt f or efficac y foll o w - u p.
A nti ne o plastic t hera py re gi me n recei ve d bet wee n E O T a n d pr o gressi o n will als o be c ollecte d 
as well as t he first re gi me n recei ve d after pr o gre ssi o n.
S ur vi v al f oll o w -u p p h a s e
All patie nts will be f oll o we d f or s ur vi val stat us at least e ver y 3 m o nt hs after ra n d o mize d 
treat me nt p hase or p ost -treat me nt f oll o w- u p p hase u nless t he y disc o nti n ue d d ue t o deat h, 
c o nse nt wit h dra wal or l ost t o f oll o w- u p. S ur vi val i nf or mati o n ca n be o btai ne d via p h o ne a n d 
i nf or mati o n will be d oc u me nte d i n t he s o urce d oc u me nts a n d e C R F. A d diti o nal s ur vi val 
assess me nts ma y  be perf or me d m ore fre q ue ntl y if a s ur vi val u p date is re q uire d f or re p orti n g 
t he res ults or t o meet safet y or re g ulat or y nee ds.


N o v arti s
C o nfi d e nti al
P a g e 4 2
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Fi g ur e 4- 1
St u d y  d e si g n


N o v arti s
C o nfi d e nti al
P a g e 4 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
4. 2
Ti mi n g of i nt eri m a n al y s e s a n d d e si g n a d a pt ati o n s
N ot a p plica ble.
4. 3
D efi niti o n of e n d of st u d y
T he pri mar y  anal ys is will occ ur w he n a p pr o xi matel y 1 1 0 P F S e ve nts ha ve bee n d oc u me nte d 
base d o n l ocal assess me nt (refer t o Secti o n 1 0. 4 ). At t his ti me, t he pri mar y  cli nical st u d y 
re p ort ( C S R) will be pr o d uce d.
After t he pri mar y  anal ys is of P F S, t he st u d y will re mai n o pe n pr o vi de d t he P F S de m o nstrates 
treat me nt be nefit. Patie nts still bei n g f oll o we d o n t he st u d y after t he pri mar y  anal y sis ti me 
p oi nt will c o nti n ue as per t he sc he d ule of assess me nts.
T he e n d of st u d y is defi ne d as t he earliest occ urre nce of o ne of t he f oll o wi n g:

All patie nts ha ve die d or disc o nti n ue d fr o m t he st u d y

A n ot her cli n ical st u dy or patie nt s u p p ort pr o gra ms bec o mes a vaila ble t hat ca n c o nti n ue t o 
pr o vi de Afi nit or i n t his patie nt p o p ulati o n a n d all patie nts o n g oi n g are eli gi ble t o be 
tra nsferre d t o t he m

Afi nit or has bee n a p pr o ve d f or t his i n dicati o n i n c o m bi nati o n wit h E xe mesta ne
T he fi nal a nal ys is of st u d y data will be c o n d ucte d at t he e n d of t he st u d y. All a vaila ble data 
fr o m all patie nts u p t o t his c ut off date will be a nal yze d.
4. 4
E arl y st u d y  t er mi n ati o n
T he st u d y ca n be ter mi nate d at a n y ti me f or a n y reas o n b y No vartis. S h o ul d t his be necessar y, 
t he patie nt will
be c o ntacte d b y t he i n vesti gat or or his/ her desi g nee . The patie nt s h o ul d be 
see n as s o o n as p ossi ble f or a n e n d of treat me nt visit / or e n d of p ost treat me nt f oll o w u p visit
a n d t he sa me assess me nts s h o ul d be perf or me d as descri be d i n Secti o n 7 f or a disc o nti n ue d or 
wit h dra w n patie nt. T he i n vesti gat or m a y  be i nf or me d of a d diti o nal pr oce d ures t o be f oll o we d 
i n or der t o e ns ure t hat a de q uate c o nsi derati o n is gi ve n t o t he pr otecti o n of t he patie nt’s 
i nterests. T he i n vesti gat or will be res p o nsi ble f or i nf or mi n g I RBs a n d/ or E Cs of t he earl y 
ter mi nati o n of t he trial.
5
P o p ul ati o n
5. 1
P ati e nt p o p ul ati o n
C hi nese P ost me n o pa usal w o me n wit h E R + H E R 2 - l ocally a d va nce d, rec urre nt, or me tastatic
breast ca ncer after rec urre nce or pr o gressi o n o n pri or letr oz ole or a nastr oz ole.
Patie nts
e nr olle d
i n t his st u d y are
n ot
pe r mitte d t o pa rtici pate i n a d diti o nal
parall el 
i n vesti gati o nal dr u g or de vice st udies. Patie nts w h o ha ve disc o nti n ue d t his st u d y w o n’t be re-
e nr olle d.
T he
i n vesti gat or or desi g nee m ust e ns ure t hat o nl y patie nts w h o
me et all t he f oll o wi n g 
i ncl usi o n a n d n o ne of t he e x cl usi o n criteria are offere d treatme nt i n t he st u d y.


N o v arti s
C o nfi d e nti al
P a g e 4 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
5. 2
I n cl u si o n crit eri a
Patie nts eli gi ble f or i ncl usi o n i n t his st u d y  ha ve t o meet all of t he f oll o wi n g criteria:
1.
W o me n ( 1 8 years or ol der) wit h l ocally a dva nce d, recu rre nt, or m etastatic br east ca ncer.
L o call y a d va nce d breast ca ncer m ust n ot be a m e na ble t o c urati ve treatme nt b y s ur ger y or
ra di ot hera py.
2.
Hist ol o gical or c yt ol o gical c o nfirma ti o n of estr o g e n-rece ptor p ositi v e ( ER + ) bre ast ca ncer
3.
P ost me n o pa usal w o m e n. P ost me n o p a usal stat us is defi ne d eit her b y:

Pri or bilateral o o p h orect o m y

Or a ge ≥6 0

Or a ge < 6 0 a n d a me n orr hea f or 1 2 or m ore m o nt hs (i n t he a bse nce of che m ot hera p y, 
ta m o xife n, t ore mife n, or o varia n s u p pressi o n), a n d F S H a n d estra di ol i n t he 
p ost me n o pa usal ra n ge (ser u m F S H > 4 0 mI U/ m L a n d estra di ol < 2 0 p g/ m L or acc or di n g t o 
t he p ost me n o pa usal ra n ge defi ne d by l ocal la b or at or y ).
F or w o me n wit h t hera p y- i n d uce d a me n orr hea, o o p h orect o my or serial meas ure me nts of
F S H a n d/ or estra di ol are nee de d t o e ns ure p ost me n o pa usal stat us.
N ote : O varia n ra diati o n or treat me nt wit h a l utei nizi n g h or m o n e-releasi n g h or m o ne ( LH- R H) 
a g o nist ( gosereli n acetate or le u pr oli de acetate) is n ot per mitte d f or i n d ucti o n of o varia n 
s u p pressi o n.
4.
Rec urre nce or pr o gressi o n o n pri or N S AI is defi ne d as:

Rec urre n ce w hile o n, or wit hi n o ne ye ar ( 1 2 m o nt hs) of e n d of a dj u va nt treatm e nt 
wit h letr ozole or a nastr oz ole
or

Pr o gressi o n w hile o n or wit hi n o ne m o nt h ( 3 0 da ys) of t he e n d of pri or treatme nt wit h 
letr oz ole or a nastroz ole
N otes:

Letr oz ole or a nastr oz ole d o n ot ha ve t o be t he last treat me nt pri o r t o t he e nr oll me nt i n t he
st u d y

Patie nts m ust ha ve im pr o ve d t o gra de 1 or better fr o m a n y a d verse e v e nts ( wit h e xce pti o n
of al o pecia) relate d t o pre v i o us t hera p y pri or t o e nroll m e nt
5.
Ra di ol o gical or o bjecti ve e vi de nce of rec urre nce or pr o gressi o n o n or after t he last 
s ystem ic t hera p y pri or t o e nr oll me nt
6.
Patie nts m ust ha ve rec o vere d t o gra de 1 fr o m a n y a d verse e ve nts (e xce pt al o pecia) relate d 
t o pri or t hera py pri or t o ra n d o mizati o n.
7.
Patie nt m ust ha ve as per R E CI S T 1. 1

meas ura ble disease
or

n o n- meas ura ble l ytic or mi xe d (l ytic + blastic) b o ne lesi o ns i n t he a bse nce of 
meas ura ble disease.
N ote : Meas ura ble 
lesi o ns i ncl u de l ytic or mi xe d
(ly tic + blastic) b o ne lesi o ns, wit h a n
i de ntifia ble s oft tiss ue c o m p o ne nt t hat meets t he meas ura bilit y
criteri a per R E C IS T 1. 1. 


N o v arti s
C o nfi d e nti al
P a g e 4 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Patie nts wit h o nl y n o n- meas ura ble lesi o ns (e. g. ple ural effusi o n, ascites) a n d n o l y tic or a mi x
of l y tic a n d blastic b o ne lesi o ns are n ot eli gi ble.
8.
Patie nt is a ble t o s wall o w a n d retai n oral me dicati o n
9.
Patie nt m ust meet t he f oll o wi n g la b orat or y  val ues at t he scree ni n g visit:

A bs ol ute Ne utr o p hil C o u nt ( A N C) ≥1. 5 x 1 0 9/ L

Platelets ≥1 0 0 x 1 0 9/ L

He m o gl o bi n ( H g b) ≥9 g/ d L

I N R≤2

Ser u m creati ni ne ≤1. 5 x U L N

T otal bilir u bi n ≤1. 5 x U L N ( ≤ 3 × U L N f or patie nts k n o w n t o ha ve Gil bert
S y n dr o me)

As partate tra nsa mi nase ( A S T) ≤ 2. 5 x U L N, e xce pt f or patie nts wit h li ver metastasis, 
w h o ma y  o nly be i ncl u de d if A S T ≤5. 0 x

Ala ni ne tra nsa mi nase ( A L T) ≤ 2. 5 x U L N, e xce pt f or patie nts wit h li ver metastasis, 
w h o ma y  o nly be i ncl u de d if A L T ≤5. 0 x U L N

Fasti n g ser u m c h olester ol ≤3 0 0 m g/ dl or 7. 7 5 m m ol/ L  a n d fasti n g tri glyc eri des ≤2. 5 
x U L N. I n case o ne or b ot h of t hese t hres h ol ds are e xcee de d, t he patie nt ca n o nl y  be
i ncl u de d after i nitiati o n of stati n t hera py a n d w he n t he a b o ve me nti o ne d val ues ha ve 
bee n ac hie ve d
1 0. Patie nt has a W H O perf or ma n ce status ≤2
1 1. Writte n i nf or me d c o nse nt m ust be o btai ne d pri or t o a n y  scree ni n g pr oce d ures.
5. 3
E x cl u si o n crit eri a
Patie nts eli gi ble f or t his st u d y  m ust n ot meet a n y of t he f oll o wi n g criteria:
1.
H E R 2- o vere x pressi n g patie nts b y  l ocal la b orat or y testi n g (I H C 3 + stai ni n g or i n sit u 
h y bri dizati o n p ositi ve), base d o n t he m ost rece nt test. N ote: Patie nts wit h I H C 2 + m ust 
ha ve a ne gati ve i n sit u h y bri dizati o n test .
2.
Patie nts w h o recei ve d m ore t ha n o ne c he m ot hera p y  li ne f or A B C
N ote: A c he m ot hera p y li ne i n a d va nce d dise ase is a n a ntica ncer re gi me n t hat c o ntai ns at least 
o ne c he m ot hera p y a ge nt a n d is gi ve n f or 2 1 da ys or l o n ger. If a c yt ot o xic c he m ot hera p y 
re gi me n was disc o nti n ue d f or a reas o n ot her t ha n disease pr o gressi o n a n d laste d less t ha n 2 1 
da y s, t he n t his re gi me n d oes n ot c o u nt as a " pri or li ne of c he m ot hera p y". C he m ot hera p y 
re gi me ns c o m p ose d of m ore t ha n o ne dr u g are c o nsi dere d as o ne li ne of t hera py.
3.
Patie nt wit h s y m pt o matic visceral disease a n d is ca n di date t o c he m ot hera p y
4.
Patie nts wit h o nl y  n o n-meas ura ble lesi o ns ot her t ha n l y tic or mi xe d (lyt ic a n d blastic)
b o ne metastasis (e. g. ple ural eff usi o n, ascites etc.)
5.
Pre vi o us treat me nt wit h e xem esta ne, m T O R i n hi bit ors, PI 3 K i n hi bit ors, A K T i n hi bit ors.
6.
K n o w n h y p erse nsiti vit y t o m T O R i nhi bit o rs, e. g. sir olim us (ra pam yci n)
7.
Patie nts w h o ha ve a hist or y  of a n ot her pri mar y mali g na nc y, wit h t he e xce pti o ns of n o n-
mela n o ma s ki n ca ncer, a n d carci n o ma i n sit u of t he cer vi x, uteri, or breast w h o ha ve bee n 
disease free f or ≥3 y ears


N o v arti s
C o nfi d e nti al
P a g e 4 6
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
8.
Ra di ot hera p y wit hi n f o ur wee ks pri or t o e nr oll me nt i n t he st u d y e xce pt i n case of 
l ocalize d palliati ve ra diot hera p y (f or a nal gesic p ur p ose) or f or l ytic lesio ns at ris k of 
fract ure w hic h was c o m plete d at least t w o wee ks pri or t o re gistrati o n i n t he c urre nt st u d y. 
Patie nts m ust ha ve rec o vere d fr o m ra di ot hera p y t o xicities.
9.
C urre ntl y recei vi n g a n y h or m o ne re placem e nt t hera p y, u nle ss disc o nti n ue d pri or t o 
re gistrati o n i n t he c urre nt st u d y.
1 0. Patie nts wit h ce ntral ner v o us s y ste m ( C N S) i n v ol ve me nt u nless t he y meet A L L of t he 
f oll o wi n g criteria:

At least 4 wee ks fr o m pri or t hera py c o m pleti o n (i ncl u di n g ra diati o n a n d/ or s ur ger y ) t o
starti n g t he st u d y treat me nt.

Cli nicall y  sta ble C N S lesi o ns at t he ti me of scree ni n g w hic h are u ntreate d or wit h o ut 
e vi de nce of pr o gressi o n f or at least 4 wee ks after treat me nt, as determi ne d b y  cli nical 
e xa mi nati o n a n d brai n i ma gi n g ( M RI or C T). Pa tie nts m ust n ot be treate d wit h 
ster oi ds f or brai n metastases d uri n g t he scree ni n g peri o d
1 1. Patie nts recei vi n g c o nc o m ita nt i m m u n os u p pressi ve a ge nts or c hr o nic c ortic oster oi ds use 
at t he time of s t u d y e ntr y e xce pt t o pical a p plicati o ns, i n hale d s pra ys, e ye dr o ps or l ocal 
i njecti o ns.
1 2. Bilat eral diff use l ym p ha n gitic carcin o ma t osis
1 3. Se verel y i m paire d l u n g f u ncti o n as defi ne d as s pir o metr y a n d D L C O t hat is 5 0 % or less of 
t he n or mal pre dicte d val ue a n d/ or O 2 sat urati o n t hat is 8 8 % or less at rest o n r o o m air
1 4. Patie nts w h o ha ve seri o us li ver disease s uc h as cirr h osis, dec o m pe nsate d li ver disease, a n d 
ac ute or c urre ntl y acti ve he patitis (i.e. q ua ntifia ble H B V- D N A a n d/ or p ositi ve H bs A g, 
q ua ntifia ble H C V -R N A)
1 5. Pa tie nts wit h a k n o w n hist or y of HI V ser o p ositi vit y. Scree ni n g f or HI V i nfecti o n at 
baseli ne is n ot re q uire d.
1 6. Acti ve, blee di n g diat hesis, or o n oral a nti-vita mi n K me dicati o n (e xce pt l o w d ose warfari n, 
L M W H a n d acet yl salicy li c aci d or e q ui vale nt , as l o n g as t he I N R is ≤2).
1 7. I m pair me nt of gastr oi ntesti nal ( GI) f u ncti o n or GI disease t hat ma y si g nifica ntl y alter t he 
a bs or pti o n of st u d y treat me nt.
1 8. U nc o ntr olle d dia betes mellit us as defi ne d b y H b A 1c > 7 % des pite a de q uate t hera p y . 
Patie nts wit h a k n o w n hist or y  of i m paire d fasti n g gl uc ose or dia betes mellit us ( D M) ma y  
be i ncl u de d, h o we ver , bl o o d gl uc ose a n d a nti dia betic treat me nt m ust be m o nit ore d cl osel y 
t hr o u g h o ut t he trial a n d a dj uste d as necessar y;
1 9. Acti ve ulcerati o n of t he u p per gastr oi ntesti nal tract.
2 0. A n y se vere a n d / or u nc o n tr olle d me dical c o n diti o ns s uc h as
a.
u nsta ble a n gi na pect oris, s y m pt o matic c o n gesti ve heart fail ure, m y ocar dial i nfarcti o n 
≤6 m o nt hs pri or t o ra n d o mizati o n, seri o us u nc o ntr olle d car diac arr h yt h mia,
b.
acti ve or u nc o ntr olle d se vere i nfecti o n,
2 1. Patie nts bei n g treate d wit h dr u gs rec o g nize d as bei n g str o n g i n hi bit ors or i n d ucers of t he 
is oe nz ym e C Y P 3 A 4 ( Rifa b uti n, Ri fam pici n, Clarit hr o m yci n, Ket oc o naz ole, Itrac o nazole, 
V oric o naz o le, Rit o na vir, Telit h r om y ci n) c on ti nu o usl y for at least 7 d a y s d uri n g a n y tim e 
peri o d i n t he last 2 wee ks pri or t o re gistrati o n i n t he c urre nt st u d y


N o v arti s
C o nfi d e nti al
P a g e 4 7
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
2 2. Patie nts w h o ha ve recei ve d li ve atte n uate d vacci nes wit hi n 1 wee k of start of st u d y  dr u g 
a n d d uri n g t he st u d y. Patie nt s h o ul d als o a v oi d cl ose c o ntact wit h ot hers w h o ha ve 
recei ve d li ve atte n uate d vacci nes. E xa m ples of li ve atte n uate d vacci nes i ncl u de i ntra nasal 
i nfl ue nza, measles, m u m ps, r u bella, oral p oli o, B C G, yell o w fe ver, varicella a n d T Y 2 1a 
t yp h oi d vacci nes;
2 3. Hist or y of n o nc o m plia nce t o medical re gime ns
2 4. Patie nts u n will i n g t o or u na ble t o c o mpl y wit h t he pr ot oc ol
2 5. Patie nts w h o are c urre ntl y  part of or ha ve partici pate d i n a n y cli nical i n vesti gati o n wit h a n 
i n vesti gati o nal dr u g wit hi n 1 m o nt h pri or t o d osi n g
6
Tr e at m e nt
6. 1
St u d y tr e at m e nt
T he i n vesti gati o nal dr u g use d i n t he c ourse of t his trial is e ver oli m us. I n a d diti o n, all patie nts
will recei ve o pe n la bel e xe mesta ne. F or t his st u d y, t he ter m “ St u d y treat me nt” is defi ne d as 
e ver oli m us + e xe mesta ne or place b o + e xe mesta ne. St u d y  dr u g is defi ne d as e ver oli m us or 
matc hi n g place b o .
I n b ot h treat me nt ar ms, t he st u d y dr u g will be a d mi nistere d b y co nti n u o us oral dail y d osi n g of
2 × 5 m g ta blets eac h m or ni n g . F or t he list of e xci pie nts, please refer t o c urre nt [In vesti gat or’s 
Br oc h ure].
6. 1. 1
D o si n g r e gi m e n
All patie nts will ta ke e veroli m us / place b o as a d ail y  dose of 1 0 m g  (2 × 5 m g ta blets at sa me 
ti me) orall y  co nti n u o usl y  per d a y  an d e xe mesta ne 2 5 m g 
( o ne ta blet) orall y  per d a y .
E ver oli m us
ta blets s h o ul d be s wall o we d w h ole
wit h
a glass of water
o nce dail y . Ta blets 
s h o ul d n ot be c he we d or cr us he d. E xe m esta ne will
be self-a d mi nistere d as descri be d i n
Ta ble 6- 1 a n d ta ke n t o get her wit h e ver oli m us. B ot h dr u gs will be ta ke n after a meal at t he 
sa me ti me eac h da y i n t he m or ni n g.
T a bl e 6- 1
D o s e a n d tr e at m e nt s c h e d ul e
St u d y  tr e at m e nt s
P h ar m a c e uti c al f or m a n d 
r o ut e of a d mi ni str ati o n
D o s e
Fr e q u e n c y  a n d/ or 
R e gi m e n
e v er oli m u s / pl a c e b o
T a bl et s f or or al u s e
1 0 m g ( 2 × 5 m g)
D ail y
e x e m e st a n e
T a bl et s f or or al u s e
2 5 m g
D ail y
6. 1. 2
A n cill ar y  tr e at m e nt s
N ot a p plica ble.
6. 1. 3
R e s c u e m e di c ati o n
N ot a p plica ble.
6. 1. 4
G ui d eli n e s f or c o nti n u ati o n of tr e at m e nt
F or g ui deli nes f or c o nti n uati o n of treat me nt, refer t o Secti o n 6. 3 D osi n g m o dificati o ns.


N o v arti s
C o nfi d e nti al
P a g e 4 8
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Patie nts w h o per ma ne ntl y disc o nti n u e o ne of t he st u d y treat me nts f or a n y reas o n ot her t ha n
disease pr o gressi o n ma y co nti n ue t he ot her st u dy treat me nt as part of t he trial t herap y at t he
i n vesti gat ors discreti o n 
u ntil 
disease
pr o gressi o n, 
u nacce pta ble
t o xicity,
deat h
or
disc o nti n uati o n fr o m st u dy treat me nt d ue t o a n y ot her reas o n a n d s h o uld f oll o w t he pr ot oc ol
safety a n d efficac y assess me nts as sc he d ule d. After
disc o nti n ui n g st u dy treat me nt, f urt her
treat me nt is left t o t he p h y sicia n’s discretio n.
6. 1. 5
Tr e at m e nt d ur ati o n
Patie nts ma y  be disc o nti n ue d fr o m treat me nt earlier d ue t o:

Disease pr o gressi o n acc or di n g t o R E CI S T 1. 1 as deter mi ne d b y  i n vesti gat or.

U nacce pta ble t o xicit y

Disc o nti n ue d treat me nt at t he discreti o n of t he i n vesti gat or or t he patie nt

Deat h

Patie nt is l ost t o f oll o w -u p

W it hdr a w t he c onse nt

Pr ot oc ol de viati o n

St u d y  ter mi nati o n b y s p o ns or

Tec h nical pr o ble ms
6. 2
D o s e e s c al ati o n g ui d eli n e s
N ot a p plica ble.
6. 3
D o s e m o difi c ati o n s
6. 3. 1
D o s e m o difi c ati o n a n d d o s e d el a y
E v er oli m u s
F or patie nts w h o d o n ot t olerate t he pr ot oc ol -s pecifie d d osi n g sc he d ule, d ose a dj ust me nts are 
per mitte d i n or der t o all o w t he patie nt t o c o nti n ue t he st u d y treat me nt. T he f oll o wi n g 
g ui deli nes ma y  be a p plie d:
If d ose re d ucti o n is re q uire d, t he s u g geste d d ose is a p pr o xi matel y 50 % l o wer t ha n t he dail y 
d ose pre vi o usl y  ad mi nistere d (Ta ble 6- 2 ). If a patie nt has alrea d y decrease d 2 d ose le vels, n o 
f urt her d ose re d ucti o n is per mitte d.
Patie nts re q uiri n g a n a d diti o nal d ose re d ucti o n will be re q uire d t o disc o nti n ue st u d y  treat me nt. 
Patie nts w h o i nterr u pt t hera p y f or m ore t ha n 4 wee ks m ust be disc o nti n ue d fr o m t he st u d y.
T hese c ha n ges m ust be rec or de d o n t he D osa ge A d mi nistrati o n Rec or d C R F.
T a bl e 6- 2
R e c o m m e n d ati o n of e v er oli m u s d o s e r e d u cti o n s
D o s e l e v el
D o s e a n d s c h e d ul e
0 = st arti n g d o s e
-1 d o s e l e v el
-2 d o s e l e v el
1 0 m g d ail y
5 m g d ail y
5 m g e v er y ot h er d a y


N o v arti s
C o nfi d e nti al
P a g e 4 9
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
All d ose m o dificati o ns s h o ul d be base d o n t he w orst prece di n g t o xicit y .
Eac h patie nt is o nl y all o we d 2 d ose re d ucti o ns. I n a d diti o n, a patie nt m ust disc o nti n ue 
treat me nt wit h e ver oli m us/ place b o if, after treat me nt is res u me d at a l o wer d ose, t he t o xicit y 
rec urs wit h t he sa me or w orse se verity. Patie nts w h o i nterr u pt t hera py f or m ore t ha n 4 wee ks 
m ust be per ma ne ntl y disc o nti n ue d fr o m t he st u d y treat me nt.
G ui deli nes f or d ose m o dificati o n a n d d ose i nterr u pti o n of e ver oli m us/ place b o are descri be d i n
Ta ble 6 - 3.
T he i n vesti gat ors are als o a d vise d t o c o ns ult t he latest versi o n of t he [I n vesti gat or‘s Br oc h ure].
O bj ecti ves a n d relate d e n d p oi nts are desc ri be d i n Ta ble 3 - 1 bel o w.
T a bl e 6- 3
Crit eri a f or i nt err u pti o n a n d r e -i niti ati o n of e v er oli m u s/ pl a c e b o
tr e at m e nt
R e c o m m e n d e d d o s e m o difi c ati o n s f or e v er oli m u s/ pl a c e b o
W o r st t o xi cit y
C T C A E Gr a d e ( v al u e)
D uri n g a c y cl e of t h er a p y
H e m at ol o gi c
N e utr o p e ni a ( A N C)
Gr a d e 1 ( A N C < L L N - 1 5 0 0/ m m 3 )
M ai nt ai n d o s e l e v el
Gr a d e 2 ( A N C < 1 5 0 0 - 1 0 0 0/ m m 3 )
M ai nt ai n d o s e l e v el
Gr a d e 3 ( A N C < 1 0 0 0 - 5 0 0/ m m 3 )
O mit d o s e u ntil r e s ol v e d t o ≤ Gr a d e 2, t h e n m ai nt ai n d o s e l e v el
Gr a d e 4 ( A N C < 5 0 0/ m m 3 )
O mit d o s e u ntil r e s ol v e d t o ≤ Gr a d e 2, t h e n ↓1 d o s e l e v el
T hr o m b o c y t o p e ni a
Gr a d e 1 ( P L T < L L N - 7 5, 0 0 0/ m m 3 )
M ai nt ai n d o s e l e v el
Gr a d e 2 ( P L T < 7 5, 0 0 0 - 5 0, 0 0 0/ m m 3 )
T e m p or ar y d o s e i nt err u pti o n u ntil r e c o v er y t o Gr a d e 1.
R e -i niti at e e v er oli m u s at t h e s a m e d o s e.
Gr a d e 3 ( P L T < 5 0, 0 0 0 - 2 5, 0 0 0/ m m 3 )
T e m p or ar y d o s e i nt err u pti o n u ntil r e c o v er y t o Gr a d e ≤1.
R e -i niti at e tr e at m e nt at a l o w er d o s e.
Gr a d e 4 ( P L T < 2 5, 0 0 0/ m m 3 )
T e m p or ar y d o s e i nt err u pti o n u ntil r e c o v er y t o Gr a d e ≤1.
R e -i niti at e tr e at m e nt at a l o w er d o s e.
F e bril e n e utr o p e ni a
Gr a d e 3
( A N C < 1. 0 x 1 09 / L wit h si n gl e 
t e m p er at ur e > 3 8. 3° C ( 1 0 1° F)
or s u st ai n e d t e m p er at ur e ≥3 8° C 
( 1 0 0. 4° F) f or > 1 h)
T e m p or ar y d o s e i nt err u pti o n u ntil r e c o v er y of ( A N C≥1. 2 5 x 1 0 9 /l) a n d n o 
f e v er.
R e -i niti at e e v er oli m u s at a l o w er d o s e.
Gr a d e 4
( Lif e-t hr e at e ni n g c o n s e q u e n c e s; 
ur g e nt i nt er v e nti o n i n di c at e d)
Di s c o nti n u e e v er oli m u s.
A n y h e m at ol o gi c t o xi cit y r e q uiri n g 
st u d y dr u g i nt err u pti o n f or > 2 8 d a y s
Di s c o nti n u e e v er oli m u s.
H e p ati c
I s ol at e d A S T or A L T el e v ati o n
> U L N - 3. 0 × U L N
M ai nt ai n d o s e l e v el


N o v arti s
C o nfi d e nti al
P a g e 5 0
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
R e c o m m e n d e d d o s e m o difi c ati o n s f or e v er oli m u s/ pl a c e b o
W o r st t o xi cit y
C T C A E Gr a d e ( v al u e)
D uri n g a c y cl e of t h er a p y
> 3. 0 - 5. 0 × U L N
F or p ati e nt s wit h b a s eli n e v al u e ≤3. 0 
× U L N
F or p ati e nt s wit h b a s eli n e v al u e > 3. 0 
-5. 0 × U L N
M ai nt ai n d o s e l e v el. R e p e at
L F T s b a s s o o n a s p o s si bl e, pr ef er a bl y 
wit hi n 4 8 -7 2 h o ur s fr o m a w ar e n e s s of t h e a b n or m al r e s ult s ; if a b n or m al 
l a b v al u e s ar e c o nfir m e d u p o n t h e r e p e at t e st, t h e n m o nit or L F T sb
w e e kl y, or m or e fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤3. 0 × 
U L N
M ai nt ai n d o s e l e v el
> 5. 0 - 1 0. 0 × U L N
F or p ati e nt s wit h b a s eli n e v al u e ≤ 3. 0 
× U L N
F or p ati e nt s wit h b a s eli n e v al u e > 3. 0 
-5. 0 × U L N
O mit d o s e. R e p e at L F T s b a s s o o n a s p o s si bl e, pr ef er a bl y wit hi n 4 8- 7 2 
h o ur s fr o m a w ar e n e s s of t h e a b n or m al r e s ult s; m o nit or L F T s b w e e kl y, or 
m or e fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤3. 0 × U L N. T h e n
If r e s ol v e d i n ≤1 4 d a y s, m ai nt ai n d o s e l e v el
If r e s ol v e d i n > 1 4 d a y s, ↓1 d o s e l e v el
M ai nt ai n d o s e l e v el. R e p e at L F T s
b a s s o o n a s p o s si bl e, pr ef er a bl y 
wit hi n 4 8 -7 2 h o ur s fr o m a w ar e n e s s of t h e a b n or m al r e s ult s; if a b n or m al 
l a b v al u e s ar e c o nfir m e d u p o n t h e r e p e at t e st, t h e n m o nit or L F T sb , 
w e e kl y, or m or e fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤5. 0 × 
U L N
> 1 0. 0 - 2 0. 0 × U L N
O mit d o s e. R e p e at L F T s b a s s o o n a s p o s si bl e, pr ef er a bl y wit hi n 4 8- 7 2 
h o ur s fr o m a w ar e n e s s of t h e a b n or m al r e s ult s ; m o nit or L F T sb w e e kl y, or 
m or e fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤b a s eli n e. T h e n ↓
1 d o s e l e v el.
> 2 0. 0 × U L N
O mit d o s e. R e p e at L F T s b a s s o o n a s p o s si bl e, pr ef er a bl y wit hi n 4 8- 7 2 
h o ur s fr o m a w ar e n e s s of t h e a b n or m al r e s ult s; m o nit or L F T s b w e e kl y, or 
m or e fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤3 x U L N ( or ≤5 
× U L N f or p ati e nt s wit h b a s eli n e v al u e > 3. 0 -5. 0 × U L N), t h e n r e s u m e 
tr e at m e nt at ↓1 d o s e l e v el. O nl y 1 d o s e r e d u cti o n i s all o w e d; if r e o c c ur s 
at > 5 × U L N, di s c o nti n u e p ati e nt fr o m st u d y tr e at m e nt.
C o m bi n e d c el e v ati o n s of A S T or A L T a n d t ot al bilir u bi n
F or p ati e nt s wit h n or m al b a s eli n e A L T 
a n d A S T a n d t ot al bilir u bi n v al u e:
A S T or A L T > 3. 0 x U L N c o m bi n e d wit h 
t ot al bilir u bi n > 2. 0 x U L N wit h o ut 
e vi d e n c e of c h ol e st a si s d
O R
( N ot e t o st u d y t e a m: If s u p p ort e d b y 
a v ail a bl e d at a)
F or p ati e nt s wit h el e v at e d b a s eli n e 
A S T or A L T or t ot al bi lir u bi n v al u e
[ A S T or A L T > 2 x b a s eli n e A N D > 3. 0 
x U L N] O R [ A S T or A L T > 8. 0 x U L N], 
c o m bi n e d wit h [t ot al bilir u bi n > 2 x 
b a s eli n e A N D > 2. 0 × U L N]
P er m a n e ntl y di s c o nti n u e p ati e nt fr o m st u d y tr e at m e nt.
R e p e at a s s o o n a s p o s si bl e, pr ef er a bl y wit hi n 4 8 h o ur s fr o m a w ar e n e s s 
of t h e a b n or m al r e s ult s, t h e n wit h w e e kl y m o nit ori n g of L F T s b ), or m or e 
fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil A S T, A L T, or bilir u bin h a v e r e s ol v e d 
t o b a s eli n e or st a bili z ati o n o v er 4 w e e k s. R ef er t o S e cti o n 6. 3. 2. 1 f or 
a d diti o n al f oll o w -u p e v al u ati o n s a s a p pli c a bl e.
M et a b oli c
( e. g. h y p e r gly c e m i a, d y s lipi d e mi a)
Gr a d e 1
M ai nt ai n d o s e l e v el , initi at e a p pr o pri at e m e di c al t h er a p y a n d m o nit or
Gr a d e 2
M ai nt ai n d o s e l e v el ,
ma n a g e wit h a p pr o pri at e
m e di c al t h er a p y a n d 
m o nit or
Gr a d e 3
O mit d o s e u ntil r e s ol v e d t o ≤gr a d e 1, t h e n ↓1 d o s e l e v el
Gr a d e 4
D i s c o nti n u e p ati e nt fr o m st u d y tr e at m e nt, a n d tr e at wit h a p pr o pri at e 
m e di c al


N o v arti s
C o nfi d e nti al
P a g e 5 1
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
R e c o m m e n d e d d o s e m o difi c ati o n s f or e v er oli m u s/ pl a c e b o
W o r st t o xi cit y
C T C A E Gr a d e ( v al u e)
D uri n g a c y cl e of t h er a p y
N o n -i nf e cti o u s p n e u m o niti s
S e e S e cti o n 6. 3. 2. 1 .
St o m atiti s
S e e S e cti o n 6. 3. 2. 2 .
Ot h er n o n -h e m at ol o gi c t o xi citi e s
( e x cl u di n g m et a b oli c e v e nt s)
Gr a d e 1
If t o xi cit y i s t ol er a bl e, n o d o s e a dj u st m e nt r e q uir e d.
I niti at e a p pr o pri at e m e di c al t h er a p y a n d m o nit or.
Gr a d e 2
If t o xi cit y i s t ol er a bl e, n o d o s e a dj u st m e nt r e q uir e d.
I niti at e a p pr o pri at e m e di c al t h er a p y a n d m o nit or.
If t o xi cit y b e c o m e s i nt ol er a bl e, t e m p or ar y d o s e i nt err u pti o n u ntil r e c o v er y 
t o Gr a d e 1. R e -i niti at e e v er oli m u s at t h e s a m e d o s e.
If t o xi cit y r e c ur s at Gr a d e 2, i nt err u pt e v er oli m u s u ntil r e c o v er y t o Gr a d e 
1. R e -i niti at e e v er oli m u s at a l o w er d o s e.
Gr a d e 3
T e m p or ar y d o s e i nt err u pti o n u ntil r e c o v er y t o Gr a d e 1.
I niti at e a p pr o pri at e m e di c al t h er a p y a n d m o nit or.
C o n si d er r e -i niti ati n g e v er oli m u s at a l o w er d o s e.
If t o xi cit y r e c ur s at Gr a d e 3, c o n si d er di s c o nti n u ati o n.
Gr a d e 4
Di s c o nti n u e e v er oli m u s a n d tr e at wit h a p pr o pri at e m e di c al t h er a p y.
All d o s e m o difi c ati o n s s h o ul d b e b a s e d o n t h e w or st pr e c e di n g t o xi cit y.
a C o m m o n T o xi cit y Crit eri a f or A d v er s e E v e nt s ( C T C A E V er si o n 4. 0 3 )
b C or e L F T s c o n si st of A L T, A S T, G G T, t ot al bilir u bi n (fr a cti o n at e d [ dir e ct a n d i n dir e ct], if t ot al bilir u bi n > 2. 0 × 
U L N), a n d al k ali n e p h o s p h at a s e (fr a cti o n at e d [ q u a ntifi c ati o n of i s of or m s], if al k ali n e p h o s p h at a s e > 2. 0 × U L N.)
c “ C o m bi n e d” d efi n e d a s t ot al bilir u bi n i n cr e a s e t o t h e d efi n e d t hr e s h ol d c o n c urr e ntl y wit h A L T/ A S T in cr e a s e t o t h e 
d efi n e d t hr e s h ol d
If c o m bi n e d el e v ati o n s of A S T or A L T a n d t ot al bilir u bi n d o n ot m e et t h e d efi n e d t hr e s h ol d s, pl e a s e f oll o w t h e 
i n str u cti o n s f or i s ol at e d el e v ati o n of t ot al bilir u bi n a n d i s ol at e d el e v ati o n of A S T/ A L T, a n d t a k e a c o n s er v ati ve 
a cti o n b a s e d o n t h e d e gr e e of t h e el e v ati o n s ( e. g. di s c o nti n u e tr e at m e nt at t h e sit u ati o n w h e n o mit d o s e i s 
n e e d e d f or o n e p ar a m et er a n d di s c o nti n u e tr e at m e nt i s r e q uir e d f or a n ot h er p ar a m et er). Aft er all el e v ati o n s 
r e s ol v e t o t h e d efi n e d t hr e s h ol d s t h at all o w tr e at m e nt r e -i niti ati o n, r e- st art t h e tr e at m e nt eit h er at t h e s a m e d o s e or 
at o n e d o s e l o w er if m e eti n g a crit eri o n f or d o s e r e d u cti o n
6. 3. 2
A d diti o n al m a n a g e m e nt a n d f oll o w - u p f or s el e ct e d t o xi citi e s
6. 3. 2. 1
M a n a g e m e nt of i nf e cti o n s
E ver oli m us has i m m u n os u p pressi ve pr o perties a n d m a y  pre dis p ose patie nts t o bacterial, 
f u n gal, viral or pr ot oz oal i nfecti o ns, i ncl u di n g i nfecti o ns wit h o p p ort u nistic pat h o ge ns. 
L ocalize d a n d s yste mic i nfecti o ns, i ncl u di n g p ne u m o nia, ot her bacterial i nfecti ons, i n vasi ve 
f u n gal i nfecti o ns, s uc h as as per gill osis, ca n di diasis or p ne u m oc y stis jir o vecii p ne u m o nia ( PJ P)
a n d viral i nfecti o ns i ncl u di n g reacti vati o n of he patitis B vir us, ha ve bee n descri be d i n patie nts 
ta ki n g e ver oli m us. S o me of t hese i nfecti o ns ha ve bee n se vere (e. g. lea di n g t o se psis, 
res pirat or y or he patic fail ure) a n d occasi o nall y ha ve ha d a fatal o utc ome.
P h y sicia ns a n d patie nts s h o ul d be a ware of t he i ncrease d ris k of i nfecti o n wit h e ver oli m us. 
Treat pre -e xisti n g i nfecti o ns pri or t o starti n g treat me nt wit h e ver oli m us. W hile 
ta ki n g 
e ver oli m us, be vi gila nt f or s ym pt o ms a n d si g ns of i nfecti o n; if a dia g n osis of i nfecti o n is 
ma de, i nstit ute a p pr o priate treat me nt pr o m ptl y  an d c o nsi der i nterr u pti o n or disc o nti n uati o n of 
e ver oli m us.


N o v arti s
C o nfi d e nti al
P a g e 5 2
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Patie nts wit h p ositi v e res ults of H B V -D N A a n d/ or H Bs A g at scree ni n g s h o ul d be gi n a 
pr o p h y la xis treat me nt f or 1- 2 wee k pri or t o be gi n ni n g e ver oli m us t hera p y. Patie nts s h o ul d 
ha ve H B V -D N A m o nit ore d fre q ue ntly t hr o u g h o ut t he c o urse of e ver oli m us t hera py f or si g ns 
of he patitis rea cti vati o n.
If a dia g n osis of i n vasi ve s yste mic f u n gal i nfecti o n is ma de, disc o nti n ue e ver oli m us a n d treat 
wit h a p pr o priate a ntif u n gal t hera p y.
Cases of PJ P, s o me wit h fatal o utc o me, ha ve bee n re p orte d i n patie nts w h o recei ve d 
e ver oli m us. PJ P ma y  be ass ociate d wit h 
c o nc o mita nt use of c ortic oster oi ds or ot her 
i m m u n os u p pressi ve a ge nts. Pr o p h y la xis f or PJ P s h o ul d be c o nsi dere d w he n c o nc o mita nt use 
of c ortic oster oi ds or ot her i m m u n os u p pressi ve a ge nts is re q uire d.
6. 3. 2. 2
M a n a g e m e nt of n o n -i nf e cti o u s p n e u m o niti s
N o n -i nfecti o us p ne u m o nitis is a k n o w n si de effect of ra pa myci n a nal o g ues. Cli nicall y
si g nifica nt p ne u m o nitis is t ypicall y acc o m pa nie d b y  no n-s pecific s ym pt o ms 
i ncl u di n g
d y s p nea, n o n pr o d ucti ve c o u g h, fati g ue, a n d fe ver. Dia g n osis is ge nerall y s us pecte d i n
i n di vi d uals recei vi n g m T O R i n hi bit ors w h o de vel o p t hese s ym pt o ms or i n as ym pt o matic
i n di vi d uals i n w h o m a r o uti ne c hest C T sca n re veals a ne w gr o u n d glass or al ve olar i nfiltrate.
T he fre q ue nc y of s ym pt o matic p ul m o nar y  to xicit y  (all gra des) was a p pr o xi matel y 13 % i n a
p hase 
III st u d y 
of e ver oli m us i n patie nts 
wit h 
metastatic 
re nal cell carci n o ma
[ C R A D 0 0 1 C 2 2 4 0]. Se vere ( C T C gra de 3) p ne u m o nitis occ urre d i n 4 % of patie nts, a n d a n
occasi o nal fatalit y was re p orte d. T he l u n g t o xicit y was partl y or c o m pletel y re versi ble i n t he
maj orit y  of cases wit h i nter ve nti o ns i ncl u di n g dr u g i nterr u pti o n, disc o nti n uati o n a n d t he use
of c ortic oster oi ds.
I n di vi d uals partici pati n g i n t his trial will be r o uti nel y q uesti o ne d as t o t he prese nce of ne w or
c ha n ge d p ul m o nar y  sy m pt o ms c o nsiste nt wi t h l u n g t o xicit y. C T sca ns a n d p ul m o nar y
f u ncti o n test s h o ul d be d o ne, as cli nicall y i n dicate d, if t here are s ym pt o ms t hat i n dicate t hat
t he patie nt has de vel o pe d n o n-i nfecti o us p ne u m o nitis. If n o n-i nfecti o us p ne u m o nitis de vel o ps,
t he g ui deli nes i n Ta ble 6- 4 s h o ul d be f oll o we d. D ose m o dificati o n i nstr ucti o ns are als o
pr o vi de d i n Ta ble 6- 4 . C o ns ultati o n wit h a p ul m o n ol o gist is rec o m me n de d f or a n y case of
p ne u m o nitis t hat de vel o ps d uri n g t he st u d y.


N o v arti s
C o nfi d e nti al
P a g e 5 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a bl e 6- 4
M a n a g e m e nt of n o n -i nf e cti o u s p n e u m o niti s
W or st Gr a d e
P n e u m o niti s
R e q uir e d I n v e sti g ati o n s
M a n a g e m e nt of
P n e u m o niti s
E V E R O LI M U S/ pl a c e b o 
D o s e
A dj u st m e nt
Gr a d e 1
C T s c a n s wit h l u n g wi n d o w s. 
R e p e at at l e a st e v er y 8 
w e e k s u ntil r et ur n t o wit hi n 
n or m al li mit s.
N o s p e cifi c t h er a p y i s 
r e q uir e d
A d mi ni st er 1 0 0 % of st u d y
tr e at m e nt d o s e.
Gr a d e 2
C T s c a n wit h l u n g wi n d o w s. 
C o n si d er p ul m o n ar y f u n cti o n 
t e sti n g i n cl u d e s: s pir o m etr y, 
D L C O, a n d r o o m air O 2
s at ur ati o n at r e st. R e p e at at 
l e a st e v er y 8 w e e k s u ntil 
r et ur n t o wit hi n n or m al li mit s. 
C o n si d er a br o n c h o s c o p y 
wit h bi o p s y a n d / or B A L.
S y m pt o m ati c o nl y. C o n si d er 
c orti c o st er oi d s if s y m pt o m s 
ar e tr o u bl e s o m e.
R e d u c e st u d y tr e at m e nt
d o s e b y 1 d o s e l e v el ( s e e
T a bl e 6 - 2) u ntil r e c o v er y t o 
< Gr a d e 1. St u d y tr e at m e nt 
m a y al s o b e i nt err u pt e d if 
s y m pt o m s ar e tr o u bl e s o m e. 
P ati e nt s wi ll di s c o nti n u e 
st u d y tr e at m e nt if t h e y f ail 
t o r e c o v er t o < Gr a d e 1 
wit hi n 2 8 d a y s.
Gr a d e 3
C T s c a n wit h l u n g wi n d o w s 
p ul m o n ar y f u n cti o n t e sti n g 
i n cl u d e s: s pir o m etr y, D L C O, 
a n d r o o m air O 2 s at ur ati o n at 
r e st. R e p e at at l e a st e v er y 6 
w e e k s u ntil r et ur n t o wit hi n 
n or m al li mit s. Br o n c h o s c o p y 
wit h bi o p s y a n d / or B A L i s
r e c o m m e n d e d.
C o n si d er c orti c o st er oi d s if 
i nf e cti v e ori gi n i s r ul e d o ut. 
T a p er a s m e di c all y i n di c at e d.
H ol d tr e at m e nt u ntil 
r e co v er y t o < Gr a d e 1. M a y 
r e st art st u d y tr e at m e nt 
wit hi n 2 8 d a y s at a r e d u c e d 
d o s e ( b y o n e l e v el) if 
e vi d e n c e of cli ni c al b e n efit.
Gr a d e 4
C T s c a n wit h l u n g wi n d o w s 
a n d r e q uir e d p ul m o n ar y 
f u n cti o n t e sti n g, if p o s si bl e, 
i n cl u d e s: s pir o m etr y, D L C O, 
a n d r o o m a ir O 2 s at ur ati o n at 
r e st. R e p e at at l e a st e v er y 6 
w e e k s u ntil r et ur n t o wit hi n 
n or m al li mit s. Br o n c h o s c o p y 
wit h bi o p s y a n d / or B A L i s 
r e c o m m e n d e d if p o s si bl e.
C o n si d er c orti c o st er oi d s if 
i nf e cti v e ori gi n i s r ul e d o ut. 
T a p er a s m e di c all y i n di c at e d.
Di s c o nt i n u e tr e at m e nt.
6. 3. 2. 3
G ui d eli n e s f or t h e pr e v e nti o n a n d t h e tr e at m e nt of st u d y dr u g i n d u c e d 
st o m atiti s/ or al m u c o siti s / m o ut h ul c er s
F or pre ve nti o n t he st o matitis, all patie nts will be i nstr ucte d t o perf or m r o uti ne “ g o o d oral 
care”
e ac h d a y  duri n g t he trial. G o o d oral care will c o nsist of: br us hi n g teet h at least t wice 
dail y  wit h s oft bristle d t o ot h br us h, c o nti n ue c urre nt dail y fl ossi n g r o uti ne (if patie nts were n ot 
alrea d y fl ossi n g dail y, t he y sh o ul d n ot be i nstr ucte d t o start fl ossi n g as t his c o ul d ca use oral 
tra u ma), a n d c o nti n ue r o uti ne de ntal care/ mai nte na nce wit h t heir de ntist, if t he y ha ve o ne. It is’
rec o m me n de d t hat patie nts s h o ul d use 1 0 m L  of a n alc o h ol-free, 0. 5 m g/ 5 m L  de xa met has o ne 
ster oi d m o ut h was h s wis h i n g a n d s pitti n g QI D , es peciall y d uri n g t he first 8 wee ks of treat me nt 
( maj orit y of st o matitis e ve nts occ ur wit hi n t he first 8 wee ks of treat me nt). T he m o ut h was h is 
t o be hel d i n m o ut h a n d s wis he d ar o u n d m o ut h t o c o me i n c o ntact wit h e ntire b uccal m uc osa 
s urface f or a mi ni m u m of t w o mi n utes, a n d t he n s pat o ut.
Patie nts wit h 
a cli nical hist or y  of st o matitis/ m uc ositis/ m o ut h ulcers a n d t h ose wit h 
gastr oi ntesti nal m or bi dit y  ass ociate d wit h m o ut h/ de ntal i nfecti o ns, irritati o n of es o p ha geal 


N o v arti s
C o nfi d e nti al
P a g e 5 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
m uc osa e. g. gastr oes o p ha geal refl u x disease ( G E R D) a n d pre -e xisti n g st o matitis/ m uc ositis 
m ust be m o nit ore d e ve n m ore cl osel y. Patie nts s h o ul d be i nstr ucte d t o re p ort t he first o nset of 
b uccal m uc osa irritati o n/re d de ni n g t o t heir st u d y p h y sicia n i m me diately.
Ge neral
g ui da nce
a n d
ma na ge me nt
i ncl u de patie nt
a ware ness
a n d
earl y i nter ve nti o n. 
St o matitis/ oral m uc ositis/ m o ut h 
ulcers d ue t o e ver oli m us s h o ul d be treate d usi n g l ocal
s u p p orti ve care. E val uati o n f or her pes vir us or f u n gal i nfecti o n s h o ul d be c o nsi dere d. Patie nts
s h o ul d be i nf or me d a b o ut t he p ossi bilit y of de vel o pi n g m o ut h
ulcers / oral m uc ositis a n d 
i nstr ucte d t o re p ort pr o m ptl y a n y si g ns or s ym pt o ms t o t heir p h y sicia n. Patie nts s h o ul d be 
e d ucate d a b o ut g o o d oral h y gie ne, i nstr ucte d t o a v oi d s pic y/aci dic/salty f o o ds, a n d s h o ul d 
f oll o w t he f oll o wi n g g ui deli nes:

F or mil d t o xicit y ( gra de 1), use c o nser vati ve meas ures s uc h as n o n-alc o h olic m o ut h was h 
or salt water ( 0. 9 %) m o ut h was h se veral ti mes a da y u ntil res ol uti o n.

F or m ore se vere t o xicit y ( gra de 2 i n w hic h case patie nts ha ve pai n b ut are a ble t o mai ntai n 
a de q uate oral a li me ntati o n, or gra de 3 i n w hic h case patie nts ca n n ot mai ntai n a de q uate
oral ali me ntati o n), t he s u g geste d treat me nts are t o pical a nal gesic m o ut h treat me nts (i.e., 
l ocal a nest hetics s uc h as be nz ocai ne, b ut yl a mi n o be nz oate, tetracai ne h y dr oc hl ori de, 
me nt h ol, or p he n ol) wit h or wit h o ut t o pical c ortic oster oi ds, s uc h as tria mci n ol o ne oral 
paste 0. 1 % ( Ke nal o g i n Ora base ® ).

A ge nts c o ntai ni n g alc o h ol, h y dr o ge n per o xi de, i o di ne, a n d t h y m e deri vati ves ma y te n d t o 
w orse n m o ut h ulcers. It is prefera ble t o a v oi d t hese age nts.

A ntif u n gal a ge nts m ust be a v oi de d u nless a f u n gal i nfecti o n is dia g n ose d. I n partic ular,
s yste mic i mi daz ole a ntif u n gal a ge nts ( ket oc o naz ole, fl uc o naz ole, itrac o naz ole, etc.)
s h o ul d be a v oi de d i n all patie nts d ue t o t heir str o n g i n hi biti o n of e ver olim us meta b olis m,
t heref ore lea di n g t o hi g her e ver oli m us e x p os ures. T heref ore, t o pical a ntif u n gal a ge nts are
preferre d if a n i nfecti o n is dia g n ose d. Si milarl y, a nti viral a ge nts s uc h as ac ycl o vir s h o ul d
be a v oi de d u nless a viral i nfecti o n is dia g n ose d.
6. 3. 2. 4
M a n a g e m e nt of h e p atiti s r e a cti v ati o n
B ot h c he m ot hera p y ( Ye o et al 2 0 0 4 ) a n d m T O R i n hi biti o n (G u o et al 2 0 0 7 ) ma y  ca use 
reacti vati o n of he patitis B.
Ta ble 6- 5 pr o vi des de tails of m o nit ori n g a n d pr o p h y lactic t hera p y acc or di n g t o t he scree ni n g 
res ults of viral l oa d a n d ser ol o gic ma r kers testi n g. If t he patie nt is alrea d y k n o w n t o ha ve a 
c hr o nic i nfecti o n wit h H B V a n d is ta ki n g a nti- HB V me dicati o n, t he site d oes n ot ha ve t o wait
f or t he scree ni n g H B V
res ults fr o m t he l ocal la b orat or y pri or t o t he first d ose of t he st u d y 
treat me nt.


N o v arti s
C o nfi d e nti al
P a g e 5 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a bl e 6- 5
A c ti o n t o b e t a k e n b a s e d o n h e p atiti s B s cr e e ni n g r e s ult s
R e s ult
R e s ult
R e s ult
R e s ult
R e s ult
H B V - D N A
+
+ or -
-
-
-
H B s A g
+ or -
+
-
-
-
H B s A b
+ o r -
+ o r -
+
a n d n o pr i or
H B V v a c c in a ti o n
+ o r -
- or +
wit h pri o r HB V
v a c c in ati o n
H B c A b
+ or -
+ or -
+ or -
+
-
R e c o m m e n d ati o n
Pr o p h yl a x is tr e at m e nt s h o u l d b e 
st ar te d 1 -2 w e e k s pri or t o fir st 
d o s e of st u d y tr e at m e nt.
M o nit or
H B V -D N A a p pr o xi m at e ly 
e v er y 4 - 8 w ee k s
(fr o m Vi sit 2 a n d o n w ar d s)
N o pr o p h yl a x i s
M o nit or
H B V -D N A a p pr o xi m at e ly 
e v er y 4 w e e k s
(fr o m Vi sit 2 a n d o n w ar d s)
N o s p e cifi c 
a cti o n
A nti viral pr o p h yl a xis t hera py s h o ul d c o nti n ue f or at least 4 wee ks after last d ose of st u d y 
treat me nt. F or he patitis B reacti vati o n, defi niti o n a n d ma na ge me nt g ui deli nes see Ta ble 6 - 6.
T a bl e 6 - 6
G ui d eli n e s f or m a n a g e m e nt
of h e p atiti s B
H B V r e a cti v ati o n ( wit h or wit h o ut cli nic al si g n s a n d s y m pt o m s)*
F or p ati e nt s wit h
b a s eli n e r e s ult s:
P o siti v e H B V -
D N A O R
P o s iti v e H B s A g
--------------------------------------
R e a c ti v ati o n is d efi n e d a s: 
[I n cr ea s e of 1 l o g i n H B V-D N A 
r el ati v e t o b as eli n e H B V - D NA 
v al u e O R n e w a p p e ar a n c e of 
m e a s ur a bl e
H B V -D N A]
Tr e at: St art a s e c o n d a nti vir al
A N D
I nt erru pt st u d y tr e at m e nt a d m i ni str ati o n u ntil r e s o luti o n:
-
≤b a s eli n e H B V -D N A l e v e l s
If r e s ol uti o n o c c ur s wit hi n 2 8 d a y s, st u d y tr e at m e nt s h o u ld b e r e- st a rt e d at 
o n e d o s e lo w e r, if a v ail a bl e. ( s e e T a bl e 6 - 2 St u d y dr u g d o s e r e d u cti o n s) If 
t h e p ati e nt i s alr e a d y r e c ei vi n g t h e l o w e st d o s e of st u d y dr u g a c c or di n g t o 
t h e pr ot o c o l, t h e p ati e nt sh o u ld r e st ar t at t h e s a m e d o s e aft er r e s ol uti o n.
B ot h a nti vir al t h er a pi e s s h o ul d c o nti n u e at l e a st 4 w e e k s aft er l a st d o s e of 
st u d y dr u g.
If r e s ol uti o n o c c ur s > 2 8 d a y s, p ati e nt s s h o ul d d is c o nt in u e st u d y tr e at m e nt 
b ut c o nt i n u e b ot h anti vir al t h er a p i e s at l e a st 4 w e e k s aft er l ast d o s e of st u d y
dr u g.
F or p ati e nt s wit h b a s eli n e r e s ult s:
N e g ati v e H B V -D N A a n d
H B s A g
A N D
[ P o siti v e H B s A b ( wit h n o pr i or 
hi st or y of v a c ci n ati o n a g ai n st 
H B V), O R p o siti v e H B c A b]
-------------------------------------
r ea c ti v ati o n i s d efi n e d a s : Ne w 
a p p e ar a n c e of m e a s ur a bl e H B V -
D N A
Tr e at : St art fir st a nti vir al m e di c ati o n
A N D
I nt erru pt st u d y dr u g a d m i ni str ati o n u ntil r e s o luti o n:
≤u n d et e c t a ble ( n e g ati v e) H B V -D N A l e v el s
If r e s ol uti o n o c c ur s wit hi n 2 8 d a y s, st u d y dr u g s h o u ld b e r e- st a rt e d at o n e 
d o s e lo w e r, if a v ail a bl e. ( s e e T a bl e 6 - 2 St u d y dr u g d o s e r e d u cti o n s) If t h e 
p ati e nt i s alr e a d y r e c ei vi n g t h e l o w e st d o s e of st u d y dr u g a c c or di n g t o t h e
pr ot o c o l, t h e p ati e nt sh o u ld r e st ar t at t h e s a m e d o s e aft er r e s ol uti o n.
A nti vir al t h er a p y s h o ul d c o nti n u e at l e a s t 4 w e e k s aft er l a st d o s e of st u d y 
dr u g.
If r e s ol uti o n o c c ur s > 2 8 d a y s, p ati e nt s s h o ul d d is c o nt in u e st u d y dr u g b ut
c o nt in u e a nti vir al th er a p y at l e a st 4 w e e k s aft er l a st d o s e o f st u d y dru g.
* All r e a cti v ati o n s of he p atiti s B ar e t o b e r e cor d e d a s gr a d e 3 ( C T C A E v 4. 0 3), u nl e s s c o n s i der e d lif e t h r e at e nin g 
b y t h e i n v e sti g at or; i n w h i ch c a s e t h e y s h o ul d b e r e c or d e d a s gr a d e 4 ( CT C A E v 4. 0 3 ). D at e of v ir al r ea c ti v ati o n i s 
t h e d at e o n w hi c h t h e r is e or r e a p p e ar a n c e of H B V- D N A w a s r ec or d e d.


N o v arti s
C o nfi d e nti al
P a g e 5 6
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
M o nit ori n g
f or h e p atiti s C fl ar e
T he f oll o wi n g t w o cate g ories of patie nts s h o ul d be m o nit ore d e ver y 8 wee ks f or H C V flare:

Patie nts wit h dete cta ble H C V R N A -P C R test at screen i n g.

Patie nts k n o w n t o ha ve a hist or y  of H C V i nfecti o n, des pite a ne gati ve viral l oa d test at
scree ni n g (i ncl u di n g t h ose t hat were treate d a n d are c o nsi dere d ‘c ure d’)
F or defi niti o n of H C V
flare a n d t he ma na g e ment g ui deli nes, see Ta ble 6- 7 G ui de lines f or 
ma na g e ment of he patitis C. If t he patie nt is alrea d y k n o w n t o ha ve a c hr o nic i nfecti o n wit h 
H C V, t he site d oes n ot ha ve t o wait f or t he scree ni n g H C V res ults fr o m t he l ocal la b orat or y 
pri or t o t he first d ose of t he st u d y treatm e nt.
T a bl e 6- 7
G ui d eli n e s f or m a n a g e m e nt of h e p atiti s C fl ar e
H C V fl ar e *
F or p ati e nt s wit h b a s eli n e r e s ult s: D ete ct a bl e H C V -R N A,
H C V fl ar e i s d efi n e d a s :
> 2 l o g 1 0 I U/ m L i n cr e as e i n H C V - R NA A N D
A L T el e v ati o n > 5 x U L N O R 3 x b a s el i ne l e v el, w h i ch e v e r i s
hi g h er
Di s c o nti n u e st u d y tr e at m e nt
F or p ati e nt s wit h b a s eli n e r e s ult s:
K n o wl e d g e of p a st h e p atiti s C i nf e cti o n wit h n o d et e ct a bl e H C V -
R N A,
H C V fl ar e i s d efi n e d a s :
N e w a p p e ar a n c e of d et e ct a bl e H C V -R N A A N D
A L T el e v ati o n > 5 × U L N O R 3 x b a s el i ne l e v el, w h i ch e v e r i s
hi g h er
Di s c o nti n u e st u d y tr e at m e nt
* All fl ar e s of h e p atiti s C ar e t o b e r e c or d e d a s g r ad e 3 ( C T C A E v 4. 0 3), u nl e s s c o n s i der e d l if e t hr e at e nin g b y t h e 
i n v e sti g at or; i n w hic h c a s e t h e y s h o ul d b e r e c o r d e d a s gr a d e 4 ( C T C A E v 4. 0 3 ). D at e of v ir al fl ar e is t h e d at e o n 
w h i ch b ot h t h e cli n i cal crit er i a de s cri b e d a b o v e w er e m et ( e. g., f or a p ati e nt w h o s e H C V- R N A i n cr e a s e d b y 2 l o g s 
o n 0 1 J A N 2 0 1 1 a n d w h o s e A L T r ea c h e d > 5 × U L N o n 2 2 J A N 2 0 1 1 ), t h e d at e of vir al fl ar e i s 2 2 J A N 2 0 1 1.
6. 3. 2. 5
M a n a g e m e nt of s ki n t o xi cit y
F or patie nts wit h gra de 1 t o xicit y, n o s pecific s u p p orti ve care is us uall y nee de d or i n dicate d. 
Ra s h m ust be r ep orte d as a n A E. P atient s w ith gr a de 2 or hi g her t oxi cit y ma y be treate d wit h 
t he f oll o wi n g s u g geste d s u p p orti ve m eas ures at t he discreti o n of t he i n vesti gat or: oral 
mi n oc y cli ne,
t o pical
tetrac ycli ne, 
t o pical
cli n dam yci n,
t o pical
sil ver
s ulfa diazi ne, 
di p he n p h y dra m i ne, oral pre d nis ol o ne (s h ort c o urse) t o pical c ortic oster oi ds or pi m ecr olim us.
6. 3. 2. 6
M a n a g e m e nt of h a e m orr h a g e
Ca uti o n is a d vise d i n patie nts ta ki n g e ver oli m us partic ularl y d uri n g c o nc o mita nt use wit h 
acti ve s u bsta nces k n o w n t o affect platelet f u ncti o n or t hat ca n i ncrease t he ris k of 
hae m orr ha ge as well 
as i n patie nts wit h 
a
hist or y  of blee di n g dis or ders. Healt hcare 
pr ofessi o nals a n d patie nts s h o ul d be vi gila nt f or si g ns a n d s ym pt o ms of blee di n g t hr o u g h o ut 
t he treat me nt peri o d, es pecially if ris k fact ors f or hae m orr ha ge are c o m bi ne d.


N o v arti s
C o nfi d e nti al
P a g e 5 7
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
6. 3. 2. 7
M a n a g e m e nt of w o u n d h e ali n g c o m pli c ati o n s
I m paire d w o u n d heali n g is a class effect of ra pa m yci n deri vati ves, i ncl u di n g e ver oli m us. 
Ca uti o n s h o ul d t heref ore be e xercise d wit h t he use of e ver oli m us i n t he peri -s ur gical peri o d.
6. 3. 2. 8
M a n a g e m e nt of la ct o s e
Patie nts wit h rare here ditar y  pr o ble ms of galact ose i nt olera nce, La p p lactase deficie nc y  or 
gl uc ose - galact ose mala bs or pti o n s h o ul d n ot ta ke t his me dici nal pr o d uct.
6. 3. 2. 9
M a n a g e m e nt of h y p erli pi d e mi a a n d h y p er gl y c e mi a
Treat me nt of h y perli pi de mia s h o ul d ta ke i nt o acc o u nt t he pre -treat me nt stat us a n d dietar y 
ha bits of t he patie nt. Gra de 2 or hi g her h y perc h olester ole mia ( > 3 0 0 m g/ d L or 7. 7 5 m m ol/ L) 
or gra de 2 h y pertri gl yc eri de mia or hi g her ( > 2. 5 x u p per n or mal li mit) s h o ul d be treate d wit h a 
3- h y dr o x y -3 -met h y l-gl utar y l ( H M G)-C o A re d uctase i n hi bit or (e. g. at or vastati n, pra vastati n, 
fl u vastati n) or a p pr o priate tri glyc eri de -l o weri n g me dicati o n, i n a d diti o n t o diet.
N ote: C o nc o mita nt t hera p y wit h fi brates a n d a n H M G -C o A re d uctase i n hi bit or is ass ociate d 
wit h 
a n i ncrease d ris k of a rare b ut seri o us s keletal m uscle 
t o xicit y 
ma nifeste d b y  
r ha b d o my ol ys is, mar ke dl y  ele vate d creati ne p h os p h o ki nase ( C P K) le vels a n d m y o gl o bi n uria, 
ac ute re nal fail ure a n d s o meti mes deat h. T he ris k vers us be nefit of usi n g t his t hera py s h o ul d 
be deter mi ne d f or i n di vi d ual patie nts base d o n t heir ris k of car di o vasc ular c o m plicati o ns of 
h y perli pi de mia.
H y per gl yce mia has bee n re p orte d i n patie nts ta ki n g e ver oli m us. M o nit ori n g of fasti n g ser u m 
gl uc ose is rec o m me n de d pri or t o t he start of st u d y dr u g a n d peri o dicall y  thereafter. M ore 
fre q ue nt m o nit ori n g is reco m me n de d w he n e ver oli m us is c o-a d mi nistere d wit h ot her dr u gs 
t hat ma y  in d uce h y per gl y ce mia. O pti mal gl yc e mic c o ntr ol s h o ul d be ac hie ve d bef ore starti n g 
a patie nt o n st u d y dr u g.
6. 3. 2. 1 0
M a n a g e m e nt of r e n al f ail ur e e v e nt s
Cases of re nal fail ure (i ncl u di n g ac ute re nal fail ure), s o me wit h a fatal o utc o me, ha ve bee n 
o bser ve d i n patie nts treate d wit h e ver oli m us. Re nal f u ncti o n of patie nts s h o ul d be m o nit ore d 
partic ularl y w here patie nts ha ve a d diti o nal ris k fact ors t hat ma y  furt her i m pair re nal f u ncti o n.
M o nit ori n g of re nal f u ncti o n, i ncl u di n g meas ure me nt of bl o o d urea nitr o ge n ( B U N), uri nar y 
pr otei n, or ser u m creati ni ne, is rec o m me n de d pri or t o t he start of st u d y dr u g a n d peri o dicall y 
t hereafter.
6. 3. 3
E x e m e st a n e
T he m ost fre q ue ntly rep orte d a d verse effects for e x em esta ne are ga str oi ntestin al di stur ba nce s, 
h ot fl us hes, art hral gia, m yal gia, s weati n g, fati g ue, a n d dizzi ness. Ot her
re p orte d effects 
i ncl u de hea dac he, i nso m nia,
s om n ole nce, de pressi o n, s ki n ras hes, al o pecia, asth e nia, an d 
peri p heral
a n d
le g oe de ma . T hr o m b oc y t o penia a n d
le uc o pe nia ha ve
bee n
re p orte d 
occasi o na lly . Re d ucti o ns i n b o ne mi neral de nsit y ca n occ ur wit h l o n g -ter m use of e xe mesta ne.
E xe mesta ne was ge nerall y  well t olerate d, a n d a d verse e ve nts were us uall y  mil d t o m o derate. 
A d verse e ve nts occ urri n g i n greater t ha n 1 0 % of patie nts i ncl u de h ot fl us hes ( 1 4 %), na usea 
( 1 1. 9 %), i ns o m nia, hea dac he, i ncrease d s weati n g, j oi nt a n d m usc ul os keletal pai n, a n d fati g ue 


N o v arti s
C o nfi d e nti al
P a g e 5 8
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
( U S PI; Ar o masi n S m P C A u g ust 2 0 0 8 ( U K as R M S f or E U M R P)). A n dr o ge nic effects were 
re p orte d i n a li mite d n u m ber ( 4. 3 %) of patie nts (B uz dar 2 0 0 3 ).
Refer t o t he pac ka ge i nsert of t he l ocal s u p pl y of e xe mesta ne f or m ore details.
6. 3. 4
F oll o w -u p f or t o xi citi e s
Patie nts w h ose treat me nt is i nterr upte d or pe r ma ne ntl y disc o nti n ue d d ue t o a n a dverse e ven t 
m ust be f oll o we d at least o nce a wee k f or 4 wee k s, a n d s u bse q ue ntl y at 4 - wee k i nter vals, u n til 
res olu ti o n o r stab ilizati o n of t he eve nt. All pa tients will
b e foll o we d f or o nset of a n y ne w 
seri o us a d verse e ve nts f or 3 0 d a y s f ollo wi n g t he last d ose of st u d y treatme nt.
If, beca use of t o xicit y, a patie nt req uires a d ose dela y of > 4 wee ks fr o m t he i nte nd e d da y of 
d ose, t he n t he patie nt m ust disc o n ti n ue st u d y treat me nt. H o we ver, t he pa tien t will c o nti n ue t o 
be f oll o we d f or t o xicit y a n d t um or assessm e nts as pre vi o usl y descri be d.
6. 4
C o n c o mit a nt m e di c ati o n s
All
me dicati o ns
(e xcl u di n g st u dy treat me nt a n d pri or a nti ne o plastic treat me nts), pr oce d ures 
a n d si g nifica nt n o n- dr u g
t hera pies (i ncl u di n g p h y sical t herap y a n d bl o o d
tra nsf usi o ns) 
a d mi nistere d wit hi n 2 8 d a y s pri or t o t he st u d y treat me nt t hr o u g h 3 0 d a y s after t he last d ose of
st u dy treat me nt (eit her e ver oli m us/ place b o or e xe mesta ne, w hic he ver is later) will be rec or de d 
in t he C o nc o mit ant me dicati o ns or S ur gical a n d me di cal pr oce d ures e C R F. Me dicati o ns
i ncl u de n ot o nly p h y sicia n prescri be d me dicati o ns,
b ut als o all o ver- t he c o u nter me dicati o ns,
her bal me dicati o ns ( pr o hi bite d) a n d f o o d or vita mi n s u p ple me nts. T he i n vesti gat or s h o ul d 
i nstr uct t he patie nt t o n otif y  the i n vesti gati o nal site a b o ut a n y ne w me dicati o ns s he ta kes after 
t he start of t he st u dy treat me nt.
T he patie nt m ust
be t ol d t o n otif y t he i n vesti gati o nal site a b o ut a n y n e w me dicati o ns
he/s he 
ta kes after t he start of t he st u dy treat me nt. All me dicati o ns ( ot h er t ha n st u dy treat me nt) a n d
si g nifica nt n o n- dr u g
t hera pies
(i ncl u di n g
p h y sical
t hera py
a n d
bl o o d
tra nsf usi o ns)
a d mi nistere d d uri n g t he st u dy m ust
b e liste d o n
t he
Co nc o mita nt
Me dicati o ns
or t he
Pr oce d ures a n d Si g nifica nt N o n -Dr u g T hera pies e C R F, res pecti vel y.
6. 4. 1
Pr o hi bit e d c o n c o mit a nt t h er a p y
T he f oll o wi n g c o nc om ita nt treatme nts are n ot all o we d d uri n g t he st u d y:

I n vesti gati o nal or c o m mercial a ntica ncer a gen ts, s uc h as c he m ot hera p y, i m m u n ot hera p y, 
tar gete d t hera p y, or e n d ocri ne t hera p y s h o ul d n ot be gi ve n t o patie nts.

H o r m o ne re placem e nt t hera py, t o pical estr o gens (i ncl udi n g a n y i ntra-va gi nal pre p arati o ns), 
me gestr ol acetate a n d selecti ve estr o ge n -rece ptor m o d ulat ors (e. g. ral o xife ne) are 
pr o hi bite d.

Pr ol o n ge d s ystem ic c ortic oster oi d treatme nt, e xce pt f or t o pical a p plicati o ns (e. g. ras h), 
i n hale d s pra ys (e. g. o bstr ucti ve air wa ys dis eases), e ye dr o ps or l ocal i njecti o ns (e. g. 
i ntraartic ular) s h o ul d n ot be gi ve n. A s h ort d urati o n ( < 2 wee ks) of s ystem ic 
c ortic oster oi ds is all o we d (e. g. c hr oni c o bstr ucti ve p ul m o nar y disease, a nti-eme tic).


N o v arti s
C o nfi d e nti al
P a g e 5 9
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

He ma t o p oietic gr o wt h fact ors (e. g. er yt hr o p oieti ns, G- C S F a n d G M -C S F) are n ot t o be 
a dmi nistere d pr o p h yl acticall y. Use of t hese s h o ul d be reser ve d t o cases of se vere 
ne utr o pe nia a n d a nem ia as per t he la beli n g of t hese a ge nts.
It is t o be n o te d t hat

L ocal ra di ot hera py f or a nal gesic p ur p oses or f or l ytic lesio ns at ris k of fract ure ma y be 
carrie d o ut if re q uire d. W he ne ver
p ossi ble, t hese patie nts s h o ul d ha ve a t um or assessm e nt 
of t he lesi on (s) bef ore t h e y act uall y recei ve t he ra di ot hera py. N o d ose m o dificati o n of 
st u d y treatme nt is nee de d d uri n g ra di ot hera py.

E ver oli m us ma y a ffect t he res p o nse t o vacci nati o ns ma ki n g it less effecti ve. Li ve vacci nes 
s h o ul d be a v oi de d w hile a patie nt is treate d wit h e ver olim us.
6. 4. 2
U s e of b i s p h o s p h o n at e s
T he use of bis p h os p h o nates f or b o ne metastatic disease is all o we d. If bis p h os p h o nate t hera py 
is i nitiate d after start of st ud y treat me nt, t he reas o n f or its use m ust be clearl y d oc u me nte d a n d 
pr o gressi o n as per R E CI S T 1. 1 m ust be r ule d o ut.
Sa me g ui deli nes s h o ul d a p pl y t o t he use of de n os u ma b i n t he treat me nt of b o ne metastatic 
disease.
6. 4. 3  
Ot h er c o n c o mit a nt m e di c ati o n s
E ver oli m us is a s u bstrate of C Y P 3 A 4, a n d a s u bstrate a n d m o derate i n hi bit or of t he m ulti dr u g 
effl u x p u m p, P g P ( P g P, M D R 1, a n d A B C B 1). T heref ore, e xte nt of a bs or pti o n a n d s u bse q ue nt 
eli mi nati o n of s yste micall y abs or be d e ver oli m us ma y  be i nfl ue nce d b y pr o d ucts t hat are 
s u bstrates, i n hi bit ors, or i n d ucers of C Y P 3 A 4 a n d/ or P g P. C o -a d mi nistrati o n wit h str o n g 
i n hi bit ors of C Y P 3 A 4 or P g P s h o ul d be a v oi de d. C o -a dm i nistrati o n wit h m o derate
C Y P 3 A 4
i n hibit ors (e. g., er yt hr o m yci n, fl uc o naz ole) or P g P i n hi bit ors s h o ul d be use d wit h
ca uti o n. 
Se ville
ora n ge, star fru it, gra pefr uit a n d t heir j uices affect
C Y P 3 A 4 a n d P g P
activ it y.
C o nc o m ita nt use s h o ul d be a v oi de d.
Please refer t o Ta ble 6- 8 listi n g rele va nt i n d ucers a n d i n hi bit ors of C Y P 3 A a n d t o Ta ble 6- 9
f or a list of rele va nt s u bstrates, i n d ucers, a n d i n hi bit ors of P g P.
E ver oli m us ma y  affect t he res p o nse t o vacci nati o ns ma ki n g t he res p o nse t o t he vacci nati o n 
less effecti ve. Li ve vacci nes s h o ul d be a v oi de d w hile a patie nt is treate d wit h e ver oli m us.


N o v arti s
C o nfi d e nti al
P a g e 6 0
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a bl e 6- 8
Cli ni c all y  r el e v a nt dr u g i nt er a cti o n s: i n d u c er s, a n d i n hi bit or s of
i s o e n z ym e C Y P 3 A
I n d u c er s
Str o n g i n d u c er s:
a v a si mi b e, c ar b a m a z e pi n e, mit ot a n e, p h e n o b ar bit al, p h e n yt oi n, rif a b uti n, rif a m pi n (rif a m pi ci n), St. J o h n' s w ort 
( h y p eri c u m p erf or at u m)
M o d er at e i n d u c er s:
b o s e nt a n, ef a vir e n z, etr a viri n e, m o d afi nil, n af cilli n, g e ni st ei n, rit o n a vir, t hi ori d a zi n e, ti pr a n a vir, s e m a g a c e st at, 
t al vir ali n e, l o pi n a vir, l er si viri n e,
W e a k i n d u c er s:
a m pr e n a vir, a pr e pit a nt, ar m o d afi nil ( R -m o d afi nil), b e x ar ot e n e, cl o b a z a m, d a n s h e n, d e x a m et h a s o n e, E c hi n a c e a, 
g arli c ( alli u m s ati v u m), gi n g k o ( gi n k g o bil o b a), gl y c yrr hi zi n, m et h yl pr e d ni s ol o n e, n e vir a pi n e, o x c ar b a z e pi n e, 
pi o glit a z o n e, pr e d ni s o n e, [ pl e c o n aril], pri mi d o n e, r alt e gr a vir , r ufi n a mi d e, s or af e ni b, t el a pr e vir, t er bi n afi n e, 
t o pir a m at e, [tr o glit a z o n e], vi n bl a sti n e e sli c ar b a z e pi n e, gi n s e n g, v e m ur af e ni b, b o c e pr e vir, s ulfi n p yr a z o n e, 
ti c a gl er or, vi cri vir o c/rit o n a vir, rit o n a vir, ti cl o pi di n e, bri v a c et a m, Stri bil d ( c o m b o of el vit e gr a vir, c o bi ci st at, 
e mtri cit a bi n e, a n d t e n of o vir), q u er c eti n.
I n hi bit or s
Str o n g i n hi bit or s:
b o c e pr e vir , cl arit hr o m y ci n, c o bi ci st at, c o ni v a pt a n, el vit e gr a vir, i n di n a vir, itr a c o n a z ol e, k et o c o n a z ol e, l o pi n a vir, 
mi b efr a dil, n ef a z o d o n e, n elfi n a vir, p o s a c o n a z ol e ( Kri s h n a et al 2 0 0 9 ), rit o n a vir, s a q ui n a vir, t el a pr e vir, 
t elit hr o m y ci n, ti pr a n a vir, tr ol e a n d a m y ci n, v ori c o n a z ol e, i n di n a vir/rit o n a vir, ti pr a n o a vir/rit o n a vir, c o bi ci st at, 
tr ol e a n d o m y ci n, d a n o pr e vir/rit o n a vir, elt e gr a vir/rit o n a vir,
M o d er at e i n hi bit or s:
a m pr e n a vir, a pr e pit a nt, at a z a n a vir, ci pr ofl o x a ci n, d ar u n a vir/rit o n a vir, dilti a z e m, er yt hr o m y ci n, fl u c o n a z ol e, 
f o s a m pr e n a vir, gr a p efr uit j ui c e, nil oti ni b i m ati ni b, t ofi s o p a m, c y cl o s p ori n, ci pr ofl o x a ci n, v er a p a mil, dr o n e d ar o n e, 
cri z oti ni b, c a s o pit a nt, a m pr e n a vir, at a z a n a vir/rit o n a vir, d ur a n a vir, n et u pit a nt, s c hi s a n dr a s p h e n a nt h er a, ci m eti di n e, 
l o mit a pi d e
W e a k i n hi bit or s:
t a bi m or eli n, r a n ol a xi n e, f o s a pr e prit a nt, S e vill e or a n g e, a ml o di pi n e, cl o z o x a z o n e, fl u v o x a mi n e, r a niti di n e, 
g ol d e n s e al, cl otri m a z ol e, t a cr oli m u s, cil o st a z ol, ti c a gr el or, i v a c aft or, r o xit hr o m y ci n, pr o pi v eri n e, i s o ni a zi d, 
b er b eri n e, or al c o ntr a c e pti v e s, p e p p er mi nt oil, d el a vir di n e, si m e pr e vir, at or v a st ati n, t ol v a pt a n, al m or e x a nt, 
li n a gli pti n, r e s v er atr ol, l a ci pi di n e, cr a n b err y j ui c e, nil oti ni b, p a z o p a ni b, e vr oli m u s, bl u e b err y j ui c e, al pr a z ol a m, 
bi c al ut a mi d e, sit a x e nt a n, a zit hr o m y ci n, gi n k g o, t erifl u n o mi d e, al pr a z ol a m, a mi o d ar o n e, a ml o di pi n e, bi c al ut a mi d e, 
cil o st a z ol, ci m eti di n e, c y cl o s p ori n e, fl u o x eti n e, i s o ni a zi d, r a niti di n e, r a n ol a zi n e, ti pr a n a vir/rit o n a vir, zil e ut o n


N o v arti s
C o nfi d e nti al
P a g e 6 1
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a bl e 6- 9
Cli ni c all y  r el e v a nt dr u g i nt er a cti o n s: s u b str at e s, i n d u c er s, i n hi bit or s 
of P g P a n d P g P/ C Y P 3 A d u al i n hi bit or s
S u b str at e s
di g o xi n, q ui ni di n e, p a clit a x el, c y cl o s p ori n e, sir oli m u s, t a cr oli m u s, f e nt a n yl, p p h e n yt oi n, ali s kir e n, a m bri s e nt a n, 
at or v a st ati n, at or v a st ati n a ci d, a zit hr o m y ci n, c eri v a st ati n, c ol c hi ci n e, C P -4 8 1, 7 1 5, c y cl o s p ori n e, d a bi g atr a n, 
di g o xi n, d o c et a x el, d o m p eri d o n e, d o x or u bi ci n, f e nt a n yl, f e x of e n a di n e, l a p ati ni b, li n e z oli d, l o p er a mi d e, m ar a vir o c, 
n e vir a pi n e, p a clit a x el, pr o g u a nil, q ui ni di n e, r a n ol a zi n e, rit o n a vir, s a q ui n a vir, si m v a st ati n, sir oli m u s, s of o s b u vir, 
t a cr oli m u s, ti c a gr el or, v o cl o s p ori n, af ati ni b, alf u z o si n, ali s kir e n, al o gli pti n, a m bri s e nt a n, a pi x a b a n, a pr e mil a st, 
a pr e pit a nt, b o c e pr e vir, b o s e nt a n, c ar v e dil ol, c ar v e dil ol, c a s p of u n gi n, c eriti ni b, cit al o pr a m, c ol c hi ci n e, c y cl o s p ori n e, 
d a bi g atr a n, di g o xi n, d o x e pi n, d o x or u bi ci n, eri b uli n, e v er oli m u s, fi d a x o mi ci n, fl u v a st ati n, f o s a m pr e n a vir, 
g atifl o x a ci n, i d el ali si b, il o p eri d o n e, i n d a c at er ol, ir b e s art a n, l a c o s a mi d e, l a p ati ni b, l e v etir a c et a m, l e v ofl o x a ci n, 
li n a gli pti n, l o s art a n, m ar a vir o c, mir a b e gr o n, m o xifl o x a ci n, n al o x eg ol, n at e gli ni d e, ni nt e d a ni b, ol o d at er ol, 
p a nt o pr a z ol e, p ar o x eti n e, p a z o p a ni b, p o s a c o n a z ol e, pr a v a st ati n, q ui ni n e, r a n ol a zi n e, ri o ci g u at, ri s p eri d o n e, 
ri v ar o x a b a n, s a q ui n a vir, sil o d o si n, si m e pr e vir, sir oli m u s, sit a gli pti n, s or af e ni b, t el a pr e vir, t e n of o vir, ti c a gr el or, 
ti pr a n a vir, t ol v a pt a n, t o p ot e c a n, u m e cli di ni u m, v al s art a n, v ar d e n afil, vi n cri sti n e, v ori c o n a z ol e
I n d u c er s
a v a si mi b e , c ar b a m a z e pi n e, ef a vir e n z, g e ni st ei n, p h e n yt oi n, q u er c eti n, rif a m pi n, St. J o h n s w ort e xtr a ct
P g P I n hi bit or s a n d P g P/ C Y P 3 A D u al I n hi bit or s
P g P I n hi bit or s
al o gli pti n, c a n a glif o zi n, cr e m o p h or R H 4 0, c ur c u mi n, k et o c o n a z ol e, l a p ati ni b, l o pi n a vir/rit o n a vir, mir a b e gr o n, 
pr o p af e n o n e, si m e pr a vir, v al s p o d ar, v a n d et a ni b, v o cl o s p ori n
P g P/ C Y P 3 A D u al I n hi bit or s
a mi o d ar o n e, a zit hr o m y ci n, c a pt o pril, c ar v e dil ol, cl arit hr o m y ci n, c o ni v a pt a n, dilti a z e m, dr o n e d ar o n e, el a cri d ar, 
er yt hr o m y ci n, f el o di pi n e, fl u v o x a mi n e, gi n k o, i n di n a vir, i n di n a vir/rit o n a vir, itr a c o n a z ol e, mi b efr a dil, mil k t hi sl e,
n elfi n a vir, nif e di pi n e, nitr e di pi n e, p ar o x eti n e, q u er c eti n, q ui ni di n e, r a n ol a zi n e, rif a m pi n, rit o n a vir, 
s e q ui n a vir/rit o n a vir, s c hi s a n dr a c hi n e si s e xtr a ct, St. J o h n’ s w ort e xtr a ct, t ali n ol ol, t el a pr e vir, t el mi s art a n, ti c a gr el or, 
ti pr a n a vir/rit o n a vir, t ol v a pt a n, v er a p a mil
R ef er e n c e: I nt er n al Cli ni c al P h ar m a c ol o g y Dr u g - dr u g i nt er a cti o n ( D DI) m e m o, u p d at e d A pril-2 0 1 5 w hi c h 
s u m m ari z e s D DI d at a fr o m t hr e e s o ur c e s i n cl u di n g t h e F D A’ s “ G ui d a n c e f or I n d u str y, Dr u g I nt er a cti o n St u di e s”, 
t h e U ni v er sit y of W a s hi n gt o n’ s Dr u g I nt er a cti o n D at a b a s e, a n d I n di a n a U ni v er sit y S c h o ol of M e di ci n e' s Dr u g 
I nt er a cti o n T a bl e.
V a c ci n ati o n s
I m m u n os u p pressa nts ma y affect t he res p o nse t o vacci nati o n a n d vacci nati o n d uri n g treat me nt 
wit h e ver oli m us m a y  theref ore be less effecti ve. T he use of li ve vacci nes s h o ul d be a v oi de d 
d uri n g trea t me nt wit h e ver oli m us.
E xa m ples of li ve vacci nes are: i ntra nasal i nfl ue nza, measles, m u m ps, r u bella, oral p oli o, B C G, 
ye ll o w fe ver, varicella, a n d T Y 2 1a ty p h oi d vacci nes.
6. 5
P ati e nt n u m b eri n g, tr e at m e nt a s si g n m e nt or r a n d o mi z ati o n
6. 5. 1
P ati e nt n u m b eri n g
Eac h patie nt is i de ntifie d i n t he st u d y  b y a S u bject n u m ber, t hat is assi g ne d w he n t he patie nt is 
first e nr olle d f or scree ni n g a n d is retai ne d as t he pri mar y  ide ntifier f or t he patie nt t hr o u g h o ut 
his/ her e ntire partici pati o n i n t he trial. T he S u bject n u m ber c o nsists of t he Ce nter N u m ber 
( Ce nter N o.) w hic h is assi g ne d b y  No vartis t o t he i n vesti gati ve site wit h a se q ue ntial patie nt 
n u m ber s uffi xe d t o it, s o t hat eac h s u bject is n u m bere d u ni q uel y acr oss t he e ntire data base. 
U p o n si g ni n g t he i nf or me d c o nse nt f or m, t he patie nt is assi g ne d t o t he ne xt se q ue ntial S u bject
n u m ber a vaila ble t o t he i n vesti gat or.


N o v arti s
C o nfi d e nti al
P a g e 6 2
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T he i n vesti gat or or desi g nate d staff will c o ntact t he I RT a n d pr o vi de t he re q ueste d i de ntif yi n g 
i nf or mati o n f or t he patie nt t o re gister t he m i nt o t he I R T. O nce assi g ne d, t he S u bject n u m ber
m ust n ot be re use d f or a n y ot her s u bject a n d t he S u bject n u m ber f or t hat i n di vi d ual m ust n ot 
be c ha n ge d, e ve n if t he patie nt is re-scree ne d. If t he patie nt fails t o be ra n d o mize d or start 
treat me nt f or a ny reas o n, t he reas o n wil l be e ntere d i nt o t he Scree ni n g Dis p ositi o n pa ge.
6. 5. 2
Tr e at m e nt a s si g n m e nt or r a n d o mi z ati o n
Patie nts will be assi g ne d t o o ne of t he t w o treat me nt ar ms (Secti o n 4. 1 a n d Secti o n 6. 1 ) i n a 
rati o of “1: 1 ”. Ra n d o mizati o n will be stratifie d b y d oc u me nte d se nsiti vit y to pri or h or m o nal 
t hera py ( yes vs. n o) a n d b y  t he prese nce of visceral disease ( y es vs. n o).
T he ra n d o mizati o n n u m bers will be ge nerate d usi n g t he f oll o wi n g pr oce d ure t o e ns ure t hat 
treat me nt assi g n me nt is u n biase d a n d c o nceale d fr o m patie nts a n d i n vesti gat or staff. A patie nt 
ra n d o mizati o n list will be pr o d uce d b y  the I nteracti ve Res p o nse Tec h n ol o g y  (I RT) pr o vi der 
usi n g a vali date d s yste m t hat a ut o mates t he ran d o m assi g n me nt of patie nt n u m bers t o 
ra n d o mizati o n n u m bers. T hese ra n d o mizati o n n u m bers are li n ke d t o t he differe nt treat me nt 
ar ms, w hic h i n t ur n are li n ke d t o me dicati o n n u m bers.
Pri or t o d osi n g, all patie nts w h o f ulfill all i ncl usi o n/e xcl usi o n criteria will be ra n d o mize d via 
I R T t o o ne of t he treat me nt ar ms. T he i n vesti gat or or his/ her dele gate will call or l o g o n t o t he 
I R T a n d c o nfir m t hat t he patie nt f ulfills all t he i ncl usi o n/e xcl usi o n criteria. T he I R T will 
assi g n a ra n d o mizati o n n u m ber t o t he patie nt, w hic h will be use d t o li n k t he patie nt t o a 
treat me nt ar m a n d will s pecif y a uni q ue me dicati o n n u m ber f or t he first pac ka ge of st u d y 
treat me nt t o be dis pe nse d t o t he patie nt. T he ra n d o mizati o n n u m ber will n ot be c o m m u nicate d 
t o t he caller.
6. 5. 3
Tr e at m e nt bl i n di n g
T his is a d o u ble bli n d st u dy. I n partic ular, patie nts, i n vesti gat ors, l ocal ra di ol o gists, st u d y 
tea m, or a n y o ne i n v ol ve d i n t he st u d y c o n d uct will re mai n bli n de d t o t he i de ntity of t he 
treat me nt fr o m t he ti me of ra n d o mizati o n u ntil u n bli n di n g.
Ra n d o mizati o n data are ke pt strictl y c o nfi de ntial u ntil t he ti me of u n bli n di n g, a n d will n ot be 
accessi ble t o a n y o ne i n v ol ve d i n t he c o n d uct of t he st u d y. T he i de ntit y of t he treat me nts will 
be c o ncealed b y t he use of i n vesti gati o nal dr u gs (e ver oli m us or place b o) t hat are i de ntical i n 
pac ka gi n g, la beli n g, sc he d ule of a d mi nistrati o n a n d i n a p peara nce. C o nfi de ntialit y
of 
ra n d o mizati o n data is re q uire d t o li mit t he occ urre nce of p ote ntial bias arisi n g fr o m t he 
i nfl ue nce t hat t he k n o wle d ge of treat me nt m a y
ha ve o n t he recr uit me nt a n d all ocati o n of 
patie nts.
U n bli n di n g will o nl y  occ ur i n t he case of patie nt e mer ge ncies (Secti o n 8. 3 ), f or re g ulat or y 
re p orti n g p ur p oses a n d at t he c o ncl usi o n of t he st u d y.
I n rare cases w he n u n bli n di n g occ urs beca use of e mer ge nc y patie nt ma na ge me nt, t he act ual 
treat me nt ar m will n ot be c o m m u nicate d t o a n y of t he N o vartis e m pl o y ees i n v ol ve d i n 
r u n ni n g t he trial i n or der t o re mai n bli n de d. T he patie nt will be wit h dra w n fr o m t he st u dy
treat me nt.


N o v arti s
C o nfi d e nti al
P a g e 6 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
At t he c o ncl usi o n of t he st u d y, w he n t he st u d y data ha ve bee n verifie d, a n d t he pr ot oc ol 
de viati o ns ha ve bee n deter mi ne d a n d t he data base l oc ke d, t he assi g ne d bli n de d dr u g c o des ca n 
be br o ke n a n d ma de a vaila ble t o t he S p o ns or f or t he fi nal a nal ys is of t he st u d y data.
6. 6
St u d y tr e at m e nt pr e p ar ati o n a n d di s p e n s ati o n
T he i n vesti gat or or res p o nsi ble site pers o n nel m ust i nstr uct t he patie nt or care gi ver t o ta ke t he 
st u d y treat me nt as per pr ot oc ol. St u d y  treat me nt will be dis pe nse d t o t he patie nt b y  a ut h orize d 
site pers o n nel o nl y. All d osa ges prescri be d t o t he patie nt a n d all d ose c ha n ges d uri n g t he 
st u d y m ust be rec or de d o n t he D osa ge A d mi nistrati o n Rec or d C R F.
Ta blets of e ver oli m us a n d e xe mesta ne i ncl u di n g i nstr ucti o ns f or a d mi nistrati o n are dis pe ns e d 
b y  st u d y pers o n nel o n a n o ut patie nt basis.
Patie nts will be pr o vi de d wit h a de q uate s u p pl y of st u d y treat me nt f or self-a d mi nistrati o n at 
h o me u ntil at least t heir ne xt sc he d ule d st u d y  visit.
6. 6. 1
St u d y tr e at m e nt p a c k a gi n g a n d l a b eli n g
Res p o nsi ble site pers o n n el will di spe nse e vero lim us / place b o t o t he patie nt b y usi n g t he I RT
a n d o btai ni n g t he me dicati o n n u m ber(s ). Site pers o n nel will
a d d t he patie nt n u m ber o n t he
la bel. E ver oli m us / place b o la bels will
be i n t he l ocal la n gua ge a n d c om p l y wit h
t he le gal
req ui re ments of C hi na. T he y will i ncl ude stor a ge c on diti o ns f or t he dr u g a n d t he me dicati o n 
n u m ber b ut n o i nf or m ati o n a b o ut t he patie nt.
C o m m erciall y availa ble e xem esta ne will be s u pp lie d t o i n vesti gator sites i n acc ord a n ce wit h 
l ocal re g ulati o ns i n C hi n a.
T a bl e 6- 1 0
P a c k a gi n g a n d l a b eli n g
St u d y  tr e at m e nt s
P a c k a gi n g
L a b eli n g ( a n d d o si n g fr e q u e n c y )
E v er oli m u s / pl a c e b o
T a bl et s i n bli st er
L a b el e d a s ‘ R A D 0 0 1’, 2 × 5 m g t a bl et s t o b e 
t a k e n or all y
E x e m e st a n e
R ef er t o l o c al pr o d u ct i nf or m ati o n  
R ef er t o l o c al pr o d u ct i nf or m ati o n
6. 6. 2
Dr u g s u p pl y  a n d st or a g e
St u d y  treat me nts m ust be recei ve d b y  desi g nate d pers o n nel at t he st u d y site, ha n dle d a n d 
st ore d safely a n d pr o perl y , a n d ke pt i n a sec ure d l ocati o n t o w hic h o nl y  the i n vesti gat or a n d 
desi g nate d site pers o n nel ha ve access. U p o n recei pt, t he st u d y treat me nt s h o ul d be st ore d 
acc or di n g t o t he i nstr ucti o ns s pecifie d o n t he dr u g la bels a n d i n t he [I n vesti gat or’s Br oc h ure].
T a bl e 6- 1 1
S u p pl y  a n d st or a g e of st u d y tr e at m e nt s
St u d y  tr e at m e nt s
S u p pl y
St or a g e
E v er oli m u s / pl a c e b o
L o c all y
R ef er t o st u d y tr e at m e nt l a b el
E x e m e st a n e
L o c all y
R ef er t o l o c al pr o d u ct i nf or m ati o n


N o v arti s
C o nfi d e nti al
P a g e 6 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
6. 6. 3
St u d y tr e at m e nt c o m pli a n c e a n d a c c o u nt a bilit y
6. 6. 3. 1
St u d y tr e at m e nt c o m pli a n c e
C o m plia nce will be assesse d b y  the i n vesti gat or a n d/ or st u d y pers o n nel at eac h patie nt visit 
a n d i nf or mati o n pr o vi de d b y  the patie nt a n d/ or care gi ver will be ca pt ure d i n t he Dr u g 
Acc o u nta bilit y  For m. T his i nf or mati o n m ust be ca pt ure d i n t he s o urce d oc u me nt at eac h 
patie nt visit.
6. 6. 3. 2
St u d y tr e at m e nt a c c o u nt a bilit y
T he i n vesti gat or or desi g nee m ust mai ntai n a n acc urate rec or d of t he s hi p me nt a n d dis pe nsi n g 
of st u d y treat me nt i n a dr u g acc o u nta bilit y lo g. Dr u g acc o u nta bilit y will be n ote d b y  the fiel d 
m o nit or d uri n g site visits a n d at t he c o m pleti o n of t he st u d y. Patie nts will be as ke d t o ret ur n 
all u n use d st u d y treat me nt a n d pac ka gi n g o n a re g ular basis, at t he e n d of t he st u d y or at t he 
ti me of st u d y  treat me nt disc o nti n uati o n.
At st u d y cl ose-o ut, a n d, as a p pr o priate d uri n g t he c o urse of t he st u d y, t he i n vesti gat or will 
ret ur n all use d a n d u n use d st u d y treat me nt, pac ka gi n g, dr u g la bels, a n d a c o p y of t he 
c o m plete d dr u g acc o u nta bilit y l o g t o t he N o vartis m o nit or or t o t he N o vartis a d dress pr o vi de d 
i n t he i n vesti gat or f ol der at eac h site.
6. 6. 4
Di s p o s al a n d d e str u cti o n
T he st u d y treat me nt s u p pl y ca n be destr o y e d at t he l ocal N o vartis facilit y, Dr u g S u p pl y  gr o u p 
or t hir d part y, as a p pr o priate .
7
Vi sit s c h e d ul e a n d a s s e s s m e nt s
7. 1
St u d y fl o w a n d vi sit s c h e d ul e
Ta ble 7- 1 lists all of t he assess me nts a n d i n dicates wit h a n “ X”, t he visits w he n t he y are 
perf or me d. All data o btai ne d fr o m t hese assess me nts m ust be s u p p orte d i n t he patie nt’s s o urce 
d oc u me ntati o n. T he ta ble i n dicates w hic h data are e ntere d i nt o t he data base ( D) or re mai n i n 
s o urce d oc u me nts o nl y ( S). Assess me nts t hat ge nerate data f or data base e ntr y an d w hic h are 
rec or de d o n e C R Fs are liste d usi n g t he e C R F na me.
N o C R F will be use d as a s o urce d oc u me nt.


N o v arti s
C o nfi d e nti al
P a g e 6 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a bl e 7- 1
Vi sit e v al u ati o n s c h e d ul e
R a n d o mi z e d tr e at m e nt p h a s e
P o st Tr e at m e nt 
F oll o w u p p h a s e
S ur vi v al f oll o w u p 
p h a s e
C at e g or y
Pr ot o c ol 
S e cti o n
S cr e e ni n g /
B a s eli n e
C y cl e 1
E v er y  2 cy c l e s 
aft er C 1 D 1
E n d of st u d y  
tr e at m e nt ( E o T)
Vi sit N a m e
S cr e e ni n g
Vi sit ( D - 2 1
t o D -1)
C 1 D 1
C 3 D 1
C 5 D 1 , et c …
E O T Vi sit ( wit hi n 
7 d of l a st d o s e)
P O S T T R T F U P 1, 2, 
e ct
S ur vi v al f u p
O bt ai n I nf or m e d C o n s e nt
D, S
X
I R T s cr e e ni n g / 
r a n d o mi z ati o n / 
di s c o nti n u ati o n / 
pr o gr e s si o n / d e at h
S
X
X
X
P ati e nt hi st or y
D
X
D e m o gr a p h y
D
X
I n cl u si o n/ e x cl u si o n crit eri a
D
X
M e di c al Hi st or y
D
X
Di a g n o si s a n d e xt e nt of 
c a n c er
D
X
S m o ki n g hi st or y
D
X
Pri or / P o st a nti n e o pl a sti c 
t h er a p y
D
X
X
Pri or/ c o n c o mit a nt 
m e di c ati o n s
D
X
C o nti n u o u s
u p t o 3 0 d a y s aft er l a st 
d o s e of tr e at m e nt
C o m pl et e P h y si c al 
e x a mi n ati o n
S
7. 2. 2. 1 . 
X
If cli ni c all y i n di c at e d
P erf or m a n c e st at u s
D
7. 2. 2. 4 . 
X
X 
X
X
H ei g ht
D
7. 2. 2. 3 . 
X
W e i g ht
D
7. 2. 2. 3 . 
X
X 
X
X
Vit al si g n s
D
7. 2. 2. 2 . 
X
X 
X
X


N o v arti s
C o nfi d e nti al
P a g e 6 6
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
R a n d o mi z e d tr e at m e nt p h a s e
P o st Tr e at m e nt 
F oll o w u p p h a s e
S ur vi v al f oll o w u p 
p h a s e
C at e g or y
Pr ot o c ol 
S e cti o n
S cr e e ni n g /
B a s eli n e
C y cl e 1
E v er y  2 cy c l e s 
aft er C 1 D 1
E n d of st u d y  
tr e at m e nt ( E o T)
Vi sit N a m e
S cr e e ni n g
Vi sit ( D - 2 1
t o D -1)
C 1 D 1
C 3 D 1
C 5 D 1 , et c …
E O T Vi sit ( wit hi n 
7 d of l a st d o s e)
P O S T T R T F U P 1, 2, 
e ct
S ur vi v al f u p
L a b or at or y  a s s e s s m e nt s
H e m at ol o g y
D
7. 2. 2. 5. 1 . 
X
X 
X
X
Bi o c h e mi str y
D
7. 2. 2. 5. 2 . 
X
X 
X
X
Li pi d P a n el
D
X
X 
X
X
C o a g ul ati o n
D
7. 2. 2. 5 . 
X
X 
X
X
H e p atiti s B a n d C 
s cr e e ni n g/ m o nit ori n g(if 
a p pli c a bl e)
D
X
X
X
T u m or e v al u ati o n ( E O T 
s c a n n ot r e q uir e d if 
pr e vi o u s s c a n w a s 
p erf or m e d wit hi n ≤2 8 
d a y s)
D
7. 2. 1 . 
X
E v er y 2 c y cl e s aft er 
C 1 D 1 ; t h e 
fr e q u e n c y will b e 
c h a n g e d t o e v er y 
1 2 w e e k s aft er d at a 
c ut -off f or pri m ar y 
a n al y si s a n d a s 
cli ni c all y i n di c at e d
X
X If n ot pr o gr e s s e d, 
e v er y 2 c y cl e s aft er 
E O T ; t h e fr e q u e n c y 
will b e c h a n g e d t o 
e v er y 1 2 w e e k s aft er 
d at a c ut -off f or pri m ar y 
a n al y si s a n d a s 
cli ni c all y i n di c at e d
E C G
D
7. 2. 2. 5. 3 . 
X
If cli ni c all y i n di c at e d
P ul m o n ar y f u n cti o n t e st
D
If cli ni c all y i n di c at e d, a n d if w arr a nt e d t o e x cl u d e or m a n a g e n o n -
i nf e cti o n p n e u m o niti s
S af et y
A d v er s e e v e nt s
D
X
C o nti n u o u s
U p t o 3 0 d a y s aft er l a st 
d o s e of tr e at m e nt
P K bl o o d s a m pli n g 1
D
7. 2. 3 . 
X1 a
X 1 , 1 a


N o v arti s
C o nfi d e nti al
P a g e 6 7
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
R a n d o mi z e d tr e at m e nt p h a s e
P o st Tr e at m e nt 
F oll o w u p p h a s e
S ur vi v al f oll o w u p 
p h a s e
C at e g or y
Pr ot o c ol 
S e cti o n
S cr e e ni n g /
B a s eli n e
C y cl e 1
E v er y  2 cy c l e s 
aft er C 1 D 1
E n d of st u d y  
tr e at m e nt ( E o T)
Vi sit N a m e
S cr e e ni n g
Vi sit ( D - 2 1
t o D -1)
C 1 D 1
C 3 D 1
C 5 D 1 , et c …
E O T Vi sit ( wit hi n 
7 d of l a st d o s e)
P O S T T R T F U P 1, 2, 
e ct
S ur vi v al f u p
St u d y  tr e at m e nt
a d mi ni str ati o n
E v er oli m u s / Pl a c e b o 
D o si n g
D
C o nti n u o u s d ail y d o si n g
E x e m e st a n e St u d y D o si n g
D
C o nti n u o u s d ail y d o si n g
S ur vi v al F oll o w -u p
D
X e v er y 1 2 w e e k s
1. Bl o o d s a m pl e s f or e v er oli m u s a n d e x e m e st a n e l e v el s will b e c oll e ct e d pr e -d o s e a n d 2 h o ur s p o st d o s e o n C y cl e 1 W e e k 4.
1 a. Bl o o d s a m pl e f or E str a di ol ( E 2) will b e c oll e ct e d at s cr e e ni n g or d a y 1 b ef or e st u d y tr e at m e nt a n d at C y cl e 1 W e e k 4.
A c y cl e i s d efi n e d a s 4 w e e k s ; Vi sit a s s e s s m e nt s wi n d o w i s ± 7 d a y s


N o v arti s
C o nfi d e nti al
P a g e 6 8
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
7. 1. 1
M ol e c ul ar pr e -s cr e e ni n g
N ot a p plica ble.
7. 1. 2
S cr e e ni n g
Writte n
i nf or me d c o nse nt m ust
be o btai ne d bef ore a n y st u dy s pecific assess me nts are 
perf or me d, i ncl u di n g scree ni n g.
T he scree ni n g assess me nts m ust be perf or me d wit hi n ma xi m u m 2 1 da y s t o c o nfir m patie nt’s 
eli gi bilit y a n d t o t he first st u d y treat me nt d ose of ra n d o mize d treat me nt p hase.
L a b orat or y, p h y sical e xa mi nati o n, perf or ma nce stat us a n d vital si g ns assess me nts s h o ul d be 
perf or me d wit hi n 7 da y s bef ore C y cle 1 Da y 1.
T u m or e val uati o n s h o ul d be perf or me d wit hi n 2 1 da y s pri or t o st u d y treat me nt start i n t he 
ra n d o mize d treat me nt p hase o n c ycle 1 da y 1 e xce pt f or b o ne sca ns as n ote d bel o w.
As part of patie nt’s r o uti ne disea se care ( pri or t o si g ni n g st u d y inf or m c o nse nt), wit h pr o per 
d oc u me ntati o n i n patie nt’s file, t he f oll o wi n g t u m or assess me nts ca n be use d:

if b o ne sca n was perf or me d wit hi n 4 wee ks pri or cyc l e 1 da y 1
or

if t u m or sca ns were perf or me d wit hi n 2 1 da ys pri or t o cyc le 1 da y 1.
F or la b orat or y eval uati o ns use d t o deter mi ne eli gi bilit y, a re peate d e val uati o n wit hi n t he 
scree ni n g wi n d o w is per mitte d f or scree ni n g res ults o ut of t he defi ne d ra n ge. If t he re peate d 
la b orat or y res ult meets t he criteria, t hat res ult ma y
be use d t o deter mi ne eli gi bilit y. If t he 
re peate d la b orat or y res ult d oes n ot meet t he criteria, t he patie nt will be c o nsi dere d a scree ni n g 
fail ure.
Perf or ma nce stat us, wei g ht, a n d vital si g ns perf or me d ≤ 7 da y s of t he first d ose of st u d y 
treat me nt d o n ot nee d t o be re peate d o n Da y  1 of C ycle 1.
7. 1. 2. 1
Eli gi bilit y  s cr e e ni n g
F oll o wi n g re gisteri n g i n t he I RT f or scree ni n g, patie nt eli gi bilit y will be c hec ke d o nce all 
scree ni n g pr oce d ures are c o m plete d. T he eli gi bilit y chec k will be e m be d de d i n t he I R T 
s yste m. Please refer a n d c o m pl y wit h detaile d g ui deli nes i n t he IR T ma n ual.
Re -scree ni n g is all o we d, o nl y, f or patie nts w h o meet all of t he i ncl usi o n/e xcl usi o n criteria, b ut
were n ot ra n d o mize d d ue t o o ne of t he f oll o wi n g a d mi nistrati ve reas o ns:

C T / M RI  res ults ha ve e x pire d ( > 2 8 da ys pri or t o ra n d o mizati o n) d ue t o u ne x pecte d
a d mi nistrati ve iss ues

U ne x pecte d dr u g s u p pl y iss ues.
Pr oce d ure f or re -scree ni n g is as f oll o ws:

Site m ust re gister t he patie nt as a scree n fail ure i n I R T

Site is t o se n d a re- scree ni n g re q uest t o the C R A wit hi n 7 da y s of t he scree n fail ure date

S u bject n u m ber will be t he sa me as t he i nitial scree ni n g


N o v arti s
C o nfi d e nti al
P a g e 6 9
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

I nf or me d c o nse nt d oes n’t nee d t o be resi g ne d.

La b assess me nts nee ds t o be t o perf or me d -7 or -1 da y s bef ore ra n d o mizati o n
A d verse e ve nts t hat be gi n or w orse n after i nf or me d c o nse nt s h o ul d be rec or de d i n t he A d verse 
E ve nts C R F. C o n diti o ns t hat were alrea d y prese nt at t he ti me of i nf or me d c o nse nt s h o ul d be 
rec or de d i n Me dical Hist or y C R F.
C R A is t o re vie w a n d c o nfir m patie nt ‘s eli gi bilit y f or re-scree ni n g wit h t he site.
Patie nts ma y  be r e-scree ne d o nl y  once a n d m ust be ra n d o mize d wit hi n 2 8 da y s after t he
rec or de d rescree ni n g date. All e val uati o ns i ncl u di n g ori gi nal assess me nts a n d re peate d
assess me nts m ust be c ollecte d o n t he e C R F.
7. 1. 2. 2
I nf or m ati o n t o b e c oll e cte d o n s cr e e ni n g f ail ur e s
Patie nts w h o si g n a n i nf or me d c o nse nt b ut fail t o be starte d o n treat me nt f or a n y reas o n will 
be c o nsi dere d a scree n fail ure. T he reas o n f or n ot bei n g starte d o n treat me nt will be e ntere d o n 
t he Scree ni n g P hase Dis p ositi o n Pa ge. T h e de m o gra p hic i nf or mati o n, i nf or me d c o nse nt, a n d 
I ncl usi o n/ E xcl usi o n pa ges m ust als o be c o m plete d f or Scree n Fail ure Patie nts. N o ot her data 
will be e ntere d i nt o t he cli nical data base f or patie nts w h o are scree n fail ures, u nless t he patie nt 
e x perie nce d a S eri o us A d verse E ve nt d uri n g t he Scree ni n g P hase (see Secti o n 8 f or S A E 
re p orti n g details). If t he patie nt fails t o be ra n d o mize d, t he IR T m ust be n otifie d wit hi n 2 da y s 
of t he scree n fail t hat t he patie n t was n ot ra n d o mize d.
7. 1. 2. 3
P ati e nt d e m o gr a p hi c s a n d ot h er b a s eli n e c h ar a ct eri sti c s
T he f oll o wi n g patie nt de m o gra p hics a n d baseli ne c haracteristics will be c ollecte d o n t he 
e C R F:

E R a n d H E R 2 stat us

De m o gra p h y i ncl u di n g year of birt h, race a n d et h nicit y

Hei g ht, wei g ht ( See Secti o n 7. 2. 2. 3 )

Dia g n osis a n d e xte nt of ca ncer (i ncl u di n g sta gi n g, hist ol o g y/c yt ol o g y a n d sites of disease 
at st u d y e ntr y)

Me dical hist or y
(e. g., i m p orta nt me dical, s ur gical, a n d aller gic c o n diti o ns fr o m t he 
patie nt’s me dical hist or y w hic h c o ul d ha ve a n i m pact o n t he patie nt’s e val uati o n) / c urre nt 
me dical c o n diti o ns (e. g., all rele va nt c urre nt me dical c o n diti o ns w hic h are prese nt at t he
ti me of si g ni n g i nf or me d c o nse nt). O n g oi n g me dical co n diti o ns, s y m pt o ms a n d disease 
w hic h are rec or de d o n t he Me dical Hist or y  e C R F s h o ul d i ncl u de t he t o xicit y gra de.

Pri or a n d c o nc o mita nt me dicati o ns

Pri or a ntica ncer t hera p y (s ur ger y, me dicati o n, ra di ot herap y); s pecificall y, f or pri or 
a ntica ncer t herap y t he f oll o wi n g data will be c ollecte d: start a n d e n d date of t hera p y , 
setti n g ( neo-a dj u va nt, a dj u va nt, metastatic), best res p o nse a n d reas o n f or disc o nti n uati o n 
of t herap y .

P h ysical E xa mi nati o n ( See Secti o n 7. 2. 2. 1 )

Vital si g ns i ncl u di n g bl o o d press ure a n d p ulse ( See Secti o n 7. 2. 2. 2 )

E C O G perf or ma nce stat us ( See Secti o n 7. 2. 2. 4 )


N o v arti s
C o nfi d e nti al
P a g e 7 0
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

E C G ( See Secti o n 7. 2. 2. 5. 3 )

T u m or e val uati o n ( See Secti o n 7. 2. 1 )

La b orat or y e val uati o ns (e. g., he mat ol o g y , c oa g ulati o n, bi oc he mistry , fasti n g ser u m li pi d 
pr ofile/ uri na lysi s) ( See Secti o n 7. 2. 2. 5 )

He patitis B ser ol ogi c mar kers a n d vi ral l oa d: H B V -D N A H Bs A g, H Bc A b, a n d H B s A b.

T he patie nts liste d i n Secti o n 6. 3. 2. 3 s h o ul d be teste d f or H C V R N A. If t he patie nt is
alrea d y k n o w n t o ha ve a c hr onic i nfecti o n wit h H B V or H C V a n d is ta ki n g a nti-H B V
me dicati o n, t he site d oes n ot ha ve t o wait f or t he scree ni n g H B V or H C V res ults pri or t o
t he first d ose of t he st u d y treatm e nt.

P ul m o nar y  f u ncti o n tests ( P F Ts) ca n be perf or me d at scree ni n g or Treat me nt Da y 1 ( pri or 
t o a d mi nistrati o n of t he st u d y treat me nt) a n d d uri n g t he trial if cli nicall y i n dicate d a n d if 
warra nte d t o e xcl u de or ma na ge n o n -i nfecti o n p ne u m o nitis. C hest C T sca ns als o be
c o nsi dere d a n d ca n be use d f or e xcl u de or ma na ge n o n -i nfecti o us p ne u m o nitis.
7. 1. 3
Tr e at m e nt p eri o d
Patie nts will be ra n d o mize d t o o ne of t he t w o treat me nt ar ms (e ver oli m us pl us e xe mesta ne 
ar m or place b o pl us e xe mesta ne ar m ) wit hi n 7 da y s bef ore C ycle 1 Da y 1. Ra n do mizati o n will 
be stratifie d acc or di n g t o visceral disease stat us a n d se nsiti vit y to pri or h or m o nal t hera py 
stat us. Patie nts will recei ve treat me nt u ntil disease pr o gressi o n, u nacce pta ble t o xicit y, deat h, 
or disc o nti n uati o n fr o m t he st u d y  treat me nt d ue t o a n y ot her reas o n.
7. 1. 4
Di s c o nti n u ati o n of st u d y tr e at m e nt
Patie nts ma y v ol u ntaril y disc o nti n ue fr o m t he st u d y treatm e nt f or a n y reas o n at a n y tim e. If a
patie nt deci des t o disc o nti n ue fr o m t he st u d y treatm e nt, t he i n vesti gat or s h o ul d ma ke a 
reas o na ble eff ort (e. g. tele p h o ne, e- mail, letter) t o u n dersta n d t he pri mar y reas o n f or t his
decisi o n a n d rec or d t his i nf or mati o n i n t he patie nt ’s c hart a n d o n t he a p pr o priate C R F pa ges.
T he y m a y be c o nsi de re d wit h dra w n if t he y state a n i nten ti o n t o wit h dra w, fail t o ret ur n f or
vis its, or bec o m e l ost t o f oll o w-u p f or a ny ot her reas o n.
T he i n vesti gat or s h o ul d disc o nti n ue st u d y treatm e nt f or a gi ve n patie nt , if he/s he belie ves t hat
c o nti n uati o n w o ul d be detri m e ntal t o t he patient ’s w ell- bei n g.
St u d y treatm e nt m ust be disc o nti n ue d u n der t he f oll o wi n g circ um sta nces:

E mer ge nce of s pecific a d verse e ve nts or la b orat or y a b n or malities u n der s o me 
circ u msta nces as o utli ne d i n Secti o n 6 .

Use of pr o hi bite d treatm e nt (refer t o Secti o n 6. 4. 1 )

A n y pr ot oc ol de viati o n t hat res ults i n a si g nifica nt ris k t o t he patie nt’s safet y
T he a p pro priate per so n nel fro m t he site a n d N o vartis will assess w het her st u d y treatm e nt
s h o ul d be disc o nti n ue d f or a n y patie nt w h ose treatm e nt c o de has bee n br o ke n i na d verte ntly
for a n y reas o n.
Patie nt s w h o
disc o nti n ue st u d y treatm e nt s h o ul d N O T
be c o nsi dere d wit h dra w n fr o m t he
st u d y. T he y s h o ul d ret ur n f or t he assessm e nts i n dicate d i n Secti o n 7. 2. 1 . If t he y fail t o ret ur n


N o v arti s
C o nfi d e nti al
P a g e 7 1
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
f or t hese assess m e nts f or u n k n o w n reas o ns, e ver y eff ort (e. g. tele p h o ne, e mail, or letter)
s h o ul d be ma de t o c o ntact t he m as s pecifie d i n Secti o n 7. 1. 7 .
Patie nts w h o disc o nti n ue st u d y  treat me nt s h o ul d u n der g o a n e n d of treat me nt visit.
F or patie nts w h o disc o nti n ue treat me nt f or reas o ns ot her t ha n d oc u me nte d disease pr o gressi o n, 
deat h, l ost t o f oll o w-u p, or wit h dra wal of c o nse nt, t u m or assess me nts m ust c o nti n ue t o be 
perf or me d per assess me nt sc he d ule u ntil d oc u me nte d disease , deat h, l ost t o f oll o w- u p, or 
wit h dra wal of c o nse nt.
T he i n vesti gat or m ust als o c ont act t he I RT t o re gister t he patie nt’s disc o nti n uati o n fr o m st u d y
treatm e nt wit hi n 2 da y s.
7. 1. 4. 1
R e pl a c e m e nt p oli c y
N ot a p plica ble.
7. 1. 5
Wit h dr a w al of c o n s e nt
Patie nts ma y v ol u ntaril y wit h dra w c o nse nt t o pa rtici pate i n t he st u d y f or a n y reas o n at a n y 
tim e. W it h dra wal of c o nse nt o cc urs o nl y w he n a patie nt d o es n ot wa nt t o p artici pate i n th e 
st u d y a n y l o n ger, a n d d oes n ot wa nt a n y f urt her visits or assessm e nts, a n d d oes n ot wa nt a n y 
f urt her st u d y relate d c o ntact.
N o vartis will c o nti n ue t o retai n a n d use all researc h res ults t hat h a ve alrea d y bee n c ollecte d 
f or t he st u d y e val uati o n. All
bi ol o gical sam p les t hat h a ve alrea d y b e e n c ollecte d m a y be 
retai ne d a n d a nal yz e d at a later date ( or as re q uire d b y  l ocal re g ulati o ns).
If a patie nt wit h dra ws
c o nse nt, t he i n vesti gat or s h o ul d m a ke a reas o na ble eff ort (e. g.
tele p h o ne, e - mail, letter) t o u n dersta n d t he pri m ar y reas o n for t his de cisio n a n d reco r d t his 
i nfor m ati o n.
St u d y treatm e nt m ust be disc o nti n ue d a n d n o f urt her assessm e nts c o n d ucte d.
F urt her
attem pts 
t o co ntact
t he p atient
ar e n ot
all o we d u nless
safet y fi n di n gs re q uire 
c o m m u nicati o n or f oll o w u p.
7. 1. 6
F oll o w -u p p eri o d
7. 1. 6. 1
F oll o w u p f or s af et y  e v al u ati o n s
All patie nts m ust ha ve safety e val uati o ns f or 3 0 da y s after t he last d ose of st u d y treat me nt. 
A d verse e ve nts a n d S A E i nf or mati o n will be c ollecte d a n d rec or de d i n t he a p pr o priate e C R Fs. 
Rec or d all c o nc o mita nt me dicati o ns or t hera pies use d/ta ke n t o treat t he S A Es.
A nti ne o plastic t hera py re gi me n recei ve d bet wee n E O T a n d pr o gressi o n will als o be c ollecte d 
as well as t he first re gi me n recei ve d after pr o gressi o n.
F or patie nts w h o are l ost t o f oll o w-u p, t he i n vesti gat or s h o ul d s h o w " d ue dili ge nce" b y  
d oc u me nti n g i n t he s o urce d oc u me nts ste ps ta ke n t o c o ntact t he patie nt, e. g., dates of 
tele p h o ne calls, re gistere d letters, etc. T he i n vesti gat or m ust deter mi ne t he pri mar y  reas o n f or 
a patie nt’s pre mat ure wit h dra wal 
fr o m t he st u d y an d rec or d t his i nf or mati o n o n t he 
a p pr o priate dis p ositi o n C R F.


N o v arti s
C o nfi d e nti al
P a g e 7 2
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
7. 1. 6. 2
P o st -tr e at m e nt foll o w -u p
All patie nts w h o disc o nti n ue d treat me nt d uri n g t he treat me nt p hase f or reas o ns ot her t ha n 
deat h, c o nse nt wit h dra wal,
l ost t o f oll o w- u p or disease pr o gressi o n as per i n vesti gat or 
assess me nt (Secti o n 7. 1. 3 ) will c o nti n ue t u m or assess me nts as per Ta ble 7- 1 t hereafter u ntil 
P D as per i n vesti gat or assess me nt, wit h dra wal of c o nse nt or deat h. O nce t he patie nt ceases 
t u m or f oll o w- u p, t he reas o n f or c o m pleti o n s h o ul d be rec or de d o n t he E n d of P ost Treat me nt 
Dis p ositi o n e C R F pa ge.
7. 1. 6. 3
S ur vi v al f oll o w -u p
All patie nts will be foll o we d f or s ur vi val stat us at least e ver y 3 m o nt hs after ra n d o mize d 
treat me nt p hase or p ost -treat me nt f oll o w- u p p hase, u nless t he y disc o nti n ue d d ue t o deat h, 
c o nse nt wit h dra wal or l ost t o f oll o w- u p. S ur vi val i nf or mati o n ca n be o btai ne d via p h o ne a n d 
i nf ormati o n will be d oc u me nte d i n t he s o urce d oc u me nts a n d e C R F. A d diti o nal
s ur vi val 
assess me nts ma y  be perf or me d m ore fre q ue ntl y if a s ur vi val u p date is re q uire d f or re p orti n g 
t he res ults or t o meet safet y or re g ulat or y re q uire me nts.
7. 1. 7
L o st t o f o llo w -u p
F or patie nts w h ose stat us is u nclear b eca use t he y fail t o a p pear f or st u d y visits wit h o ut statin g 
a n i nte nti o n t o wit h dra w c o nse nt, t he i n vesti gat or s h o ul d s h o w " d ue dili ge nce" b y c o ntacti n g 
t he patie nt, fam il y or fam il y ph y sicia n as ag ree d i n t he i nf orm e d c o nse nt a n d b y d oc u m e nti n g 
i n t he s o urce d oc u m e nts ste ps ta ke n t o c o ntact t he patie nt, e. g. dates of tele p h o ne calls, 
re gistere d letters, etc. A patie nt s h ou l d n ot be c o nsi dere d l ost t o foll o w - u p u ntil d ue dili g e nce 
has bee n c o m plete d. Patie nts l ost t o f oll o w u p s h o ul d be rec or de d as s uc h o n t he a p pr o priate 
Dis p ositi o n C R F.
7. 2
A s s e s s m e nt t y p e s
7. 2. 1
Effi c a c y  a s s e s s m e nt s
Effi c a c y  a s s e s s m e nt s
T u m or res p o nse will be assesse d l ocally a n d ce ntrall y acc or di n g t o t he N o vartis g ui deli ne 
versi o n 3. 2 ( A p pe n di x 1 ) base d o n R E CI S T 1. 1 (Eise n ha uer et al 2 0 0 9 ). T he i ma gi ng 
assess me nt c ollecti o n pla n is prese nte d i n Ta ble 7- 2 . Details of t he ce ntral re vie w pr ocess will 
be descri be d i n t he i n de pe n de nt re vie w c harter.
I ma gi n g data will be ce ntrall y collecte d a n d c hec ke d f or q ualit y b y  an i ma gi n g C o ntract 
Researc h Or ga nizati o n ( C R O) desi g nate d b y  No vartis. C e ntral re vie w s h o ul d st o p after t he 
n u m ber of e ve nts is reac he d f or t he p ri mar y P F S a nal ysis. T he res ults of t he l ocal 
i n vesti gat or’s assess me nt will be use d f or pri mar y a nalys is p ur p oses.


N o v arti s
C o nfi d e nti al
P a g e 7 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a bl e 7- 2
I m a gi n g a s s e s s m e nt c oll e cti o n p l a n
Pr o c e d ur e
S cr e e ni n g/ B a s eli n e
D uri n g Tr e at m e nt/ F oll o w- u p
C h e st, a b d o m e n a n d p el vi s C T or 
M RI( wit h i n tr a v e n o u s c o ntr a st 
e n h a n c e m e nt)
M a n d at e d
M a n d at e d, e v er y 8 w e e k s aft er 
r a n d o mi z ati o n d at e u ntil P D ( ± 7 
d a y s) ; t h e a s s e s s m e nt will b e 
p erf or m e d v er y 1 2 w e e k s aft er
pri m ar y a n al y si s d at a c ut - off or a s 
cli ni c all y i n di c at e d, u ntil P D( ± 7 
d a y s )
Br ai n C T or M RI
M a n d at e d
M a n d at e d
if l e si o n s w er e 
d o c u m e nt e d at b a s eli n e, f oll o w 
s a m e s c h e d ul e a s C T/ M RI of 
c h e st, a b d o m e n, a n d p el vi s
W h ol e b o d y b o n e s c a n
M a n d at e d
If cli ni c all y i n di c at e d
L o c ali z e d b o n e C T, M RI or x- r a y
F or a n y l e si o n s i d e ntifi e d o n t h e w h ol e 
b o d y b o n e s c a n t h at ar e n ot vi si bl e o n 
t h e c h e st, a b d o m e n a n d p el vi s C T or 
M RI
M a n d at e d if l e si o n s w er e 
d o c u m e nt e d at b a s eli n e, f oll o w 
s a m e s c h e d ul e a s C T/ M RI of 
c h e st, a b d o m e n, a n d p el vi s
C ol or p h ot o gr a p h y ( wit h 
s c al e/r ul er)
F or a n y s ki n l e si o n s pr e s e nt
M a n d at e d if l e si o n s w er e 
d o c u m e nt e d at b a s eli n e, f oll o w 
s a m e s c h e d ul e a s C T/ M RI of 
c h e st, a b d o m e n, a n d p el vi s
C T or M RI of ot h er m et a st ati c 
sit e s ( e. g., n e c k)
If cli ni c all y i n di c at e d
M a n d at e d if l e si o n s w er e 
d o c u m e nt e d at b a s eli n e, f oll o w 
s a m e s c h e d ul e a s C T/ M RI of 
c h e st, a b d o m e n, a n d p el vi s
B a s eli n e i m a gi n g a s s e s s m e nt s
I ma gi n g assess me nts will be perf or me d at scree ni n g/ baseli ne wit hi n 2 1 da y s bef ore start of 
treat me nt.
A n y  ima gi n g assess me nts alrea d y c o m plete d d uri n g t he re g ular w or k -u p of t he patie nt wit hi n 
2 1 da y s pri or t o start of treat me nt, i ncl u di n g bef ore si g ni n g the mai n st u d y IC F, ca n b e 
c o nsi dere d as t he baseli ne i ma ges f or t his st u d y. A n y i ma gi n g assess me nts o btai ne d after 
ra n d o mizati o n ca n n ot be c o nsi dere d baseli ne i ma ges. T he f oll o wi n g assess me nts are re q uire d 
at scree ni n g/ baseli ne:

C hest, a b d o me n a n d pel vis C T or M RI

Brai n C T or M RI

W h ole b o d y  b o ne sca n

L ocalize d b o ne C T, M RI or x -ra y, f or a n y lesi o ns i de ntifie d o n t he w h ole b o d y b o ne sca n 
t hat are n ot visi ble o n t he c hest, a b d o me n a n d pel vis C T or M RI

C ol or p h ot o gra p h y f or a n y s ki n lesi o ns prese nt

C T or M RI  of ot her metastatic sites (e. g., nec k), if cli nicall y i n dicate d
If a patie nt is k n o w n t o ha ve a c o ntrai n dicati o n t o C T i ntra ve n o us (I V) c o ntrast me dia or 
de vel o ps a c o ntrai n dicati o n d uri n g t he trial, a n o n- c o ntrast C T of t he c hest ( M RI is n ot 
rec o m me n de d d u e t o res pirat or y artifacts, h o we ver if C T is n ot feasi ble per l ocal re g ulati o ns, 
M RI  ca n be perf or me d i nstea d) pl us a c o ntrast-e n ha nce d M RI  (if p ossi ble) of t he a b d o me n 
a n d pel vis s h o ul d be perf or me d.


N o v arti s
C o nfi d e nti al
P a g e 7 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
If brai n metastases are s us pecte d at baseli ne, brai n M R I or C T s h o ul d be c o m plete d. C o ntrast 
e n ha nce d brai n M RI  is preferre d, h o we ver, if M RI  co ntrast is c o ntrai n dicate d, t he n M R I 
wit h o ut c o ntrast or C T wit h/ wit h o ut c o ntrast is acce pta ble.
A w h ole b o d y  bo ne sca n s h o ul d be perf or me d per i nstit uti o nal sta n dar d of care [e. g., Tc - 9 9 
b o ne sca n, w h ole b o d y  bo ne M RI , Fl u or o de o x y gl uc ose p ositr o n e missi o n t o m o gra p hy ( F D G-
P E T) or s o di u m fl u ori de ( Na F) P E T]. After scree ni n g, w h ole b o d y b o ne sca ns is n ot re q uire d, 
u nless cli nicall y  i n dicate d. If i n dicate d, t he sa me met h o dol o g y  as at scree ni n g s h o ul d be use d.
L ocalize d C T, M RI  or X- ra ys s h o ul d be ac q uire d f or all s keletal lesi o ns i de ntifie d o n t he 
scree ni n g w h ole b o d y  bo ne sca n, w hic h are n ot visi ble o n t he c hest, a b d o me n a n d pel vis 
C T/ M RI . If s keletal lesi o ns are d oc u me nte d at baseli ne, sca ns nee d t o be c o nti n ue d f oll o wi n g
t he sa me sc he d ule as C T/ M RI  of c hest, a b d o me n a n d pel vis. T he sa me met h o d ol o g y
as at 
scree ni n g s h o ul d be use d.
If cli nicall y in dicate d, C T or M RI  of ot her areas (e. g., nec k) of disease as a p pr o priate s h o ul d 
be perf or me d.
If s ki n lesi o ns are prese nt at scree ni n g, c ol or p h ot o gra p h y  sh o ul d be ac q uire d usi n g a di gital 
ca mera i n clear f oc us, i ncl u di n g a scale/r uler, i n s uc h a w a y  that t he size of t he lesi o n(s) ca n 
be deter mi ne d fr o m t he p h ot o gra p h.
A n y  pote ntia ll y meas ura ble lesi o n t hat has bee n pre vi o usl y  treate d wit h ra di ot hera py s h o ul d 
be c o nsi dere d as a n o n- meas ura ble lesi o n. H o we ver, if a lesi o n pre vi o usl y  treate d wit h 
ra di ot hera py has clearl y pr o gresse d si nce t he ra di ot hera py,  it ca n be c o nsi dere d as a 
mea s ura ble lesi o n.
C hest x -ra ys a n d ultras o u n d s h o ul d n ot be use d t o meas ure t u m or lesi o ns.
P o st -b a s eli n e i m a gi n g a s s e s s m e nt s
I ma gi n g assess me nts as descri be d i n Ta ble 7- 2 s h o ul d be perf or me d at t he ti me-p o i nts 
s pecifie d usi n g t he sa me i ma gi n g m o dalit y  use d at baseli ne, irres pecti ve of st u d y treat me nt 
i nterr u pti o n or act ual d osi n g (see Ta ble 7 - 1). I ma gi n g assess me nts f or res p o nse e val uati o n 
will be perf or m e d e ver y 8 wee ks ( ± 7 d a y s) after ra n d o mizati o n. T u m or assess me nts are t o b e 
perf or me d e ver y 12 wee ks after pri mar y  an al y sis data c ut-off a n d as cli nicall y in dicate d, u ntil 
disease pr o gressi o n.
A d diti o nal i ma gi n g assess me nts ma y  be perf or me d at a n y ti me d u ri n g t he st u d y at t he 
i n vesti gat or’s discreti o n t o s u p p ort t he efficac y e val uati o ns f or a s u bject, as necessar y . 
Cli nical s us pici o n of disease pr o gressi o n at a n y ti me re q uires a p h y sical e xa mi nati o n a n d 
i ma gi n g assess me nts t o be perf or me d pr o m ptl y  rat her tha n waiti n g f or t he ne xt sc he d ule d 
i ma gi n g assess me nt.
Eac h lesi o n t hat is meas ure d at baseli ne m ust be meas ure d b y  the sa me met h o d (eit her sa me 
i ma gi n g met h o d or b y  ph ot o gra p h y, i ncl u di n g a metric r uler) a n d w he n p ossi ble, t he sa me 
l ocal ra di ol o gist/ p h ysicia n t hr o u g h o ut t he st u d y s o t hat t he c o m paris o n is c o nsiste nt. If a n off-
sc he d ule i ma gi n g assess me nt is perf or me d beca use pr o gressi o n is s us pecte d, s u bse q ue nt 
i ma gi n g assess me nts s h o ul d be perf or me d i n acc or da nce wit h t he ori gi nal i ma gi n g sc he d ule.


N o v arti s
C o nfi d e nti al
P a g e 7 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
C o m bi n e d P E T/ C T ma y be use d o nl y if t he C T is of si milar dia g n ostic q ualit y  as a C T 
perf or me d wit h o ut P E T, i ncl u di n g t he utilizati o n of I V c o ntrast me dia. At t he discreti o n of t he 
I n vesti gat ors, F D G -P E T sca ns m a y  be perf or me d t o d oc u me nt pr o gressi ve disease per 
R E CI S T 1. 1 ( A p pe n di x 1 ).
All st u d y ima gi n g (i ncl u di n g a n y off -sc he d ule i ma gi n g st u dies) s h o ul d be s u b mitte d t o t he 
desi g nate d i ma gi n g C R O f or q ualit y  c o ntr ol a n d ce ntral re vie w.
7. 2. 2
S af et y  a n d t ol er a bilit y as s e s s m e nt s
Safet y  assess me nts will c o nsist of m o nit ori n g 
a n d rec or di n g all a d verse e ve nts ( A Es), 
i ncl u di n g seri o us a d verse e ve nts ( S A Es), t he re g ular m o nit ori n g 
of he mat ol o g y , ser u m 
c he mistr y, coa g ulati o n, r o uti ne m o nit ori n g of vital si g ns ( heart rate, bl o o d press ure, a n d b o d y 
te m perat ure), wei g ht, E C O G perf or ma nce stat us, C T sca ns of t he c hest, a b d o mi nal, a n d pel vic 
area, p h y sical e xa mi nati o ns, a n d p ul m o nar y  fu ncti o n tests ( P F Ts) if cli nicall y i n dicate d. F or 
details o n A E c ollecti o n a n d re p orti n g, refer t o Secti o n 8 .
T hese assess me nts s h o ul d be perf or me d ± 7 da y s of t he sc he d ule d da y of assess me nt (Ta ble 7 -
1 ) e xce pt f or a d verse e ve nts a n d c o nc o mita nt me dicati o ns t hat will be e val uate d a n d rec or de d 
c o nti n u o usl y t hr o u g h o ut t he st u d y.
Si g nifica nt fi n di n gs of a n y safet y e val uati o n m ust be rec or de d eit her o n t he Me dical Hist or y  
e C R F (if prese nt bef ore si g ni n g i nf or me d c o nse nt) or o n t he A d verse E ve nts e C R F (if ne wl y 
occ urri n g or w orse ni n g si nce si g ni n g i nf or me d c o nse nt).
7. 2. 2. 1
P h y si c al e x a mi n ati o n
A c o m plete p h y sical e xa mi nati o n m ust be perf or me d at scree ni n g a n d later as cli nicall y 
i n dicate d a n d will i ncl u de t he e xa mi nati o n of ge neral a p peara nce, s ki n, nec k (i nclu di n g 
t h yr oi d), e yes, ears, n ose, t hr oat, l u n gs, heart, a b d o me n, bac k, l ym p h n o des, e xtre mities, 
vasc ular a n d ne ur ol o gical. If i n dicate d base d o n me dical hist or y  an d/ or s ym pt o ms, rectal, 
e xter nal ge nitalia, breast, a n d pel vic e xa ms will be perf or me d.
A s h ort p h y sical e xa m will i ncl u de t he e x a mi nati o n of ge neral a p peara nce a n d vital si g ns 
( bl o o d press ure [ B P] a n d p ulse).
Si g nifica nt fi n di n gs t hat were prese nt pri or t o t he si g ni n g of i nf or me d c o nse nt m ust be 
i ncl u de d i n t he Me dical Hist or y  pa ge o n t he patie nt ’s C R F. Si g nifica nt ne w fi n di n gs t hat 
be gi n or w orse n after i nf or me d c o nse nt m ust be rec or de d o n t he A d verse E ve nt pa ge of t he 
patie nt’s C R F.
7. 2. 2. 2
Vit al si g n s
Vital si g ns i ncl u de bl o o d press ure (s u pi ne p ositi o n preferre d w he n E C G is c ollecte d), p ulse 
meas ure me n t, a n d b o d y te m perat ure.
7. 2. 2. 3
H ei g ht a n d w ei g ht
Hei g ht will be meas ure d at scree ni n g.
B o d y wei g ht (i n i n d o or cl ot hi n g, b ut wit h o ut s h oes) will be meas ure d at scree ni n g a n d at 
s u bse q ue nt ti me p oi nts as s pecifie d i n Ta ble 7 - 1.


N o v arti s
C o nfi d e nti al
P a g e 7 6
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
7. 2. 2. 4
P erf or m a n c e st at u s
Assess me nt of E C O G perf or ma nce stat us will be perf or me d as per t he assess me nt sc he d ule i n 
Ta ble 7- 1 ,. M ore fre q ue nt e xa mi nati o ns ma y  be perf or me d at t he i n vesti gat or’s discreti o n, if 
me dicall y  i n dicate d.
T a bl e 7 - 3
E C O G P erf or m a n c e St at u s S c al e
S c or e 
P erf or m a n c e St at u s
0
F ull y a cti v e, a bl e t o c arr y o n all pr e- di s e a s e p erf or m a n c e wit h o ut r e stricti o n.
1
R e stri ct e d i n p h y s ic all y st re n u o u s a c ti vit y b ut a m b ul at or y a n d a bl e t o c arr y o ut w or k of a li g ht or 
s e d e n t ar y n at ur e, e. g ., li g ht h o u s e wor k, offi c e w or k.
2
A m b ul at or y a n d c a p a b le of all s elf - c ar e b ut u n a bl e t o c arr y o ut a n y w or k a c ti viti e s. U p an d a b o ut m o r e 
t h a n 5 0 % of w a kin g h o u r s.
3
C a p a bl e of o nl y li mit e d s e lf- car e, c o nfi n e d t o b e d or c h air m o r e t ha n 5 0 % of w a ki n g h o u r s.
4
C o m p let el y di s a b le d. C a n n ot c arr y o n a n y s e lf-c ar e. T ot all y c o nfi n e d t o b e d or c h air
5  
D e a d
7. 2. 2. 5
L a b or at or y  e v al u ati o n s
T he sta n dar d cli nical la b orat or y anal y ses descri be d bel o w are t o be perf or me d b y  the st u d y 
site’s l ocal la b orat ories acc or di n g t o t he Visit Sc he d ule, o utli ne d i n Ta ble 7- 1 . M ore fre q ue nt 
e xa mi nati o ns ma y  be perf or me d at t he i n vesti gat or’s discreti o n if me dicall y i n dicate d; res ults 
s h o ul d be rec or de d i n t he e C R Fs.
N o vartis m ust be pr o vi de d wit h a c o p y of t he la b orat or y certificati o n a n d a ta b ulati o n of t he 
n or mal ra n ges f or eac h para meter re q uire d. I n a d diti o n, if at a n y ti me a patie nt has la b orat or y 
para meters o btai ne d fr o m a differe nt o utsi de la b orat or y, N o vartis m ust be pr o vi de d wit h a 
c o p y of t he certificati o n a n d a ta b ulati o n of t he n or mal ra n ges f or t hat la b orat or y.
A b n or mal la b orat or y par a meters w hic h are cli nicall y rele va nt (e. g., re q uire d ose m o dificati o n 
a n d/ or i nterr u pti o n of st u d y treat me nt, lea d t o cli nical s ym pt o ms 
or si g ns or re q uire 
t hera pe utic i nter ve nti o n), w het her s pecifically re q ueste d i n t he pr ot oc ol or n ot, m ust be 
rec or de d i n t he e C R F. W he n a b n or mal la b orat or y val ues or test res ults c o nstit ute a n a d verse 
e ve nt (Secti o n 8. 1. 1 ) it m ust be rec or de d o n t he e C R F A d verse E ve nts pa ge.
He mat ol o g y , bi oc he mistr y , li pi d pa nel, a n d c oa g ulati o n assess me nts perf or me d ≤ 7 d a y s of 
t he first d ose of st u dy treat me nt d o n ot nee d t o be re peate d o n Da y 1 of C ycle 1.
T he fre q ue nc y of t he assess m e nts is i n dicate d i n Ta ble 7- 1 a n d is t o be re peate d if cli nicall y 
i n dicate d.


N o v arti s
C o nfi d e nti al
P a g e 7 7
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a bl e 7- 4
L o c al c li ni c al l a b or at or y p ar a m et er s c oll e cti o n pl a n
T e st C at e g or y
T e st N a m e
H e m at ol o g y
H e m at o crit, H e m o gl o bi n, Pl at el et s, R e d bl o o d c ell s, W hit e bl o o d c ell s, Diff er e nti al 
( B a s o p hil s, E o si n o p hil s, L y m p h o c yt e s, M o n o c yt e s, N e utr o p hil s)
Bi o c h e mi str y
Al b u mi n, Al k ali n e p h o s p h at a s e, A L T, A S T, G a m m a -gl ut a m yl -tr a n sf er a s e ( G G T), L a ct at e 
d e h y dr o g e n a s e ( L D H), C al ci u m, M a g n e si u m, P h o s p h or u s, S o di u m, P ot a s si u m, T ot al 
Pr ot ei n, Cr e ati ni n e, Cr e ati n e ki n a s e, Dir e ct Bilir u bi n, T ot al Bilir u bi n, L D L, H D L Bl o o d Ur e a 
Nitr o g e n ( B U N) or Ur e a, Uri c A ci d , Gl u c o s e (f a sti n g)
C o a g ul ati o n
I nt er n ati o n al n or m ali z e d r ati o [I N R], A cti vat e d p arti al t hr o m b o pl a sti n ti m e ( A P T T)
S er u m li pi d pr ofil e
T ot al c h ol e st er ol a n d tri gl y c eri d e s
H e p atiti s m ar k er s
H B V -D N A, H b s A g, H b s A b, H b c A b, H C V R N A -P C R ( b a s eli n e)
7. 2. 2. 5. 1 H e m at ol o g y
He mat ol o g y  tests i ncl u de a c o m plete bl o o d c o u nt ( C B C). A t otal w hite bl o o d cell ( W B C)
wit h a bs ol ute differe ntials (i ncl u di n g ne utr o p hil c o u nt pl us ba n ds, l ym p h oc y te, m o n oc y te,
e osi n o p hil, bas o p hil c o u nts), he m o gl o bi n ( H g b), a n d a platelet c o u nt. He mat ol o gic tests will 
be perf or me d at scree ni n g or o n C 1 D 1 (re peate d pri or t o a d mi nistrati o n of t he st u d y treat me nt, 
if greater t ha n 7 da ys si nce scree ni n g), a n d t he n e ver y 2 c ycles after C 1 D 1.
7. 2. 2. 5. 2 Cli ni c al c h e mi str y / s er u m li pi d pr ofil e
Ser u m c he mistr y tests i ncl u de Al b u mi n, Al kali ne p h os p hatase, A L T, A S T, Ga m ma -gl uta m yl -
tra nsferase ( G G T), La ctate de h y dr o ge nase ( L D H), Calci u m, 
Ma g nesi u m, 
P h os p h or us, 
S o di u m, P otassi u m, Creati ni ne, Creati ne ki nase, Direct Bilir u bi n, T otal Bilir u bi n, T otal 
P r otei n, T otal C h olester ol , L D L,  HD L, T otal Tri gl yceri des, Bl o o d Urea Nitr o ge n ( B U N) or 
Urea, Uric Aci d , Gl uc ose(fasti n g state f or at least 1 2 h o urs). Ser u m c he mistries m ust be 
perf or me d at scree ni n g or o n C 1 D 1 (re peate d pri or t o a d mi nistrati o n of t he st u d y treat me nt, if 
greater t ha n 7 da y s si nce scree ni n g), a n d t he n e ver y 2 c ycles after C 1 D 1.
7. 2. 2. 5. 3 El e ctr o c ar di o gr a m ( E C G)
A sta n dar d 1 2 lea d E C G will be perf or me d

A t scree ni n g a n d/ or baseli ne

If cli nically i n dicate d
Eac h E C G traci n g s h o ul d be la bele d wit h t he st u d y n u m ber, patie nt i nitials ( w here re g ulati o ns 
per mit), s u bjectn u m ber, date, a n d ke pt i n t he s o urce d oc u me nts at t he st u d y site. Cli nicall y 
si g nifica nt a b n or malities prese nt w he n t he patie nt si g ne d i nf or me d c o nse nt s h o ul d be re p orte d 
o n t he Me dical Hist or y C R F pa ge. Cli nicall y si g nifica nt fi n di n gs m ust be disc usse d wit h 
N o vartis pri or t o e nr olli n g t he patie nt i n t he st u d y. Ne w
(i ncl u di n g ne w or w orse ne d)
cli nicall y si gnifica nt fi n di n gs occ urri n g after i nf or me d c o nse nt m ust be rec or de d o n t he 
A d verse E ve nts C R F pa ge.
Baseli ne E C G is a sta n dar d 1 2 lea d a n d m ust be perf or me d wit hi n 1 4 da y s of first d ose f or 
patie nts e nr olle d a n d ma y be re peate d at t he i n vesti gat or’s discreti o n if cli nicall y in dicate d.
Sta n dar d tri plicate 1 2 lea d E C G rec or di n g will be perf or me d after t he patie nt has bee n resti n g 
f or a p pr o xi matel y 1 0 mi n pri or t o eac h E C G c ollecti o n ti me poi nt .


N o v arti s
C o nfi d e nti al
P a g e 7 8
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
A d diti o nal, u nsc he d ule d, safet y EC Gs m a y  be re peate d at t he discreti o n of t he i n vesti gat or at 
a n y ti me d uri n g t he st u d y as cli nicall y in dicate d. U nsc he d ule d 
E C Gs wit h 
cli nicall y 
si g nifica nt fi n di n gs s h o ul d be c ollecte d i n tri plicate. L o cal car di ol o gist E C G assess me nt ma y 
als o be perf or me d at a n y ti me d uri n g t he st u dy at t he discreti o n of t he i n vesti gat or.
7. 2. 3 
P h ar m a c o ki n eti c s
P har mac o ki netic bl o o d sa m ple c ollecti o n a n d ha n dli n g are descri be d i n Secti o n 7. 2. 3. 1 .
Bl o o d sa m ples f or Estra di ol ( E 2) le vels will be o btai ne d at scree ni n g ( or at Da y  1 pri or t o 
st u d y treat me nt) a n d at C y cle 1 Wee ks 4 or a n y later o ne of t he sc he d ule d visits. T his will 
all o w e val uati o n of c ha n ges i n estra di ol le vels after 4 wee ks of st u d y treat me nt.
Pre -d ose bl o o d sa m ples f or e ver oli m us a n d e xe mesta ne tr o u g h le vels will be c ollecte d at 
stea d y state at C y cle 1 Wee k 4 or a n y o ne of later sc he d ule d visits. Stea d y -state is defi ne d as 
ha vi n g n o d ose a dj ust me nt/i nterr u pti o n of e ver oli m us a n d e xe mesta ne i n t he pre vi o us 4 d a y s 
pri or t o t he da y  of t he pre-d ose P K sa m ple c ollecti o n.
O n t he d a y s of pre -d ose P K sa m ple c ollecti o n, patie nts s h o ul d c o me bac k t o t he cli nic t o g et 
t heir me dicati o ns a n d i n gest t he me dicati o ns at t he cli nic i m me diately after c ollecti o n of t he 
pre -d ose bl o o d sa m ples. T hese pre -d ose bl o o d sa m ples will all o w deter mi nati o n of C mi n f or 
e ver oli m us a n d e xe mesta ne.
Patie nts w h o ha ve i n geste d t heir me dicati o ns at h o me pri or t o t he st u d y visit or ha ve d ose 
a dj ust me nt/i nterr u pti o n i n t he pre vi o us 4 d a y s s h o ul d n ot ha ve t heir P K bl o o d sa m ples 
c ollecte d at t hat st u d y visit, a n d t he c ollecti o n of t he P K bl o o d sa m ples will be p ost p o ne d t o 
t he ne xt sc he d ule d visit.
T he c ollecti o n date a n d ti me of all pre -d ose P K sa m ples m ust be d oc u me nte d ( b ot h f or 
e ver oli m us a n d e xe mesta ne, se parately) i n t he P har mac o ki netic Bl o o d C ollecti o n e C R F pa ges. 
T he e xact date a n d ti me of t he e ver oli m us a n d e xe mesta ne d oses a d mi nistere d o n t he pre vi o us 
da y  pri or t o t he visit da y for t he pre -d ose P K sa m ple m ust be e ntere d o n t he e C R F. I n a d diti o n, 
t he e xact date a n d ti me of t he e ver oli m us a n d e xe mesta ne d oses a d mi nistere d i m me diately 
after t he pre -d ose P K sa m ple c ollecti o n o n t he visit da y  m ust be e ntere d o n t he e C R F.
If t he patie nt v o mits wit hi n t he first 4 h o urs f oll o wi n g st u d y-dr u g a d mi nistrati o n o n t he da y of 
or t he d a y bef ore p har mac o ki netic bl o o d sa m pli n g, t he ti me ( usi n g t he 2 4- h o urs cl oc k) of 
v o miti n g s h o ul d be rec or de d o n t he A E e C R Fs, a n d t he c ollecti o n of t he P K bl o o d sa m ples 
will be p ost p o ne d t o t he ne xt sc he d ule d visit.
N o a d diti o nal trial me dicati o n s h o ul d be ta ke n t hat d a y  in a n eff ort t o re place t he st u d y dr u g 
t hat has bee n v o mite d.
If e ver oli m us a d mi nistrati o n has bee n i nterr u pte d d ue t o st u d y dr u g s us pecte d t o xicities, t he n 
t he P K sa m ple c ollecti o n s h o ul d be p ost p o ne d t o t he ne xt visit.
7. 2. 3. 1
P h ar m a c o ki n eti c bl o o d s a m pl e c oll e cti o n a n d h a n dli n g
Bl o o d P K sa m ples will be c ollecte d b y  eit her direct ve ni p u nct ure or a n i n d welli n g ca n n ula 
i nserte d i n a f orear m vei n ( 2 ml of ve n o us bl o o d f or e ver oli m us le vels, 4 m L  for e xe mesta ne 


N o v arti s
C o nfi d e nti al
P a g e 7 9
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
f or deter mi nati o n i n plas ma, 5 ml f or estra di ol le vels) acc or di n g t o t he f oll o wi n g sc he d ules 
(Ta ble 7 - 5) descri be d a b o ve.
E v er oli m u s
At
C y cle 1 Wee k 
4, a n y da y duri n g wee k 4,
i m me diatel y bef ore a n d 2 h o urs after 
a d mi nistrati o n of e ver oli m us o n t hat d a y , 2 m L of bl o o d will be c ollecte d i nt o a n E D T A 
c o ntai ni n g t u be. I m me diatel y after eac h t u be of bl o o d is dra w n, it s h o ul d be i n verte d ge ntl y 
se veral ti mes t o e ns ure t he mi xi n g of t u be c o nte nts (e. g., a ntic oa g ula nt). Pr ol o n ge d c o ntact 
m ust be a v oi de d wit h r u b ber st o p per. T he w h ole bl o o d sa m ple will t he n be tra nsferre d t o a 
la bele d p ol y pr o p yl e ne scre w ca p t u be a n d st ore d at -2 0° C or bel o w wit hi n 6 0 mi n utes of t he 
dra w ti me.
E x e m e st a n e
At C y cle 1 Wee k 
4, a n y da y duri n g wee k 4 , i m me diatel y bef ore a n d 2 h o urs after 
a d mi nistrati o n of e xe mesta ne, 4 ml of bl o o d will be c ollecte d i n he pari nize d t u bes, c hille d i n 
a n ice-water bat h a n d ce ntrif u ge d at 4° C ( 1 2 0 0 g, 1 0 mi n) wit hi n 3 0 mi n, t o a v oi d p ossi ble 
de gra dati o n of pare nt dr u g. Plas ma sa m ples will be st ore d at - 2 0° C or bel o w u ntil a nal ysis 
a n d wit hi n 6 0 mi n of t he dra w ti me.
E str a di ol ( E 2 )
At scree ni n g or at da y  1 bef ore st u d y treat me nt a n d at Cycle 1 Wee k 4 , a n y da y d uri n g wee k 4, 
visit 4 ( wee k 4) bef ore a d mi nistrati o n of e ver oli m us a n d e xe mesta ne, 5 ml of bl o o d will be 
c ollecte d i n he pari nize d vials. Plas ma will be se parate d b y  ce ntrif u gati o n wit hi n 3 0 mi n a n d 
st ore d at - 2 0 ° C or bel o w u ntil a nal y sis a n d wit hi n 6 0 mi n of t he dra w ti me.


N o v arti s
C o nfi d e nti al
P a g e 8 0
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a b l e 7- 5
P K bl o o d c oll e cti o n s c h e d ul e
A n al yt e / 
Dr u g
Vi sit
N a m e
D a y
Ti m e p oi nt
P K 
S a m pl e 
n u m b er
D o s e 
R ef er e n c e I D
Bl o o d 
V ol. 
( m L)
E str a di ol ( E 2 )
S cr e e ni n g/ b
a s eli n e
-7 t o 1
Fr o m -7 d a y s b ef or e 
t o d a y 1 at pr e-d o s e 
( pri or t o a n y st u d y 
dr u g)
1
1
5 m L
E str a di ol ( E 2 )
C y cl e 
1/ w e e k 4
W e e k 4
Pr e- d o s e ( pri or t o a n y 
st u d y dr u g)
2
2/ 3*
5 m L
E v er oli m u s/
Pl a c e b o
C y cl e 
1/ w e e k 4
W e e k 4
Pr e- d o s e ( pri or t o 
e v er oli m u s 
a d mi ni str ati o n)
1 0 1
1 0 1/ 1 0 2*
2 ml
E v er oli m u s/
Pl a c e b o
C y cl e 
1/ w e e k 4
W e e k 4
2 h o ur s p o st 
e v er oli m u s 
a d mi ni str ati o n
1 0 2
1 0 1
2 ml
E x e m e st a n e
C y cl e 
1/ w e e k 4
W e e k 4
Pr e- d o s e ( pri or t o 
e x e m e st a n e 
a d mi ni str ati o n)
2 0 1
2 0 1/ 2 0 2*
4 m L
E x e m e st a n e
C y cl e 
1/ w e e k 4
W e e k 4
2 h o ur s p o st 
e x e m e st a n e 
a d mi ni str ati o n
2 0 2
2 0 1
4 m L

E x a ct d at e a n d ti m e of l a st tr e at m e nt a d mi ni str ati o n ( e v er oli m u s a n d e x e m e st a n e s e p ar at el y) m u st b e 
r e c or d e d o n t h e e C R F. Al s o, e x a ct d at e s a n d ti m e s of s a m pl e c oll e cti o n m u st b e r e c or d e d o n t h e 
P h ar m a c o ki n eti c Bl o o d C oll e cti o n e C R F. E x a m pl e: F or e v er oli m u s pr e - d o s e 2 m L bl o o d s a m pl e, t h e ti m e 
a n d t h e d at e of t h e e v er oli m u s a d mi ni str ati o n o n t h e e v er oli m u s P K bl o o d s a m pl e s c oll e cti o n d a y s h o ul d b e 
r e c or d e d. I n a d diti o n t h e ti m e a n d d at e of t h e l a st e v er oli m u s a d mi ni str ati o n o n t h e pr e vi o u s d a y s h o ul d 
al s o b e r e c or d e d.

If P K s a m pl e s c a n n ot b e c oll e ct e d fr o m a p ati e nt at t h e s c h e d ul e d vi sit ( We e k 4) f or r e a s o n s s u c h a s t h e 
s a m pl e w o ul d n ot b e at st e a d y -st at e d u e t o d o s e i nt err u pti o n or v o miti n g of t h e pri or d o s e, t h e p ati e nt 
s h o ul d c o m e b a c k at t h e n e xt s c h e d ul e d vi sit t o h a v e t h e P K s a m pl e s c oll e ct e d.

T h e fir st d o s e r ef er e n c e I D r ef er s t o t h e fir st d o s e of e v er oli m u s r e c ei v e d aft er c oll e cti o n of t h e pr e-d o s e P K 
s a m pl e, w hil e t h e s e c o n d d o s e r ef er e n c e I D i s t h e l a st d o s e t h e s u bj e ct r e c ei v e d pri or t o t h e c oll e cti o n of 
t h e pr e-d o s e P K s a m pl e
P h ar m a c o ki n eti c s a m pl e s hi p m e nt
All sa m ples m ust be la bele d a n d fr oze n u p o n c ollecti o n bel o w -2 0° C a n d ke pt fr oze n 
t hereafter. At t he e n d of eac h treat me nt peri o d, all sa m ples m ust be caref ull y pac ke d i n 
s uita ble pac ki n g material c o ntai ni n g s ufficie nt dr y ice t o kee p t he m fr oze n d uri n g s hi p me nt.
A list of sa m ples, i ncl u di n g t he date, s u bject i nitials a n d n u m ber, a n d ti me of sa m pli n g has t o 
be se nt wit h t he sa m ples. A n y  missi n g sa m ples s h o ul d be fla g ge d o n t he list.
A nal y sis of p har mac o ki netic sa m ples will be ce ntralize d. Details re gar di n g a d dresses of 
s hi p me nts, carrier rec o m me n dati o ns, la beli n g of t he parcels, d a y s of s hi p me nts, c o ntact 
details a n d ot her sa m ples l o gistics will be pr o vi de d i n a se parate d la b orat or y  ma n ual.
7. 2. 3. 2
A n al y ti c al m et h o d
E ver oli m us c o nce ntrati o ns i n w h ole bl o o d will be deter mi ne d b y  a LC- M S/ M S met h o d. T he 
l o wer li mit of q ua ntitati o n ( L L O Q) will be 0. 3 n g/ m L.


N o v arti s
C o nfi d e nti al
P a g e 8 1
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
E xe mesta ne will be deter mi ne d i n plas ma usi n g a L C -M S/ M S met h o d. T he me t h o d has a 
l o wer li mit of q ua ntificati o n ( L L O Q) of 2 0 p g/ m L.
Estra di ol will be deter mi ne d i n plas ma usi n g c o m petiti ve i m m u n oassa y. T he L L O Q of t he 
assa y is e q ui vale nt t o 2. 0 p m ol/ L estra di ol i n plas ma sa m ples.
7. 2. 4
Bi o m ar k er s
N ot a p plica ble.
7. 2. 5
R e s o ur c e utili z ati o n
N ot a p plica ble.
7. 2. 6
P ati e nt r e p ort e d o ut c o m e s
N ot a p plica ble
8
S af et y  m o nit ori n g a n d r e p orti n g
8. 1
A d v er s e e v e nt s
8. 1. 1
D efi niti o n s a n d r e p orti n g
A n a d verse e ve nt is defi ne d as t he a p peara nce of ( or w orse ni n g of a n y pre-e xisti n g) 
u n desira ble si g n(s), s ym pt o m(s), or me di cal c o n diti o n(s) t hat occ ur after patie nt’s si g ne d 
i nf or me d c o nse nt has bee n o btai ne d.
A b n or mal la b orat or y val ues or test res ults occ urri n g after i nf or me d c o nse nt c o nstit ute a d verse 
e ve nts o nl y  if t he y in d uce cli nical si g ns or s ym pt o ms, are c o nsi dere d cli nicall y si gnifica nt, 
re q uire t hera p y (e. g., he mat ol o gic a b n or malit y t hat re q uires tra nsf usi o n or he mat ol o gical ste m 
cell s u p p ort), or re q uire c ha n ges i n st u d y  me dicati o n(s).
A d verse e ve nts t hat be gi n or w orse n after i nf or me d c o nse nt s h o ul d be rec or de d i n t h e A d verse 
E ve nts eC R F . C o n diti o ns t hat were alrea d y prese nt at t he ti me of i nf or me d c o nse nt s h o ul d be 
rec or de d i n t he Me dical Hist or y  CR F pa ge of t he patie nt’s C R F. A d verse e ve nt m o nit ori n g 
s h o ul d be c o nti n ue d f or at least 3 0 da y s f oll o wi n g t he last d ose o f st u d y treat me nt. A d verse 
e ve nts (i ncl u di n g la b a b n or malities t hat c o nstit ute A Es) s h o ul d be descri be d usi n g a dia g n osis 
w he ne ver p ossi ble, rat her t ha n i n di vi d ual u n derl y i n g si g ns a n d s ym pt o ms. W he n 
a clear 
dia g n osis ca n n ot be i de ntifie d, eac h si g n or s ym pt o m s h o ul d be re p orte d as a se parate 
A d verse E ve nt.
T he a d verse e ve nts of s pecial i nterest ( A E SIs) i ncl u de t he f oll o wi n g cate g or y

St o matitis/

Pre -e xisti n g i nfecti o n (reacti vati o n, a g gra vati o n, or e xacer bati o n)

Car diac fail ure
A d verse e ve nts will be assesse d acc or di n g t o t he C o m m o n Ter mi n ol o g y  Criteria f or A d verse 
E ve nts ( C T C A E) versi o n 4. 0 3.


N o v arti s
C o nfi d e nti al
P a g e 8 2
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
If C T C A E gra di n g is n ot a vaila ble f or a n a d verse e ve nt, t he se verit y of mil d, m o derate, se vere, 
a n d life-t hreate ni n g, deat h relate d t o t he A E c orres p o n di n g t o Gr a des 1 - 5, res pecti vel y, will 
be use d. I nf or mati o n a b o ut a n y deat hs (relate d t o a n A d verse E ve nt or n ot) will als o be 
c ollecte d t h o u g h a Deat h f or m .
T he occ urre nce of a d verse e ve nts s h o ul d be s o u g ht b y  n o n-directi ve q uesti o ni n g of t he patie nt 
(s u bject) d u ri n g t he scree ni n g pr ocess after si g ni n g i nf or me d c o nse nt a n d at eac h visit d uri n g 
t he st u d y. A d verse e ve nts als o m a y  be detecte d w he n t he y are v ol u nteere d b y  the patie nt 
(s u bject) d uri n g t he scree ni n g pr ocess or bet wee n visits, or t hr o u g h p h ysical e xa mi nati o n, 
la b orat or y test, or ot her assess me nts. As far as p ossi ble, eac h a d verse e ve nt s h o ul d be 
e val uate d t o deter mi ne:
1.
T he se verit y gra de ( C T C A E Gra de 1 - 5)
2.
Its d urati o n ( Start a n d e n d dates)
3.
Its relati o ns hi p t o t he st u d y treat me nt ( Reas o na ble p ossi bilit y t hat A E is relate d: [ N o ; Yes , 
Yes, i n vesti gati o nal treat me nt; Y es, ot her st u d y treat me nt ( n o n-i n vesti gati o nal); Y es, b ot h 
a n d/ or i n disti n g uis ha ble ]
4.
Acti o n ta ke n wit h res pect t o st u d y  or i n vesti gati o nal treat me nt (d ose i ncrease d, d o se n ot 
c ha n ge d, d ose re d uce d, dr u g i nterr u pte d, dr u g wit h dra w, u n k n o w n, n ot a p plica ble
5.
W het her me dicati o n or t hera p y was gi ve n ( n o c o nc o mita nt me dicati o n/ n o n -dr u g t hera p y,  
c o nc o mita nt me dicati o n/ n o n -dr u g t hera p y)
6.
W het her it is seri o us, w here a seri o us a d verse e ve nt ( S A E) is de fi ne d as i n Secti o n 8. 2. 1
a n d w hic h seri o us ness criteria ha ve bee n met
7.
O utc o me ( n ot rec o vere d/ n ot res ol ve d, rec o vere d/res ol ve d, rec o veri n g/res ol vi n g, 
rec o vere d/res ol ve d wit h se q ualae, fatal, u n k n o w n)
If t he e ve nt w orse ns t he e ve nt s h o ul d be re p orte d a sec o n d ti me i n t he C R F n oti n g t he start 
date w he n t he e ve nt w orse ns i n t o xicit y. F or gra de 3 a n d 4 a d verse e ve nts o nl y , if 
i m pr o ve me nt t o a l o wer gra de is deter mi ne d a ne w e ntr y for t his e ve nt s h o ul d be re p orte d i n 
t he C R F n oti n g t he start date w he n t he e ve nt i m pr o ve d fr o m ha vi n g bee n Gra de 3 or Gra de 4.
All a d verse e ve nts s h o ul d be treate d a p pr o priatel y. If a c o nc o mita nt me dicati o n or n o n- dr u g 
t hera py is gi ve n, t his acti o n s h o ul d be rec or de d o n t he A d verse E ve nt C R F.
O nce a n a d verse e ve nt is detecte d, it s h o ul d be f oll o we d u ntil its res ol uti o n or u ntil it is 
j u d ge d t o be per ma ne nt, a n d assess me nt s h o ul d be ma de at eac h visit ( or m ore fre q ue ntl y, if 
necessar y ) of a n y c ha n ges i n se verity, t he s us pecte d relati o ns hi p t o t he st u d y treat me nt, t he 
i nter ve nti o ns re q uire d t o treat it, a n d t he o utc o me.
8. 1. 2
L a b or at or y  t e st a b n or m aliti e s
8. 1. 2. 1
D efi niti o n s a n d r e p orti n g
La b orat or y  ab n or malities t hat c o nstit ute a n A d verse e ve nt i n t heir o w n ri g ht (are c o nsi dere d 
cli nicall y si gnifica nt, i n d uce cli nical si g ns or s ym pt o ms, re q uire c o nc o mita nt t hera p y or 
re q uire c ha n ges i n st u d y treat me nt), s h o ul d be rec or de d o n t he A d verse E ve nts C R F. 
W he ne ver 
p ossi ble, a dia g n osis, rat her t ha n a s ym pt o m s h o ul d be pr o vi de d (e. g. a ne mia 
i nstea d of l o w he m o gl o bi n). L a b orat or y ab n or malities t hat meet t he criteria f or A d verse 
E ve nts s h o ul d be f oll o we d u ntil t he y ha ve ret ur ne d t o n or mal or a n a de q uate e x pla nati o n of 


N o v arti s
C o nfi d e nti al
P a g e 8 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
t he a b n or malit y is f o u n d. W he n 
a n a b n or mal la b orat or y or test res ult c orres p o n ds t o a 
si g n/s ym pt o m of a n a lrea d y re p orte d a d verse e ve nt, it is n ot necessar y t o se paratel y rec or d t he 
la b/test res ult as a n a d diti o nal e ve nt.
La b orat or y  ab n or malities, t hat d o n ot meet t he defi niti o n of a n a d verse e ve nt, s h o ul d n ot be 
re p orte d as a d verse e ve nts. A Gra de 3 or 4 e ve nts (se vere) as per C T C A E d oes n ot 
a ut o maticall y in dicate a S A E u nless it meets t he defi niti o n of seri o us as defi ne d bel o w a n d/ or 
as per i n vesti gat or’s discreti o n. A d ose h ol d or me dicati o n f or t he la b a b n or malit y ma y be 
re q uire d b y  the pr ot oc ol i n w hic h case t he la b a b n or malit y wo ul d still, b y defi niti o n, be a n 
a d verse e ve nt a n d m ust be re p orte d as s uc h.
8. 2
S eri o u s a d v er s e e v e nt s
8. 2. 1
D efi niti o n s
Seri o us a d verse e ve nt ( S A E) is defi ne d as o ne of t he f oll o wi n g:

Is fatal or life-t hreate ni n g

Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y

C o nstit utes a c o n ge nital a n o mal y / birt h defect

Is me dically si g nifica nt, i.e., defi ne d as a n e ve nt t hat je o par dizes t he patie nt or ma y 
re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve

Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n,

N ote t hat h os pitalizati o ns f or t he f oll o wi n g reas o ns s h o ul d n ot be re p orte d as seri o us 
a d verse e ve nts:

R o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass ociate d wit h a n y  
deteri orati o n i n c o n diti o n

Electi ve or pre -pla n ne d treat me nt f or a pre -e xisti n g c o n diti o n t hat is u nrelate d t o t he 
i n dicati o n u n der st u d y a n d has n ot w orse ne d si nce si g ni n g t he i nf or me d c o nse nt

S ocial reas o ns a n d res pite care i n t he a bse nce of a n y deteri orati o n i n t he patie nt’s 
ge neral c o n diti o n

N ote t hat treat me nt o n a n e mer ge nc y o ut patie nt basis t hat d oes n ot res ult i n h os pital 
a d missi o n a n d i n v ol ves a n e ve nt n ot f ulfilli n g a n y of t he defi niti o ns of a S A E gi ve n a b o ve 
is n ot a seri o us a d verse e ve nt
8. 2. 2
R e p orti n g
T o e ns ure patie nt safety, e ver y SA E, re gar dless of s us pecte d ca usalit y, occ urri n g after t he 
patie nt has pr o vi de d i nf or me d c o nse nt a n d u ntil at least 3 0 da y s after t he patie nt has st o p pe d 
st u d y treat me nt m ust be re p orte d t o N o vartis wit hi n 2 4 ho urs of lear ni n g of its occ urre nce.
A n y  ad diti o nal i nf or mati o n f or t he S A E i ncl u di n g c o m plicati o ns, pr o gressi o n of t he i nitial 
S A E, a n d rec urre nt e pis o des m ust be re p orte d as f oll o w- u p t o t he ori gi nal e pis o de wit hi n 2 4 
h o urs of t he i n vesti gat or recei vi n g t he f oll o w -u p i nf or mati o n. A n S A E occ urri n g at a differe nt 
ti me i nter val or ot her wise c o nsi dere d c o m pletel y unrelate d t o a pre vi o usl y  re p orte d o ne 
s h o ul d be re p orte d se paratel y as a ne w e ve nt.


N o v arti s
C o nfi d e nti al
P a g e 8 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
A n y  SA Es e x perie nce d after t he 3 0 d a y  safet y e val uati o n f oll o w- u p peri o d s h o ul d o nl y  be 
re p orte d t o N o vartis if t he i n vesti gat or s us pects a ca usal relati o ns hi p t o t he st u d y treat me nt.
I nf or mati o n a b o ut all S A Es is c ollecte d a n d rec or de d o n t he Seri o us A d verse E ve nt Re p ort 
F or m; all a p plica ble secti o ns of t he f or m m ust be c o m plete d i n or der t o pr o vi de a cli nicall y 
t h or o u g h re p ort. T he i n vesti gat or m ust assess a n d rec or d t he relati o ns hi p of eac h S A E t o eac h 
s pecific st u d y treat me nt (if t here is m ore t ha n o ne st u d y treat me nt), c o m plete t he S A E Re p ort 
F or m i n E n glis h, a n d su b mit t he c o m plete d f or m wit hi n 2 4 h o urs t o N o vartis. Detaile d 
i nstr ucti o ns re gar di n g t he S A E s u b missi o n pr ocess a n d re q uire me nts f or si g nat ures are t o be 
f o u n d i n t he i n vesti gat or f ol der pr o vi de d t o eac h site.
F oll o w - u p i nf or mati o n is s u b mitte d i n t he sa me wa y  as t he ori gi nal S A E Re p ort. Eac h re-
occ urre nce, c o m plicati o n, or pr o gressi o n of t he ori gi nal e ve nt s h o ul d be re p orte d as a f oll o w-
u p t o t hat e ve nt re gar dless of w he n it occ urs. T he f oll o w- u p i nf or mati o n s h o ul d descri be 
w het her t he e ve nt has res ol ve d or c o nti n ues, if a n d h o w it was treate d, w het her t he bli n d was 
br o ke n or n ot, a n d w het her t he patie nt c o nti n ue d or wit h dre w fr o m st u d y  partici pati o n.
If t he S A E is n ot pre vi o usl y  doc u me nte d i n t he I n vesti gat or’s Br oc h ure or Pac ka ge I nsert 
( ne w occ urre nce) a n d is t h o u g ht t o be relate d t o t he N o vartis st u d y treat me nt, a n o nc ol o g y 
C hief Me dical 
Office a n d Patie nt Safet y ( C M O & P S) de part me nt ass ociate m a y  ur ge ntly 
re q uire f urt her i nf or mati o n fr o m t he i n vesti gat or f or Healt h A ut h ority re p orti n g. N o vartis ma y 
nee d t o iss ue a n I n vesti gat or N otificati o n (I N), t o i nf or m all i n vesti gat ors i n v ol ve d i n a n y 
st u d y wit h t he sa me dr u g t hat t his S A E has bee n re p orte d. S us pecte d U ne x pecte d Seri o us 
A d verse Reacti o ns ( S U S A Rs) will be c ollecte d a n d re p orte d t o t he c o m pete nt a ut h orities a n d 
rele va nt et hics c o m mittees i n acc or da nce wit h Directi ve 2 0 0 1/ 2 0/ E C or as per nati o nal 
re g ulat or y re q uire me nts i n partici pati n g c o u ntries.
8. 3
E m er g e n c y  u n bli n di n g of tr e at m e nt a s si g n m e nt
E mer ge nc y  un bli n di n g s h o ul d o nl y  be u n derta ke n w he n it is essential f or effecti ve treat me nt 
of t he patie nt. M ost ofte n, st u d y treat me nt disc o nti n uati o n a n d k n o wle d ge of t he p ossi ble 
treat me nt assi g n me nts are s ufficie nt t o treat a st u d y patie nt w h o prese nts wit h a n e mer ge nc y 
c o n diti o n. E mer ge nc y  co de brea ks are perf or me d usi n g t he I R T. W he n 
t he i n vesti gat or 
c o ntacts t he I RT t o u n bli n d a patie nt, he/s he m ust pr o vi de t he re q ueste d patie nt i de ntif yi n g 
i nf or mati o n a n d c o nfir m t he necessit y  to u n bli n d t he patie nt. T he i n vesti gat or will t he n 
recei ve details of t he dr u g treatme nt f or t he s pecifie d patie nt a n d a fa x c o nfir mi n g t his 
i nf or mati o n. T he s yste m will a ut o maticall y inf or m t he N o vartis m o nit or f or t he site a n d t he 
St u d y  Lea d t hat t he c o de has bee n br o ke n.
It is t he i n vesti gat or’s res p o nsi bilit y t o e ns ure t hat t here is a pr oce d ure i n place t o all o w access 
t o t he I RT i n case of e mer ge nc y. T he i n vesti gat or will i nf or m t he patie nt h o w t o c o ntact 
his/ her bac k u p i n cases of e mer ge nc y whe n he/s he is u na vaila ble. T he pr ot oc ol n u m ber, st u d y 
treat me nt na me if a vaila ble, patie nt’s n u m ber s, a n d i nstr ucti o ns f or c o ntacti n g t he l ocal 
N o vartis C P O ( or a n y e ntit y to w hic h it has dele gate d res p o nsi bilit y for e mer ge nc y co de 
brea ks) will be pr o vi de d t o t he patie nt i n case e mer ge nc y un bli n di n g is re q uire d at a ti me 
w he n t he i n vesti gat or a n d bac k u p are u na vaila ble. H o we ver, if a mec ha nis m is alrea d y i n 
place t o e ns ure t hat t he i n vesti gat or a n d/ or bac k - u p ca n al wa ys be reac he d i n case of 
e mer ge nc y t he n t he pr oce d ure a b o ve is n ot re q uire d.


N o v arti s
C o nfi d e nti al
P a g e 8 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
St u d y  treat me nt m ust be disc o nti n ue d o nce e mer ge nc y u n bli n di n g has occ urre d.
8. 4
Pr e g n a n ci e s
N ot a p plica ble.
8. 5
W ar ni n g s a n d pr e c a uti o n s
N o e vi de nce a vaila ble at t he ti me of t he a p pr o val of t his st u d y pr ot oc ol i n dicate d t hat s pecial 
war ni n gs or preca uti o ns were a p pr o priate, ot her t ha n t h ose n ote d i n t he pr o vi de d I nves ti gat or 
Br oc h ure. A d diti o nal safet y inf or mati o n c ollecte d bet wee n I B u p dates will be c o m m u nicate d 
i n t he f or m of I nvesti gat or N otificati o ns. T his i nf or mati o n will be i ncl u de d i n t he patie nt 
i nf or me d c o nse nt a n d s h o ul d be disc usse d wit h t he patie nt d uri n g the st u d y as nee de d.
8. 6
D at a M o nit ori n g C o m mitt e e
N ot A p plica ble
8. 7
St e eri n g C o m mitt e e
A steeri n g c o m mittee ( S C) will be esta blis he d c o m prisi n g i n vesti gat ors partici pati n g i n t he 
trial, i.e. n ot bei n g me m bers of t he N o vartis re prese ntati ves fr o m t he Cli nical Trial Tea m.
T he S C will e ns ure tra ns pare nt ma na ge me nt of t he st u d y acc or di n g t o t he pr ot oc ol t hr o u g h 
rec o m me n di n g a n d a p pr o vi n g m o dificati o ns as circ u msta nces re q uire. T he S C will re vie w 
pr ot oc ol a me n d me nts as a p pr o priate. T he S C will 
re vie w bli n de d p o ole d
safety data 
a p pr o xi matel y ever y  6 mo nt hs (after t he first ra n d o mize d patie nt has starte d st u d y treat me nt) 
a n d pr o vi de rec o m me n dati o ns t o t he s p o ns or re gar di n g t he c o n d uct of t he st u d y. T o get her 
wit h t he cli nical trial tea m, t he S C will als o de vel o p rec o m me n dati o ns f or p u blicati o ns of 
st u d y res ults i ncl u di n g a ut h ors hi p r ules. T he details of t he r ole of t he Steeri n g C o m mittee will 
be defi ne d i n a Steeri n g C o m mittee c harter.
9
D at a c oll e cti o n a n d m a n a g e m e nt
9. 1
D at a c o nfi d e nti alit y
I nf or mati o n a b o ut st u d y su b jects will be ke pt c o nfi de ntial a n d ma na ge d u n der t he a p plica ble 
la ws a n d re g ulati o ns. T h ose re g ulati o ns re q uire a si g ne d s u bject a ut h orizati o n i nf or mi n g t he 
s u bject of t he f oll o wi n g:

W hat pr otecte d healt h i nf or mati o n ( P HI) will be c ollecte d fr o m s u bjects i n t his st u d y

W h o will ha ve access t o t hat i nf or mati o n a n d w h y

W h o will use or discl ose t hat i nf or mati o n

T he ri g hts of a researc h s u bject t o re v o ke t heir a ut h orizati o n f or use of t heir P HI .
I n t he e ve nt t hat a s u bject re v o kes a ut h orizati o n t o c ollect or us e P HI , t he i n vesti gat or, b y  
re g ulati o n, retai ns t he a bilit y t o use all i nf or mati o n c ollecte d pri or t o t he re v ocati o n of s u bject 
a ut h orizati o n. F or s u bjects t hat ha ve re v o ke d a ut h orizati o n t o c ollect or use P HI , atte m pts 


N o v arti s
C o nfi d e nti al
P a g e 8 6
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
s h o ul d be ma de t o o btai n per missi o n t o c ollect f oll o w- u p safety i nf or mati o n (e. g. has t he 
s u bject e x perie nce d a ny ne w or w orse ne d A Es) at t he e n d of t heir sc he d ule d st u d y  peri o d.
T he data c ollecti o n s yste m f or t his st u d y uses b uilt -i n sec urit y feat ures t o e ncr ypt all data f or 
tra ns missi o n i n b ot h directi o ns, pre ve nti n g u na ut h orize d access t o c o nfi de ntial partici pa nt 
i nf or mati o n. Access t o t he s yste m will be c o ntr olle d b y  a se q ue nce of i n di vi d uall y assi g ne d 
user i de ntificati o n c o des a n d pass w or ds, ma de a vaila ble o nl y t o a ut h orize d pers o n nel w h o 
ha ve c o m plete d prere q uisite trai ni n g.
Pri or t o e nteri n g k e y  se nsiti ve pers o nall y  ide ntifia ble i nf or mati o n ( S u bject I nitials a n d e xact 
Date of Birt h), t he s yste m will pr o m pt site t o verif y t hat t his data is all o we d t o be c ollecte d. If 
t he site i n dicates that c o u ntr y rules or et hics c o m mittee sta n dar ds d o n ot per mit c ollecti o n of 
t hese ite ms, t he s yste m will n ot s olicit S u bject I nitials. Year of birt h will be s olicite d (i n t he 
place of e xact date of birt h) t o esta blis h t hat t he s u bject satisfies pr ot oc ol a ge re q uire me nts 
a n d t o e na ble a p pr o priate a ge-relate d n or mal ra n ges t o be use d i n assessi n g la b orat or y test 
res ults.
9. 2
Sit e m o nit ori n g
Bef ore st u d y initiati o n, at a site i nitiati o n visit or at a n i n vesti gat or’s meeti n g, N o vartis 
pers o n nel ( or desi g nate d C R O) will re vie w t he pr ot oc ol a n d C R Fs wit h t he i n vesti gat ors a n d 
t heir staff. D uri n g t he st u d y, t he fiel d m o nit or will visit t he site re g ularl y t o c hec k t he 
c o m plete ness of patie nt rec or ds, t he acc urac y of e ntries o n t he C R Fs, t he a d here nce t o t he 
pr ot oc ol t o G o o d Cli nical Practice, t he pr o gress of e nr oll me nt, a n d t o e ns ure t hat st u d y 
treat me nt is bei n g st ore d, dis pe nse d, a n d acc o u nte d f or acc or di n g t o s pecificati o ns. Ke y  st u dy 
pers o n nel m ust be a vaila ble t o assist t he fiel d m o nit or d uri n g t hese visits.
T he i n vesti gat or m ust mai ntai n s o urce d oc u me nts f or eac h patie nt i n t he st u d y, c o nsisti n g of 
case a n d visit n otes ( h os pital or cli nic me dical rec or ds) c o ntai ni n g de m o gra p hic a n d me dical 
i nf or mati o n, la b orat or y data, electr ocar di o gra ms, a n d t he res ults of a n y ot her tests or 
assess me nts. All i nf or mati o n rec or de d o n C R Fs m ust be tracea ble t o s o urce d oc u me nts i n t he 
patie nt's file. T he i n vesti gat or m ust als o kee p t he ori gi nal si g ne d i nf or me d c o nse nt f or m (a 
si g ne d c o py is gi ve n t o t he patie nt).
T he i n vesti gat or m ust g i ve t he m o nit or access t o all rele va nt s o urce d oc u me nts t o c o nfir m 
t heir c o nsiste nc y wit h t he C R F e ntries. N o vartis m o nit ori n g sta n dar ds re q uire f ull verificati o n 
f or t he prese nce of i nf or me d c o nse nt, a d here nce t o t he i ncl usi o n/e xcl usi o n criteria a n d 
d oc u m e ntati o n of S A Es. A d diti o nal c hec ks of t he c o nsiste nc y of t he s o urce data wit h t he 
C R Fs are perf or me d acc or di n g t o t he st u d y- s pecific m o nit ori n g pla n.
9. 3
D at a c oll e cti o n
T he desi g nate d i n vesti gat or staff will e nter t he data re q uire d b y  the pr ot oc ol i nt o t he 
E lectr o nic Case Re p ort F or ms (e C R F). T he e C R Fs ha ve bee n b uilt usi n g f ully vali date d 
sec ure we b -e na ble d s oft ware t hat c o nf or ms t o 2 1 C F R Part 1 1 re q uire me nts, I nvesti gat or site 
staff will n ot be gi ve n access t o t he E D C s yste m u ntil t he y ha ve bee n trai ne d. A ut o matic 
vali dati o n pr o gra ms c hec k f or data discre pa ncies i n t he e C R Fs a n d, all o w m o dificati o n or 
verificati o n of t he e ntere d data b y t he i n vesti gat or staff.


N o v arti s
C o nfi d e nti al
P a g e 8 7
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T he Pri nci pal I n vesti gat or is res p o nsi ble f or ass uri n g t hat t he data e ntere d i nt o e C R F is 
c o m plete, acc urate, a n d t hat e ntr y a n d u p dates are perf or me d i n a ti mel y ma n ner.
Ra di ol o gical data will 
be ac q uire d b y  the sites a n d i nter prete d l ocall y. A d diti o nall y , 
ra di ol o gical data will be tra ns mitte d b y  the sites t o t he res pecti ve C R O desi g nate d t o u n der g o 
q ualit y  chec ks a n d ce ntral re vie w. Details re gar di n g all C R O pr oce d ures i ncl u di n g c ollecti o n 
a n d s hi p me nt of data will be descri be d i n t he ma n ual pr o vi de d b y  t he res pecti ve C R O.
I n a d diti o n, data e ntere d i nt o I RT f or scree ni n g, ra n d o mizati o n, disc o nti n uati o n, s u bse q ue nt 
dr u g assi g n me nt a n d patie nt i de ntifiers (i.e. date of birt h, ge n der, a n d patie nt I D) will b e 
tra nsferre d electr o nicall y to N o vartis as descri be d i n t he Data Tra nsfer S pecificati o n f or 
desi g nate d I R T ve n d or.
9. 4
D at a b a s e m a n a g e m e nt a n d q u alit y  c o ntr ol
N o vartis pers o n nel ( or desi g nate d C R O) will re vie w t he data e ntere d b y  in vesti gati o nal staff 
f or c o m plete ness a n d acc urac y. Electr o nic data q ueries stati n g t he nat ure of t he pr o ble m a n d 
re q uesti n g clarificati o n will be create d f or discre pa ncies a n d missi n g val ues a n d se nt t o t he 
i n vesti gati o nal site via t he E D C s yste m. Desi g nate d i n vesti gat or site staffs are re q uire d t o 
res p o n d pr o m ptl y t o q ueries a n d t o ma ke a n y necessar y c ha n ges t o t he data.
C o nc o mita nt treat me nts a n d pri or me dicati o ns e ntere d i nt o t he data base will be c o de d usi n g 
t he W H O 
Dr u g Refere nce List, w hic h e m pl o ys t he A nat o mical T hera pe utic C he mical 
classificati o n s yste m. Me dical hist or y /c urre nt me dical c o n diti o ns a n d a d verse e ve nts will be 
c o de d usi n g t he Me dical dicti o nar y f or re g ulat or y acti vities ( Me d D R A) ter mi n ol o g y.
D ata will be pr ocesse d ce ntrall y an d t he res ults will be se nt electr o nicall y t o N o vartis ( or a 
desi g nate d C R O). Data t hat will be pr ocesse d ce ntrall y  i ncl u des:

I R T data i ncl u di n g i nf or mati o n re gar di n g scree ni n g, ra n d o mizati o n, s u bse q ue nt dr u g 
assi g n me nts a n d disc o nti n uati o n

Ce ntral i ma gi n g re vie w data (i.e., C T/ M RI, B o ne sca ns a n d p h ot o gra p h y  res ults)
Ra n d o mizati o n c o des a n d data a b o ut all st u d y treat me nts dis pe nse d t o t he patie nt a n d all I R T 
assi g ne d d osa ge c ha n ges will be trac ke d usi n g a n I nteracti ve Res p o nse Tec h n ol o g y . T he 
s yste m will be s u p plie d b y  a ve n d or(s), w h o will ma na ge I R T a n d its data base. T he data will 
be se nt electr o nicall y t o N o vartis pers o n nel ( or desi g nate d C R O).
At t he c o ncl usi o n of t he st u d y, t he occ urre nce of a n y e mer ge nc y co de brea ks will be 
deter mi ne d after ret ur n of all c o de brea k re p orts a n d u n use d dr u g s u p plies t o N o vartis 
pers o n nel ( or desi g nate d C R O). T he occ urre nce of a n y  pr ot oc ol vi olati o ns will be deter mi ne d. 
After t hese acti o ns ha ve bee n c o m plete d a n d t he data has bee n verifie d t o be c o m plete a n d 
acc urate, t he data base will be declare d l oc ke d a n d t he treat me nt c o des will be u n bli n de d a n d 
ma de a vaila ble f or data a nal y sis.
1 0
St ati sti c al m et h o d s a n d d at a a n al y si s
It is pla n ne d t hat t he data fr o m all ce nters partici pati n g i n t he trial will be c o m bi ne d, s o t hat a n 
a de q uate n u m ber of patie nts are a vaila ble f or a nal y sis. N o vartis a n d/ or a desi g nate d C R O will 


N o v arti s
C o nfi d e nti al
P a g e 8 8
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
perf or m all t he a nal ys es. A n y  ad diti o nal data a nal ys es perf or me d i n de pe n de ntly b y  an y  
i n vesti gat or s h o ul d be s u b mitte d t o N o vartis bef ore p u blicati o n or prese ntati o n.
T he pri mar y  an al y sis f or safet y an d efficac y will be c o n d ucte d w he n a p pr o xi matel y 1 1 0 P F S 
e ve nts ha ve bee n d oc u me nte d.
T he a d diti o nal data f or a n y patie nts c o nti n ui n g t o receive st u d y treat me nt, as all o we d b y  the 
pr ot oc ol, will be f urt her s u m marize d i n a re p ort o nce t hese patie nts c o m plete d t he st u d y 
(a d de n d u m of t he cli nical st u d y re p ort).
1 0. 1
A n al y si s s et s
1 0. 1. 1
F ull A n al y si s S et
T he F ull A nal ys is Set ( F A S) c o m prises all patie nts t o w h o m st u d y treat me nt has bee n 
assi g ne d b y ra n d o mizati o n. Acc or di n g t o t he i nte nt t o treat pri nci ple, patie nts will be a nal yze d 
acc or di n g t o t he treat me nt a n d strata t he y ha ve bee n assi g ne d t o d uri n g t he ra n d o mizati o n 
pr oce d ure.
1 0. 1. 2
S af et y  s et
T he S afet y S et c o nsists of all patie nts w h o recei ve d at least o ne d ose of st u d y treat me nt.
Patie nts will be a nal yz e d acc or di n g t o treat me nt act uall y recei ve d, w here treat me nt recei ve d is 
defi ne d as t he ra n d o mize d treat me nt if t he patie nt t o o k at least o ne d ose of t hat treat me nt or 
t he first treat me nt recei ve d if t he ra n d o mize d treat me nt was ne ver recei ve d.
1 0. 1. 3
P h ar m a c o ki n eti c s et ( P A S)
T he P A S c o nsists of all patie nts wit h at least o ne a vaila ble c o nce ntrati o n
1 0. 2
P ati e nt d e m o gr a p hi c s/ ot h er b a s eli n e c h ar a ct eri sti c s
Baseli ne de m o gra p hi c a n d disease c haracteristics data will 
be liste d a n d s u m marize d
descri pti vel y b y treat me nt gr o u p usi n g t he F A S.
Cate g orical data will be prese nte d as fre q ue ncies a n d perce nta ges. F or c o nti n u o us data, mea n, 
sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m will be prese nte d. M e dical hist or y a n d 
c urre nt me dical at baseli ne will be s u m marize d se parately b y  s yste m or ga n class a n d preferre d 
ter m, b y treat me nt gr o u p.
1 0. 3
Tr e at m e nt s ( st u d y tr e at m e nt, c o n c o mit a nt t h er a pi e s, c o m pli a n c e)
T he safet y s et will be use d f or t he a nal yses bel o w.
D urati o n 
of e ver oli m us, exe mesta ne
a n d place b o treat me nt, as well as d ose i nte nsit y
(c o m p ute d as t he rati o of act ual d ose recei ve d t o act ual d urati o n) a n d relati ve d ose i nte nsit y 
(c o m p ute d as t he rati o of t he d ose i nte nsit y t o pla n ne d dose recei ve d/ pla n ne d d urati o n) will be
liste d a n d s u m marize d usi n g descri pti ve statistics, b y  treat me nt wit hi n eac h treat me nt ar m.
T he n u m ber of patie nts wit h d ose c ha n ges/i nterr u pti o ns a n d t he reas o ns will be prese nte d b y  
treat me nt f or eac h treat me nt ar m; all d osi n g data will be liste d.


N o v arti s
C o nfi d e nti al
P a g e 8 9
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
C o nc o mita nt me dicati o ns a n d si g nifica nt n o n -dr u g t hera pies pri or t o a n d after t he start of t he 
st u d y treat me nt will be liste d a n d s u m marize d acc or di n g t o t he A nat o mical T hera pe utic 
C he mical ( A T C) classificati o n s y ste m, b y treat me nt ar m.
T hese s u m maries will i ncl u de me dicati o ns starti n g o n or after t he start of st u d y treat me nt or 
me dicati o ns starti n g pri or t o t he start of st u d y treat me nt a n d c o nti n ui n g after t he start of st u d y 
treat me nt. A n y pri or c o nc o mita nt me dicati o ns or si g nifica nt n o n -dr u g t hera pies starti n g a n d 
e n di n g pri or t o t he start of st u d y  treat me nt will be liste d.
1 0. 4
Pri m ar y  o bj e cti v e
T he pri mar y  objecti ve i n t his st u d y is t o assess P F S o n t he c o m bi nati o n treat me nt of 
e ver oli m us + e xe mesta ne a n d place b o + e xe mesta ne i n C hi nese p ost me n o pa usal w o me n wit h 
estr o ge n rece pt or p ositi ve , H E R 2-ne gati ve , l ocall y ad va nce d, rec urre nt, or metastatic breast 
ca ncer after rec urre nce or pr o gressi o n o n pri or letr oz ole or a nastr oz ole.
1 0. 4. 1
V ari a bl e
T he pri mar y  en d p oi nt of t his st u d y  is P F S , defi ne d as t he ti me fr o m t he date of ra n d o mizati o n 
t o t he date of first d oc u me nte d pr o gressi o n or deat h d ue t o a n y ca use. A patie nt w h o has n ot 
pr o gresse d or die d at t he date of t he a nal ys is c ut-off or recei ves a n ot her a ntica ncer t hera py 
will ha ve t heir P F S ce ns ore d at t he ti me of t he last a de q uate t u m or e val uati o n bef ore t he 
earlier of t he c ut-off date or t he a ntica ncer t hera p y date. Disease pr o gressi o n f or pri mar y 
efficac y en d p oi nt deri vati o n will be assesse d usi n g t he l ocal (treati n g ce nter’s ra di ol o gist’s) 
i n vesti gat or’s t u m or assess me nt.
1 0. 4. 2
St ati sti c al h y p ot h e si s, m o d el, a n d m et h o d of a n al y si s
N o h y p ot hesis testi n g will be perf or me d a n d t he o bjecti ve of t his st u d y is t o esti mate hazar d 
rati o of ever oli m us i n c o m bi nati o n wit h exe mesta ne c o m pare d t o exe mesta ne al o ne .
P F S as deter mi ne d b y l ocal e val uati o n will be a nal yze d base d o n t he data fr o m F A S acc or di n g 
t o t he treat me nt ar m a n d ra n d o mizati o n strata t o w hic h 
patie nts were 
assi g ne d . T he 
distri b uti o n of P F S will be esti mate d usi n g t he Ka pla n -Meier met h o d. T he me dia n P F S al o n g 
wit h 9 0 % CI  will be prese nte d b y  treat me nt ar m. T he Ka pla n -Meier c ur ves will be dis pla y e d
a n d the n u m ber of patie nts at ris k at certai n ti me p oi nts will be s h o w n o n t he pl ot.
A
C o x re gressi o n m o del stratifie d b y  ra n d o mizati o n stratificati o n fact ors will be use d t o 
esti mate t he hazar d rati o ( H R) of P F S, al o n g wit h 9 0 % CI . As t his is a n esti mati o n base d 
a p pr oac h, n o p- val ue will be pr o vi de d.
1 0. 4. 3
H a n dli n g of mi s si n g v al u e s/ c e n s ori n g/ di s c o nti n u ati o n s
P F S will be ce ns ore d if n o P F S e ve nt is o bser ve d bef ore t he c ut-off date or bef ore t he start 
date of a ne w a ntica ncer t hera p y  or a n ot her i n vesti gati o nal treat me nt, w hic he ver occ urs earlier. 
T he ce ns ori n g date will be t he date of last a de q uate t u m or assess me nt bef ore eit her of t hese 
t w o dates. If a P F S e ve nt is d oc u me nte d after t w o or m ore missi n g assess me nts or n o n-
a de q uate t u m or assess me nts, t he n t he date of P F S will be ce ns ore d at t he date of t he last 
a de q uate t u m or assess me nt. If a P F S e ve nt is o bser ve d after a si n gle missi n g or n o n- a de q uate 
t u m or assess me nt, t he act ual date of e ve nt will be use d.


N o v arti s
C o nfi d e nti al
P a g e 9 0
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
1 0. 4. 4
S u p p orti v e a n d s e n siti vit y a n al y s e s
A n u n -stratifie d C o x m o del
ma y  be use d t o esti mate t he H R (t o get her wit h ass ociate d 9 0 % 
c o nfi de nce i nter val) as s u p p orti ve a nal ys is, if a p pr o priate. T he pri mar y  a nal ysis f or P F S will 
be re peate d wit h data base d o n ce ntral re vie w f or assess me nts of P F S a n d usi n g t he sa me 
a nal yt ical c o n ve nti o ns as t he pri mar y  anal ys is b ut as a sec o n dar y su p p orti ve a nal ys is.
A d diti o nal se nsiti vit y  a nal yses mi g ht be f urt her s pecifie d i n statistical a nal ysis pla n.
1 0. 5
S e c o n d ar y  o bj e cti v e s
1 0. 5. 1
S e c o n d ar y  effi c a c y o bj e cti v e s
T he sec o n dar y efficac y o bjecti ves i n t his st u d y are t o assess P F S i n t he t w o treat me nt ar ms as 
deter mi ne d b y  a Bli n de d I nde pe n de nt Re vie w C o m mittee ( BIR C) (Ce ntral re vie w s h o ul d be 
ter mi nate d after t he n u m ber of e ve nts is reac he d f or t he pri mar y  PF S a nal ysis), t o assess t he 
t w o treat me nt gr o u ps wit h res pect t o O S, O R R, deteri orati o n i n t he E C O G P S, a n d C B R. 
A d diti o nall y , ti me t o res p o nse a n d d urati o n of res p o nse will be s u m marize d bet wee n t he 
treat me nt gr o u ps. A d diti o nal sec o n dar y  o bjecti ves are t o assess t he t w o treat me nt gr o u ps wit h 
res pect t o safety a n d t olera bilit y.
1 0. 5. 1. 1
O v er all R e s p o n s e R at e ( O R R)
O R R is defi ne d as t he pr o p orti o n of patie nts wit h best o verall res p o nse of C R or P R acc or di n g 
t o R E CI S T 1. O R R will be calc ulate d base d o n t he F A S acc or di n g t o t he I T T pri nci ple, usi n g 
l ocal ra di ol o gist’s/i n vesti gat or’s t u m or assess me nt. O R R will be esti mate d a n d t he e xact 
bi n o mial 9 0 % CI  will be re p orte d b y  treat me nt ar m (Cl o p per a n d Pears o n 1 9 3 4 ). T he a b o ve 
a nal ys es will als o be re peate d usi n g data fr o m t he i n de pe n de nt ce ntral re vie w as sec o n dar y 
s u p p orti ve a nalys is.
1 0. 5. 1. 2
O v er all s ur vi v al
O verall s ur vi val is defi ne d as t he ti me fr o m date of ra n d o mizati o n t o date of deat h d ue t o a n y 
ca use. If t he patie nt is ali ve at t he date of t he a nal ysis c ut-off or l ost t o f oll o w- u p, t he n O S 
will be ce ns ore d at t he last c o ntact date pri or t o data c ut off date. T he a nal yses f or O S will be 
base d o n t he dat a fr o m F A S o n a n I TT basis, acc or di n g t o t he treat me nt gr o u p patie nts are 
ra n d o mize d t o at baseli ne. T he distri b uti o n f u ncti o n of O S will be esti mate d usi n g t he Ka pla n -
Meier met h o d. T he me dia n O S al o n g wit h 9 0 % c o nfi de nce i nter vals will be prese nte d b y  tw o
treat me nt gr o u ps, al o n g wit h pr o p orti o n of patie nts ali ve at 3, 6, 9, 1 2 a n d 1 8 m o nt hs a n d t he 
ass ociate d 9 0 % c o nfi de nce i nter vals. T he stratifie d C o x re gressi o n will be use d t o esti mate t he 
H R of O S, al o n g wit h 9 0 % c o nfi de nce i nter val.
1 0. 5. 1. 3
Cli ni c al b e n efit r at e
C B R is defi ne d as t he pr o p orti o n of patie nts wit h best o verall res p o nse of C R, P R or S D wit h 
d urati o n of 2 4 wee ks or l o n ger. C B R will be calc ulate d base d o n t he F A S acc or di n g t o t he 
I T T pri nci ple, usi n g l ocal ra di ol o gist’s/i n vesti gat or’s t u m or assess ment. C B R will 
be 
s u m marize d f or t he t w o treat me nt gr o u ps usi n g descri pti ve statistics al o n g wit h e xact 9 0 % 
c o nfi de nce i nter vals. T he a b o ve a nal ys es will 
als o be re peate d usi n g data fr o m t he 
i n de pe n de nt ce ntral re vie w as sec o n dar y s u p p orti ve a nalys es.


N o v arti s
C o nfi d e nti al
P a g e 9 1
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
1 0. 5. 1. 4
Ti m e t o r e s p o n s e
Ti me t o o verall res p o nse ( T T R) of C R or P R is defi ne d as t he ti me fr o m ra n d o mizati o n t o first 
d oc u me nte d res p o nse ( C R or P R, w hic h m ust be c o nfir me d s u bse q ue ntly)  for patie nts wit h a 
c o nfir me d C R or P R. T T R will be s u m marize d i n 3- m o nt h i nter vals usi n g descri pti ve 
statistics. T he a nal ysis will be perf or me d base d o n i n vesti gat or assess me nt a n d als o re peate d 
usi n g data fr o m t he i n de pe n de nt ce ntral re vie w as s u p p orti ve a nal ys es.
1 0. 5. 1. 5
D ur ati o n of r e s p o n s e
A m o n g patie nts wit h a c o nfir me d res p o nse ( P R or C R ) per R E CI S T 1. 1 b y  in vesti gat or , D O R 
is defi ne d as t he ti me fr o m first d oc u me nte d res p o nse ( P R or C R) t o t he date of first
d oc u me nte d disease pr o gressi o n or deat h d ue t o a n y ca use. D O R will be s u m marize d usi n g 
descri pti ve statistics. T he a nal ysis will be perf or me d base d o n i n vesti gat or assess me nt a n d 
als o re peate d usi n g data fr o m t he i n de pe n de nt ce ntral re vie w as s u p p orti ve a nal ys es.
1 0. 5. 1. 6
E C O G P erf or m a n c e St at u s
E C O G P S scale as descri be d i n Secti o n 7. 2. 2. 4 will be use d t o assess p h y sical healt h of 
patie nts. A n a nal ys is of t he ti me t o defi niti ve deteri orati o n of t he E C O G P S b y  one cate g or y 
of t he sc ore fr o m baseli ne will be perf or me d. Deteri orati o n is c o nsi dere d defi niti ve if n o 
i m pr o ve me nts i n t he E C O G P S stat us is o bser ve d at a s u bse q ue nt ti me of meas ure me nt d uri n g 
t he treat me nt peri o d f oll o wi n g t he ti me p oi nt w here t he deteri orati o n is o bser ve d. Deat h will 
be c o nsi dere d as w orse ni n g of t he E C O G P S if it occ urs cl ose t o t he last a vaila ble assess me nt, 
w here “cl ose ” is defi ne d as t wice t he pla n ne d peri o d bet wee n t w o assess me nts. Patie nts w h o 
die after m ore t ha n t wice t he pla n ne d peri o d bet wee n t w o assess me nts are ce ns ore d at t he date 
of t heir last assess me nt bef ore t he c ut -off.
Patie nts recei vi n g a n y f urt her a ntica ncer t hera p y pri or t o defi niti ve w orse ni n g will be 
ce ns ore d at t heir date of last assess me nt pri or t o start of t hera py. Patie nts t hat ha ve n ot 
w orse ne d at t he data c ut-off p oi nt will be ce ns ore d at t he date of last assess me nt pri or t o c ut 
off. Ka pla n -Meier 
met h o d will be use d t o esti mate t he distri b uti o n f u ncti o n of ti me t o 
defi niti ve w orse ni n g . T he esti mate d treat me nt-s pecific me dia n ti mes t o defi niti ve w orse ni n g
will be prese nte d al o n g wit h a 9 0 % c o nfi de nce i nter val f or t he t w o treat me nt ar ms.
1 0. 5. 2
S af et y  o bj e cti v e s
1 0. 5. 2. 1
A n al y si s s et a n d gr o u pi n g f or t h e a n al y s e s
F or all safet y a nal ys es, t he safet y set will be use d.
T he o verall o bser vati o n peri o d will be di vi de d i nt o t hree m ut uall y  e xcl usi ve se g me nts:
1.
pre -treat me nt peri o d: fr o m da y of patie nt’s i nf or me d c o nse nt t o t he da y bef ore first d ose 
of st u d y  treat me nt
2.
o n -treat me nt peri o d: fr o m da y of first d ose of st u d y treat me nt t o 3 0 d a y s after last d ose of 
st u d y treat me nt
3.
p ost -treat me nt peri o d: starti n g at da y 3 1 after last d ose of st u d y treat me nt.


N o v arti s
C o nfi d e nti al
P a g e 9 2
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T he assess me nt of saf et y will be base d mai nl y  on t he fre q ue nc y of a d verse e ve nts a n d o n t he 
n u m ber of la b orat or y  val ues t hat fall o utsi de of pre-deter mi ne d ra n ges. Ot her safet y data (e. g., 
electr ocar di o gra m, vital si g ns) will be c o nsi dere d as a p pr o priate.
1 0. 5. 2. 2
A d v er s e e v e nt s ( A E s)
T he safety s u m mar y ta bles will i ncl u de o nl y assess me nts fr o m t he o n- treat me nt peri o d, t he 
treat me nt-e mer ge nt A Es.
H o we ver, all safety data (i ncl u di n g t h ose fr o m t he pre a n d p ost -
treat me nt peri o ds) will be liste d a n d t h ose c ollecte d d uri n g t he pre -treat me nt a n d p ost -
treat me nt peri o d are t o be fla g ge d.
All safet y data c ollecte d i n t he st u d y will be liste d re gar dless of t he st u d y peri o d.
T he i nci den ce of treat me nt -eme r gen t a d verse e ve nts ( ne w or w orse ni n g fro m baseli ne) will be 
s u m marize d b y s yste m or ga n class a n d/ or preferre d term,
se verity ( base d o n C T C gra des), 
t ype of a d verse e ve nt a n d relati o n t o st u d y treat me nt b y  treat me nt gr o u p . Seri o us a d verse 
e ve nts a n d n o n- seri o us a d verse e ve nts d uri n g t he o n-treat me nt peri o d will be ta b ulate d.
T he a d verse e ve nts of s pecial i nterest ( A E SIs) i ncl u de t he f oll o wi n g cate g ory

St o matitis

Pre -e xisti n g i nfecti o n (reacti vati o n, a g gra vati o n, or e xacer bati o n)

Car diac fail ure
T he
n u m ber a n d perce nta ge of patie nts wit h at least o ne A E SI will be s u m marize d b y  
treat me nt ar m.
All A Es, deat hs a n d seri o us a d verse e ve nts will be liste d ; assess me nts c ollecte d o utsi de of t he 
o n- treat me nt peri o d will be fla g ge d.
1 0. 5. 2. 3
L a b or at or y  a b n or m aliti e s
Gra di n g of la b orat or y val ues will be assi g ne d pr o gra m maticall y as per N CI  C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E) versi o n 4. 0 3. T he calc ulati o n of C T C A E 
gra des will be base d o n t he o bser ve d la b orat or y val ues o nl y, cli nical assess me nts will n ot be 
ta ke n i nt o acc o u nt.
C T C A E G ra de 0 will be assi g ne d f or all n o n- missi n g val ues n ot gra de d as 1 or hi g her. Gra de 
5 will n ot be use d.
F or la b orat or y  tests w here gra des are n ot defi ne d b y C T C A E v 4. 0 3, res ults will be cate g orize d 
as l o w/ n or mal/ hi g h base d o n la b orat or y  n or mal ra n ges.
T he f oll o wi n g s u m maries will be ge nerate d se parately f or hae mat ol o g y , a n d bi oc he mistr y 
tests:

Listi n g of all la b orat or y  data wit h val ues fla g ge d t o s h o w t he c orres p o n di n g C T C A E 
v 4. 0 3 gra des if a p plica ble a n d t he classificati o ns relati ve t o t he la b orat or y  n or mal ra n ges

Listi n g of n ota ble la b orat or y  a b n or malities (i.e. ne wl y occ urri n g C T C A E gra de 3 or 4 
la b orat or y t o xicities)
F or la b orat or y  tests w here gra des are defi ne d b y C T C A E v 4. 0 3


N o v arti s
C o nfi d e nti al
P a g e 9 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

W orst p ost - baseli ne C T C A E gra de (re gar dless of t he baseli ne stat us). Eac h patie nt will be 
c o u nte d o nl y  o nce f or t he w orst gra de o bser ve d p ost- baseli ne.

S hift ta bles usi n g C T C A E gra des t o c o m pare baseli ne t o t he w orst o n -treat me nt val ue
F or la b orat or y  tests w here gra des are n ot defi ne d b y C T C A E v 4. 0 3,

S hift ta bles usi n g t he l o w/ n or mal/ hi g h/ (l o w a n d hi g h) classificati o n t o c o m pare baseli ne 
t o t he w orst o n- treat me nt val ue.
1 0. 5. 2. 4
Ot h er s af et y  d at a
Data fr o m ot her tests (e. g. vital si g ns) will be liste d, n ota ble val ues will be fla g ge d, a n d a n y 
ot her i nf or mati o n c ollecte d will be liste d as a p pr o priate.
1 0. 5. 2. 5
S u p p orti v e a n al y s e s f or s e c o n d ar y  o bj e cti v e s
N ot a p plica ble
1 0. 5. 2. 6
T ol er a bilit y
T olera bilit y
of
st u d y treat me nt will
be
assesse d b y s u m marizi n g the
n u m ber
of
d ose
i nterr u pti o ns a n d d ose
re d ucti o ns. Reas o ns
f or d o se i nterr u pti o n a n d d ose
re d ucti o ns,
c um ulati ve d ose a n d d ose i nte nsit y will be liste d b y patie n t.
1 0. 5. 3
P h ar m a c o ki n eti c s
C o nce ntrati o ns will be e x presse d i n mass per v ol u me u nits.
Vali d C mi n is defi ne d as a pre -d ose sa m ple c ollecte d at stea dy -state, at 2 4 +/ - 4 h o urs after t he 
last d ose, a n d c ollecte d pri or t o t he ne xt d ose.
Stea d y -state c o n diti o n f or C mi n is defi ne d as n o d ose i nterr u pti o n/a dj ust me nt i n t he last 4 da y s 
pri or t o t he pre -d ose sa m ple, n o v o miti n g wit hi n 4 h o urs f oll o wi n g st u d y dr u g a d mi nistrati o n 
o n t he da y  of or t he da y bef ore p har mac o ki netic bl o o d sa m pli n g.
Vali d C 2 h is defi ne d as a 2 h o ur p ost- d ose sa m ple c ollecte d at stea d y-state.
Stea d y -state c o n diti o n f or C 2 h is defi ne d as n o d ose i nterr u pti o n/a dj ust me nt i n t he last 4 d a y s 
pri or t o t he C 2 h sa m ple, n o v o miti n g wit hi n 4 h o urs f oll o wi n g st u d y dr u g a d mi nistrati o n o n 
the da y  of or t he da y bef ore p har mac o ki netic bl o o d sa m pli n g.
C mi n a n d C 2 h of e ver oli m us will be b ot h s u m marize d b y  treat me nt gr o u p, a n d b y  act ual lea d 
d ose, f or patie nts wit h vali d P K sa m ples.
T o assess t he effect of e ver oli m us o n e xe mesta ne e x p os ure, C mi n a n d C 2 h of e xe mesta ne wit h 
a n d wit h o ut 
c o-a d mi nistrati o n of e ver oli m us will 
be c o m pare d se parately after l o g-
tra nsf or mati o n usi n g a n A N O V A m o del wit h treat me nt as a fi xe d effect. C mi n a n d C 2 h rati os 
wit h e ver oli m us t o t h ose wit h o ut e ver oli m us a n d t heir 9 0 % CI  will be calc ulate d fr o m t he 
fitte d m o dels.
T o assess t he effect of e ver oli m us o n estra di ol ( E2) le vel, c ha n ges i n estra di ol le vels fr o m 
baseli ne t o wee k 4 will be s u m marize d f or t he patie nts wit h vali d P K sa m ples. T he 
relati o ns hi p bet wee n e ver oli m us C m i n a n d c ha n ge fr o m baseli ne i n estra di ol at Wee k 4 will 


N o v arti s
C o nfi d e nti al
P a g e 9 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
als o be a nal yze d b y  a mo del -base d a p pr oac h. T his a nal ysis will be re peate d a dj uste d b y  the 
c o nc o mita nt use of m o derate/str o n g 
C Y P 3 A 4/ P g P i n d ucer/i n hi bit or via a n a p pr o priate 
c o variate i n t he m o del.
C m i n a n d C 2 h will be a nal yze d base d o n wit h or wit h o ut c o nc o mita nt use of C Y P 3 A 4/ P g P 
m o derate/str o n g i n hi bit or or i n d ucer t o assess t heir effect o n e x p os ure of e ver oli m us
P o p ulati o n P K m o dels will be use d t o i de ntif y an d q ua ntif y  pote ntial c o variates t hat i nfl ue nce 
e ver oli m us P K. Details of t his a nal ysis will be c o vere d i n a se parate d oc u me nt.
A m o del -base d a p pr oac h will be use d t o e x pl ore:

t he p ote ntial relati o ns hi ps bet wee n efficac y ( meas ure d b y a p pr o priate efficac y e n d p oi nts 
s uc h as P F S) a n d e ver oli m us e x pos ure base d o n C mi n

t he p ote ntial relati o ns hi p bet wee n a p pr o priate safet y e n d p oi nts a n d e ver oli m us e x p os ure 
base d o n C mi n or C 2 h

t he p ote ntial relati o ns hi p bet wee n efficac y ( meas ure d b y a p pr o priate efficac y e n d p oi nts 
s uc h as P F S) a n d c ha n ges i n Estra di ol ( E 2) ass u mi n g a D DI of e ver oli m us wit h 
e xe mesta ne
1 0. 6
S a m pl e si z e c al c ul ati o n
As t his is a bri d gi n g st u d y for C hi na re gistrati o n, this st u d y will p urs ue a n esti mati o n strate g y 
rat her t ha n f or mal hy p ot hesis testi n g.
Base d o n t he res ults of R A D 0 0 1 Y 2 3 0 1 st u d y, t he me dia n P F S f or t he e xe mesta ne ar m was 
4. 1 m o nt hs, a n d t he e ver oli m us pl us e x e mesta ne ar m i m pr o ve d me dia n P F S i n Asia n patie nts 
b y  38 %. Ass u mi n g t he sa me hazar d rati o of 0. 6 2 i n C hi nese patie nts , t his will res ult i n a n 
i ncrease i n me dia n P F S fr o m 4. 1 m o nt h s t o 6. 6 m o nt hs
f or t he ever oli m us pl us e xe mesta ne
ar m, u n der t he e x p o ne ntial m o del .
If t he o bser ve d hazar d rati o is 0. 6 2, t he 9 0 % CI of t he hazar d rati o base d o n a t otal of 1 1 0 P F S 
e ve nts will be ( 0. 4 5, 0. 8 5). Ass u mi n g e nr ol me nt will c o nti n ue f or a p pr o xi matel y  1 8 m o nt hs at 
a u nif or m rate, a n d a b o ut 1 0 % of t he patie nts will be l ost t o f oll o w-u p f or P F S e val uati o n ,
a p pr o xi matel y 1 6 0 patie nts will nee d t o be ra n d o mize d t o t he t w o treat me nt gr o u ps i n 1 : 1 
rati o t o o bser ve t he 1 1 0 P F S e ve nts at a p pr o xi matel y 2 2 m o nt hs f oll o wi n g t he ra n d o mizati o n 
of t he first patie nt i n t his st u d y .
Bel o w ta ble s h o ws t he 9 0 % CI s f or vari o us o bser ve d hazar d rati os.
T a bl e 1 0 - 1
9 0 % CI s f or v ari o u s o b s er v e d h a z ar d r ati o s
pl a c e b o + e x e m e st a n e
(m P F S )
e v er oli m u s + e x e m e st a n e
(m P F S )
H a z ar d r ati o
9 0 % CI
4. 1
9. 1
0. 4 5
0. 3 3
0. 6 2
4. 1
6. 6
0. 6 2
0. 4 5
0. 8 5
4. 1
4. 9
0. 8 4
0. 6 1
1. 1 5
1 0. 7
P o w er f or a n al y si s of k e y s e c o n d ar y  vari a bl e s
N ot a p plica ble.


N o v arti s
C o nfi d e nti al
P a g e 9 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
1 1
Et hi c al c o n si d er ati o n s a n d a d mi ni str ati v e pr o c e d ur e s
1 1. 1
R e g ul at or y  a n d et hi c al c o m pli a n c e
T his cli nical st u d y was desi g ne d, s hall be i m ple me nte d a n d re p orte d i n acc or da nce wit h t he 
I C H Har m o nize d Tri partite G ui deli nes f or G o o d Cli nical Practice, w it h a p plica ble l ocal 
re g ulati o ns (i ncl u di n g E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C a n d U S C o de of Fe deral Re g ulati o ns 
Title 2 1), a n d wit h t he et hical pri nci ples lai d d o w n i n t he Declarati o n of Helsi n ki.
1 1. 2
R e s p o n si biliti e s of t h e i n v e sti g at or a n d I R B/I E C/ R E B
T he pr ot oc ol a n d t he pr o p ose d i nf or me d c o nse nt f or m m ust be re vie we d a n d a p pr o ve d b y  a 
pr o perl y c o nstit ute d I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee/ Researc h 
Et hics B oar d (I R B/I E C/ R E B) bef ore st u d y start. Pri or t o st u d y start, t he i n vesti gat or is 
re q uire d t o si g n a pr ot oc ol si g nat ure pa ge c o nfir mi n g his/ her a gree me nt t o c o n d uct t he st u d y 
i n acc or da nce wit h t hese d oc u me nts a n d all of t he i nstr ucti o ns a n d pr oce d ures f o u n d i n t his 
pr ot oc ol a n d t o gi ve access t o all rele va nt data a n d rec or ds t o N o var tis m o nit ors, a u dit ors, 
N o vartis 
Cli nical 
Q ualit y  
Ass ura nce re prese ntati ves, desi g nate d a ge nts of N o vartis, 
I RBs/I E Cs/ R E Bs a n d re g ulat or y  a ut h orities as re q uire d.
1 1. 3
I nf or m e d c o n s e nt pr o c e d ur e s
Eli gi ble patie nts ma y  onl y  be i ncl u de d i n t he st u d y after pr o vi di n g writte n ( wit nesse d, w here 
re q uire d by la w or re g ulati o n), I R B/I E C/ R E B -a p pr o ve d i nf or me d c o nse nt
I nf or me d c o nse nt m ust be o btai ne d bef ore c o n d ucti n g a n y st u d y-s pecific pr oce d ures (i.e. all 
of t he pr oce d ures descri be d i n t he pr ot oc ol). T he pr ocess of o bta i ni n g i nf or me d c o nse nt 
s h o ul d be d oc u me nte d i n t he patie nt s o urce d oc u me nts. T he date w he n a s u bject’s I nf or me d 
C o nse nt was act uall y o btai ne d will be ca pt ure d i n t heir C R Fs.
N o vartis will pr o vi de t o i n vesti gat ors, i n a se parate d oc u me nt, a pr o p ose d i nf or med c o nse nt 
f or m (IC F) t hat is c o nsi dere d a p pr o priate f or t his st u d y an d c o m plies wit h t he I CH G C P 
g ui deli ne a n d re g ulat or y re q uire me nts. A n y c ha n ges t o t his I CF s u g geste d b y  the i n vesti gat or 
m ust be a gree d t o b y  No vartis bef ore s u b missi o n t o t he I RB/I E C/ R E B , a n d a c o p y of t he 
a p pr o ve d versi o n m ust be pr o vi de d t o t he N o vartis m o nit or after I R B/ I E C/ R E B a p pr o val.
A d diti o n al c o n s e nt f or m
N ot a p plica ble.
1 1. 4
Di s c o nti n u ati o n of t h e st u d y
N o vartis reser ves t he ri g ht t o disc o nti n ue t his st u d y un der t he c o n diti o ns s pecifie d i n t he 
cli nical st u d y agree me nt. S pecific c o n diti o ns f or ter mi nati n g t he st u d y are o utli ne d i n Secti o n 
4. 4 .
1 1. 5
P u bli c ati o n of st u d y  pr ot o c ol a n d r e s ult s
N o vartis ass ures t hat t he k e y  desi g n ele me nts of t his pr ot oc ol will be p oste d i n a p u blicl y 
accessi ble data base s uc h as cli nicaltrials. g o v. I n a d diti o n, u p o n st u d y co m pleti o n a n d 


N o v arti s
C o nfi d e nti al
P a g e 9 6
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
fi nalizati o n of t he st u d y re p ort t he res ults of t his st u d y will be eit her s u b mitte d f or p u blicati o n 
a n d/ or p oste d i n a p u blicl y accessi ble data base of cli nical st u d y res ults.
1 1. 6
St u d y d o c u m e nt ati o n, r e c or d k e e pi n g a n d r et e nti o n of 
d o c u m e nt s
Eac h partici pati n g site will mai ntai n a p pr o priate me dical a n d researc h rec or ds f or t his trial, i n 
c o m plia nce wit h 
Secti o n 4. 9 of t he I CH 
E 6 G C P,
a n d re g ulat or y a n d i nstit uti o nal 
re q uire me nts f or t he pr otecti o n of c o nfi de ntialit y of s u bjects. As part of partici pati n g i n a 
N o vartis -s p o ns ore d st u d y, eac h site will per mit a ut h orize d re prese ntati ves of t he s p o ns or(s) 
a n d re g ulat or y age ncies t o e xa mi ne (a n d w he n re q uire d b y  ap plica ble la w, t o c o p y)  cli nical 
rec or ds f or t he p ur p oses of q ualit y ass ura nce re vie ws, a u dits a n d e val uati o n of t he st u d y 
safety a n d pr o gress.
S o urce data are all i nf or mati o n, ori gi nal rec or ds of cli nical fi n di n gs, o bser vati o ns, or ot her 
acti vities i n a cli nical trial necessar y  for t he rec o nstr ucti o n a n d e val uati o n of t he trial. 
E xa m ples of t hese ori gi nal d oc u me nts a n d data rec or ds i ncl u de, b ut are n ot li mite d t o, h os pital 
rec or ds, cli nical a n d office c harts, la b orat or y n otes, me m ora n da, s u bjects’ diaries or 
e val uati o n c hec klists, p har mac y  dis pe nsi n g rec or ds, rec or de d data 
fr o m a ut o mate d 
i nstr u me nts, c o pies or tra nscri pti o ns certifie d after verificati o n as bei n g acc urate a n d c o m plete, 
micr ofic hes, p h ot o gra p hic ne gati ves, micr ofil m or ma g netic me dia, x- ra ys, a n d s u bject files 
a n d rec or ds ke pt at t he p har mac y , at t he la b orat ories, a n d me dic o -tec h nical de part me nts 
i n v ol ve d i n t he cli nical trial.
Data c ollecti o n is t he res p o nsi bilit y  of t he cli nical trial staff at t he site u n der t he s u per visi o n of 
t he site Pri nci pal In vesti gat or. T he st u d y  case re p ort f or m ( C R F) is t he pri mar y data c ollecti o n 
i nstr u me nt f or t he st u d y. T he i n vesti gat or s h o ul d e ns ure t he acc urac y, c o m plete ness, le gi bilit y, 
a n d ti meli ness of t he data re p orte d i n t he C R Fs a n d all ot her re q uire d re p orts. Data re p orte d 
o n t he C R F, t hat are deri ve d fr o m s o urce d oc u me nts, s h o ul d be c o nsiste nt wit h t he s o urce 
d oc u me nts or t he discre pa ncies s h o ul d be e x plai ne d. All data re q ueste d o n t he C R F m ust be 
rec or de d. A n y missi n g data m ust be ex plai ne d. A n y c ha n ge or c orrecti o n t o a pa per C R F 
s h o ul d be date d, i nitiale d, a n d e x plai ne d (if necessar y ) a n d s h o ul d n ot o bsc ure t he ori gi nal 
e ntr y. F or electr o nic C R Fs a n a u dit trail will be mai ntai ne d b y  the s yste m. T he i n vesti gat or 
s h o ul d retai n rec or ds of t he c ha n ges a n d c orrecti o ns t o pa per C R Fs.
T he i n vesti gat or/i nstit uti o n s h o ul d mai ntai n t he trial d oc u me nts as s pecifie d i n Esse ntial 
D oc u me nts f or t he C o n d uct of a Cli nical Trial (IC H E 6 Secti o n 8) a n d as re q uire d b y  
a p plica ble re g ulati o ns a n d/ or g ui deli nes. T he i n vesti gat or/i nstit uti o n s h o ul d ta ke meas ures t o 
pre ve nt acci de ntal or pre mat ure destr ucti o n of t hese d oc u me nts.
Esse ntial d oc u me nts ( writte n a n d electr o nic) s h o ul d be retai ne d f or a peri o d of n ot less t ha n 
fiftee n ( 1 5) ye ars fr o m t he c o m pletio n of t he Cli nical Trial u nless S p o ns or pr o vi des writte n 
per missi o n t o dis p ose of t he m or, re q uires t heir rete nti o n f or a n a d diti o nal peri o d of ti me 
beca use of a p plica ble la ws, re g ulati o ns a n d/ or g ui deli nes.


N o v arti s
C o nfi d e nti al
P a g e 9 7
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
1 1. 7
C o nfi d e nti alit y  of st u d y d o c u m e nt s a n d p ati e nt re c or d s
T he i n vesti gat or m ust e ns ure a n o n y m it y of t he patie nts; patie nts m ust n ot be i de ntifie d b y  
na mes i n a n y d oc u me nts s u b mitte d t o N o vartis. Si g ne d i nf or me d c o nse nt f or ms a n d patie nt 
e nr oll me nt l o g m ust be ke pt strictl y  c o nfi de ntial t o e na ble patie nt i de ntificati o n at t he site.
1 1. 8
A u dit s a n d i n s p e cti o n s
S o urce data/ d oc u me nts m ust be a vaila ble t o i ns pecti o ns b y  No vartis or desi g nee or Healt h 
A ut h orities.
1 1. 9
Fi n a n ci al di s cl o s ur e s
Fi na ncial discl os ures s h o ul d be pr o vi de d b y  st u d y pers o n nel w h o are directl y  in v ol v e d i n t he 
treat me nt or e val uati o n of patie nts at t he site - pri or t o st u d y  start.
1 2
Pr ot o c ol a d h er e n c e
I n vesti gat ors ascertai n t he y will a p pl y due dili ge nce t o a v oi d pr ot oc ol de viati o ns. U n der n o 
circ u msta nces s h o ul d t he i n vesti gat or c o ntact N o vartis or its a ge nts, if a n y, m o nit ori n g t he 
st u d y t o re q uest a p pr o val of a pr ot oc ol de viati o n, as n o a ut h orize d de viati o ns are per mitte d. If 
t he i n vesti gat or feels a pr ot oc ol de viati o n w o ul d i m pr o ve t he c o n d uct of t he st u d y this m ust 
be c o nsi dere d a pr ot oc ol a me n d me nt, a n d u nless s uc h a n a me n d me nt is a gree d u p o n b y  
N o vartis a n d a p pr o ve d b y  the I R B/I E C/ R E B it ca n n ot be i m ple me nte d. All si g nifica nt 
pr ot oc ol de viati o ns will be rec or de d a n d re p orte d i n t he C S R.
1 2. 1
A m e n d m e nt s t o t h e pr ot o c ol
A n y  c ha n ge or a d diti o n t o t he pr ot oc ol ca n o nly be ma de i n a writte n pr ot oc ol a me n d me nt t hat 
m ust be a p pr o ve d b y  No vartis, Healt h A ut h orities w here re q uire d, a n d t he I R B/I E C/ R E B. 
O nl y  ame n d me nts 
t hat are re q uire d f or patie nt safet y 
ma y be i m ple me nte d pri or
t o 
I RB/I E C/ R E B 
a p pr o val. N ot wit hsta n di n g 
t he nee d f or a p pr o val of f or mal pr ot oc ol 
a me n d me nts, t he i n vesti gat or is e x pecte d t o ta ke a n y im me diate acti o n re q uire d f or t he safety 
of a n y patie nt i ncl u de d i n t his st u d y, e ve n if t his acti o n re prese nts a de viati o n fr o m t he 
pr ot oc ol. I n s uc h cases, N o vartis s h o ul d be n otifie d of t his acti o n a n d t he I R B/I E C at t he st u d y 
site s h o ul d be i nf or me d acc or di n g t o l ocal re g ulati o ns (e. g. U K re q uires t he n otificati o n of 
ur ge nt safet y meas ures wit hi n 3 da ys) b ut n ot later t h a n 1 0 w or ki n g da ys.


N o v arti s
C o nfi d e nti al
P a g e 9 8
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
1 3
R ef er e n c e s ( a v ail a bl e u p o n r e q u e st)
A bra ha m R T , et al ( 2 0 0 7) T he Ma m malia n Tar get of Ra pa m yci n Si g nali n g Pat h wa y: T wists 
a n d T ur ns i n t he R oa d t o Ca ncer T hera p y. Cli n Ca ncer Res 1 3; 3 1 0 9 - 3 1 1 4.
A wa da A , et al ( 2 0 0 8) T he oral m T O R i n hi bit or R A D 0 0 1 (e ver oli m us) i n c o m bi nati o n wit h 
letr oz ole i n patie nts wit h a d va nce d breast ca ncer: res ults of a p hase I st u d y wit h 
p har mac o ki netics. E ur J Ca ncer. 2 0 0 8 Ja n; 4 4( 1): 8 4 -9 1.
Bac hel ot T , et al ( 2 0 1 2) Ra n d o mize d p hase II trial of e ver oli m us i n c o m bi nati o n wit h 
ta m o xife n i n patie nts wit h h or m o ne rece pt or-p ositi ve, h u ma n e pi der mal gr o wt h fact or 
rece pt or 2-ne gati ve metastatic breast ca ncer wit h pri or e x p os ure t o ar o matase i n hi bit ors: a 
GI N E C O st u d y . J Clin O nc ol. 2 0 1 2 A u g 1; 3 0( 2 2): 2 7 1 8- 2 4.
Basel ga J , et al ( 2 0 0 9) P hase II ra n d o mize d st u d y  of ne oa dj u va nt e ver oli m us pl us letr oz ole 
c o m pare d wit h place b o pl us letr oz ole i n patie nts wit h estr o ge n rece pt or -p ositi ve breast ca ncer. 
J Cli n O nc ol. 2 0 0 9 J u n 1; 2 7( 1 6): 26 3 0- 7.
Beslija S , et al (2 0 0 9 ) T hir d c o nse ns us o n me dical treat me nt of metastatic breast ca ncer. A n n 
O nc ol. 2 0 0 9 N o v; 2 0( 1 1): 1 7 7 1 - 8 5.
Be u vi n k I , et al ( 2 0 0 5) T he m T O R I n hi bit or R A D 0 0 1 Se nsitizes T u m or Cells t o D N A -
Da ma ge d I n d uce d A p o pt osis t hr o u g h I n hi biti o n of p 2 1 Tra nslati o n; Cell; v ol 1 2 0 7 4 7 -7 5 9.
Bj or nsti M - A, et al ( 2 0 0 4) T he T O R pat h wa y : A tar get f or ca ncer c he m ot hera p y Nat ure 
Re vie ws Ca ncer 4: 3 3 5 -4 8.
B o ula y  A 1, La ne H A (2 0 0 7 ) Rece nt Res ults Ca ncer Res. T he ma m malia n tar get of ra pa m yci n 
ki nase a n d t u m o r gr o wt h i n hi biti o n. 2 0 0 7; 1 7 2: 9 9- 1 2 4.
B urstei n HJ , et al ( 2 0 1 1) N o vel a ge nts a n d f ut ure directi o ns f or refract or y  breast ca ncer. 
Se mi n O nc ol. 2 0 1 1 J u n; 3 8 S u p pl 2: S 1 7 - 2 4.
B uz dar A ( 2 0 0 3) P har mac ol o g y  a n d P har mac o ki netics of t he Ne wer Ge nerati o n Ar o matase 
I nhi bit ors. Cli nical Ca ncer Researc h 9, 4 6 8s- 4 7 2s, ( S u p pl.) .
Ca m p bell R A , et al ( 2 0 0 1) P h os p hati d y li n osit ol 3- ki nase/ A K T me diate d acti vati o n of 
estr o ge n rece pt or al p ha: a ne w m o del f or a nti -estr o ge n resista nce. J Bi ol C he m; 2 7 6: 9 8 1 7 –
9 8 2 4.
Car d os o F , et al ( 2 0 1 2) 1st I nter nati o nal c o nse ns us g ui deli nes f or a d va nce d breast ca ncer 
( A B C 1). Breast. 2 0 1 2 J u n; 2 1( 3): 2 4 2- 5 2.
Cl o p per , et al ( 1 9 3 4) T he use of c o nfi de nce or fi d ucial li mits ill ustrate d i n t he case of t he 
bi n o mial. Bi o metri ka 2 6: 4 0 4 -4 1 3.
Cr o we A , et al ( 1 9 9 8) I n vitr o a n d i n sit u a bs or pti o n of S D Z-R A D usi n g a h u ma n i ntesti nal 
cell li ne ( Cac o -2) a n d a si n gle pass perf usi o n m o del i n rats: c o m paris o n wit h ra pa m yci n. 
P har m Res. 1 9 9 8 N o v; 1 5( 1 1): 1 6 6 6 -7 2.
De mers L M, Li pt o n A, Har ve y  H A, et al ( 1 9 9 3) T he efficac y  of C G S 2 0 2 6 7 i n s u p pressi n g 
estr o ge n bi os y nt hesis i n patie nts wit h a d va nce d sta ge breast ca ncer. J Ster oi d Bi oc he m M ol 
Bi ol 4 4: 6 8 7 – 6 9 1.


N o v arti s
C o nfi d e nti al
P a g e 9 9
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Efe y a n A, Sa bati ni D M ( 2 0 1 0) m T O R a n d ca ncer: ma n y  l o o ps i n o ne pat h wa y. C urr O pi n 
Cell Bi ol. 2 0 1 0 A pr; 2 2( 2): 1 6 9 -7 6.
Eis e n ha uer E A , et al (2 0 0 9 ) Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: re vise d 
R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer. 2 0 0 9 Ja n; 4 5( 2): 2 2 8 -4 7. d oi: 
1 0. 1 0 1 6/j.ejca. 2 0 0 8. 1 0. 0 2 6.
Ellar d S L , et al (2 0 0 9 ) Ra n d o mize d p hase II st u d y  c o m pari n g t w o sc he d ules of e ver oli m us i n 
patie nts wit h rec urre nt/ metastatic breast ca ncer: N CI C Cli nical Trials Gr o u p I N D. 1 6 3. J Cli n 
O nc ol. 2 0 0 9 Se p 2 0; 2 7( 2 7): 4 5 3 6 -4 1.
Fratti ni M , et al ( 2 0 0 5) P h os p hatase pr otei n h o m ol o g ue t o te nsi n e x pressi o n a n d 
p h os p hati d y li n osit ol- 3 p h os p hate ki nase m utati o ns i n c ol orectal ca ncer. Ca ncer Res. 2 0 0 5 Dec 
1; 6 5( 2 3): 1 1 2 2 7.
G L O B O C A N 2 0 0 8: Ca ncer I nci de nce a n d M ortalit y  W orl d wi de htt p:// w w w.iarc.fr/e n/ me dia-
ce ntre/iarc ne ws/ 2 0 1 0/ gl o b oca n 2 0 0 8. p h p.
G oel A , et al ( 2 0 0 4) Fre q ue nt i nacti vati o n of P T E N b y  pr o m oter h yper met h y lati o n i n 
micr osatellite i nsta bilit y -hi g h s p ora dic c ol orectal ca ncers. Ca ncer Res. 2 0 0 4 Ma y  
1; 6 4( 9): 3 0 1 4 - 2 1.
G u o H , et al ( 2 0 0 7) Re g ulati o n of he patiti s B vir us re plicati o n by t he p h os p hati d yli n osit ol 3 -
ki nase -a kt si g nal tra ns d ucti o n pat h wa y. J Vir ol. 2 0 0 7 Se p; 8 1( 1 8): 1 0 0 7 2-8 0.
Je mal A, et al ( 2 0 1 1) Gl o bal ca ncer statistics; C A Ca ncer J Cli n. 2 0 1 1 Mar -A pr; 6 1( 2): 6 9 - 9 0.
J o h nst o n S R ( 2 0 0 6) Cli nical eff orts t o c o m bi ne e n d ocri ne a ge nts wit h tar gete d t hera pies 
a gai nst e pi der mal gr o wt h fact or rece pt or/ h u ma n e pi der mal gr o wt h fact or rece pt or 2 a n d 
ma m malia n tar get of ra pa m y ci n i n breast ca ncer. Cli n Ca ncer Res. 2 0 0 6 Fe b 1; 1 2( 3 Pt 
2): 1 0 6 1s -1 0 6 8s.
K u h n B , et al (2 0 0 1) Meta b olis m of sir oli m us a n d its deri vati ve e ver oli m us b y  c yt oc hr o me 
P 4 5 0 3 A 4: i nsi g hts fr o m d oc ki n g, m olec ular d y na mics, a n d q ua nt u m c he mical calc ulati o ns. J 
Me d C he m. 2 0 0 1 J u n 7; 4 4( 1 2): 2 0 2 7 - 3 4.
La pla nte A , et al ( 2 0 0 2) I nteracti o n of i m m u n os u p pressi ve a ge nts ra pa myci n a n d its a nal o g ue 
S D Z -R A D wit h e n d ot helial P -g p. Tra ns pla nt Pr oc. 2 0 0 2 Dec; 3 4( 8): 3 3 9 3 - 5.
Li n os E , et al ( 2 0 0 8) Effects of re pr o d ucti ve a n d de m o gra p hic c ha n ges o n breast ca ncer 
i nci de nce i n C hi na: a m o deli n g a nalys is; J Natl Ca ncer I nst. 2 0 0 8 Oct 1; 1 0 0( 1 9): 1 3 5 2- 6 0.
Miller T W,
et al ( 2 0 1 0) H y peracti vati o n of p h os p hati d y li n osit ol- 3 ki nase pr o m otes esca pe 
fr o m h or m o ne de pe n de nce i n estr o ge n rece pt or-p ositi ve h u ma n breast ca ncer. J Cli n I n vest. 
2 0 1 0 J ul; 1 2 0( 7): 2 4 0 6 - 1 3.
N o g uc hi S , et al ( 2 0 1 4) Efficac y  of e ver oli m us wit h e xe mesta ne vers us e xe mesta ne al o ne i n 
Asia n patie nts wit h H E R 2 -ne gati ve, h or m o ne -rece pt or- p ositi ve breast ca ncer i n B O L E R O- 2. 
Breast Ca ncer. 2 0 1 4 N o v; 2 1( 6): 7 0 3- 1 4.
Piccart M , et al (2 0 1 4) E ver oli m us pl us e xe mesta n e f or h or m o ne- rece pt or-p ositi ve, h u ma n 
e pi der mal gr o wt h fact or rece pt or - 2-ne gati ve a d va nce d breast ca ncer: o verall s ur vi val res ults 
fr o m B O L E R O-2. A n n O nc ol. 2 0 1 4 Dec; 2 5( 1 2): 2 3 5 7- 6 2.
Pl o ur de P V, D y r off M, D o wsett M, et al ( 1 9 9 5) A RIMI D E X: a ne w oral, o nce -a-d a y  
ar o matase i n hi bit or. J Ster oi d Bi oc he m M ol Bi ol 5 3: 1 7 5 – 1 7 9.


N o v arti s
C o nfi d e nti al
P a g e 1 0 0
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Sa nte n RJ , et al ( 2 0 0 5) A da pti ve h y perse nsiti vit y  t o estr o ge n: mec ha nis ms a n d cli nical 
rele va nce t o ar o matase i n hi bit or t hera py i n breast ca ncer treat me nt. J Ster oi d Bi oc he m M ol 
Bi ol 9 5: 1 5 5 – 1 6 5.
Sar bass o v D D, Ali S M, Ki m D -H, et al ( 2 0 0 4) Rict or, a N o vel Bi n di n g Part ner of m T O R, 
Defi nes a Ra pa m yci n -I nse nsiti ve a n d Ra pt or-I n de pe n de nt Pat h wa y t hat Re g ulates t he 
C y t os kelet o n C urre nt Bi ol; 1 4: 1 2 9 6– 3 0 2.
Sc hiff R , et al (2 0 0 4) Cr oss -tal k bet wee n estr o ge n rece pt or a n d gr o wt h fact or pat h wa y s as a 
m olec ular tar get f or o verc o mi n g e n d ocri ne resista nce. Cli n Ca ncer Res. 2 0 0 4 Ja n 1; 1 0( 1 Pt 
2): 3 3 1 S -6 S.
Ta ber ner o J , et al (2 0 0 8) D ose - a n d sc he d ule-de pe n de nt i n hi biti o n of t he ma m malia n tar get of 
ra pa myc i n pat h wa y wit h e ver oli m us: a p hase I t u m or p har mac o dy n a mic st u d y i n patie nts wit h 
a d va nce d s oli d t u m ors. J Cli n O nc ol. 2 0 0 8 A pr 1; 2 6( 1 0): 1 6 0 3- 1 0.
T herasse P , et al (2 0 0 0) Ne w g ui deli nes t o e val uate t he res p o nse t o treat me nt i n s oli d t u m ors. 
E ur o pea n Or ga n izati o n f or Researc h a n d Treat me nt of Ca ncer, Nati o nal Ca ncer I nstit ute of 
t he U nite d States, Nati o nal Ca ncer I nstit ute of Ca na da. J Natl Ca ncer I nst. 2 0 0 0 Fe b 
2; 9 2( 3): 2 0 5 - 1 6.
T o k u na ga E , et al ( 2 0 0 6) A kt is fre q ue ntl y acti vate d i n H E R 2/ ne u -p ositi ve breast ca ncers a n d 
ass ociate d wit h p o or pr o g n osis a m o n g h or m o ne -treate d patie nts. I nt J Ca ncer; 1 1 8: 2 8 4– 2 8 9.
Vel h o S , et al (2 0 0 5) T he pre vale nce of PI K 3 C A m utati o ns i n gastric a n d c ol o n ca ncer. E ur J 
Ca ncer. 2 0 0 5 J ul; 4 1( 1 1): 1 6 4 9 - 5 4.
Ya m ni k R L , et al (2 0 1 0) m T O R/ S 6 K 1 a n d M A P K/ R S K si g nali n g pat h wa y s c o or di nately 
re g ulate estr o ge n rece pt or al p ha seri ne 1 6 7 p h os p h or ylati o n. F E B S Lett. 2 0 1 0 Ja n 
4; 5 8 4( 1): 1 2 4 -8.
Ya m ni k , et al ( 2 0 0 9) S 6 ki nase 1 re g ulates estr o ge n rece pt or al p ha i n c o ntr ol of breast ca ncer 
cell pr oliferati o n.J Bi ol C he m. 2 0 0 9 Mar 6; 2 8 4( 1 0): 6 3 6 1-9.
Yar dle y  D A, et al ( 2 0 1 3) E ver oli m us pl us e xe mesta ne i n p ost me n o pa usal patie nts wit h H R( +) 
breast ca ncer: B O L E R O -2 fi nal pr o gressi o n -free s ur vi val a nalys is. A d v T her. 2 0 1 3 
Oct; 3 0( 1 0): 8 7 0 - 8 4.
Ye o W, et al ( 2 0 0 4) C o m pre he nsi ve a nal ys is of ris k fact ors ass ociati n g wit h He patitis B vir us 
( H B V) reacti vati o n i n ca ncer patie nts u n der g oi n g c yt ot o xic c he m ot hera p y. Br J Ca ncer. 2 0 0 4 
A pr 5; 9 0( 7): 1 3 0 6 - 1 1.
Y ue W , et al ( 2 0 0 7) Mec ha nis ms of ac q uire d resista nce t o e n d ocri ne t her a p y i n h or m o ne-
de pe n de nt breast ca ncer cells. J Ster oi d Bi oc he m M ol Bi ol; 1 0 6: 1 0 2 -1 1 0.


N o v arti s
C o nfi d e nti al
P a g e 1 0 1
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
1 4
A p p e n di c e s
1 4. 1
A p p e n di x 1: G ui d eli n e s f or R e s p o n s e, D ur ati o n of O v er all 
R e s p o n s e, T T F, T T P, Pr o gr e s si o n -Fr e e S ur vi v al a n d O v er all 
S ur vi v al ( v er si o n 3. 2, b a s e d o n R E CI S T 1. 1)
Gl o s s ar y
C R
C o m pl et e r e s p o n s e
C R F
C a s e R e p ort F or m
C S R
Cli ni c al St u d y R e p ort
C T
C o m p ut e d t o m o gr a p h y
D F S
Di s e a s e -fr e e s ur vi v al
e C R F
El e ctr o ni c C a s e R e p ort F or m
F P F V
Fir st p ati e nt fir st vi sit
G B M
Gli o bl a st o m a m ultif or m e
M RI
M a g n eti c r e s o n a n c e i m a gi n g
L P L V
L a st p ati e nt l a st vi sit
O S
O v er all s ur vi v al
P D
Pr o gr e s si v e di s e a s e
P F S
Pr o gr e s si o n -fr e e s ur vi v al
P R
P arti al r e s p o n s e
R A P
R e p orti n g a n d A n al y si s Pl a n
R E CI S T
R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s
S D
St a bl e di s e a s e
S O D
S u m of Di a m et er
T T F
Ti m e t o tr e at m e nt f ail ur e
T T P
Ti m e t o pr o gr e s si o n
U N K
U n k n o w n




N o v arti s
C o nfi d e nti al
P a g e 1 0 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

C y stic lesi o ns:

Lesi o ns t hat meet t he criteria f or ra di o gra p hicall y defi ne d si m ple c y sts (i.e., s p herical 
str uct ure wit h a t hi n, n o n-irre g ular, n o n-n o d ular a n d n o n -e n ha nci n g wall, n o 
se ptati o ns, a n d l o w C T de nsit y [ water-li ke] c o nte nt) s h o ul d n ot be c o nsi dere d as 
mali g na nt lesi o ns ( neit her meas ura ble n or n o n -meas ura ble) si nce t he y  are, b y 
defi niti o n, si m ple c y sts.

‘ C ystic lesi o ns’ t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d as 
meas ura ble lesi o ns, if t he y meet t he defi niti o n of meas ura bilit y  descri be d a b o ve. 
H o we ver, if n o nc y stic lesi o ns are prese nt i n t he sa me patie nt, t hese are preferre d f or 
selecti o n as tar get lesi o ns.

N o n -meas ura ble le si o ns - all ot her lesi o ns are c o nsi dere d n o n -meas ura ble, i ncl u di n g s mall 
lesi o ns (e. g. l o n gest dia meter < 1 0 m m wit h C T/ M RI or pat h ol o gical l ym p h n o des wit h 1 0 
t o < 1 5 m m s h ort a xis), as well as tr ul y n o n-meas ura ble lesi o ns e. g., blastic b o ne lesi o ns, 
le pt ome ni n geal disease, ascites, ple ural/ pericar dial eff usi o n, i nfla m mat or y bre ast disease, 
l ym p ha n gitis c utis/ p ul m o nis, a b d o mi nal masses/a b d o mi nal or ga n o me gal y i de ntifie d b y
p h y sical e xa m t hat is n ot meas ura ble by re pr o d uci ble i ma gi n g tec h ni q ues.
1 4. 1. 2. 1. 2
Eli gi bilit y b a s e d o n m e a s ur a bl e di s e a s e
If n o
meas ura ble lesi o ns are i de ntifie d at baseli ne, t he patie nt ma y be all o we d t o e nter t he 
st u dy i n s o me sit uati o ns (e. g. i n P hase III st u dies w here P F S is t he pri mar y e n d p oi nt) . 
H o we ver, it is rec o m me n de d t hat patie nts be e xcl u de d fr o m trials w her e t he mai n f oc us is o n 
t he O verall
Res p o nse Rate
( O R R). G ui da nce o n h o w patie nts wit h j ust n o n- meas ura ble 
disease at baseli ne will be e val uate d f or res p o nse a n d als o ha n dle d i n t he statistical a na l yses is 
gi ve n i n Secti o n 1 4. 1. 3. 2. 9 .
1 4. 1. 2. 2
M et h o d s
of t u m or m e a s ur e m e nt - g e n er al g ui d eli n e s
I n t his d oc u me nt, t he ter m “c o ntrast” refers t o i ntra ve n o us (i. v.) c o ntrast. T he f oll o wi n g 
c o nsi derati o ns are t o be ma de w he n e val uati n g t he t u m or:

Al l meas ure me nts s h o ul d be ta ke n a n d rec or de d i n metric n otati o n ( m m), usi n g a r uler or
cali pers. All baseli ne e val uati o ns s h o ul d be perf or me d as cl osel y as p ossi ble t o t he 
be gi n ni n g of treat me nt a n d ne ver m ore t ha n 4 wee ks bef ore t he be gi n ni n g of t he treat m e nt.

I ma gi n g-base d e val uati o n is preferre d t o e val uati o n b y cli nical e xa mi nati o n w he n b ot h 
met h o ds ha ve bee n use d t o assess t he a ntit u m or effect of a treat me nt.

F or o pti mal e val uati o n of patie nts, t he sa me met h o ds of assess me nt a n d tec h ni q ue s h o ul d 
be use d t o c haracterize eac h i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w-
u p. C o ntrast- e n ha nce d C T of c hest, a b d o me n a n d pel vis s h o ul d prefera bl y be perf or me d 
usi n g a 5 m m slice t hic k ness wit h a c o nti g u o us rec o nstr ucti o n al g orit h m. C T/ M RI  sca n 
slice t hic k ness s h o ul d n ot e xcee d 8 m m c uts usi n g a c o nti g u o us rec o nstr ucti o n al g orit h m. 
If, at baseli ne, a patie nt is k n o w n t o ha ve a me dical c o ntrai n dicati o n t o C T c o ntrast or 
de vel o ps a c o ntrai n dicati o n d uri n g t he trial, t he f oll o wi n g c ha n ge i n i ma gi n g m o dalit y will 
be acce pte d f or f oll o w u p: a n o n- c o ntrast C T of c hest ( M RI n ot rec o m me n de d d ue t o 
res pirat or y artifacts) pl us c o ntrast-e n ha nce d M RI of a b d o me n a n d pel vis.


N o v arti s
C o nfi d e nti al
P a g e 1 0 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

A c ha n ge i n met h o d ol o g y  ca n be defi ne d as eit her a c ha n ge i n c o ntrast use (e. g. kee pi n g
t he sa me tec h ni q ue, li ke C T, b ut s witc hi n g fr o m wit h t o wit h o ut c o ntrast use or vice- versa, 
re gar dless of t he j ustificati o n f or t he c ha n ge) or a maj or c ha n ge i n tec h ni q ue (e. g. fr o m C T 
t o M RI, or vice-versa), or a c ha n ge i n a n y ot her i ma gi n g m o dalit y. A c h a n ge fr o m 
c o n ve nti o nal t o s piral C T or vice versa will n ot c o nstit ute a maj or “c ha n ge i n met h o d” f or 
t he p ur p oses of res p o nse assess me nt. A c ha n ge i n met h o d ol o g y will res ult b y defa ult i n a 
U N K o verall lesi o n res p o nse assess me nt as per N o vartis calc ulate d res p o nse. H o we ver, 
a n ot her res p o nse assess me nt t ha n t he N o vartis calc ulate d U N K res p o nse ma y be acce pte d 
fr o m t he i n vesti gat or or t he ce ntral bli n de d re vie wer if a defi niti ve res p o nse assess me nt
ca n be j ustifie d, base d o n t he a vaila ble i nf or mati o n.

F D G -P E T : ca n c o m ple me nt C T sca ns i n assessi n g pr o gressi o n ( partic ularly p ossi ble f or
‘ ne w’ disease). Ne w lesi o ns o n t he basis of F D G-P E T i ma gi n g ca n be i de ntifie d acc or di n g 
t o t he f oll o wi n g al g orit h m:

Ne gati ve F D G -P E T at baseli ne, wit h a p ositi ve F D G -P E T at f oll o w- u p is a si g n of P D
base d o n a ne w lesi o n.

N o F D G - P E T at baseli ne wit h a p ositi ve F D G-P E T at f oll o w - u p:

If ne w disease is i n dicate d b y a p ositi ve P E T sca n b ut is n ot c o nfir me d b y C T ( or s o me 
ot her c o n ve nti o nal tec h ni q ue s uc h as M RI) at t he sa me assess me nt , t he n f oll o w- u p 
assess me nts b y C T will be nee de d t o deter mi ne if t here is tr uly pr o gressi o n occ urri n g at 
t hat site. In all cases P D will be t he date of c o nfir mati o n of ne w disease b y C T ( or s o me 
ot her c o n ve nti o nal tec h ni q ue s uc h as M RI) rat her t ha n t he da te of t he p ositi ve P E T sca n. 
If t here is a p ositi ve P E T sca n wit h o ut a ny c o nfir me d pr o gressi o n at t hat site b y C T, t he n 
a P D ca n n ot be assi g ne d.

If t he p ositi ve F D G-P E T at f oll o w -u p c orres p o n ds t o a pre -e xisti n g site of disease o n
C T t hat is n ot pr o gressi n g o n t he basis of t he a nat o mic i ma ges, t his is n ot P D.

C hest x -ra y: Lesi o ns o n c hest x-ra y are acce pta ble as meas ura ble lesi o ns w he n t he y 
are clearl y defi ne d a n d s urr o u n de d b y aerate d l u n g. H o we ver, C T is prefera ble.

P h y sical e xa ms: E val uati o n of lesi o ns b y p h y sical e xa mi nati o n is acce pte d w he n 
lesi o ns are s u perficial, wit h at least 1 0 m m size, a n d ca n be assesse d usi n g cali pers.

Ultras o u n d: W he n t he pri mar y  e n d p oi nt of t he st u d y is o bjecti ve res p o nse e val uati o n, 
ultras o u n d ( U S) s h o ul d n ot be use d t o meas ure t u m or lesi o ns, u nless pre-s pecifie d b y 
t he pr ot oc ol. It is, h o we ver, a p ossi ble alter nati ve t o cli nical meas ure me nts of 
s u perficial pal pa ble ly m p h n o des, s u bc uta ne o us lesi o ns a n d t h y r oi d n o d ules. U S 
mi g ht als o be usef ul t o c o nfir m t he c o m plete disa p peara nc e of s u perficial lesi o ns 
us uall y  assesse d b y cli nical e xa mi nati o n.

E n d osc o p y  a n d la par osc o p y: T he utilizati o n of e n d osc o p y a n d la par osc o p y f or 
o bjecti ve t u m or e val uati o n has n ot y et bee n f ull y a n d wi del y vali date d. T heir uses i n 
t his s pecific c o nte xt re q uire s o p histicate d e q ui p me nt a n d a hi g h le vel of e x pertise t hat 
ma y  o nly be a vaila ble i n s o me ce nters. T heref ore, t he utilizati o n of s uc h tec h ni q ues 
f or o bjecti ve t u m or res p o nse s h o ul d be restricte d t o vali dati o n p ur p oses i n s pecialize d 
ce nters. H o we ver, s uch tec h ni q ues ca n be usef ul i n c o nfir mi n g c o m plete pat h ol o gical 
res p o nse w he n bi o psies are o btai ne d.


N o v arti s
C o nfi d e nti al
P a g e 1 0 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

T u m or mar kers: T u m or mar kers al o ne ca n n ot be use d t o assess res p o nse. H o we ver, 
s o me disease s pecific a n d m ore vali date d t u m or mar kers (e. g. C A-1 2 5 f or o vari a n 
ca ncer, P S A f or pr ostate ca ncer, al p ha - F P, L D H a n d Beta- h C G f or testic ular ca ncer) 
ca n be i nte grate d as n o n -tar get disease. If mar kers are i nitiall y a b o ve t he u p per 
n or mal li mit t he y  m ust n or malize f or a patie nt t o be c o nsi dere d i n c o m plete cli nical 
resp o nse w he n all lesi o ns ha ve disa p peare d.

C y t ol o g y a n d hist ol o g y: C yt ol o g y a n d hist ol o g y ca n be use d t o differe ntiate bet wee n 
P R a n d C R i n rare cases (i.e., after treat me nt t o differe ntiate bet wee n resi d ual be ni g n 
lesi o ns a n d resi d ual mali g na nt lesi o ns i n tu m or t y pes s uc h as ger m cell t u m ors). 
C y t ol o gic c o nfir mati o n of ne o plastic nat ure of a n y eff usi o n t hat a p pears or w orse ns 
d uri n g treat me nt is re q uire d w he n t he meas ura ble t u m or has met t he criteria f or 
res p o nse or sta ble disease. U n der s uc h circ u msta nces, t he c yt ol o gic e xa mi nati o n of 
t he fl ui d c ollecte d will per mit differe ntiati o n bet wee n res p o nse a n d sta ble disease (a n 
eff usi o n ma y be a si de effect of t he treat me nt) or pr o gressi ve disease (if t he ne o plastic 
ori gi n of t he fl ui d is c o nfir me d).

Cli nical e xa mi nati o n: Cli nical lesi o ns will o nl y  be c o nsi dere d meas ura ble w he n t he y 
are s u perficial (i.e., s ki n n o d ules a n d pal pa ble l y m p h n o des). F or t he case of s ki n 
lesi o ns, d oc u me ntati o n b y c ol or p h ot o gra p hy, i ncl u di n g a r uler t o esti mate t he size of 
t he lesi o n, is rec o m me n de d.
1 4. 1. 2. 3
B a s eli n e d o c u m e nt ati o n of t ar g et a n d n o n- t ar g et l e si o n s
F o r t he e val uati o n of lesi o ns at baseli ne a n d t hr o u g h o ut t he st u d y, t he lesi o ns are classifie d at 
baseli ne as eit her tar get or n o n- tar get lesi o ns:

Tar get lesi o ns: All meas ura ble lesi o ns ( n o dal a n d n o n -n o dal) u p t o a ma xi m u m of fi ve 
lesi o ns i n t otal (a n d a ma xi m u m of t w o lesi o ns per or ga n), re prese ntati ve of all i n v ol ve d 
or ga ns s h o ul d be i de ntifie d as tar get lesi o ns a n d rec or de d a n d meas ure d at baseli ne. Tar get 
lesi o ns s h o ul d be selecte d o n t he basis of t heir size (lesi o ns wit h t he l o n gest dia meter) a n d 
t heir s uita bilit y f or acc urate re peate d meas ure me nts (eit her b y i ma gi n g tec h ni q ues or 
cli nicall y ). Eac h tar get lesi o n m ust be u ni q uel y a n d se q ue ntiall y n u m bere d o n t he C R F 
(e ve n if it resi des i n t he sa me orga n).
Mi ni m u m t ar g et l e si o n si z e at b a s eli n e

N o n -n o d al t ar get: N o n -n o dal tar get lesi o ns i de ntifie d b y met h o ds f or w hic h slice 
t hic k ness is n ot a p plica ble (e. g. cli nical e xa mi nati o n, p h ot o gra p hy) s h o ul d be at least 1 0 
m m i n l o n gest dia meter. See Secti o n 1 4. 1. 2. 1. 1 .

N o d al t ar get: See Secti o n 1 4. 1. 2. 1. 1 .
A s um o f dia meter s (l o ng a xis f or n o n- n o da l lesi o ns, s h ort a xis f or n o dal ) f or all tar get lesi o ns 
will be calc ulate d a n d re p orte d as t he baseli ne s um of dia meters ( S O D). T he baseli ne s u m of 
dia meters will
b e use d as refere nce b y w hic h
t o c haracterize t he o bjecti ve t u m or res p o nse. 
Eac h tar get lesi o n i de ntifie d at baseli ne m ust be f oll o we d at eac h s u bse q ue nt e val uati o n a n d 
d oc u me nte d o n e C R F.

N o n -t ar get lesi o ns: All ot her lesi o ns are c o nsi dere d n o n -tar get lesi o ns, i.e. lesi o ns n ot 
f ulfilli n g t he criteria f or tar get lesi o ns at baseli ne. Prese nce or a bse nce or w orse ni n g of
n o n- tar get lesi o ns s h o ul d be assesse d t hr o u g h o ut t he st u d y; meas ure me nts of t hese lesi o ns 


N o v arti s
C o nfi d e nti al
P a g e 1 0 6
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
are n ot re q uire d. M ulti ple n o n -tar get lesi o ns i n v ol ve d i n t he sa me or ga n ca n be assesse d as 
a gr o u p a n d rec or de d as a si n gle ite m (i.e. m ulti ple li ver metastases). Eac h n o n -tar get 
lesi o n i de ntifie d at baseli ne m ust be f oll o we d at eac h s u bse q ue nt e val uati o n a n d 
d oc u me nte d o n e C R F.
1 4. 1. 2. 4
F oll o w -u p e v al u ati o n of t ar g et a n d n o n -t ar g et l e si o n s
T o assess t u m or res p o nse, t he s u m of dia meters f or all tar get lesi o ns will be calc ulate d (at 
baseli ne a n d t hr ou g h o ut t he st u d y). At eac h assess me nt res p o nse is e val uate d first se paratel y 
f or t he tar get (Ta ble 1 4- 1 ) a n d n o n- tar get lesi o ns (Ta ble 1 4 - 2) i de ntified at baseli ne. T hese 
e val uati o ns are t he n use d t o calc ulate t he o verall lesi o n res p o nse c o nsi deri n g b ot h t he tar get 
a n d n o n -tar get lesi o ns t o get her (Ta ble 1 4 - 3) as well as t he prese nce or a bse nce of ne w lesi o ns.
1 4. 1. 2. 4. 1
F oll o w -u p a n d r e c or di n g of l e si o n s
At each visit a n d f or eac h lesi o n t he act ual date of t he sca n or pr oce d ure w hic h was use d f or 
t he e val uati o n of each s pecific lesi on s h o uld b e rec or de d. T hi s a p plies to tar get a nd n o n- tar get 
lesi o ns as well
as ne w lesi o ns t hat are detecte d. At
t he assess me nt visit all of t he se parate 
lesi o n e val uati o n data are e xa mi ne d b y t he i n vesti gat or i n or der t o deri ve t he o verall visit 
res p o nse. T heref ore all s uc h data a p plica ble t o a partic ular visit s h o ul d be ass ociate d wit h t he 
sa me assess me nt n u m ber.
1 4. 1. 2. 4. 1. 1 N o n- n o d al l e si o n s
F oll o wi n g treat me nt, lesi o ns ma y ha ve l o n gest dia meter meas ure me nts s maller t ha n t he i ma ge 
rec o nstr ucti o n i nter val. Lesi o ns s maller t ha n t wice t he rec o nstr ucti o n i nter val are s u bject t o 
s u bstantial “ partial v ol u me” effects (i.e., size ma y be u n deresti mate d beca use of t he dista nce 
of t he c ut fr o m t he l o n gest dia meter; s uc h lesi o ns ma y a p pear t o ha ve res p o n de d or pr o gresse d 
o n s u bse q ue nt e xa mi nati o ns, w he n, i n fact, t he y re mai n t he sa me size).
If t he lesi o n has c om pletel y disa p peare d, t he lesi o n size s h o ul d be re p orte d as 0 m m. 
Meas ure me nts
of n o n- n o dal tar get lesi o ns t hat bec o me 5 m m or
less i n l o n gest dia meter are
li kely t o b e n o n- re pr o d uci ble. T heref ore, it is rec o m me n ded t o re p ort a defa ul t val ue of 5 mm, 
i nstea d of t he act ual meas ure me nt.
T his defa ult val ue is deri ve d fr o m t he 5 m m
C T slice 
t hic k ness ( b ut s h o ul d n o t be c ha n ge d wit h var y i n g C T slice t hic k ness). Act ual meas ure me nt 
s h o ul d be gi ve n f or all lesi o ns lar ger t ha n 5 m m i n l o n gest dia meter irres pecti ve of slice 
t hic k ness/rec o nstr ucti o n i nter val.
I n ot her cases w here t he lesi o n ca n n ot be relia bl y meas ure d f or reas o ns ot her t ha n its size (e. g., 
b or ders of t he lesi o n are c o nf o u n de d b y nei g h b ori n g a nat o mical str uct ures), n o meas ure me nt 
s h o ul d be e ntered a n d t he lesi o n ca n n ot be e val uate d.
1 4. 1. 2. 4. 1. 2 N o d al l e si o n s
A n o dal lesi o n less t ha n 1 0 m m i n size b y s h ort a xis is c o nsi dere d n or mal. L y m p h n o des are 
n ot e x pecte d t o disa p pear c o m pletel y , s o a “ n o n-zer o size” will al wa ys persist.
Meas ure me nts
of n o dal tar get lesi o ns t hat bec o me 5 m m or less i n s h ort a xis are li kely t o b e 
n o n- re pr o d uci ble. T heref ore, it is rec o m me n de d t o re p ort a defa ult val ue of 5 m m, i nstea d of 
t he act ual meas ure me nt. T his defa ult val ue is deri ve d fr o m t he 5 m m C T slice t hic k ness ( b ut 


N o v arti s
C o nfi d e nti al
P a g e 1 0 7
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
s h o ul d n ot be c ha n ged wit h var y i n g C T slice t hic k ness). Act ual meas ure me nt s h o ul d be gi ve n 
f or all lesi o ns lar ger t han 5 m m i n s h ort a xis irres pecti ve of slice t hic k ness/rec o nstr ucti o n 
i nter val.
H o we ver,
o nce a tar get n o dal lesi o n s hrin ks t o less t ha n 1 0
m m i n its s h ort a xis, it will be 
c o nsi dere d n or mal f or res p o nse p ur p ose deter mi nati o n. T he l ym p h n o de meas ure me nts
will 
c o nti n ue t o be rec or de d t o all o w t he val ues t o be i ncl u de d i n t he s u m of dia meters f or tar get 
lesi o ns, w hic h ma y be re q uire d s u bse q ue ntl y f or res p o nse deter mi nati o n.
1 4. 1. 2. 4. 2
D et er mi n ati o n of t ar g et l e si o n r e s p o n s e
T a bl e 1 4 - 1
R e s p o n s e crit eri a f or t ar g et l e si o n s
R e s p o n s e Crit eri a
E v al u ati o n of t ar g et l e si o n s
C o m pl et e R e s p o n s e ( C R):
Di s a p p e ar a n c e of all n o n -n o d al t ar g et l e si o n s. I n a d diti o n, a n y p at h ol o gi c al l y m p h 
n o d e s a s si g n e d a s t ar g et l e si o n s m u st h a v e a r e d u cti o n i n s h ort a xi s t o < 1 0 m m .1
P arti al R e s p o n s e ( P R):
At l e a st a 3 0 % d e cr e a s e i n t h e s u m of di a m et er of all t ar g et l e si o n s, t a ki n g a s 
r ef er e n c e t h e b a s eli n e s u m of di a m et er s.
Pr o gr e s si v e Di s e a s e ( P D):
At l e a st a 2 0 % i n cr e a s e i n t h e s u m of di a m et er of all m e a s ur e d t ar g et l e si o n s, t a ki n g 
a s r ef er e n c e t h e s m all e st s u m of di a m et er of all t ar g et l e si o n s r e c or d e d at or aft er 
b a s eli n e. I n a d diti o n t o t h e r el ati v e i n cr e a s e of 2 0 %, t h e s u m m u st al s o d e m o n str at e 
a n a b s ol ut e i n cr e a s e of at l e a st 5 m m. 2
St a bl e Di s e a s e ( S D):
N eit h er s uffi ci e nt s hri n k a g e t o q u alif y f or P R or C R n or a n i n cr e a s e i n l e si o n s w hi c h 
w o ul d q u alif y f or P D.
U n k n o w n ( U N K)
Pr o gr e s si o n h a s n ot b e e n d o c u m e nt e d a n d o n e or m or e t ar g et l e si o n s h a v e n ot 
b e e n a s s e s s e d or h a v e b e e n a s s e s s e d u si n g a diff er e nt m et h o d t h a n b a s eli n e. 3
1.
S O D f or C R m a y n ot b e z er o w h e n n o d al l e si o n s ar e p art of t ar g et l e si o n s
2.
F oll o wi n g a n i niti al C R, a P D c a n n ot b e a s si g n e d if all n o n - n o d al t ar g et l e si o n s ar e still n ot pr e s e nt a n d all 
n o d al l e si o n s ar e < 1 0 m m i n si z e. I n t hi s c a s e, t h e t ar g et l e si o n r e s p o n s e i s C R
3.
I n e x c e pti o n al cir c u m st a n c e s a n U N K r e s p on s e d u e t o c h a n g e i n m et h o d c o ul d b e o v er -r ul e d b y t h e 
i n v e sti g at or or c e ntr al r e vi e w er u si n g e x p ert j u d g m e nt b a s e d o n t h e a v ail a bl e i nf or m ati o n ( s e e N ot e s o n 
t ar g et l e si o n r e s p o n s e a n d m et h o d ol o g y c h a n g e i n S e cti o n 1 4. 1. 2. 2 ).
N ot e s o n t ar g et l e si o n r e s p o n s e
Re a p pe ar a nce o f lesi o ns: If t he lesi o n a p pears at t he sa me a nat o mical l ocati o n w here a tar get 
lesi o n ha d pre vi o usl y disa p peare d, it is a d vise d t hat t he ti me p oi nt of lesi o n disa p peara nce 
(i.e., t he “ 0 m m” rec or di n g) be r e-e val uate d t o ma ke s ure t hat t he lesi o n was n ot act ually 
pr ese nt a n d/ or n ot vis ualize d f or tec h nical reas o ns i n t his pre vi o us assess me nt. If it is n ot 
p ossi ble t o c ha n ge t he 0 val ue, t he n t he i n vesti gat or/ra di ol o gist has t o deci de bet wee n t he 
f oll o wi n g p ossi bilities:

T he lesi o n is a ne w lesi o n, i n w hic h case t he o verall t u m or assess me nt will be c o nsi dere d 
as pr o gressi ve disease

T he lesi o n is clear l y a rea p peara nce of a pre vi o usl y disa p peare d le si o n, i n w hic h case t he 
size of t he lesi o n has t o be e ntere d i n t he C R F a n d t he t u m or assess me nt will re mai n base d 
o n t he s u m of t u m or meas ure me nts as prese nte d i n Ta ble 1 4 - 1 a b o ve (i.e., a P D will be 
de ter mi ne d if t here is at least 2 0 % i ncrease i n t he s u m of dia meters of all meas ure d tar get 
lesi o ns, ta ki n g as refere nce t he s mallest s u m of dia meters of all tar get lesi o ns rec or de d at 
or after baseli ne wit h at least 5 m m i ncrease i n t he a bs ol ute s u m of t he dia meters). Pr o per 
d oc u me ntati o n s h o ul d be a vaila ble t o s u p p ort t his decisi o n. T his a p plies t o patie nts w h o 


N o v arti s
C o nfi d e nti al
P a g e 1 0 8
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
ha ve n ot ac hie ve d tar get res p o nse of C R. F or patie nts w h o ha ve ac hie ve d C R, please refer
t o last b ullet i n t his secti o n.

F or t h ose patie nts w h o ha ve o nl y o ne tar get lesi o n at baseli ne, t he rea p peara nce of t he 
tar get lesi o n w hic h disa p peare d pre vi o usly, e ve n if still s mall, is c o nsi dere d a P D.

Missi n g meas ure me nts: I n cases w here meas ure me nts are missi n g f or o ne or m ore tar get 
lesi o ns it is s o meti mes still p ossi ble t o assi g n P D base d o n t he meas ure me nts of t he 
re mai ni n g lesi o ns. F or e xa m ple, if t he s u m of dia meters for 5 tar get lesi o ns at baseli ne is

1 0 0 m m at baseli ne a n d t he s u m of dia meters f or 3 of t h ose lesi o ns at a p os t-baseli ne visit
is 1 4 0 m m ( wit h data f or 2 ot her lesi o ns missi n g) t he n a P D s h o ul d be assi g ne d. H o we ver, 
i n ot her cases w here a P D ca n n ot defi nitel y be attri b ute d, t he tar get lesi o n res p o nse w o ul d 
be U N K.

N o dal lesi o n decrease t o n or mal size: W he n n o dal disease is i ncl u de d i n t he s u m of tar get 
lesi o ns a n d t he n o des decrease t o “ n or mal” size t he y s h o ul d still ha ve a meas ure me nt 
rec or de d o n sca ns. T his meas ure me nt s h o ul d be re p orte d e ve n w he n t he n o des are n or mal 
i n or der n ot t o o verstate pr o gressi o n s h o ul d it be base d o n i ncrease i n t he size of n o des.

Lesi o ns s plit: In s o me circ u msta nces, disease t hat is meas ura ble as a tar get lesi o n at 
baseli ne a n d a p pears t o be o ne mass ca n s plit t o bec o me t w o or m ore s maller s u b -lesi o ns. 
W he n t his occ urs, t he dia meters (l o n g a xis - n o n- n o dal lesi o n, s h ort a xis - n o dal lesi o ns) 
of t he t w o s plit lesi o ns s h o ul d be a d de d t o get her a n d t he s u m rec or de d i n t he dia meter 
fiel d o n t he case re p ort f or m u n der t he ori gi nal lesi o n n u m ber. T his val ue will be i ncl u de d 
i n t he s u m of dia meters w he n deri vi n g tar get lesio n res p o nse. T he i n di vi d ual s plit lesi o ns 
will n ot be c o nsi dere d as ne w lesi o ns, a n d will n ot a ut o maticall y tri g ger a P D desi g nati o n.

Lesi o ns c oalesce d: C o n verse ly, it is als o p ossi ble t hat t w o or m ore lesi o ns w hic h were 
disti nctl y se parate at baseli ne beco me c o nfl ue nt at s u bse q ue nt visits. W he n t his occ urs a 
pla ne bet wee n t he ori gi nal lesi o ns ma y be mai ntai ne d t hat w o ul d ai d i n o btai ni n g dia meter 
meas ure me nts of eac h i n di vi d ual lesi o n. If t he lesi o ns ha ve tr ul y c oalesce d s uc h t hat t he y 
are n o l o n ger se para ble, t he ma xi mal dia meters (l o n g a xis - n o n-n o dal lesi o n, s h ort a xis -
n o dal lesi o ns) of t he “ mer ge d lesi o n” s h o ul d b e use d w he n calc ulati n g t he s u m of 
dia meters f or tar get lesi o ns. O n t he case re p ort f or m, t he dia meter of t he “ mer ge d lesi o n” 
s h o ul d be rec or de d f or t he size of o ne of t he ori gi nal lesi o ns w hile a size of “ 0” m m s h o ul d 
be e ntere d f or t he re mai ni n g lesi o n n u m bers w hic h ha ve c oalesce d.

T he me as ure me nts f or n o d al lesi o ns , e ve n if less t ha n 1 0 m m i n size, will c o ntri b ute t o 
t he calc ulati o n of tar get lesi o n res p o nse i n t he us ual wa y wit h sli g ht m o dificati o ns.

Si nce lesi o ns less t ha n 1 0 m m are c o nsi dere d n or mal, a C R f or tar get lesi o n res p o nse 
s h o ul d be assi g ne d w he n all n o dal tar get lesi o ns s hri n k t o less t ha n 1 0 m m a n d all n o n-
n o dal tar get l esi o ns ha ve disa p peare d.

O nce a C R tar get lesi o n res p o nse has bee n assi g ne d a C R will c o nti n ue t o be a p pr o priate
(i n t he a bse nce of missi n g data) u ntil pr o gressi o n of tar get lesi o ns.

F oll o wi n g a C R, a P D ca n s u bse q ue ntl y o nl y be assi g ne d f or tar get lesi o n res p o nse if 
eit her a n o n -n o dal tar get lesi o n “rea p pears” or if a n y si n gle n o dal lesi o n is at least 1 0 m m 
a n d t here is at le ast 2 0 % i ncrease i n s u m of t he dia meters of all n o dal tar get lesi o ns 
relati ve t o na dir wit h at least 5 m m i ncrease i n t he a bs ol ute s um of t he dia meters.


N o v arti s
C o nfi d e nti al
P a g e 1 0 9
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

A c ha n ge i n met h o d f or t he e val uati o n of o ne or m ore lesi o ns will us uall y lea d t o a n U N K 
tar get lesi o n res p o nse u nless t here is pr o gressi o n i n dicate d b y t he re mai ni n g lesi o ns w hic h 
ha ve bee n e val uate d b y t he sa me met h o d. I n e xce pti o nal circ u msta nces a n i n vesti gat or or 
ce ntral re vie wer mi g ht o ver- r ule t his assi g n me nt t o p ut a n o n- U N K res p o nse usi n g e x pert 
j u d g me nt base d o n t he a vaila ble i nf or mati o n. E. g. a c ha n ge t o a m ore se nsiti ve met h o d 
mi g ht i n dicate s o me t u m or s hri n ka ge of tar get les i o ns a n d defi nitely r ule o ut pr o gressi o n 
i n w hic h case t he i n vesti gat or mi g ht assi g n a n S D tar get lesi o n res p o nse; h o we ver, t his 
s h o ul d be d o ne wit h ca uti o n a n d c o nser vati vel y as t he res p o nse cate g ories ha ve well 
defi ne d criteria.
1 4. 1. 2. 4. 3
D et er mi n ati o n of n o n- t ar get l e si o n r e s p o n s e
T a bl e 1 4 - 2
R e s p o n s e crit eri a f or n o n -t ar g et l e si o n s
R e s p o n s e Crit eri a
E v al u ati o n of n o n -t ar g et l e si o n s
C o m pl et e R e s p o n s e ( C R):
Di s a p p e ar a n c e of all n o n -t ar g et l e si o n s. I n a d diti o n, all l y m p h n o d e s a s si g n e d a 
n o n -t ar g et l e si o n s m u st b e n o n-p at h ol o gi c al i n si z e ( < 1 0 m m s h ort a xi s)
Pr o gr e s si v e Di s e a s e ( P D):
U n e q ui v o c al pr o gr e s si o n of e xi sti n g n o n -t ar g et l e si o n s.1
N o n - C R/ N o n-P D:
N eit h er C R n or P D
U n k n o w n ( U N K)
Pr o gr e s si o n h a s n ot b e e n d o c u m e nt e d a n d o n e or m or e n o n -t ar g et l e si o n s h a v e 
n ot b e e n a s s e s s e d or h a v e b e e n a s s e s s e d u si n g a diff er e nt m et h o d t h a n 
b a s eli n e 2.
1.
T h e a s si g n m e nt of P D s ol el y b a s e d o n c h a n g e i n n o n -t ar g et l e si o n s i n li g ht of t ar g et l e si o n r e s p o n s e of C R, 
P R or S D s h o ul d b e e x c e pti o n al. I n s u c h cir c u m st a n c e s, t h e o pi ni o n of t h e i n v e sti g at or or c e ntr al r e vi e w er 
d o e s pr e v ail
2.
It i s r e c o m m e n d e d t h at t h e i n v e sti g at or a n d/ or c e ntr al r e vi e w er s h o ul d u s e e x p ert j u d g m e nt t o a s si g n a N o n-
U N K r e s p o n s e w h er e v er p o s si bl e ( s e e n ot e s s e cti o n f or m or e d et ail s)
N ot e s o n n o n -t ar g et l e si o n r e s p o n s e

T he i n vesti gat or a n d/ or ce ntral re vie wer ca n use e x pert j u d g me nt t o assi g n a n o n -U N K 
res p o nse w here ver p ossi ble, e ve n w here lesi o ns ha ve n ot bee n f ull y assesse d or a differe nt 
met h o d has bee n use d. I n ma n y of t hese sit uati o ns it ma y still be p ossi ble t o i de ntif y 
e q ui v ocal pr o gressi o n ( P D) or defi niti vel y r ule t his o ut ( n o n- CR/ N o n -P D) base d o n t he 
a vaila ble i nf or mati o n. I n t he s pecific case w here a m ore se nsit i ve met h o d has bee n use d 
i n dicati n g t he a bse nce of a n y n o n-tar get lesi o ns, a C R res p o nse ca n als o be assi g ne d.

T he res p o nse f or n o n -tar get lesi o ns is C R o nl y if all n o n -tar get n o n-n o dal lesi o ns w hic h 
were e val uate d at baseli ne are n o w all a bse nt a n d wit h all n o n-tar get n o dal lesi o ns 
ret ur ne d t o n or mal size (i.e. < 1 0 m m). If an y of t he n o n -tar get lesi o ns are still prese nt, or 
t here are an y a b n or mal n o dal lesi o ns (i.e. ≥1 0 m m) t he res p o nse ca n o n l y be ‘N o n -
C R/ N o n- P D ’ u nless t here is u ne q ui v ocal pr o gressi on of t he n o n -tar get lesi o ns (i n w hic h 
case res p o nse is P D ) or it is n ot p ossi ble t o deter mi ne w het her t here is u ne q ui v ocal 
pr o gressi o n (i n w hic h case res p o nse is U N K).

U ne q ui v ocal pr o gressi o n: T o ac hie ve “ u ne q ui v ocal pr o gressi o n” o n t he basis of n o n -tar get
disease t here m ust be a n o verall le vel of s u bsta ntial w orse ni n g i n n o n- tar get disease s uc h 
t hat, e ve n i n prese nce of C R, P R or S D i n tar get disease, t he o verall t u m or b ur de n has 
i ncrease d s ufficie ntly t o merit disc o nti n uati o n of t hera p y. A m o dest “i ncreas e” i n t he size 
of o ne or m ore n o n -tar get lesi o ns is us uall y n ot s ufficie nt t o q ualif y f or u ne q ui v ocal 
pr o gressi o n stat us. T he desi g nati o n of o verall pr o gressi o n s olel y o n t he basis of c ha n ge i n 


N o v arti s
C o nfi d e nti al
P a g e 1 1 0
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
n o n -tar get disease i n t he face of C R, P R or S D of tar get disease is t heref ore e x pecte d t o be 
rare. I n or der f or a P D t o be assi g ne d o n t he basis of n o n-tar get lesi o ns, t he i ncrease i n t he 
e xte nt of t he disease m ust be s u bsta ntial e ve n i n cases w here t here is n o meas ura ble

disease at baseli ne. If t here is u ne q ui v ocal pr o gressi o n of n o n -tar get lesi o n(s), t he n at least 
o ne of t he n o n -tar get lesi o ns m ust be assi g ne d a stat us of “ W orse ne d”. W here p ossi ble, 
si milar r ules t o t h ose descri bed i n Secti o n 1 4. 1. 2. 4. 4 f or assi g ni n g P D f ollo wi n g a C R f or 
t he n o n-tar get lesi o n res p o nse i n t he prese nce of n o n-tar get lesi o ns n o dal lesi o ns s h o ul d be 
a p plie d.
1 4. 1. 2. 4. 4
N e w l e si o n s
T he ap peara nce of a ne w lesi o n is al way s ass ociate d wit h Pr o gressi ve Disease ( P D) a n d has t o 
be rec or de d as a ne w lesi o n i n t he Ne w Lesi o n C R F pa ge.

If a ne w lesi o n is e q ui v oc al , f or e xa m ple beca use of its s mall size, c o nti n ue d t herap y a n d 
f oll ow- u p e val uati o n will clarif y if it re prese nts tr ul y ne w disease. If re peat sca ns c o nfir m 
t here is defi nitely a ne w lesi o n, t he n pr o gressi o n s h o ul d be declare d usi n g t he date of t he 
first o bser vati o n of t he lesi o n

If ne w disease is o bser ve d i n a re gi o n w hic h was n ot sc a n ne d at b aseli ne or w here t he 
partic ular baseli ne sca n is n ot a vaila ble f or s o me reas o n, t he n t his s h o ul d be c o nsi dere d as 
a P D. T he o ne e xce pti o n t o t his is w he n t here are n o baseli ne sca ns at all a vaila ble f or a 
patie nt i n w hic h case t he res p o nse s h o ul d be U N K, as f or a n y of t his patie nt's assess me nt 
(see Secti o n 1 4. 1. 2. 5 ).

A l y m p h n o de is c o nsi dere d as a “ ne w lesi o n ” a n d, t heref ore, i n dicati ve of pr o gressi ve 
disease if t he s h ort a xis i ncreases i n size t o ≥1 0 m m f or t he first ti me i n t he st u d y pl us 5 
m m a bs ol ute i ncrease.
F D G -P E T : ca n c o m ple me nt C T sca ns i n assessi n g pr o gressi o n ( partic ularl y p ossi ble f or
‘ ne w’ disease). See Secti o n 1 4. 1. 2. 2 .
1 4. 1. 2. 5
E v al u ati o n of o v er all l e si o n r e s p o n s e
T he e val uati o n of o verall lesi o n res p o nse at eac h assess me nt is a c o m p osite of t he tar get 
lesi o n res p o nse, n o n- tar get lesi o n res p o nse a n d prese nce of ne w lesi o ns as s h o w n bel o w i n 
Ta ble 1 4 - 3.


N o v arti s
C o nfi d e nti al
P a g e 1 1 1
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a bl e 1 4 - 3
O v er all l e si o n r e s p o n s e at e a c h a s s e s s m e nt
T ar g et l e si o n s
N o n -t ar g et l e si o n s
N e w  L e si o n s
O v er all
l e si o n r e s p o n s e
C R
C R
N o
C R 1
C R
N o n - C R/ N o n-P D 3
N o
P R
C R, P R, S D
U N K
N o
U N K
P R
N o n -P D a n d n ot U N K
N o
P R 1
S D
N o n -P D a n d n ot U N K
N o
S D 1, 2
U N K
N o n -P D or U N K
N o
U N K 1
P D
A n y
Y e s or N o
P D
A n y
P D
Y e s or N o
P D
A n y
A n y
Y e s
P D
1.
T hi s o v er all l e si o n r e s p o n s e al s o a p pli e s w h e n t h er e ar e n o n o n -t ar g et l e si o n s i d e ntifi e d at b a s eli n e.
2.
O n c e c o nfir m e d P R w a s a c hi e v e d, all t h e s e a s s e s s m e nt s ar e c o n si d er e d P R.
3.
A s d efi n e d i n S e cti o n 1 4. 1. 2. 4 .
If t here are n o baseli ne sca ns a vaila ble at all, t he n t he o verall lesi o n res p o nse at eac h 
assess me nt s h o ul d be c o nsi dere d U n k n o w n ( U N K).
I n s o me circ u msta nces it ma y be diffic ult t o disti n g uis h resi d ual disease fr o m n or mal tiss ue. 
W he n
t he e val uati o n of c o m plete res p o nse de pe n ds o n t his deter mi nati o n, it is rec o m me n de d 
t hat t he resi d ual lesi o n be i n vesti gate d (fi ne nee dle as pirate/ bi o ps y ) t o c o nfir m t he C R.
1 4. 1. 3 
Effi c a c y d efi niti o n s
T he f oll o wi n g defi niti o ns pri maril y relate t o patie nt s w h o ha v e meas ura bl e diseas e at baseli ne. 
Secti o n 1 4. 1. 3. 2. 9 o utli nes t he s pecial c o nsi derati o ns t hat nee d t o be gi ve n t o patie nts wit h n o 
meas ura ble disease at baseli ne i n or der t o a p p l y the sa me c o nce pts.
1 4. 1. 3. 1
B e st o v er all r e s p o n s e
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he treat me nt u ntil 
disease pr o gressi o n /rec urre nce (ta ki n g as refere nce f or P D t he s mallest meas ure me nts
rec or de d si nce t he treat me nt starte d). I n ge neral, t he patie nt's best res p o nse assi g n me nt will 
de pe n d o n t he ac hie ve me nt of b ot h meas ure me nt a n d c o nfir mati o n criteria.
T he best o v erall res p o nse will us uall y  be deter mi ne d fr o m res p o nse assess me nts u n derta ke n 
w hile o n treat me nt. H o we ver, if a n y assess me nts occ ur after treat me nt wit h dra wal
t he 
pr ot oc ol s h o ul d s pecificall y desc ri be if t hese wil l be i ncl u de d i n t he deter mi nati o n of best
o verall res p o nse a n d/ or w het her t hese a d diti o nal assess me nts will be re q uired f or se nsiti vit y 
or s u p p orti ve a nal y ses. As a defa ult, a n y assess me nts ta ke n m ore
t ha n 3 0 da y s after t he last 
d ose of s t u dy treat me nt will
n ot be i ncl u de d i n t he best o verall resp o nse deri vati o n. If a n y 
alter nati ve ca ncer t hera p y is ta ke n w hile
o n
st u dy a n y s u bse q ue nt assess me nts w o ul d 
or di naril y  b e e xcl u de d fr o m t he best o verall res p o nse deter mi nati o n. If res p o nse assess m e nts 
ta ke n after wit h dra wal fr om
st u dy treat me nt a n d/ or alter nati ve t hera py a re t o be i ncl u de d i n 
t he mai n e n d p oi nt deter mi nati o n, t he n t his s h o ul d be descri be d a n d j ustifie d i n t he pr ot oc ol.
W her e a st u dy re q uires c o nfir mati o n of res p o nse ( PR or C R) , c han ges i n t u m or meas ure me nts 
m us t be c o nfir med b y re peat assess me nt s t hat s h o uld be perf or me d n ot less t han 4 wee ks after 
t he criteria f or res p o nse are first met.


N o v arti s
C o nfi d e nti al
P a g e 1 1 2
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
L o n ger i nter vals ma y als o be a p pr o priate. H o we ver, t his m ust be clear ly state d i n t he pr ot oc ol. 
T he mai n
g oa l of c o nfir mati o n of o bjecti ve res p o nse is t o a v oi d o veresti mati n g t he res p o nse 
rate o bser ve d. I n cases w her e c o nfir mati o n o f res p o nse is n o t feasi ble, it s h o uld b e ma d e clear 
w he n re p orti n g t he o utc o me of s uc h st u dies t hat t he res p o nses are n o t c o nfir me d.

F or n o n- ra n d o mize d trials w here res p o nse is t he pri mar y e n d p oi nt, c o nfir mati o n is nee de d.

F or trials i nte n de d t o s u p p ort accelerate d a p pr o val, c o nfir mati o n is nee de d

F or all ot her trials, c o nfir mati o n of res p o nse ma y be c o nsi dere d o pti o nal.
T he best o verall res p o nse f or eac h patie nt is deter mi ne d fr o m t he se q ue nce of o verall (lesi o n)
res p o nses acc or di n g t o t he f oll o wi n g r ules:

C R = at least t w o deter mi nati o ns of C R at least 4 wee ks a part bef ore pr o gressi o n w here 
c o nfir mati o n re q uire d or o ne deter mi nati o n of C R pri or t o pr o gressi o n w here c o nfir mat i o n 
n ot re q uire d

P R = at least t w o deter mi nati o ns of P R or better at least 4 wee ks a part bef ore pr o gressi o n 
(a n d n ot q ualify i n g f or a C R) w here c o nfir mati o n re q uire d or o ne deter mi nati o n of P R 
pri or t o pr o gressi o n w here c o nfir mati o n n ot re q uire d

S D = at le ast o ne S D assess me nt ( or better) > 6 wee ks after ra n d o mizati o n/start of 
treat me nt (a n d n ot q ualif yi n g f or C R or P R).

P D = pr o gressi o n ≤1 2 wee ks after ra n d o mizati o n/ start of treat me nt (a n d n ot q ualif y i n g 
f or C R, P R or S D).

U N K = all ot her cases (i.e. n ot q ualif y i n g f or c o nfir me d C R or P R a n d wit h o ut S D after 
m ore t ha n 6 wee ks or earl y pr o gressi o n wit hi n t he first 1 2 wee ks)
T he ti me d urati o ns s pecifie d i n t he S D/ P D/ U N K defi niti o ns a b o ve are defa ults base d o n a 6 
wee k t u m or assess me nt fre q ue ncy. H o we ver t hese ma y b e
m o difie d f or s pecific i n dicati o ns 
w hic h are m ore or less a g gressi ve. I n a d diti o n, it is e n visa ge d t hat t he ti me d urati o n ma y als o 
ta ke i nt o acc o u nt assess me nt wi n d o ws.
E. g . if t he assess me nt occ urs e ver y 6
w ee ks wit h
a 
ti me wi n d o w of +/- 7 da y s, a B O R of S D w o ul d re q uire a S D or bette r res p o nse l o n ger t han 5 
wee ks after ra n d o mizati o n/start of treat me nt.
O verall
lesi o n res p o nses of
C R m ust
stay t he sa me u ntil pr o gressi o n sets i n, wit h
t he 
e xce pti o n of a U N K stat us. A patie nt w h o ha d a C R ca n n ot s u bse q ue ntly ha ve a l o wer stat us 
ot her t ha n a P D, e. g. P R or S D, as t his w o ul d
i m ply a p r o gressi o n base d o n o ne or m ore 
lesi o ns rea p peari n g, i n w hic h case t he stat us w o ul d bec o me a P D.
O nc e a n o verall lesi o n res p o nse of P R is o bser ve d ( w hic h ma y ha v e t o be a c o nfir me d P R 
de pe n di n g o n t he st u d y) t his assi g n me nt m ust
stay t h e sa me or i m pr o ve o ver ti me u ntil 
pr o gressi o n sets i n, wit h
t he e xce pti o n of a n U N K stat us. H o we ver,
i n st u dies w here 
c o nfir mati o n of res p o nse is re q uire d, if a patie nt has a si n gle P R ( ≥3 0 % re d ucti o n of t u m or 
b ur de n c o m pare d t o baseli ne ) at o ne assess me nt , f oll o wed b y a < 3 0 % re d ucti on fr om baseli ne 
at t he ne x t assess me nt ( b ut n ot ≥2 0 % i ncrease fr o m pre vi o us s mallest s u m), t he o bjecti ve 
stat us at t hat assess me nt s h o ul d be S D . O nce
a c o nfir me d P R was
see n, t he o verall lesi o n 
res p o nse s h o ul d be c o nsi dere d P R ( or U N K ) u ntil pr o gressi o n is d oc u me nte d or t he lesi o ns 
t otally disa p pe ar i n w hic h case a C R assi g n me nt is a p plica ble. I n st u dies w her e c o nfir mati o n 
of res p o nse is n ot re q uire d after a si n gle P R t he o verall lesi o n res p o nse s h o ul d still be 


N o v arti s
C o nfi d e nti al
P a g e 1 1 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
c o nsi dere d P R ( or U N K) u ntil pr o gressi o n is d oc u me nte d or t he lesi o n t otally disa p pears i n 
w hic h case a C R assi g n me nt is a p plica ble.
E xa m ple: I n a case w here c o nfir mati o n of res p o nse is re q uire d t he s u m o f lesi o n dia meters is
2 0 0 m m
at baseli ne a n d t he n 1 4 0 m m
- 1 5 0
m m - 1 4 0 m m
- 1 6 0 m m
- 1 6 0 m m
at t he 
s u bse q ue nt visits. Ass u mi n g
t hat n o n- targ et lesi o ns di d n o t pr o gress, t he o verall lesi o n 
res p o nse w o ul d be P R - S D - P R - P R - P R. T he sec o n d assess me nt wit h 1 4 0 m m c o nfir ms t he 
P R 
f or t his patie nt. All 
s u bse q ue nt assess me nts are c o nsi dere d
P R 
e ve n if t u m or 
meas ure me nts
decrease o nl y b y 2 0 % c o m p are d t o baseli ne ( 2 0 0 m m t o
1 6 0 m m)
at t he 
f oll o wi n g assess me nts.
If t he patie nt pr o gresse d b ut c o nti n ues st u d y treat me nt, f urt her assess me nts are n ot c o nsi dere d 
f or t he deter mi nati o n of best o verall res p o nse.
N ote: t hese cases ma y b e descri be d as a se parate fi n di n g i n t he C S R b ut n ot i ncl u de d i n t he 
o verall res p o nse or disease c o ntr ol rates.
T he best o verall res p o nse f or a patie nt is al wa ys calc ulate d, base d o n t he se q ue nce of o verall 
lesi on res p o nses. H o we ver , t he o veral l lesi on res p o nse at a gi ve n assess me n t ma y b e pr o vi de d 
fr o m differe nt s o urces:

I n vesti gat or o verall lesi o n res p o nse

Ce ntral Bli n de d Re vie w o verall lesi o n res p o nse

N o vartis calc ulate d o verall lesi o n res p o nse ( base d o n meas ure me nts fr o m eit her
I n vesti gat or or Ce ntral Re vie w)
T he
pri ma ry a nal ysis of t he bes t o verall
res p o nse will
be
base d
o n
t he se q ue nce of 
i n vesti gat or/ce ntral bli n de d re vie w/calc ulate d (i n vesti gat or)/calc ulate d (ce ntral) o verall lesi o n 
res p o nses.
Base d o n t he patie nts’ bes t o verall res p o nse d uri n g t he st u d y, t he f oll o win g rates are t he n 
calc ulate d:
O ver all res p o nse r ate ( O R R) is t he pr o p orti o n of patie nts wit h a best o verall res p o nse of C R
or P R. T his is als o referre d t o as ‘ O bjecti ve res p o nse rate’ i n s o me pr ot oc ols or p u blicati o ns.
Dise ase c o ntr ol r ate ( D C R) is t he pr o p orti o n of patie nts wit h a best o verall res p o nse o f C R 
or P R or S D. T he o bjecti ve of t his e n d p oi nt is to s u m marize patie nts wit h si g ns of “acti vit y” 
defi ne d as eit her s hri n ka ge of t u m or (re gar dless of d urati o n) or sl o wi n g d o w n o f t u m or 
gr o wt h.
Cli nic al be nefit r ate ( C B R) is t he pr o p orti o n of patie nts wit h a best o verall res p o nse of C R 
or P R, or a n o verall lesi o n res p o nse of S D or N o n- C R/ N o n -P D w hic h lasts f or a mi ni m u m 
ti me d urati o n ( wit h a defa ul t of at least 2 4
wee ks i n breast ca ncer st u dies). T his e n d p oi nt 
meas ures si g ns of acti vit y ta ki n g i nt o acc o u nt d urati o n of disease sta bilizati o n.
A n ot her a p pr oac h is t o s u m marize t he pr o gressi o n rate at a certai n ti me p oi nt after baseli ne. I n 
t his case, t he f oll o wi n g defi niti o n is use d:
E arl y pr o gressi o n r at e ( EP R ) is t he pr o p orti o n of patie nts wit h pr o gressi ve disease wit hi n 8 
wee ks of t he start of treat me nt.


N o v arti s
C o nfi d e nti al
P a g e 1 1 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T he pr ot oc ol s h o ul d defi ne p o p ulati o ns f or w hic h t hese will be calc ulate d. T he ti me p oi nt f or 
E P R is st u dy s pecific. E P R is use d f or t he m ulti n o mial
desi g ns of De nt a n d Zee ( 2 0 0 1) a n d 
c o u nts all patie nts w h o at t he s pecifie d assess me nt (i n t his e xa m ple t he assess me nt w o ul d be 
at 8 wee ks ± wi n d o w) d o n ot ha ve a n o verall lesi o n res p o nse of S D, P R or C R. Patie nts wit h 
a n u n k n o w n ( U N K) assess me nt at t hat ti me p oi nt a n d n o P D bef ore, will n ot be c o u nte d as 
earl y pr o gress ors i n t he a nal ys is b ut ma y  be i ncl u de d i n t he de n o mi nat or of t he E P R rate, 
de pe n di n g o n t he a nal ys is p o p ulati o n use d. Si milarl y w he n e xa mi ni n g o verall res p o nse a n d 
disease c o ntr ol, patie nts wit h a best o verall res p o nse assess me nt of u n k n o w n ( U N K) will n ot 
be re gar de d as “res p o n ders” b ut m a y  be i ncl u de d i n t he de n o mi nat or f or O R R a n d D C R 
calc ulati o n de pe n di n g o n t he a nal ys is p o p ulati o n (e. g. p o p ulati o ns base d o n a n I T T a p pr oac h).
1 4. 1. 3. 2
Ti m e t o e v e nt v ari a bl e s
T he pr ot oc ol s h o ul d st ate w hic h of t he f oll o wi n g v ari a bles is use d i n t h at st u dy.
1 4. 1. 3. 2. 1
Pr o gr e s si o n- fr e e s ur vi v al
Us uall y  in
all
O nc ol o g y st u dies,
patie nts
are
f oll o we d f or t u m or pr o gressi o n
after 
disc o nti n uati o n of st u dy me dicati o n f or reas o ns ot her t ha n pr o gre ssi o n or deat h. If t his is n ot 
use d, e. g. i n P hase I or II st u dies, t his s h o ul d be clearl y state d i n t he pr ot oc ol. N ote
t hat
ra n d o mize d trials ( prefera bl y bli n de d) are rec o m me n de d w her e P F S is t o be t he pri mar y 
e n d p oi nt.
Pr o gressi o n- free s ur vi v al ( P F S) is t he ti me fr o m date of ra n d o mizati o n/start of treat me nt t o 
t he date of e ve nt defi ne d as t he first d oc u me nte d pr o gressi o n or deat h d ue t o a n y ca use. If a 
patie nt has n ot ha d a n e ve nt, pr o gressi o n -free s ur vi val is ce ns ore d at t he date of last a de q uate 
t u m or assess me nt.
P F S
rate at x
wee ks
is a n a d diti o nal meas ure
use d
t o q ua ntif y
P F S
e n d p oi nt. It is 
rec o m me n de d t hat a Ka pla n Meier esti mate is use d t o assess t his e n d p oi nt.
1 4. 1. 3. 2. 2
O v er all s ur vi v al
Al l patie nt s s h o uld b e f oll o wed u nti l deat h o r u nti l patie n t ha s ha d a de q uat e f oll o w- up ti me as 
s pecifie d i n t he pr ot oc ol w hic he ver c o mes first. T he f oll ow- u p data s h o uld c o ntai n t he date 
t he patie nt was last see n ali ve / last k n o w n date patie nt ali ve, t he date of deat h a n d t he reas o n 
of deat h (“ St u d y i n dicati o n” or “ Ot her”).
O ver all s ur vi v al ( O S) is defi ne d as t he ti me fr o m date of ra n d o mizati o n/start of treat me nt t o 
date of deat h d ue t o a n y ca use. If a patie nt is n ot k n o w n t o ha v e die d, s ur vi val will
be 
ce ns ore d at t he date of last k n o w n date patie nt ali v e.
1 4. 1. 3. 2. 3 
Ti m e t o pr o gr e s si o n
S o me st u dies mi g ht
c o nsi der o nl y deat h relate d t o u n der l yi n g ca ncer as an e ve nt w hic h 
i n dicates pr o gressi o n. I n t his case t he varia ble “ Ti me t o pr o gressi o n” mi g ht b e use d. T T P is 
defi ne d as P F S e xce pt f or deat h u nrelate d t o u n derl y i n g ca ncer.
T i me t o pr o gressi o n ( T T P) is t he ti me fr o m date of ra n d o mizati o n/start of treat me nt t o t he 
date of e ve nt defi ne d as t he first d oc u me nte d pr o gressi o n or deat h d ue t o u n derl yi n g ca ncer. If 


N o v arti s
C o nfi d e nti al
P a g e 1 1 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
a patie nt has n ot ha d a n e ve nt, ti me t o pr o gressi o n is ce ns ore d at t he date of last a de q uate 
t u m or assess me nt.
1 4. 1. 3. 2. 4
P F S 2
A rece nt E M A g ui da nc e (E M A 2 0 1 2 ) rec o m me n ds a s u bstit ute e n d p oi nt i nter me diate t o P F S 
a n d O S calle d P F S 2, a s urr o gate f or O S w he n O S ca n n ot be meas ure d relia bly , w hic h assesses 
t he i m pact of t he e x peri me ntal t hera p y on ne xt -li ne treat me nt. T he mai n
p ur p ose of t his 
e n d p oi nt is t o asses s l o ng term mai nte na nc e strate gies, partic ularl y of rese nsitizi ng a ge nt s a n d 
w here it is necessar y t o e xa mi ne t he o verall “fiel d of i nfl ue nce”.
P F S 2, w hic h co ul d be ter me d P F S deferre d , P F S dela y e d, ta n de m P F S, or P F S versi o n 2. 0, is 
t he ti me fr o m date o f ra n d o mizati o n/start of treat me nt t o t he date of e ve nt defi ne d as t he first 
d oc u me nte d pr o gressi o n o n ne xt -li ne treat me nt or deat h fr o m a n y ca use. T he ce ns ori n g r ules 
f or t his e n d p oi nt will i nc or p orate t he sa me pri nci ples as t h ose c o nsi dere d f or P F S i n t his 
d oc u me nt, a n d i n a d diti o n ma y i n v ol ve ot her c o nsi derati o ns w hic h will nee d t o be detaile d i n 
t he pr ot oc ol.
Please n ote t hat data c ollecti o n f or t he P F S 2 is li mite d t o t he date of pr o gressi o n a n d n ot 
s pecific rea d of t he t u m or assess me nts.
It is str o n gl y rec o m me n de d t hat t he tea ms c o ns ult re g ulat or y age ncies f or scie ntific a d vice 
gi ve n t he li mite d e x perie nce wit h
t he use of t his e n d p oi nt i n re g ulat or y setti n g i n li g ht of 
met h o d ol o gical iss ues w.r.t. ce ns ori n g f oresee n.
1 4. 1. 3. 2. 5
Ti m e t o tr e at m e nt f ail ur e
T his e n d p oi nt is ofte n a p pr o priate i n st u dies of a d va nce d disease w here earl y disc o nti n uati o n 
is t ypical l y relate d t o i nt olera nce of t he st u dy d r u g. I n s o me pr ot oc ols, ti me t o treat me nt 
fail ure ma y be c o nsi dere d as a se nsiti vit y a nal ysis f or ti me t o pr o gressi o n. T he
list of 
disc o nti n uati o n reas o ns t o be c o nsi dere d or n ot as treat me nt fail ure ma y be a da pte d acc or di n g 
t o t he s pecificities of t he st u d y or t he disease.
Ti me t o tre at me nt f ail ure ( T T F) is t he ti me fr om dat e o f ra n d o mizati o n/start o f treat me nt t o 
t he earliest of date of pr o gressi o n, date o f deat h d ue t o a n y ca use, or date of disc o nti n uati o n 
d ue t o reas o ns ot her t ha n ‘ Pr ot oc ol vi olati o n’ or ‘ A d mi nistrati ve pr o bl ems’.
T he ti me t o 
treat me nt fail ure f or patie nts w h o di d n ot e x perie nce treat me nt fail ure will be ce ns ore d at last 
a de q uate t u m or assess me nt.
1 4. 1. 3. 2. 6
D ur ati o n of r e s p o n s e
T he
a nal ysis of t he f oll o wi n g varia bles s h o uld be perf or me d wit h
m uc h
ca uti o n w he n 
restricte d t o res p o n ders si nce treat me nt bias c o ul d ha ve bee n i ntr o d uce d . T here ha ve bee n 
re p orts w here a treat me nt wit h a si g nifica ntly hi g her res p o nse rate ha d a si g nifica ntl y s h orter 
d urati o n of res p o nse b ut w her e t his p r o ba bl y p ri maril y reflecte d selecti o n bias w hic h
is 
e x plai ne d as f oll o ws: It is p ost ulate d t hat t here are t w o gr o u ps of patie nts: a g o o d ris k gr o u p 
a n d a p o or ris k gr o u p . G o o d
ris k patie nts te n d t o ge t i nt o res p o nse rea dily (a n d relati vely 
q uic kl y) a n d te n d t o re mai n i n res p o nse after t hey ha ve a res p o nse. P o or ris k patie nts te n d t o 
be diffic ult t o ac hie ve a res p o nse, ma y ha v e a l o n ger ti me t o res p o n d, a n d te n d t o rela pse 
q uic kl y w he n t hey d o res p o n d. P ote nt a ge nts i n d uce a res p o nse i n b ot h g o o d ris k a n d p o or 


N o v arti s
C o nfi d e nti al
P a g e 1 1 6
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
ris k patie nts. Les s p ote nt a ge nts i n d uce a res p o nse mai nl y i n g o o d ris k patie nts o nl y . T his is 
de scri be d i n m ore detail b y M or ga n ( 1 9 8 8) .
It is rec o m me n de d t hat a n a nal y sis of all patie nts ( b ot h res p o n ders a n d n o n -res p o n ders) b e 
perf or me d w het her or n ot a “ res p o n ders o nl y” descri pti ve a na l ysis is prese nte d. A n a nalys is of 
res p o n ders s h o ul d o nl y
be
perf or me d
t o pr o vi de
descri pti ve
statistics a n d
e ve n
t he n 
i nter prete d wit h
ca uti o n b y eval uati n g t he res ults i n t he c o nte xt of t he o bser ve d res p o nse 
rates… If
a n i nfere ntial c o m paris o n bet wee n treat me nts is re q uire d t his s h o ul d o nl y b e 
perf or me d o n all patie nts (i.e. n ot restricti n g t o “res p o n ders” o nl y ) usi n g a p pr o priate statistical 
met h o ds s uc h as t he tec h ni q ues descri be d i n Ellis et al ( 2 0 0 8). It sh o ul d als o be state d i n t he 
pr ot oc ol if d urati o n of res p o nse is t o be calc ulate d i n a d diti o n f or u nc o nfir me d res p o nse.
F o r s u m mary statistics o n “res p o n ders” o nl y t he f oll o wi n g defi niti o ns are a p pr o priate. 
( S pecific defi niti o ns f or a n all-patie nt a nal ysi s o f t hese e n d p oi nts are n o t a p pr o priate si nce t he 
stat us of patie nts t hr o u g h o ut t he st u d y is us uall y ta ke n i nt o acc o u nt i n t he a nal ysis).
D ur ati o n of o ver all res p o nse ( CR or P R ): F or patie nts wit h a C R or P R ( w hic h m a y ha v e t o 
be c o nfir me d t he start date is t he date of first d oc u me nte d res p o nse ( C R or P R) a n d t he e n d 
date a n d ce ns ori n g is defi ne d t he sa me as t hat f or ti me t o pr o gressi o n.
T he f oll o wi n g t wo d urati o ns mi g ht
be calc ulate d i n a d diti o n f or a lar ge P hase III st u dy i n 
w hic h a reas o na ble n u m ber of res p o n ders is see n.
D ur ati o n of o ver all c o m plete res p o nse ( C R): F o r patie nt s wit h a C R ( w hich ma y ha v e t o be 
c o nfir me d) t he start date is t he date of first d oc u me nte d C R a n d t he e n d d at e a n d ce ns ori n g is 
defi ne d t he sa me as t hat f or ti me t o pr o gressi o n.
D ur ati o n of st a ble dise ase ( C R/ P R/ S D): F o r patie nt s wit h a C R or P R ( w hic h ma y ha v e t o 
be c o nfir me d) or S D t he start a n d e n d dat e as wel l as ce ns ori n g is defi ne d t he sa me as t hat f or 
ti me t o pr o gressi o n.
1 4. 1. 3. 2. 7
Ti m e t o r e s p o n s e
Ti m e t o o ver all res p o nse ( CR or
P R ) is t he ti me bet wee n date of ra n d o mizati o n/start of 
treat me nt u ntil first d oc u me nte d res p o nse ( CR or P R ). T he res p o nse ma y
nee d t o be 
c o nfi r me d de pe n di n g o n t he t yp e of st u dy a nd its i m p orta nce. W her e t he res p o nse nee d s t o be 
c o nfir me d t he n ti me t o res p o nse is t he ti me t o t he first C R or P R o bser ve d.
Alt h o u g h
a n a nal y sis o n t he f ull p o p ulati o n is preferre d a descri pti ve a nal y sis ma y b e 
perf or me d o n t he “ res p o n ders” s u bset o n l y, i n w hic h
case t he res ults s h o uld be i nter prete d 
wit h ca uti o n a n d i n t he c o nte xt of t he o verall res p o nse rates, si nce t he sa me ki n d of selecti o n 
bias ma y be i ntr o d uce d as descri be d f or d urati o n of res p o nse i n Secti o n 1 4. 1. 3. 2. 6 . It is 
rec o m me n de d t hat a n a nal ys is of all patie nts ( b ot h res p o n ders a n d n o n- res p o n ders) be 
perf or me d w het her or n ot a “res p o n ders o nl y”  descri pti ve a nal ys is is prese nte d. W here 
a n 
i nfere ntial statistical c o m paris o n is re q uire d, t he n all patie nts s h o ul d defi nitel y be i ncl u de d i n 
t he a nal ysis t o e ns ure t he statistical test is vali d. F or a nal ys is i ncl u di n g all patie nts, patie nts 
w h o di d n ot ac hie ve a res p o nse ( w hic h ma y  ha ve t o be a c o nfir me d res p o nse) will be ce ns ore d 
usi n g o ne of t he f oll o wi n g o pti o ns.

at ma xi m u m f oll o w- u p (i.e. F P F V t o L P L V use d f or t he a na l ysis) f or patie nts w h o ha d a 
P F S e ve nt (i.e. pr o gresse d or die d d ue t o a n y ca use). I n t his case t he P F S e ve nt is t he 


N o v arti s
C o nfi d e nti al
P a g e 1 1 7
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
w orst p ossi ble o ut c o me as it mea ns t he patie nt ca n n ot s u bse q ue ntl y res p o n d. Si nce t he 
statistical a naly sis us uall y ma kes use of t he ra n ki n g of ti mes t o res p o nse it is s ufficie nt t o 
assi g n t he w orst p ossi ble ce ns ori n g ti me w hic h c o ul d be o bser ve d i n t he st u d y w hic h is 
e q ual t o t he ma xi m u m f oll ow- u p ti me (i.e. ti me fr o m F P F V t o L P L V)

at last a de q uate t u m or assess me nt date ot her wis e. In t his case patie nts ha ve n ot y et 
pr o gresse d s o t he y t he oreticall y still ha ve a c ha nce of res p o n di n g
Ti m e t o o ver all c o m plete res p o nse ( C R) is t he ti me bet wee n date s o f ra n d o mizati o n/start of 
treat me nt u ntil first d oc u me nte d C R. Si milar a nalys is c o nsiderati o ns i ncl u di n g (if a p pr o priate) 
ce ns ori n g r ules a p pl y f or t his e n d p oi nt descri be d f or t he ti me t o o verall res p o nse e n d p oi nt.
1 4. 1. 3. 2. 8
D efi niti o n of st art a n d e n d d at e s f or ti m e t o e v e nt v ari a bl e s
A s s e s s m e nt d at e
F o r eac h assess me nt (i.e. e val uati o n n u m ber), t he assess me nt d ate is calc ulate d as t he latest 
of all meas ure me nt 
dates (e. g. X- r a y, C T-sca n) if t he o verall lesi o n res p o nse at t hat 
assess me nt is C R/ P R/ S D/ U N K. Ot her wise
- if o verall lesi o n res p o nse is pr o gressi o n - t he
assess me nt date is calc ulate d as t he earliest date of all meas ure me nt
date s at t hat e val uati o n 
n u m ber.
I n t he calc ulati o n of t he assess me nt date f or ti me t o e ve nt varia bles, a n y u nsc he d ule d 
assess me nt s h o ul d be treate d si milarl y t o ot her e val uati o ns.
St art d at e s
F o r all “ti me t o e ve nt” varia bles, ot her t ha n d urati o n of res p o nse, t he ra n d o mizati o n/ date of 
treat me nt start will be use d as t he start date.
F or t he calc ulati o n of d urati o n of res p o nse t he f oll o wi n g start date s h o ul d be use d:

Date of first d oc u me nte d res p o nse is t he assess me nt date o f t he first o verall lesi o n 
res p o nse of C R (f or d urati o n of o verall c o m plete res p o nse) or C R / P R (f or d urati o n of 
o verall res p o nse) res p ecti vel y , w he n t his stat us is later c o nfir me d.
E n d d at e s
T he e n d dates w hic h are use d t o calc ulate ‘ti me t o e ve nt’ vari ables are defi ne d as f oll o ws:

Date of deat h ( d uri n g treat me nt as rec or de d o n t he treat me nt c o m pleti o n pa ge or d uri n g 
f oll ow- u p as rec or de d o n t he st u d y e val uati o n c o m pleti o n pa ge or t he s ur vi val f oll o w- u p 
pa ge).

Date of pr o gressi o n is t he first assess me nt date at w hic h t he o verall lesi o n res p o nse was 
rec or de d as pr o gressi ve disease.

Date of last a de q uate t u m or assess me nt is t he date t he last t u m or assess me nt wit h o verall 
lesi o n res p o nse of C R, P R or S D w hic h was ma de bef ore a n e ve nt or a ce ns ori n g reas o n 
occ urre d. I n t his case t he last t u m or e val uati o n date at t hat assess me nt is use d. If n o p ost -
baseli ne assess me nts are a vaila ble ( be f ore a n e ve nt or a ce ns ori n g reas o n occ urre d) t he 
date of ra n d o mizati o n/start of treat me nt is use d.


N o v arti s
C o nfi d e nti al
P a g e 1 1 8
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

Date of ne xt sc he d ule d assess me nt is t he date of t he last a de q uate t u m or assess me nt pl us 
t he pr ot oc ol s pecifie d ti me i nter val f or assess me nts. T his date ma y be use d if bac k - dati n g 
is c o nsi dere d w he n t he e ve nt occ urre d bey o n d t he acce pta ble ti me wi n d o w f or t he ne xt 
t u m or assess me nt as per pr ot oc ol (see Secti o n 1 4. 1. 3. 2. 9 ).
E x a m ple (if pr ot oc ol defi ne d sc he d ule of assess me nts is 3 m o nt hs):
t u m or assess me nts at 
baseli ne - 3 m o nt hs
- 6 m o nt hs
- missi n g - missi n g - P D. Da te of ne xt sc he d ule d assess me nt 
w o ul d t he n c orres p o n d t o 9 m o nt hs.

Date of disc o nti n uati o n is t he date of t he e n d of treat me nt visit.

Date of last c o ntact is defi ne d as t he last date t he patie nt was k n o w n t o be ali ve. T his 
c orres p o n ds t o t he latest date f or eit her t he visit date, la b sa m ple date or t u m or assess me nt 
date. If a vaila ble, t he last k n o w n date patie nt ali ve fr o m t he s ur vi val foll o w- u p pa ge is 
use d. If n o s ur vi val f oll o w- u p is a vaila ble, t he date of disc o nti n uati o n is use d as last 
c o ntact date.

Date of sec o n dar y a nti-ca ncer t herap y is defi ne d as t he start date of a n y a d diti o nal
(sec o n dary) a nti ne o plastic t hera p y or s ur ger y.
1 4. 1. 3. 2. 9
H a n d li n g of p ati e nt s wit h n o n- m e a s ur a bl e di s e a s e o nl y at b a s eli n e
It is p ossi ble t hat patie nts wit h o nl y n o n- meas ura ble disease prese nt at baseli ne are e ntere d 
i nt o t he st u dy , eit her beca use of a pr ot oc ol vi olati o n or b y desi g n (e. g. i n P hase III st u dies 
wit h P F S as the pri mar y e n d p oi nt). I n suc h cases t he ha n dli n g of t he res p o nse data re q uires 
s pecial c o nsi derati o n wit h res pect t o i ncl usi o n i n a n y ana l ysis of e n d p oi nts base d o n t he 
o verall res p o nse e val uati o ns.
It is rec o m me n de d t hat a n y p atie nts wit h o nl y n o n- meas ura ble disease at baseli ne s h o ul d be 
i ncl u de d i n t he mai n (I T T) a nal ysis of eac h of t hese e n d p oi nts.
Alt h o u g h t he te xt of t he defi niti o ns descri be d i n t he pre vi o us secti o ns pri maril y relates t o 
patie nts wit h meas ura ble disease at baseli ne, patie nts wi t h o ut meas ura ble disease s h o ul d als o 
be i nc or p orate d i n a n a p pr o priate ma n ner.
T he
o verall res p o nse f or patie nts wit h
n o n-
meas ura ble disease is deri ve d sli g htl y differe ntl y acc or di n g t o Ta ble 1 4 -4 .
T a bl e 1 4 - 4
O v er all l e si o n r e s p o n s e at e a c h a s s e s s m e nt: p ati e nt s wit h n o n -t ar g et 
di s e a s e o nl y
N o n -t ar g et l e si o n s
N e w L e si o n s
O v er all l e si o n r e s p o n s e
C R
N o
C R
N o n - C R/ N o n-P D 1
N o
N o n- C R/ n o n- P D
U N K
N o
U N K
P D
Y e s or N o
P D
A n y
Y e s
P D
1 A s d efi n e d i n S e cti o n 1 4. 1. 2. 4 .
I n ge neral, t he n o n- C R/ n o n - P D res p o nse f or t hese patie nt s is c o nsi dered e q ui vale nt t o a n S D 
res p o nse i n e n d p oi nt deter mi nati o n. I n su m mar y ta bles f or best o verall res p o nse patie nts wit h 
o nl y n o n- meas ura ble disease m a y be hi g hli g hte d i n a n a p pr o priate fas hi o n e. g. i n partic ular b y 
dis pla y i n g t he s pecific n u m bers wit h t he n o n-C R/ n o n -P D cate g or y.


N o v arti s
C o nfi d e nti al
P a g e 1 1 9
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
I n c o nsi deri n g h o w t o i nc or p orate data fr o m t hese patie nts i nt o t he a nal ys is t he i m p orta nce t o 
each e n d p oi nt of bei n g a ble t o i de ntif y a P R a n d/ or t o deter mi ne t he occ urre nce a n d ti mi n g of 
pr o gressi o n ne eds t o be ta ke n i nt o acc o u nt.
F or O R R
it is rec o m me n de d t hat t he mai n
(I T T) a nal y sis i ncl u des data fr o m patie nts wit h 
o nl y n o n- meas ura ble
disease at baseli ne, ha n dli n g patie nts wit h
a best res p o nse of C R
as 
“res p o n ders” wit h res pect t o O R R a n d all ot her patie nts as “ n o n -res p o n ders”.
F or P F S , it is a gai n rec o m me n de d t hat t he mai n
IT T a nal y ses o n t hese e n d p oi nts i ncl u de all 
patie nts wit h
o nl y n o n- meas ura ble
disease at baseli ne, wit h
p ossi ble se nsiti vit y ana l yses 
w hic h
e xcl u de t hese partic ular patie nts. E n d p oi nts
s uc h as P F S w hic h
are relia nt o n t he 
deter mi nati o n a n d/ or ti mi n g of pr o gressi o n can i nc or p orate data fr o m patie nts wit h o nl y n o n-
meas ura ble disease.
1 4. 1. 3. 2. 1 0
S e n siti vit y a n al y s e s
T his secti o n o utli nes t he p ossi ble e ve nt a n d ce ns ori n g dates f or pr o gressi o n, as w ell as 
a d dress es t he iss ues of missi n g
t u m or assess me nts d uri n g t he st u d y. F or i nsta nce, if o ne or 
m ore
assess me nt visits are misse d
pri or t o t he pr o gressi o n e ve nt, t o w hat
date s h o ul d t he
pr o gressi o n e ve nt be assi g ne d? A n d s h o ul d pr o gressi o n e ve nt be i g nore d if it occ urre d after a 
l o n g peri o d of a patie nt bei n g l ost t o f oll ow- u p? It
is i m p orta nt t hat t he pr ot oc ol a n d R A P 
s pecif y t he pri mar y a nal ysis i n detail wit h
res pect t o t he defi niti o n o f e ve nt a n d ce ns ori n g 
dates a n d als o i ncl u de a descri pti o n of o ne or m ore se nsiti vit y a nal yses t o be perf or me d.
Base d o n defi niti o ns o utli ne d i n Secti o n 1 4. 1. 3. 2. 8 , a n d usi n g t he draf t F D A g ui deli ne o n 
e n d p oi nts (Cli nical Trial E n d p oi nts f or t he A p pr o val of Ca ncer Dr u gs a n d Bi ol o gics -A pril 
2 0 0 5 ) as a refere nce, t he f oll o wi n g a naly ses ca n be c o nsi dere d:


N o v arti s
C o nfi d e nti al
P a g e 1 2 0
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
T a bl e 1 4 - 5
O pti o n s f or e v e nt d at e s u s e d i n P F S, T T P, d ur ati o n of r e s p o n s e
Sit u ati o n
O pti o n s f or e n d -d at e ( pr o gr e s si o n or 
c e n s ori n g) 1
( 1) = d ef a ult u nl e s s s p e cifi e d diff er e ntl y i n t h e 
pr ot o c ol or R A P
O ut c o m e
A
N o b a s eli n e a s s e s s m e nt
( 1) D at e of r a n d o mi z ati o n/ st art of tr e at m e nt3
C e n s or e d
B
Pr o gr e s si o n at or b ef or e n e xt s c h e d ul e d 
a s s e s s m e nt
( 1) D at e of pr o gr e s si o n
( 2) D at e of n e xt s c h e d ul e d a s s e s s m e nt2
Pr o gr e s s e d
Pr o gr e s s e d
C 1
Pr o gr e s si o n or d e at h aft er e x a ctl y o n e
mi s si n g a s s e s s m e nt
( 1) D at e of pr o gr e s si o n ( or d e at h)
( 2) D at e of n e xt s c h e d ul e d a s s e s s m e nt2
Pr o gr e s s e d
Pr o gr e s s e d
C 2
Pr o gr e s si o n o r d e at h aft er t w o or m or e
mi s si n g a s s e s s m e nt s
( 1) D at e of l a st a d e q u at e a s s e s s m e nt2
( 2) D at e of n e xt s c h e d ul e d a s s e s s m e nt2
( 3) D at e of pr o gr e s si o n ( or d e at h)
C e n s or e d
Pr o gr e s s e d
Pr o gr e s s e d
D
N o pr o gr e s si o n
( 1) D at e of l a st a d e q u at e a s s e s sm e nt
C e n s or e d
E
Tr e at m e nt di s c o nti n u ati o n d u e t o 
‘ Di s e a s e pr o gr e s si o n’ wit h o ut 
d o c u m e nt e d pr o gr e s si o n, i. e. cli ni c al 
pr o gr e s si o n b a s e d o n i n v e sti g at or cl ai m
( 1) I g n or e cli ni c al pr o gr e s si o n a n d f oll o w 
sit u ati o n s a b o v e
( 2) D at e of di s c o nti n u ati o n ( vi sit d at e at w hi c h 
cli ni c al pr o gr e s si o n w a s d et er mi n e d)
A s p er 
a b o v e 
sit u ati o n s
Pr o gr e s s e d
F
N e w a nti c a n c er t h er a p y gi v e n
( 1) I g n or e t h e n e w a nti c a n c er t h er a p y a n d f oll o w 
sit u ati o n s a b o v e (I T T a p pr o a c h)
( 2) D at e of l a st a d e q u at e a s s e s s m e nt pri or t o 
n e w a nti c a n c er t h er a p y
( 3) D at e of s e c o n d ar y a nt i-c a n c er t h er a p y
( 4) D at e of s e c o n d ar y a nti-c a n c er t h er a p y
A s p er 
a b o v e 
sit u ati o n s
C e n s or e d
C e n s or e d
E v e nt
G
D e at h s d u e t o r e a s o n ot h er t h a n 
d et eri or ati o n of ‘ St u d y i n di c ati o n’
( 1) D at e of l a st a d e q u at e a s s e s s m e nt
C e n s or e d 
( o nl y T T P 
a n d d ur ati o n 
of r e s p o n s e)
1. = D efi niti o n s c a n b e f o u n d i n S e cti o n 1 4. 1. 3. 2. 8 .
2. = Aft er t h e l a st a d e q u at e t u m or a s s e s s m e nt. “ D at e of n e xt s c h e d u l e d a s s e s s m e nt” i s d efi n e d i n S e cti o n 
1 4. 1. 3. 2. 8 .
3. = T h e r ar e e x c e pti o n t o t hi s i s if t h e p ati e nt di e s n o l at er t h a n t h e ti m e of t h e s e c o n d s c h e d ul e d a s s e s s m e nt a s 
d efi n e d i n t h e pr ot o c ol i n w hi c h c a s e t hi s i s a P F S e v e nt at t h e d at e of d e at h.
T he pri mar y a na l ysis a n d t he se nsiti vit y a nal yses m ust
be s pecifie d i n t he pr ot oc ol. Clear ly 
defi ne if a n d w h y o pti o ns ( 1) are n ot use d f or sit uati o ns C, E a n d (if a p plica ble) F.
Sit uati o ns C ( C 1 a n d C 2 ): Pr o gressi o n or deat h after o ne or m o re missi n g
assess me nts: T he 
pri mar y a nal ysis is us uall y usi n g o pti o ns ( 1) f or sit uati o ns C 1 a n d C 2, i.e.

( C 1) ta ki n g t he act ual pr o gressi o n or deat h date, i n t he case of o nl y o ne missi n g 
assess me nt.

( C 2) ce ns ori n g at t he date of t he last a de q uate assess me nt, i n t he case of t w o or m ore 
c o nsec uti ve missi n g assess me nts.
I n t he case of t wo or missi n g assess me nt s (sit uati on C 2) , o pti o n ( 3) ma y b e c o nsi dered j oi ntl y 
wit h
o pti o n ( 1) i n sit uati o n C 1 as se nsiti vit y a nal ysis. A
varia nt of t his se nsiti vit y a nal ysis 
c o nsists of bac k dati n g t he date of e ve nt t o t he ne xt sc he d ule d assess me nt as pr o p ose d wit h 
o pti o n ( 2) i n sit uati o ns C 1 a n d C 2.


N o v arti s
C o nfi d e nti al
P a g e 1 2 1
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
Sit u ati o n
E:
Tre at me nt
disc o nti n u ati o n 
d ue
t o
‘ Dise ase
pr o gressi o n’
wit h o ut 
d oc u me nte d pr o gressi o n: B y d efa ult, o pti o n ( 1) is use d for sit uati o n E as patie nts wit h o ut 
d oc u me nte d P D s h o uld be f oll o we d f or pr o gressi o n after disc o nti n uati o n of treat me nt. 
H o we ver, o pti o n ( 2) ma y be use d as se nsiti vit y a nal ysis. If pr o gressi o n is clai me d base d o n 
cli nical deteri orati o n i nstead of t u m or assess me nt b y e. g. C T-sca n, o pti on ( 2) ma y b e use d f or 
i n dicati o ns wit h hi g h earl y p r o gressi o n rate or diffic ulties t o assess t he t u m or d ue t o cli nical 
deteri orati o n.
Sit u ati o n F: Ne w c a ncer t her a p y gi ve n: t he ha n dli n g of t his sit uati o n m ust
be s pecifie d i n 
detail i n t he pr ot oc ol. H o we ver, o pti o n ( 1) (I T T) is t he rec o m me n de d a p pr oac h; e ve nts 
d oc u me nte d after t he i nitiati o n of ne w ca ncer t hera py w ill be c o nsi dere d f or t he pri mar y  
a nal y sis i.e. pr o gressi o ns a n d deat hs d oc u me nte d after t he i nitiati o n of ne w ca ncer t hera p y 
w o ul d be i ncl u de d as e ve nts. T his will re q uire c o nti n ue d f oll ow- u p f or pr o gressi o n after t he 
start of t he n e w ca ncer t hera p y. I n s uc h cases, it is rec o m me n de d t hat an a d diti o nal se nsiti vit y 
a nal ysis be perf or me d b y ce ns ori n g at last a de q uate assess me nt pri or t o i nitiati o n of ne w 
ca ncer t herap y .
O pti o n ( 2), i.e. ce ns ori n g at last a de q uate assess me nt ma y b e use d as a se nsiti vity a na l ysis. If 
a hi g h
ce ns ori n g rate d ue
t o start of
ne w
ca ncer t hera p y is e x pecte d, a wi n d o w
of 
a p pr o xi matel y 8
w ee ks perf or me d after t he start of ne w ca ncer t hera py c a n be use d t o 
calc ulate t he date of t he e ve nt or ce ns ori n g. T hi s s h o ul d be clearly s pecifie d i n t he a nal ysis 
pla n.
I n s o me s pecific setti n gs, l ocal treat me nts (e. g. ra diati o n/s ur gery) ma y n ot be c o nsi dere d as 
ca ncer t hera pies f or assess me nt of e ve nt/ce ns ori n g i n P F S/ T T P/ D o R a nal ysis. F o r e xa m ple, 
palliati ve ra di ot herap y gi ve n i n t he trial f or a nal gesic p ur p oses or f or l ytic lesi o ns at ris k of 
fract ure will n ot be c o nsi dered as ca ncer t hera py f or t he assess me n t of B O R a nd P F S a nal y ses. 
T he
pr ot oc ol
s h o ul d clearl y state t he
l ocal treat me nts w hic h
are
n ot
c o nsi dere d
as 
a nti ne o plastic t hera pies i n t he P F S/ T T P/ D o R a nal ysis.
T he pr ot oc ol s h o ul d state t hat t u m or assess me nts will
be perf or me d e ver y x wee ks
u ntil 
ra di ol o gical pr o gressi o n irres pecti ve of i nitiati o n of ne w a nti ne o plastic t hera p y. It is str o n gly 
rec o m me n de d t hat a t u m or assess me nt is perf or me d bef ore t he patie nt is s witc he d t o a ne w 
ca ncer t herap y .
A d diti o n al s u g g e sti o n s f or s e n siti vit y a n al y s e s
Ot her
s u g gesti o ns f or a d diti o nal se nsiti vit y a nal yses ma y i ncl u de a nalys es t o c hec k f or 
p ote ntial bias i n f oll ow- u p sc he d ules f or t u m or assess me nts, e. g. b y a ssi g ni n g t he dates f or 
ce ns ori n g a n d e ve nts o nl y at sc hed ule d visit dates. T he latter c o ul d be ha n dle d b y re placi n g i n
Ta ble 1 4- 5 t he “ Date of last a de q uate assess me nt” b y  the “ Date of pre vi o us sc he d ule d 
assess me nt (fr o m baseli ne)”, wit h t he f oll o wi n g defi niti o n:

D ate of pre vi o us sc he d ule d assess me nt (fr o m b aseli ne) is t he date w he n a t u m or 
assess me nt w o ul d ha ve ta ke n place, if t he pr ot oc ol assess me nt sc he me was strictl y  
f oll o we d fr o m baseli ne, i m me diatel y bef ore or o n t he date of t he last a de q uate t u m or 
assess me nt.
I n a d diti o n , a nal ys es c o uld be re peated usi n g t he I nvesti gat ors’ assess me nts of res p o nse rat her 
t ha n t he calc ulate d res p o nse. T he nee d f or t hese t yp e s of se nsiti vit y a nal yses will de pe n d o n 


N o v arti s
C o nfi d e nti al
P a g e 1 2 2
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
t he i n di vi d ual re q uire me nts f or t he s pecific st u d y a n d disease area a n d ha ve t o be s pecifie d i n 
t he pr ot oc ol or R A P d oc u me ntati o n.
1 4. 1. 4
D at a h a n dli n g a n d pr o gr a m mi n g r ul e s
T he f oll o wi n g secti o n s h o ul d be use d as g ui da nc e f or de vel o p me nt of t he pr ot oc ol, data 
ha n dli n g pr oce d ures or pr o gra m mi n g re q uire me nts (e. g. o n i nc o m plete dates).
1 4. 1. 4. 1
St u d y / pr oj e ct s p e cifi c d e ci si o n s
F or eac h st u d y ( or pr oject) vari o us iss ues nee d t o be a d dresse d a n d s pecifie d i n t he pr ot oc ol or 
R A P d oc u me ntati o n. A n y de viati o ns fr o m pr ot oc ol m ust be disc usse d a n d defi ne d at t he latest 
i n t he R A P d oc u me ntati o n.
T he pr o p ose d pri mar y a nal ysis a n d p ote ntial se nsiti vit y a nal yses s h o uld be disc usse d a n d 
a gree d wit h t he healt h a ut h orities a n d d oc u me nte d i n t he pr ot oc ol ( or at t he latest i n t he R A P 
d oc u me ntati o n bef ore data base l oc k).
1 4. 1. 4. 2
E n d of tr e at m e nt p h a s e c o m pl eti o n
Patie nts ma y v ol u ntaril y wit h dra w
fr o m t he st u dy treat me nt or ma y b e ta ke n off t he st u d y 
treat me nt at t he discreti o n of t he i n vesti gat or at a n y ti me. F o r patie nts w h o are l ost t o f oll ow-
u p, t he i n vesti gat or or desi g nee s h o ul d s h o w " d ue dili ge nce" b y d oc u me nti n g i n t he s o urce 
d oc u me nts ste ps ta ke n t o c o ntact t he patie nt, e. g., dates of tele p h o ne calls, re gistere d letters, 
etc.
T he e n d of treat me nt visit a n d its ass ociate d assess me nts s h o ul d occ u r wit hi n 7 da ys of t he 
last st u d y treat me nt.
Patie nts ma y disc o nti n ue st u d y treat me nt f or an y of t he f oll o wi n g reas o ns:

A d verse e ve nt(s)

L ost t o f oll o w- u p

P h y sicia n decisi o n

Pre g na nc y

Pr ot oc ol de viati o n

Tec h nical pr o ble ms

S u bject/ g uar dia n decisi o n

P r o gressive disease

St u d y ter mi nate d b y t he s p o ns or

N o n -c o m plia nt wit h st u d y treat me nt

N o l o n ger re q uires treat me nt

Treat me nt d urati o n c o m plete d as per pr ot oc ol ( o pti o nal, t o be use d if o nl y a fi xe d n u m ber 
of c ycles is gi ve n)
Deat h is a reas o n w hic h “ m us t” lea d t o disc o nti n uati o n of patie nt fr o m trial.


N o v arti s
C o nfi d e nti al
P a g e 1 2 3
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
1 4. 1. 4. 3
E n d of p o s t-tr e at m e nt f oll ow- u p ( st u d y p h a s e c o m pl eti o n)
E n d
of p ost- treat me nt f oll ow- u p
visit will
be c o m plete d after disc o nti n uati o n of st u d y 
treat me nt a n d p ost-treat me nt e val uati o ns b ut pri or t o c ollecti n g s ur vi val f oll ow- u p.
Patie nts ma y pr o vi de st u d y p ha se c o m pleti o n i nf or mati o n f or o ne of t he f oll o wi n g reas o ns:

A d ve rse e ve nt

L ost t o f oll o w - u p

P h y sicia n decisi o n

Pre g na nc y

Pr ot oc ol de viati o n

Tec h nical pr o ble ms

S u bject/ g uar dia n decisi o n

Deat h

P r o gressive disease

St u d y ter mi nate d b y t he s p o ns or
1 4. 1. 4. 4
M e di c al
v ali d ati o n of pr o gr a m m e d o v er all l e si o n r e s p o n s e
I n
or der t o b e as
o b jecti ve as p ossi ble t he R E C IS T pr o gra m me d
calc ulate d res p o nse 
assess me nt is ver y  strict re gar di n g meas ure me nt
met h o ds
(i.e. a n y assess me nt wit h m ore
or 
less se nsiti ve met h o d
t ha n t he o ne use d t o assess t he lesi o n at baseli ne is c o nsi dere d U N K) 
a n d n ot a vaila ble e val uati o ns (i.e. if a n y tar get or n o n- tar get lesi o n was
n ot e val uate d t he 
w h ole
o verall lesi o n res p o nse is U N K u nless re mai ni n g lesi o ns q ualifie d f or P D ). T his 
c o ntrasts wit h
t he sli g htly m ore
fle xi ble g ui da nce gi ve n t o l ocal i n vesti gat ors (a n d t o t he 
ce ntral re vie wers) t o use e x pert j u d g me nt i n deter mi ni n g res p o nse i n t hese t yp e of sit uati o ns, 
a n d t heref ore as a c o nse q ue nce discre pa ncies bet wee n t he differe nt s o urces of res p o nse 
assess me nt ofte n arise. T o e ns ure t he q uali ty of res p o nse assess me n ts fr o m t he l ocal site 
a n d/ or t he ce ntral re vie wer, t he res p o nses ma y be re-e val uate d b y cli nicia ns ( base d o n l ocal 
i n vesti gat or data rec or de d i n e C R F or base d o n ce ntral re vie wer data e ntere d i n t he data base) 
at N o vartis or e xter nal e x perts. I n ad diti o n, data re vie w re p orts will b e a vaila ble t o i de ntify 
assess me nts f or w hic h
t he i n vesti gat ors’ or ce ntral rea der’s o pi ni o n d oes n ot matc h t he 
pr o gra m me d
calc ulate d res p o nse base d
o n
R E C IS T
criteria. T his
ma y be
q uerie d
f or 
clarificati o n. H o we ver, t he i n vesti gat or or ce ntral rea der’s res p o nse assess me nt will ne ve r be 
o verr ule d.
If N o vartis elect t o i n vali date a n o verall lesi o n res p o nse as e val uate d b y t he i n vesti gat or or 
ce ntral rea der u p o n i nter nal or e xter nal re vie w of t he data, t he calc ulate d o verall lesi o n 
res p o nse at t hat s pecific assess me nt is t o be ke pt i n a dataset. T his
m ust
be clearl y 
d oc u me nte d i n t he R A P d oc u me ntati o n a n d a gree d bef ore data base l oc k. T his dataset s h o ul d 
be create d a n d st ore d as part of t he ‘ra w’ data.
A n y disc o nti n uati o n d ue t o ‘ Disease pr o gressi o n’ wit h o ut
d oc u me ntati o n of pr o gressi o n b y  
R E C IS T criteria s h o ul d be caref ul ly re vie we d. O nl y patie nts wit h d oc u me nte d deteri orati o n of 
s ym pt o ms
i n dicati ve of pr o gressi o n of disease s h o uld ha ve t his reas o n f or disc o nti n uati o n of 
treatme nt or st u d y e val uati o n.


N o v arti s
C o nfi d e nti al
P a g e 1 2 4
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2
1 4. 1. 4. 5
Pr o gr a m mi n g r ul e s
T he f oll o wi n g s h o ul d be use d f or pr o gra m mi n g of efficac y res ults:
1 4. 1. 4. 5. 1
C al c ul ati o n of ‘ti m e t o e v e nt’ v ari a bl e s
Ti me t o e ve nt = e n d date - start date + 1 (i n day s)
W he n n o p ost- baseli ne t u m or assess me nts are a vaila ble, t he date of ra n d o mizati o n/start of 
treat me nt will be use d as e n d date ( d urati o n = 1 day ) w he n ti me is t o be ce ns ored at last t u m or 
assess me nt, i.e. ti me t o e ve nt varia bles ca n ne ver be ne gati ve.
1 4. 1. 4. 5. 2
I n c o m pl et e a s s e s s m e nt d at e s
All i n vesti gati o n date s (e. g. X- ra y, C T sca n) m ust be c o m plete d wit h day, m o nt h a n d y ear.
If o ne or m ore
i n vesti gati o n dates are i nc o m plete b ut ot her i n vesti gati o n dates are a vaila ble, 
t his/t hese i nc o m plete date(s) are n ot c o nsi dere d for calc ulati o n of t he assess me nt date (a n d 
assess me nt date is calc ulate d as o utli ne d i n Secti o n 1 4. 1. 3. 2. 8 ). If all meas ure me nt dates ha ve 
n o da y  rec or de d, t he 1st of t he m o nt h is use d.
If t he m o nt h is n ot c o m plete d, f or a n y of t he i n vesti gati o ns, t he res pecti ve assess me nt will be 
c o nsi dere d t o be at t he date w hic h is e xactl y b e t wee n pre vi o us a n d f oll o wi n g assess me nt. If a 
pre vi o us a n d f oll o wi n g assess me nt is n ot a vaila ble, t his assess me nt will n o t be use d f or a n y 
calc ulati o n.
1 4. 1. 4. 5. 3
I n c o m pl et e d at e s f or l a st k n o w n d at e p ati e nt ali v e or d e at h
All dates m ust
be c o m plete d wit h da y , m o nt h
a n d year . If t he da y is missi n g,
t he 1 5 t h of t he 
m o nt h will be use d f or i nc o m plete deat h dates or dates of last c o ntact.
1 4. 1. 4. 5. 4
N o n- t ar g et l e si o n r e s p o n s e
If n o n o n- tar get lesi o ns are i de ntifie d at baseli ne (a n d t heref ore n ot f oll o we d t hr o u g h o ut t he 
st u d y), t he n o n- tar get lesi o n res p o nse at eac h assess me nt will be c o nsi dere d ‘ n ot a p plica ble 
( N A)’.
1 4. 1. 4. 5. 5
St u d y/ pr oj e ct s p e cifi c pr o gr a m mi n g
T he sta n dar d a na l ysis pr o gra ms nee d t o be a da pte d f or eac h st u dy / pr oject.
1 4. 1. 4. 5. 6
C e n s ori n g r e a s o n
In or der t o s u m marize t he vari o us reas o ns f or ce ns ori n g, t he f oll o wi n g cate g ories will
be 
calc ulate d f or eac h ti me t o e ve nt varia ble base d o n t he treat me nt c o m pleti o n pa ge , t he st u d y 
e val uati o n c o m pleti o n pa ge a n d t he s ur vi val pa ge.
F or s ur vi val t he f oll o wi n g ce ns ori n g reas o ns are p ossi ble:

Ali ve

L ost t o f oll o w- u p
F o r P F S a n d T T P (a n d t heref ore d urati o n of res p o nses) t he f oll o wi n g ce ns ori n g reas o ns are 
p ossi ble:


N o v arti s
C o nfi d e nti al
P a g e 1 2 5
A m e n d e d Pr ot o c ol V er si o n 0 1 (Cl e a n )
Pr ot o c ol N o. C R A D 0 0 1 Y 2 2 0 2

O n g oi n g wit h o ut e ve nt

L ost t o f oll o w- u p

Wit h dre w c o nse nt

A de q uate assess me nt n o l o n ger a vaila ble *

E ve nt d oc u me nte d after t w o or m ore missi n g t u m or assess me nts ( o pti o nal, see Ta ble 1 4 - 5)

Deat h d ue t o reas o n ot her t ha n u n der ly i n g ca ncer ( o nly use d f or T T P a n d d ur ati o n of 
res p o nse)

I nitiati o n of ne w a nti-ca ncer t hera p y
* A de q uate assess me nt is defi ne d i n Secti o n 1 4. 1. 3. 2. 8 . T his reas o n is a p plica ble w he n 
a de q uate e val uati o ns are missi n g
f or a s pecifie d peri o d pri or t o data c ut-off ( or pri or t o a n y 
ot her ce ns ori n g reas o n) c orres p o n di n g t o t he u na vaila bilit y  of t w o or m ore
pla n ne d t u m or 
assess me nts pri or t o t he c ut-off date. T he f oll o wi ng clarificati o ns c o ncer ni n g t his reas o n 
s h o ul d als o be n ote d:

T his ma y  be w he n t here has bee n a defi nite decisi o n t o st o p e val uati o n (e. g. 
reas o n =“ S p o ns or decisi o n” o n st u d y e val uati o n c o m pleti o n pa ge), w he n patie nts are n ot 
f oll o we d f or pr o gressi o n after treat me nt c o m pleti o n or w he n o nly U N K assess me nts are 
a vaila ble j ust pri or t o data c ut-off).

T he reas o n " A de q uate assess me nt n o l o n ger a vaila ble" als o pre vails i n sit uati o ns w he n 
a n ot her ce ns ori n g reas o n (e. g. wit h dra wal of c o nse nt, l oss t o f oll o w -u p or alter nati ve a nti -
ca ncer t herap y) has occ urre d m ore t ha n t he s pecifie d peri o d f oll o wi n g t he last a de q uate 
assess me nt.

T his reas o n will als o be use d t o ce ns or i n case of n o baseli ne assess me nt.
1 4. 1. 5
R ef er e n c e s ( a v ail a bl e u p o n r e q u e st)
De nt S, Ze e ( 2 0 0 1) a p plicati o n of a ne w m ulti n o mial p hase II st o p pi n g r ule usi n g res p o nse 
a nd earl y pr o gressi o n, J Cli n O nc ol; 1 9: 7 8 5 - 7 9 1.
Eise n ha uer E, et al ( 2 0 0 9) Ne w res p o nse e val uati o n criteria i n s oli d t u m ors: re vise d R E C IS T
g ui deli ne ( versi o n 1. 1). E ur o pea n J o ur nal of Ca ncer, V ol. 4 5: 2 2 8 - 4 7.
Ellis S, et al ( 2 0 0 8) A nal ysis of d urati o n of res p o nse i n o nc ol o g y trials. C o nte m p Cli n Trials
2 0 0 8; 2 9: 4 5 6 - 4 6 5.
E M A G ui da nce: 2 0 1 2 G ui deli ne o n t he e val uati o n of a ntica ncer me dici nal pr o d ucts i n ma n .
F D A G ui deli nes: 2 0 0 5 Cli nical Trial E n d p oi nts f or t he A p pr o val of Ca ncer Dr u gs a n d
Bi ol o gics, A pril 2 0 0 5 .
F D A G u i deli nes: 2 0 0 7 Cli nical Trial E n d p oi nts f or t he A p pr o val of Ca ncer Dr u gs a n d
Bi ol o gics, M a y 2 0 0 7.
M or ga n T M ( 1 9 8 8) A nal y sis of d urati o n of res p o nse: a pr o ble m of o nc ol o gy trials. C o nt Cli n
Trials; 9: 1 1 - 1 8.
T herasse P, Ar b uc k S, Eise n ha uer E, et al ( 2 0 0 0) Ne w G ui deli nes t o E val uate t he Res p o nse t o
Treat me nt i n S oli d T u m ors, J o ur nal of Nati o nal Ca ncer I nstit ute, V ol. 9 2; 2 05- 1 6.

SAP_001.pdf: 
Clinical Development
RAD001(everolimus)
CRAD001Y2202 / NCT03312738
A randomized, double-blind, placebo controlled, phase II
study of Everolimus in combination with Exemestane in the 
treatment of Chinese postmenopausal women with estrogen 
receptor positive, HER-2 negative, locally advanced, recurrent, or 
metastatic breast cancer after recurrence or progression on prior 
letrozole or anastrozole
Statistical Analysis Plan (SAP) for Final CSR
Document type:
SAP Documentation
Document status:
Final
Release date:
11-Jul-2022
Number of pages:
34
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Final CSR SAP
Study No. CRAD001Y2202
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for update
Section and title 
impacted (Current)
11-Jul-2022
Prior to 
final DB 
lock
Creation of final 
version
N/A - First version
NA


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Final CSR SAP
Study No. CRAD001Y2202
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................7
2
Statistical methods...............................................................................................................8
2.1
Data analysis general information ...........................................................................8
2.1.1
General definitions..................................................................................8
2.1.2 
Date of first administration of study drug...............................................9
2.1.3 
Date of last administration of study drug................................................9
2.1.4 
Date of first administration of study treatment .......................................9
2.1.5 
Date of last administration of study treatment ........................................9
2.1.6 
Study day.................................................................................................9
2.1.7
Baseline...................................................................................................9
2.1.8 
On-treatment assessment/event.............................................................10
2.1.9 
Last contact date....................................................................................10
2.2
Analysis sets ..........................................................................................................11
2.2.1 
Subgroup of interest ..............................................................................11
2.3
Subject disposition, demographics and other baseline characteristics ..................11
2.3.1
Subject disposition ................................................................................11
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................12
2.4.1
Study treatment / compliance................................................................12
2.4.2
Duration of study treatment exposure...................................................12
2.4.3
Cumulative dose....................................................................................12
2.4.4
Dose intensity and relative dose intensity.............................................12
2.4.5
Dose reductions or interruptions...........................................................13
2.4.6
Prior, concomitant and post therapies...................................................13
2.4.7
Inducers, inhibitors and substrates of CYP3A......................................14
2.4.8
Further anti-neoplastic therapy .............................................................14
2.5
Analysis of the primary objective..........................................................................14
2.5.1
Primary endpoint...................................................................................15
2.5.2 
Statistical hypothesis, model, and method of analysis..........................15
2.5.3
Handling of missing values/censoring/discontinuations.......................16
2.5.4
Sensitivity and other supportive analyses .............................................16
2.6
Analysis of the key secondary objective ...............................................................16


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Final CSR SAP
Study No. CRAD001Y2202
2.7
Analysis of secondary efficacy objective(s)..........................................................16
2.7.1
Secondary endpoints .............................................................................18
2.7.2
Statistical hypothesis, model, and method of analysis..........................18
2.7.3
Handling of missing values/censoring/discontinuations.......................20
2.8
Safety analyses.......................................................................................................20
2.8.1
Adverse events (AEs)............................................................................21
2.8.2
Deaths....................................................................................................24
2.8.3
Laboratory data .....................................................................................24
2.8.4
Other safety data ...................................................................................26
2.9
Interim analysis......................................................................................................27
3
Sample size calculation .....................................................................................................27
4
Change to protocol specified analyses ..............................................................................27
5
Appendix ...........................................................................................................................27
5.1
Baseline comparability ..........................................................................................27
5.2
Time-to-event analyses..........................................................................................28
5.2.1
Analysis of time to event data with ties ................................................28
5.2.2
Kaplan-Meier survival function estimation ..........................................28
5.2.3
Hazard ratio estimation .........................................................................28
5.3
Median follow-up of the study ..............................................................................28
5.4
Imputation rules.....................................................................................................29
5.4.1
Study drug.............................................................................................29
5.4.2
AE date imputation ...............................................................................30
5.4.3
Concomitant medication date imputation .............................................30
5.4.4
Death date imputation ...........................................................................32
5.5
AEs coding/grading ...............................................................................................32
5.6
Laboratory parameters derivations ........................................................................32
3
Reference...........................................................................................................................34


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Final CSR SAP
Study No. CRAD001Y2202
List of abbreviations
ABC
Advanced Breast Cancer
AE
Adverse Event
ASCO
American Society of Clinical Oncology
BC
Breast Cancer
BIRC
Blinded independent review committee
CBR
Clinical Benefit Rate
CI
Confidence Interval
CL
Clearance
Cmax
Maximum Concentration
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DNA
Deoxyribonucleic Acid
DOR
Duration of Response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report/Record Form
EDC
Electronic Data Capture
EOT
End of Treatment
ER
Estrogen receptor
EU
European Union
FAS
Full Analysis Set
HER2
Human epidermal growth factor receptor 2
HER2-
Human epidermal growth factor receptor 2 negative
HER2+
Human epidermal growth factor receptor 2 positive
HR
Hazard ratio
INR
International Normalized Ratio
IRT
Interactive Response Technology
LC-MS/MS
Liquid chromatography tandem mass spectrometry
MBC
Metastatic breast cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
N
Sample size
ORR
Objective Response Rate
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetics
PR
Partial Response
RECIST
Response Evaluation Criteria In Solid Tumors
SAE
Serious Adverse Event
SC
Steering Committee
SD
Stable disease
UNK
Unknown


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Final CSR SAP
Study No. CRAD001Y2202
ULN
Upper Limit of Normal
WHO
World Health Organization


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Final CSR SAP
Study No. CRAD001Y2202
1
Introduction
This document describes the detailed statistical methodology of the Statistical Analysis Plan 
(SAP) for the final Clinical Study Report (CSR) at the end of CRAD001Y2202: A randomized, 
double-blind, placebo controlled, phase II study of Everolimus in combination with Exemestane 
in the treatment of Chinese postmenopausal women with estrogen receptor (ER) positive, HER-
2 negative, locally advanced, recurrent, or metastatic breast cancer after recurrence or 
progression on prior letrozole or anastrozole. The data will be analyzed by Novartis. It is 
planned that data from all centers that participate in this study will be used. This document 
refers to the study protocol Version 1.0 dated May 23 2017. The the indication of 
“Postmenopausal women with advanced hormone receptor-positive, HER2-negative breast 
cancer in combination with exemestane after failure of treatment with letrozole or anastrozole”
has been approved by the Chinese Health Authorities February 09 2022.
1.1
Study design
This is a multicenter, double-blind, randomized, placebo-controlled, phase II study evaluating 
treatment with everolimus (10 mg daily) versus placebo in combination with exemestane 
(25 mg daily) in Chinese postmenopausal women with locally advanced, recurrent or metastatic
ER positive HER2-negative breast cancer refractory to non-steroidal aromatase inhibitors.
Approximately 160 subjects will be randomized in 1:1 ratio to receive either everolimus or 
matching placebo in a blinded manner in addition to open label exemestane (25 mg daily 
tablets).
All eligible subjects will be randomized within 7 days before Cycle 1 Day 1 to one of the two 
treatment arms: everolimus plus exemestane arm or placebo plus exemestane arm. 
Randomization will be stratified according to the presence of visceral disease and sensitivity 
to prior hormonal therapy status. Visceral refers to lung, liver, brain, pleural and peritoneal 
involvement.
Randomized subjects will start the study treatment at Cycle 1 Day 1. Subjects will receive 
everolimus/placebo (10 mg daily oral tablets) in addition to exemestane (25 mg daily oral 
tablets) continuously.
Subjects will receive treatment until disease progression (assessed by RECIST 1.1), 
unacceptable toxicity, death or discontinuation from treatment for any other reason. Tumor 
assessments will be performed every 8 weeks after randomization until radiological 
progression per local assessment.
There won’t be any interim analysis for this study.
1.2
Study objectives and endpoints
The primary objective is to assess the progression-free survival (PFS) as determined by 
investigator assessment of everolimus plus exemestane and of placebo plus exemestane.
The secondary objectives are:

To assess PFS in the two treatment arms as determined by a Blinded Independent Review 
Committee (BIRC)


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Final CSR SAP
Study No. CRAD001Y2202

To assess overall survival (OS) in the two treatment arms

To assess the following efficacy endpoints in the two treatment arms based on both local 
investigator’s assessment and BIRC

Overall response rate (ORR)

Clinical benefit rate (CBR)

Time to response and duration of response

To assess time to deterioration of ECOG Performance Status (PS)

To characterize the safety and tolerability of everolimus and exemestane versus 
placebo and exemestane

Characterize the pharmacokinetics of everolimus pre-dose concentration (Cmin) and 
concentration at 2 hours post dose (C2h) when administered in combination with 
exemestane

Compare the two treatment arms with respect to pre-dose concentration (Cmin) and
concentration at 2 hours post dose (C2h) of exemestane and to compare the two
treatment arms with respect to estradiol (E2) changes from baseline.
For secondary objectives with regards to BIRC assessment and PK analyses, the analysis will 
not be repeated for the final CSR as per protocol. The results were addressed in the primary 
CSR (DCO:19-May-2020).
2
Statistical methods
2.1
Data analysis general information
Novartis and/or a designated CRO will perform all the analyses. Any additional data analyses
performed independently by any investigator should be submitted to Novartis before 
publication or presentation. The end of study is defined as the earliest occurrence of one of the 
following:

All patients have died or discontinued from the study

Another clinical study or patient support programs becomes available that can continue to
provide Afinitor in this patient population and all patients ongoing are eligible to be
transferred to them

Afinitor has been approved for this indication in combination with Exemestane
The final analysis for safety and efficacy will be conducted at the end of the study. All available 
data from all patients up to this cutoff date will be analyzed per protocol.
SAS® version 9.4 or later will be used in all analyses.
2.1.1
General definitions
Study drug is defined as everolimus, or matching placebo. Study treatment is defined as 
everolimus + exemestane or placebo + exemestane.


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2.1.2
Date of first administration of study drug
The date of first administration of study drug is derived as the first date when a non-zero dose 
of study drug is administered and recorded on the dose administration record (DAR) eCRF. For 
the sake of simplicity, the date of first administration of study drug will also be referred to as 
the start of study drug.
2.1.3 
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug is administered and recorded on the DAR eCRF.
2.1.4
Date of first administration of study treatment
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of any component of study treatment is administered and recorded on the DAR eCRF. For 
the sake of simplicity, the date of first administration of study treatment will also be referred to 
as the start of study treatment.
2.1.5 
Date of last administration of study treatment
The date of last administration of study treatment is defined as the last date when a non-zero 
dose of any component of study treatment was administered and recorded on the DAR eCRF.
2.1.6 
Study day
The study day for safety assessments (e.g., adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption, etc.) will be calculated as the difference 
between the date of the assessment and the start of study treatment plus 1. (Note: except in the 
case when the assessment is before start of study treatment in which case study day is calculated 
as the difference between the date of the assessment and the start of study treatment. In this 
particular case, the study day displayed on the listing will be negative.)
The study day for all other, i.e., non-safety assessments (tumor assessment, death, disease 
progression, tumor response, ECOG performance status) will be calculated as the difference 
between the date of the event and the randomization date plus 1. In other words, all efficacy 
time-to-event variables (e.g., progression-free survival, overall survival, time to response) will 
be calculated from date of randomization. (Example: if randomization date is 02JAN2007, start 
of study drug is on 05JAN2007, and the date of death is 09JAN2007, then the study day when 
death occurred is 8.) 
The study day will be displayed in data listings.
2.1.7 
Baseline
Baseline value(s) is (are) the result of an investigation describing the “true” uninfluenced state 
of the subject. 
For efficacy evaluations, the last available assessment before or at the date of randomization is 
taken as ‘baseline’ value or ‘baseline’ assessment. In the context of the definition of baseline, 


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efficacy evaluations also include the ECOG performance status, subject-reported outcome 
measures and clinical measurements included in the stratification.
For safety evaluations (i.e., laboratory and vital signs), the last available assessment before or 
at the date of the start of study treatment is taken as ‘baseline’ assessment.
2.1.8 
On-treatment assessment/event
On-treatment assessment/event is defined as any assessment/event obtained in the time 
interval:[date of first administration of study treatment; date of last administration of study 
treatment + 30 days], i.e., including the lower and upper limits. (Note: The calculation of study 
treatment duration, however, may use different rules as specified in Section 2.4.1.)
2.1.9 
Last contact date
The last contact date will be derived for subjects not known to have died at the final analysis 
cut-off using the sources presented in Table 2-1 below:
Table 2-1
Last contact date data sources
Source data
Condition
Last contact date/last date subject was known to 
be alive from survival follow-up page 
Subject status is reported to be alive.
Do not use if subject status is reported 
unknown.
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term.
Start/End dates from drug administration record 
Non-missing dose. Doses of 0 are allowed.
End of treatment date from end of treatment page
No condition.
Tumor (RECIST) assessment date
Evaluation is marked as ‘done’.
Laboratory collection dates
Sample collection marked as done. 
Vital signs date
At least one non-missing parameter value.
Performance status date
Non-missing performance status.
Start/End dates of AE 
Non-missing verbatim term.
The last contact date on or before the data cut-off date should be used; the cut-off date should 
not be used as the censoring date (even in presence of post cut-off data) unless the subject was 
seen or contacted on the cut-off date.
Imputed dates (e.g., analysis cut-off date programmatically imputed to replace the missing end 
date of a dose administration record) will not be used to derive the last contact date. Partially 
imputed dates (i.e., only day or day and month imputed) are allowed to be used for last contact 
date only if coming from Survival Follow-up page.


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The last contact date will be used for censoring of subjects in the analysis of overall survival.
2.2
Analysis sets
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned
by randomization. According to the intent to treat principle, subjects will be analyzed according
to the treatment and strata they have been assigned to during the randomization procedure.
The Safety Set (SAF) consists of all subjects who received at least one dose of study
treatment. Subjects will be analyzed according to treatment actually received, where treatment 
received is defined as the randomized treatment if the subject took at least one dose of that
treatment or the first treatment received if the randomized treatment was never received.
The actual treatment received corresponds to:
-
the randomized treatment if subjects took at least one dose of that treatment
-
the first treatment received if the randomized treatment was never received
2.2.1 
Subgroup of interest
Not Applicable.
2.3
Subject disposition, demographics and other baseline 
characteristics
Subjects who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. The reason for not being started on treatment will be entered on 
the Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure Subjects.A summary of 
the demographic, baseline disease characteristics and prior antineoplastic therapy of the study 
population was provided in the primary CSR [Study Y2202-Section 10.4].
2.3.1
Subject disposition
The Full Analysis Set will be used for subject disposition summaries. Based on the two eCRF 
pages ‘End of Treatment’ and ‘End of Post Treatment Disposition eCRF page’ there will be one 
combined summary, stratified by treatment, showing:

Number (%) of subjects who discontinued the study treatment (based on the ‘End of 
Treatment’ page);

Reasons for study treatment discontinuation (based on the ‘End of Treatment’ page).

Number (%) of subjects who entered the post-treatment evaluation phase (based on the 
‘End of Treatment’ page);

Number (%) of subjects who discontinued from the post-treatment evaluations (based 
on the ‘End of Post Treatment Disposition eCRF page’ page); 

Reasons for discontinuation from the post-treatment evaluations phase (based on the 
‘End of Post Treatment Disposition eCRF page’ page).


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of study treatment exposure, cumulative dose, dose intensity (DI) and relative dose 
intensity (RDI) will be summarized by treatment. In addition, the duration of exposure to study 
treatment will be categorized into time intervals; frequency counts and percentages will be 
presented for the number of subjects in each interval. The number of subjects, who have dose 
reductions or interruptions, and the reasons, will be summarized by treatment.
Listings of all doses of the study treatment along with dose change reasons will be produced. 
The Safety Set will be used for all summaries and listings of study treatment.
2.4.2
Duration of study treatment exposure
The following algorithm will be used for everolimus and exemestane to calculate the duration 
of study treatment exposure for subjects who took at least one dose of any of the components 
of the study treatment:
Duration of exposure (days) = (date of last administration of study treatment) – (date of first 
administration of study treatment) + 1.
Total duration of exposure will be derived as the sum of the cycle duration of exposure.
The duration includes the periods of temporary interruption (of any component of the study 
treatment for any reason).
Duration of exposure to each component of the study treatment will also be calculated.
2.4.3
Cumulative dose
Cumulative dose is defined as the total dose given during the study treatment exposure period 
and will be summarized for each of the study treatment components separately. For subjects 
who do not receive any drug, the cumulative dose will be set to zero.
2.4.4
Dose intensity and relative dose intensity
Dose intensity (DI) for subjects with non-zero duration of exposure is defined as follows:
DI (dosing unit / unit of time) = Cumulative dose (dosing unit) / Duration of exposure (unit of 
time).
For subjects who do not receive any drug, the DI will be set to zero.
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to subjects 
as per protocol in the same dose unit and unit of time as that of the Dose Intensity. 
Relative dose intensity (RDI) is defined as follows:
RDI = DI (dosing unit / unit of time) / PDI (dosing unit / unit of time).


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DI and RDI will be summarized separately for each of the study treatment components, but 
using the duration of the study treatment exposure, not the duration of exposure to each of the 
components.
2.4.5
Dose reductions or interruptions
The number of subjects, who have dose reductions or interruptions, and the reasons for such 
reductions/interruptions, will be summarized separately for each of the study treatment 
components.
An interruption is defined as a 0 mg dose given on one or more days. However, for last records, 
it will be counted as an interruption only if there are 2 or more last records with 0 mg dose. 
If a subject moves from a dose level that is higher than the studied dose under the protocol to 
the dose level that is being studied in the protocol, such changes will not be counted as 
reductions. However, if any subject moves directly from a higher than studied dose down to a 
lower than protocol-studied dose, or to the dose level being studied under the protocol but on a 
less frequent regimen, such changes will be counted as reductions. If first dose is lower than the 
studied dose under the protocol, it will be counted as a dose reduction.
For everolimus and exemestane, reductions count should be based on the actual total daily dose 
(mg). 
If one drug is permanently discontinued (before a protocol-planned discontinuation date) while 
the other is ongoing, such discontinuations will be classified as interruptions.
Dose reductions and interruptions will be tabulated both separately and in a combined fashion. 
In the combined summary, dose interruptions will be considered as dose reductions to 0 mg, 
and therefore all reductions/interruptions will be labeled as reductions and tabulated in one table. 
2.4.6
Prior, concomitant and post therapies
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
besides the study treatment that were administered to a subject, preceding or coinciding with 
the study assessment period (within 28 days prior to the study treatment through 30 days after 
the last dose of study treatment). 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List to allow for categorization by preferred term. In addition to categorizing 
medication data by preferred term, drugs will be classified according to their ATC classification 
in order to present and compare how they are being utilized. 
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drug(s) will be listed and summarized by ATC class, preferred term and treatment arm by means 
of frequency counts and percentages. These summaries will include medications starting on or 
after the start of study treatment or medications starting prior to the start of study treatment and 
continuing after the start of study treatment.
Prior concomitant medications or significant non-drug therapies starting and ending prior to the 
start of study treatment were summarizedsummarized in the primary CSR and will not be 
repeated for the final CSR.


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The Safety Analysis Set will be used for all concomitant medication tables and listings.
2.4.7
Inducers, inhibitors and substrates of CYP3A
Everolimus is a substrate of CYP3A4, and a substrate and moderate inhibitor of the multidrug
efflux pump, PgP (PgP, MDR1, and ABCB1). Extent of absorption and subsequent elimination 
of systemically absorbed everolimus may be influenced by products that are substrates, 
inhibitors, or inducers of CYP3A4 and/or PgP. Therefore:

Co-administration with strong inhibitors of CYP3A4 or PgP should be avoided;

Co-administration with moderate CYP3A4 inhibitors (e.g., erythromycin, 
fluconazole) or PgP inhibitors should be used with caution;

Seville orange, star fruit, grapefruit and their juices affect CYP3A4 and PgP activity 
concomitant use should be avoided.
Please refer to Table 6-8 of the protocol for the list of relevant inducers and inhibitors of CYP3A 
and to Table 6-9 of the protocol for the list of relevant substrates, inducers, and inhibitors of 
PgP. Despite the fact that some of these drugs should be avoided completely and some used 
with caution, there may be subjects who took these drugs during the study. In that case, the 
concomitant medications need to be identified and classified as protocol deviations (review to 
be performed by a Clinical Pharmacologist) and then tabulated and/or listed in the Clinical 
Study Report as appropriate. 
2.4.8
Further anti-neoplastic therapy
Anti-neoplastic therapy regimen received between EOT and progression will also be collected 
as well as the first regimen received after progression. Additionally, the tumortumor response 
classification was described in Table 14-5 of the protocol after the start of anti-neoplastic drugs.
For details on the censoring rules, see [Appendix 1 of the study protocol].
Clinical review of study data will be performed to identify anti-neoplastic medications that are 
not allowed during study treatment.
Anti-neoplastic therapies since discontinuation of study drug will be listed and summarized by 
ATC class, preferred term and treatment arm by means of frequency counts and percentages in 
separate summaries using the Full Analysis Set.
2.5
Analysis of the primary objective
The primary objective in this study is to assess PFS based on investigator’s assessment on the 
combination treatment of everolimus + exemestane and placebo + exemestane in Chinese 
postmenopausal women with estrogen receptor positive, HER2-negative, locally advanced, 
recurrent, or metastatic breast cancer after recurrence or progression on prior letrozole or 
anastrozole. The primary analysis for efficacy was conducted when approximately 110 PFS 
events have been documented，the corresponding results for the PFS are provided in the 
primary CSR [Study Y2202-Section 11.1] (DCO: 19 May-2020).


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2.5.1
Primary endpoint
Progression-free survival (PFS) derived from an investigator’s assessment of radiology data 
will be used as the primary efficacy variable. Disease  progression for primary efficacy endpoint 
derivation will be assessed using the local (treating center’s radiologist’s) investigator’s tumor 
assessment per RECIST 1.1.
The PFS is defined as the time from the date of randomization to the date of the first documented 
disease progression or death due to any cause, whichever occurs first. If a subject has not 
progressed or died at the analysis cut-off date, or if she receives any further anti-cancer therapy, 
PFS will be censored at the time of the last adequate tumor assessment before the cut-off date 
or the anti-cancer therapy date, whichever occurs first. Disease progression for primary efficacy 
endpoint derivation will be assessed using the local (treating center’s radiologist’s) 
investigator’s tumor assessment.
Definitions and further details on PFS can be found in
Appendix 1 of the protocol.
Discontinuation due to disease progression (collected on the “End of treatment” and “End of 
Post Treatment Disposition eCRF page” page) without supporting objective evidence satisfying 
progression criteria per RECIST 1.1 will not be considered a progressive disease. 
Data included in efficacy analyses
Thefinal analysis for safety and efficacy will be conducted closeout at the end of the study.
Efficacy analyses will include all data observed in subjects from the FAS regardless of whether 
the data were observed on-treatment or after the study treatment discontinuation until the 
analysis cut-off date. In particular, the “30 days” rule applied to all safety analyses will NOT 
be used for efficacy analyses.
2.5.2 
Statistical hypothesis, model, and method of analysis
No hypothesis testing will be performed and the primary objective of this study is to estimate 
hazard ratio of everolimus in combination with exemestane compared to placebo plus 
exemestane.
Thefinal analysis of PFS will be based on data from investigator/local radiology review. The 
analysis will be performed on the FAS following the intention-to-treat (ITT) principle, i.e., 
subjects will be analyzed according to the treatment group they were randomized and the 
stratum they were assigned to at baseline. The analysis will use the default censoring and event 
date definitions from Table 14-5 of Appendix 1 of the study protocol, i.e. A(1), B(1), C1(1), 
C2(1), D(1), E(1), and F(1). In particular, PFS will be censored at the last adequate tumor 
assessment if one of the following occurs: absence of a PFS event; a PFS event occurs after a 
new anticancer therapy is given; a PFS event occurs after two or more missing tumor 
assessments. Discontinuation of study treatment (for any reason) will not be considered as a 
reason for censoring. 
Kaplan-Meier estimates
The Kaplan-Meier (KM) estimate of the progression-free survival function will be computed 
for each treatment group. The results will also be plotted graphically (Kaplan-Meier curves) by 


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treatment and by randomization strata as assigned through IRT. The plots will display the 
number of subjects at risk at equidistant time points. 
The estimated median PFS for each treatment group will be provided along with the 
approximate 90% confidence intervals (Brookmeyer and Crowley, 1982). Additionally, the 25th
and 75th percentiles will also be computed. The log-log will be used to compute the confidence 
intervals.
Hazard ratio estimate
The hazard ratio estimate of a PFS event comparing the everolimus + exemestane combination 
therapy with placebo + everolimus, along with the two-sided 90% confidence interval, will be 
obtained from the stratified Cox proportional hazards model using the stratification information 
obtained through IRT. The model will include the indicator of assignment to the everolimus + 
exemestane arm or placebo + exemestane arm as the covariate. The baseline hazard function 
will be allowed to vary across strata. As this is an estimation based approach, no p-value will 
be provided.
2.5.3
Handling of missing values/censoring/discontinuations
PFS will be censored if no PFS event is observed before the cut-off date or before the start date 
of a new anticancer therapy or another investigational treatment, whichever occurs earlier.
The censoring date will be the date of last adequate tumor assessment before either of these two 
dates. If a PFS event is documented after two or more missing assessments or nonadequate 
tumor assessments, then the date of PFS will be censored at the date of the last adequate tumor 
assessment. If a PFS event is observed after a single missing or non-adequate tumor assessment, 
the actual date of event will be used.
2.5.4
Sensitivity and other supportive analyses
No sensitivity analysis will be performed for final CSR.
2.6
Analysis of the key secondary objective
Not applicable. There is no key secondary endpoint in this study.
2.7
Analysis of secondary efficacy objective(s)
The secondary efficacy objectives in this study are the two treatment groups with respect to OS, 
ORR, deterioration in the ECOG PS, and CBR.
Additionally, ORR, deterioration in the ECOG PS, CBR, time to response and duration of 
response will be summarized between the treatment groups in the final CSR. The analysis 
results for the other secondary efficacy endpoints were provided in the primary CSR [Study 
Y2202-Section 11]. The analysis of all secondary efficacy endpoints (mentioned below) will be 
performed on the FAS.


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Overall survival (OS)
Overall survival (OS) is defined as the time from the date of randomization to the date of death 
due to any cause. If the subject is alive at the date of the analysis cut-off or lost to follow-up, 
then OS will be censored at the last contact date prior to data cutoff date. Only one OS analysis 
will be performed at the end of the study.The OS analysis will be based on data from the FAS 
on the ITT basis, i.e., according to the treatment group subjects are randomized to at baseline.
Overall response rate (ORR)
Overall response rate (ORR) is defined as the proportion of subjects with best overall response 
of complete response (CR) or partial response (PR) according to RECIST 1.1 (Appendix 1 of 
the protocol). ORR will be calculated based on the FAS according to the ITT principle, using 
local radiologist’s/investigator’s tumor assessment. Subjects with bone lesions only at baseline 
will be included in the numerator if they achieve a complete response. 
Clinical benefit rate (CBR)
Clinical benefit rate (CBR) is defined as the proportion of subjects with best overall response 
of CR, PR, or overall lesion response of stable disease (SD for measurable disease and non-
CR/non-PD (NCRNPD) for non-measurable disease) with duration of 24 weeks or longer. A 
subject will be considered to have a SD/NCRNPD for 24 weeks or longer if SD/NCRNPD is 
recorded at 24 weeks or later after randomization. Taking into account the allowed time window 
for tumor assessment visits, the SD/NCRNPD response has to be recorded at 23 weeks or later 
after randomization to be included in the CBR calculation. Best overall response of CR, PR and 
overall lesion response of SD/NCRNPD are defined according to RECIST 1.1 (see Appendix 
1). CBR will be calculated based on the FAS according to the ITT principle, using local 
radiologist’s/investigator’s tumor assessment. Subjects with non-measurable disease only at 
baseline will be included in the numerator if they achieve a complete response. 
Time to response (TTR)
Time to overall response (TTR) of CR or PR is defined as the time from randomization to first
documented response (CR or PR, which must be confirmed subsequently) for subjects with a
confirmed CR or PR. It will be summarized using local radiologist’s/investigator’s tumor 
assessment.
Duration of Response (DOR)
Among subjects with a confirmed response (PR or CR) per RECIST 1.1 by investigator, DOR
is defined as the time from first documented response (PR or CR) to the date of first documented 
disease progression or death due to any cause. It will be summarized using local 
radiologist’s/investigator’s tumor assessment.
ECOG performance status
ECOG performance status (PS) scale will be used to assess physical health of subjects, ranging 
from 0 (most active) to 5 (least active) given in Table 2.2.
ECOG PS will be evaluated at the following visits:


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
Baseline (≤ 7 days prior to administration of the study drugs)

Cycle 1 Day 1 (prior to administration of the study drugs)

Every 2 Cycles after Cycle 1 Day 1(Cycle 3 Day 1, Cycle 5 Day 1 and etc)

End of treatment
Table 2-2
ECOG Performance Status Scale
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than  50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
ECOG performance status will be assessed and recorded at baseline, and every two cycles 
thereafter as well as at discontinuation from the study treatment (within one week after 
discontinuation). 
2.7.1
Secondary endpoints
Overall survival (OS), Objective Response Rate (ORR), Clinical Benefit Rate (CBR), Time to 
overall response(TTR) and Duration of Response (DOR), Time to deterioration of ECOG 
Performance Status.
2.7.2
Statistical hypothesis, model, and method of analysis
Overall Survival
Distribution of OS in each of the two treatment arms will be assessed using the Kaplan-Meier 
(KM) estimation method, and the treatment-specific KM curves will be graphically displayed. 
The estimated median OS and probability of surviving at the estimated median OS, along with 
90% confidence intervals, will be presented for the two treatment arms. Stratified Cox 
regression models will be used to estimate the hazard ratio (HR) of death from any cause, along 
with the associated 90% confidence interval, comparing the everolimus + exemestane 
combination therapy with placebo + everolimus therapy where the stratification information 
will be obtained through IRT and the baseline hazard functions will be allowed to vary across 
strata.


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Overall Response Rate
ORR estimates will be presented by treatment group along with exact 90% confidence intervals 
(Clopper and Pearson 1934). The estimation procedure will be repeated based on data for a 
subset of subjects in the FAS with measurable disease only at baseline.
Clinical Benefit Rate
CBR estimates will be presented by treatment group along with exact 90% confidence intervals.
Time to response
TTR will be summarized in 3-month intervals using descriptive statistics: mean, median, q1, 
q3, minimum and maximum. The analysis will be performed based on investigator assessment.
Duration of response
DOR will be summarized using descriptive statistics (count, mean, median, standard deviation, 
first and third quartile). The analysis will be performed based on investigator assessment.
ECOG performance status
Time windows will be defined for summaries of ECOG data. If more than one assessment is 
available in the same time window, the assessment closest to the planned date will be considered. 
If two assessments are obtained with the same time difference compared to the scheduled visit 
day, the assessment with the worst value will be considered. Data obtained at the end of 
treatment will be classified as other assessment in the corresponding time window. Note that 
only data collected under treatment (i.e. while the subject is treated and up to 7 days after last 
dose intake) will be included in the time to deterioration analysis. Post-treatment data will be 
summarized separately. The end of treatment assessment will be included if collected within 7 
days of the last dose intake. 
Time Window
Planned visit timing
Time Window Definition
Baseline
On or before Study Day 1
<= Study Day 1
Cycle 1 Day 1
Study Day 1
Study Days 1-8
Cycle 3 Day 1
Study Day 57
Study Days 50-64
Cycle 5 Day 1
Study Day 113
Study Days 106-120
Every 2 Cycles thereafter,
Cycle X Day 1; X>1
Study Day ((X-1)*4)*7+1
Study Days ((x-1)*4)*7-6 to 
((x-1)*4)*7+8
Note: EOT data visit are 
included if obtained within 7 
days of last non-0 dose intake. 
Study Day 1 = randomization date 


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Frequencies of subjects with ECOG PS values of 0, 1 or >=2 will be used to summarize the 
ECOG PS data at each time window. 
An analysis of the time to definitive deterioration of the ECOG PS by at least one category of 
the score from baseline will be performed. A deterioration will be considered definitive if no 
improvements in the ECOG PS are observed at subsequent measurement times during the 
treatment period following the time point at which the deterioration is observed. (Example 1: if 
the score is 1 at baseline and then 1, 2, 1, 2, 3 at study days 28, 57, 83, 115, 150, respectively, 
then the time to definitive worsening is 115 days. Example 2: if the score is 1 at baseline and 
then 1, 1, 2 at study days 28, 57, 83, respectively, with no assessment of the ECOG performance 
status after day 83, then the time to definitive worsening is 83 days.)
Death will be considered as worsening of the ECOG PS if it occurs close to the last available 
assessment where “close” is defined as being within twice the planned period between two 
assessments. Subjects who die after more than twice the planned period between two 
assessments will be censored at the date of their last assessment before the cut-off. This avoids 
overestimating the time to definitive worsening in subjects dying after an irregular assessment 
scheme. For example, if the last assessment is at week 6 and the subject dies at week 16, the 
definitive deterioration date will be week 16. On the other hand, if the last assessment is at week 
6 and the subject dies at week 22, which is after more than twice the planned period between 
two assessments (6 weeks) since the last assessment (at week 6), then the subject is censored 
for definitive deterioration and the censoring date will be week 6. Subjects receiving any further 
anti-neoplastic therapy prior to definitive worsening will be censored at their date of last 
assessment prior to the start of therapy. Subjects that have not worsened at the data cut-off point 
will be censored at the date of last assessment prior to the cutoff.
The Kaplan-Meier estimation method will be used to assess the distribution of time to definitive 
worsening in the ECOG PS score, stratified by treatment. The estimated treatment-specific 
median times to definitive worsening will be presented along with 90% confidence intervals. 
The stratified Cox regression model will be used to estimate the hazard ratio of a definitive 
worsening in the ECOG PS score, along with the associated 90% confidence interval, 
comparing the everolimus + exemestane combination therapy with placebo + everolimus 
therapy.  
2.7.3
Handling of missing values/censoring/discontinuations
The same statistical principles will be applied, and supportive analyses conducted as described 
in Section 2.5.3 for the handling of missing values/censoring/discontinuations.
The partial missing death date will be imputed following the rules in Section 5.4.4, but the 
complete missing death date won’t be imputed. For the purpose of analysis, the patient with a 
complete missing death date will be censored at the last contact date.
2.8
Safety analyses
For all safety analyses, the safety set will be used. The assessment of safety will be based on 
the frequency of adverse events and on the number of laboratory values that fall outside of pre-
determined ranges.


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The overall observation period will be divided into three mutually exclusive segments:

pre-treatment period: from day of subject’s informed consent to the day before first 
dose of study treatment

on-treatment period: from day of first dose of study medication to 30 days after last 
dose of study treatment

post-treatment period: starting on day 31 after last dose of study treatment.
Safety summary tables will only include on-treatment events/assessments, i.e., those collected 
no later than 30 days after the date of the last study treatment administration. All safety 
events/assessments will be listed and those collected in the pre- and post-treatment period will 
be flagged.
2.8.1
Adverse events (AEs)
2.8.1.1
Coding of AEs
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology Version 25.0.
2.8.1.2
Grading of AEs
AEs will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE v4.03 grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 AE is not necessarily twice as severe as a grade 1 AE).
If CTCAE grading is not available for an adverse event, the severity of mild, moderate, severe,
and life-threatening, death related to the AE corresponding to Grades 1 - 5, respectively, will 
be used. Information about any deaths (related to an Adverse Event or not) will also be collected 
though a Death form and “End of Post Treatment Disposition eCRF page”.
2.8.1.3
General rules for AE Reporting
AE summaries will include all AEs starting on or after study day 1 (i.e., on or after the day of 
the first intake of study treatment) and starting no later than 30 days after the last 
treatment/exposure date. All AEs, deaths and serious adverse events will be listed. AEs starting 
prior to study day 1 and AEs starting later than 30 days after the last treatment/exposure date 
will be flagged in the listings.
AEs will be summarized by presenting the number and percentage of subjects having at least 
one AE and having at least one AE in each body system/primary system organ class, and for 
each preferred term using MedDRA coding. A subject with multiple occurrences of an AE will 
be counted only once in the AE category.


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Separate AE summaries will be presented by primary system organ class, preferred term, and 
maximum CTC grade. A subject with multiple CTC grades for an AE will be summarized under 
the maximum CTC grade recorded for the event. In the summaries presented by grade, all AEs 
will be pooled regardless of whether they are CTC gradable or not, i.e., regardless of whether 
the question “CTC AE” on the Adverse Events eCRF is answered ‘Yes’ or ‘No’.
The frequency of CTC grade 3 and 4 AEs will be summarized separately as well as summaries
of all deaths and on-treatment deaths.
Any information collected (e.g., CTC grades, relatedness to study drug, action taken, etc.) will 
be listed as appropriate.
2.8.1.4
AE summaries
The following adverse event summaries will be produced:

Adverse events, regardlessd of study drug relationship by primary system organ class, 
preferred term and maximum CTC

Adverse events with suspected relationship to study drug by primary system organ class, 
preferred term and maximum CTC

Adverse events with an overall incidence rate of 5% or more in either treatment arm, 
regardless of study drug relationship by primary system organ class and preferred term 

CTC grade >=3 adverse events, regardless of study drug relationship by primary system 
organ class and preferred term

CTC grade >=3 adverse events with suspected study drug relationship by primary 
system organ class and preferred term

Deaths, by primary system organ class and preferred term

On-treatment deaths, by primary system organ class and preferred term

Serious adverse events, regardless of study drug relationship, by primary system organ 
class and preferred term

Serious adverse events with suspected study drug relationship, by primary system organ 
class and preferred term

Serious adverse events with fatal outcome

Non-Serious AEs (threshold>=5%), regardless of study drug relationship, by primary 
system organ class and preferred term

Adverse events leading to study drug discontinuation, regardless of study drug 
relationship, by primary system organ class and preferred term

Adverse events leading to study drug discontinuation, with suspected study drug 
relationship, by primary system organ class and preferred term

Adverse events requiring dose adjustment or study-drug interruption, regardless of study 
drug relationship, by primary system organ class and preferred term


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
Adverse events requiring additional therapy, regardless of study drug relationship, by 
grade, primary system organ class and preferred term
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment adverse events which are not serious adverse events with an incidence greater than 5% 
and on on-treatment serious adverse events and SAE suspected to be related to study treatment 
will be provided by system organ class and preferred term on the safety set population.
If for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.1.5
Adverse events of special interest / grouping of AEs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound everolimus. These groupings are defined using 
MedDRA terms, SMQs (standardized MedDRA queries), HLGTs (high level group terms), 
HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA 
queries, NMQ) may also be used. A NMQ is a customized group of search terms which defines 
a medical concept for which there is no official SMQ available or the available SMQ does not 
completely fit the need. It may include a combination of single terms and/or an existing SMQ, 
narrow or broad. For each specified AESI, number and percentage of subjects with at least one 
event of the AESI occurring during on treatment period will be summarized by treatment arm.
Time to first occurrence of AESI by variable was provided in the primary CSR (DCO: 05-May-
2020) and hence will not be repeated in the report. The updated information will be provided in 
the listings.
A Case Retrieval Sheet (CRS) with the exact composition of the AE groupings is to be used to
map reported AEs to the AESI groupings. This file may be updated (i.e. it is a living document) 
based on review of accumulating trial data, and therefore the groupings are also subject to 
potential change. Table 2-3 provides the latest groupings at the time of the finalization of the 
SAP. The most up-to-date version of the CRS will be used at the time of the analysis.
Table 2-3 
AESI groupings
AESI grouping
MedDRA category
Wound healing complications
CMQ


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Thrombotic and embolic events
Stomatitis
Severe infections
Pre-existing infection (reactivation, aggravation, or exacerbation)
Muscle wasting / Muscle loss
Renal failure
Hypophosphatemia
Hyperglycemia/ new onset of diabetes mellitus
Haemorrhages
Dyslipidemia
Cytopenia
Cardiac failure                                                                       
CMQ
CMQ
SOC
CMQ
CMQ
CMQ
SMQ
SMQ
SMQ
SMQ
CMQ
SMQ
Hypersensitivity (anaphylactic reactions)
Non infectious pneumonitis
SMQ
SMQ
2.8.2
Deaths
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. Summaries of all 
deaths and on-treatment deaths will be provided.
2.8.3
Laboratory data
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF.
All laboratory values will be converted into SI units and the severity grade calculated using 
appropriate common toxicity criteria (CTCAE).
Laboratory abnormalities that meet the criteria for Adverse Events should be followed until 
they have returned to normal or an adequate explanation of the abnormality is found.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 events (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious adverse event. 
A listing of laboratory values will be provided by laboratory parameter, subject, and treatment 
group. A separate listing will display notable laboratory abnormalities (i.e., newly occurring 
CTCAE grade 3 or 4 laboratory toxicities). The frequency of laboratory abnormalities will be 
displayed by parameter and treatment group.


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Laboratory data summaries will include all laboratory assessments collected no later than 30
days after the last treatment/exposure date. All laboratory assessments will be listed and those 
collected later than 30 days after the last treatment/exposure date will be flagged in the listings.
Laboratory data will be classified (by Novartis biostatistics/SAS programming) into CTC 
grades according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03. A severity grade of 0 will be assigned when the value is within normal limits. In the case 
when a local laboratory normal range overlaps into the higher (i.e., non-zero) CTC grade, the 
laboratory value will still be taken as within normal limits and assigned a CTC grade of zero.
The following rules will be applied: 

Conflict between normal range and grade definition: because many institutions have 
differences for normal ranges of metabolic laboratory and hematology values, the 
CTCAE often uses the terms 'Upper Limit of Normal (ULN)' and 'Lower Limit of 
Normal (LLN)' in lieu of actual numerical values. In some cases, an institution's LLN 
might be beyond the range specified for a grade. In this case, the institutional limits of 
normal should take precedence over the CTCAE values: the laboratory value will still 
be taken as within normal limits and assigned a CTC grade of zero.

For the few parameters having comparison to baseline in CTCAE grading definition 
(Fibrinogen, INR, Hemoglobin, Creatinine), the highest grade will be retained. In other 
words, in the particular case when a value is grade x as per CTC grade definition based 
on threshold/ranges and grade x+1 when comparing to baseline, grade x+1 is retained. 

Grade values will be integers from 1 to 4. Grade 5 will only be used if the laboratory 
abnormality results in Death.

For calcium, CTCAE grading is based on Corrected Calcium and not on Calcium. 
Corrected Calcium (CALC) will be calculated from Albumin and Calcium: Corrected 
Calcium (mg/dL) = Calcium (mg/dL) –0.8 [Albumin (g/dL)-4].

For creatinine clearance (CRCLCG parameter), no calculation of CTC grade will be 
done.
The following summaries will be produced for the laboratory data (by laboratory parameter and 
treatment):

Number and percentage of subjects with worst post-baseline CTC grade (regardless of 
the baseline status). Each subject will be counted only for the worst grade observed 
post-baseline.

Shift tables using CTC grades to compare baseline to the worst post-baseline value 
will be produced for hematology and biochemistry laboratory parameters with CTC 
grades.

For laboratory parameters where CTC grades are not defined, shift tables to the worst 
post-baseline value will be produced using the low/normal/high classifications based 
on laboratory reference ranges.
The following listings will be produced for the laboratory data:

Listing of subjects with laboratory values outside the laboratory reference ranges with 
values flagged to show the corresponding CTC grades and the classifications relative 
to the laboratory reference ranges. 


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
Listing of all laboratory data with values flagged to show the corresponding CTC 
grades and the classifications relative to the laboratory reference ranges.
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal 
ranges

Listing of notable laboratory abnormalities (i.e., newly occurring CTCAE grade 3 or 4 
laboratory toxicities)
For laboratory tests where grades are defined by CTCAE v4.03.

Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject
will be counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value

For laboratory tests where grades are not defined by CTCAE v4.03, shift tables using 
the low/normal/high/ (low and high) classification to compare baseline to the worst 
on-treatment value.
2.8.4
Other safety data
Data from other tests (e.g., electrocardiogram) will be summarized and listed, notable values 
will be flagged, and any other information collected will be listed as appropriate.
All assessments collected later than 30 days after the last treatment/exposure date will be 
flagged in the listings.
Any statistical tests performed to explore the data will be used only to identify any interesting 
comparisons that may warrant further consideration.
2.8.4.1
Vital signs
Vital sign assessments will be performed in order to characterize basic body function. The 
parameters expected to be collected include height (cm), weight (kg), body temperature (°C), 
pulse rate (beats per minute), systolic and diastolic blood pressure (mmHg).
The criteria for clinically notable abnormalities are defined as follows:
Clinically notable elevated values

systolic BP: ≥ 180 mmHg and an increase ≥ 20 mmHg from baseline

diastolic BP: ≥ 105 mmHg and an increase ≥ 15 mmHg from baseline

body temperature: ≥ 39.1°C


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
weight: increase from baseline of ≥ 10%

pulse rate: ≥ 120 bpm with increase from baseline ≥ 15 bpm
Clinically notable below normal values

systolic BP: ≤ 90 mmHg and a decrease ≥ 20 mmHg from baseline

diastolic BP: ≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline

body temperature: ≤ 35°C

weight: decrease from baseline of ≥ 10%

pulse rate: ≤ 50 bpm with decrease from baseline ≥ 15 bpm.
The following summaries will be produced for each vital sign parameter:

summary statistics for change from baseline to the worst post-baseline value (in both 
directions, i.e., from baseline to the highest post-baseline and from baseline to the lowest 
post-baseline value)

number and percentage of subjects with at least one post-baseline vital sign abnormality 
(in both directions, i.e., both elevated and below normal values).
In addition, the following two listings will be produced by treatment group:

subjects with clinically notable vital sign abnormalities

all vital sign assessments will be listed by subject and vital sign parameter.
In both listings, the clinically notable values will be flagged and also the assessments collected 
later than 30 days after the last treatment/exposure date will be flagged.
2.9
    Interim analysis
Not applicable.
3
Sample size calculation
Refer to CRAD001Y2202 SAP Addendum 1 for details. 
4
Change to protocol specified analyses
No change from protocol specified analysis was made.
5
Appendix
5.1
Baseline comparability
Appropriate descriptive statistics of baseline variables will be provided as in-text tables in the 
core CSR and also in Section 14 in the post-text tables. The summaries will be presented by 
treatment group, but no p-values will be provided.


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5.2
Time-to-event analyses
The following sections present a general methodology to be used to analyze the following time-
to-event variables:

Progression-free survival

Overall survival

Time to definitive deterioration in the ECOG score by one category of the score from 
baseline
5.2.1
Analysis of time to event data with ties
The STRATA statement in the SAS LIFETEST procedure will be used to analyze time-to-event 
data with ties. The SAS PHREG procedure with option TIES=EXACT will be used to fit the 
Cox proportional hazards model.
5.2.2
Kaplan-Meier survival function estimation
The survival function in each treatment group will be estimated using the Kaplan-Meier 
(product-limit) method as implemented in PROC LIFETEST (see Figure 4-2 below). In each 
treatment group, the estimated median PFS time, along with the approximate 90% confidence 
interval, will be obtained from the PROC LIFETEST output. The log-log transformation option 
available within PROC LIFETEST will be used to compute the confidence intervals. The 
Kaplan-Meier graphs will be obtained from the SAS software. The hazard ratio point and 
interval estimates will be displayed in the figures.
5.2.3
Hazard ratio estimation
The hazard ratio as a measure of treatment effect will be derived from the Cox proportional 
hazards model using SAS procedure PHREG with TIES=EXACT option in the MODEL 
statement. The stratified unadjusted Cox model will be used (where the baseline hazard 
function is allowed to vary across strata) for the primary andandsecondaryandandsecondary 
analyses, i.e., the MODEL statement will include the indicator of assignment to the everolimus 
+ exemestane arm as the only covariate, and the STRATA statement will include the 
stratification variable obtained through IRT.
The two-sided 90% asymptotic confidence interval for the hazard ratio will be based on the 
Wald test.
5.3
Median follow-up of the study
Median study follow-up (in months) in this study will be calculated as 
([analysis cut-off date] - [median randomization date] + 1)/30.4375, where 30.4375 is the 
average duration of a month in days: 365.25/12 ≈ 30.4375.
The median randomization date is obtained by first sorting all subjects in the FAS by the 
randomization dates, respectively, and then taking the date of the median subject (i.e., the 
subject in the middle of the sorted list in case of an odd number of subjects or the average 
between the two subjects in the middle of the sorted list in case of an even number of subjects).


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The time from last contact date to data cut-off date will be summarized by time intervals in 
increments of 6 weeks.
The number of subjects at risk of death and the number of deaths in intervals of time with 
increments of 6 weeks will be summarized during the course of the trial using the life table 
method. The Kaplan-Meier estimates of survival probabilities and associated standard errors 
will be provided.
5.4
Imputation rules
5.4.1
Study drug
The following rule should be used for the imputation of date of the last administration for a 
given study treatment component:
Scenario 1: If the date of last administration is completely missing and there is no EOT page
and no death date, the subject is considered as on-going:
The subject should be treated as on-going and the cut-off date should be used as the dose end 
date. The scenario is only used for interim analysis. 
Scenario 2: If the date of last administration is completely or partially missing and the EOT 
page is available:
Case 1: The date of last administration is completely missing, and the EOT  completion date 
is complete, then this latter date should be used.  
Case 2: Only Year(yyyy) of the date of last administration is available and yyyy < the year of 
EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the date of last administration sis available and yyyy  = the year 
of EOT date:
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for the date of last administration, 
and yyyy  = the year of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
Case 5: Both Year (yyyy) and Month(mm) are available for the date of last administration, 
and yyyy = the year of EOT and mm = the month of EOT date, use EOT date if day of EOT 
not missing or use the first day of month if date of EOT missing. 
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Subjects with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.


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5.4.2
AE date imputation
No imputation of missing or incomplete data will occur except for AE start dates in the 
determination of treatment emergence as described below:
If the date is completely missing, then it will be set to the first dose date.
If the day is missing, then the first day of the month will be used. If this date is before the first 
dose date and the months are the same, then the first dose date will be used.
If the day and month are missing, then the first day of the year will be used.  If this date is before 
the first dose date and the years are the same, then the first dose date will be used.
If the imputed AE onset date is after the AE stop date, then the AE stop date will be used.
The original partial or missing dates rather than the imputed dates will be presented in data 
listings.  Missing AE start times will not be imputed.
5.4.3
Concomitant medication date imputation
5.4.3.1
Prior therapies date imputation
For prior or concomitant medications, including rescue medications, incomplete (ie, partially 
missing) start dates and/or stop dates will be imputed.  When the start date and stop date are 
both missing start dates and/or stop dates will be imputed.  When the start date and stop date 
are both incomplete for a subject, impute the start date first.
Incomplete Start Dates
If the field of year is missing, then no value will be imputed.  The following rules will be applied 
to impute the incomplete start date, assuming year is available.  If the stop date is complete and 
the imputed start date is after the stop date, then the start date will be imputed using the stop 
date.
Missing Day and Month
If the year of the incomplete start date is the same as the year of the date of the first dose of 
study treatment, then the day and month of the date of the first dose of study treatment will be 
assigned to the missing fields.
If the year of the incomplete start date is before the year of the date of the first dose of study 
treatment, then December 31 will be assigned to the missing fields.
If the year of the incomplete start date is after the year of the date of the first dose of study 
treatment, then January 1 will be assigned to the missing fields.
Missing Month Only
The day will remain the same as observed and the month will be replaced according to the
procedure in the preceding subsection.


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Missing Day Only
If the month and year of the incomplete start date are the same as the month and year of the date 
of the first dose of study treatment, then the day of the date of the first dose of study treatment 
will be assigned to the missing day.
If either the year is before the year of the date of the first dose of study treatment or if both years 
are the same but the month is before the month of the date of the first dose of study treatment, 
then the last day of the month will be assigned to the missing day.
If either the year is after the year of the date of the first dose of study treatment or if both years 
are the same but the month is after the month of the date of the first dose of study treatment, 
then the first day of the month will be assigned to the missing day.
Incomplete Stop Dates 
If the field of year is missing, then no value will be imputed.  The following rules will be applied 
to impute the missing numerical fields, assuming year is available.  If the date of the last dose 
of study treatment is missing, then replace it with the last visit date.  If the imputed stop date is 
before the start date (imputed or non-imputed start date), then the stop date will be imputed 
using the start date.
Missing Day and Month
If the year of the incomplete stop date is the same as the year of the date of the last dose of study 
treatment, then the day and month of the date of the last dose of study treatment will be assigned 
to the missing fields.
If the year of the incomplete stop date is before the year of the date of the last dose of study 
treatment, then December 31 will be assigned to the missing fields.
If the year of the incomplete stop date is after the year of the date of the last dose of study 
treatment, then January 1 will be assigned to the missing fields.
Missing Month Only
The day will be the same as observed and the month will be replaced according to the procedure 
in the preceding subsection.
Missing Day Only
If the month and year of the incomplete stop date are the same as the month and year of the date 
of the last dose of study treatment, then the day of the date of the last dose of study treatment 
will be assigned to the missing day.
If either the year is before the year of the date of the last dose of study treatment or if both years 
are the same but the month is before the month of the date of the last dose of study treatment, 
then the last day of the month will be assigned to the missing day.
If either the year is after the year of the date of the last dose of study treatment or if both years 
are the same but the month is after the month of the date of the last dose of study treatment, 
then the first day of the month will be assigned to the missing day.


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5.4.3.2
Post therapies date imputation
The date imputation method will be similar to the above section.
5.4.4
Death date imputation
If the day is missing, then a) if the year and month of EOT is the same as year and month of 
death, then use the EOT date; b) if the year of death is later than year of EOT, then use the first 
day of the first month in this year; c) if the year of the death is the same as year of EOT and 
month is later than month of EOT, then use the first day of the month. If the month and day are 
missing, then a) if the year of EOT is the same as year of death, then use the EOT date; b) if the 
year of death is later than the year of EOT, then use the first day of the first month in this year 
(JAN01). 
5.5
AEs coding/grading
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
AEs will be graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE v4.03 grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 AE is not necessarily twice as severe as a grade 1 AE).
If CTCAE grading is not available for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding to Grades 1 - 5, respectively, will
be used. Information about any deaths (related to an Adverse Event or not) will also be collected 
though a Death form.
5.6
Laboratory parameters derivations
All laboratory values will be converted into SI units and the severity grade calculated using 
appropriate common toxicity criteria (CTCAE).
A listing of laboratory values will be provided by laboratory parameter, subject, and treatment 
group. A separate listing will display notable laboratory abnormalities (i.e., newly occurring 
CTCAE grade 3 or 4 laboratory toxicities). The frequency of laboratory abnormalities will be 
displayed by parameter and treatment group.
Laboratory data summaries will include all laboratory assessments collected no later than 30 
days after the last treatment/exposure date. All laboratory assessments will be listed and those 
collected later than 30 days after the last treatment/exposure date will be flagged in the listings.
Laboratory data will be classified (by Novartis biostatistics/SAS programming) into CTC 
grades according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03. A severity grade of 0 will be assigned when the value is within normal limits. In the case 


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For business use only
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Final CSR SAP
Study No. CRAD001Y2202
when a local laboratory normal range overlaps into the higher (i.e., non-zero) CTC grade, the 
laboratory value will still be taken as within normal limits and assigned a CTC grade of zero.


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For business use only
Page 34 of 34
Final CSR SAP
Study No. CRAD001Y2202
3
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