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
Phase: PHASE2
Conditions: Advanced Breast Cancer
Sponsor: Novartis Pharmaceuticals

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.