A National Phase IIIb, Multi-center, Open Label Study for Women and Men With Hormone-receptor Positive, HER-2 Negative Locally Advanced or Metastatic Breast Cancer Treated With Ribociclib (LEE011) in Combination With Letrozole
Phase: PHASE3
Conditions: Advanced Metastatic Breast Cancer
Sponsor: Novartis Pharmaceuticals

Cli ni c al D e v el o p m e nt 
L E E 0 1 1 ( Ri b o ci cli b) 
  Cli ni c al Tri al Pr ot o c ol C L E E 0 1 1 X D E 0 1  / N C T 0 3 0 9 6 8 4 7
A n ati o n al p h ase III b, m ulti- ce nter, o pe n l a bel st u d y f or 
w o me n a n d me n wit h h or m o n e-rece pt or p ositi ve, H E R 2-
ne g ati ve l oc all y a d v a nce d or met ast atic bre ast c a ncer 
tre ate d wit h ri b ocicli b ( L E E 0 1 1) i n c o m bi n ati o n wit h 
letr oz ole  
RI B E C C A
Ri b ocicli b  f or t he trE at me nt of a d va n C e d breast C a ncer 
A ut h or s 
  
D o c u m e nt t y p e  
O n c ol o g y Cli ni c al Tri al Pr ot o c ol 
E U D R A C T n u m b er   
2 0 1 6- 0 0 2 5 5 6- 2 4 
V er si o n n u m b er  
0 4 ( A m e n d m e nt 4) 
D e v el o p m e nt p h a s e  
III B 
D o c u m e nt st at u s  
Fi n al 2 0 1 9- 0 6- 0 5 
R el e a s e d at e 
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 
Te m plate versi o n 1 5- Fe b- 2 0 1 2

N o v arti s 
C o nfi d e nti al 
P a g e 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Si g n at ure P a ges 
 
C o m p o u n d n a me / n u m ber: Ri b ocicli b / L E E 0 1 1 
Pr ot oc ol n u m ber: C L E E 0 1 1 X D E 0 1 
 
A p pr o ve d b y t he f oll o wi n g 
 
 
Si g n at ures of N o v artis Pers o n nel: 
 
 
 
Dr. 
 
(
) 
Si g nat ure  
  
Date 
 
 
 
 
Dr. 
 
( Trial Statisticia n) 
Si g nat ure  
  
Date 
 
 
 
 
Dr.  
   
(
) 
Si g nat ure  
  
Date 
 
 
 
 
Dr.
  
( 
 Nati o nal Pr ot oc ol Re vie w 
C o m mittee) 
 
 
Si g nat ure  
  
Date 

N o v arti s 
C o nfi d e nti al 
P a g e 3 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Si g n at ur e of Pri n ci p al I n v e sti g at or: 
 
 
 
 
Pr of. Dr. me d. 
 
( Pri nci pal I n vesti gat or) 
 
Si g nat ure   
  
Date 
 
Si g n at ure P a ge f or I n vesti g at or 
 
C o m p o u n d n a me / n u m ber: Ri bc ocicli b / L E E 0 1 1 
 
Pr ot oc ol n u m ber: C L E E 0 1 1 X D E 0 1 
 
 
I ha ve rea d t his pr ot oc ol a n d a gree t o c o n d uct t his trial i n acc or da nce wit h all sti p ulati o ns of 
t he pr ot oc ol a n d i n acc or da nce wit h t he pri nci ples o utli ne d i n t he Declarati o n of Helsi n ki. 
 
 
 
 
 
t y pe/ pri nt na me   
(I n vesti gat or) 
 
Si g nat ure   
  
Date 
 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 4 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
T a bl e of c o nt e nt s 
Ta ble of c o nte nts ............................................. ....................................................... 4 
List of fi g ures ......................................................................................................... 7  
List of ta bles ........................................................................................................... 7  
List of a b bre viati o ns ............................................................................................... 8  
Gl ossar y of ter ms ............................................. ..................................................... 1 0 
Pr ot oc ol s u m mar y ................................................................................................. 1 1  
1  
Bac k gr o u n d ........................................................................................................... 2 0  
1. 1  
O ver vie w of disease pat h o ge nesi s, e pi de mi ol o g y a n d c urre nt treat me nt . 2 0 
1. 1. 1  
R ole of t he estr o ge n pat h w a y i n breast ca ncer ......................... 2 0  
1. 1. 2  
R ole of cell c ycle relate d ge nes a n d pr otei ns i n ca ncer ....... .... 2 0 
1. 1. 3  
R ole of c ycli n D ki nases i n hi bit ors i n breast ca ncer .......... ...... 2 1 
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 2  
1. 2. 1  
O ver vie w of ri b ocicli b ........................................ ..................... 2 2 
1. 2. 2  
O ver vie w of letr oz ole ............................................................... 2 8  
1. 2. 3  
O ver vie w of g osereli n .............................................................. 2 9  
1. 2. 4  
L o w p ote ntial f or i nteracti o n bet w ee n ri b ocicli b a n d letr oz ole 2 9  
1. 2. 5  
L o w p ote ntial f or dr u g- dr u g i nt eracti o ns wit h g osereli n ....... .. 3 0 
1. 2. 6  
S u m mar y of a vaila ble res ults f r o m patie nts treate d wit h t he 
c o m bi nati o n of ri b ocicli b 6 0 0 m g a n d letr oz ole 2. 5 m g dail y . 3 0  
2  
Rati o nale ............................................................................................................... 3 6  
2. 1  
St u d y rati o nale a n d p ur p ose...................................................................... 3 6  
2. 2  
Rati o nale f or t he st u d y desi g n ................................ .................................. 3 7 
2. 3  
Rati o nale f or d ose a n d re gi me n selecti o n ...................... ........................... 3 8 
2. 4  
Rati o nale f or c h oice of c o m bi nati o n dr u gs ..................... .......................... 3 8 
3  
O bjecti ves a n d e n d p oi nts ...................................................................................... 3 9  
4  
St u d y desi g n ......................................................................................................... 4 3  
4. 1  
Descri pti o n of st u d y desi g n ...................................................................... 4 3  
4. 2  
Ti mi n g of i nteri m a nal yses .................................... ................................... 4 4 
4. 3  
Defi niti o n of e n d of t he st u d y ................................ ................................... 4 4 
4. 4  
Earl y st u d y ter mi nati o n........................................ ..................................... 4 4 
5  
P o p ulati o n .................................................... ......................................................... 4 4 
5. 1  
Patie nt p o p ulati o n ............................................ ......................................... 4 4 
5. 2  
I ncl usi o n criteria ....................................................................................... 4 5 
5. 3  
E xcl usi o n criteria ............................................ .......................................... 4 7 
6  
Treat me nt ..................................................... ......................................................... 4 9 
6. 1  
St u d y treat me nt ......................................................................................... 4 9  
6. 1. 1  
D osi n g re gi me n ................................................ ........................ 5 0 
6. 1. 2  
Treat me nt d urati o n ................................................................... 5 1  
6. 2  
D ose m o dificati o ns ............................................ ....................................... 5 1 

N o v arti s 
C o nfi d e nti al 
P a g e 5 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
6. 2. 1  
D ose m o dificati o n a n d d ose dela y .............................. ............. 5 1 
6. 2. 2  
A ntici pate d ris ks a n d safet y c o ncer ns of t he st u d y dr u g ....... ... 5 9 
6. 3  
C o nc o mita nt me dicati o ns ....................................... .................................. 5 9 
6. 3. 1  
Per mitte d c o nc o mita nt t hera p y ................................. ............... 5 9 
6. 3. 2  
Per mitte d c o nc o mita nt t hera p y re q uiri n g ca uti o n a n d/ or 
acti o n ........................................................................................ 6 0 
6. 3. 3  
Pr o hi bite d c o nc o mita nt t hera p y ................................ ............... 6 1 
6. 3. 4  
Dr u gs wit h Q T pr ol o n gati o n .................................... ................ 6 1 
6. 4  
Patie nt n u m beri n g, treat me nt a ssi g n me nt or ra n d o mizati o n .................... 6 1 
6. 4. 1  
Patie nt n u m beri n g .................................................................... 6 1  
6. 4. 2  
Treat me nt assi g n me nt or ra n d o mizati o n ......................... ......... 6 2 
6. 4. 3  
Treat me nt bli n di n g ............................................ ....................... 6 2 
6. 5  
St u d y dr u g pre parati o n a n d dis pe nsati o n ....................... ........................... 6 2 
6. 5. 1  
St u d y dr u g pac ka gi n g a n d la beli n g ............................. ............. 6 2 
6. 5. 2  
Dr u g s u p pl y a n d st ora ge ....................................... .................... 6 3 
6. 5. 3  
St u d y dr u g c o m plia nce a n d acc o u nta bilit y ...................... ........ 6 3 
6. 5. 4  
Dis p osal a n d destr ucti o n .......................................................... 6 4  
6. 6  
St u d y dr u g disc o nti n uati o n ....................................................................... 6 4  
7  
Visit sc he d ule a n d assess me nts ............................................................................ 6 5  
7. 1  
St u d y fl o w a n d visit sc he d ule ................................. .................................. 6 5 
7. 1. 1  
Scree ni n g ..................................................... ............................. 6 9 
7. 1. 2  
Treat me nt peri o d .............................................. ........................ 7 0 
7. 1. 3  
E n d of treat me nt visit i ncl u di n g st u d y c o m pleti o n a n d 
pre mat ure wit h dra wal .......................................... ..................... 7 0 
7. 1. 4  
F oll o w u p peri o d ...................................................................... 7 1  
7. 1. 5  
S ur vi val 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 3 
7. 2. 3  
Bi o mar kers .................................................... ........................... 7 7 
7. 2. 4  
Patie nt re p orte d o utc o mes ..................................... ................... 8 0 
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 2  
8. 2. 1  
Defi niti o ns ................................................................................ 8 2  
8. 2. 2  
Re p orti n g ..................................................... ............................. 8 3 
8. 3  
Pre g na ncies ................................................... ............................................ 8 4 
8. 4  
War ni n gs a n d preca uti o ns....................................... .................................. 8 4 

N o v arti s 
C o nfi d e nti al 
P a g e 6 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
8. 5  
Steeri n g C o m mittee ............................................ ...................................... 8 4 
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 5 
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 6 
1 0   Statistical met h o ds a n d data a nal ysis ......................... .......................................... 8 6 
1 0. 1  
A nal ysis sets ............................................................................................. 8 7  
1 0. 1. 1  
F ull A nal ysis Set ............................................. ......................... 8 7 
1 0. 1. 2  
Safet y Set ................................................................................. 8 7  
1 0. 1. 3  
Per- Pr ot oc ol Set .............................................. ......................... 8 7 
1 0. 2  
Patie nt de m o gra p hics/ ot her ba seli ne c haracteristics ................................ 8 7 
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 8 
1 0. 4. 1  
Varia ble .................................................................................... 8 8  
1 0. 4. 2  
Statistical h y p ot hesis, m o de l, a n d met h o d of a nal ysis ............. 8 9 
1 0. 4. 3  
Ha n dli n g of missi n g val ues/ce ns o ri n g/ disc o nti n uati o ns .......... 8 9 
1 0. 4. 4  
S u p p orti ve a nal yses .................................................................. 8 9  
1 0. 5  
Sec o n dar y o bjecti ves ................................................................................ 8 9  
1 0. 5. 1  
Efficac y (sec o n dar y) .......................................... ...................... 8 9 
1 0. 5. 2  
Safet y o bjecti ves ...................................................................... 9 0  
1 0. 5. 3  
Bi o mar kers .................................................... ........................... 9 2 
1 0. 5. 4  
Patie nt-re p orte d o utc o mes ........................................................ 9 3  
1 0. 6  
E x pl orat or y o bjecti ves .............................................................................. 9 3  
1 0. 7  
I nteri m a nal ysis ......................................................................................... 9 3 
1 0. 8  
Sa m ple size calc ulati o n............................................................................. 9 3  
1 0. 9  
P o wer f or a nal ysis 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 m i nistrati ve pr oce d ures ......................................... 9 4 
1 1. 1  
Re g ulat or y a n d et hical c o m plia nce ............................. .............................. 9 4 
1 1. 2  
Res p o nsi bilities of t he i n v esti gat or a n d I R B/I E C/ R E B .......... .................. 9 4 
1 1. 3  
I nf or me d c o nse nt pr oce d ures .................................................................... 9 4 
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 5 
1 1. 7  
C o nfi de ntialit y of st u d y d oc u m e nts a n d patie nt rec or ds ........ .................. 9 6 
1 1. 8  
A u dits a n d i ns pecti o ns .............................................................................. 9 6  
1 2   Pr ot oc ol a d here nce ............................................................................................... 9 6  
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  

N o v arti s 
C o nfi d e nti al 
P a g e 7 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
1 4   A p pe n dices ......................................................................................................... 1 0 2  
1 4. 1  
A p pe n di x 1 – C o nc o mita nt Me dicati o ns .......................... ...................... 1 0 2 
1 4. 2  
A p pe n di x 2: G ui deli nes f or res p o nse, d urati o n of o verall res p o n se, 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 ( base d o n R E CI S T 
1. 1) .......................................................................................................... 1 0 5  
1 4. 3  
A p pe n di x 3: Patie nt re p orte d o utc o mes .................................................. 1 2 8  
 
Li st of fi g ur e s 
Fi g ure 4- 1  
St u d y desi g n ............................................................................. 4 3  
 
Li st of t a bl e s 
Ta ble 1- 1  
Seri o us a d verse e ve nts wit h a s us pecte d ca usal relati o ns hi p 
wit h ri b ocicli b si n gle a ge nt .................................. .................... 2 6 
Ta ble 1- 2  
A d verse e ve nts s us pecte d t o be  st u d y dr u g-relate d ( All- Gra de 
≥1 5 % i n all pts) ........................................................................ 3 0  
Ta ble 1- 3  
P K Para meters of ri b ocicli b a n d letr oz ole i n all patie nts 
( N = 4 7) ...................................................................................... 3 1 
Ta ble 1- 4  
S u m mar y of best o verall res p o nse f o r t he treat me nt- nai ve gr o u p 
per i n vesti gat or assess me nt ................................... ................... 3 2 
Ta ble 1- 5  
A d verse e ve nts wit h s us pecte d r elati o ns hi p t o st u d y treat me nt 
i n st u d y ( C L E E 0 1 1 A 2 3 0 1) ...................................................... 3 5 
Ta ble 3- 1  
O bjecti ves a n d relate d e n d p oi nts ............................................. 4 0  
Ta ble 6- 1  
D ose a n d treat me nt sc he d ule ................................... ................. 5 0 
Ta ble 6- 2  
D ose M o dificati o n g ui deli nes .................................. ................ 5 2 
Ta ble 6- 3  
Ri b ocicli b d ose a dj ust me nt a n d m a na ge me nt rec o m me n dati o ns 
f or he mat ol o gical a d verse reacti o ns ......................................... 5 2 
Ta ble 6- 4  
Ri b ocicli b d ose a dj ust me nt a n d ma na ge me nt rec o m me n dati o n 
f or he patic t o xicities ................................................................. 5 4 
Ta ble 6- 5  
Ri b ocicli b d ose a dj ust me nt a n d ma na ge me nt rec o m me n dati o n 
f or Q Tc pr ol o n gati o n................................................................ 5 7 
Ta ble 6- 6  
Ri b ocicli b d ose a dj ust me nt a n d ma na ge me nt rec o m me n dati o n 
f or all ot her a d verse reacti o ns .................................................. 5 8 
Ta ble 6- 7  
Pre parati o n a n d dis pe nsi n g ...................................................... 6 2  
Ta ble 7- 1  
Visit e val uati o n sc he d ule ..................................... .................... 6 6 
Ta ble 7- 2  
E C O G Perf or ma nce Stat us Scale ................................. ............ 7 5 
Ta ble 7- 3  
L ocal Cli nical la b orat or y pa ra meters c ollecti o n pla n .............. 7 5 
Ta ble 7- 4  
E C G c ollecti o n pla n ................................................................. 7 7  
Ta ble 7- 5  
Bi o mar ker sa m ple c ollecti o n pla n .............................. .............. 7 8 
Ta ble 1 4- 1  
List of pr o hi bite d me dicati o ns d u ri n g st u d y dr u g treat me nt .. 10 2  
Ta ble 1 4- 2  
List of me di cati o ns t o be use d wit h ca uti o n d uri n g st u d y dr u g 
treat me nt ................................................................................. 1 0 4 

N o v arti s 
C o nfi d e nti al 
P a g e 8 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 9 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Li st of a b br e vi ati o n s 
 
a B C 
A E 
A d v a n c e d Br e a st C a n c er 
A d v er s e E v e nt 
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 S T  
A s p art at e a mi n otr a n sf er a s e/ g l ut a mi c o x al o a c eti c tr a n s a mi n a se/ G O T 
β- h C G  
β- s u b u nit of h C G g o n a d ot r o pi n – fr e e h C G g o n a d otr o pi n 
B L R M  
B a y e si a n L o gi sti c R e gr e s si o n M o d el  
C B R 
CI S H 
Cli ni c al b e n efit r at e 
C hr o m o g e n-i n sit u- H y bri di si er u n g 
C N S 
C e ntr al n er v o u s s y st e m 
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 S R 
a d d e n d u m 
C T 
D DI 
D F S 
A n a d d e n d u m t o Cli ni c al St u d y R e p o rt ( C S R) t h at c a pt ur e s all t he a d diti o n al 
i nf or m ati o n t h at i s n ot i n cl u d e d i n t h e C S R 
C o m p ut e d t o m o gr a p h y 
Dr u g- Dr u g-I nt er a cti o n 
Di s e a s e-fr e e s ur vi v al 
D L T 
D o s e Li miti n g T o xi cit y 
D S & E  
Dr u g S af et y a n d E pi d e mi ol o g y 
E C G 
El e ctr o c ar di o gr a m 
E C O G  
E a st er n c o o p er a ti v e o n c ol o g y gr o u p 
E R 
FI S H 
F S H 
G B M 
E str o g e n r e c e pt or 
Fl u or e s z e n z-i n- sit u- H y bri di z ati o n 
f olli k el sti m uli er e n d e s H or m o n 
Gli o bl a st o m a m ultif or m e 
i. v. 
i ntr a v e n o u s(l y) 
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 R B 
I n stit uti o n al R e vi e w B o ar d 
L P F T 
L P F V 
L P L T 
L P L V 
L a st P ati e nt Fir st Tr e at m e nt 
L a st P ati e nt Fir st Vi sit 
L a st P ati e nt L a st Tr e at m e nt 
L a st P ati e nt L a st Vi sit 
 
 
 
M T D 
M a xi m u m T ol er at e d D o s e 
N CI- C T C A E  
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 g y crit eri a f or a d v er s e e v e nt s 
N C R N P D  
n eit h er c o m pl et e r e s p o n s e n or pr o gr e s si v e di s e a s e 
P D 
P F S 
Pr o gr e s si v e di s e a s e 
Pr o gr e s si o n Fr e e S ur vi v al 
p. o. 
p er o s / b y m o ut h/ or all y 
P HI 
Pr ot e ct e d H e alt h I nf or m ati o n 

N o v arti s 
C o nfi d e nti al 
P a g e 1 0 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
P g R 
P R 
Q T c F 
Pr o g e st er o n e r e c e pt or 
P arti al R e s p o n s e 
Q T c orr e ct e d f or H R u si n g Fri d eri ci a' s m et h o d 
O R R 
O v er all r e s p o n s e r at e 
O S 
O v er all s ur vi v al 
R A P 
T h e R e p ort a n d A n al y si s Pl a n ( R A P) i s a r e g ul at or y d o c u m e nt  w hi c h pr o vi d e s 
e vi d e n c e of pr e pl a n n e d a n al y s e s 
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 
S A E 
S eri o u s A d v er s e E v e nt 
S D 
SI S H 
S m P C 
S O D   
St a bl e di s e a s e 
sil v er-i n sit u- H y bri di s ati o n 
S u m m ari e s of Pr o d u ct C h ar a ct eri sti c s 
S u m of Di a m et er 
S O P 
T T F 
T T P 
U N K 
St a n d ar d O p er ati n g Pr o c e d ur e 
Ti m e t o tr e at m e nt f ail ur e 
Ti m e t o Pr o gr e s si o n 
U n k n o w n 

N o v arti s 
C o nfi d e nti al 
P a g e 1 1 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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 stu d y 
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 a l 
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 etit i 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) 
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 n t 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 ed (i. e. pri or t o st arti n g a n y o f 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 tre 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 ho 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 th 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 t h 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 
Pr e m at ur e p ati e nt 
wit h dr a w al 
P oi nt/ti m e w h e n t h e p ati e nt e xit s fr o m t h e st u d y pri or t o t h e 
pl a n n e d c o m pl eti o n of all st u d y tr e at m e nt a d mi ni str ati o n a n d/ or  
a s s e s s m e nt s; at t hi s ti m e all st u d y tr e at m e nt a d mi ni str ati o n i s  
di s c o nti n u e d a n d n o f urt h er a s s e s s m e nt s ar e pl a n n e d, u nl e s s t h e 
p ati e nt will b e f oll o w e d f or pr o gr e s si o n a n d/ or s ur vi v al 
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 of 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 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 s t 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 mp ort a nt t o j u d g e i n v e sti g ati o 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 stig 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 nt l 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; m a y or m a y n ot al s o b e t h e p oi nt/ti m e of pr e m atur e 
p ati e nt wit h dr a w al 
V ari a bl e 
I d e ntifi er u s e d i n th 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 

N o v arti s 
C o nfi d e nti al 
P a g e 1 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Pr ot o c ol s u m m ar y 
 
Pr ot o c ol n u m b er 
C L E E 0 1 1 X D E 0 1 
Titl e 
A nati o nal p hase III b, m ulti-ce nter, o pe n la bel st u d y f or w o me n  
a n d me n wit h h or m o ne-rece pt or p ositi ve, H E R 2- ne gati ve l ocall y 
a d va nce d  or  metastatic  breast  ca ncer  treate d  wit h  ri b ocicli b 
( L E E 0 1 1) i n c o m bi nati o n wit h letr oz ole:  
RI B E C C A  ( Ri b ocicli b  f or  t he  t r Eat me nt  of  a d va n Ce d  breast 
C A ncer)  
Bri ef titl e 
St u d y  of  ri b ocicli b  i n  c o m bi na ti o n  wit h  letr oz ole  f or  t he 
treat me nt of a d va nce d breast ca ncer  
S p o n s or  a n d  Cli ni c al 
P h a s e 
N o vartis  
P hase III b  
I n v e sti g ati o n t y p e 
Dr u g;  
St u d y t y p e 
I nter ve nti o nal 
P ur p o s e a n d r ati o n al e 
T o s u p p ort t he e nc o ura gi n g res ults of M o na L E Esa- 2, t he mai n 
p ur p ose of t his st u d y is t o c ollect a d diti o nal efficac y a n d saf et y 
data f or t he c o m bi nati o n of ri b oc icli b a n d letr oz ole i n a patient 
p o p ulati o n a d diti o nal t o t he M o na L E Esa- 2 st u d y a n d t o pr o vi de 
access  t o  ri b ocicli b  t o  patie nts  f or  w hic h  a vaila ble  treat me nt 
o pti o ns are n ot satisfact or y tr eat me nt alter nati ves u ntil t he d r u g 
is a p pr o ve d f or t his i n dicati o n. F urt her m ore, t his trial ai ms at 
c ollecti n g data f or t he c o m bi nati o n of ri b ocicli b a n d letr oz ole  i n 
t he c o nte xt of c urre nt l ocal ro uti ne t hera p y al g orit h ms f or t he 
treat me nt of metastatic an d a d va nce d breast ca ncer. 
 
Precli nical  a n d  earl y  cli nical  data  s u g gests  t hat  C D K 4/ 6 
i n hi biti o n pla y a ke y r ole i n t he treat me nt of s u bsets of breast 
ca ncer  b y  a br o gati n g  e n d ocri ne-r esista nt  cell  pr oliferati o n. 
T heref ore, t he a d diti o n of a C D K 4 / 6 i n hi bit or s uc h as ri b ociclib 
t o  sta n dar d  e n d ocri ne t hera p y  (letr oz ole  or  letr oz ole  a n d 
g osereli n  f or  pre me n o pa usal  pat ie nts,  res pecti vel y)  is  a 
pr o misi n g  t hera pe utic  a p pr oac h  t hat  will  be  e x pl ore d  i n  t his 
st u d y.  Letr oz ole  is  t he  AI  t hat  will  ser ve  as  e n d ocri ne 
c o m bi nati o n  part ner  i n  t his  st u d y.  It  has  bee n  e xte nsi vel y 
st u die d  i n  t he  p ost me n o pa usal  setti n g  a n d  was  c h ose n  as 
e n d ocri ne  c o m bi nati o n  part ner  i n   t he  pi v otal  p hase  III  trial 
M o na L E Esa- 2. 
 
T he prese nt m ulti-ce nter, o pe n-la bel, si n gle-ar m st u d y ai ms t o 
e val uate  t he  efficac y  a n d  safet y,  a n d  q ualit y  of  life  f or  t he 
c o m bi nati o n of ri b ocicli b a n d letr oz ole i n a patie nt p o p ulati o n  
i n a d diti o n t o t he M o na L E Esa- 2 st u d y, i.e. i n patie nts pretreate d 
wit h o ne li ne of c he m ot hera p y a n d/ or a ma xi m u m of t w o li nes 
of  e n d ocri ne  t hera p y,  i n  pre me n o pa usal  patie nts,  wit h o ut 

N o v arti s 
C o nfi d e nti al 
P a g e 1 3 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
li mitati o ns re gar di n g t he pr o gressi o n free i nter val after a dj u va nt 
t hera p y  as  well  as  i n  me n  wit h  h or m o ne  rece pt or  p ositi ve, 
H E R 2- ne gati ve breast ca ncer. T he e x pl orat or y o bjecti ves of t his  
st u d y will c ollect data, are h y p ot hesis ge nerati n g a n d will c o ver 
a nal yses  of  cr ucial  scie ntific  i nterest, 
 
 
 
 
 
Pri m ar y O bj e cti v e  
 T he pri mar y o bjecti ve of t his st u d y is t he assess me nt of t he 
cli nical be nefit rate f or t he t otal p o p ulati o n a n d f or c o h orts A 
a n d B se paratel y: 
o  T o assess t he cli nical be nefit rate ( C B R) after 2 4 
wee ks  f or  ri b ocicli b  ( L E E 0 1 1)  i n  c o m bi nati o n 
wit h  letr oz ole  a m o n g  p ost me n o pa usal  w o me n 
a n d  me n  w h o  recei ve d  n o  pri or  treat me nt  f or 
a d va nce d  disease.  (a p pr o x. 7 0 %  of  patie nts, 
c o h ort A). 
o  T o assess t he cli nical be nefit rate ( C B R) after 2 4 
wee ks  f or  ri b ocicli b  ( L E E 0 1 1)  i n  c o m bi nati o n 
wit h  letr oz ole  a n d  g osereli n  a m o n g  pre-,  a n d 
peri me n o pa usal  w o me n  w h o  recei ve d  n o  pri or 
treat me nt  f or  a d va nce d  disease  as  well  as  pre-, 
peri-  a n d  p ost me n o pa usal  w o me n  a n d  me n  w h o 
recei ve d  pri or  treat me nt  f or  a d va nce d  disease 
(a p pr o x. 3 0 % of patie nts, c o h ort B). 
S e c o n d ar y O bj e cti v e s 
 T o assess t he cli nical be nef it rate ( C B R) after 2 4 wee ks 
a m o n g pre-, peri- a n d p ost me n o pa usal w o me n a n d me n 
wit h o ut pri or t hera p y f or a d va nce d disease. 
 T o assess t he cli nical be nefit rate ( C B R) after 2 4 wee ks 
f or  ri b ocicli b  a m o n g  pre-,  peri-  a n d  p ost me n o pa usal 
w o me n  a n d  me n  w h o  were  pretreate d  f or  a d va nce d 
disease. 
 T o  assess  pr o gressi o n-free  s ur vi val  ( P F S)  f or  t he  t hree 
differe nt  p o p ulati o ns  ( p ost me n o pa usal  w o me n  or  me n 
wit h o ut  pri or  treat me nt  f or  a d va nce d  disease,  pre-  or 
peri me n o pa usal  w o me n  wit h o ut  pri or  treat me nt  f or 
a d va nce d disease, pre-, peri-, or p ost me n o pa usal w o me n 
or me n pretreate d f or  a d va nce d disease). 
 O verall s ur vi val ( O S) f or t h e t hree differe nt p o p ulati o ns, 
defi ne d as t he ti me fr o m date of start of treat me nt t o 
date of deat h d ue t o a n y ca use.  
 
 O verall res p o nse rate ( O R R)  f or t he t hree differe nt 
p o p ulati o ns, defi ne d as c o m p lete res p o nse or partial 
res p o nse as defi ne d b y R E CI S T 1. 1 

N o v arti s 
C o nfi d e nti al 
P a g e 1 4 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 T o e val uate t he safet y a n d t olera bilit y of ri b ocicli b i n 
c o m bi nati o n wit h letr oz ole (a n d g osereli n i n 
pre me n o pa usal patie nts). 
 T o e val uate patie nt re p orte d o utc o mes f or healt h-relate d 
q ualit y of life. 
St u d y d e si g n 
T his  is  a  nati o nal,  m ulti-ce nter,  o pe n-la bel,  p hase  III b  trial t o 
deter mi ne t he efficac y a n d safet y of treat me nt wit h ri b o ci cli b 
( L E E 0 1 1) pl us letr oz ole i n w o me n a n d me n wit h H R +, H E R 2-
ne gati ve a d va nce d or metastatic breast ca ncer. 
P o p ul ati o n 
T his  st u d y  will  be  perf or me d  i n  5 0 0  patie nts  wit h  h or m o ne 
rece pt or  p ositi ve  l ocall y  a d va nce d  or  metastatic  breast  ca ncer 
pr o gressi n g as defi ne d b y:  
 C o h ort A: a p pr o x. 7 0 % of patie nts m ust be p ost me n o pa usal 
w o me n or me n wit h o ut a n y treat me nt f or a d va nce d disease 
 C o h ort  B:  a p pr o x.  3 0 %  of  patie nts  ca n  be  pre-  or 
peri me n o pa usal  or  p ost me n o pa usal  w o me n  or  me n,  m ust 
ha ve n o m ore t ha n 1 c he m ot hera p y li ne f or a d va nce d disease, 
a n d a ma xi m u m of 2 li nes of e n d ocri ne t hera p y f or a d va nce d 
disease ( or a c o m bi nati o n of t hese criteria). 
Patie nts  m ust  ha ve  d oc u me nte d  e vi de nce  of  rec urre nce  or 
pr o gressi o n d uri n g or aft er t he last t hera p y pri or t o e nr oll me n t.  
I n cl u si o n crit eri a 
 Patie nt is a n a d ult, ≥ 1 8 years  ol d at t he ti me of i nf or me d 
c o nse nt a n d has si g ne d i nf or me d c o nse nt bef ore a n y trial 
relate d acti vities a n d acc or di n g t o l ocal g ui deli nes. 
 Patie nts wit h a d va nce d (l oc ore gi o nall y rec urre nt or 
metastatic) breast ca ncer n ot a me na ble t o c urati ve t hera p y. 
 Patie nt has a hist ol o gicall y a n d/ or c yt ol o gicall y c o nfir me d 
dia g n osis of estr o ge n-rece pt or  p ositi ve a n d/ or pr o gester o ne 
rece pt or p ositi ve a n d H E R 2- ne gati ve breast ca ncer b y l ocal 
la b orat or y. L ocal pat h ol o g y is s ufficie nt f or assess me nt. 
 Patie nt m ust ha ve eit her: 
o  Meas ura ble disease, i.e., at least o ne 
meas ura ble lesi o n as per R E CI S T 1. 1 criteria 
( T u m or lesi o ns pre vi o usl y irra diate d or 
s u bjecte d t o ot her l oc ore gi o nal t hera p y will 
o nl y be c o nsi dere d meas ura ble if disease 
pr o gressi o n at t he t reate d site after 
c o m pleti o n of t hera p y is clearl y 
d oc u me nte d). 
o  B o ne lesi o ns: l ytic or mi xe d (l ytic + 
scler otic) i n t he a bse nce of meas ura ble 
disease 
o  N o n- meas ura ble disease 
 Patie nt has a n Easter n C o o perati ve O nc ol o g y Gr o u p 
( E C O G) perf or ma nce stat us ≤2.  
 Patie nt has a de q uate b o ne marr o w a n d or ga n f u ncti o n.  

N o v arti s 
C o nfi d e nti al 
P a g e 1 5 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
E x cl u si o n crit eri a 
 Patie nt w h o recei ve d a n y C D K 4 / 6 i n hi bit or or a n y m T O R 
i n hi bit or. 
 Patie nt has a k n o w n h y perse nsiti v it y t o a n y of t he e xci pie nts 
of ri b ocicli b or letr oz ole. 
 Patie nts wit h c urre nt i nf la m mat or y breast ca ncer. 
 Patie nt has recei ve d > 1 c he m ot hera p y f or t he treat me nt of 
a d va nce d/ metastatic breast ca ncer. 
Patie nt has recei ve d > 2 e n d ocri ne t hera pies f or t he treat me nt of 
a d va nce d/ metastatic breast ca ncer. Patie nt has ce ntral ner v o us 
s yste m ( C N S) i n v ol ve me nt.       If patie nt is f ulfilli n g t he 
f oll o wi n g 3 criteria s he/ he is eli gi ble f or t he trial. 
o  c o m plete d pri or t herap y (i ncl u di n g ra diati o n 
a n d/ or s ur ger y) f or C N S metastases ≥ 2 8 
da ys pri or t o t he start of st u d y a n d 
o  C N S t u m or is cli nicall y sta ble at t he ti me of 
scree ni n g a n d 
o  Patie nt is n ot recei vi n g ster oi ds a n d e nz y me 
i n d uci n g a nti-e pile ptic me dicati o ns f or brai n 
metastases 
 Patie nt has acti ve car diac dis ease or a hist or y of car diac 
d ysf u ncti o n. 
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 
Ri b ocicli b  6 0 0 m g  i n  c o m bi nati o n  wit h  letr oz ole  2. 5 m g. 
Pre me n o pa usal patie nts will a d diti o nall y recei ve g osereli n; me n  
ma y  als o  be  treate d  wit h  g oser eli n  at  t he  discreti o n  of  t he 
i n vesti gat or. 
Effi c a c y a s s e s s m e nt s 
 C T e ver y 1 2 wee ks u ntil disease pr o gressi o n, deat h, 
wit h dra wal of c o nse nt, l o ss t o f oll o w- u p, or s u bject 
decisi o n. 
 Brai n C T or M RI as cli nicall y i n dicate d.  
 W h ole b o d y b o ne sca n ( u nless perf or me d wit hi n 5 6 da ys 
pri or t o C 1 D 1). 
 B o ne X-ra y, C T (if b o ne lesi o n at scree ni n g) e ver y 1 2 
wee ks 
 S ur vi val stat us re gar dless of treat me nt. 
S af et y a s s e s s m e nt s 
 P h ysical e xa mi nati o ns 
 E C O G perf or ma nce stat us 
 Hei g ht, wei g ht, a n d vital si g ns 
 1 2 lea d E C Gs 
 La b orat or y assess me nts i ncl u di n g he mat ol o g y, 
bi oc he mistr y, li pi d pa nel, he patic safet y mar kers, a n d 
uri nal ysis 
 N CI- C T C A E assess me nt 
Ot h er a s s e s s m e nt s 

N o v arti s 
C o nfi d e nti al 
P a g e 1 6 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 
P atie nt-re p orte d o utc o m es: Patie nt q uesti o n naires ( E O R T C-
Q L Q- C 3 0, B R- 2 3) will be c ollecte d t o assess healt h-relate d 
q ualit y- of-life, healt h stat us , f u ncti o ni n g, disease s y m pt o ms, 
si de effects, a n d ca ncer-relate d pai n. 
D at a a n al y si s 
T he  pri mar y  o bjecti ve  of  t his  st u d y  is  t he  assess me nt  of  t he 
cli nical  be nefit  rate  f oll o wi n g  R E CI S T  1. 1  f or  t he  t otal 
p o p ulati o n a n d f or c o h orts A a n d B se paratel y: 
 T o assess t he cli nical be nefit rate ( C B R) after 2 4 wee ks f or 
ri b ocicli b  ( L E E 0 1 1)  i n  c o m bi nati o n  wit h  letr oz ole  a m o n g 
p ost me n o pa usal  w o me n  a n d  me n  wit h  h or m o ne  rece pt or 
p ositi ve,  H E R 2-  ne gati ve,  a d va nce d  breast  ca ncer  w h o 
recei ve d n o pri or treat me nt for a d va nce d disease ( C o h ort A). 
 T o assess t he cli nical be nefit rate ( C B R) after 2 4 wee ks f or 
ri b ocicli b  ( L E E 0 1 1)  i n  c o m bi nati o n  wit h  letr oz ole  a n d 
g osereli n  a m o n g  pre-,  a n d  peri me n o pa usal  w o me n  w h o 
recei ve d n o pri or treat me nt f or a d va nce d disease as well as 
pre-,  peri-  a n d  p ost me n o pa usal  w o me n  a n d  me n  wit h 
h or m o ne rece pt or p ositi ve, H E R 2- ne gati ve, a d va nce d breast 
ca ncer w h o recei ve d n o m ore t ha n 1 pri or c he m ot hera p y a n d 
2  pri or  li nes  of  e n d ocri ne  t hera p y  f or  a d va nce d  disease 
( C o h ort B) 
I n t his si n gle-ar m trial, t he pri mar y o bjecti ve is t o esti mate t he 
C B R. T heref ore, n o statistical h y p ot hesis or m o del is u n derl yi n g 
t he a nal ysis. 
T he C B R ( best o verall res p o nse of C R or P R or S D) as well as 
i n di vi d ual res p o nse cate g ories ( C R, P R, S D, P D, N C R N P D or 
u n k n o w n)  will  be  s u m marize d  usi n g  fre q ue nc y  ta bles  t o get her 
wit h t heir ass ociate d t w o-si de d e xact 9 5 % c o nfi de nce i nter vals 
( Cl o p per- Pears o n  met h o d).  T he  F ull  A nal ysis  Set  will  be  use d 
f or t he pri mar y efficac y a nal ysis. 
 
K e y w or d s 
H R- p ositi ve, H E R 2- ne gati ve, a d va nce d breast ca ncer, ri b ocicli b,  
letr oz ole,  C D K 4/ 6,  P hase  III b,  E R- p ositi ve,  P R- p ositi ve, 
p ost me n o pa usal, pre me n o pa usal, metastatic breast ca ncer 
 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 1 7 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
A m e n d m e nt 4  
 
St u d y C L E E 0 1 1 X D E 0 1 was i nitiate d o n 2 4- Oct- 2 0 1 6 a n d e nr oll me nt is c o m plete d. 
 
A me n d me nt r ati o n ale  
T he c urre nt a me n d me nt is i nte n de d t o: 
1.  U p date  t he  d ose  a dj ust me nt  a n d  ma na ge me nt  rec o m me n dati o ns  f or  Q Tc F 
pr ol o n gati o n. A nal yses of precli nical a n d rece nt cli nical data wit h ri b ocicli b ha ve 
de m o nstrate d t hat ri b ocicli b pr ol o n gs t he Q T i nter val i n a c o nc e ntrati o n- de pe n de nt 
ma n ner. As a res ult, t his a me n d me nt i ncl u des a n u p date t o t he d osa ge ma na ge me nt 
g ui da nce f or patie nts w h o e x perie nce Q Tc pr ol o n gati o n. 
2.  U p date t he pr o hi bite d c o nc o mita nt  me dicati o ns base d o n rece nt co m pilati o n of dr u g-
dr u g i nteracti o n a n d c o- me di cati o n c o nsi derati o ns 
3.  C orrect mi n or mista kes i n t he pr ot oc ol. 
 
C h a n ges t o t he pr ot oc ol 
C ha n ges t o s pecific secti o ns of t he pr ot oc ol are s h o w n i n t he trac k c ha n ges versi o n of t he 
pr ot oc ol  usi n g  stri ke t hr o u g h  re d f o nt  f or  deleti o ns  a n d  re d  u nderli ne  f or  i nserti o ns.  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 n c or p orate d i n t he f oll o wi n g 
secti o ns: 
 
 Secti o n 4. 3 a n d 7. 1. 3. 1: clarifi cati o n of e n d of st u d y 
 Secti o n 6. 1. 1. 1: u p date d g ui da nce relate d t o her bal or dietar y s u p ple me nts. 
 Secti o n 6. 2. 1. 2: A d diti o nal f oll o w- u p f or he patic t o xicities u p date d t o i ncl u de 
i nf or mati o n o n t he L E E 0 1 1 X 2 1 0 9 st u d y as well as u p date d te xt t o ma n date 
disc o nti n uati o n, w he n li ver test ele vati o n is n ot d ue t o c h oles tasis. 
 Secti o n 6. 2. 1. 4. 1: A dj ust me nt of starti n g d ose i n s pecial p o p ul ati o ns u p date d t o 
i ncl u de i nf or mati o n o n t he L E E 0 1 1 A 2 1 1 6 st u d y 
 Ta ble 6- 5: d ose a dj ust me nt a n d m a na ge me nt rec o m me n dati o ns f or Q Tc F 
pr ol o n gati o n u p date d  
 Secti o n 6. 2. 2 A ntici pate d ris ks a n d safet y c o ncer ns of t he st u d y dr u g c orrecte d 
 Secti o n 6. 3. 2: C o nc o mita nt t hera p y re q uiri n g ca uti o n- u p date d i nf or mati o n o n 
c o nc o mita nt t hera p y re q uiri n g ca uti o n 
 Secti o n 6. 3. 3: Pr o hi bite d c o nc o mita nt t hera p y- u p date d list of pr o hi bite d 
c o nc o mita nt t hera p y 
 Secti o n 6. 4. 4: Dr u gs wit h Q T pr ol o n gati o n- f urt her clarifie d t h e c o-a d mi nistrati o n 
of dr u gs wit h k n o w n ris k of t or sa des de p oi ntes ( T d P) 
 Secti o n 7. 1. 1: Rescree ni n g clarifie d 
 Secti o n 7. 2. 2. 3: Mista ke c orre cte d: C ycle 1 Da y 1 5 delete d 
 Ta ble 7- 1 a n d 7- 4: E C G C ollecti o n Pla n u p date d 
 Secti o n 8. 1. 1: Mista ke c orre cte d: deat h f or m delete d 
 Secti o n 1 4 A p pe n di x 1: C o nc o mita nt  me dicati o ns: list of pr o hi bite d c o nc o mita nt 
me dicati o ns u p date d base d o n t he  o nc ol o g y cli nical p har mac ol o g y g ui da nce, dr u g-
dr u g i nteracti o n a n d c o- me dicati o n c o nsi derati o ns ( v 0 7, release date: Ja n 2 0 1 8) 
o  Ta ble 1 4- 1 : List of pr o hi bite d me dicati o ns d uri n g st u d y dr u g t reat me nt 
o  Ta ble 1 4- 2: List of me dicati o ns t o be use d wit h ca uti o n d uri n g st u d y dr u g 
treat me nt 
 

N o v arti s 
C o nfi d e nti al 
P a g e 1 8 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
A m e n d m e nt 3 
 
St u d y C L E E 0 1 1 X D E 0 1 was i nitiate d o n 2 4- Oct- 2 0 1 6 a n d e nr oll me nt is c urre ntl y o n g oi n g. 
 
A me n d me nt r ati o n ale  
T he c urre nt a me n d me nt is i nte n de d t o c orrect mista kes i n t he pr ot oc ol.  
 
C h a n ges t o t he pr ot oc ol 
C ha n ges t o s pecific secti o ns of t he pr ot oc ol are s h o w n i n t he t rac k c ha n ges versi o n of t he 
pr ot oc ol usi n g stri ke t hr o u g h re d f o nt f or deleti o ns a n d re d u n derli ne f or i nserti o ns. 
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 ar e i nc or p orate d i n t he 
f oll o wi n g secti o ns: 
 Ge neral:  c ha n ge of na me fr o m 
 t o 
, d ue t o marria ge 
 Secti o n 5. 2: i ncl usi o n criteri o n # 3: t u bal li gati o n delete d bec a use t his is n o 
criteri o n f or p ost me n o pa usal stat us  
 Secti o n 5. 2: i ncl usi o n c riteri o n # 1 2: t y p o c orrecte d 
 Secti o n 6. 3. 1: c o nc o mita nt t hera p y u ntil Safet y F oll o w U p a d de d  t o matc h wit h 
Ta ble 7- 1  
 Secti o n 6. 6: re place me nt of t he w or d “ri b ocicli b” wit h t he w or d “st u d y dr u g”, f or 
clarificati o n p ur p ose   
 Secti o n 7. 1: F S H/estra di ol  meas ure me nt clarifie d 
 Ta ble 7- 1: Mista ke c orrecte d: Assess me nt of Vital si g ns, Wei g ht , P h ysical 
e xa mi nati o n, E C O G stat us, Hei g ht c ha n ge d fr o m C 1 2 D 1 t o C 1 3 D 1  
 Secti o n 7. 2. 4: e diti n g t he f oll o wi n g se nte nces f or p ur p ose of c larificati o n:  
“ C o m plete d q uesti o n naires, i ncl u di n g b ot h res p o nses t o t he q uesti o ns a n d a n y 
u ns olicite d c o m me nts writte n b y t he patie nt, m ust be re vie we d a n d assesse d b y t he 
i n vesti gat or f or res p o nses w hich ma y i n dicate p ote ntial A Es or S A Es. T his re vie w 
s h o ul d be d oc u me nte d i n t he st u d y s o urces.  
If a n A E or S E A is c o nfir me d t he n t he i n vesti gat or s h o ul d rec or d t he e ve nt as 
i nstr ucte d i n Secti o n 8 of t his pr ot oc ol. I n vesti gat or s h o ul d not e nc o ura ge t he 
patie nts t o c ha n ge res p o nses  re p orte d i n q uesti o n naires.   
U p o n ra di ol o gic pr o gressi o n acc o r di n g t o R E CI S T 1. 1 treat me nt wit h st u d y dr u g 
ma y be c o nti n ue d at t he discreti o n of t he i n vesti gat or u ntil a cli nicall y s y m pt o matic 
pr o gress occ urs. I n t his case, t he q ualit y of lif e q uesti o n naires m ust be c o m plete d 
acc or di n g t o Visit sc he d ule. If ra di ol o gic pr o gressi o n occ urs, bef ore C ycle 1 3 
m o nt hl y a n d after C ycle 1 3 e ver y 1 2 wee ks u ntil s y m pt o matic pr o gressi o n or E n d 
of st u d y as well as u p o n s y m pt o matic pr o gressi o n.” 
 
 
 
 
A m e n d m e nt 2 
 
St u d y C L E E 0 1 1 X D E 0 1 was i nitiate d o n 2 4- Oct- 2 0 1 6 a n d e nr oll me nt is c urre ntl y o n g oi n g. 
 
A me n d me nt r ati o n ale  

N o v arti s 
C o nfi d e nti al 
P a g e 1 9 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
T he c urre nt a me n d me nt is i nte n de d t o u p date t he e xisti n g i nf or m ati o n a b o ut ri b ocicli b, t o 
clarif y s pecific as pects of t he  ori gi nal pr ot oc ol a n d
 
 A s u m mar y of t he ke y 
c ha n ges pr o p ose d i n t his a me n d me nt is liste d bel o w: 
 Ri b ocicli b i nf or mati o n was u p date d base d o n t he data a vaila ble o n t he c urre nt I B 
versi o n ( v 1 0, release date: Oct- 1 0- 2 0 1 6; safet y c ut- off date: J ul- 5- 2 0 1 6)). 
 Detaile d i nf or mati o n fr o m t h e pi v otal st u d y C L E E 0 1 1 A 2 3 0 1 ( M O N A L E E S A- 2) 
s u p p orti n g t he use of ri b ocicli b + letr oz ole i n a B C has bee n i ncl u de d t o stre n gt he n 
t he st u d y rati o nale. 
 Male patie nts e nteri n g t he st u d y m a y als o recei ve g osereli n c o n c urre ntl y wit h 
ri b ocicli b + letr oz ole base d o n the c urre nt sta n dar d of care i n  t his patie nt 
p o p ulati o n a n d t o a v oi d p ote ntial i ncrease of F S H a n d test oster o ne (i ncreasi n g 
p ote ntial s u bstrates f or ar o matizati o n) w hic h c o ul d be ass ociat e d wit h pr ol o n ge d 
a d mi nistrati o n of AIs. 
 U p o n ra di ol o gic pr o gressi o n, acc or di n g t o R E CI S T 1. 1, patie nts ma y c o nti n ue t o 
recei ve st u d y me dicati o n u ntil a cli nicall y s y m pt o matic pr o gressi o n occ urs. T his 
decisi o n is at t he discret i o n of t he i n vesti gat or. 
 
A me n d me nt 0 2 als o i ncl u des mi n or e dit orial c ha n ges a n d a d diti o n al clarificati o ns t o 
a d dress i n vesti gat ors’ q uesti o ns a s descri be d i n t he list of c ha n ges bel o w. 
 
C h a n ges t o t he pr ot oc ol 
C ha n ges t o s pecific secti o ns of t he pr ot oc ol are s h o w n i n t he t rac k c ha n ges versi o n of t he 
pr ot oc ol usi n g stri ke t hr o u g h re d f o nt f or deleti o ns a n d re d u n derli ne f or i nserti o ns. 
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 ar e i nc or p orate d i n t he 
f oll o wi n g secti o ns: 
 T hr o u g h o ut t he d oc u me nt: A d diti o n of la n g ua ge t o refer t o m ost rece nt versi o n of 
t he L E E 0 1 1 I n vesti gat or’s Br oc h ure a n d mi n or te xt e dit orial c ha n ges. 
 T hr o u g h o ut t he d oc u me nt: T y p o gra p hi cal a n d gra m matical c orrecti o ns. 
 Secti o n 1: U p date d base d o n ne w da ta fr o m o n g oi n g a n d c o m plete d trials wit h 
ri b ocicli b. 
 Secti o n 1. 2. 6: A d de d C L E E 0 1 1 A 2 3 0 1 ( M O N A L E E S A- 2) trial ke y effic ac y a n d 
safet y res ults of pre- pla n ne d interi m a nal ysis. Als o u p date d re s ults of 
C L E E 0 1 1 X 2 1 0 7 trial. 
 Secti o n 2. 4: U p date d trial res ults. 
 Secti o n 5. 2: i ncl usi o n cri teria n u m bers a d de d. 
 Secti o n 5. 2: i ncl usi o n criteri o n # 3: clarificati o n of p ost m e n o pa usal stat us a d de d. 
 Secti o n 5. 2: i ncl usi o n criteri o n # 4: a d de d e x pla nati o n f or C o h o rts A/ B. 
 Secti o n 5. 2: i ncl usi o n criteri o n # 9: re p hrase d f or clarificati o n. 
 Secti o n 5. 2: i ncl usi o n criteri o n # 1 1: creati ni ne cleara nce a d de d, M or b us 
Me ule n grac ht a d de d. 
 Secti o n 5. 2: i ncl usi o n criteri o n # 1 2: clarificati o n f or c orrect e d calci u m a d de d. 
 Secti o n 5. 3: e xcl usi o n criteri o n # 6 a n d # 7: pretreat me nt wit h a r o matase i n hi bit or 
t hera p y f or u p t o 2 1 da ys n ot c o u nte d as t hera p y li ne; was h- o ut peri o d f or pre vi o us 
treat me nt delete d an d n ote re gar di n g o verla p pi n g t o xicit y a d de d . 
 Secti o n 5. 3: e xcl usi o n criteri o n # 1 0: delete d as t his is a re q u ire me nt wit h 
F ul vestra nt as c o m bi nati o n part ner, n ot letr oz ole. 

N o v arti s 
C o nfi d e nti al 
P a g e 2 0 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 Secti o n 5. 3: e xcl usi o n criteri o n # 1 2: delete d beca use c o nc o mita nt palliati ve 
ra di ot hera p y is all o we d. 
 Secti o n 5. 3: e xcl usi o n criteri o n # 1 7: Dietar y s u p ple me nts are a ll o we d if t he y 
c o ntai n o nl y n utrie nts, mi nerals a n d/ or vita mi ns. 
 Secti o n 5. 3: e xcl usi o n criteri o n # 2 1: h or m o nal c o ntrace pti o n me t h o ds delete d. 
 Secti o n 6. 1: a d de d g osereli n as tr eat me nt o pti o n f or me n; per mi tte d dietar y 
s u p ple me nts a d de d. 
 Secti o n 6. 1. 2: 
 
 Secti o n 6. 2. 1. 1: i nf or mati o n re gar di n g i na d verte nt d osi n g of ri b ocicli b o n a rest 
da y. 
 Secti o n 6. 2. 1. 1, Ta ble 6. 3: le u k oc yt e c o u nt a d de d, rec o m me n dati o n f or Gra de 3 
Ne utr o pe nia u p date d. 
 Secti o n 6. 2. 1. 3, Ta ble 6- 5: Q Tc c ha n ge d t o Q Tc F, asteris k re m o v e d. 
 Secti o n 6. 2. 1. 4: i nf or mati o n o n bis p h os p h o nate use a n d calci u m a d de d. 
 Secti o n 6. 2. 1. 4. 1: U p date d i nf or mati o n o n re nal i m pair me nt a n d he patic 
i m pair me nt a d de d. 
 Secti o n 6. 3. 1: c o nc o mita nt t hera p y 3 0 da ys bef ore st u d y start a d de d. 
 Secti o n 6. 3. 1. 4: i nf or mati o n a b o ut irra diate d lesi o ns a d de d. 
 Secti o n 6. 3. 3: dietar y s u p ple me nts all o we d.  
 Secti o n 6. 4. 2: treat me nt assi g n me nt clarifie d. 
 Secti o n 6. 5: clarifi cati o n of st u d y dr u g di s pe nsi n g u p date d. 
 Secti o n 6. 5. 2: te m perat ure  l o g i nf or mati o n u p date d. 
 Secti o n 7. 1: Visit e val uati o n sc h e d ule u p date d acc or di n g t o c ha n ges ma de i n 
A me n d me nt 2. 
 Secti o n 7. 1. 1: Rescree ni n g a d de d as o pti o n. 
 Secti o n 7. 1. 1. 2: U p date d re q uire d assess me nts. 
 Secti o n 7. 1. 2: Me n a d de d t o g osereli n secti o n. 
 Secti o n 7. 1. 5: S ur vi val f oll o w u p a d de d. 
 Secti o n 7. 2. 1: Ti me wi n d o w f or ra di ol o gic assess me nts c ha n ge d f r o m +/- 3 t o +/- 7 
da ys; c ol or p h ot o gra p h y of  s ki n lesi o ns a d de d.  
 Secti o n 7. 2. 1. 1: Secti o n a d de d f or treat me nt be y o n d pr o gressi o n . 
 Secti o n 7. 2. 2. 4: I N R a d de d i n Ta ble 7- 3; i nf or mati o n of uri nal y sis t y pe a d de d 
( di pstic k); si m ulta ne o us F S H a n d/or Estra di ol meas ure me nt s h o ul d be perf or me d 
wit h pre g na nc y tests. 
 Secti o n 7. 2. 4: C ollecti o n sc he d ule f or Q o L q uesti o n naires u p dat e d. 
 Secti o n 8. 2. 2: a d de d i nf or mati o n t ha t a n S A E t hat is c o nsi dere d c o m pletel y 
u nrelate 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 pa ratel y as a ne w 
e ve nt. 
 
 
 
A m e n d m e nt 1 
 
St u d y C L E E 0 1 1 X D E 0 1 has n ot yet bee n i nitiate d. N o patie nts ha ve bee n e nr olle d s o far. 
 
A me n d me nt r ati o n ale 

N o v arti s 
C o nfi d e nti al 
P a g e 2 1 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
T he p ur p ose of t his a me n d me nt is  t o i ncl u de fee d bac k recei ve d fr o m Bf Ar M a n d E Cs 
d uri n g t he assess me nt of t he  i nitial a p plicati o n. 
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  
R ol e of t h e e str o g e n p at h w a y i n br e a st c a n c er 
E x pressi o n  of  t he  estr o ge n  rece pt or  ( E R)  a n d/ or  pr o gester o ne  re ce pt or  ( P g R)  is  o ne  of 
t he  m ost  i m p orta nt  pr o g n ostic  fact ors  i n  i n vasi ve  breast  ca ncer  a n d  is  detecte d  i n 
a p pr o xi matel y 7 0 % of cases. Estr o ge n de pri vati o n t hera p y is t he c ore treat me nt m o dalit y 
i n  patie nts  wit h  h or m o ne  rece pt or  p ositi ve  ( H R +)  a d va nce d  breast  ca ncer.  E n d ocri ne 
t hera p y  o pti o ns  f or  p ost me n o pa usal  w o me n  wit h  E R +  a d va nce d  breast  ca ncer  (l ocall y 
a d va nce d, rec urre nt, or metastatic breast ca ncer) i ncl u de selecti ve E R m o d ulat ors ( S E R M; 
ta m o xife n), E R a nta g o nists (f ulvestra nt), selecti ve n o nster oi da l ar o matase i n hi bit ors ( N S AI; 
a nastr oz ole  a n d  letr oz ole)  a n d  st er oi dal  ar o matase  i n hi bit ors  ( e xe mesta ne).  Bl oc ki n g 
estr o ge n 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 5  years.  I n  p ost me n o pa usal  w o me n,  ar o matase  i n hi bit ors  ( AI)  re d uce 
peri p heral estr o ge n s y nt hesis b y bl oc ki n g t he c o n versi o n of a n d r o ge ns t o estr o ge ns i n n o n-
o varia n  tiss ues;  s y nt hesis  i n  t he se  tiss ues  is  t he  pri mar y  s o urce  of  estr o ge ns  i n 
p ost me n o pa usal w o me n. AIs are ge ne rall y use d as t he first li ne of t hera p y f or w o me n wit h 
H R + breast ca ncer ( Beslija 2 0 0 9; N C C N 1 3 2 0 1 3). 
 
1. 1. 2  
R ol e of c ell c y cl e r el at e d g e n e s a n d pr ot ei n s i n c a n c er 
I n t he ma m malia n cell c ycle, e ntr y i nt o S p hase is ac hie ve d b y c ycli n- de pe n de nt ki nases 4 
a n d 6 ( C D K 4/ 6). T he c ycli n D pr otei ns act t hr o u g h t he C D K 4 a n d C D K 6 pr otei n ki nases 
( p ositi ve  re g ulat ors)  t o  pr o m ote  G 1  pr o gressi o n  ( M us gr o ve  2 0 1 1).  C D K 4  a n d  C D K 6,  i n 
t ur n, h y per p h os p h or ylate a n d acti vate t he reti n o blast o ma pr otei n ( p R b) t o pr o m ote cell c ycle 
e ntr y a n d cell pr oliferati o n ( Fi g ure 1- 1). Mit o ge nic si g nals c o n ver ge at t he le vel of c ycli n 
D 1  u pre g ulati o n  a n d  C D K 4/ 6  ass ociati o n,  l ocalizati o n,  a n d  ki nas e  acti vit y.  C D K 4/ 6 
p h os p h or ylates a n d i nacti vates R b  t u m or s u p press or pr otei ns, lea di n g t o diss ociati o n of E 2 F 
tra nscri pti o n fact ors a n d tra nscri pti o nal re g ulati o n of ge nes im p orta nt f or G 1/ S tra nsiti o n 
a n d cell c ycle pr o gressi o n t hr o u g h t he restricti o n p oi nt.  
D-c ycli ns are t he p ositi ve re g ulat ors of t hese ki nases, w hile t he p 1 6 pr otei n e n c o de d b y t he 
I N K 4a  ge ne  f u ncti o ns  as  t heir  maj or  i n hi bit or.  U p o n  mit o ge n  stim ulati o n,  si g nal 
tra ns d ucti o n  pat h wa ys  i ncl u di n g  MA P K  a n d  PI 3 K  i ncrease  cell  pr o liferati o n  b y 
u pre g ulati n g t he e x pressi o n of D -c ycli ns, w hic h i n t ur n acti vate t he ki nases. 
A  wi de  ra n ge  of  h u ma n  t u m ors  har b or  ge netic  a berrati o ns  t hat  i n crease  t he  acti vit y  of 
C D K 4/ 6.  F urt her m ore,  f ocal  c o p y  n u m ber  a b n or malities  t hat  res ult  i n  i ncrease d  C D K 
acti vit y  are  a m o n g  t he  m ost  c o m m o nl y  descri be d  m utati o ns  o bser ve d  i n  di verse  t u m or 
t y pes; t hese m utati o ns i ncl u de am plificati o ns of t he ge nes t hat  e nc o de c ycli n D 1 or C D K 4, 
a n d deleti o ns affecti n g t he C D K N 2 A  l oc us, w hic h e nc o des t he p 1 6I N K 4a i n hi bit or of C D K 
acti vit y  ( Ber o u k hi m  2 0 1 0) .  Fi nall y,  t he  p R b  is  a  t u m or  s u p pressor  pr otei n  t hat  is 
d ysf u ncti o nal i n se veral maj or ca ncers ( M ur p hree a n d Be ne dict 1 9 8 4). Direct a nal yses of 
pri mar y  t u m ors  ha ve  re veale d  l oss  of  p R b  e x pressi o n  i n  2 0- 3 5 %  o f  t u m ors,  a n d  l oss  of 

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heter oz y g osit y or ot her alterati o ns of t he p R b l oc us i n 7. 4 % of  t u m ors ( Pietilai ne n 1 9 9 5; 
B or g 1 9 9 2; Oesterreic h 1 9 9 9; C ha n o 2 0 0 2). 
 
Fi g ure 1- 1  
Re g ul ati o n of cell c ycle c hec k p oi nt c o ntr ol  
 
 
A d a pte d fr o m La n g e a n d Y ee ( 2 0 1 1). 
Refer t o ri b ocicli b I n v esti g at ors Br o c h ur e f or m or e details. 
 
1. 1. 3  
R ol e of c y cli n D ki n a s e s i n hi bit or s i n br e a st c a n c er 
 
Cell  c ycle  relate d  ge nes  a n d  pr ot ei ns  are  fre q ue ntl y  dere g ulate d  i n  breast  ca ncer. 
A p pr o xi matel y 1 5 %- 2 0 % of h u ma n b reast ca ncers e x hi bit a m plificati o n of t he c ycli n D 1 
( C C N D 1)  ge ne  ( B uc kle y  1 9 9 3;  Dic ks o n  1 9 9 5;  L u n d gre n  2 0 1 2)  w hile t he  maj orit y  of 
h u ma n ma m mar y carci n o mas o vere x press C C N D 1 pr otei n ( Bart k o va 1 9 9 4; Gillett 1 9 9 4; 
McI nt os h 1 9 9 5;  Gillet 1 9 9 6). O vere x pressi o n  of  C C N D 1  is  see n  ea rl y i n  breast  ca ncer, 
a n d it is mai ntai ne d at all sta ges of breast ca ncer pr o gressi o n , i ncl u di n g metastatic lesi o ns 
( Bart k o va  1 9 9 4;  Gillett  1 9 9 4;  McI nt os h  1 9 9 5)  a n d  t he  c o nti n ue d prese nce  of  C D K 4-
ass ociate d ki nase acti vit y is act uall y re q uire d t o mai ntai n bre ast t u m ori ge nesis ( Y u 2 0 0 6). 
 
Data  fr o m  t he  Ca ncer  Ge n o me  Atla s  hi g hli g ht  t he  i m p orta nce  of  the  C ycli n/ C D K/ R b 
pat h wa y  i n  l u mi nal  breast  ca ncer  ( T he  Ca ncer  Ge n o me  Atlas  Net w o r k  2 0 1 2). 
A b n or malities t hat res ult i n C D K acti vati o n are hi g hl y e nric he d  i n t he l u mi nal A a n d B 
m olec ularl y defi ne d s u b gr o u ps, a p pr o xi matel y 8 5 % of w hic h were E R +/ H E R 2 -ne gati ve. 
C ycli n D 1 a m plificati o ns were o bser ve d i n 2 9 % a n d 5 8 % of t he l u mi nal A a n d B s u bt y pes, 
res pecti vel y, a n d C D K 4 a m plificati o ns were o bser ve d i n 1 4 % a n d 2 5 % of l u mi nal A a n d 
B s u bt y pes, res pecti vel y. L u mi nal A s u bt y pe t u m ors als o ha ve l o ss  of C D K N 2 C, w hic h 
e nc o des p 1 6 I N K 4a, a C D K i n hi bit or. Alt h o u g h I n precli nical m o dels, p R b de pleti o n a p pears 
t o be ass ociate d wit h resista nce t o a ntiestr o ge n t hera p y ( B osc o 2 0 0 7), t he l u mi nal s u bt y pes 
als o mai ntai n e x pressi o n of R b ( T he Ca ncer Ge n o me Atlas Net w or k  2 0 1 2), w hic h w o ul d 
be esse ntial f or be nefit fr o m treat me nt wit h a C D K 4/ 6 i n hi bit or . Of n ote, t he p 1 6I N K 4a ge ne 
pr o m oter is tra nscri pti o nall y acti ve i n se nesce nt, b ut n ot n o n- se nesce nt cells ( Ba ker 2 0 1 1). 
F urt her m ore,  rece nt  data  e x pl ori n g  4 7  h u ma n  breast  ca ncer  cell li nes  de m o nstrate d 
prefere ntial se nsiti vit y t o C D K 4 / 6 i n hi bit ors i n E R/ H E R 2 + cell li nes ( Fi n n 2 0 0 9). Fi nall y, 

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rece nt  precli nical  data  s u g gest  that  des pite  estr o ge n  de pri vati o n,  E R α  retai ns  ge n o mic 
acti vit y a n d dri ves a C D K 4/ E 2 F de pe n de nt tra nscri pti o nal pr o gra m ( Miller 2 0 1 1). 
I bra nce®  ( pal b ocicli b) is a C D K 4/ 6i, i n hibit or i n dicate d i n c o m bi nati o n  wit h letr oz ole f or 
t he  treat me nt  of  p ost me n o pa usal  w o me n  wit h  h or m o ne  rece pt or  ( E R)- p ositi ve,  H E R 2-
ne gati ve a d va nce d breast ca ncer as i nitial e n d ocri ne- base d t her a p y f or metastatic disease 
(I bra nce®   Prescri pti o n  I nf or mati o n).  A  ra n d o mize d,  o pe n-la bel,  m ultice nter  st u d y  of 
pal b ocicli b pl us letr oz ole vers us letr oz ole al o ne c o n d ucte d i n 1 6 5 p ost me n o pa usal w o me n 
wit h  E R- p ositi ve,  H E R 2- ne gati ve  a d va nce d  breast  ca ncer  wit h  n o pre vi o us  s yste mic 
treat me nt f or t heir disease s h o we d a statisticall y si g nifica nt i m pr o ve me nt i n P F S wit h t he 
a d diti o n of pal b ocicli b t o letr oz ole ( me dia n P F S 2 0. 2 m o nt hs vers us 1 0. 2 m o nt hs ( H R 0. 4 9; 
9 5 %  CI: 0. 3 2  t o  0. 7 5;  P = 0. 0 0 0 4)  ( Fi n n  2 0 1 4).  T his  was  c o nfir me d i n  a  ra n d o mize d, 
m ultice nter, d o u ble- bli n d p hase 3 s t u d y of pal b ocicli b pl us letr oz ole vers us place b o pl us 
letr oz ole i n p ost me n o pa usal w o me n w h o ha d n ot recei ve d a n y pri or s yste mic a nti-ca ncer 
treat me nt  f or  a d va nce d  disease.  T he  me dia n  P F S  i n  t his  st u d y  was  2 4. 8  m o nt hs  f or  t he 
C D K 4/ 6  i n hi bit or  i n  c o m bi nati o n wit h  letr oz ole  vers us  1 4. 5  m o nt hs f or place b o pl us 
letr oz ole  ( H R = 0. 5 8  [ 0. 4 6  t o  – 0. 7 2],  P < 0. 0 0 0 0 0 1).  ( Fi n n  et  al., A bstract  5 0 7,  oral 
prese ntati o n at A S C O 2 0 1 6, C hica g o) 
A p hase III st u d y i n 5 2 1 patie nts wit h a d va nce d H R +, H E R 2- ne gat i ve a d va nce d B C t hat 
ha d rela pse d or pr o gresse d d uri n g pri or e n d ocri ne t hera p y s h o we d a  me dia n P F S of 9. 2 
m o nt hs ( 9 5 % CI, 7. 5 t o n ot esti ma b le) wit h pal b ocicli b i n c o m binati o n wit h f ul vestra nt vs 
3. 8 m o nt hs ( 9 5 % CI, 3. 5 t o 5. 5) wit h place b o a n d f ul vestra nt ( H R f or disease pr o gressi o n 
or deat h, 0. 4 2; 9 5 % CI, 0. 3 2 t o 0. 5 6; P < 0. 0 0 1) ( T ur ner 2 0 1 5). I n t his st u d y, pre me n o pa usal 
a n d  p ost me n o pa usal  patie nts  were  e nr olle d  a n d  c o nsiste nt  be nefi t  fr o m  pal b ocicli b  was 
see n i n pre- a n d p ost- me n o pa usal w o me n. Pre- a n d peri- me n o pa usa l w o me n als o recei ve d 
g osereli n i n a d diti o n t o t he st u d y me dicati o n. T he relati ve dif fere nce i n pr o gressi o n-free 
s ur vi val bet wee n pal b ocicli b a n d place b o was si milar i n pre me n opa usal or peri me n o pa usal 
patie nts a n d p ost me n o pa usal patie nts ( hazar d rati o f or disease pr o gressi o n or deat h, 0. 4 4 
a n d  0. 4 1,  res pecti vel y;  P  =  0. 9 4  f or  i nteracti o n  bet wee n  t he  st u d y- dr u g  assi g n me nt  a n d 
me n o pa usal stat us) ( T ur ner 2 0 1 5). 
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) 
1. 2. 1  
O v er vi e w of ri b o ci cli b 
Ri b ocicli b ( L E E 0 1 1) is a n orall y bi oa vaila ble a n d hi g hl y select i ve s mall m olec ule i n hi bit or 
of t he C D K 4/c ycli n- D 1 a n d C D K 6/ c ycli n- D 3 e nz y me c o m ple xes wit h  I C 5 0’s of 0. 0 1 a n d 
0. 0 3 9 μ M i n bi oc he mical assa ys, res pecti vel y. Refer t o ri b ocicl i b I n vesti gat ors Br oc h ure 
f or details. 
1. 2. 1. 1  
N o n cli ni c al e x p eri e n c e of ri b o ci cli b  
1. 2. 1. 1. 1 N o n cli ni c al p h a r m a c ol o g y of ri b o ci cli b  
 
A pa nel of h u ma n breast ca ncer cell li nes was treate d wit h i ncr easi n g d oses of ri b ocicli b 
a n d  d ose- de pe n de nt  i n hi biti o n  of   pr oliferati o n  was  o bser ve d  across  t he  pa nel  wit h 
e n ha nce d acti vit y a gai nst E R + breast ca ncer cell li nes wit h I C 5 0 < 1 µ M bei n g o bser ve d 
f or m ost E R + breast ca ncer li nes ( N o vartis i nter nal data, ri b ocicli b I n vesti gat or Br oc h ure 
fi g ure  4- 3).  Ri b ocicli b  as  a  si n gl e  a ge nt  has  bee n  s h o w n  t o  ha ve  acti vit y i n  precli nical 
m o dels of E R + br east ca ncer  ( N o vartis  i nter nal  data). I n  i n- vi v o- st u dies,  c o m bi nati o ns 

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wit h  t he  m T O R  i n hi bit or  R A D 0 0 1 a n d  PI 3 K  i n hi bit or,  B Y L 7 1 9,  res u lte d  i n  eit her 
i m pr o ve d or pr ol o n ge d a nti-t u m or effects i n t u m or m o dels deri ved fr o m E R + breast ca ncer. 
 
I n J e k o- 1 M C L cells t hat o vere x press c ycli n D 1 as a res ult of the t( 1 1; 1 4) c hr o m os o mal 
tra nsl ocati o n, L E E 0 1 1 i n hi bits t he p h os p h or ylati o n of p R b at C DK 4/ 6-s pecific sites wit h 
a n a vera ge I C 5 0 of 6 0 n M. I n n u de rats beari n g Je k o- 1 s u bc uta ne o us xe n o grafts, ri b ocicli b 
de m o nstrates  d ose- de pe n de nt tar get i n hi biti o n i n t he t u m ors.  L E E 0 1 1  d oses t hat i n d uce 
> 7 5 % i n hi biti o n  of  p R b  p h os p h or ylati o n  i n  t his  m o del  are  ass ociate d  wit h  c o m plete  
t u m or  re gressi o n  (see  ri b ocicli b I n vesti gat or  Br oc h ure  Secti o ns  4. 1. 1. 2. 1,  4. 1. 1. 2. 2). 
Ri b ocicli b  als o  i n hi bits  t he  gr o wt h of  ma n y ot her  t u m or  cell  t y pes  i n  vitr o  a n d  i n  vi v o, 
i ncl u di n g  li p osarc o ma,  mela n o ma, r ha b d oi d  ca ncer,  a n d  carci n o mas  of  t he  es o p ha g us, 
breast, l u n g a n d pa ncreas. Re gar dless of t he vari o us ge netic a berrati o ns t hat ma y be prese nt 
i n t he ca ncer cells, t he a nti- tu m or acti vit y of ri b ocicli b re q uires t he prese nce of f u ncti o nal 
p R b. Refer t o ri b ocicli b I n vesti gat ors Br oc h ure f or m ore detail s. 
 
Precli nical data ge nerate d usi n g a pri mar y m o del of E R + breast ca ncer c o m pare d ri b ocicli b 
at cli nicall y  rele va nt  d oses  wit h  t he  c o m bi nati o n  of  ri b ocicli b  pl us  letr oz ole  (ri b ocicli b 
I n vesti gat or  Br oc h ure  Fi g ure  4- 1 0).  A ni mals  treate d  wit h  t he  c om bi nati o n  s h o we d 
c o m plete i n hi biti o n of t u m or gr o wt h. B o d y wei g ht was m o nit ore d t hr o u g h o ut t he treat me nt 
s h o wi n g  c o m para ble  res ults  i n all  gr o u ps  s u p p orti n g  t he  pre dict e d  lac k  of  o verla p pi n g 
t o xi cit y bet wee n ri b ocicli b a n d letr oz ole. 
 
1. 2. 1. 1. 2 N o n cli ni c al p h ar m a c o ki n eti c s a n d m et a b oli s m of ri b o ci cli b  
T he p har mac o ki netics ( P K) of ri b oc icli b was i n vesti gate d i n m o use, rat, d o g a n d m o n ke y. 
Ri b ocicli b s h o we d hi g h cleara nce ( C L) i n t he m o use, rat, d o g a n d m o n ke y. T he v ol u me of 
distri b uti o n  was  l ar ge  acr oss  s pecies  a n d  t he  ter mi nal  eli mi nat i o n  h alf-life  ( T1/ 2)  was 
m o derate i n r o de nts a n d m o n ke y ( ~ 2 t o 5 h) a n d l o n ger i n d o g ( 1 8 h). 
Bi oa vaila bilit y was l o w t o m o derate i n rat ( 3 7 %) a n d c y n o m ol g us  m o n ke y ( 1 7 %); m o derate 
i n  m o use  ( 6 5 %)  a n d  d o g  ( 6 4 %).  F oll o wi n g  oral  a d mi nistrati o n,  time  t o  reac h  ma xi mal 
plas ma c o nce ntrati o ns ( T ma x ) occ urre d bet wee n 2 t o 4 h acr oss s pecies. 
Ge n der de pe n de nt t o xic o ki netics were o bser ve d i n rats wit h hi g h er e x p os ure t o ri b ocicli b i n 
males as c o m pare d t o fe males a n d hi g her e x p os ure t o t he meta b ol ite, L E Q 8 0 3. Plas ma pr otei n 
bi n di n g was m o derate i n all s pecies ( u n b o u n d fracti o n (f u) i n h u ma n: 3 0 %). 
I n  a  rat  A D M E  (a bs or pti o n,  distri b uti o n,  meta b olis m  a n d  e xcretio n)  st u d y,  e xte nsi ve 
distri b uti o n  of  [ 3 H]-ri b ocicli b  a n d  its  meta b olites  was  o bser ve d.  I n  pi g me nte d  rats, 
ra di oacti vit y was s pecificall y f ou n d i n mela ni n-c o ntai ni n g str u ct ures; t he hi g hest e x p os ure t o 
t otal ra di ola bele d c o m p o ne nts was o bser ve d i n e ye ciliar y b o d y, e ye c h or oi d, me ni n ges, tactile 
hair  a n d  hair  f ollicles.  Ra di oacti vit y  was  n ot  detecte d  i n  t he brai n.  T last  (last  o bser vati o n 
ti me p oi nt) was ≤ 4 8 h f or m ost tiss ues, b ut l o n g ( 1 6 8 t o 8 4 0 h) f or l y m p h n o des, pre p utial gla n d, 
testis,  e ye  a n d  me ni n ges.  At  o ne  wee k  ≤  0. 0 4 %  of  t he  d ose  was  retai ne d  i n  t he  carcass. 
L E Q 8 0 3 ( N- de met h ylati o n) was a pr o mi ne nt meta b olite f o u n d i n m o use, rat, d o g, m o n ke y 
a n d  h u ma n  he pat oc ytes. T his  metab olite retai ns  s o me p har mac ol o g ic acti vit y a n d i nteracts 
wit h h u ma n Et her-a- g o- g o Relate d Ge ne ( h E R G) c ha n nels i n vitr o.  I n male rats, u nc ha n ge d 
ri b ocicli b ( 2 4. 7 % of [ 3 H] A U C0- 2 4 h) a n d its meta b olite M 1 1 ( 2 6. 3 % of [ 3 H] A U C0- 2 4 h) were 
t he maj or c o m p o ne nts i n plas ma. 
I n  rats,  ri b ocicli b  was  eli mi nate d  mai nl y  b y  meta b olis m  wit h  direct  s ulfati o n  as  t he  maj or 
pat h wa y.  Direct  ri b ocicli b  secreti o n  acc o u nte d  f or  1 8. 2 %  of  t he   t otal  plas ma  cleara nce.  I n 
male d o gs, meta b olis m was t he maj or eli mi nati o n r o ute. T he m ost  pr o mi ne nt c o m p o ne nts i n 

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plas ma  were  ri b ocicli b  ( 5 5. 9 %  of  [ 1 4 C] A U C 0- 4 8 h)  a n d  its  meta b olite  L E Q 8 0 3  ( 1. 6 1 %  of 
[ 1 4 C] A U C0- 4 8 h).  
Res ults fr o m t he A D M E ( male rats) st u d y s h o we d t hat 3 H-c o m p o ne n ts were pre d o mi na ntl y 
e xcrete d wit h bile ( 6 1. 4 % of d ose). Mi n or uri nar y e xcreti o n was  o bser ve d ( 5. 9 % of d ose after 
p. o.). T he maj orit y of t he a d mi nistere d d ose ( 8 7. 3 %) was e xcret e d wit hi n 2 4 h via uri ne, feces 
(e nteric secreti o n) a n d bile. 
I n vitr o, ri b ocicli b was a re versi ble i n hi bit or of c yt oc hr o me P4 5 0 ( C Y P) e nz y mes C Y P 1 A 2, 
C Y P 2 E 1 a n d C Y P 3 A 4 a n d a ti me- de pe n de nt i n hi bit or of C Y P 3 A 4. Ri b ocicli b ma y i n hi bit 
C Y P 3 A 4 u n der t hera pe utic c o n diti o ns. N o i n d ucti o n of C Y P 1 A 2, C Y P 2 B 6 or C Y P 3 A 4 was 
o bser ve d. T he i n vitr o i n hi bit or y p ote nc y of ri b ocicli b o bser ve d f or t he tra ns p orters O A T P 1 B 1 
( or ga nic a ni o n tra ns p orti n g p ol y pe pti de 1 B 1), B C R P ( breast ca ncer resista nce pr otei n), O C T 1 
( or ga nic  cati o n  tra ns p orter  1),  O C T 2,  M A T E 1  ( m ulti dr u g  a n d  t o xi n  e xtr usi o n  pr otei n  1), 
M A T E 2 K a n d B S E P ( bile salt e x p or t p u m p) ma y tra nslate i nt o cli nicall y rele va nt i n hi biti o n 
at t hera pe utic d oses.  
Eli mi nati o n of ri b ocicli b is d o mi nate d b y o xi dati ve meta b olis m mai nl y via C Y P 3 A 4 wit h a 
mi n or  c o ntri b uti o n  b y  fla vi n-c o ntai ni n g  m o n o o x y ge nase  3  ( F M O 3).   T he  eli mi nati o n  of 
ri b ocicli b ma y be affecte d b y c o-a d mi nistere d dr u gs t hat i n hi bit or i n d uce C Y P 3 A 4. Alt h o u g h 
ri b ocicli b is a s u bstrate of t he P- gl yc o pr otei n ( P- g p) effl u x tra ns p orter, t his pr ocess is li kel y 
n ot cli nicall y rele va nt d ue t o t he hi g h passi ve per mea bilit y of  ri b ocicli b. 
Refer t o ri b ocicli b I n vesti gat ors Br oc h ure f or m ore details. 
1. 2. 1. 2  
Cli ni c al e x p eri e n c e wit h ri b o ci cli b  
Ri b ocicli b is c urr e ntl y bei n g i n vesti gat e d i n patie nts as a si n gle a ge nt i n 3 p has e I st u dies: 
( C L E E 0 1 1 X 1 1 0 1,  C L E E 0 1 1 X 2 1 0 1,  C L E E 0 1 1 X 2 1 0 2)  i n  2  p hase  II  st u dies: 
( C L E E 0 1 1 X 2 2 0 1, C L E E 0 1 1 X U S 0 3).  
Ri b ocicli b  is  bei n g  e val uate d  i n   se veral  c o m bi nati o n  trials:  letr oz ole  ( C L E E 0 1 1 A 2 2 0 1, 
C L E E 0 1 1 A 2 3 0 1, C L E E 0 1 1 A 2 1 1 5 C), letr oz ole a n d al pelisi b ( C L E E 0 1 1 X 2 1 0 7), letr oz ole 
a n d  b u parlisi b  ( C L E E 0 1 1 A 2 1 1 2 C);  g os ereli n,  letr oz ole,  a nastr oz ole,  a n d  ta m o xife n 
( C L E E 0 1 1 E 2 3 0 1);  
f ul vestra nt  
( C L E E 0 1 1 F 2 3 0 1),  
f ul vestra nt  
a n d  
b u parlisi b 
( C L E E 0 1 1 X 2 1 0 8),  
e ver oli m us  
a n d  
e xe mesta ne  
( C L E E 0 1 1 X 2 1 0 6),  
ceriti ni b 
( C L E E 0 1 1 X 2 1 1 0 C)  L D K 3 7 8  ( C L E E 0 1 1 X 2 11 0 C),  H D M 2 0 1  ( C H D M 2 0 1 X 2 1 0 3 C),  
L G X 8 1 8  ( C L E E 0 1 1 X 2 1 0 5,  C L G X 8 1 8 X 2 1 0 2),  L G X 8 1 8,  M E K 1 6 2  ( bi ni meti ni b) 
b u parlisi b  or  L G X 8 1 8,  bi ni meti ni b  a n d  I N C 2 8 0  or  L G X 8 1 8,  bi ni met i ni b  a n d  B GJ 3 9 8 
( C L G X 8 1 8 X 2 1 0 9)  bi ni meti ni b  ( C M E K 1 6 2 X 2 1 1 4),  or  bi ni meti ni b  a n d  LG X 8 1 8 
( C M E K 1 6 2 X 2 1 1 0).  
T hese  trials  are  o n g oi n g  wit h  t he  e xce pti o n  of  C L E E 0 1 1 A 2 2 0 1  a n d   C L E E 0 1 1 A 2 1 1 2 C 
w here  recr uit me nt  was  pre mat urel y  ter mi nate d  o n  2 8-J ul y- 2 0 1 4  a n d  2 0- Mar- 2 0 1 5 
res pecti vel y.  C L E E 0 1 1 A 2 3 0 1,  C L E E0 1 1 X 2 1 0 2  a n d  C L E E 0 1 1 X 2 1 0 5  ha ve als o  cl ose d 
e nr ol me nt.  T he  res ults  of  t he  p hase  I  c o m bi nati o n  of  letr oz ole 
a n d  L E E 0 1 1 
( C L E E 0 1 1 X 2 1 0 7)  are  detaile d  i n  Secti o n  1. 2. 6.  T he  p hase  III  trial  C L E E 0 1 1 A 2 3 0 1, 
i n vesti gati n g  t he  c o m bi nati o n of  letr oz ole  a n d  ri b ocicli b,  reac he d  its  pri mar y  e n d p oi nt 
pre mat urel y at t he pre pl a n ne d i nteri m a nal ysis. 
Ri b ocicli b is als o bei n g i n vesti g at e d i n 4 cli nical p har mac ol o g y st u dies: C L E E 0 1 1 A 2 1 0 2, 
C L E E 0 1 1 A 2 1 0 3,  C L E E 0 1 1 A 2 1 0 9  a n d  C L E E 0 1 1 2 1 1 6.  T hree  cli nical  p har mac ol o g y 
st u dies  i n  healt h y  s u bjects  ha ve  bee n  c o m plete d:  C L E E 0 1 1 A 2 1 0 1, C L E E 0 1 1 A 2 1 0 6  a n d 
C L E E 0 1 1 A 2 1 1 1.  
Refer t o t he ri b ocicli b I n vesti g at or Br oc h ure f or a d diti o nal de tails. 

N o v arti s 
C o nfi d e nti al 
P a g e 2 6 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
1. 2. 1. 2. 1 Cli ni c al s af et y o f ri b o ci cli b a s si n gl e a g e nt 
As of 1 5-J u n- 2 0 1 5, 1 5 7 patie nts ha ve bee n treate d wit h si n gle a ge nt ri b ocicli b i n t he first-
i n- h u ma n ( FI H) p hase I st u d y; 85 patie nts ha ve bee n treate d i n t he i nitial d ose escalati o n 
part f or t he 3 wee k o n/ 1 wee k of f re gi me n a n d 4 7 patie nts i n t he d ose e x pa nsi o n part of t he 
st u d y; 1 8 patie nts were e nr olle d f or t he c o nti n u o us d osi n g re gime n wit h ri b ocicli b a n d, 7 
patie nts were e nr olle d i n t h e li q ui d f or m ulati o n c o h ort.  
Patie nts wit h a d va nce d s oli d t u m ors or l y m p h o mas were treate d w it h i ncreasi n g d oses of 
ri b ocicli b orall y, o nce dail y ( q d) f or 2 1 da ys f oll o we d b y a 1-wee k rest ( 2 8- da y c ycle). D oses 
ra n gi n g  fr o m  5 0  m g  t o  1 2 0 0  m g  were  e val uate d  o n  t his  sc he d ule. Treat me nt  has  bee n 
disc o nti n ue d i n 1 2 0 ( 9 0 %) patie nts; t he pri mar y reas o ns f or tre at me nt disc o nti n uati o n were: 
disease pr o gressi o n ( 1 0 6 [ 8 0 %] pa tie nts); a d verse e ve nts ( A Es) ( 7 [ 5 %] patie nts); deat h ( 2 
[ 1. 5 %]  patie nts);  wit h dra wal  of  c o nse nt  ( 3  [ 2 %]  patie nt);  a n d  loss  t o  f oll o w  u p  ( 1  [ 1 %] 
patie nt). 
T he m ost fre q ue ntl y re p orte d A Es ( ≥1 0 %), re gar dless of gra de, c a usalit y a n d ri b ocicli b d ose 
were: na usea ( 5 2. 3 %); fati g ue ( 4 0. 9 %); diarr hea ( 3 7. 1 %); v o miti n g ( 3 5. 6 %); ne utr o pe nia 
( 3 4. 1 %); a ne mia ( 3 2. 6 %); decrease d a p petite, t hr o m b oc yt o pe nia (2 3. 5 % eac h); w hite bl o o d 
cell  c o u nt  decrease  ( 2 2. 7 %);  leu k o pe nia  ( 2 2 %);  c o nsti pati o n  ( 2 1 . 2 %);  d ys p nea  ( 2 0. 5 %); 
ast he nia  ( 1 9. 7 %);  c o u g h  ( 1 8. 2 %);  h y per gl yce mia  ( 1 7. 4 %);  hea dac h e,  h y p oal b u mi ne mia 
( 1 6. 7 % eac h); E C G Q T pr ol o n ge d ( 1 5. 9 %); a b d o mi nal pai n, bac k pai n, l y m p h oc yte c o u nt 
decrease,  p yre xia  ( 1 5. 2 %  eac h);  A S T  i ncrease,  bl o o d  creati ni ne i ncrease d,  dizzi ness, 
l y m p h o pe nia ( 1 4. 4 % eac h); peri p heral e de ma ( 1 3. 6 %); ne utr o p hil c o u nt decrease d ( 1 2. 9 %); 
A L T i ncrease, pai n i n e xtre mit y ( 1 2. 1 % eac h) a n d h y p ocalce mia ( 1 1. 4 %). 
F or eit her c o nti n u o us or i nter mitte nt d osi n g, t he o nset of ne ut r o pe nia ( m ost fre q ue ntl y Gra de 
2) occ urs b y Da y 1 5, reac hi n g a na dir i n t he t hir d or f o urt h we e k wit h rec o ver y d uri n g t he 
wee k of dr u g h oli da y f or t he t hree wee ks o n/ o ne wee k off sc he d u le. S o me patie nts re q uire 
a d diti o nal ti me f or rec o ver y ( 7 t o 1 4 da ys). Q T c ha n ges bec o me e vi de nt i n t he first c ycle b y 
Da y 8 a n d later ( o nce stea d y state is reac he d), are ass ociate d wit h t he ma xi m u m dr u g le vels 
bet wee n 1 t o 8 h p ost- d ose, a n d re mai n sta ble or i m pr o ve i n s u b se q ue nt c ycles. 
As of 1 5-J u n- 2 0 1 5, as y m pt o matic Gra de 2 Q Tc F pr ol o n gati o n was o bser ve d wit h i ncreasi n g 
fre q ue nc y w he n i ncreasi n g t he d ose starti n g at 6 0 0 m g: te n patie nts ( 1 3. 5 %) i n t he 6 0 0 m g 
c o h ort, t hree patie nts ( 2 1 %) i n t he 7 5 0 m g c o h ort, f o ur patie nt s ( 3 1 %) i n t he 9 0 0 m g c o h ort, 
a n d t w o patie nts ( 6 7 %) i n t he 1 2 0 0 m g c o h ort. F o ur patie nts ( 5. 4 %) at 6 0 0  m g a n d t w o 
patie nts  ( 1 5 %)  at  9 0 0 m g  ha d  as y m pt o matic  Q Tc F  pr ol o n gati o n  t ha t  res ulte d  i n a  Q Tc F 
i nter val of 5 0 0 ms or m ore. As c o m pare d t o baseli ne val ue, Q Tc F pr ol o n gati o n was at least 
3 0 msec i n 2 patie nts ( 5 0 %) at 2 5 0 m g, 2 ( 4 0 %) at 3 5 0 m g a n d 4 0 0  m g, 5 9 ( 7 9. 7 %) at 6 0 0 
m g, 1 1 ( 7 8. 6 %) at 7 5 0 m g, 1 1 ( 8 5 %) at 9 0 0 m g a n d 2 ( 6 7 %) at 1 2 0 0 m g; a n d at least 6 0 
msec  i n  2 3 %,  0 %,  3 9 %  a n d  6 7 %  of  patie nts at  6 0 0  m g,  7 5 0  m g,  9 0 0   m g  a n d  1 2 0 0  m g, 
res pecti vel y. O ne gra de 1 atri o ventric ular bl oc k of first de gre e was re p orte d as relate d t o 
ri b ocicli b gi ve n at t he d ose of 1 4 0 m g. O ne gra de 1 atri o ve ntri c ular bl oc k of first de gree 
was  re p orte d  as  relate d  t o  ri b oc icli b  gi ve n  at  t he  d ose  of  1 4 0 m g. N o ot her car diac 
a b n or malities were o bser ve d as relate d a d verse e ve nts i n a n y pa tie nt. 
T here ha ve bee n n o deat hs relate d t o st u d y dr u g re p orte d o n st u d y [ C L E E 0 1 1 X 2 1 0 1]. T he 
f oll o wi n g seri o us a d verse e ve nts s h o w n i n Ta ble 1- 1 ha ve bee n re p orte d wit h a s us pecte d 
ca usal relati o ns hi p i n st u d y [ C L E E 0 1 1 X 2 1 0 1] as of 6- A u g- 2 0 1 5. For a c o m plete list of A Es, 
all gra des a n d Gra de 3/ 4 t hat are s us pecte d t o be relate d t o ri b ocicli b refer t o t he ri b ocicli b 
I n vesti gat ors Br oc h ure. 

N o v arti s 
C o nfi d e nti al 
P a g e 2 7 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
T a bl e 1- 1  
S eri o u s a d v er s e e v e nt s wit h a s u s p e ct e d c a u s al r el ati o n s hi p wit h 
ri b o ci cli b si n gl e a g e nt  
S eri o us s us p e ct e d a d v ers e e v e nts  w hi c h h a v e o c c urr e d wit h ri b o ci cli b ( si n gl e a g e nt) 
S yst e m Or g a n Cl ass Pr ef err e d T er m  
Pr ef err e d T er m  
Bl o o d a n d l y m p h ati c s y st e m di s or d er s  
A n a e mi a, F e bril e n e utr o p e ni a, 
N e utr o p e ni a, T hr o m b o c yt o p e ni a  
G a str oi nt e sti n al di s or d er s  
Di arr h o e a, N a u s e a , P a n cr e atiti s 
G e n er al di s or d er s a n d a d mi ni str ati o n sit e c o n diti o n s  
G e n er ali z e d o e d e m a  
I nf e cti o n s a n d i nf e st ati o n s 
H er p e s si m pl e x  
I n v e sti g ati o n s 
Bl o o d cr e ati ni n e i n cr e a s e d, El e ctr o c ar di o gr a m Q T 
pr ol o n g e d  
E v e nt s i n it ali c f o nt i n di c at e t h o s e e v e nt s w hi c h ar e n e wl y i n cl u d e d si n c e t h e pr e vi o u s e diti o n of t h e 
r ef er e n c e s af et y i nf or m ati o n. 
Refer t o ri b ocicli b I n vesti gat ors Br oc h ure f or m or e det ails. 
1. 2. 1. 2. 2 Cli ni c al effi c a c y wit h ri b o ci cli b a s si n gl e a g e nt 
Preli mi nar y  a nti-t u m or  acti vit y   of  ri b ocicli b  fr o m  trial  [ C L E E 01 1 X 2 1 0 1]  was  assesse d 
acr oss all d ose le vels ( 5 0 m g – 1 2 0 0 m g). O ut of 1 1 4 e val ua ble s u bjects as of 2 4- A pr- 2 0 1 4, 
3 partial res p o nses were o bser ve d at t he 6 0 0 m g d ose le vel; o ne  eac h i n B R A F/ N R A S wil d 
t y pe wit h C C N D 1 a m plifie d mela n o ma, a n d hea d a n d nec k aci nar carci n o ma wit h C D K N 2 A 
l oss  ( b ot h  o n  t he  3  wee ks  o n/ 1  wee k  off  re gi me n),  a n d  E R +/ H E R 2-,  PI K 3 C A  m uta nt, 
C C N D 1 a m plifie d breast ca ncer ( o n t he c o nti n u o us dail y d osi n g r e gi me n). Sta ble disease 
( S D)  was  t he  best  o verall  res p o nse  i n  4 1  ( 3 7 %)  patie nts.  E nr oll me nt  i n  t his  st u d y  is 
c o m plete d. Sta ble disease ≥4 c ycles a n d ≥6 c ycles was o bser ve d i n 2 6 ( 2 4 %) a n d 1 7 ( 1 5 %) 
patie nts, res pecti vel y. Si x patie nts wit h S D ≥4 c ycles recei ve d  treat me nt f or > 1 year, of t hese 
2 patie nts were o n st u d y f or > 2 year s (Jeffre y R I nfa nte A S C O 20 1 4 a bstract 2 5 2 8). 
Refer t o ri b ocicli b I n vesti gat or s Br oc h ure f or m ore det ails. 
 
1. 2. 1. 2. 3 Cli ni c a l p h ar m a c o ki n eti c s of ri b o ci cli b 
As of 1 5-J u n- 2 0 1 5, preli mi nar y P K data were a vaila ble fr o m a p pr o xi matel y 1 4 3 patie nts 
fr o m t he first-i n h u ma n ( FI H) st u d y [ C L E E 0 1 1 X 2 1 0 1] acr oss t he d ose ra n ge of 5 0 t o 1 2 0 0 
m g.  F oll o wi n g oral d osi n g, ri b ocicli b was ra pi dl y a bs or be d wit h me dia n Tma x  ra n gi n g fr o m 
1  t o  4  h o urs.  Ri b ocicli b  plas ma  e x p os ure  ( C ma x   a n d  A U C0- 2 4 h)  e x hi bite d  sli g htl y  o ver-
pr o p orti o nal i ncreases i n e x p os ur e acr oss t he d ose ra n ge teste d . Stea d y-state was ge nerall y 
reac he d b y Da y 8 a n d t he mea n effecti ve T1/ 2 base d o n acc u m ulati o n rati o (i.e., T 1/ 2, acc) 
ra n ge d fr o m 1 2. 3 t o 4 2. 9. T he mea n acc u m ulati o n rati o ( Racc) calc ulate d fr o m A U C0- 2 4 h at 
stea d y-state a n d A U C 0- 2 4 h after a si n gle d ose acr oss t he st u die d d oses ra n ge d fr o m 1. 3 5 t o 
3. 1 1.   
At  t he  rec o m me n de d  d ose  f or  f ut ure  de vel o p me nt  ( 6 0 0  m g),  stea d y -state  plas ma  C ma x 
( n = 5 6) ra n ges fr o m 6 0 6- 6 1 7 0 n g/ m L ( ge o metric mea n = 1 7 9 0 n g/ m L or 4. 1 µ M), me dia n 
T ma x   ( n = 7 2)  is  2. 1  h, a n d  A U C0- 2 4 h ( n = 5 3) ra n ges fr o m 6 7 7 0- 9 0 6 0 0 n g * h/ m L ( ge o metric 
mea n = 2 3 6 0 0 h * n g/ m L). At t his d ose,  i nter- patie nt varia bilit y i n Cma x  a n d A U C is 6 2 % a n d 
6 6 %, res pecti vel y, as assesse d b y ge o metric c oefficie nt of vari ati o n ( C V %). At t he 6 0 0 m g 
d ose  le vel,  L E Q 8 0 3,  a n  acti ve  me ta b olite  of  ri b ocicli b,  acc o u nte d  f or  a p pr o xi matel y  8 % 
( ge o metric  mea n)  of  ri b ocicli b  A U C0- 2 4 h after  si n gle  a n d  m ulti ple  d oses.  Refer  t o  t he 
ri b ocicli b [I n vesti gat ors Broc h ure] f or m ore details. 

N o v arti s 
C o nfi d e nti al 
P a g e 2 8 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
I n a f o o d effect st u d y [ C L E E 0 1 1 A 2 1 1 1] i n 2 4 healt h y s u bjects, a si n gle d ose of ri b ocicli b 
( 6 0 0 m g) was a d mi nistere d as dr u g-i n-ca ps ule ( Di C) wit h a hi g h-fat, hi g h-cal orie meal a n d 
u n der faste d c o n diti o ns. C o m pare d t o t he faste d state, oral a d m i nistrati o n of a si n gle 6 0 0 
m g d ose of ri b ocicli b Di C wit h a hi g h-fat, hi g h-cal orie meal de crease d t he rate of a bs or pti o n 
of  ri b ocicli b  res ulti n g  i n  a  2 3 %  decrease  i n  C ma x   ( ge o metric  mea n  rati o:  0. 7 7 5;  9 0 % 
c o nfi de nce i nter val [ CI]: 0. 7 0 0, 0. 8 5 8) a n d a me dia n differe nce  i n Tma x  of 2 h o urs. H o we ver, 
t here was n o effect o n t he e xte nt of a bs or pti o n of ri b ocicli b as t he o verall e x p os ure ( A U C i nf) 
was u naffecte d u n der fe d c o n diti o ns ( ge o metric mea n rati o: 0. 9 9 4; 9 0 % CI: 0. 9 2 5, 1. 0 7 0). 
A si milar tre n d was o bser ve d f or L E Q 8 0 3, a n acti ve meta b olite o f ri b ocicli b, wit h a decrease 
i n Cma x  ( 3 2 %), a dela y i n me dia n T ma x, a n d n o s u bsta ntial effect o n o verall e x p os ure. Base d 
o n t hese data, ri b ocicli b Di C ca n be ta ke n wit h o ut re gar d t o me als. 
I n t he h u ma n A D M E st u d y [ C L E E 0 1 1 A 2 1 0 2], a si n gle oral d ose of 60 0 m g [ 1 4C] L E E 0 1 1 
was a d mi nistere d t o 6 healt h y male s u bjects. T he maj orit y of t h e a d mi nistere d d ose was 
e xcrete d i n feces ( 6 9. 1 %), wit h a mi n or a m o u nt e xcrete d i n uri n e ( 2 2. 6 %). A bs or pti o n was 
esti mate d t o be a p pr o xi matel y 5 8. 8 %. Ri b ocicli b acc o u nte d f or a p pr o xi matel y 2 3 % of t he 
t otal ra di oacti vit y i n plas ma, base d o n A U Ci nf. Meta b olites M 1 ( gl uc ur o ni dati o n of M 1 5), 
M 4  ( L E Q 8 0 3,  N- de met h ylati o n)  a n d  M 1 3  ( C CI 2 8 4,  N- h y dr o x ylati o n) were  t he  m ost 
a b u n da nt meta b olites i n plas ma, re prese nti n g a n esti mate d 7. 7 8 % , 8. 6 0 % a n d 9. 3 9 % of t otal 
[1 4C] A U C 0- 4 8 h, a n d 1 7. 9 %, 1 9. 8 % a n d 2 1. 6 % of ri b ocicli b A U C0- 4 8 h, base d o n meta b olite 
pr ofiles. 
A D DI st u d y wit h rit o na vir (a str o n g C Y P 3 A 4 i n hi bit or) a n d rifa m pici n (a str o n g C Y P 3 A 4 
i n d ucer) was c o n d ucte d i n 4 8 healt h y s u bjects [ C L E E 0 1 1 A 2 1 0 1]. Co m pare d t o ri b ocicli b 
al o ne, rit o na vir ( 1 0 0 m g bi d f or 1 4 da ys) i ncreas e d ri b ocicli b C ma x  a n d A U Ci nf b y 1. 7-f ol d 
a n d  3. 2-f ol d,  res pecti vel y,  f oll o wi n g  a  si n gle  oral  d ose  of  4 0 0  m g  ri b ocicli b.  Cma x   a n d 
A U C last  decrease d  b y  9 6 %  a n d  9 8 %,  res pecti vel y.  T hese  res ults  de m o nstrate d  t hat 
c o nc urre nt use of str o n g C Y P 3 A 4 i n hi bit ors ma y mar ke dl y i ncrease ri b ocicli b e x p os ure a n d 
are pr o hi bite d. 
C o m pare d t o ri b ocicli b al o ne, rifa m pici n ( 6 0 0 m g dail y f or 1 4 da ys) decrease d ri b ocicli b 
C ma x  a n d A U Ci nf b y 8 1 % a n d 8 9 %, res pecti vel y, f oll o wi n g a si n gle oral d ose of 6 0 0 m g 
ri b ocicli b. Cma x  i ncrease d 1. 7-f ol d a n d A U Ci nf decrease d b y 2 7 %, res pecti vel y. T hese res ults 
de m o nstrate d  t hat  c o nc urre nt  use  of  str o n g  C Y P 3 A 4  i n d ucers  ma y mar ke dl y  decrease 
ri b ocicli b e x p os ure a n d are pr o hi bite d. 
A  D DI  c oc ktail  st u d y  wit h  mi daz ola m  (a  se nsiti ve  C Y P 3 A 4  s u bstra te)  a n d  caffei ne  (a 
se nsiti ve C Y P 1 A 2 s u bstrate) c o n d ucte d i n 2 5 healt h y s u bjects [ C L E E 0 1 1 A 2 1 0 6] i n dicate d 
t hat ri b ocicli b ( 4 0 0 m g) is a m o derate i n hi bit or of C Y P 3 A 4, b ut di d n ot ha ve a s u bsta ntial 
effect o n C Y P 1 A 2 s u bstrates i n h u ma ns. P K data i n dicate d t hat c o m pare d t o mi daz ola m a n d 
caffei ne al o ne, m ulti ple d oses of ri b ocicli b ( 4 0 0 m g q d f or 8 d a ys) i ncrease d mi daz ola m 
C ma x   a n d  A U Ci nf  b y  2. 1-f ol d  a n d  3. 8-f ol d,  res pecti vel y.  T he  effect  of  m ulti ple d oses of 
ri b ocicli b o n caffei ne was mi ni mal, wit h Cma x  decrease d b y a p pr o xi matel y 1 0 % a n d A U Ci nf 
i ncrease d sli g htl y b y 2 0 %. Base d o n t hese data, ri b ocicli b ( 4 0 0 m g) is a m o derate C Y P 3 A 4 
i n hi bit or ( ≥ 2- f ol d b ut < 5-f ol d i ncrease i n A U C). C o nc urre nt use of se nsiti ve C Y P 3 A 4 
s u bstrates wit h a narr o w t hera pe utic i n de x is pr o hi bite d. 
Ri b ocicli b  ( 4 0 0  m g)  di d  n ot  ha ve  a  s u bsta ntial  effect  o n  C Y P 1 A 2   i n  h u ma ns;  t heref ore, 
c o nc urre nt use of C Y P 1 A 2 s u bstrat es is n ot e x pecte d t o lea d t o cli nicall y si g nifica nt D DIs. 
Refer t o t he ri b ocicli b I n vesti g at ors Br oc h ure f or m ore details . 

N o v arti s 
C o nfi d e nti al 
P a g e 2 9 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
1. 2. 1. 2. 4 Cli ni c a l p h ar m a c o d y n a mi c s of ri b o ci cli b 
Paire d  s ki n  bi o psies  fr o m  5 5  pa tie nts  treate d  wit h  L E E 0 1 1  at  d oses  ra n gi n g  fr o m  5 0  t o 
9 0 0 m g a n d paire d t u m or bi o psies fr o m 2 0 patie nts ( 1 6 patie nts at 6 0 0 m g, 2 patie nts at 
9 0 0 m g, a n d 1  patie nt eac h at 7 0 a n d 7 5 0 m g) were assesse d f or c ha n ges i n Ki 6 7 a n d p R b 
le vels. Preli mi nar y r es ults i n dicate t he f oll o wi n g: i n s ki n bi opsies, re d ucti o ns i n Ki 6 7 fr o m 
baseli ne were o bser ve d acr oss all d ose le vels wit h a m ore c o nsi ste nt tre n d fr o m 4 0 0 m g 
o n war ds;  i n  t u m or  bi o psies,  re d ucti o ns  i n  Ki 6 7  fr o m  baseli ne  we re  o bser ve d  i n  1 8/ 2 0 
patie nts; h o we ver, li mite d sa m ples a n d varie d t u m or t y pes pre ve nt c o ncl usi o ns a b o ut a n y 
d ose-res p o nse relati o ns hi p  fr o m   bei n g  dra w n.  C ha n ges  i n  p R b  were  n ot  si g nifica nt  or 
c o nsiste nt  i n  eit her s ki n or t u mor sa m ples, p ossi bl y d ue t o var ie d t u m or t y pes. F or f urt her 
details see Secti o n 5. 2. 1 of t he  ri b ocicli b ( L E E 0 1 1) i n vesti gator’s br oc h ure. 
 
1. 2. 2  
O v er vi e w of l etr o z ol e 
Use of e n d ocri ne ne oa dj u va nt t he ra p y was i nitiall y restricte d to el derl y E R + patie nts base d 
o n t he fact t hat h or m o ne rece pt or p ositi ve t u m ors were res p o n di n g less t o c he m ot hera p y 
as c o m pare d  t o  ot her  breast  ca ncer  t y pes  ( Gia n ni  2 0 0 5;  Berr y  2 0 0 6).  M ore rece nt trials 
ha ve s h o w n t he lac k of i nteracti o n bet wee n ne oa dj u va nt e n d ocri n e t hera p y o utc o me a n d 
a ge  ( Ols o n  2 0 0 9),  a n d  c o m para ble  o utc o me  bet wee n  c he m ot hera p y  a n d  e n d ocri ne 
ne oa dj u va nt  t hera p y  i n  E R +  B C  pa tie nts  ( Se mi glaz o v  2 0 0 7).  Ne oa dj u va nt  e n d ocri ne 
treat me nt ca n t h us n o w be pr o p ose d t o p ost me n o pa usal w o me n as n e oa dj u va nt treat me nt 
re gar dless of t heir a ge ( N C C N g ui deli nes 3. 2 0 1 3). 
Letr oz ole  ( Fe mara ® )  is  a  n o nster oi dal  c o m petiti ve  i n hi bit or  of  t he  ar o matase  e nz yme 
s yste m wit h 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 H R + 
breast ca ncer.  Letr oz ole  acts  b y i n hi biti n g  i n  a  hi g hl y  selective  fas hi o n  t he  c o n versi o n 
of  a dre nal  a n dr o ge ns  t o  estr o ge ns ,  w hic h  is  t he  pri mar y  s o urce  of  estr o ge ns  i n 
p ost me n o pa usal w o me n. Letr oz ole is  a hi g hl y selecti ve i n hi bit or of ar o matase t hat i n d uces 
a 7 5 % t o 9 5 % decrease of estr o ge n le vels after t w o wee ks of treat me nt usi n g dail y d oses 
of 0. 1 t o 5 m g, wit h n o si g nifi ca nt cli nical a n d la b orat or y t o x icities n or c ha n ges i n le vels 
of ot her h or m o nes of t he e n d ocri ne s yste m as s h o w n i n earl y p ha se I ( Li pt o n 1 9 9 5; Tr u net 
1 9 9 6). It is i n dicate d f or t he a dj u va nt treat me nt of w o me n wit h H R + earl y breast ca ncer as 
well as t he e xte n de d a dj u va nt treat me nt of patie nts w h o ha ve re cei ve d 5 years of ta m o xife n 
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  H R +  breast  ca ncer,  b ot h  i n 
t he  first-li ne  setti n g  as  well  as  i n patie nts w h o ha ve disease pr o gressi o n f oll o wi n g a nti-
estr o ge n t hera p y. Letr oz ole was c o m pare d wit h ta m o xife n i n a p h ase III trial i n t he first 
li ne setti n g i n E R +/ H E R 2 + breast ca ncer.  Letr oz ole  was  s u peri or  t o  ta m o xife n  f or  ti me 
t o  pr o gressi o n  ( me dia n,  9. 4  v.  6. 0 m o nt hs) a n d me dia n O S tre n ded s u peri or f or letr oz ole 
( me dia n,  3 4  vers us  3 0  m o nt hs)  b ut  t his  differe nce  was  n ot  statisticall y  si g nifica nt 
( M o uri dse n 2 0 0 1). 
 
Letr oz ole  is  a d mi nistere d  orall y   o nce  dail y  at  a  d ose  of  2. 5  m g  a n d  is  ra pi dl y  a n d 
c o m pletel y a bs or be d  fr o m  t he  gastr oi ntesti nal  tract.  C o nc o mita nt  i nta ke  of  f o o d  has 
n o  effect  o n  t he e xte nt  of  letr oz ole  a bs or pti o n  a n d  o nl y a  mi n o r  effect  o n  t he  rate  of 
a bs or pti o n,  w hic h  is c o nsi dere d t o be of n o  cli nical rele va nce.  T he ter mi nal eli mi nati o n 
half-life of letr oz ole is 2 da ys a n d stea d y-state plas ma c o nce n trati o n wit h dail y d osi n g at 
t he  sta n dar d  d ose  is  reac he d  i n  2- 3  wee ks.  Letr oz ole  is  meta b olize d  via  C Y P 3 A 4  t o  a 
p har mac ol o gicall y-i nacti ve car bi n ol meta b olite ( 4, 4’- met ha n ol- b is be nz o nitrile) a n d re nal 
e xcreti o n of t he gl uc ur o ni de c o nj u gate of t his meta b olite is t h e maj or pat h wa y of letr oz ole 

N o v arti s 
C o nfi d e nti al 
P a g e 3 0 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
cleara nce. I n a d diti o n, C Y P 2 A 6 f or ms t he car bi n ol meta b olite as  well as its ket o ne a nal o g 
[ Fe mara® Pr escri bi n g I nf or mati o n, N o vartis]. 
 
T he m ost fre q ue ntl y re p orte d a d verse e ve nts t hat were si g nifica ntl y differe nt fr o m place b o 
f or  letr oz ole  i n  t he  a dj u va nt  a n d  e xte n de d  a dj u va nt  setti n g  i ncl u de  h ot  flas hes, 
art hral gia/art hritis  a n d  m yal gia.  I n  t he  first  li ne  setti n g,  t h e  m ost  fre q ue ntl y  re p orte d 
a d verse e ve nts i ncl u de m usc ul os keletal pai n ( b o ne/ bac k pai n a n d  art hral gia), h ot flas hes, 
na usea a n d d ys p nea a n d i nci de nces of a d verse e ve nts were si mila r f or  ta m o xife n i n t his 
setti n g. I n ge neral, t he o bser ve d a d verse reacti o ns are mil d t o  m o derate i n nat ure [ Fe mara® 
Prescri bi n g I nf or mati o n, N o vartis]. 
 
I n  t he  ne oa dj u va nt  setti n g  f or  w o me n  wit h  u nresecta ble  h or m o ne rece pt or  p ositi ve 
earl y breast ca ncer, letr oz ole was ass ociate d wit h si g nifica ntl y hi g her res p o nse rate t ha n 
ta m o xife n  ( 6 0 %  vers us  4 8 %,  P = 0. 0 0 4)  a n d  a  hi g her  perce nta ge  of patie nts  u n der we nt 
breast c o nser vati ve s ur ger y ( 4 8 % vers us 3 6 %, P = 0. 0 3 6) ( Ellis 2 0 0 1). 
 
1. 2. 3  
O v er vi e w of g o s er eli n 
G osereli n  ( Z ola de x ® )  is  a  s y nt hetic  deca pe pti de  a nal o g  of  g o na d otr o pi n  releasi n g 
h or m o ne ( G n R H) i n dicate d  f or pr ost atic carci n o ma, e n d o metri osis , e n d o metrial t hi n ni n g, 
a n d a d va nce d breast  ca ncer.  G osereli n  is  a d mi nistere d  s u bc uta ne o usl y  e ver y  2 8  d a ys  at 
a  d ose  of  3. 6  m g.  F oll o wi n g  s u bc uta ne o us  a d mi nistrati o n  of  g ose reli n  ( 3. 6  m g  f or  2 
m o nt hs),  T ma x   was  1 2- 1 5 da ys  p ost- d ose  i n  males  a n d  8- 2 2  d a ys  p ost- d ose  i n  f e males. 
T he meta b olis m of g osereli n is n ot C Y P- me diate d; rat her it is m eta b olize d b y h y dr ol ysis 
of  C-ter mi nal  a mi n o  aci ds.  M ore t ha n  9 0 %  of  a  ra di ola bele d  d ose   was  e xcrete d  i n  t he 
uri ne, wit h a p pr o xi matel y 2 0 % of t he d ose i n uri ne acc o u nte d f o r b y u nc ha n ge d g osereli n. 
T he  a d verse  e ve nts  occ urri n g  i n  >  2 0 %  of  w o me n  i ncl u de d  h ot  fl u s hes,  hea dac he, 
s weati n g,  ac ne,  e m oti o nal  la bilit y,  de pressi o n, decrease d li bi do, va gi nitis, breast atr o p h y, 
se b orr hea a n d p eri p heral  e de ma ( Z ola de x ® Prescri bi n g I nf or mati o n). 
 
F or i nf or mati o n o n g osereli n a n d m a na ge me nt of g osereli n relate d a d verse e ve nts refer t o 
t he Z ola de x ® S m P C or Prescri bi n g I nf or mati o n. 
 
1. 2. 4  
L o w p ot e nti al f or i nt er a cti o n b et w e e n ri b o ci cli b a n d l etr o z ol e 
Letr oz ole  is  n ot  e x pecte d  t o  aff ect  t he  meta b olis m  of  ri b ocicli b, w hic h is 
mai nl y 
m eta b olize d b y C Y P 3 A 4 wit h a 1 5- 2 6 % c o ntri b uti o n b y t he p ol y m or p hic e nz y me F M O 3 
(fla vi n-c o ntai ni n g m o n o o x y ge nase 3) base d o n i n vitr o data. Letr oz ole i n hi bits C Y P 2 A 6 
( Ki  =  4. 6 µ M)  a n d  C Y P 2 C 1 9  ( Ki  =  4 2  µ M)  i n  vitr o  [Je o n g  2 0 0 9;  Femara ® Prescri bi n g 
I nf or mati o n], b ut is n ot a n i n hi bit or of C Y P 3 A 4 or F M O 3 a n d is t heref ore n ot e x pecte d t o 
affect ri b ocicli b meta b olis m. 
 
Ri b ocicli b  ma y i ncrease  t he  e x p os ure  of  c o- me dicati o ns  t hat  are  s u bstrates of C Y P 3 A 4 
d ue t o ti me- de pe n de nt  i n hi biti o n  of  t his  e nz y me.  I n  vitr o  st u dies  i n dicate  L E E 0 1 1  is  a 
re versi ble i n hi bit or of C Y P 3 A 4 ( Ki = 3 5 μ M) a n d a ti me- de pe n de nt i n hi bit or of C Y P 3 A 4 
( KI = 5. 0 6 μ M, ki nact = 0. 0 2 4 5 mi n- 1). Letr oz ole is meta b olize d via C Y P 3 A 4 a n d C Y P 2 A 6 
[ Fe mara® Pr escri bi n g I nf or mati o n] a n d he nce letr oz ole c o nce ntrati o ns c o ul d be affecte d b y 
c oa d mi nistrati o n wit h ri b ocicli b. Preli mi nar y P K data f or t he c o m bi nati o n of ri b ocicli b ( 6 0 0 
m g) a n d letr oz ole ( 2. 5 m g) i n dicate t hat ri b ocicli b a n d letr oz o le e x p os ures are wit hi n t he 
ra n ge of val ues f or t he res pecti ve si n gle a ge nt a n d t he c o m bi nati o n is safe a n d t olera ble. 

N o v arti s 
C o nfi d e nti al 
P a g e 3 1 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 
1. 2. 5  
L o w p ot e nti al f or dr u g- dr u g i nt er a cti o n s wit h g o s er eli n 
T he meta b olis m of g osereli n is n ot C Y P- me diate d; rat her h y dr ol y sis of C-ter mi nal a mi n o 
aci ds  is  t he  maj or  cleara nce  mec ha nis m.  N o  f or mal  cli nical  D DI st u dies  ha ve  bee n 
c o n d ucte d or r e p orte d wit h g oser eli n. Base d o n t he a vaila ble i n f or mati o n, g osereli n is n ot 
e x pecte d t o affect t he meta b olis m of n or be affecte d b y c o-a d mi nistere d dr u gs ( Z ola de x ® 
Prescri bi n g I nf or mati o n). 
 
1. 2. 6  
S u m m ar y of a v ail a bl e r e s ult s fr o m p ati e nt s tr e at e d wit h t h e 
c o m bi n ati o n of ri b o ci cli b 6 0 0 m g  a n d l etr o z ol e 2. 5 m g d ail y 
St u d y  C L E E 0 1 1 X 2 1 0 7,  is  a  m ultice nter  p hase  I b/II  d ose  escalati o n/e x pa nsi o n  st u d y  of 
L E E 0 1 1 a n d B Y L 7 1 9 i n c o m bi nati o n w it h letr oz ole i n a d ult patie nts wit h a d va nce d estr o ge n 
rece pt or  p ositi ve  ( E R +)  breast  ca ncer. Patie nts  m ust  be  p ost me no pa usal  wit h  metastatic 
or l ocall y a d va nce d E R +, H E R 2- ne gati ve breast ca n cer. D osi n g i n  Ar m 1 (letr oz ole 2. 5 m g 
o nce dail y o n da ys 1- 2 8 wit h L E E 0 1 1 6 0 0 m g o nce dail y o n da ys 1 - 2 1 of a 2 8 da y c ycle 
si nce t here is  a 7 da y rest  fr o m  L E E 0 1 1 treat me nt i n  eac h c ycle) be ga n o n  Dece m ber 3, 
2 0 1 3, a n d as of Oct o ber 3 0, 2 0 1 5, 4 7  patie nts ha ve bee n treate d ( d ose escalati o n a n d d ose 
e x pa nsi o n).  1 7  of  1 9  patie nts  ( 9 0 %)  i n  d ose  escalati o n  were  pre vi o usl y  treate d  f or  A B C 
( pre vi o usl y treate d gro u p), 2 7 of 2 8 patie nts ( 9 6 %) i n d ose e x pa nsi o n were treat me nt- naï ve 
f or A B C (treat me nt- naï ve gr o u p). 
Treat me nt has bee n disc o nti n ue d i n all 1 9 pre vi o usl y treate d pts ( 1 0 0 %) d ue t o pr o gressi o n 
of disease ( 1 5 pts [ 7 9 %]), A Es ( 2 pts [ 1 1 %]: Gra de 3 ala ni ne a mi n otra nsferase i ncrease d 
a n d  Gra de  4  m yel o d ys plastic  s y n dr o me),  a n d  p h ysicia n  decisi o n  ( 2  pts  [ 1 1 %]).  Te n  pts 
( 3 6 %)  i n  t he  treat me nt- naï ve  gr o u p  ha ve  disc o nti n ue d  treat me nt d ue  t o  pr o gressi o n  of 
disease ( 8 pts [ 2 9 %]) a n d p h ysicia n decisi o n ( 2 pts [ 7 %]). T he me dia n (ra n ge) d urati o n of 
treat me nt  e x p os ure  was  1 6  ( 9 – 6 5)  wee ks  i n  t he  pre vi o usl y  treated  gr o u p  a n d  3 6  ( 9 – 7 4) 
wee ks i n t he treat me nt- naï ve gr o u p; 6 pre vi o usl y treate d pts ( 3 2 %) a n d 2 2 treat me nt- naï ve 
pts  ( 7 9 %)  recei ve d  treat me nt  f or  ≥6  c ycles.  Ri b ocicli b  d ose  re d ucti o ns  occ urre d  i n  4 
pre vi o usl y  treate d  pts  ( 2 1 %;  1  re d ucti o n  eac h)  a n d  i n  4  treat me nt- naï ve  pts  ( 1 4 %;  1 
re d ucti o n  eac h).  Ri b ocicli b  treat ment  i nterr u pti o ns  d ue  t o  A Es occ urre d  i n  6  pre vi o usl y 
treate d pts ( 3 2 %) a n d i n 1 0 treat me nt- naï ve pts ( 3 6 %).  
T a bl e 1- 2  
A d v er s e e v e nt s s u s p e ct e d t o b e st u d y dr u g-r el at e d ( Al l- Gr a d e 
≥1 5 % i n all pt s)  
 
P r e vi o usl y T r e at e d 
G r o u p ( n = 1 9)  
T r e at m e nt- n aï v e 
G r o u p ( n = 2 8)  
All Pts  
( N = 4 7) 
A E  
All G r a d es  
n ( %)  
G r a d e 3/ 4  
n ( %)  
All G r a d es  
n ( %)  
G r a d e 3/ 4  
n ( %)  
All G r a d es  
n ( %)  
G r a d e 3/ 4  
n ( %)  
N e utr o p e ni a 
1 3 ( 6 8)  
7 ( 3 7)  
2 0 ( 7 1)  
1 3 ( 4 6)  
3 3 ( 7 0)  
2 0 ( 4 3) 
N a us e a 
7 ( 3 7)  
0  
1 3 ( 4 6)  
0  
2 0 ( 4 3)  
0 
F ati g u e 
7 ( 3 7)  
0  
5 ( 1 8)  
0  
1 2 ( 2 6)  
0 
Al o p e ci a 
0 
0  
1 1 ( 3 9)  
0  
1 1 ( 2 3)  
0 
A n e mi a 
4 ( 2 1)  
0  
7 ( 2 5)  
0  
1 1 ( 2 3)  
0 
Di arr h e a 
3 ( 1 6)  
0  
8 ( 2 9)  
0  
1 1 ( 2 3)  
0 

N o v arti s 
C o nfi d e nti al 
P a g e 3 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Ast h e ni a 
0 
0  
1 0 ( 3 6)  
0  
1 0 ( 2 1)  
0 
N e utr o p hil 
c o u nt 
d e cr e as e d 
3 ( 1 6)  
2 ( 1 1)  
5 ( 1 8)  
3 ( 1 1)  
8 ( 1 7)  
5 ( 1 1) 
A L T i n cr e as e d 
1 ( 5)  
1 ( 5)  
6 ( 2 1)  
1( 4)  
7 ( 1 5)  
2 ( 4) 
A S T i n cr e as e d 
1 ( 5)  
1 ( 5)  
6 ( 2 1)  
0  
7 ( 1 5)  
1 ( 2) 
Dr y s ki n 
0 
0  
7 ( 2 5)  
0  
7 ( 1 5)  
0 
H e a d a c h e 
2 ( 1 1)  
0  
5 ( 1 8)  
0  
7 ( 1 5)  
0 
Pr urit us 
0 
0  
7 ( 2 5)  
0  
7 ( 1 5)  
0 
V o miti n g 
1 ( 5)  
0  
6 ( 2 1)  
0  
7 ( 1 5)  
0 
 
 
 
T he me dia n relati ve d ose i nte ns it y of ri b ocicli b was > 9 8 % i n b ot h gr o u ps. A Es s us pecte d t o 
be st u d y dr u g-relate d (all Gra de ≥1 5 % i n all pts) are s u m marize d i n Ta ble 1- 2 . T he m ost 
c o m m o n ( > 3 0 % of pts) all- Gra de A Es were ne utr o pe nia ( 3 3 pts [ 7 0 %]) a n d na usea ( 2 0 pts 
[ 4 3 %]). T he m ost c o m m o n ( > 5 % of pts) Gra de 3/ 4 A Es s us pecte d t o be dr u g-relate d were: 
ne utr o pe nia ( 2 0 pts [ 4 3 %]), ne ut r o p hil c o u nt decrease d ( 5 pts [1 1 %]), a n d w hite bl o o d cell 
c o u nt  decrease d  ( 3  pts  [ 6 %]). P K   data  c ollecte d  fr o m  patie nts  i n  [ C L E E 0 1 1 X 2 1 0 7]  are 
s u m marize d  i n Ta ble  1- 3 .  Ri b ocicli b  e x p os ure  ( Cma x   a n d  A U C0 – 2 4 h; Ta ble  1- 3 )  i n 
c o m bi nati o n wit h letr oz ole was c o nsiste nt wit h ri b ocicli b si n gle-a ge nt data, i n dicati n g n o 
P K  dr u g – dr u g  i nteracti o n.  Ri b ocicli b  acc u m ulate d  2. 4-f ol d  f oll o wi n g  m ulti ple  d oses, 
p ossi bl y d ue t o a c o m bi ne d effect of dr u g acc u m ulati o n a n d a ut o -i n hi biti o n of C Y P 3 A 4. 
Letr oz ole  e x p os ure ( C ma x   a n d  A U C0 – 2 4 h;  Ta ble 1- 3)  o n  C 1 D 2 1  was  si milar  t o  or sli g htl y 
l o wer t ha n pre vi o usl y re p orte d i n st u dies wit h letr oz ole. Variabilit y i n attai n me nt of stea d y-
state f or letr oz ole ( 2 – 6 wee ks) c o ul d acc o u nt f or differe nces. Letr oz ole acc u m ulati o n was 
5. 2-f ol d f oll o wi n g m ulti ple d oses, c o nsiste nt wit h t he l o n g hal f-life re p orte d f or letr oz ole 
( ≈2 da ys). 
T a bl e 1- 3  
P K P ar a m et er s of ri b o ci cli b a n d l etr o z ol e i n all p ati e nt s ( N = 4 7) 
A n al yte  
D a y  
T m a x  ( h) * 
C m a x  
( n g/ m L)† 
A U C 0- 2 4 
( h. n g/ m L)† 
R acc † 
T 1/ 2, acc 
( h)† 
C L/ F 
( L/ h)† 
Ri b ocicli b 
C 1 D 1  
2. 1 ( 1. 0-
4. 2) [ 4 1] 
1 1 3 0 ± 4 8 6 
[ 4 1] 
1 0 9 0 0 ± 3 7 5 0 
[ 3 7] 
-  
- 
- 
C 1 D 2 1  
2. 1 ( 1. 0-
7. 7) [ 2 8] 
1 8 7 0 ± 7 5 0 
[ 2 8] 
2 5 9 0 0 ± 1 1 
6 0 0 [ 2 3] 
2. 4 ± 0. 8 
[ 1 9] 
3 2. 5 ± 1 2. 5 
[ 1 8] 
3 0. 1 ± 1 7 
[ 2 0] 
Letr oz ole 
C 1 D 1  
2. 0 ( 0. 5-
8. 0) [ 4 2] 
2 5. 7 ± 1 3 
[ 4 2] 
3 7 8 ± 2 9 7 
[ 3 8] 
-  
- 
- 
C 1 D 2 1  
2. 0 ( 0. 7-
8. 0) [ 3 4] 
9 3. 4 ± 3 6 
[ 3 4] 
1 8 4 0 ± 8 2 7 
[ 3 1] 
5. 2 ± 2. 2 
[ 2 4] 
7 7. 3 ± 3 6. 6 
[ 2 4] 
1. 7 ± 0. 8 
[ 2 9] 
A U C 0 – 2 4 h, area u n der c ur ve bet wee n 0 a n d 2 4 h o urs; C, C ycle; C L / F, a p pare nt oral cleara nce of dr u g; 
C ma x, ma xi m u m plas ma c o nce ntra ti o n; D, Da y; pts, patie nts; Racc, acc u m ulati o n rati o; S D, sta n dar d 
de viati o n; T 1/ 2, acc, eli mi nati o n half-life; T ma x, ti me t o reac h ma xi m u m plas ma c o nce ntrati o n. * Mea n 
(ra n ge) [ n]. † Mea n ± S D [ n].  
Data c ut- off: Oct o ber 3 0, 2 0 1 5.  
 
Of  t he  4 7  pts  e val ua ble  f or  res p o nse  per  R E CI S T  v 1. 1,  o ne  c o m pl ete  res p o nse  ( C R; 
treat me nt- naï ve  gr o u p)  was  o bser ve d.  I n  t he  pre vi o usl y  treate d gr o u p,  1  pt  ( 5 %)  ha d  a 
c o nfir me d partial res p o nse ( P R),  7 pts ( 3 7 %) ha d neit her c o m plete res p o nse n or pr o gressi ve 
disease  ( N C R N P D;  n o n- meas ura ble  disease),  7  pts  ( 3 7 %)  ha d  sta bl e  disease  ( S D; 

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Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
meas ura ble  disease),  a n d  4  pts  ( 2 1 %)  ha d  pr o gressi ve  disease  ( P D).  A  s u m mar y  of  best 
o verall  res p o nses  f or  pts  i n  t he  treat me nt- naï ve  gr o u p  is  s h o w n  i n Ta ble  1- 4 .  As  of  t he 
Oct o ber 3 0, 2 0 1 5 data c ut- off date, t he me dia n P F S i n t he treat me nt- naï ve gr o u p ha d n ot 
bee n reac he d; pts are bei n g m o n it ore d f or disease pr o gressi o n. 
As of A u g ust 1 9, 2 0 1 6, 4 7 patie nts ha d bee n treate d wit h ri b oci cli b 6 0 0 m g Q D ( 3- wee ks-
o n/ 1- wee k- off) + letr oz ole 2. 5 m g Q D (c o nti n u o us; Ta ble 1). Ta ble 1- 1 ).  1 7 of 1 9 patie nts 
( 8 9 %) i n d ose escalati o n were pre vi o usl y treate d f or a B C ( pre vio usl y treate d gr o u p). 2 7 of 
2 8 patie nts ( 9 6 %) i n d ose e x pa nsi o n were treat me nt- naï ve f or a B C (first-li ne gr o u p). 
Treat me nt has bee n disc o nti n ue d i n all 1 9 patie nts i n t he pre vio usl y treate d gr o u p ( 1 0 0 %) 
a n d 1 5 patie nts ( 5 4 %) i n t he first-li ne gr o u p. 
Me dia n pr o gressi o n-free s ur vi val  ( P F S) i n t he first-li ne gr o u p was 2 5. 3 m o nt hs; 1 1 patie nts 
ha d  disease  pr o gressi o n  a n d  1 7  patie nts  were  ce ns ore d  at  t he  da ta  c ut- off  date,  wit h  1 3 
patie nts still o n g oi n g f or  f urt her P F S f oll o w u p. 
T w o c o m plete res p o nses ( C Rs) we re o bser ve d i n t he first-li ne gro u p; o verall res p o nse rate 
was 4 6 % a n d cli nical b e nefit rate was 7 9 %.  
Me dia n P F S i n t he pre vi o usl y treate d gr o u p was 5. 5 m o nt hs ( 9 5 % c o nfi de nce i nter val: 2. 3 –
8. 1); 1 4 patie nts ha d disease pr o g ressi o n a n d 5 patie nts were ce ns ore d at t he data c ut- off 
date,  wit h  n o  patie nts  o n g oi n g  f or  f urt her  P F S  f oll o w- u p.  ( M u ns ter et al. prese nte d at 
S A B C S, Sa n A nt o ni o, T X, 6 – 1 0 Dece m ber 2 0 1 6, A bstract P- 4- 2 2- 1 8) . 
 
 
 
 
T a bl e 1- 4  
S u m m ar y of b e st o v er all r e s p o n s e f or t h e tr e at m e nt- n ai v e gr o u p 
p er i n v e sti g at or a s s e s s m e nt 
 
Tre at me nt- n aï ve Gr o u p  
All Pts  
( N = 2 8) 
Pts Wit h Meas ura ble 
Disease ( n = 2 4) 
Best o verall res p o nse, n ( %) 
C R 
1( 4) 
1 ( 4) 
P R 
1 0 ( 3 6) 
1 0 ( 4 2) 
S D 
1 0 ( 3 6) 
1 0 ( 4 2) 
P D 
3 ( 1 1) 
3 ( 1 3) 
N C R N P D 
4 ( 1 4) 
- 
O bjecti ve res p o nse rate (c o nfir me d C R + P R), % ( 9 5 % Cl)  
3 9 ( 2 2- 5 9)  
4 6 ( 2 6- 6 7) 
Disease  c o ntr ol  rate  (c o nfir me d  C R  +  P R  +  S D  + 
N C R N P D), % ( 9 5 % Cl) 
8 9 ( 7 2- 9 8)  
8 8 ( 6 8- 9 7) 
Cli nical be nefit rate (c o nfir me d C R + P R + S D > 2 4 wee ks + 
N C R N P D > 2 4 wee ks), % ( 9 5 % Cl) 
7 9 ( 5 9- 9 2)  
7 9 ( 5 8- 9 3) 
CI, c o nfi de nce i nter val; C R, c o m plete res p o nse; N C R N P D, neit her  c o m plete res p o nse n or pr o gressi ve disease 
( n o n- meas ura ble disease); P D, pr ogressi ve disease; P R, partial res p o nse; pts, patie nts; S D, sta ble disease. 
Data c ut- off: Oct o ber 3 0, 2 0 1 5. 
 
I n  s u m mar y,  ri b ocicli b  i n  c o m bi nati o n  wit h  letr oz ole  de m o nstrate d  e nc o ura gi n g  cli nical 
acti vit y, partic ularl y i n t he  o n g oi n g treat me nt- naï ve gr o u p ( 4 6% o bjecti ve res p o nse rate, 
8 8 %  disease  c o ntr ol  rate,  7 9 %  cli nical  be nefit  rate  i n  pts  wit h   meas ura ble  disease).  T he 
c o m bi nati o n of ri b ocicli b a n d letr oz ole has a n acce pta ble safet y pr ofile i n pts wit h E R p os, 
H E R 2 ne g a B C. Ne utr o pe nia o bser ve d wit h ri b ocicli b is a n o n-tar g et, a nti pr oliferati ve si de 
effect  of  C D K 4/ 6  i n hi biti o n.  A Es   were  ge nerall y  t olera ble  a n d  ma na ge d  t hr o u g h  d ose 
re d ucti o ns a n d i nterr u pti o ns. (J uric et al. Prese nte d at A S C O An n ual Meeti n g, C hica g o, I L, 

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Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
3 – 7 J u ne 2 0 1 6, A bstract 5 6 8; M u nster et al. prese nte d at S A B C S,  Sa n A nt o ni o, T X, 6 – 1 0 
Dece m ber 2 0 1 6, A bstract P- 4- 2 2- 1 8). 
 
A d diti o nall y, t he o n g o i n g P hase III M O N A L E E S A- 2 st u d y ( C L E E 0 1 1 A2 3 0 1) of ri b ocicli b 
i n c o m bi nati o n wit h letr oz ole f or t he first-li ne treat me nt of p ost me n o pa usal w o me n wit h 
H R +,  H E R 2- ne gati ve  a d va nce d  ( metastatic  or  l oc o  re gi o nall y  rec u rre nt)  breast  ca ncer, 
w hic h  has  c o m plete d  e nr oll me nt  ( N C T 0 1 9 5 8 0 2 1),  met  its  pri mar y  e n d p oi nt  earl y  at  t he 
pre pla n ne d  i nteri m  a nal ysis..  Data  a nal ysis  has  bee n  c o m plete d a n d  data  ha ve  bee n 
p u blis he d i n Oct o ber 2 0 1 6:  
 
Ri b ocicli b i n c o m bi nati o n wit h letr oz ole de m o nstrate d statistic all y si g nifica nt be nefit o ver 
place b o i n c o m bi nati o n wit h let r oz ole i n pr ol o n gi n g P F S base d on I n vesti gat or assess me nt. 
Cli nical be nefit was e vi de nt relati ve t o place b o pl us letr oz ole  wit h a 4 4. 4 % esti mate d ris k 
re d ucti o n i n t he pri mar y P F S e n d p oi nt as per I n vesti gat or assess me nt ( H R = 0. 5 5 6, 9 5 % CI: 
0. 4 2 9, 0. 7 2 0; p = 3. 2 9 × 1 0- 6). 
 
As of 5 Mar 2 0 1 5, 6 6 8 patie nts were ra n d o mize d; 3 3 4 patie nts ea c h t o t he ri b ocicli b pl us 
letr oz ole ar m  a n d  t he place b o pl us letr oz ole ar m. T he me dia n stu d y y  f oll o w- u p  was 1 5. 3 
m o nt hs, as of t he 2 9-Ja n- 2 0 1 6 data c ut- off date, a n d t he pr o p or ti o n of patie nts c o nti n ui n g 
t o  recei ve  treat me nt  i n  t he  ri b ocicli b  pl us  letr oz ole  ar m  was  hi g her  t ha n  i n  place b o  pl us 
letr oz ole ar m ( 5 8. 4 % vs 4 6. 1 %, res pecti vel y). Disease pr o gressio n was t he pri mar y reas o n 
f or  treat me nt  disc o nti n uati o n  a nd  was  m ore  fre q ue nt  i n  t he  place b o  pl us  letr oz ole  ar m 
c o m par e d t o t he ri b ocicli b pl us letr oz ole ar m ( 4 3. 7 % vs. 2 6 %). A d verse e ve nts le d t o t he 
disc o nti n uati o n of st u d y treat me nt i n 3 2 patie nts ( 4. 8 %): 2 5 pa tie nts ( 7. 5 %) i n ri b ocicli b 
pl us letr oz ole ar m a n d se ve n patie nts ( 2. 1 %) i n place b o pl us le tr oz ole ar m. 
 
T he  me dia n  a ge  of  patie nts  was  6 2  years  (ra n ge:  2 3- 9 1)  a n d  4 4. 2 %  were  of  ≥  6 5  years 
ol d.  T he  maj orit y  of  t he  pati e nts  were  Ca ucasia n  ( 8 2. 2 %).  All  p atie nts  ha d  E C O G 
perf or ma nce stat us of eit her 0 o r 1. A p pr o xi matel y o n e-t hir d ( 34. 0 %) of t he patie nts i n t his 
st u d y  w ere  d e  n o v o  breast  ca ncer  patie nts.  Nearl y  t w o-t hir ds  ( 5 8. 8 %)  of  patie nts  ha d 
visceral disease ( 1 9. 8 % wit h li v er a n d 4 5. 4 % wit h l u n g i n v ol ve m e nt) a n d 2 2. 0 % ha d b o ne 
o nl y metastases at st u d y e ntr y. All e xce pt f o ur patie nts ha d st a ge I V disease at t he ti me of 
st u d y  e ntr y  ( ot her  f o ur  ha d  sta ge  III  disease).  O ne-t hir d  ( 3 4. 0%)  of  t he  patie nts  ha d  ≥  3 
metastatic sites. 
 
T he  me dia n  d urati o n  of  e x p os ure  t o  st u d y  treat me nt  was  1 3. 0  m o n t hs  i n  t he  ri b ocicli b 
ar m a n d 1 2. 4 m o nt hs i n t he place b o ar m. T he me dia n d urati o n of e x p os ure t o ri b ocicli b/ 
place b o was 1 2. 2 m o nt hs i n t he ri b ocicli b ar m a n d 1 2. 4 m o nt hs i n t he place b o ar m; 2 4 0 
patie nts  ( 7 1. 9 %)  were  e x p ose d  t o  ri b ocicli b  pl us  letr oz ole  t her a p y  f or  ≥  9  m o nt hs. 
Me dia n  relati ve d ose i nte nsit y was 8 7. 5 % f or ri b ocicli b a n d 1 0 0 % f or place b o. Ri b ocicli b 
d ose i nterr u pti o ns occ urre d i n 2 5 7 ( 7 6. 9 %) patie nts, a n d letr oz ole was i nterr u pte d i n 1 3 2 
( 3 9. 5 %) patie nts i n t he ri b ocicli b ar m. Place b o was i nterr u pte d i n 1 3 4 ( 4 0. 6 %) patie nts a n d 
letr oz ole  was  i nterr u pte d  i n  1 0 7  ( 3 2. 4 %)  patie nts  i n  t he  place bo  ar m.  D ose  re d ucti o ns 
occ urre d i n 5 3. 9 % a n d 7. 0 % of patie nts i n  t he ri b ocicli b a n d pl ace b o  ar ms, res pe cti vel y, 
m ost  c o m m o nl y  f or  a d verse  e ve nts  ( 1 6 9  [ 5 0. 6 %]  vs.  1 4  [ 4. 2 %]  pat ie nts;  ri b ocicli b  vs. 
place b o ar m). D ose re d ucti o n d ue t o ne utr o pe nia occ urre d i n 6 5 %  of patie nts w h o ha d a 
d ose re d ucti o n d ue t o A Es i n t he ri b ocicli b ar m. 
 

N o v arti s 
C o nfi d e nti al 
P a g e 3 5 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Maj orit y  of  t he  patie nts  e x perie nce d  at  least  o ne  A E  i n  b ot h  treat me nt  gr o u ps  ( 9 8. 5 % 
vs. 9 7 %);  t he  m ost  c o m m o nl y  ( ≥  3 0 %)  re p orte d  A Es  i n  ri b ocicli b  pl us  letr oz ole  gr o u p 
irres pecti ve  of  ca usalit y  were: ne utr o pe nia  ( 6 0. 8 %),  na usea  ( 5 1 . 5 %),  fati g ue  ( 3 6. 5 %), 
diarr hea  ( 3 5 %),  a n d  al o pecia  ( 3 3. 2 %).  A Es  w here  a  hi g her  pr o p or ti o n  of  ri b ocicli b  pl us 
letr oz ole-treate d patie nts re p orted e ve nts (a n d w here t here was  a ≥ 1 0 % differe nce t o t he 
place b o  pl us  letr oz ole  gr o u p)  i ncl u de d  ne utr o pe nia  ( + 5 6. 6 %),  na usea  ( + 2 3 %),  decrease d 
ne utr o p hil c o u nt ( + 1 8 %), al o peci a ( + 1 7. 7 %), decrease d w hite bl o o d cell c o u nt ( + 1 7. 4 %), 
v o miti n g ( + 1 3. 8 %), a ne mia ( + 1 3. 8 %), diarr hea ( + 1 2. 9 %), le u k o pe nia ( + 1 2. 9 %), i ncrease d 
A L T ( + 1 1. 7 %), a n d i ncrease d A S T ( + 1 1. 4 %). T he i nci de nce of S A Es  was 2 1. 3 % a n d 1 1. 8 % 
i n t he ri b ocicli b pl us letr oz ole a n d place b o pl us letr oz ole ar ms, res pecti vel y. T we nt y-fi ve 
patie nts  ( 7. 5 %)  fr o m  t he  ri b ocicli b  pl us  letr oz ole  gr o u p  e x peri e nce d  S A Es  t hat  were 
c o nsi dere d b y t he I n vesti gat or t o be relate d t o st u d y treat me nt . Fe brile ne utr o pe nia was t he 
o nl y s us pecte d S A E re p orte d i n > 1 % of patie nts ( 1. 2 %). Per ma ne n t disc o nti n uati o ns d ue t o 
a d verse e ve nts was re p orte d i n 7. 5 % of patie nts recei vi n g ri b oc icli b pl us letr oz ole a n d 2. 1 % 
i n patie nts recei vi n g place b o pl us letr oz ole. T he m ost c o m m o n A Es lea di n g t o treat me nt 
disc o nti n uati o n of b ot h ri b ocicli b a n d letr oz ole were A L T i ncre ase d ( 2. 7 %), A S T i ncrease d 
( 2. 4 %) a n d v o miti n g ( 1. 5 %). 
 
Ne utr o pe nia, Q T pr ol o n gati o n a n d he pat o biliar y t o xicit y are i m p orta nt i de ntifie d ris ks wit h 
ri b ocicli b treat me nt: 
 Ne utr o pe nia, irres pecti ve of ca usa lit y, was t he m ost c o m m o n a d verse e ve nt i n t he 
ri b ocicli b pl us letr oz ole ar m. All gra de ne utr o pe nia occ urre d in 6 0. 8 % of patie nts, 
wit h gra de 3 ne utr o pe nia i n 3 9. 5 % a n d gra de 4 i n 8. 7 % of patie n ts. T here were fi ve 
( 1. 5 %) cases of fe brile ne utr o pe nia. 
 Gra de 3 or 4 i ncreases i n A L T ( 1 0. 2 % vs. 1. 2 %) a n d A S T ( 6. 9 % vs . 1. 5 %) were 
re p orte d i n t he ri b ocicli b pl us letr oz ole a n d place b o pl us letroz ole ar ms res pecti vel y. 
F o ur patie nts met t he criteria f or H y’s La w i n ri b ocicli b pl us letr oz ole gr o u p, 3 of 
t hese cases were c o nfir me d wit h bi o psies. All li ver f u ncti o n test ele vati o ns i n t hese 
patie nts were re versi ble a n d ret ur ne d t o n or mal val ues after st o p pi n g ri b ocicli b. 
 T here were 1 1 patie nts ( 3. 3 %) wit h a ne w Q Tc F > 4 8 0 ms p ost- base li ne (a vera ge of 
tri plicate Q Tc F) a n d 9 ( 2. 7 %) wit h a > 6 0 ms i ncrease fr o m baseli ne i n t he ri b ocicli b 
pl us letr oz ole gr o u p (si x o ut of 1 1 patie nts w h o ha d ne w Q Tc F 4 8 0 ms pl us t hree 
ot hers). 
 
T here were 4 deat hs ( 3 [ 0. 9 %] i n t he ri b ocicli b gr o u p a n d 1 ( 0. 3 %) i n t he place b o gr o u p). 
O ne  patie nt  i n  eac h  gr o u p  die d  fr o m  t he  pr o gressi o n  of  u n derl yi n g  breast  ca ncer.  T he 
re mai ni n g 2 deat hs  i n  t he  ri b ocicli b  gr o u p  were  d ue  t o  s u d de n  deat h  a n d  deat h  fr o m  a n 
u n k n o w n  ca use. T he case of s u d de n deat h was c o nsi dere d t o be re l ate d t o ri b ocicli b a n d 
occ urre d o n da y 1 1 i n c ycle  2  i n  ass ociati o n  wit h  gra de  3  h y p o k ale mia  (treate d  wit h  oral 
p otassi u m  s u p ple me nts) a n d  a  gra d e  2  pr ol o n gati o n  i n  t he  Q Tc F  i nter val  o n  da y  1  of 
c ycle 2.  T he  patie nt  w h o  die d fr o m a n u n k n o w n ca use recei ve d ri b ocicli b f or 4 da ys bef ore 
wit h dra wi n g c o nse nt a n d disc o nti n ui n g  t he  st u d y  treat me nt;  her  deat h  was  re p orte d  1 9  
d a ys  later  a n d  was  n ot c o nsi d ere d t o be relate d t o ri b ocicl i b b y t he i n vesti gat or. 
 
Ke y efficac y res ults: 
 
St u d y A 2 3 3 0 1 met its pri mar y o bjecti ve at t he pri mar y a nal ysis,  wit h c o m pelli n g e vi de nce 
of cli nical be nefit i n patie nts wit h H R- p ositi ve, H E R 2- ne gati ve  a d va nce d breast ca ncer. A 
4 4. 4 % esti mate d ris k r e d ucti o n i n ri b ocicli b pl us letr oz ole tre ate d patie nts was e vi de nt i n 

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C o nfi d e nti al 
P a g e 3 6 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
t he pri mar y P F S e n d p oi nt as per i n vesti gat or assess me nt ( H R = 0. 55 6, 9 5 % CI: 0. 4 2 9, 0. 7 2 0; 
o ne si de d p- val ue = 3. 2 9 × 1 0 - 6). Res ults were c o nsiste nt acr oss t he s u b gr o u ps of a ge, race, 
pri or  a dj u va nt  or  ne o-a dj u va nt  c he m ot hera p y  or  h or m o nal  t hera pi es,  li ver  a n d/ or  l u n g 
i n v ol ve me nt, b o ne o nl y metastasis disease. 
 
O verall  s ur vi val  data  were  i m mat ure  at  t he  ti me  of  t his  i nteri m   a nal ysis  wit h  4 3 deat hs 
bei n g  re p orte d  ( 2 3  patie nts  [ 6. 9 % ]  a n d  2 0  patie nts  [ 6. 0 %],  res pecti vel y),  fr o m  t he 
ri b ocicli b  pl us letr oz ole a n d place b o pl us letr oz ole treat me nt ar ms. 
 
I m pr o ve d O R R of 4 0. 7 % vers us 27. 5 % a n d C B R of 7 9. 6 % vs 7 2. 8 % we re re p orte d f or t he 
ri b ocicli b pl us letr oz ole ar m relati ve t o place b o pl us letr oz ole ar m, s u p p orti n g t he pri mar y 
e n d p oi nt of efficac y of ri b ocicli b pl us letr oz ole o ver place b o pl us letr oz ole. T he me dia n 
ti me t o res p o nse a n d d ur ati o n of res p o nse were n ot ac hie ve d i n eit her treat me nt ar ms. T he 
O R R  ( 5 2. 7 %  vs.  3 7. 1 %)  a n d  C B R  ( 8 0. 1 %  vs.  7 1. 8 %)  i n  t he  s u b gr o u p   of  patie nts  wit h 
meas ura ble disease at baseli ne were c o nsiste nt wit h t he pri mar y  a nal ysis res ults. 
 
 
T a bl e 1- 5  
A d v er s e e v e nt s wit h s u s p e ct e d r el ati o n s hi p t o st u d y t r e at m e nt i n 
st u d y ( C L E E 0 1 1 A 2 3 0 1) 
 
A d verse e ve nts wit h s us pecte d 
relati o ns hi p t o st ud y treat me nt b y 
preferre d ter m a n d ma xi m u m 
gra de ( greater 5 % i n eit her ar m) 
( Safet y set) 
Ri b ocicli b + Letr oz ole 
n = 3 3 4 
Place b o + Letr oz ole 
n = 3 3 0 
Preferre d Ter m 
All gra des 
( %) 
Gra de 3 n 
( %) 
Gra de 4 n 
( %) 
All gra des n 
( %) 
Gra de 3 n 
( %) 
Gra de 4 n 
( %) 
T otal 
3 1 9 ( 9 5. 5)  
1 9 9 ( 5 9. 6)  
4 3 ( 1 2. 9)  
2 4 9 ( 7 5. 5)  
2 7 ( 8. 2)  
1 ( 0. 3) 
Ne utr o pe nia 
1 9 9 ( 5 9. 6)  
1 3 0 ( 3 8. 9)   
2 9 ( 8. 7)  
1 3 ( 3. 9)  
2 ( 0. 6)  
0 
Na usea 
1 4 4 ( 4 3. 1)  
6 ( 1. 8)  
0 
5 4 ( 1 6. 4)  
0 
0 
Al o pecia 
9 5 ( 2 8. 4)  
0 
0 
4 4 ( 1 3. 3)  
0 
0 
Fati g ue 
9 2 ( 2 7. 5)  
5 ( 1. 5)  
1 ( 0. 3)  
6 4 ( 1 9. 4)  
2 ( 0. 6)  
0 
Diarr hea 
7 2 ( 2 1. 6)  
3 ( 0. 9)  
0 
3 9 ( 1 1. 8)  
0 
0 
Ne utr o p hil c o u nt decrease d  
6 3 ( 1 8. 9)  
4 4 ( 1 3. 2)  
3 ( 0. 9)  
3 ( 0. 9)  
1 ( 0. 3)  
0 
V o miti n g 
6 2 ( 1 8. 9)  
6 ( 1. 8)  
0 
2 2 ( 6. 7)  
1 ( 0. 3)  
0 
W hite bl o o d cell c o u nt decrease d 
5 7 ( 1 7. 1)  
3 7 ( 1. 1)  
2 ( 0. 6)  
5 ( 1. 5)  
1 ( 0. 3)  
0 
H ot fl us h 
5 1 ( 1 5. 3)  
1 ( 0. 3)  
0 
6 3 ( 1 9. 1)  
0 
0 
Art hral gia 
4 8 ( 1 4. 4)  
1 ( 0. 3)  
0 
5 2 ( 1 5. 8)  
1 ( 0. 3)  
0 
Le u k o pe nia 
4 8 ( 1 4. 4)  
2 5 ( 7. 5)  
1 ( 0. 3)  
9 ( 2. 7)  
1 ( 0. 3)  
0 
A ne mia 
4 6 ( 1 3. 8)  
2 ( 0. 6)  
0 
9 ( 2. 7)  
3 ( 0. 9)  
0 
Ras h 
4 5 ( 1 3. 5)  
2 ( 0. 6)  
0 
1 0 ( 3. 0)  
0 
0 
Ala ni ne a mi n otra nsferase 
i ncrease d 
4 2 ( 1 2. 6)  
2 2 ( 6. 6)  
5 ( 1. 5)  
8 ( 2. 4)  
1 ( 0. 3)  
0  
C o nsti pati o n 
4 0 ( 1 2. 0)  
0  
0  
2 0 ( 6. 1)  
0  
0  
Decrease d a p petite 
3 9 ( 1 1. 7)  
3 ( 0. 9)  
0  
1 8 ( 5. 5)  
0  
0  
As partate a mi n otra nsferase 
i ncrease d 
3 6 ( 1 0. 8)  
1 2 ( 3. 6)  
2 ( 0. 6)  
8 ( 2. 4)  
3 ( 0. 9)  
0  
St o matitis 
3 3 ( 9. 9)  
1 ( 0. 3)  
0  
1 5 ( 4. 5)  
0  
0  
Pr urit us 
3 0 ( 9. 0)  
1 ( 0. 3)  
0  
3 ( 0. 9)  
0  
0  
Ast he nia 
2 7 ( 8. 1)  
1 ( 0. 3)  
0  
2 3 ( 7. 0)  
1 ( 0. 3)  
0  
Hea dac he 
2 7 ( 8. 1)  
1 ( 0. 3)  
0  
2 4 ( 7. 3)  
0  
0  
D ys ge usia 
2 3 ( 6. 9)  
0  
0  
1 2 ( 3. 6)  
0  
0  
Dr y m o ut h 
2 1 ( 6. 3)  
1 ( 0. 3)  
0  
1 4 ( 4. 2)  
0  
0  
Dizzi ness 
1 9 ( 5. 7)  
0  
0  
2 1 ( 6. 4)  
0  
0  
T hr o m b oc yt o pe nia 
1 9 ( 5. 7)  
1 ( 0. 3)  
0  
0  
0  
0  
L y m p h oc yte c o u nt decrease d 
1 8 ( 5. 4)  
1 2 ( 3. 6)  
0  
3 ( 0. 9)  
2 ( 0. 6)  
0  
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 3 7 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 
T he o n g oi n g p hase III st u d y M O N A L E E S A- 3 ( C L E E 0 1 1 F 2 3 0 1) i n vesti g ates ri b ocicli b i n 
c o m bi nati o n wit h t he selecti ve estr o ge n rece pt or de gra der f ul ve stra nt f or t he treat me nt of 
me n  a n d  p ost me n o pa usal  w o me n  wit h  h or m o ne  rece pt or  p ositi ve,  H E R 2- ne gati ve, 
a d va nce d breast ca ncer w h o ha ve recei ve d n o or o nl y o ne li ne of  pri or e n d ocri ne treat me nt. 
Pre me n o pa usal  patie nts  are  c urre ntl y  i n vesti gate d  i n  t he  o n g oi n g  p hase  III  st u d y 
M O N A L E E S A- 7  ( C L E E 0 1 1 E 2 3 0 1),  w hic h  is  a  ra n d o mize d,  d o u ble- bli n d ,  place b o-
c o ntr olle d 
st u d y of L E E 0 1 1 or place b o i n c o m bi nati o n wit h ta m o xife n a n d g osereli n or a n o n-ster oi dal 
ar o matase i n hi bit or ( N S AI) a n d g os ereli n f or t he treat me nt of w o me n wit h h or m o ne rece pt or 
p ositi ve, H E R 2- ne gati ve, a d va nce d breast ca ncer. 
Res ults f or b ot h p hase III trials are e x pecte d t o be a vaila ble i n 2 0 1 7. 
 
 
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 
I n i nter nati o nal g ui deli nes f or a d va nce d breast ca ncer, e n d ocri ne treat me nt is t he preferre d 
treat me nt  o pti o n  f or  pre me n o pa usal  a n d  p ost me n o pa usal  w o me n  a n d  me n wit h H R-
p ositi ve,  H E R 2- ne gati ve  a d va nce d  breast  ca ncer,  u nless  t here  is   c o ncer n  or  pr o of  of 
e n d ocri ne  resista nce or  r a pi dl y  pr o gressi ve  disease  re q uiri n g  a   fast  res p o nse  ( Car d os o 
2 0 1 2).  
M ulti ple pat h wa ys ar e k n o w n i n w hic h alterati o ns ca n facilitate  e n d ocri ne resista nce. T w o 
relate d e mer gi n g mec ha nis ms of e nd ocri ne resista nce i ncl u de t he  dec o u pli n g of cell c ycle 
c o ntr ol fr o m E R-si g nali n g a n d t he  utilizati o n of alter nate gr o wt h si g nali n g pat h wa ys s uc h 
as t he PI 3 K pat h wa y ( Miller et al 2 0 1 1; La n ge a n d Yee 2 0 1 1). T h e c urre ntl y a vaila ble 
sta n dar d  o pti o n  f or  o verc o mi n g  en d ocri ne  resista nce  tar gets  t he   PI 3 K/ A K T/ m T O R 
pat h wa y  as  well  as  t he  estr o ge n  rece pt or  pat h wa y  b y  c o m bi ni n g  t he  m T O R  i n hi bit or 
Afi nit or  (e ver oli m us)  wit h  t he  ster oi dal  ar o matase  i n hi bit or  e x e mesta ne.  T his 
c o m bi nati o n de m o nstrate d s u peri or efficac y wit h a ma na gea ble sa fet y pr ofile c o m pare d 
t o e xe mesta ne m o n ot hera p y. T he me dia n pr o gressi o n free s ur vi val i n t he pi v otal p hase III 
trial  B O L E R O- 2  was  7, 8  m o nt hs  f or  t he  c o m bi nati o n  of  e ver oli m us  pl us  e xe mesta ne 
vers us  3. 2  m o nt hs  f or  e xe mesta ne a n d  place b o  ( hazar d  rati o  =  0. 4 5;  9 5 %  c o nfi de nce 
i nter val 0. 3 8 – 0. 5 4); l o g-ra n k P< 0. 0 0 0 1) ( Yar dle y 2 0 1 3).  
Besi des t he PI 3 K/ A K T/ m T O R pat h wa y, o ne of t he m ost fre q ue ntl y a ltere d pat h wa ys i n 
br east ca ncer is t he cell c ycl e r e g ulati o n b y c ycli n D 1 a n d c yc li n de pe n de nt ki nases 4 a n d 
6. B y t ar geti n g t w o disti nct pat h wa ys (ar o matase i n hi biti o n b y letr oz ole, C D K 4/ 6 pat h wa y 
i n hi biti o n b y ri b ocicli b), it is h y p ot hesize d t hat t his c o m bi nati o n will res ult i n pr ol o n ge d 
pr o gressi o n free s ur vi val. First  cli nical res ults de m o nstrate d pr o misi n g efficac y a n d safet y 
data i n a P hase I b trial ( C L E E 0 1 1 X 2 1 0 7). I n t his st u d y, ri b ocic li b i n c o m bi nati o n wit h 
letr oz ole  de m o nstrate d  e nc o ura gi ng  cli nical  acti vit y,  i n  b ot h  t he  treat me nt- naï ve  gr o u p 
( 4 6 % o bjecti ve res p o nse rate, 8 8 % disease c o ntr ol rate, 7 9 % clinical be nefit rate i n pts wit h 
meas ura ble disease) as well as pretreate d patie nts ( 1 pt ( 5 %) h a d a c o nfir me d P R, 7 pts 
( 3 7 %) ha d N C R N P D ( n o n- meas ura ble disease), 7 pts ( 3 7 %) ha d S D (meas ura ble disease), 
a n d 4 pts ( 2 1 %) ha d P D). T he m ost c o m m o n a d verse e ve nts s us pecte d t o be st u d y dr u g 
relate d were Ne utr o pe nia ( 7 0 % all gra des, 4 3 % gra de 3/ 4), Na usea ( 4 3 % all gra des, n o 
gra de 3/ 4), Fati g ue ( 2 6 % all gra des, n o gra de 3/ 4), Al o pecia, A ne mia a n d Diarr hea ( 2 3 % 
all gra des, n o gra de 3/ 4, res pecti vel y). 

N o v arti s 
C o nfi d e nti al 
P a g e 3 8 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
M o na L E Esa- 2 ( C L E E 0 1 1 A 2 3 0 1) is t he f ull y recr uite d, o n g oi n g plac e b o c o ntr olle d p hase 
III st u d y of ri b ocicli b i n c o m bi nati o n wit h letr oz ole i n p ost men o pa usal w o ma n w hic h has 
s h o w n  t o  pr ol o n g  P F S  i n  patie nts  wit h  H R +  a n d  H E R 2-  a d va nce d  breast ca ncer w h o 
recei ve d  n o  pri or  t hera p y  f or  a d va nce d  disease.  T he  st u d y  has  met  its  pri mar y  e n d p oi nt, 
pr o gressi o n-free  s ur vi val  usi n g  R E CI S T  1. 1  criteria,  i n  a  pre pl a n ne d  i nteri m  a nal ysis  as 
rec o m me n de d b y a n i n de pe n de nt data m o nit ori n g c o m mittee. T he i nteri m a nal ysis all o we d 
st o p pi n g t he st u d y f or o utsta n di n g efficac y f or t he ri b ocicli b c o ntai ni n g t hera p y ar m. T he 
statistical  a nal ysis  was  perf or me d  b y  a n  i n de pe n de nt  statisticia n  ( n ot  i n v ol ve d  wit h  t he 
c o n d uct of t he st u d y). T he res ults  of t his i nterim a nal ysis wil l be re p orte d later t his year. 
Ri b ocicli b i n c o m bi nati o n wit h ar o matase i n hi bit or t hera p y a n d g osereli n is c urre ntl y 
i n vesti gate d i n pre me n o pa usal patie nts i n t he p hase III trial Mo na L E Esa- 7 
( C L E E 0 1 1 F 2 3 0 1). Pal o ma- 3, a p hase III trial wit h a differe nt C DK 4/ 6 i n hi bit or i n 
c o m bi nati o n wit h f ul vestra nt, de m o nstrate d e q ual efficac y i n pr e me n o pa usal patie nts a n d 
p ost me n o pa usal patie nts. Pre me n o pa usal patie nts i n t his trial a ls o recei ve d g osereli n i n 
a d diti o n t o t he C D K 4/ 6 i n hi b it or a n d f ul vestra nt. 
T o s u p p ort t he e nc o ura gi n g res u lts of M o na L E Esa- 2, t he mai n p urp ose of t his st u d y is t o 
c ollect a d diti o nal efficac y a n d safet y data f or t he c o m bi nati o n  of ri b ocicli b a n d letr oz ole 
i n  a  patie nt  p o p ulati o n  a d diti o nal  t o  t he  M o na L E Esa- 2  st u d y  a n d  t o  pr o vi de  access  t o 
ri b ocicli b t o patie nts f or w hic h a vaila ble treat me nt o pti o ns ar e n ot satisfact or y treat me nt 
alter nati ves u ntil t he dr u g is a p pr o ve d f or t his i n dicati o n. F u rt her m ore, t his trial ai ms t o 
c ollect data f or t he c o m bi nati o n of ri b ocicli b a n d letr oz ole i n t he c o nte xt of c urre nt l ocal 
r o uti ne t hera p y al g orit h ms f or t he treat me nt of metastatic a n d a d va nce d breast ca ncer. 
Precli nical a n d earl y cli nical dat a s u g gests t hat C D K 4/ 6 i n hi bi ti o n ma y pla y a ke y r ole i n 
t he  treat me nt  of  s u bsets  of  breast  ca ncer  b y  a br o gati n g  e n d ocri ne-resista nt  cell 
pr olifer ati o n. T heref ore, t he a d diti o n of a C D K 4/ 6 i n hi bit or s u c h as ri b ocicli b t o sta n dar d 
e n d ocri ne  t hera p y  (letr oz ole  or  letr oz ole  a n d  g osereli n  f or  pre me n o pa usal  patie nts, 
res pecti vel y)  is  a  pr o misi n g  t hera pe utic  a p pr oac h  t hat  will  be e x pl ore d  i n  t his  st u d y. 
Letr oz ole is t he AI t hat will se r ve as e n d ocri ne c o m bi nati o n part ner i n t his st u d y. It has 
bee n  e xte nsi vel y  st u die d  i n  t h e  p ost me n o pa usal  setti n g  a n d  was c h ose n  as  e n d ocri ne 
c o m bi nati o n part ner i n  t he pi v otal p hase III trial M o na L E Esa- 2. 
T he prese nt m ulti-ce nter, o pe n-la bel, si n gle-ar m st u d y ai ms t o e val uate t he efficac y a n d 
safet y,  a n d  q ualit y  of  life  f or  t he  c o m bi nati o n  of  ri b ocicli b  an d  letr oz ole  i n  a  patie nt 
p o p ulati o n a d diti o nal t o t he M o na L E Esa- 2 st u d y, i.e. i n patie nts pretreate d wit h o ne li ne 
of  c he m ot hera p y  a n d/ or  a  ma xi m u m  of  t w o  li nes  of  e n d ocri ne  t hera p y  as  well  as 
pre me n o pa usal  patie nts,  wit h o ut  l i mitati o ns  re gar di n g  t he  disease  free  i nter val  after 
a dj u va nt t hera p y. T he e x pl orat or y o bjecti ves of t his st u d y are h y p ot hesis ge nerati n g a n d 
will c o ver a nal yses of cr ucial scie ntific i nterest. 
Si nce t he c o m bi nati o n was s h o w n t o si g nifica ntl y i m pr o ve P F S i n t he M o na L E Esa- 2 trial, 
f or et hical reas o ns n o e n d ocri ne c o m parat or dr u gs will be i n vesti gate d i n t he prese nt st u d y. 
T he d urati o n of st u d y treat me nt of 8 0 wee ks is a de q uate t o dete r mi ne t he pri mar y, sec o n dar y 
a n d e x pl orat or y st u d y para meters. T he sa m ple size is s uita ble t o esti mate t he C B R i n t his 
patie nt p o p ulati o n wit h r eas o na ble precisi o n. 
2. 2  
R ati o n al e f or t h e st u d y d e si g n 
C urre nt  treat me nt  o pti o ns  f or  a d va nce d  H R p os/ H E R 2 ne g  breast  ca n cer  dela y  t u m or 
pr o gressi o n, b ut ulti matel y lea d t o a rela pse. T heref ore ne w tr eat me nt o pti o ns are nee de d t o 
better  c o ntr ol  t u m or  gr o wt h.  T he  p hase  III  M o na L E Esa- 2  trial  de m o nstrate d  si g nifica nt 
efficac y  f or  t he  c o m bi nati o n  treat me nt  of  ri b ocicli b  a n d  letr oz ole  c o m pare d  t o  letr oz ole 

N o v arti s 
C o nfi d e nti al 
P a g e 3 9 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
m o n ot hera p y i n a d va nce d H R p os/ H E R 2 ne g breast ca ncer patie nts w h o were naï ve t o pri or 
treat me nt f or t he metastatic setti n g at t he pre pla n ne d i nteri m a nal ysis.  
T he  prese nt  nati o nal,  m ulti-ce nter,  o pe n-la bel,  si n gle-ar m  st u d y  ai ms  t o  e val uate  t he 
efficac y,  safet y  a n d  q ualit y  of  life  of  t he  c o m bi nati o n  of  ri b o cicli b  a n d  letr oz ole  i n  a n 
a d diti o nal patie nt p o p ulati o n c o m pare d t o M O N A L E E S A- 2, f or w hic h e xisti n g treat me nt 
o pti o ns are n ot satisfact or y treat me nt alter nati ves, i.e. wit h fe wer restricti o ns re gar di n g pri or 
t hera pies f or t he a d va nce d setti n g ( u p t o o ne pri or c he m ot hera py all o we d, u p t o t w o li nes of 
pri or  e n d ocri ne  t hera p y  all o we d,  pre me n o pa usal  patie nts  all o we d ,  me n  all o we d).  T he 
e x pl orat or y o bjecti ves of t his s t u d y are h y p ot hesis ge nerati n g a n d will c o ver a nal yses of 
cr ucial scie ntific i nterest, 
 
 
Si nce t he c o m bi nati o n was s h o w n t o si g nifica ntl y i m pr o ve P F S i n t he pre vi o us M o na L E Esa-
2 trial, f or et hical reas o ns n o e n d ocri ne c o m parat or dr u gs will  be i n vesti gate d i n t he prese nt 
st u d y.  T he  sa m ple  size  is  s uita ble  t o  esti mate  t he  C B R  i n  t his patie nt  p o p ulati o n  wit h 
reas o na ble precisi o n. 
Ri b ocicli b a n d letr oz ole (a n d g os ereli n) will be pr o vi de d b y t h e s p o ns or t o all patie nts w h o 
were e nr olle d pri or t o c o m mercial a vaila bilit y of ri b ocicli b. P atie nts w h o were e nr olle d i nt o 
t he st u d y after c o m mercial a vaila bilit y of t he trial a n d are treate d acc or di n g t o t he S m P C 
will recei ve c o m mercial dr u g (ri b ocicli b + letr oz ole). All pati e nts w h o are treate d o utsi de of 
t he la bel of t he S m P C will still be s u p plie d wit h ri b ocicli b a nd letr oz ole wit hi n t he trial. 
 
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  d ose  of  ri b ocicli b  is  6 0 0  m g  dail y  orall y  f or  2 1  da ys,  f oll o we d  b y  7  wit h o ut  ta ki n g 
ri b ocicli b.  T he  rec o m me n de d  dail y  d ose  of  Letr oz ole  is  2. 5  m g  via  oral  a d mi nistrati o n 
c o nti n u o usl y. 
B ot h dr u gs were s h o w n t o be safe a n d effecti ve i n t he res pecti v e d ose a n d re gi me ns. T he 
rec o m me n de d d ose f or g osereli n is 3, 6 m g a d mi nistere d as s u bc uta ne o us i m pla nt o nce a 
m o nt h. 
 
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  
I n t his st u d y ri b ocicli b will be a d mi nistere d i n c o m bi nati o n wit h letr oz ole, w hic h is a n o n-
ster oi dal  ar o matase  i n hi bit 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/ M B C.  
Letr oz ole is i n dicate d f or t he  f oll o wi n g patie nt p o p ulati o ns: 
 A dj u va nt treat me nt of p ost me n o pa usal w o me n wit h h or m o ne rece pt o r p ositi ve 
( H R p os) earl y B C. 
 E xte n de d a dj u va nt treat me nt of  earl y breast ca ncer i n p ost me n o pa usal w o me n w h o 
ha ve recei ve d 5 years of a dj u va nt ta m o xife n t hera p y. 
 First-li ne treat me nt of p ost me n o pa usal w o me n wit h H R p os or h or m o ne rece pt or 
u n k n o w n l ocall y a d va nce d or metastatic breast ca ncer. 
A d va nce d  breast  ca ncer  i n  p ost me n o pa usal  w o me n  wit h  disease  pr o gressi o n  f oll o wi n g 
a ntiestr o ge n t hera p y or w h ose di sease has pr o gresse d f oll o wi n g a ntiestr o ge n t hera p y.  

N o v arti s 
C o nfi d e nti al 
P a g e 4 0 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Preli mi nar y  P K  data  f or  t he  c o m bi nati o n  of  ri b ocicli b  ( 6 0 0  m g) a n d  letr oz ole  ( 2. 5  m g) 
i n dicate  t hat  ri b ocicli b  a n d  letroz ole  e x p os ures  are  wit hi n  t he   ra n ge  of  val ues  f or  t he 
res pecti ve si n gle a ge nt a n d t he c o m bi nati o n is safe a n d t olera ble. 
I n  st u d y  C L E E 0 1 1 X 2 1 0 7,  ri b ocicli b  i n  c o m bi nati o n  wit h  letr oz ole  de m o nstrate d 
e nc o ura gi n g  cli nical  acti vit y,  partic ularl y  i n  t he  treat me nt- na ï ve  gr o u p  ( 4 6 %  o bjecti ve 
res p o nse rate, 
8 9 %  disease  c o ntr ol  rate,  7 9 %  cli nical  be nefit  rate  i n  pts  wit h   meas ura ble  disease).  T he 
c o m bi nati o n of ri b ocicli b a n d letr oz ole has a n acce pta ble safet y pr ofile i n pts wit h E R p os, 
H E R 2 ne g a B C. Ne utr o pe nia o bser ve d wit h ri b ocicli b is a n o n-tar g et, a nti pr oliferati ve si de 
effect  of  C D K 4/ 6  i n hi biti o n.  A Es   were  ge nerall y  t olera ble  a n d  ma na ge d  t hr o u g h  d ose 
re d ucti o ns a n d i nterr u pti o ns. ( M u nster et al. prese nte d at S A B CS, Sa n A nt o ni o, T X, 6 – 1 0 
Dece m ber 2 0 1 6, A bstract P- 4- 2 2- 1 8). 
Rece ntl y,  t he  M O N A L E E S A- 2  trial  re p orte d  a  si g nifica nt  be nefit f or  h or m o ne  rece pt or 
p ositi ve H E R 2- ne gati ve p ost me n o pa usal w o me n w h o were naï ve t o t reat me nt f or a d va nce d 
breast ca ncer b y c o m bi ni n g ri b ocicli b ( L E E 0 1 1) wit h letr oz ole. I n t his ra n d o mize d, d o u ble 
bli n d,  place b o-c o ntr olle d  trial  a   statisticall y  si g nifica nt  i m pr o ve me nt  i n  pr o gressi o n-free 
s ur vi val ( P F S) b y a d di n g ri b ociclib t o letr oz ole vers us letr oz o le al o ne was re p orte d. 
Pre me n o pa usal patie nts i n t his st u d y will be a d mi nistere d g osereli n i n a d diti o n t o ri b ocicli b 
a n d letr oz ole. Estr o ge n de pri va ti o n t hera p y is t he c ore treat ment m o dalit y i n patie nts wit h 
E R +  a d va nce d  breast  ca ncer.  E n d oc ri ne  t hera p y  o pti o ns  f or  pre men o pa usal  w o me n  wit h 
E R +  a d va nce d  breast  ca ncer  (l oca ll y  a d va nce d,  rec urre nt,  or  metastatic  breast  ca ncer) 
i ncl u de  selecti ve  E R  m o d ulat ors ( S E R M;  e. g.  ta m o xife n,  ral o xifene),  a n d  l utei nizi n g 
h or m o ne-releasi n g h or m o ne a g o nists ( L H R Ha; e. g. g osereli n). Bl oc ki n g estr o ge n 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 pre m e n o pa usal w o me n wit h 
E R +  breast  ca ncer  f or  o ver  3 5  years.  C urre nt  g ui deli nes  als o  re c o m me n d  treati n g 
pre me n o pa usal  w o me n  wit h  a d va nce d  H R +  breast  ca ncer  wit h  a n  o va ria n  f u ncti o n 
s u p pressi o n  treat me nt  a n d  f oll owi n g  treat me nt  rec o m me n dati o ns  f or  p ost- me n o pa usal 
w o me n, s uc h as n o n-ster oi dal AI s ( N C C N breast ca ncer g ui deli nes versi o n 3. 2 0 1 4). 
O varia n s u p pressi o n of estr o ge n release wit h L H R H a g o nists s uc h  as g osereli n is effecti ve 
i n pre ve nti n g rela pse i n pre me n o pa usal w o me n wit h earl y sta ge ER + breast ca ncer ( Klij n 
2 0 0 1). 
3  
O bj e cti v e s a n d e n d p oi nt s 
O bjecti ves a n d relate d e n d p oi nts are descri be d i n Ta ble 3- 1  bel o w. 
 

N o v arti s 
C o nfi d e nti al 
P a g e 4 1 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4) 
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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 h e pri mar y o bjecti ve of t his st u d y is t he assess me nt of 
t he  cli nical  be n efit  rate  f or  t he  t otal  p o p ulati o n  a n d  f or 
c o h orts A a n d B se paratel y: 
o  T o assess t he cli nical be nefit rate ( C B R) after 
2 4  wee ks  f or  ri b ocicli b  ( L E E 0 1 1)  i n 
c o m bi n ati o n  
wit h  
letr oz ole  
a m o n g 
p ost me n o pa usal  w o me n  a n d  me n  wit h 
h or m o ne  rece pt or  p ositi ve,  H E R 2-  ne gati ve, 
a d va nce d breast ca ncer w h o recei v e d n o pri or 
treat me nt f or a d va nce d disease. ( 7 0 % gr o u p) 
o  T o assess t he cli nical be nefit rate ( C B R) after 
2 4  wee ks  f or  ri b ocicli b  ( L E E 0 1 1)  i n 
c o m bi n ati o n  wit h  letr oz ole  a n d  g osereli n 
a m o n g pre-, a n d peri me n o pa usal w o me n w h o 
recei v e d  n o  pri or  treat me nt  f or  a d va nce d 
disease 
as 
well 
as 
pre-, 
peri- 
a n d 
p ost me n o pa usal  w o me n  a n d  me n  wit h 
h or m o ne  rece pt or  p ositi ve,  H E R 2-  ne gati ve, 
a d va nce d breast ca n cer w h o recei ve d n o m ore 
t ha n 1 pri or c h e m ot hera p y a n d 2 pri or li n es of 
e n d ocri ne t hera p y f or a d va nce d disease ( 3 0 % 
gr o u p) 
 
Cli nical  Be nefit  Rate  ( C B R)  after  2 4 
wee ks  of  treat me nt  as  d efi ne d  b y 
R E CI S T  1. 1  as  p erce nta ge  of  patie nts 
wit h C R, P R or S D lasti n g 2 4 wee ks or 
l o n ger as well as patie nts wit h N C R N P D 
> 2 4  f or  patie nts  wit h  n o n- meas ura ble 
disease 
 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 4 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4) 
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
O bj e cti v e 
E n d p oi nt 
A n al y si s 
S e c o n d ar y 
 
R ef er t o  S e cti o n 
1 0. 5. 1 
 T o assess t he cli nical be n ef it rate ( C B R) after 2 4 wee ks 
a m o n g pre- a n d peri me n o pa usal w o me n wit h o ut pri or 
t hera p y f or a d va nce d disease 
 T o assess t he cli nical be nefit rate ( C B R) after 2 4 wee ks 
f or  ri b ocicli b  a m o n g  pre-,  peri-  a n d  p ost me n o pa usal 
w o me n  a n d  me n  w h o  were  pretreate d  f or  a d va n ce d 
disease  
Cli nical  Be nefit  Rate  ( C B R)  after  2 4 
wee ks  of  treat me nt  as  d efi ne d  b y 
R E CI S T  1. 1  as  p erce nta ge  of  patie nts 
wit h C R, P R or S D lasti n g 2 4 wee ks or 
l o n ger as well as patie nts wit h N C R N P D 
> 2 4  f or  patie nts  wit h  n o n- meas ura ble 
disease 
 
 
 Pr o gressi o n-free s ur vi val ( P F S) f or t he t hree differe nt 
p o p ulati o ns ( p ost me n o pa usal w o me n a n d me n wit h o ut 
pri or treat me nt f or a d va nce d disease, pre- or 
p eri me n o pa usal w o me n wit h o ut pri or treat me nt f or 
a d va nce d disease, pre-, peri-, or p ost me n o p a usal w o me n 
a n d me n pretreate d f or a d va nce d disease)  
P F S  base d o n  ra di ol o gic  assess me nt  b y 
i n vesti gat or  usi n g  R E CI S T  1. 1  criteria 
(e. g.  m P F S,  P F S  rate  at  1 2  a n d  1 8 
m o nt hs)  
 
 
 O verall s ur vi val ( O S) f or t he t hree differe nt p o p ulati o ns, 
defi n e d as t he ti me fr o m date of start of treat me nt t o date 
of deat h d ue t o a n y ca use.  
 O verall res p o nse rate ( O R R) f or t he t hree differe nt 
p o p ulati o ns, d efi ne d as c o m plete res p o nse or partial 
res p o nse as d efi ne d b y R E CI S T 1. 1 
 T o e v al uate t he safet y a n d t olera bilit y of ri b ocicli b i n 
c o m bi nati o n wit h letr oz ole (a n d g osereli n i n 
pre me n o pa usal patie nts) 
 T o e v al uate patie nt re p orte d o utc o mes f or healt h relate d 
q ualit y of life 
O verall s ur vi val ( O S) (e. g. O S rate at 1 2 
a n d 2 4 m o nt hs) 
 
O verall  Res p o nse  Rate  ( O R R)  after  2 4 
wee ks 
 
Fre q ue nc y/se verit y  
of  
A Es  
a n d 
la b orat or y val ues 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 4 3 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4) 
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
O bj e cti v e 
E n d p oi nt 
A n al y si s 
Ti me t o 1 0 % deteri orati o n i n t h e gl o b al 
healt h  stat us/ Q O L  scale  sc ore  of  t he 
E O R T C Q L Q- C 3 0 
C ha n ge  fr o m  baseli ne  i n  t h e  gl o b al 
healt h  stat us/ Q O L  scale  sc ore  of  t he 
E O R T C Q L Q- C 3 0 
 
E x pl or at or y 
 
R ef er t o  S e cti o n 
1 0. 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     A nal ysis met h o ds a n d e n d p oi nts will be    
     use d t hat rese m ble t h e c urre nt scie ntific  
     sta n d ar d at t he ti me of a nal ysis. 
 
     S uc h a n al yses will be descri be d i n a    
     se parate a n al ysis pla n  
 
 
 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 4 4 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol  ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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 nati o nal, m ulti-ce nter, o pe n-la bel, p hase III b trial t o deter mi ne t he efficac y a n d 
safet y of treat me nt wit h ri b o ci cli b ( L E E 0 1 1) pl us letr oz ole i n patie nts wit h H R +, H E R 2-
ne gati ve a d va nce d (rec urre nt or metastatic) breast ca ncer. 
I n t his trial a t otal of 5 0 0 patie nts fr o m a p pr o x. 1 0 0 ce nters will be recr uite d. 
 
Fi g ur e 4- 1  
St u d y d e si g n 
 
 
T he st u d y is s u b- di vi de d i n  t he f oll o wi n g peri o ds: 
O nce t he Patie nt I nf or me d C o nse nt F or m has bee n si g ne d a n d eli g i bilit y is c o nfir me d (all 
i ncl usi o n/e xcl usi o n criteria ha ve bee n verifie d), t he patie nt ca n be e nr olle d. All scree ni n g 
e val uati o ns s h o ul d be perf or me d wit hi n 2 1 da ys pri or t o treat me nt Da y 1.  
Patie nts  will  be  treate d  wit h  dail y  d oses  of  6 0 0  m g  ri b ocicli b ( 3- wee ks- o n/ 1- wee k- off 
sc he d ule) i n c o m bi nati o n wit h 2. 5 m g letr oz ole dail y (c o nti n u o us d osi n g). D ose a dj ust me nts 
( d ose  re d ucti o n  or  i nterr u pti o n)  acc or di n g  t o  safet y  fi n di n gs  will  be  all o we d.  D uri n g  t he 
st u d y, visits will be perf or me d at baseli ne, c ycle 1 o n da y 1 & 1 5 a n d c ycles 2- E O T o n da y 
1.  St u d y  treat me nt  will  c o nti n ue  u ntil  pr o gressi o n,  u nacce pta bl e  t o xicit y,  wit h dra wal  of 
c o nse nt or 8 0 wee ks after t he last patie nt has bee n e nr olle d i n  t he trial, w hic he ver c o mes 
first.  
N o vartis will pr o vi de ri b ocicli b a n d letr oz ole (a n d g osereli n f or pre me n o pa usal patie nts) f or 
all  patie nts  w h o  are  e nr olle d  pri or  t o  c o m mercial  a vaila bilit y of  ri b ocicli b.  F or  patie nts 
e nr olle d after war ds wit hi n t he a p pr o ve d i n dicati o n acc or di n g t o  S m P C, t he i n vesti gat or will 
prescri be b ot h ri b ocicli b a n d le tr oz ole after e val uati o n of t he i n di vi d ual me dical patie nt nee d 
f or t he treat me nt wit h ri b ocicli b a n d letr oz ole. Patie nts w h o are e nr olle d o utsi de of t he la bel 
acc or di n g t o S m P C will be pr o vi de d wit h st u d y dr u g b y N o vartis (i.e. patie nts i n c o h ort B). 
F urt her  treat me nt  after  pr o gressi o n  will  be  at  t he  i n vesti gat or’s  discreti o n.  T u m or 
e val uati o ns  t hr o u g h  C T  will  be  perf or me d  f or  Scree ni n g  a n d  e ver y  1 2  wee ks  d uri n g  t he 
P ati e nt  p o p ul ati o n  
•
p ati e nts  wit h 
H R p os/ H E R 2 n e g 
a d v a nc e d  br e ast 
c a nc er 
•
N o  pri or  C D K 4/ 6i  
•
N o  pri or  m T O Ri  
Ri b ocicli b  6 0 0  m g ( 2 1  d a ys  o n /  7  off)  
+ L etr oz ol  2. 5  m g  q . d. 
Pri m ar y  E n d p oi nt  
•
C B R  aft er  2 4  w e e ks  
S ec o n d ar y  E n d p oi nts 
•
P F S  
•
I nci d e nc e  of ( S) A Es 
•
O S  
•
Q oL  ov er ti m e  
E x pl or at or y  E n d p oi nts 
•
 
 
 
 
 
 
 
 
 
~ 7 0  %  of  p ati e nts 
1st li n e  p ost m e n o p a us al 
w o m e n  or  m e n 
( C o h ort  A)  
~ 3 0  %  of  p ati e nts 
l at er li n es 
Pr e *‐  a n d  p ost m e n o p a us al 
w o m e n  a n d  m e n 
( pri or  e n d ocri n e t h er a p y  or 
c h e m o  all o w e d) 
* pr e m e n o p a u s al p ati e nt s will al s o 
r e c ei v e G n R H- a n al o g u e g o s er eli n  

N o v arti s 
C o nfi d e nti al 
P a g e 4 5 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
st u d y as well as f or E n d of treat me nt, i n case pr o gressi o n as meas ure d b y C T was n ot t he 
reas o n f or e n d of t he treat me nt.  
Patie nts  will  be  f oll o we d  u p  f or safet y  f or  3 0  da ys  after  t he  last  d ose  of  st u d y  dr u g. 
A Es/ S A Es wit h a s us pecte d ca usalit y t o t he st u d y dr u g m ust be r e p orte d be y o n d t his 3 0 da ys 
safet y i nter val. 
4. 2  
Ti mi n g of i nt eri m a n al y s e s 
T hree  i nteri m  a nal yses  are  pla n ne d  d uri n g  t he  st u d y.  T he  first i nteri m  a nal ysis  will  be 
c o n d ucte d  o ne  year  after  t he  first  patie nt  has  bee n  e nr olle d  a n d  i ncl u de  a  preli mi nar y 
a nal ysis o n safet y. T he sec o n d i n teri m a nal ysis will be c o n d ucte d 1 2 m o nt hs after L P F V i n 
t he 3 0 % pretreate d a n d pre me n o pausal c o h ort a n d will i ncl u de a preli mi nar y a nal ysis o n 
safet y, efficac y a n d q ualit y of life. T he t hir d i nteri m a nal ysis will ta ke place 6 m o nt hs after 
t he  last  patie nt  has  bee n  recr uite d  a n d  will  i ncl u de  a  preli mi nar y  a nal ysis  o n  safet y  a n d 
efficac y. 
4. 3  
D efi niti o n of e n d of t h e st u d y 
T he e n d of treat me nt ( L P L T = E O T) f or all patie nts is pla n ne d 8 0 w ee ks after recr uit me nt of 
t he last patie nt ( L P F T) or pr o gressi o n of disease of of all patie nts, w hic he ver occ urs first. 
Base d o n t he data of t he M o naleesa- 2 st u d y a n d t he i nteri m a nal ysis, o bser vati o n ti me mi g ht 
be a dj uste d i n or der t o ac hie ve me dia n P F S.  
Patie nts will be f oll o we d f or safe t y f or 3 0 da ys after t he i n di vi d uall y last d ose of st u d y dr u g 
t o  ac hie ve  t he  e n d  of  st u d y  ( L P L V).  After  last  patie nt  last  treat me nt  ( L P L T),  t he  p ost-
a nti ne o plastic treat me nt, t he c urre nt pr o gressi o n a n d s ur vi val stat us f or all patie nts will be 
u p date d fi nall y a n d rec or de d i n t he e C R F. 
4. 4  
E arl y st u d y t er mi n ati o n 
N o vartis a n d t he st u d y steeri n g c o m mittee ca n deci de t o ter mi na te t he st u d y earl y, e. g. f or 
c ha n ges i n Ris k- Be nefit- Rati o or F utilit y. A d diti o nall y, N o vart is ca n ter mi nate t he st u d y f or 
reas o ns sti p ulate d i n t he cli nical trial a gree me nt. S h o ul d t his be necessar y, t he patie nt s h o ul d 
be see n as s o o n as p ossi ble f or t he fi nal 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  Ta ble  7- 1  f or  a  pre mat urel y  wit h dra w n  patie nt. T he  i n vesti gat or  ma 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 nter ests. N o vartis will be res p o nsi ble 
f or i nf or mi n g t he et hics c o m mittee 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 
T his  st u d y  will  be  perf or me d  i n  5 0 0  patie nts  wit h  h or m o ne  rece p t or  p ositi ve  l ocall y 
a d va nce d or metastatic br east ca ncer as defi ne d b y:  
 C o h ort A: a p pr o x. 7 0 % of patie nts m ust be p ost me n o pa usal w o me n or me n wit h o ut a n y 
treat me nt f or a d va nce d disease. 
 C o h ort  B:  a p pr o x.  3 0 %  of  patie nts  ca n  be  pre-  or  peri me n o pa usal  
w o me n or 
p ost me n o pa usal  w o me n  or  me n,  m ust  ha ve  n o  m ore  t ha n  1  c he m ot her a p y  li ne  f or 
a d va nce d disease, a n d ma xi m u m 2 li nes of e n d ocri ne t hera p y f or a d va nce d disease ( or 
a c o m bi nati o n of t hese criteria). 

N o v arti s 
C o nfi d e nti al 
P a g e 4 6 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
W he n t he n u m ber of patie nts f or o ne of t he c o h orts is reac he d, n o m ore patie nts will be 
i ncl u de d i n t his c o h ort. 
Patie nts m ust ha ve d oc u me nte d e v i de nce of rec urre nce or pr o gressi o n d uri n g or after t he 
last t hera p y pri or t o e nr oll me nt (e xce pt f or de n o v o metastasize d patie nts).  
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.  Patie nts 
i nca pa ble of gi vi n g c o nse nt perso nall y ma y n ot be i ncl u de d i n t his st u d y. 
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  meet  all  t he  f oll o wi n g 
i ncl usi o n a n d n o ne of t he e xcl usi o n criteria are offere d e nr ollme nt i n t he st u d y.  
5. 2  
I n cl u si o n crit eri a 
Patie nts eli gi ble f or i ncl u si 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.  Patie nt is a n a d ult, ≥ 1 8 years ol d at t he ti me of i nf or me d c o n se nt a n d has si g ne d 
i nf or me d c o nse nt bef ore a n y trial relate d acti vities.  
2.  W o me n a n d me n wit h a d va nce d (l oc o re gi o nall y rec urre nt or metastatic) breast 
ca ncer n ot a me na ble t o c urati ve t hera p y. 
3.  A) F or i ncl usi o n i n c o h ort A:   Patie nt  is  p ost me n o pa usal  w o ma n  or  ma n. 
P ost me n o pa usal stat us is defi ne d eit her b y: 
 Pri or bilateral o o p h orect o m y 
 A ge ≥6 0 
 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  
c he m ot hera p y, t a 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 per l ocal n or mal ra n ge 
 
N ote: W o me n are c o nsi dere d p ost- me n o pa usal a n d n ot of c hil d beari n g p ote ntial if 
t he y ha ve ha d 1 2 m o nt hs of nat ural (s p o nta ne o us) a me n orr hea with a n a p pr o priate 
cli nical pr ofile (e. g. a ge a p pr o priate, hist or y of vas o m ot or s ym pt o ms) or ha ve ha d 
s ur gical  bilateral  o o p h orect o m y  ( wit h  or  wit h o ut  h ysterect o m y).  I n  t he  case  of 
o o p h orect o m y  al o ne,  o nl y  w he n  t he  re pr o d ucti ve  stat us  of  t he  w o ma n  has  bee n 
c o nfir me d  b y  f oll o w  u p  h or m o ne  le vel  assess me nt  is  s he  c o nsi der e d n ot of c hil d 
beari n g p ote ntial. 
O varia n ra diati o n is n ot per mitte d f or i n d ucti o n of o varia n s u p pressi o n i n t his trial. 
Pati e nts  treat e d  wit h  a  l utei nizi n g  h or m o ne-releasi n g  h or m o ne  a g o nist  ( L H R Ha) 
( g osereli n acetate) will be e nr olle d i n c o h ort B. 
 
B) F or c o h ort B , als o pre me n o pa usal or peri me n o pa usal patie nts ma y be i ncl u de d. 
Pre me n o pa usal stat us is  defi ne d as eit her:  
 Patie nt ha d last me nstr ual peri o d wit hi n t he last 1 2 m o nt hs,  
O R  
 If o n ta m o xife n wit hi n t he past 1 4 da ys, plas ma estra di ol m ust be ≥1 0 p g/ m L 
a n d  F S H  ≤4 0 I U/l  or  i n  t he  pre me n o pa usal  ra n ge,  acc or di n g  t o  l o cal 
la b orat or y defi niti o n, 
O R  
 I n case of t hera p y i n d uce d a me n orr hea, wit h a plas ma estra di ol ≥1 0 p g/ m L 
a n d/ or  F S H  ≤4 0 I U/l  or  i n  t he  pre me n o pa usal  ra n ge  acc or di n g  t o l ocal 
la b orat or y defi niti o n.  

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4.  Patie nts  
w h o  ha ve  u n der g o ne  bilateral  o o p h orect o m y  are  c o nsi der e d 
p ost me n o pa usal: C o h ort A wit h o ut pretreat me nt f or a d va nce d or m etastatic sit uati o n, 
C o h ort B wit h pretreat me nt f or a d va nce d or metastatic disease.  
5.  Peri me n o pa usal stat us is defi ne d as neit her pre me n o pa usal n or p ost me n o pa usal. 
6.  F or  pre me n o pa usal  patie nts:  C o nfir me d  ne gati ve  ser u m  pre g na nc y test  ( β- h C G) 
bef ore starti n g st u d y treat me nt  or patie nt has ha d a h ysterect om y. 
7.  Patie nt has a hist ol o gicall y a n d / or c yt ol o gicall y c o nfir me d diag n osis of estr o ge n-
rece pt or p ositi ve a n d/ or pr o gester o ne rece pt or p ositi ve breast ca ncer b y l ocal 
la b orat or y. 
8.  Patie nt has H E R 2- ne gati ve breast  ca ncer defi ne d as a ne gati ve in sit u h y bri dizati o n 
test or a n I H C stat us of 0, 1 + or 2 +. If I H C is 2 +, a ne gati ve i n sit u h y bri dizati o n 
( FI S H, CI S H, or SI S H) test is re q uire d b y l ocal la b orat or y testi n g. 
9.  Patie nt m ust ha ve eit her: 
 Meas ura ble disease, i.e., at least o ne meas ura ble lesi o n as per  R E CI S T 1. 1 
criteria  
O R 
 B o ne lesi o ns: l ytic or mi xe d (l ytic + scler otic) i n t he a bse nce of meas ura ble 
disease 
O R 
 N o n- meas ura ble disease (i ncl u di n g oste o blastic b o ne lesi o ns) 
N ote: T u m or  lesi o ns  pre vi o usl y  irra diat e d  c urati vel y  or  s u bjecte d  t o ot her 
l oc ore gi o nal t hera p y will o nl y be c o nsi dere d meas ura ble if disease pr o gressi o n 
at t he treate d site after c o m ple ti o n of t hera p y is clearl y d oc ume nte d. 
1 0.  Patie nt has a n Easter n C o o pera ti ve O nc ol o g y Gr o u p ( E C O G) perf orma nce stat us 0 
or 1 or 2 
1 1.  Patie nt has a de q uate b o ne marr o w a n d or ga n f u ncti o n as defi ne d b y t he f oll o wi n g 
la b orat or y val ues (as assesse d b y l ocal la b orat or y): 
 A bs ol ute ne utr o p hil c o u nt ≥ 1. 5 × 1 0 9/ L 
 Platelets ≥ 1 0 0 × 1 0 9/ L 
 He m o gl o bi n ≥ 9. 0 g/ d L 
 I N R ≤1. 5 
 Ser u m creati ni ne < 1. 5 m g/ dl or creati ni ne cleara nce ≥ 5 0 m L/ mi n.  
 T otal bilir u bi n ≤ U L N e xce pt f o r patie nts wit h Gil bert’s s y n dr ome ( M or b us 
Me ule n grac ht) w h o ma y o nl y be i nc l u de d if t he t otal bilir u bi n is ≤ 3. 0 × 
U L N or direct bilir u bi n ≤ 1. 5 × U L N. 
 As partate tra nsa mi nase ( A S T) < 2. 5 ×  U L N, e xce pt f or patie nts wit h li ver 
metastasis, w h o are o nl y i nc l u de d if t he A S T is < 5 ×  U L N 
 Ala ni ne tra nsa mi nase ( A L T) < 2. 5 ×  U L N, e xce pt f or patie nts with li ver 
metastasis, w h o are o nl y i ncl u de d if t he A L T is < 5 × U L N 
1 2.  Patie nt m ust ha ve t he f oll o wi n g la b orat or y val ues wit hi n n or mal  li mits or c orrecte d 
t o wit hi n n or mal li mits wit h s u p ple me nts bef ore t he first d ose of st u d y me dicati o n: 
 S o di u m 
 P otassi u m 
 Ma g nesi u m 
 T otal Calci u m (c orrecte d f or s er u m al b u mi n i n patie nts wit h 
h y p oal b u mi ne mia) 
1 3.  Sta n dar d 1 2-lea d E C G val ues assesse d b y t he l ocal la b orat or y 
 Q Tc F i nter val at scree ni n g < 4 5 0 m sec ( usi n g Fri dericia’s c orrecti o n) 

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1 4.  Resti n g heart rate 5 0- 9 0 b p m 
 
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.  Patie nt  wit h  s y m pt o matic  visceral  disease  or  a n y  disease  b ur de n   t hat  ma kes  t he 
patie nt i neli gi ble f or e n d ocri n e t hera p y per t he i n vesti gat or’s best j u d g me nt.   
2.  Patie nt w h o recei ve d a n y pri or C D K 4/ 6 i n hi bit or 
3.  Patie nt w h o recei ve d a n y pri or m T O R-i n hi bit or 
4.  Patie nt has a k n o w n h y perse nsiti vit y t o a n y of t he e xci pie nts o f ri b ocicli b, letr oz ole 
( or g osereli n if pre- or peri me n o pa usal) 
5.  Patie nts wit h c urre nt i nfla m mat or y breast ca nce r ( < 4 wee ks before e nr oll me nt). 
6.  F or C o h ort A:  pri or treat me nt f or a d va nce d or metastatic disease 
 Patie nts w h o recei ve d ≤ 2 1 da ys of ar o matase i n hi bit or treat me n t f or a d va nce d 
disease pri or t o e nr oll me nt are eli gi ble. 
N ote:  Patie nts starti n g st u d y treat me nt directl y after a n y e n d ocri ne a nti-ca ncer 
t hera p y wit hi n less t ha n 5 half-li ves of t he pre vi o us t hera p y sh o ul d be m o nit ore d 
cl osel y f or p ossi ble o v erla p pi n g t o xicities.  
7.  F or C o h ort B:  
 Patie nt w h o has recei ve d m ore t h a n o ne pri or c he m ot hera p y re gi m e n f or 
a d va nce d breast ca ncer  
A N D/ O R 
 Patie nt w h o has recei ve d m ore t h a n t w o pri or h or m o nal t hera p y r e gi me ns f or 
a d va nce d breast ca ncer. ( Treat me nt f or ≤ 2 1 da ys wit h a n ar o mat ase i n hi bit or 
f or a d va nce d disease is n ot co nsi dere d a n e n d ocri ne t hera p y li n e).  
8.  Patie nt is c o nc urre ntl y usi n g ot he r a nti-ca ncer t hera p y. ( Treatme nt wit h 
bis p h os p h o nates or de n os u ma b is ge nerall y n ot c o nsi dere d a nti-c a ncer t hera p y). 
9.  Patie nt has ha d maj or s ur ger y w it hi n 1 4 da ys pri or t o starti n g st u d y dr u g or has n ot 
rec o vere d fr o m maj or si de effects. 
1 0.  Patie nt has n ot rec o vere d fr o m all t o xicities relate d t o pri or a ntica ncer t hera pies t o 
N CI C T C A E versi o n 4. 0 3 Gra de ≤1. E xce pti o n t o t his criteri o n: p atie nts wit h a n y 
gra de of al o pecia are all o we d t o e nter t he st u d y. 
1 1.  Patie nt has a c o nc urre nt mali g na nc y or mali g na nc y wit hi n 3 year s of e nr oll me nt, 
wit h t he e xce pti o n of a de q uatel y  treate d, basal or s q ua m o us cell s ki n carci n o ma, 
n o n- mela n o mat o us s ki n ca ncer or c u rati vel y resecte d cer vical cancer. 
1 2.  Patie nts wit h ce ntral ner v o us s yste 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 her a p y c o m pleti o n (i ncl u di n g ra dia ti 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 t u m or at t he ti me of scree ni n g a n d n ot recei vi n g ster oi ds 
a n d/ or e nz y me i n d uci n g a nti-e pile ptic me dicati o ns f or brai n met astases. 
1 3.  Patie nt has i m pair me nt of gastr oi n testi 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 t he st u d y dr u gs (e. g., ulcerati ve diseases, 
u nc o ntr olle d na usea, v o miti n g, diarr hea, mala bs or pti o n s y n dr o me , or s mall b o wel 
resecti o n) 
1 4.  Patie nt has a k n o w n hist or y of H I V i nfecti o n (testi n g n ot ma n dat or y). 
1 5.  Patie nt has a n y ot her c o nc urre nt  se vere a n d/ or u nc o ntr olle d me dical c o n diti o n t hat 
w o ul d,  i n  t he  i n vesti gat or’s  j u d g me nt,  ca use  u nacce pta ble  safet y  ris ks, 

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c o ntrai n dicate patie nt partici pati o n i n t he cli nical st u d y or c o m pr o mise c o m plia nce 
wit h t he pr ot oc ol: (e. g. c hr o nic pa ncreatitis, c hr o nic acti ve h e patitis, acti ve u ntreate d 
or u nc o ntr olle d f u n gal, bacterial  or viral i nfecti o ns, etc.). 
1 6.  Cli nicall y si g nifica nt, u nc o ntr o lle d heart disease a n d/ or car diac re p olarizati o n 
a b n or malit y, i ncl u di n g a n y of t he f oll o wi n g: 
 Hist or y of ac ute c or o nar y s y n dr o m es (i ncl u di n g m y ocar dial i nfar cti o n, u nsta ble 
a n gi na, c or o nar y arter y b y pass  grafti n g, c or o nar y a n gi o plast y, or ste nti n g) or 
s y m pt o matic pericar ditis wit hin 6 m o nt hs pri or t o scree ni n g. 
 Hist or y of d oc u me nte d c o n gesti ve he art fail ure ( Ne w Y or k Heart Ass ociati o n 
f u ncti o nal classificati o n III-I V). 
 D oc u me nte d car di o m y o pat h y. 
 Cli nicall y si g nifica nt car diac arr h yt h mias (e. g. ve ntric ular ta c h ycar dia), 
c o m plete left b u n dle bra nc h bl oc k, hi g h- gra de A V bl oc k (e. g. bi fascic ular 
bl oc k, M o bitz t y pe II a n d t hir d- de gree A V bl oc k). 
 L o n g Q T s y n dr o me or fa mil y hist or y of i di o pat hic s u d de n deat h o r c o n ge nital 
l o n g Q T s y n dr o me, or a n y of t he f oll o wi n g: 
o  Ris k fact ors f or T orsa des de P oi nte ( T d P) i ncl u di n g u nc orrecte d  
h y p o kale mia or h y p o ma g nese mia, hist or y of car diac fail ure, or h ist or y of 
cli nicall y si g nifica nt/s ym pt o matic bra d ycar dia. 
o  C o nc o mita nt use of me dicati o n(s) wit h a k n o w n ris k t o pr ol o n g t he Q T 
i nter val a n d/ or k n o w n t o ca use T orsa des de P oi nte t hat ca n n ot be 
disc o nti n ue d ( wit hi n 5 half-li ves  or 7 da ys pri or t o starti n g st u d y dr u g) or 
re place d b y safe alter nati ve me dicati o n. 
o  I na bilit y t o deter mi ne t he Q T i nter val o n scree ni n g ( Q Tc F, usi ng 
Fri dericia’s c orrecti o n).  
o  S yst olic bl o o d press ure ( S B P)  > 1 6 0 m m H g or < 9 0 m m H g at scree ni ng.  
1 7.  Patie nt is c urre ntl y recei vi n g a n y of  t he f oll o wi n g s u bsta nces a n d ca n n ot be 
disc o nti n ue d 7 da ys pri or t o C ycle 1 Da y 1: 
 K n o w n str o n g i n d ucers or i n hi bit o rs of C Y P 3 A 4/ 5, i ncl u di n g gra pefr uit, 
gra pefr uit h y bri ds, p o mel os, sta r-fr uit, a n d Se ville ora n ges. 
 T hat ha ve a narr o w t hera pe utic wi n d o w a n d are pre d o mi na ntl y met a b olize d 
t hr o u g h C Y P 3 A 4/ 5. 
 Her bal pre parati o ns/ me dicati o ns . Dietar y s u p ple me nts are all o we d if t he y 
c o ntai n o nl y n utrie nts, mi nerals a n d/ or vita mi ns. 
1 8.  Patie nt is c urre ntl y recei vi n g or has recei ve d s yste mic c ortic o ster oi ds ≤ 2 wee ks 
pri or t o starti n g st u d y dr u g, or w h o ha ve n ot f ull y rec o vere d fr o m si de effects of 
s uc h treat me nt. 
N ote: T he f oll o wi n g uses of c ortic oster oi ds are per mitte d: si n gle d oses, t o pical 
a p plicati o ns (e. g., f or ras h), i n hale d s pra ys (e. g., f or o bstr u cti ve air wa ys diseases), 
e ye dr o ps or l ocal i njecti o ns (e. g., i ntra- artic ular). 
1 9.  Partici pati o n i n a pri or i n ve sti gati o nal st u d y wit hi n 3 0 da ys pri or t o e nr oll me nt or 
wit hi n 5- half-li ves of t he i n vest i gati o nal pr o d uct, w hic he ver is l o n ger. 
2 0.  F or pre me n o pa usal w o me n: Pre g na nt or n ursi n g (lactati n g) w o me n,  w here 
pre g na nc y is defi ne d as t he stat e of a fe male after c o nce pti o n a n d u ntil t he 
ter mi nati o n of gestati o n, c o nfir me d b y a p ositi ve h C G la b orat ory test. 
2 1.  W o me n of c hil d- beari n g p ote ntial , defi ne d as all w o me n p h ysi ol ogicall y ca pa ble         
of bec o mi n g pre g na nt, u nless t he y are usi n g hi g hl y effecti ve met h o ds of 
c o ntrace pti o n d uri n g d osi n g of st u d y treat me nt . Hi g hl y effecti ve c o ntrace pti o n 
met h o ds i ncl u de: 

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 T otal a bsti ne nce ( w he n t his is i n li ne wit h t he preferre d a n d u s ual lifest yle 
of t he s u bject. Peri o dic a bs ti ne nce (e. g., cale n dar, o v ulati o n, 
s y m pt ot her mal, p ost- o v ulati o n meth o ds) a n d wit h dra wal are n ot a cce pta ble 
met h o ds of c o ntrace pti o n 
 Fe male sterilizati o n ( ha ve ha d s ur gical bilateral o o p h orect o m y wit h or 
wit h o ut h ysterect o m y) or t u bal li gati o n at least si x wee ks bef ore ta ki n g 
st u d y treat me nt. I n case of o o p h orect o m y al o ne, o nl y w he n t he 
re pr o d ucti ve stat us of t he w o man has bee n c o nfir me d b y f oll o w u p 
h or m o ne le vel assess me nt 
 Male sterilizati o n (at least 6 m o nt hs pri or t o scree ni n g). F or fe male s u bjects 
o n t he st u d y t he vasect o mize d mal e part ner s h o ul d be t he s ole p art ner f or 
t hat s u bject. 
 C o m bi nati o n of: 
 Place me nt of a n i ntra uteri ne de vi ce (I U D) or i ntra uteri ne s yste m (I U S) 
 Barrier met h o ds of c o ntrace pti o n: C o n d o m or Occl usi ve ca p 
( dia p hra g m or cer vical/ va ult ca ps) wit h s per mici dal 
f oa m/ gel/fil m/crea m/ va gi nal s u p p osit or y  
N ote:  se x uall y acti ve males s h o ul d use a c o n d o m d uri n g i nterc o urse while ta ki n g 
dr u g a n d f or 2 1 da ys aft er st o p pi n g me dicati o n a n d s h o ul d n ot f at her a c hil d i n t his 
peri o d. A c o n d o m is re q uire d t o be use d als o b y vasect o mize d me n as well as d uri n g 
i nterc o urse wit h a male part ner i n or der t o pre ve nt deli ver y of t he dr u g via se mi nal 
fl ui d.  
6  
Tr e at m e nt 
6. 1  
St u d y tr e at m e nt 
F or  t his  st u d y,  t he  ter m  “i n vesti gati o nal  dr u g”  refers  t o  N o var tis  st u d y  dr u g  ri b ocicli b 
( L E E 0 1 1). T he ot her i n vesti gati o nal dr u gs t o be use d i n t his stu d y are letr oz ole as well as 
g osereli n  acetate  f or  pre-a n d  peri me n o pa usal  w o me n;  me n  ma y  als o  be  treate d  wit h 
g osereli n acetate at t he discre ti o n of t he i n vesti gat or. St u d y treat me nt i n t his st u d y refers t o 
t he c o m bi nati o n of dr u gs a n d i ncl u des i n vesti gati o nal dr u g (ri bocicli b) as well as letr oz ole 
a n d g osereli n acetate. 
N o vartis  will  pr o vi de  ri b ocicli b  a n d  letr oz ole  (a n d  g osereli n) f or  all  patie nts  w h o  are 
e nr olle d  pri or  t o  c o m mercial  a vaila bilit y  of  ri b ocicli b.  F or  pa tie nts  e nr olle d  after war ds 
wit hi n  t he  a p pr o ve d  i n dicati o n  a cc or di n g  t o  S m P C,  t he  i n vesti ga t or  will  prescri be  b ot h 
ri b ocicli b  a n d  letr oz ole  after  e val uati o n  of  t he  i n di vi d ual  me dical  patie nt  nee d  f or  t he 
treat me nt  wit h  ri b ocicli b  a n d  letr oz ole.  Patie nts  w h o  are  e nr olle d  o utsi de  of  t he  la bel 
acc or di n g t o S m P C will be pr o vi de d wit h st u d y dr u g b y N o vartis (i.e. patie nts i n c o h ort B). 
Patie nts  e nr olle d  after  c o m mercial  a vaila bilit y  of  ri b ocicli b  a n d  letr oz ole,  w h o  are  t o  be 
treate d  wit hi n  t he  la bel  a n d  are c o vere d  b y  pri vate  healt h  i ns u ra nce  s h o ul d  c o ntact  t heir 
pri vate healt h i ns ura nce t o e ns ure t hat t he i ns ura nce will c o ve r t he c osts of t he prescri pti o n. 
Ri b ocicli b  will  be  s u p plie d  b y  N o vartis  or  its  desi g nee  as  2 0 0 m g  fil m-c oate d  ta blets  as 
i n di vi d ual patie nt s u p pl y pac ka ge d i n b ottles or blisters. Letr oz ole a n d g osereli n acetate will 
be  pr oc ure d  l ocall y  as  it  is  c o m merciall y  a vaila ble  i n  Ger ma n y.   St ora ge  c o n diti o ns  are 
descri be d i n t he me dicati o n la bel. 

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Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
All d osa ges prescri be d a n d dis pe nse d t o t he patie nt a n d all d os e 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 e C R F. O n t he first da y of eac h c ycle, 
patie nts  will  recei ve  a n  a de q uate  dr u g  s u p pl y  ( bef ore  c o m mercia l  a vaila bilit y)  or  a 
prescri pti o n (after c o m mercial a vaila bilit y) f or self-a d mi nistr ati o n at h o me.  
T he i n vesti gat or m ust e m p hasize c o m plia nce a n d will i nstr uct t h e patie nt t o ta ke ri b ocicli b 
( L E E 0 1 1) a n d letr oz ole as well as g osereli n e xactl y as prescri be d.  
6. 1. 1  
D o si n g r e gi m e n 
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 
Ri b ocicli b  
Ta blet f or oral use  
6 0 0  
m g 
( 3 x 2 0 0 m g) 
O n c e d ail y - D a y s 1- 2 1 
of e a c h 2 8 d a y c y cl e  
Letr oz ole 
Ta blet f or oral use  
2. 5 m g  
O n c e d ail y  
G osereli n 
(f or pre me n o pa usal patie nts) 
S u bc uta ne o us i m pla nt 
3. 6 m g  
D a y 1 of e a c h c y cl e 
Ri b ocicli b will be gi ve n orall y o nce a da y o n da ys 1- 2 1 of eac h  2 8 da y c ycle. Da ys 2 2- 2 8 
will be a “rest” fr o m ri b ocicli b. Letr oz ole will be gi ve n e ver y  da y. G osereli n will be i njecte d 
m o nt hl y f or pre- or peri m e n o pa usal patie nts o nl y. 
Ri b ocicli b, letr oz ole a n d g osereli n will be a d mi nistere d as a f lat-fi xe d d ose, a n d n ot b y b o d y 
wei g ht or b o d y s urface area. 
T he i n vesti gat or or res p o nsi ble  site pers o n nel s h o ul d i nstr uct t he patie nt t o ta ke t he st u d y 
dr u gs as per pr ot oc ol ( pr o m ot e c o m plia nce). Dr u g acc o u nta bilit y  m ust be perf or me d o n a 
re g ular basis. Patie nts will be i nstr ucte d t o ret ur n u n use d st ud y dr u gs t o t he site at t he e n d 
of eac h c ycle. T he site pers o n nel will e ns ure t hat t he a p pr o priate d ose of eac h st u d y dr u g is 
pr o vi de d at eac h visit. 
6. 1. 1. 1  
Ri b o ci cli b d o si n g 
Ri b ocicli b s h o ul d be ta ke n as f oll o ws: 
- 
Ri b ocicli b is d ose d f or t he  first 2 1 da ys o ut of t he 2 8 da y c ycle. 
- 
Patie nts s h o ul d be i nstr ucte d t o ta ke t he st u d y dr u g c o m bi nati o n of ri b ocicli b a n d 
letr oz ole wit h a lar ge glass of water ( ~ 2 5 0 m L) at t he sa me ti me eac h da y . E ve ni n g 
d oses are str o n gl y n ot rec o m me n de d.  
- 
Ri b ocicli b ca n be a d mi nistere d wit h or wit h o ut f o o d; h o we ver di etar y ha bits 
ar o u n d t he ti me of d osi n g s h o ul d be a s c o nsiste nt as p ossi ble t hr o u g h o ut t he st u d y. 
- 
Patie nts s h o ul d be i nstr ucte d t o s wall o w t he ri b ocicli b w h ole an d n ot t o c he w or 
cr us h t he m. 
- 
If v o miti n g occ urs d uri n g t he co urse of treat me nt, n o re- d osi n g  of t he patie nt is 
all o we d bef ore t he ne xt sc he d ule d d ose. T he occ urre nce a n d fre q ue nc y of a n y 
v o miti n g d uri n g a treat me nt c ycle  m ust be n ote d i n t he a d verse e ve nts secti o n of 
t he e C R F. 
- 
A n y d oses t hat are misse d ( n ot ta k e n wit hi n 6 h o urs of t he i nte n de d ti me) s h o ul d 
be s ki p pe d a n d s h o ul d n ot be re pl ace d or ma de u p o n a s u bse q ue n t da y. 

N o v arti s 
C o nfi d e nti al 
P a g e 5 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
- 
Patie nts m ust a v oi d c o ns u m pti o n of  gra pefr uit, gra pefr uit h y brids, p o mel os, star-
fr uit, Se ville ora n ges or pr o d ucts c o ntai ni n g t he j uice of eac h d uri n g t he e ntire 
st u d y a n d prefera bl y 7 da ys bef ore t he first d ose of st u d y me dicati o ns, d ue t o 
p ote ntial C Y P 3 A 4 i nteracti o n w it h t he st u d y me dicati o ns.  
N ote:  Ora n ge j uice is all o we d. 
1.   Her bal or dietar y s u p ple me nts k n o w n as str o n g i n hi bit ors or i n d ucers of C Y P 3 A 4 
or t h ose wit h a k n o w n ris k of Q T pr ol o n gati o n are n ot per mitte d . 
.  
2.  M ulti vita mi ns are per mitte d. 
6. 1. 1. 2  
A d diti o n al d o si n g g ui d eli n e s f or E C G/ C h e mi str y p a n el/ Li pi d P a n el 
c oll e cti o n  
O n da ys wit h E C G sa m pli n g, c he mistr y pa nel a n d/ or li pi d pa nel s a m pli n g, t he f oll o wi n g 
a d diti o nal g ui deli nes s h o ul d be f oll o we d: 
 O n a da y of c he mistr y pa nel, he pa tic safet y mar kers a n d/ or li pid pa nel sa m pli n g, 
patie nts m ust be fasti n g fr o m a ll f o o d a n d dri n k f or at least 8  h o urs o ver ni g ht. Water is 
all o we d d uri n g all fasti n g peri o ds ; h o we ver c offee, tea a n d j uice are n ot per mitte d 
d uri n g t he fasti n g peri o d. Patie nt s m ust als o ta ke st u d y treat me nt i n t he cli nic u n der t he 
s u per visi o n of t he I n vesti gat or or desi g nee. O n all ot her da ys patie nts ma y ta ke t he 
st u d y treat me nt at h o me. 
 If a pre- d ose E C G meas ure me nt s h o ul d be c ollecte d, t he n t he E C G meas ure me nt 
s h o ul d occ ur bef ore d osi n g of t he st u d y treat me nt 
 
6. 1. 2  
Tr e at m e nt d ur ati o n 
Patie nt ma y c o nti n ue treat me nt wit h t he st u d y dr u g u ntil patie n t e x perie nces u nacce pta ble 
t o xicit y, disease pr o gressi o n (a n y ra di ol o gic acc or di n g t o R E CIS T 1. 1) a n d/ or treat me nt is 
disc o nti n ue d  at  t he  discreti o n  of  t he  i n vesti gat or  or  wit h dra wa l  of  c o nse nt  m ust  be 
d oc u me nte d acc or di n gl y. 
 
 
St u d y dr u g i nterr u pti o n refers 
t o a patie nt st o p pi n g eit her stu d y dr u g d uri n g t he c o urse of t h e st u d y, b ut t he n re-starti n g it 
at  a  later  ti me  i n  t he  st u d y.  If  o ne  of  t he  st u d y  dr u gs  is  disc o nti n ue d,  t he  ot her  m ust  be 
disc o nti n ue d as well. If t he st u d y dr u g ri b ocicli b or letr oz ol is i nterr u pte d f or m ore t ha n 4 
wee ks, t he patie nt will be per m a ne ntl y disc o nti n ue d fr o m t he st u d y treat me nt. 
6. 2  
D o s e m o difi c ati o n s 
6. 2. 1  
D o s e m o difi c at i o n a n d d o s e d el a y 
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 nee d t o be a p plie d:  

N o v arti s 
C o nfi d e nti al 
P a g e 5 3 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
T a bl e 6- 2  
D o s e M o difi c ati o n g ui d eli n e s 
 
Ri b o ci cli b 
D o s e 
N u m ber of t a blets 
& stre n gt h 
St arti n g d o s e 
6 0 0 m g 
3 x 2 0 0 m g ta blets 
Fir st d o s e r e d u cti o n  
4 0 0 m g  
2 x 2 0 0 m g t a bl et s 
S e c o n d d o s e r e d u cti o n  
2 0 0 m g  
1 x 2 0 0 m g t a bl et s 
 
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. 
6. 2. 1. 1  
Ri b o ci cli b 
Rec o m me n dati o ns  f or  d ose  re d ucti o n,  i nterr u pti o n  or  disc o nti n ua ti o n  of  ri b ocicli b  i n  t he 
ma na ge me nt of st u d y dr u g relate d a d verse reacti o ns are s u m mariz e d i n Ta ble 6- 3 , Ta ble 6-
4 , Ta ble 6- 5  a n d Ta ble 6- 6 .   
Cli nical  j u d g me nt  of  t he  treati n g  p h ysicia n  s h o ul d  g ui de  t he  ma na ge me nt  pla n  of  eac h 
patie nt  base d  o n  i n di vi d ual  be nefit/ris k  assess me nt.  H o we ver,  f or  e ve nts  re q uiri n g  a 
disc o nti n uati o n i n Ta ble 6- 3 , Ta ble 6- 4 , Ta ble 6- 5  a n d Ta ble 6- 6  or liste d i n Secti o n 7. 1, 
treat me nt m ust be disc o nti n ue d. 
If a patie nt i na d verte ntl y d oses ri b ocicli b o n a rest da y (e. g. da ys 2 2- 2 8 of a n y gi ve n c ycle), 
ri b ocicli b s h o ul d be i nterr u pte d t o e ns ure 7 c o nsec uti ve rest da ys a n d a v oi d o ver d ose. T he 
visit sc he d ule will  n ot be a dj uste d. 
 
T a bl e 6- 3  
Ri b o ci cli b d o s e a dj u st m e nt a n d m a n a g e m e nt r e c o m m e n d at i o n s f or 
h e m at ol o gi c al a d v er s e r e a cti o n s  
T o xi cit y/ Gr a d e 
D o s e A dj u st m e nt a n d M a n a g e m e nt 
R e c o m m e n d ati o n s 
T hr o m b o c yt o p e ni a 
Gr a d e 1( ≥7 5 x 1 0 9 / L) 
N o d o s e a dj u st m e nt r e q uir e d. 
Gr a d e 2 ( ≥5 0 x 1 0 9 / L – < 7 5 x 1 09 / L) 
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 ri b o ci cli b at t h e s a m e d o s e. 
Gr a d e 3 ( ≥2 5 x 1 0 9 / L - < 5 0 x 1 09 / L) 
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 ri b o ci cli b at t h e s a m e d o s e l e v el. 
If t o xi cit y r e c ur s at gr a d e 3: t em 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 a n d r e d u c e ri b o ci cli b t o t h e 
n e xt l o w er d o s e l e v el. 
Gr a d e 4( < 2 5 x 1 0 9 / L) 
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 ri b o ci cli b at t h e n e xt l o w er d o s e l e v el. 
If t o xi cit y r e c ur s at gr a d e 4: di s c o nti n u e ri b o ci cli b 
A b s ol ut e n e utr o p hil c o u nt ( A N C),  
Gr a d e 1 ( ≥1. 5 x 1 0 9 / L) 
N o d o s e a dj u st m e nt r e q uir e d. 
Gr a d e 2 ( ≥1. 0 - < 1. 5 x 1 0 9 / L) 
N o d o s e a dj u st m e nt r e q uir e d. 

N o v arti s 
C o nfi d e nti al 
P a g e 5 4 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
T o xi cit y/ Gr a d e 
D o s e A dj u st m e nt a n d M a n a g e m e nt 
R e c o m m e n d ati o n s 
Gr a d e 3 ( ≥0. 5 - < 1. 0 x 1 0 9 / L) 
D o s e i nt err u pti o n u ntil r e c o v er y t o ≥1. 0 x 1 0 9 / L. 
R e-i niti at e ri b o ci cli b at t h e s a m e d o s e l e v el. 
If t o xi cit y r e c ur s at gr a d e 3: t em 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  ≥ 1. 0 x 1 09 / L. 
If r e s ol v e d i n ≤7 d a y s, t h e n m ai nt ai n d o s e l e v el. 
If r e s ol v e d i n > 7 d a y s, t h e n r e d u c e ri b o ci cli b d o s e t o 
t h e n e xt l o w er d o s e l e v el. 
 
F or Gr a d e 3 n e utr o p e ni a wit h o ut f e v er or si g n s of 
i nf e cti o n o n D a y 1 4 of t h e fir st 2 c y cl e s: 
C o n si d er t o c o nti n u e ri b o ci cli b at c urr e nt d o s e l e v el t o 
c o m pl et e c y cl e. R e p e at c o m pl et e bl o o d c o u nt o n D a y 
2 1. 
C o n si d er d o s e r e d u cti o n b a s e d o n t h e n e utr o p e ni a 
r e c o v er y ( < 7 d a y s / > 7 d a y s). 
Gr a d e 4 ( < 0. 5 x 1 0 9 / L) 
D o s e i nt err u pti o n u ntil  r e c o v er y t o ≥ 1. 0 x 1 09 / L. 
R e-i niti at e ri b o ci cli b at t h e n e xt l o w er d o s e l e v el. 
If t o xi cit y r e c ur s at gr a d e 4: t em 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 ≥1. 0 x 1 0 9 / L a n d r e d u c e ri b o ci cli b at 
t h e n e xt l o w er d o s e l e v el. 
L e u k o c yt e c o u nt ( W B C) 
Gr a d e 1 ( < L L N - 3. 0 x 1 09 / L) 
 
N o d o s e a dj u st m e nt r e q uir e d.  
Gr a d e 2 ( < 3. 0 - 2. 0 x 1 09 / L) 
N o d o s e a dj u st m e nt r e q uir e d.  
Gr a d e 3 ( < 2. 0 - 1. 0 x 1 09 / L) 
D o s e i nt err u pti o n u ntil  r e c o v er y t o ≥2. 0 x 1 09 / L. 
R e-i niti at e ri b o ci cli b at t h e s a m e d o s e l e v el. 
If t o xi cit y r e c ur s at gr a d e 3: t em 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  ≥ 1. 0 x 1 09 / L. 
If r e s ol v e d i n ≤7 d a y s, t h e n m ai nt ai n d o s e l e v el. 
If r e s ol v e d i n > 7 d a y s, t h e n r e d u c e ri b o ci cli b d o s e t o 
t h e n e xt l o w er d o s e l e v el. 
Gr a d e 4 ( < 1. 0 x 1 0 9 / L) 
D o s e i nt err u pti o n u ntil r e c o v er y t o ≥ 1. 0 x 1 0 9 / L. 
R e-i niti at e ri b o ci cli b at t h e n e xt l o w er d o s e l e v el. 
If t o xi cit y r e c ur s at gr a d e 4: t em 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 ≥1. 0 x 1 0 9 / L a n d r e d u c e ri b o ci cli b at 
t h e n e xt l o w er d o s e l e v el. 
F e bril e n e utr o p e ni a 
Gr a d e 3 
A N C < 1. 0 x 1 0 9 / L wit h a si n gl e t e m p er at ur e of 
> 3 8. 3 º C ( 1 0 1 º F) or a s u st ai n e d t e m p er at ur e 
of ≥3 8 º C ( 1 0 0. 4 º F) f or m or e t h a n o n e h o ur 
D o s e i nt err u pti o n u ntil i m pr o v e m e nt of A N C ≥ 1. 0 x 
1 0 9 / L a n d n o f e v er. R e st art at t h e n e xt l o w er d o s e 
l e v el. 
If f e bril e n e utr o p e ni a r e c ur s, di s c o nti n u e ri b o ci cli b. 
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 ri b o ci cli b. 
A n e mi a 
( H e m o gl o bi n) 
Gr a d e 1 ( ≥1 0. 0 – L L N g/ d L) 
N o d o s e a dj u st m e nt r e q uir e d. 
Gr a d e 2 ( ≥8. 0 – < 1 0. 0 g/ d L) 
N o d o s e a dj u st m e nt r e q uir e d. 
Gr a d e 3 ( < 8. 0 g/ d L) 
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  2. 
R e-i niti at e ri b o ci cli b at t h e s a m e 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 ri b o ci cli b. 

N o v arti s 
C o nfi d e nti al 
P a g e 5 5 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
T a bl e 6- 4  
Ri b o ci cli b d o s e a dj u st m e nt a n d m a n a g e m e nt r e c o m m e n d at i o n f or 
h e p ati c t o xi citi e s 
H E P A T O T O XI CI T Y ( BI LI R U BI N, S G P T/ A L T, S G O T/ A S T) 
T O T A L BI LI R U BI N wit h o ut A L T/ A S T  i n cr e a s e a b o v e b a s eli n e v al u e 
Gr a d e 1 ( > U L N – 1. 5 x U L N) 
( c o nfir m e d 4 8- 7 2 h l at er) 
M ai nt ai n d o s e l e v el wit h L F T s m o nit or e d bi- w e e kl y 
Gr a d e 2 ( > 1. 5 – 3. 0 x U L N)  
D o s e i nt err u pti o n of ri b o ci cli b  
If r e s ol v e d t o ≤ gr a d e 1 i n ≤ 2 1 d a y s, t h e n m ai nt ai n 
d o s e l e v el  
If r e s ol v e d t o ≤ gr a d e 1 i n > 2 1 d a y s or t o xi cit y 
r e c ur s, t h e n r e d u c e 1 d o s e l e v el 
R e p e at li v er e n z y m e a n d b ilir u bi n t e st s t wi c e w e e kl y 
f or 2 w e e k s aft er d o s e r e s u m pti o n  
If t o xi cit y r e c ur s aft er t w o d o s e r e d u cti o n s, 
di s c o nti n u e ri b o ci cli b 
Gr a d e 3 ( > 3. 0 – 1 0. 0 x U L N)  
D o s e i nt err u pti o n of ri b o ci cli b 
If r e s ol v e d t o ≤ gr a d e 1 i n ≤ 2 1 d a y s, l o w er 1 d o s e 
l e v el of ri b o ci cli b 
R e p e at li v er e n z y m e a n d b ilir u bi n t e st s t wi c e w e e kl y 
f or 2 w e e k s aft er d o s e r e s u m pti o n  
 
If r e s ol v e d t o ≤ gr a d e 1 i n > 2 1 d a y s or t o xi cit y 
r e c ur s, di s c o nti n u e ri b o ci cli b  
Gr a d e 4 ( > 1 0. 0 x U L N) 
Di s c o nti n u e ri b o ci cli b  
C o nf o u n di n g f a ct or s a n d/ or alt er n ati v e c a u s e s f or i n cr e a s e of t ot al bilir u bi n s h o ul d b e e x cl u d e d b ef or e 
d o s e i nt err u pti o n/r e d u cti o n. T h e y i n cl u d e b ut ar e n ot li mit e d t o: e vi d e n c e of o b str u cti o n, s u c h a s el e v at e d 
A L P a n d G G T t y pi c al of g all bl a d d er or bil e d u c t di s e a s e, h y p erbilir u bi n e mi a d u e t o t h e i n dir e ct 
c o m p o n e nt o nl y (i. e. d ir e ct bilir u bi n c o m p o ne nt ≤ 1 x U L N) d u e t o h e m ol y si s or Gil b ert S y n dr o m e, 
p h ar m a c ol o gi c tr e at m e nt, vir al h e p atiti s, al c o h oli c or a ut oi m m u n e h e p atiti s, ot h er h e p at ot o xi c dr u g s. 
F or p ati e nt s wit h Gil b ert S y n dr o m e, t h e s e d o s e m o difi c ati o n s a p pl y t o c h a n g e s i n dir e ct bilir u bi n o nl y. 
Bilir u bi n will b e fr a c ti o n at e d if el e v at e d. 
A S T or A L T 
A S T or A L T wit h o ut bilir u bi n el e v ati o n > 2 x U L N 
S a m e gr a d e a s b a s eli n e or i n cr e a s e fr o m 
b a s eli n e gr a d e 0 t o gr a d e 1 
( c o nfir m e d 4 8 – 7 2 h l at er) 
 
N o d o s e a dj u st m e nt r e q uir e d wit h L F T s m o nit or e d 
p er pr ot o c ol if s a m e gr a d e a s b a s eli n e or bi- w e e kl y 
i n c a s e of i n cr e a s e fr o m b a s eli n e gr a d e 0 t o 1 
I n cr e a s e fr o m b a s eli n e gr a d e 0 or 1 t o gr a d e 2 ( > 
3. 0 – 5. 0 x U L N) 
 
 
 
 
 
 
 
D o s e i nt err u pti o n of ri b o ci cli b  
If r e s ol v e d t o ≤ b a s eli n e gr a d e i n ≤ 2 1 d a y s, t h e n 
m ai nt ai n d o s e l e v el 
If r e s ol v e d t o ≤ b a s eli n e gr a d e i n > 2 1 d a y s or 
t o xi cit y r e c ur s, t h e n r e d u c e 1 d o s e l e v el 
R e p e at li v er e n z y m e a n d b ilir u bi n t e st s t wi c e w e e kl y 
f or 2 w e e k s aft er d o s e r e s u m pti o n  
 
 
If t o xi cit y r e c ur s aft er t w o d o s e r e d u cti o n s or 
r e c o v er y t o ≤ b a s eli n e gr a d e  i s > 2 8 d a y s, 
di s c o nti n u e ri b o ci cli b 
 
I n cr e a s e fr o m b a s eli n e gr a d e 0 or 1 t o gr a d e 3 ( > 
5. 0 – 2 0. 0 x U L N) 
D o s e i nt err u pti o n of ri b o c i cli b u ntil r e s ol v e d t o ≤ 
b a s eli n e gr a d e, t h e n l o w er 1 d o s e l e v el of ri b o ci cli b  
R e p e at li v er e n z y m e a n d b ilir u bi n t e st s t wi c e w e e kl y 
f or 2 w e e k s aft er d o s e r e s u m pti o n  
 
If r e c o v er y t o ≤ b a s elin e gr a d e i s > 2 8 d a y s, 
di s c o nti n u e ri b o ci cli b 
If t o xi cit y r e c ur s, dis c o nti n u e ri b o ci cli b  
I n cr e a s e fr o m b a s eli n e gr a d e 2 t o gr a d e 3 ( > 5. 0 
– 2 0. 0 x U L N) 
 
D o s e i nt err u pti o n of ri b o c i cli b u ntil r e s ol v e d t o ≤ 
b a s eli n e gr a d e, t h e n l o w er 1 d o s e l e v el of ri b o ci cli b  
R e p e at li v er e n z y m e a n d b ilir u bi n t e st s t wi c e w e e kl y 
f or 2 w e e k s aft er d o s e r e s u m pti o n  

N o v arti s 
C o nfi d e nti al 
P a g e 5 6 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 
 
If t o xi cit y r e c ur s aft er t w o d o s e r e d u cti o n s or 
r e c o v er y t o ≤ b a s eli n e gr a d e i s > 2 8 d a y s, 
di s c o nti n u e ri b o ci cli b. 
 
Gr a d e 4 ( > 2 0. 0 x U L N) 
Di s c o nti n u e ri b o ci cli b  
A S T or A L T a n d c o n c urr e nt Bilir u bi n 
F or p ati e nt s wit h n or m al  A L T a n d A S T a n d t ot al 
bilir u bi n at b a s eli n 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 x U L N wit h o ut 
e vi d e n c e of c h ol e st a si s 
Or 
F or p ati e nt wit h el e v at e d A S T or A L T or t ot al 
bilir u bi n at b a s eli n e:  b a s eli n 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]- w hi c h e v er i s l o w er- c o m bi n e d wit h  [t ot al 
bilir u bi n > 2 x b a s el i n e A N D > 2. 0 x U L N] 
 
 
 
 
Di s c o nti n u e ri b o ci cli b 
C o nf o u n di n g f a ct or s a n d/ or alt er n ati v e c a u s e s f or i n cr e a s e d tr a n s a mi n a s e s s h o ul d b e e x cl u d e d b ef or e 
d o s e i nt err u pti o n/r e d u cti o n. T h e y i n cl u d e b ut ar e n ot li mit e d t o: c o n c o mit a nt m e di c ati o n s, h er b al 
pr e p ar ati o n s or di et ar y s u p pl e m e nt s, i nf e cti o n, h e p at o- bili ar y di s or d er or o b str u cti o n, n e w or pr o gr e s si v e 
li v er m et a st a si s, a n d al c o h ol i nt a k e.  
 
6. 2. 1. 2  
A d diti o n al f oll o w- u p f or h e p ati c t o xi citi e s 
I ncrease  i n  tra nsa mi nases  c o m bi ne d  wit h  t otal  bilir u bi n  ( T BI L) i ncrease  ma y  be 
i n dicati ve of dr u g-i n d uce d li ver i nj ur y ( DI LI), a n d s h o ul d be co nsi dere d as cli nicall y 
i m p orta nt e ve nts. A st u d y wit h ri b ocicli b i n n o n-ca ncer patie nts wit h var yi n g de grees of 
he patic  i m pair me nt  ( mil d,  m o derate,  se vere  base d  o n  C hil d- P u g h classificati o n) 
matc he d s u bjects wit h n or mal he patic f u ncti o n was c o m plete d ( C L E E 0 1 1 A 2 1 0 9). Refer 
t o [ Ri b ocicli b I n vesti gat ors Broc h ure] f or m ore details. 
T he t hres h ol d f or p ote ntial DI LI ma y de pe n d o n t he patie nt’s ba seli ne A S T/ A L T a n d 
T BI L val ue; patie nts meeti n g a n y of t he f oll o wi n g criteria will  re q uire f urt her f oll o w- u p 
as o utli ne d bel o w: 
 F or patie nts wit h n or mal A L T a n d A S T a n d T BI L val ue at baseli ne: A S T or A L T 
> 3. 0 x U L N c o m bi ne d wit h T BI L > 2. 0 x U L N  
 F or patie nts wit h ele vate d A S T or A L T or T BI L val ue at baseli ne : [ A S T or A L T 
> 2 x baseli ne A N D > 3. 0 x U L N] O R [ A S T or A L T > 8. 0 x U L N], w h ic he ver 
is l o wer, c o m bi ne d wit h [ T BI L > 2 x baseli ne A N D > 2. 0 x U L N] 
Me dical re vie w nee ds t o e ns ure t hat li ver test ele vati o ns are n ot ca use d b y c h olestasis, 
defi ne d  as:  A L P  ele vati o n  >  2. 0  x  U L N  wit h  R  val ue  <  2  i n  patie nts  wit h o ut  b o ne 
metastasis, or ele vati o n of A L P li ver fracti o n i n patie nts wit h b o ne metastasis. 
N ote: T he R v al ue is c alc ul ate d by divi di n g t he A L T by t he A L P, usi n g m ulti ples of t he 
U L N f or b ot h v al ues. It de n otes t he rel ative p a tter n of A L T a n d/ or A L P elev ati o n is d ue 
t o c h olest atic or he p at ocell ul ar liver i nj ury or mixe d ty pe i nj ury ). 
I n t he a bse nce of c h olestasis, t hese patie nts s h o ul d be i m me diatel y disc o nti n ue d fr o m 
st u d y dr u g treat me nt, a n d re peat L F T testi n g as s o o n as p ossi ble, prefera bl y wit hi n 4 8 
h o urs  fr o m  t he  a ware ness  of  t he  a b n or mal  res ults.  T he  e val uati o n  s h o ul d  i ncl u de 

N o v arti s 
C o nfi d e nti al 
P a g e 5 7 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
la b orat or y  tests,  detaile d  hist or y,  p h ysical  assess me nt  a n d  t he  p ossi bilit y  of  li ver 
metastasis or ne w li ver lesi o ns , o bstr ucti o ns/c o m pressi o ns, etc.  
 
He patic  t o xicit y  m o nit ori n g  i ncl u des  t he  f oll o wi n g  L F Ts:  al b u mi n,  A L T,  A S T,  t otal 
bilir u bi n,  direct  a n d  i n direct  bilir u bi n,  al kali ne  p h os p hatase (fracti o nate d  if  al kali ne 
p h os p hatase is gra de 2 or hi g her),  creati ne ki nase ( C K), pr ot hro m bi n ti me ( P T)/I N R a n d 
G G T.  F or  patie nts  wit h  Gil bert  S y n dr o me:  t otal  a n d  direct  bilir u bi n  m ust  be  m o nit ore d, 
i nte nsifie d m o nit ori n g a p plies t o c ha n ges i n direct bilir u bi n onl y. 
Cl ose o bser vati o n is rec o m me n de d i n case of A S T, A L T, a n d/ or bilir u bi n i ncrease re q uiri n g 
d ose i nterr u pti o n, w hic h i n v ol ves: 
 Re peati n g  li ver  e nz y me  a n d  ser u m  bilir u bi n  tests t w o  or  t hree  ti mes  wee kl y. 
Fre q ue nc y of re-testi n g ca n decrease t o o nce a wee k or less if a b n or malities sta bilize 
or ret ur n t o n or mal val ues.  
 O btai ni n g a m ore detaile d hi st or y of c urre nt s y m pt o ms.  
 O btai ni n g  a  m ore  detaile d  hist or y  of  pri or  a n d/ or  c o nc urre nt  di seases,  i ncl u di n g 
hist or y of a n y pre-e xisti n g li v er c o n diti o ns or ris k fact ors. 
 O btai ni n g a hist or y of c o nc o m ita nt dr u g use (i ncl u di n g n o n- prescri pti o n me dicati o ns, 
her bal a n d dietar y s u p ple me nts), alc o h ol use, recreati o nal dr u g  use, a n d s pecial diets. 
 R uli n g o ut ac ute viral he patitis t y pes A, B, C, D, a n d E; he pat otr o pic vir us i nfecti o ns 
( C M V, E B V or H S V); a ut oi m m u ne or alc o h olic he patitis; N A S H; h y po xic/isc he mic 
he pat o pat h y; a n d biliar y tract disease. 
 O btai ni n g a hist or y of e x p os ure t o e n vir o n me ntal c he mical a ge nt s. 
 O btai ni n g a d diti o nal tests t o e val uate li ver f u ncti o n, as a p pr o priate (e. g., I N R, direct 
bilir u bi n). 
 C o nsi deri n g gastr oe nter ol o g y or he pat ol o g y c o ns ultati o ns. 
 Assessi n g  car di o vasc ular  d ysf u nc ti o n  or  i m paire d  li ver  o x y ge nati o n,  i ncl u di n g 
h y p ote nsi o n or ri g ht heart fail ure  as p ossi ble eti ol o gies f or li ver d ysf u ncti o n.  
 Li ver  bi o ps y  as  cli nicall y  i n dicate d  t o  assess  pat h ol o gical  c ha n ge  a n d  de gree  of 
p ote ntial li ver i nj ur y. 
All cases c o nfir me d o n r e peat testi n g meeti n g t he la b orat or y cr iteria defi ne d a b o ve, wit h n o 
ot her alter nati ve ca use f or L F T a b n or malities i de ntifie d, s h o ul d be c o nsi dere d as “ me dicall y 
si g nifica nt”, t h us met t he defi niti o n of S A E ( Secti o n 8. 2. 1), an d re p orte d as S A E usi n g t he 
ter m  “ p ote ntial  dr u g-i nd uce d  li ver  i nj ur y”.  All  e ve nts  s h o ul d  b e  f oll o we d  u p  wit h  t he 
o utc o me clearl y d oc u me nte d. 
 
 
 
 
 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 5 8 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
6. 2. 1. 3  
A d diti o n al f oll o w- u p f or Q T c pr ol o n g ati o n 
T a bl e 6- 5  
Ri b o ci cli b d o s e a dj u st m e nt a n d m a n a g e m e nt r e c o m m e n d at i o n f or 
Q T c pr ol o n g ati o n ( C T C A E v 4. 0 3) 
 
Gr a d e 
D o s e M o difi c ati o n 
F or All Gr a d e s 
1.  
C h e c k t h e q u al it y of t h e E C G a n d t h e Q T v al u e a n d r e p e at if 
n e e d e d. 
2.  
P erf or m a n al y si s of s er u m el e ctr ol yt e s ( K +, C a + +, P h o s, M g + + ). If 
o ut si d e of t h e n or m al r a n g e, i nt err u pt ri b o ci cli b a d mi ni str ati o n, 
c orr e ct wit h s u p pl e m e nt s or a p pr o pri at e t h er a p y a s s o o n a s 
p o s si bl e, a n d r e p e at el e ctr ol yt e s u ntil d o c u m e nt e d a s n or m al. 
3.  
R e vi e w c o n c o mit a nt m e di c ati o n u s a g e f or t h e p ot e nti al t o i n h i bit 
C Y P 3 A 4 a n d/ or t o pr ol o n g t h e Q T i nt er v al. 
4.  
C h e c k c o m pli a n c e wit h c orr e ct d o s e a n d a d mi ni str ati o n of ri b o ci cli b. 
 
C o n si d er c oll e cti n g a ti m e m at c h e d P K s a m pl e; r e c or d d at e a n d t i m e of 
l a st st u d y dr u g i nt a k e. 
1 
Q T c F 4 5 0- 4 8 0 m s 
P erf or m st e p s 1- 4 a s dir e ct e d i n “ F or All Gr a d e s”. N o d o s e a dj u st m e nt 
r e q uir e d. 
2 
Q T c F 4 8 1- 5 0 0 m s 
I nt err u pt ri b o ci cli b. P erf or m st e p s 1- 4 a s dir e ct e d i n “ F or All 
Gr a d e s.”  
P erf or m a r e p e at E C G wit hi n o n e h o ur of t h e fir st Q T c F of ≥ 4 8 1  m s. 
R e p e at E C G a s cli ni c all y i n di c a t e d u ntil t h e Q T c F r et ur n s t o < 4 8 1 m s, 
r e st art L E E 0 1 1 wit h d o s e r e d u c e d b y 1 d o s e l e v el. 
 
If Q T c F ≥ 4 8 1 m s r e c ur s, ri b o ci cli b s h o ul d b e r e d u c e d b y 1 d o s e l e v el.  
R e p e at E C G s 7 d a y s a n d 1 4 d a y s  aft er d o s e r e s u m pti o n (t h e n a s 
cli ni c all y i n di c at e d) f or a n y p at i e nt s w h o h a d t h er a p y i nt err u pt e d d u e t o 
Q T c F ≥ 4 8 1 m s. 
3 
Q T c F ≥ 5 0 1 m s o n at l e a st 
t w o s e p ar at e E C G s 
I nt err u pt ri b o ci cli b. P erf or m st e p s 1- 4 a s dir e ct e d i n “ F or All 
Gr a d e s.”  
Tr a n s mit E C G i m m e di at el y a n d c o nf ir m pr ol o n g ati o n/ a b n or m aliti e s. 
 
P erf or m a r e p e at E C G wit hi n o n e h o ur of t h e fir st Q T c F of ≥ 5 0 1  m s. 
 
If Q T c F r e m ai n s ≥ 5 0 1 m s, c o n s ult wit h a c ar di ol o gi st ( or q u ali fi e d 
s p e ci ali st) a n d r e p e at c ar di a c m o nit ori n g a s i n di c at e d u ntil t h e Q T c F 
r et ur n s t o < 4 8 1 m s. 
 
If Q T c F r et ur n s t o < 4 8 1 m s, rib o ci cli b will b e r e d u c e d b y 1 d o s e l e v el.  
 
If Q T c F r e m ai n s ≥ 4 8 1 m s aft er p erf or mi n g st e p s 1- 4 a s dir e ct e d i n “ F or 
All Gr a d e s,” di s c o nti n u e L E E 0 1 1. 
 
R e p e at E C G s 7 d a y s a n d 1 4 d a y s  aft er d o s e r e s u m pti o n (t h e n a s 
cli ni c all y i n di c at e d) f or a n y p at i e nt s w h o h a d t h er a p y i nt err u pt e d d u e t o 
Q T c F ≥ 5 0 1 m s. 
 
If Q T c F of ≥ 5 0 1 m s r e c ur s, di s c o nti n u e ri b o ci cli b. 
4 
[ Q T/ Q T c F ≥ 5 0 1 or > 6 0 m s 
c h a n g e fr o m b a s eli n e] 
a n d 
[ T or s a d e s d e p oi nt e s or 
p ol y m or p hi c v e ntri c ul ar 
t a c h y c ar di a, or 
si g n s/ s y m pt o m s of s eri o u s 
arr h yt h mi a] 
Di s c o nti n u e ri b o ci cli b. P erf or m st e p s 1- 4 a s dir e ct e d i n “ F or A ll 
Gr a d e s.” 
  
O bt ai n l o c al c ar di ol o gi st ( or q u alifi e d s p e ci ali st) c o n s ult ati o n a n d 
r e p e at c ar di a c m o nit ori n g a s i n dic at e d u ntil t h e Q T c F r et ur n s t o 
< 4 8 1 m s. 
 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 5 9 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
6. 2. 1. 4  
G ui d a n c e f or all ot h er a d v er s e r e a cti o n s 
C o nsi der perf or mi n g a n a nal ysis of ser u m p otassi u m, calci u m, p h os p h or us, a n d ma g nesi u m 
f or all a d verse reacti o ns, if i n dicate d. If electr ol yte val ues are o utsi de of t he n or mal ra n ge, 
i nterr u pt  ri b ocicli b  a d mi nistrati o n,  c orrect  electr ol ytes  wit h s u p ple me nts  or  a p pr o priate 
t hera p y as s o o n as p ossi ble, a n d re peat electr ol yte testi n g u ntil d oc u me nte d n or malizati o n 
of t he electr ol ytes. 
Patie nts w h o e x perie nce re nal i m pair me nt ( n ot d ue t o ot her c o nt ri b uti n g fact ors) of gra de 2 
or hi g her d uri n g t he treat me nt p eri o d s h o ul d disc o nti n ue treat m e nt a n d s h o ul d be f oll o we d 
f or safet y assess me nts.  
F or  patie nts  ta ki n g  bis p h os p h o nates,  t he  c o nc o mita nt  use  of  cal ci u m  is  all o we d  f or  t he 
treat me nt  or  pre ve nti o n  of  h y p ocalce mia.  Patie nts  e x perie nci n g Gra de  3/ 4  h y p ocalce mia 
s h o ul d d ose i nterr u pt ri b ocicli b u ntil rec o ver y t o gra de 1 a n d c o nti n ue wit h t he sa me d ose 
le vel. 
F or all ot her a d verse e ve nts please f oll o w rec o m me n dati o ns i n Ta ble 6- 6 . 
T a bl e 6- 6  
Ri b o ci cli b d o s e a dj u st m e nt a n d m a n a g e m e nt r e c o m m e n d at i o n f or 
all ot h er a d v er s e r e a cti o n s 
 
Gr a d e  
D o s e A dj u st m e nt a n d M a n a g e m e nt R e c o m m e n d ati o n s 
1  
N o d o s e a dj u st m e n t r e c o m m e n d 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. 
2 
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. 
R e-i niti at e ri b o ci cli b at t h e s a m e d o s e. 
If t h e s a m e t o xi cit y r e c ur s at gra d e 2, i nt err u pt ri b o ci cli b u n til r e c o v er y t o gr a d e 1. R e-i niti at e 
ri b o ci cli b at t h e n e xt l o w er d o s e l e v el. 
3 
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. 
R e-i niti at e ri b o ci cli b at t h e n e xt l o w er d o s e l e v el.  
If t o xi cit y r e c ur s at gr a d e 2: t e mp or ar y d o s e i nt err u pti o n u nti l r e c o v er y t o gr a d e 1 a n d r e d u c e 
ri b o ci cli b d o s e t h e n e xt l o w er d o s e l e v el. 
If t o xi cit y r e c ur s at gr a d e 3, di s c o nti n u e ri b o ci cli b. 
4  
Di s c o nti n u e ri b o ci cli b a n d tr e at wit h a p pr o pri at e m e di c al t h e r a p y. 
 
6. 2. 1. 4. 1 A dj u st m e nt of st arti n g d o s e i n s p e ci al p o p ul ati o n s 
R e n al I m p air m e nt 
I ns ufficie nt data are a vaila ble t o pr o vi de a d osa ge rec o m me n dati o n f or ri b ocicli b i n patie nts 
wit h  re nal  i m pair me nt.  A  st u d y  i n  n o n-ca ncer  patie nts  wit h  var y i n g  de grees  of  re nal 
i m pair me nt a n d matc he d s u bjects wit h n or mal re nal f u ncti o n is on g oi n g ( C L E E 0 1 1 A 2 1 1 6). 
Refer  t o  [ Ri b ocicli b  I n vesti gat ors  Br oc h ure]  f or  m ore  details. Base d  o n  rat  A D M E  data, 
ri b ocicli b was pre d o mi na ntl y e xcrete d i n t he bile as meta b olites, wit h li mite d e xcreti o n of 
u nc ha n ge d dr u g i n uri ne.  
Patie nts w h o e x perie nce re nal i m pair me nt ( n ot d ue t o ot her c o nt ri b uti n g fact ors) of gra de 2 
or hi g her d uri n g t he treat me nt p eri o d s h o ul d disc o nti n ue treat m e nt a n d s h o ul d be f oll o we d 
f or safet y assess me nts. 
Re nal i m pair me nt d oes n ot affect letr oz ole P K i n h u ma ns ( Fe mara ®  Prescri bi n g I nf or mati o n 
N o vartis). 

N o v arti s 
C o nfi d e nti al 
P a g e 6 0 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
St u dies wit h g osereli n i n fe male patie nts wit h re nal i m pair me nt  d o n ot i n dicate a nee d f or 
d ose a dj ust me nt wit h t he use of t he de p ot f or m ulati o n ( Z ola de x ®  Prescri bi n g I nf or mati o n 
Astra Ze neca). 
H e p ati c I m p air m e nt 
A st u d y i n n o n-ca ncer patie nts wit h var yi n g de grees of he patic i m pair me nt ( mil d, m o derate, 
se vere  base d  o n  C hil d- P u g h  classificati o n)  a n d  matc he d  patie nts   wit h  n or mal  he patic 
f u ncti o n is o n g oi n g ([ C L E E 0 1 1 A 2 1 0 9]). I nteri m res ults i n dicate d t hat t he e x p os ure ( A U C 
a n d  C ma x )  of  ri b ocicli b  was  si milar  bet wee n  t he  mil d  he patic  i m pair me nt  c o h ort  a n d  t he 
n or mal c o h ort, was c o m para ble i n t he m o derate a n d se vere c o h ort s, a n d b ot h a p pr o xi matel y 
3 0 % hi g her t ha n i n t he n or mal c o h ort.I n patie nts wit h se vere he patic i m pair me nt ( C hil d-
P u g h  C),  s yste mic  e x p os ure  a n d  ter mi nal  half-life  of  letr oz ole was  t w of ol d  i ncrease d 
c o m pare d t o healt h y s u bjects. T he se patie nts s h o ul d t heref ore be m o nit ore d cl osel y. 
El d erl y 
I ns ufficie nt  data  is  a vaila ble  t o  pr o vi de  a  s pecific  d osa ge  reco m me n dati o n  i n  el derl y 
p o p ulati o n. 
6. 2. 1. 5  L etr o z ol e 
T he esta blis he d cli nical d ose of  letr oz ole ( 2. 5 m g/ da y) will be use d a n d n o d ose m o dificati o n 
of  letr oz ole  is  pla n ne d  i n  t his  st u d y.  T he  letr oz ole  pac ka ge  i n sert  s h o ul d  be  c o ns ulte d 
re gar di n g f ull prescri bi n g i nf or mati o n a n d ma na ge me nt of a d verse e ve nts. 
6. 2. 2  
A nti ci p at e d ri s k s a n d s af et y c o n c er n s of t h e st u d y dr u g 
A p pr o priate eli gi bilit y criteria as well as s pecific d ose m o dif icati o n a n d st o p pi n g r ules are 
i ncl u de d i n t his pr ot oc ol. Rec om me n de d g ui deli nes f or pr o p h ylac tic or s u p p orti ve treat me nt 
f or e x pecte d t o xicities, i ncl u di n g ma na ge me nt of st u d y- dr u g i n duce d a d verse e ve nts, e. g., 
ne utr o pe nia,  li ver  t o xicit y  a n d  Q T- pr ol o n gati o n  are  pr o vi de d  i n   Secti o n  6. 2. 1.  Refer  t o 
precli nical t o xicit y a n d or cli nical data f o u n d i n t he I n vesti g at or’s Br oc h ure. 
6. 3  
C o n c o mit a nt m e di c ati o n s 
6. 3. 1  
P er mitt e d c o n c o mit a nt t h er a p y 
Me dicati o ns  r e q uir e d  t o  tr eat  A Es,  ma na g e  ca ncer  s y m pt o ms,  c o nc urr e nt  diseases  a n d 
s u p p orti ve car e a ge nts, s uc h as pai n me dicati o ns, a nti- e metics a n d a nti- diarr he al ar e all o we d. 
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 ne w me dicati o ns he/s he 
ta kes after t he start of t he st u d y dr u g. All me dicati o ns ( ot her t ha n st u d y dr u g) a n d si g nifica nt 
n o n- dr u g  t hera pies  (i ncl u di n g  p h ysi cal  t hera p y,  her bal/ nat ural me dicati o ns  a n d  bl o o d 
tra nsf usi o ns)  a d mi nistere d  3 0  days  bef ore  e nteri n g  t he  st u d y  a n d  d uri n g  t he  st u d y  u ntil 
safet y  f oll o w  u p  m ust  be  liste d  o n  t he  C o 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 C R F. 
6. 3. 1. 1  
Bi s p h o s p h o n a t e s a n d d e n o s u m a b  
 
Bis p h os p h o nates a n d de n os u ma b are  ge nerall y all o we d wit h t he f oll o wi n g c o m me nts: 
 C hr o nic c o nc o mita nt bis p h os p h o nate / de n os u ma b t hera p y f or t he pre ve nti o n of b o ne 
metastasis is n ot per mitte d. 

N o v arti s 
C o nfi d e nti al 
P a g e 6 1 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 Bis p h os p h o nate/ de n os u ma b t hera p y f or t he treat me nt of oste o p or o sis is per mitte d. 
 Bis p h os p h o nate/ de n os u ma b t hera p y f or t he pre ve nti o n of s keletal  relate d e ve nts f or 
patie nts wit h b o ne metastases is per mitte d. 
Patie nts ta ki n g c o nc o mita nt me d icati o n c hr o nicall y s h o ul d be mai ntai ne d o n t he sa me d ose 
a n d d ose sc he d ule t hr o u g h o ut t he  st u d y peri o d, as me dicall y feasi ble. 
 
6. 3. 1. 2  
C orti c o st er oi d s 
C hr o nic d osi n g of c ortic oster oi ds  s uc h as de xa met has o ne a n d pred nis o ne is k n o w n t o lea d 
t o  i n d ucti o n  of  C Y P 3 A  e nz y mes,  t here b y  p ote ntiall y  i ncreasi n g  the  ris k  of  re d uci n g 
ri b ocicli b dr u g e x p os ure t o s u bt hera pe utic le vels. S yste mic c ortic oster oi d treat me nt s h o ul d 
n ot be gi ve n d uri n g t he st u d y, 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 u cti ve air wa ys diseases), 
e ye dr o ps or l ocal i njecti o ns (e. g., i ntra-artic ular). 
A s h ort d urati o n ( < 5 da ys) of s ys te mic c ortic oster oi ds ≤ t o t he a nti-i nfla m mat or y 
p ote nc y of 4 m g de xa met has o ne ( e. g. f or c hr o nic o bstr ucti ve    p ul m o nar y disease, or as 
a n a ntie metic) will be acce pte d. 
6. 3. 1. 3   H e m at o p oi eti c gr o wt h f a ct or s 
 
He mat o p oietic gr o wt h fact ors ma y be use d acc or di n g t o A S C O g ui d eli nes ( S mit h 2 0 0 6). 
6. 3. 1. 4  P alli ati v e r a di ot h er a p y 
 
Palliati ve ra diati o n is per mitte d. It s h o ul d n ot be deli vere d t o a tar get lesi o n a n d it s h o ul d 
n ot e nc o m pass m ore t ha n 2 5 % of irra diate d b o ne marr o w. Palliati ve ra diate d lesi o ns ca n n ot 
be c o nsi dere d f or e val uati o n of t u m or res p o nse. 
If palliati ve ra di ot hera p y is i nitiate d after t he start of st u dy 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 u st be r ule d o ut. 
N o d ose m o dificati o n of st u d y tr eat me nt is nee de d d uri n g pallia ti ve ra di ot hera p y. 
Refer  t o  t he  ri b ocicli b I n vesti g at ors  Br oc h ure  a n d  letr oz ole  or   g osereli n  acetate  pac ka ge 
i nsert a n d A p pe n di x 1 4. 1 .  f or  i nf or mati o n o n p ossi ble i nt eracti o ns wit h ot her dr u gs. 
 
6. 3. 2  
P er mitt e d c o n c o mit a nt t h er a p y r e q uiri n g c a uti o n a n d/ or a c ti o n 
Me dicati o ns t o be use d wit h ca uti o n d uri n g c o m bi ne d ri b ocicli b a n d letr oz ole treat me nt i n 
t his st u d y are liste d bel o w (see Ta ble 1 4- 2  i n A p pe n di x 1 4. 1 , t his list is n ot c o m pre he nsi ve 
a n d  is  o nl y  mea nt  t o  be  use d  as  a  g ui de.  Please  c o ntact  t he  me d ical  m o nit or  wit h  a n y 
q uesti o ns). T hese me dicati o ns s h o ul d be e xcl u de d fr o m patie nt use if p ossi ble. If t he y m ust 
be  gi ve n  base d  o n  t he  i n vesti gat or’s  j u d g me nt,  t he n  use  wit h  ca uti o n  a n d  c o nsi der  a 
ri b ocicli b i nterr u pti o n if t he c o nc o mita nt me dicati o n is o nl y nee de d f or a s h ort ti me.  
 M o derate i n hi bit ors or i n d uc ers of C Y P 3 A 4/ 5  
 Se nsiti ve s u bstr at es of C Y P 3 A 4/ 5 t hat d o n ot ha ve narr o w t her a p e utic i n de x 
 I n hi bit ors of B S E P ( base d o n i n vitr o data c o-a d mi nistrati o n wit h L E E 0 1 1 ma y 
lea d t o i ntra he patic c h olestasis) 
 Me dicati o ns t hat carr y a p ossi ble ris k f or Q T pr ol o n gati o n 

N o v arti s 
C o nfi d e nti al 
P a g e 6 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 Se nsiti ve s u bstrates of t he re nal tra ns p orters M A T E 1/ 2 a n d a n d O C T 1/ 2 ( p ote ntial 
t o i ncrease e x p os ure t o s u bstrates of t hese tra ns p orters, alt h o u g h n o a ni mal or 
cli nical data are a vaila ble t o s u p p ort t hese state me nts) 
 Se nsiti ve s u bstrates of B C R P ( p ot e ntial t o i ncrease e x p os ure t o s u bstrates of t hese 
tra ns p orters, alt h o u g h n o a ni mal or cli nical data are a vaila ble t o s u p p ort t hese 
state me nts)) 
 S u bstrates  meta b olize d  pre d o mi na ntl y  b y  C Y P 2 C 1 9  or  C Y P 2 A 6  wit h a  narr o w 
t hera pe utic i n de x (t hat c o uld be affecte d b y letr oz ole) 
 
6. 3. 3  
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 me dicati o ns are pr o hi bite d d uri n g st u d y treat me nt  i n t he st u d y (see Ta ble 1 4-
1  i n A p pe n di x 1 4. 1 , t his list is n ot c o m pre he nsi ve a n d is o nl y mea nt t o be use d as a g ui de. 
Please c o ntact t he me dical m o nit or wit h a n y q uesti o ns): 
 Str o n g i n hi bit ors or i n d ucers of C Y P 3 A 4/ 5 
 S u bstrates of C Y P 3 A 4/ 5 wit h a narr o w t hera pe utic i n de x 
 Me dicati o ns wit h a k n o w n ris k f or Q T pr ol o n gati o n a n d/ or T d P 
 Ot her i n vesti gati o nal a n d a nti ne o plastic t hera pies 
 Her bal pre parati o ns/ me dicati o ns a n d dietar y s u p ple me nts t hat ar e str o n g i n hi bit ors or 
i n d ucers of C Y P 3 A 4/ 5 or t h ose wit h a k n o w n ris k of Q T pr ol o n gat i o n. T hese i ncl u de 
b ut are n ot li mite d t o: St. J o h n’s w ort, Ka va, e p he dra ( ma h ua n g), gi n g k o bil o ba, 
de h y dr oe pia n dr oster o ne ( D H E A), y o hi m be, sa w pal mett o a n d gi nse n g.  Patie nts 
s h o ul d st o p usi n g t hese pre parati ons/ me dicati o ns at least 7 da ys pri or t o first d ose of 
st u d y treat me nt. 
6. 3. 4  
Dr u g s wit h Q T pr ol o n g ati o n 
As  far  as  p ossi ble,  a v oi d  c o-a d mi nisteri n g  me dicati o ns  wit h  a  “ K n o w n”,  “ P ossi ble”  or 
“ C o n diti o nal”  ris k  of  T d P  ( qt dr u gs. or g)  or  a n y  ot her  me dicati o n  wit h t he p ote ntial t o 
i ncrease t he ris k of dr u g-relate d Q T pr ol o n gati o n (e. g. via a pote ntial D DI i ncreasi n g t he 
e x p os ure of L E E 0 1 1/ place b o or t he e x p os ure of t he Q T pr ol o n gi n g dr u g). If c o nc o mita nt 
a d mi nistrati o n  of  dr u gs  wit h  a  k n o w n  ris k  of  T d P  is  re q uire d  a n d  ca n n ot  be  a v oi de d, 
L E E 0 1 1/ place b o  m ust  be  i nterr u pte d.  If  d uri n g  t he  c o urse  of  t he   st u d y,  c o nc o mita nt 
a d mi nistrati o n of a dr u g wit h “ P ossi ble ris k” or “ C o n diti o nal r is k” of T d P is re q uire d, base d 
o n  t he  i n vesti gat or  assess me nt a n d  cli nical  nee d,  st u d y  treat me nt  ma y  be  res u me d  u n der 
cl ose cli nical a n d E C G m o nit ori n g t o e ns ure patie nt safet y. A l ist of dr u gs ass ociate d wit h 
Q T  pr ol o n gati o n  a n d/ or  T d P  is a vaila ble  o nli ne  ( w w w. qt dr u gs. or g ).    Me dicati o ns  wit h  a 
k n o w n ris k f or Q T pr ol o n gati o n are  pr o hi bite d d uri n g st u d y treat me nt. 
6. 4  
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. 4. 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 ( S ubject N o.), 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 i de 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 o. c o nsists of 
t he Ce nter N u m ber ( Ce nter N o.) (as assi g ne d b y N o 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 

N o v arti s 
C o nfi d e nti al 
P a g e 6 3 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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 o. a va ila ble t o t he i n vesti gat or.  
6. 4. 2  
Tr e at m e nt a s si g n m e n t or r a n d o mi z ati o n 
T he assi g n me nt of a patie nt t o a c o h ort will be c o or di nate d b y t he s p o ns or or desi g nate d 
C R O b y i ncl usi o n fa x w he n all i n cl usi o n a n d e xcl usi o n criteria are f ulfille d. T he C 1 D 1 visit 
s h o ul d occ ur wit hi n 3 da ys after se n di n g t he fa x.  
If o ne of t he c o h orts reac hes t he pla n ne d patie nt n u m ber, t he incl usi o n of ne w patie nts i n 
t his c o h ort will be st o p pe d a n d all i n vesti gat ors will be i nf or me d acc or di n gl y. 
6. 4. 3  
Tr e at m e nt bli n di n g 
T his is a n o pe n la bel st u d y. 
 
6. 5  
St u d y dr u g pr e p ar ati o n a n d di s p e n s ati o n 
Patie nts will be pr o vi de d wit h a n a de q uate s u p pl y of st u d y dr u g  f or self-a d mi nistrati o n at 
h o me, i ncl u di n g i nstr ucti o ns f or a d mi nistrati o n, u ntil at least  t heir ne xt sc he d ule d st u d y visit. 
Patie nts  will  recei ve  ri b ocicli b  o n  a n  o ut patie nt  basis.  T he  i n vesti gat or  s hall  pr o vi de  t he 
patie nt wit h i nstr ucti o ns f or ri b ocicli b a d mi nistrati o n acc or di n g t o t he pr ot oc ol. 
Letr oz ole a n d g osereli n s h o ul d be dis pe nse d acc or di n g t o t he l o cal prescri bi n g i nf or mati o n 
a n d practice. 
T he i n vesti gat or or res p o nsi ble site pers o n nel m ust i nstr uct t h e patie nt or care gi ver t o ta ke 
t he st u d y dr u gs as per pr ot oc ol. St u d y dr u g(s) will be dis pe nsed 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.  
All st u d y dr u gs will be pr o vi de d b y N o vartis t o t he partici pati n g sites f or all patie nts e nr olle d 
i n t his st u d y u ntil a p pro val of Ri b ocicli b (see Ta ble 6- 1 ) a n d will be dis pe nse d b y t he st u d y 
ce nter pers o n nel o n a n o ut patie nt basis. F or t hese patie nts st u d y dr u gs will be pr o vi de d b y 
N o vartis t hr o u g h o ut t he st u d y. After ri b ocicli b is c o m merciall y  a vaila ble, t he i n vesti gat or 
will  prescri be  all  dr u gs  acc or di n g  t o  t he  la bel  t o  all  patie nts   w h o  will  be  e nr olle d  after 
c o m mercial a p pr o val. 
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 e C R F. 
T a bl e 6- 7  
Pr e p ar ati o n a n d di s p e n si n g  
St u d y dr u g s  
Di s p e n si n g 
Pr e p ar ati o n 
Ri b o ci cli b 
L etr o z ol e 
T a bl et s  
i n cl u di n g  
i n str u cti o n s  
f or 
a d mi ni str ati o n ar e di s p e n s e d b y     st u d y 
p er s o n n el o n a n o ut p ati e nt b a si s. 
N ot a p pli c a bl e 
G o s er eli n 
M o nt hl y s u b c ut a n e o u o s i m pl a nt  
R ef er t o l o c al pr o d u ct i nf or m ati o n 
 
6. 5. 1  
St u d y dr u g p a c k a gi n g a n d l a b eli n g 
Ri b ocicli b is f or m ulate d as ta blets of 2 0 0 m g stre n gt h f or oral  a d mi nistrati o n. C o m merciall y 
a vaila ble ri b ocicli b will be s u p plie d as ta blets of 2 0 0 m g stre n gt h f or oral a d mi nistrati o n i n 

N o v arti s 
C o nfi d e nti al 
P a g e 6 4 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
blisters. C o m plete g ui deli nes f or ma na ge me nt a n d a d mi nistrati o n  of letr oz ole a n d g osereli n 
ca n  be  f o u n d  i n  t he  pac ka ge  i nsert.  Ri b ocicli b  st u d y  me dicati o n   will  be  pac ka ge d  i nt o 
b ottles or blisters. T he b ottles s h o ul d be o pe ne d o nl y at t he ti me of a d mi nistrati o n, as t he 
dr u g  is  h y gr osc o pic  a n d  li g ht  se nsiti ve.  All  b ottles  will  c o nf o r m  t o  all  l ocal  re g ulat or y 
re q uire me nts. 
6. 5. 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 h e st u d y site, ha n dle d a n d 
st ore d safel y 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 t he 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 dy tre at 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 acc or di n g t o i nstr ucti o ns i n t he 
I n vesti gat or’s Br oc h ure.  
St ora ge c o n diti o ns f or ri b ocicli b, letr oz ole a n d g osereli n will  be descri be d o n t he me dicati o n 
la bel/l ocal pac ka ge i nsert. T he st u d y dr u g s h o ul d be st ore d i n a sec ure, l oc ke d area w hile 
u n der t he res p o nsi bilit y of t he i n vesti gat or. A n a ut h orize d per s o n at t he i n vesti gat or’s site 
t hr o u g h o ut t he e ntire st u d y m ust rec or d recei pt a n d dis pe nsi n g of s u p plie d st u d y dr u gs. 
As l o n g as t he st u d y dr u gs are s u p plie d b y N o vartis, t he y are t o be st ore d bet wee n 2° C a n d 
2 5° C a n d pr otect fr o m m oist ure. T he st ora ge te m perat ure m ust be  rec or de d dail y (e xce pt 
wee ke n ds a n d ba n k h oli da ys) i n t he te m perat ure l o g. 
6. 5. 3  
St u d y dr u g c o m pli a n c e a n d a c c o u nt a bilit y 
6. 5. 3. 1  St u d y dr u g c o m pli a n c e 
T he  i n vesti gat or  a n d/ or  st u d y  pers o n nel  will  assess  c o m plia nce at  eac h  patie nt  visit.  T o 
acc uratel y  deter mi ne  t he  patie nt’s  dr u g  e x p os ure  t hr o u g h o ut  t he   st u d y,  t he  f oll o wi n g 
i nf or mati o n  m ust  be  re p orte d  o n  t he  Dr u g  A d mi nistrati o n  Rec or d C R F  f or  ri b ocicli b, 
letr oz ole a n d g osereli n pa ges an d i n t he s o urce d oc u me nt. 
 Pla n ne d d ose a d mi nistrati o n 
 Act ual t otal dail y d ose a d mi nistere d 
 Start a n d e n d date of dr u g a d mi nistrati o n 
 D ose c ha n ge ( n o or yes) 
 Reas o n f or d ose c ha n ge (e. g. a d ve rse e ve nt, d osi n g err or, la b test a b n or malit y etc.). 
6. 5. 3. 2  St u d y dr u g 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 o f t he s hi p me nt of st u d y dr u gs 
s u p plie d b y N o vartis as well as of t he prescri pti o ns of ri b ocic li b, letr oz ole a n d g osereli n 
after  ri b ocicli b  bec o mes  c o m merci all y  a vaila ble.  T he  i n vesti gat or  will  be  a d vise d  t o 
d oc u me nt  t he  dis pe nsi n g  a n d  ret ur n  of  ri b ocicli b,  letr oz ole  a n d   g osereli n  t hr o u g h o ut  t he 
e ntire st u d y i n a dr u g acc o u nta bilit y l o g. T he fiel d m o nit or will re vie w dr u g acc o u nta bilit y 
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. T he pati e nt will be a d vise d t o c o m plete 
a st u d y dr u g diar y a n d prese nt t he b ottles or blisters at t he s u bse q ue nt st u d y visits a n d at t he 
ti me  of  st u d y  dr u g  disc o nti n uati o n  t o  re vie w  c o m plia nce  a n d  allo w  t he  i n vesti gat or  t o 
d oc u me nt i n t he patie nt file a n d c o m plete a dr u g acc o u nta bilit y  c hec k. 
T he  patie nt  diar y  is  n ot  re gar de d  as  st u d y  d oc u me ntati o n  b ut  is   re gar de d  as  ai d  f or 
disc ussi o ns bet wee n i n v esti gat or a n d patie nt.  
Patie nts will be as ke d t o ret ur n all u n use d N o vartis-s u p plie d s t u d y dr u gs a n d pac ka gi n g o n 
a n o n g oi n g basis or at t he ti me  of st u d y dr u g disc o nti n uati o n. 

N o v arti s 
C o nfi d e nti al 
P a g e 6 5 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
6. 5. 3. 3  
H a n dli n g of ot h er st u d y tr e at m e nt 
N ot a p plica ble. 
6. 5. 4  
Di s p o s al a n d d e str u cti o n 
T he dr u g s u p pl y s h o ul d be destr o ye d at t he l ocal N o vartis facil it 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.  Destr ucti o n  at  t he  site  is  all o we d  o nl y  if  per mitte d  b y  l ocal 
re g ulati o ns a n d a ut h orize d b y N o vartis.  
 
6. 6  
St u d y dr u g di s c o nti n u ati o n 
St u d y dr u g i nterr u pti o n refers t o a patie nt st o p pi n g eit her st u d y dr u g d uri n g t he c o urse of 
t he  st u d y,  b ut  t he n  re-starti n g  it  at  a  later  ti me  i n  t he  st u d y.  If  o ne  of  t he  st u d y  dr u gs  is 
disc o nti n ue d, t he ot her m ust be disc o nti n ue d as well. If t he st u d y dr u g ri b ocicli b or letr oz ole 
is i nterr u pte d f or m ore t ha n 4 wee ks, t he patie nt will be per ma ne ntl y disc o nti n ue d fr o m t he 
st u d y treat me nt. 
All st u d y dr u g i nterr u pti o ns m ust be rec or de d o n t he a p pr o priat e D osa ge A d mi nistrati o n 
C R F. 
Patie nts  w h ose  ri b ocicli b  treat me nt  is  i nterr u pte d  d ue  t o  a n  a d verse  e ve nt  or  a b n or mal 
la b orat or y val ue m ust be f oll o we d at least o nce a wee k f or 2 8 da ys a n d s u bse q ue ntl y at 2 8 
da y i nter vals, u ntil res ol uti o n or sta bilizati o n of t he e ve nt, w hic he ver c o mes first. 
St u d y dr u g disc o nti n uati o n refers  t o a patie nt’s wit h dra wal fr om ri b ocicli b. T he reas o n f or 
disc o nti n uati o n fr o m treat me nt m ust be rec or de d o n t he E n d of t reat me nt C R F.  
Patie nts ma y be wit h dra w n fr o m t he st u d y treat me nt if a n y of t h e f oll o wi n g occ ur: 
 A d verse  E ve nt  (i ncl u di n g,  b ut  n ot  li mite d  t o  Q Tc F  ≥  5 0 1  msec,  c o nfir me d  at 
re peate d  E C G  meas ure me nts  a n d  rec urre nt  after  d ose  a dj ust me nt  was  perf or me d; 
D oc u me nte d e pis o de of ve ntric ula r tac h ycar dia, or ve ntric ular fi brillati o n; C o m plete 
heart bl oc k ( Gra de III A V bl oc k) or Sec o n d de gree A V bl oc k M o bi tz t y pe II). 
 P h ysicia n decisi o n  
 Pr o gressi ve Disease  
 Pr ot oc ol de viati o n  
 St u d y ter mi nate d b y s p o ns or  
 A dj ust me nts t o st u d y treat me nt  t hat res ult i n disc o nti n uati o n.  
 Use of pr o hi bite d me dicati o n. Please refer t o Secti o n 6. 3. 3. 
Patie nts w h o disc o nti n ue ri b ocic li b > 2 8 da ys s h o ul d be sc he d ule d f or a n E n d of Treat me nt 
Visit, w he ne ver p ossi ble, after  disc o nti n ui n g ri b ocicli b, at w hic h ti me all of t he assess me nts 
liste d  f or  t he  E n d  of  Treat me nt  Visit  ( E o T)  will  be  perf or me d. T he  c o m plete  E n d  of 
Treat me nt  e C R F  d oc u me ntati o n  s h o ul d  be  d o ne  wit hi n  o ne  wee k.  If   ri b ocicli b  is 
per ma ne ntl y disc o nti n ue d, t he patie nt will be c o nsi dere d t o ha v e c o m plete d st u d y treat me nt. 
All  patie nts  m ust  ha ve  safet y  e val uati o ns  f or  3 0  da ys  after  t he  last  d ose  of  st u d y  dr u g. 
A Es/ S A Es wit h a s us pecte d ca usalit y t o st u d y treat me nt m ust be re p orte d be y o n d t his 3 0 
da y safet y i nter val. 
Patie nts w h o disc o nti n ue st u d y treat me nt s h o ul d N O T be c o nsi der e 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 assess me nts i n dicate d i n Secti o n 7- 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 6 6 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
f or t hese assess me 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, letter) s h o ul d 
be ma de t o c o ntact t he m. 
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.  

N o v arti s 
C o nfi d e nti al 
P a g e 6 7 
O nc ol o g y Cli nical Trial Pr ot oc ol ( Versi o n 0 4)  
  
Pr ot oc ol N o. C L E E 0 1 1 X D E 0 1 
T a bl e 7- 1  
Vi sit e v al u ati o n s c h e d ul e  
  
S cr e e ni n g/ 
B a s eli n e 
D a y - 2 1 t o 
C 1 D 1  
C y cl e 1 
D a y 1 
C y cl e 1 
D a y 1 5 
( +/- 3 d) 
C y cl e 2 
D a y 1 
( +/- 3 d) 
C y cl e 2 
D a y 1 5 
( +/- 3 d) 
C y cl e 3 
D a y 1 
( +/- 3 d) 
C y cl e 5 
D a y 1 
( +/- 3 d) 
C y cl e 6 
D a y 1 
( +/- 3 d) 
C y cl e 7 
D a y 1 
( +/- 3 d) 
F urt h er 
c y cl e s 
( +/- 3 d) 
S y m pt
o m ati c 
Pr o gr e
s s 1 0  
E O T 
F oll o w 
u p 
P & S 
F oll o w 
u p 
Vi sit n o. 
1 
2 
3 
4 
5 
6 
8 
9 
1 0 
1 1- n 
S 
N 
E O T + 
3 0 
d a y s 
P F S- F U 
D e m o gr a p h y/ 
i nf or m e d c o n s e nt  
X  
   
   
   
  
  
   
   
  
   
  
   
   
 
I n cl u si o n/ e x cl u si o n 
crit eri a  
X  
   
   
   
  
  
   
   
  
   
  
   
   
 
R el e v a nt m e di c al 
hi st or y/ c urr e nt 
m e di c al c o n diti o n s  
X  
   
  
   
  
  
   
   
  
   
  
   
   
 
Di a g n o si s a n d e xt e nt 
of c a n c er  
X  
   
   
   
  
  
   
   
  
   
  
   
   
 
Pri or/ p o st 
a nti n e o pl a sti c 
t h er a p y 
X  
   
   
   
  
  
   
   
  
   
  
  
X 
( X)7  
Vit al si g n s, W ei g ht, 
P h y si c al e x a mi n ati o n, 
E C O G st at u s, H ei g ht 6  
X 
X 
 
X  
 
X 
X 
X 
X 
E v er y c y cl e 
u ntil C 1 3, 
t h e n e v er y 
1 2 w e e k s  
X 
X  
   
 
Pri or/ c o n c o mit a nt 
m e di c ati o n s 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
Pr e g n a n c y T e st (f or 
pr e m e n o p a u s al 
w o m e n) 8 : 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nfir m e d n e g ati v e 
s er u m pr e g n a n c y t e st  
pr e g n a n c y t e st,  
 
X  
 
X  
 
X 
X 
X 
X 
X 
X 
X 
X  
 
F S H, e str a di ol 1 1  
X 
X  
 
X  
 
X 
X 
X 
X 
X 
X 
X 
X  
 
A d v er s e e v e nt s 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 6 8 
O nc ol o g y Cli nical Trial Pr ot oc ol ( Versi o n 0 4)  
  
Pr ot oc ol N o. C L E E 0 1 1 X D E 0 1 
 
S cr e e ni n g/ 
B a s eli n e 
D a y - 2 1 t o 
C 1 D 1  
C y cl e 1 
D a y 1 
 
C y cl e 
1 D a y 
1 5 
( +/- 3 d) 
C y cl e 2 
D a y 1 
( +/- 3 d) 
C y cl e 2 
D a y 1 5 
( +/- 3 d) 
C y cl e 
3 D a y 
1 
( +/- 3 d) 
C y cl e 
5 D a y 
1 
( +/- 3 d) 
C y cl e 
6 
D a y 1 
( +/- 3 d) 
C y cl e 7 
D a y 1 
( +/- 3 d) 
F urt h er 
c y cl e s 
( +/- 3 d) 
S y m pt
o m ati c 
Pr o gr e
s s 1 0 
E O T 
F oll o
w u p 
P & S 
F oll o w 
U p 
H e m at ol o g y, 
Bi o c h e mi str y 8   
X 
(f a sti n g) 
( X)* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
   
 
Pl e a s e d o c u m e nt if 
cli ni c all y 
i n di c at e d/ si g nifi c a nt 
E C G 9  
X ( D- 7 t o - 1) 
( a n yti m e) 
 
X 
( a n yti m e ) 
X 
( a n yti m e ) 
X 
( a n yti m e ) 
X 
( a n yti m e ) 
X 
( a n yti m e 
) 
X 
( a n yti m e ) 
If cli ni c all y i n di c at e d 
( a n yti m e ) 
X 
( a n yti m e) 
 
 
Uri n al y si s, S er u m 
Li pi d Pr ofil e, I N R 8  
X 
(f a sti n g) 
 
c all y i n di c at e d 
  
 
T u m or e v al u ati o n: 
X 1   
   
   
   
  
  
   
  
X 
( e v er y 1 2 
w e e k s)  
X 
( X)2, § 
  
( X)2, 5  
C T f or c h e st, a b d o m e n, 
p el vi s 
T u m or e v al u ati o n: 
( X)1   
   
   
   
 
 
 
  
( X)2 
( e v er y 1 2 
w e e k s)
2 
( X)2 
( X)2, § 
  
( X)2, 5  
C T / M RI f or Br ai n 
 if cli ni c all y i n di c at e d 
T u m or e v al u ati o n: 
B o n e S c a n 
X 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T u m or e v al u ati o n: 
B o n e X- R a y / B o n e C T, S ki n 
l e si o n p h ot o gr a p h y 
( X)4 
  
 
  
 
  
 
 
 
  
  
 
  
( X)4 
( e v er y 1 2 
w e e k s)
4 
( X)4 
( X)2, § 
  
( X)2, 5  
Ri b o ci cli b/ l etr o z ol e 
( a n d g o s er eli n) 
D o si n g 
  
C o nti n u
 t h e tri al 
 
   
 
P ati e nt Di ar y  
  
X  
 
X  
 
X 
X  
X 
X 
X 
X 
X 
 
 
E O R T C Q L Q- C 3 0 & 
m o d ul e B R- 2 3 
 
X  
 
X  
 
X 
X 
X 
X 
E v er y c y cl e 
u ntil C 1 3, 
t h e n e v er y 
1 2 w e e k s  
X 
X 
X  
 
Pr o gr e s si o n / 
s ur vi v al st at u s 7  
 
 
 
 
 
 
 
 
 
 
 
 
P & S 7 
X 

N o v arti s 
C o nfi d e nti al 
P a g e 6 9 
O nc ol o g y Cli nical Trial Pr ot oc ol ( Versi o n 0 4)  
  
Pr ot oc ol N o. C L E E 0 1 1 X D E 0 1 
 
 
N ot e: 1 C y cl e = 2 8 d a y s 
  
 
 
 
 
 
 
* n ot n e c e s s ar y if l a st a s s e s s m e nt w a s wit hi n 7 d a y s b ef or e fir st i nt a k e of st u d y m e di c ati o n. 
§ if E O T o c c ur s f or ot h er r e a s o n t h a n pr o gr e s si o n a n d p ati e nt wit h dr a w s c o n s e nt f or P F S f oll o w u p , if l a st t u m or e v al u ati o n i s ol d er t h a n 1 2 w e e k s.  
 
1E xi sti n g  r a di ol o gi c a s s e s s m e nt s c a n b e u se d if a s s e s s e d u p t o 2 8 d a y s pri or t o C 1 D 1. A c orr e s p o n di n g R E CI S T e v al u ati o n s h o ul d b e p erf or m e d a n d d o c u m e nt e d. 
 
2If fi n di n g s at b a s eli n e e v al u ati o n. 
 
 
³ E xi sti n g b o n e s c a n s c a n b e u s e d if a s s e s s e d u p t o 5 6 d a y s pri or t o C 1 D 1.  
4 P o siti v e ar e a s o n b o n e s c a n s m u s t b e a s s e s s e d b y X-r a y or C T s ca n wit h b o n e wi n d o w s o n s cr e e ni n g / b a s eli n e a n d s h o ul d c o nti n u e t o b e a s s e s s e d u si n g t h e s a m e m o d alit y. 
( X-r a y or C T s c a n wit h b o n e wi n d o w s) e v er y 1 2 w e e k s. N ot all p ositi v e ar e a s n e e d t o b e f oll o w e d u p ( n o n-t ar g et l e si o n s) if si g nifi c a nt a n d r el e v a nt t u m o r b ur d e n c a n b e a s s e s s e d 
b y C T. 
5 All p ati e nt s b ei n g di s c o nti n u e d fr o m t h e st u d y m e di c ati o n f or ot h er r e a s o n s t h a n t u m or pr o gr e s si o n ( or d e at h) s h o ul d b e s c h e d u l e d f or t u m or e v al u ati o n at 1 2 w e e k i nt er v al s 
aft er di s c o nti n u ati o n u ntil pr o g r e s si o n or L P L V o c c ur s, w hi c h e ver o c c ur s fir st. 
6 H ei g ht i s r e q uir e d o nl y at b a s eli n e 
7 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 e v er y 1 2 w e e k s, 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 r el e v a nt e C R F s. 
Aft er t h e l a st p ati e nt i n t h e tr i al h a s t a k e n t h e l a st d o s e of Ri b o ci cli b, t h e p o st- a nti n e o pl a sti c tr e at m e nt, c urr e nt pr o gr e s s i o n a n d s ur vi v al st at u s f or all p ati e nt s will b e u p d at e d 
fi n all y a n d r e c or d e d i n t h e C R F. 
8 E x ci sti n g a s s e s s m e nt r e s ult s c a n b e u s e d if a s s e s s e d u p t o 2 1 d a y s pri or t o C 1 D 1. 
9 E x ci siti n g E C G a s s e s s m e nt c a n b e u s e d if it w a s wit hi n 7 d a y s b ef or e fir st i nt a k e of st u d y m e di c ati o n. 
 
 
1 1  F or pr e m e n o p a u s al p ati e nt s; f or p o st m e n o p a u s al pati e nt s, m e n o p a u s al st at u s s h o ul d b e c o nfir m e d a c c or di n g t o l o c al st a n d ar d 
 
 
 
P P D

N o v arti s 
C o nfi d e nti al 
P a g e 7 0 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
7. 1. 1  
S cr e e ni n g 
T he scree ni n g/ baseli ne visit will occ ur ma xi m u m 2 1 da ys pri or t o first d ose of t he st u d y 
dr u g ri b ocicli b a n d starts wit h t he si g nat ure of  t he i n di vi d ual I C F. 
Patie nt  m ust  pr o vi de  a  si g ne d  I nf or me d  C o nse nt  F or m  (I C F)  pri or   t o  a n y  st u d y  s pecific 
scree ni n g e val uati o ns.  
T he  i n vesti gat or  m ust  re vie w  i nc l usi o n/e xcl usi o n  criteria  a n d  doc u me nt  t he  patie nt’s 
eli gi bilit y i n t he patie nt rec or d. 
Re-scree ni n g of patie nts is o nl y all o we d o nce per patie nt if t h e patie nt was n ot re gistere d as 
e nteri n g t he treat me nt p hase bef ore (i.e. first st u d y dr u g i nta ke). I n t his case t he S u bject N o. 
assi g ne d  t o  t he  patie nt  i nitiall y  will  be  use d  a n d  t he  patie nt will  be  i de ntifie d  wit h  t his 
n u m ber t hr o u g h o ut his/ her e ntire  partici pati o n t o t he st u d y.  
I n  case  re-scree ni n g  occ urs,  all  e val uati o ns  re-assesse d  s h o ul d  meet  t he  eli gi bilit y 
criteria. T he f oll o wi n g data will  be c ollecte d f or all scree ni n g fail ures: 
 I nf or me d c o nse nt si g ne d 
 I ncl usi o n/e xcl usi o n (reas o n f or faili n g) 
 De m o gra p hics 
 S A E data (if a p plica ble). 
7. 1. 1. 1  I nf or m ati o n t o b e c ol l e ct e d o n s cr e e ni n g f ail ur e s 
Patie nts w h o si g ne d t he i nf or me d c o nse nt a n d are scree ne d a n d d o n ot meet all e ntr y criteria 
will n ot be e ntere d i nt o t he st u d y. S uc h patie nts are c o nsi dere d t o be scree n fail ures. T he 
reas o n  f or  n ot  bei n g  starte d  will  be  e ntere d  i n  t he  site’s  scree ni n g  fail ure  l o g  a n d  o n 
scree ni n g fail ure pa ge i n C R F. 
7. 1. 1. 2  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 assess me nts a n d pr oce d ures will be perf or me d wit h i n 2 1 da ys pri or t he start 
of st u d y treat me nt: 
 O btai n patie nt’s writte n i nf or me d c o nse nt f or m. 
 Ge neral de m o gra p h y i nc l u di n g a ge a n d ge n der. 
 Me dical  hist or y/c urre nt  me dical   c o n diti o ns  (i ncl u di n g  pri or  c o nc o mita nt  me dicati o ns 
wit hi n t he last 4 wee ks pri or t o Da y 1). 
 Hist or y a n d c urre nt disease stat us (i ncl u di n g sta gi n g, dia g n osi s i nf or mati o n, pre vi o us 
a nti-ca ncer treat me nts a n d sites of disease). T he f oll o wi n g i nf or mati o n m ust be c ollecte d 
f or all pre vi o us a ntica ncer t hera pies: date start, date e n d, setti n g ( ne oa dj u va nt, a dj u va nt, 
metastatic), best res p o nse, r eas o n f or treat me nt disc o nti n uati o n. 
A d diti o nall y, t o deter mi ne eli gi bilit y at t he scree ni n g visit, t he f oll o wi n g assess me nts will 
be perf or me d: 
 P h ysical e xa mi nati o n, hei g ht a n d wei g ht.  
 Vital si g ns i ncl u di n g bl o o d press ure a n d heart rate. 
 E xisti n g E C G assess me nt ca n be use d if it was wit hi n 7 da ys bef ore first i nta ke of st u d y 
me dicati o n. 
 E C O G perf or ma nce stat us 

N o v arti s 
C o nfi d e nti al 
P a g e 7 1 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 Safet y la b orat or y assess me nts s uc h  as he mat ol o g y, bi oc he mistr y,  ser u m li pi d pr ofile, 
c oa g ulati o n a n d uri nal ysis s h o ul d be perf or me d l ocall y at t he i n vesti gat or’s discreti o n 
a n d  are  n ot  ca pt ure d  o n  t he  C R F.  La b orat or y  assess me nts  perf or m e d  wit hi n  2 1  da ys 
pri or  t o  C 1 D 1  ma y  be  use d.  If,  at  scree ni n g,  la b orat or y  res ults   are  o ut  of  ra n ge  a n d 
cli nicall y  si g nifica nt,  t hese  res ults  s h o ul d  be  ca pt ure d  o n  t he   me dical  hist or y/c urre nt 
me dical c o n diti o ns C R F. 
 Ra di ol o gical t u m or assess me nts at baseli ne:  
 C T f or c hest a b d o me n a n d pel vis u nless perf or me d wit hi n 2 8 da ys  pri or t o C 1 D 1. 
C T  sca n  wit h  c o ntrast  me dia  s h o ul d  be  use d  e xce pt  f or  patie nts 
w h o  are 
aller gic/se nsiti ve t o t he ra di o gra p hic c o ntrast me dia. C T f or c hest a n d a b d o me n ma y 
be  re place d  b y  M RI  if  cli nicall y   c o ntrai n dicate d,  e. g.  aller g y/se nsiti vit y  t o  t he 
ra di o gra p hic  c o ntrast  me dia,  metastatic  prese ntati o n,  after  prior  c o ns ultati o n  a n d 
a p pr o val b y N o vartis. 
 Brai n: C T or M RI if C N S metastas es are prese nt u nless perf or me d  wit hi n 2 8 da ys 
pri or t o C 1 D 1. 
 W h ole B o d y B o ne Sca n u nless perf or me d wit hi n 5 6 da ys pri or t o C 1 D 1. 
7. 1. 2  
Tr e at m e nt p eri o d 
Ri b ocicli b will be d ose d starti n g o n treat me nt Da y 1 ( Visit 2).  Patie nts will be i nstr ucte d t o 
ta ke 3 ta blets of 2 0 0 m g ri b ocicli b orall y wit h a lar ge glass of water, o nce dail y at t he sa me 
ti me eac h da y wit h or wit h o ut f o o d f or 2 1 da ys, f oll o we d b y 7 da ys wit h o ut ta ki n g ri b ocicli b. 
Patie nts will be i nstr ucte d t o i nf or m t he i n vesti gat or of t he d ate of first ri b ocicli b st u d y dr u g 
i nta ke. 
Letr oz ole will be d ose d starti n g o n treat me nt Da y 1 ( Visit 2). Patie nts will be i nstr ucte d t o 
ta ke 1 ta blet of 2. 5 m g letr oz ole orall y wit h a lar ge glass of water at t he sa me ti me eac h da y 
i n t he m or ni n g. Pac ka ge i nsert instr ucti o ns s h o ul d be f oll o we d.  
F or pre me n o pa usal w o me n a n d me n, g osereli n will be s u bc uta ne o us l y i njecte d o n Da y 1 of 
eac h c ycle. Pac ka ge i nsert i nstr ucti o ns s h o ul d be f oll o we d. 
Patie nts will c o nti n ue t o be treate d per pr ot oc ol u ntil d oc u me n tati o n of disease pr o gressi o n, 
u nacce pta ble t o xicit y, deat h or disc o nti n uati o n d ue t o a n y ot he r reas o n. Treat me nt be y o n d 
pr o gressi o n is at t he discreti o n of t he i n vesti gat or. I nf or mati o n o n dr u g e x p os ure will be 
c ollecte d o n t he D osa ge A d mi nis trati o n Rec or d pa ge of t he e C R F. 
F or details of assess me nts, refer t o Ta ble 7- 1. T he i n vesti gat o r a n d/ or st u d y pers o n nel will 
assess c o m plia nce at  eac h patie nt visit. 
7. 1. 3  
E n d of tr e at m e nt vi sit i n c l u di n g st u d y c o m pl eti o n a n d pr em at ur e 
wit h dr a w al 
At t he ti me patie nts disc o nti n ue  st u d y treat me nt a visit s h o ul d be sc he d ule d n o m ore t ha n 7 
da ys later, at w hic h ti me all of t he assess me nts liste d f or t he  E n d of Treat me nt ( E O T) visit 
will be perf or me d. A n E n d of Treat me nt P hase Dis p ositi o n C R F pa ge s h o ul d be c o m plete d, 
gi vi n g t he date a n d reas o n f or s t o p pi n g t he st u d y treat me nt. 
At a mi ni m u m, all patie nts w h o disc o nti n ue st u d y treat me nt, i nc l u di n g t h ose w h o ref use t o 
ret ur n f or a fi nal visit, will be c o ntacte d f or safet y e val uatio ns d uri n g t he 3 0  da ys f oll o wi n g 
t he 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 7 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Patie nts  w h o  disc o nti n ue  st u d y  treat me nt  f or  ot her  reas o ns  t ha n   pr o gressi o n  als o  s h o ul d 
ret ur n f or t u m or assess me nts e ver y 1 2 wee ks u ntil disease pr o gressi o n a n d s h o ul d n ot be 
c o nsi dere d wit h dra w n fr o m t he st u d y. If patie nts ref use t o ret u r n f or t hese visits or are u na ble 
t o  d o  s o,  e ver y  eff ort  s h o ul d  be  ma de  t o  c o ntact  t he m  or  a  k n o wle d gea ble  i nf or ma nt  b y 
tele p h o ne t o deter mi ne t he pr o gressi o n of t he disease. 
If a st u d y wit h dra wal occ urs, or if t he patie nt fails t o ret ur n f or visits, 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 a n d rec or d 
t his i nf or mati o n o n t he E n d of Treat me nt Dis p ositi o n C R F pa ge. 
If  a  patie nt  disc o nti n ues  st u d y  treat me nt,  b ut  c o nti n ues  st u d y assess me nts,  t he  patie nt 
re mai ns  o n  st u d y  u ntil  s uc h  ti me  as  he/s he  c o m pletes  pr ot oc ol  criteria  f or  e n di n g  st u d y 
assess me nts. At t hat ti me, t he reas o n f or st u d y c o m pleti o n s h o u l d be rec or de d o n t he St u d y 
P hase C o m pleti o n Dis p ositi o n C R F ( S E C) pa ge. 
E n d of treat me nt/ Pre mat ure wit h dr a wal visit is n ot c o nsi dere d a s t he e n d of t he st u d y. 
7. 1. 3. 1  St u d y c o m pl eti o n 
T he e n d of treat me nt ( L P L T = E O T) f or all patie nts is pla n ne d 8 0 w ee ks after t he first i nta ke 
of ri b ocicli b of t he last patie nt ( L P F T) or pr o gressi o n of dise ase of all patie nts, w hic he ver 
occ urs first. Patie nts will be f oll o we d f or safet y f or 3 0 da ys after t he i n di vi d uall y last d ose 
of st u d y dr u g t o ac hie ve t he e n d of st u d y ( L P L V). After last pa tie nt last treat me nt ( L P L T), 
t he p ost-a nti ne o plastic treat me nt, t he c urrent pr o gressi o n a n d s ur vi val stat us f or all patie nts 
will be u p date d fi nall y a n d rec or de d i n t he e C R F. 
7. 1. 3. 2  
Crit eri a f or pr e m a t ur e p ati e nt wit h dr a w al 
Patie nts ma y v ol u ntaril y wit h dra w f r o m t he st u d y or be dr o p pe d fr o m it at t he discreti o n of 
t he i n vesti gat or at a n y ti me.  
Patie nts m ust be wit h dra w n fr o m t he st u d y treat me nt if a n y of the f oll o wi n g occ ur: 
 Pre g na nc y 
 S u bject decisi o n 
 L ost t o f oll o w u p 
7. 1. 4  
F oll o w u p p eri o d 
All  patie nts  m ust  be  f oll o we d  f or  3 0  da ys  after  t he  last  d ose  o f  st u d y  dr u g  f or  safet y 
assess me nt ( A Es a n d/ or S A Es). 
All ne w a ntica ncer t hera pies gi v e n after t he last d ose of t he s t u d y dr u g ri b ocicli b will be 
rec or de d  o n  e C R F  pa ges  desi g ne d  t o  ca pt ure  a nti ne o plastic  t herapies  wit hi n  3 0  da ys 
f oll o wi n g disc o nti n uati o n fr o m t he st u d y. 
All  patie nts  bei n g  disc o nti n ue d  fr o m  t he  st u d y  me dicati o n  f or  o t her  reas o ns  t ha n  t u m or 
pr o gressi o n ( or deat h) s h o ul d be sc he d ule d f or t u m or e val uati o n  at 1 2 wee k i nter vals after 
disc o nti n uati o n u ntil pr o gressi o n o r L P L V occ urs, w hic he ver occurs first. 
S ur vi val  stat us  a n d  t he  c urre nt  pr o gressi o n  will  be  u p date d  f or   all  patie nts  fi nall y  a n d 
rec or de d  i n  t he  e C R F  after  last  patie nt  last  treat me nt  ( L P L T)  until  L P L V.  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 rele va nt e C R Fs.  

N o v arti s 
C o nfi d e nti al 
P a g e 7 3 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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 C R F. 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 doc 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 te le p h o ne calls, re gistere d letters, 
etc. 
7. 1. 5  
S ur vi v al f oll o w u p 
All patie nts will be f oll o we d u p f or s ur vi val stat us e ver y 1 2 w ee ks re gar dless of treat me nt 
disc o nti n uati o n reas o n u ntil deat h, l ost t o f oll o w- u p, or wit h d ra wal of c o nse nt t o s ur vi val 
f oll o w- u p. A d diti o nal s ur vi val assess me nts ma y be perf or me d o utsi de t he 1 2 wee ks f oll o w 
u p sc he d ules if a s ur v i val is re q uire d f or a n i nteri m assess me nt t o meet safet y or re g ulat or y 
nee ds.  
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 rele va nt e C R Fs. 
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 
T u m or  assess me nt  a n d  res p o nse  will  be  e val uate d  acc or di n g  t o  R E CI S T  ( Versi o n  1. 1) 
( Pr ot oc ol P ost-te xt S u p ple me nt: 1). All ra di ol o gic assess me nts m ust be perf or me d wit hi n a 
+/- 7 da y wi n d o w of t he visit. 
Patie nts s h o ul d ha ve eit her at least o ne lesi o n t hat ca n be mea s ure d as per R E CI S T criteria 
O R ha ve b o ne lesi o ns: l ytic or mi xe d (l ytic + scler otic) i n t he  a bse nce of meas ura ble disease 
O R ha ve n o n- meas ura ble disease. 
F or  patie nts  wit h  meas ura ble  disease  at  scree ni n g  (as  per  R E CI S T  criteria),  t u m or 
pr o gressi o n will be e val uate d e ver y 1 2 wee ks u ntil pr o gressi o n or E n d of st u d y, w hic he ver 
is first (acc or di n g t o t he R E CI S T 1. 1 criteria). All t u m or e valuati o ns perf or me d r o uti nel y i n 
a d diti o n t o t he a b o ve me nti o ne d will be e val uate d a n d d oc u me nte d acc or di n g t o R E CI S T 
1. 1 as well. All patie nts bei n g disc o nti n ue d fr o m t he st u d y f or  disease pr o gressi o n m ust ha ve 
t heir pr o gressi o n d oc u me nte d usi n g t he criteria s pecifie d i n R ECI S T 1. 1. 
B o ne sca ns m ust be perf or me d at scree ni n g wit hi n 5 6 da ys bef ore  C 1 D 1. P ositi ve areas o n 
b o ne sca ns m ust be assesse d b y X-ra y or C T sca n wit h b o ne wi n d o ws, pri or t o C 1 D 1 a n d 
s h o ul d c o nti n ue t o be assesse d usi n g t he sa me m o dalit y ( X-ra y or C T sca n) e ver y 1 2 wee ks 
u ntil pr o gressi o n or E n d of st u d y. A d diti o nal b o ne sca ns s h o ul d  be perf or me d if cli nicall y 
i n dicate d. A b n or malities f o u n d o n s u bse q ue nt b o ne sca ns m ust be c o nfir me d b y X-ra y or 
C T sca n. B o ne sca ns ma y be re place d b y w h ole b o d y C T, pr o vi de d t hat t his is l ocal sta n dar d. 
T he w h ole- b o d y C T m ust be perf or me d wit hi n a +/- 7 da ys wi n d o w of t he visit. 
C ol or  p h ot o gra p h y,  i ncl u di n g  a  metric  r uler  t o  esti mate  t he  siz e  of  t he  lesi o n,  m ust  be 
ac q uire d f or all s ki n lesi o ns prese nt at baseli ne. T hese s h o ul d  be f oll o we d t hr o u g h o ut t he 
st u d y acc or di n g t o t he sc he d ule o utli ne d i n Ta ble 7- 1. 
All patie nts bei n g disc o nti n ue d f r o m t he st u d y f or ot her reas o ns t ha n t u m or pr o gressi o n ( or 
deat h) s h o ul d be sc he d ule d f or t u m or e val uati o n at 1 2 wee k i nte r vals after disc o nti n uati o n 
u ntil L P L V occ urs. 
T he sa me met h o d of assess me nt a n d t he sa me 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 f or eac h st u d y t u m or assess me nt after start of st u d y 
treat me nt.   

N o v arti s 
C o nfi d e nti al 
P a g e 7 4 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Res p o nse  will  be  assesse d  b y  l ocal  ra di ol o g y  re vie w.  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, t here will be n o ce ntral re vie w i n t his 
st u d y.  T he  sa me  ra di ol o gist/ p h ysicia n  s h o ul d  perf or m  t he  e val uati o n  f or  eac h  i n di vi d ual 
patie nt f or t he e ntire  d urati o n of t he st u d y. 
A C T sca n of t he c hest, a b d o me n a n d pel vis will be perf or me d at  scree ni n g ( ≤ 4 wee ks pri or 
t o t he first d ose of Ri b ocicli b) a n d peri o dicall y as i n dicate d i n Ta ble 7- 1 . C T Sca ns wit h 
c o ntrast  me dia  s h o ul d  be  use d  e xce pt  f or  patie nts  w h o  are  aller gic/se nsiti ve  t o  t he 
ra di o gra p hic c o ntrast me dia.  
All patie nts s h o ul d ha ve at leas t o ne lesi o n t hat ca n be acc uratel y meas ure d i n at least o ne 
di me nsi o n ≥ 1 0 m m wit h c o n ve nti o nal i ma gi n g tec h ni q ues or ≥ 1 0 m m wit h s piral C T O R 
b o ne lesi o ns s uc h as l ytic or mi xe d (l ytic + scler otic) i n t he a bse nce of meas ura ble disease 
O R  ot her  lesi o ns,  i ncl u di n g  s mall  lesi o ns  (l o n gest  dia meter  < 2 0   m m  wit h  c o n ve nti o nal 
tec h ni q ues  or  < 1 0  m m  wit h  s piral  C T  sca n),  i.e.,  le pt o me ni n geal  disease,  ascites, 
ple ural/ pericar dial eff usi o n, l y m p ha n gitis c utis/ p ul m o nis, c yst ic lesi o ns, a n d als o a b d o mi nal 
masses t hat are n ot c o nfir me d a n d f oll o we d b y i ma gi n g tec h ni q ue s. 
F or patie nts wit h meas ura ble disease at baseli ne, pr o gressi o n w ill be deter mi ne d acc or di n g 
t o t he R E CI S T 1. 1 criteria (see A p pe n di x 1 4. 2. f or details).  
I n  t he  a bse nce  of  meas ura ble  disease  at  baseli ne,  t he  f oll o wi n g  will  be  c o nsi dere d 
pr o gressi o n a m o n g patie nts wit h l ytic or mi xe d (l ytic + scler ot ic) b o ne lesi o ns: 
 T he a p peara nce of o ne or m ore ne w l ytic lesi o ns i n b o ne 
 T he a p peara nce of o ne or m ore ne w lesi o ns o utsi de of b o ne 
 U ne q ui v ocal pr o gressi o n of  e xisti n g b o ne lesi o ns 
N ote: Pat h ol o gic fract ure, ne w c o m pressi o n fract ure, or c o m plic ati o ns of b o ne metastases 
will  n ot  be  c o nsi dere d  as  e vi de nce  of  disease  pr o gressi o n,  u nle ss  o ne  of  t he  a b o ve-
me nti o ne d criteria is f ulfille d. 
N o n meas ura ble disease: 
C o m plete Res p o nse ( C R) is c o nsi dere d as disa p peara nce of all n o n-tar get lesi o ns. All l y m p h 
n o des m ust be n o n- pat h ol o gical i n size ( < 1 0 m m s h ort a xis).  
N C R N P D is c o nsi dere d as persiste nce of o ne or m ore n o n-tar get l esi o n(s).   
Pr o gressi ve  Disease  ( P D)  is  c o nsi dere d  as  a p peara nce  of  o ne  or m ore ne w lesi o ns a n d/ or 
u ne q ui v ocal pr o gressi o n of e xisti n g n o n-tar get lesi o ns. U ne q ui v ocal pr o gressi o n s h o ul d n ot 
n or mall y tr u m p tar get lesi o n stat us. It m ust be re prese ntati ve of o verall disease stat us c ha n ge, 
n ot a si n gle lesi o n i ncrease. 
7. 2. 1. 1  Tr e at m e nt b e y o n d pr o gr e s si o n 
U p o n ra di ol o gic pr o gressi o n acc or di n g t o R E CI S T 1. 1 treat me nt wit h st u d y dr u g ma y be 
c o nti n ue d  at  t he  discreti o n  of  t he  i n vesti gat or  u ntil  a  cli nica ll y  s y m pt o matic  pr o gressi o n 
occ urs. S y m pt o matic pr o gressi o n will be assesse d e ver y 1 2 wee ks  u ntil pr o gressi o n or E n d 
of  st u d y.  Cli nicall y  s y m pt o matic  pr o gress  is  j u d ge d  b y  t he  i n ve sti gat or  a n d  m ust  be 
d oc u me nte d acc or di n gl y i n t he s o urce d oc u me ntati o n a n d e C R F. A ra di ol o gic assess me nt 
m ust be perf or me d u p o n s y m pt o matic pr o gressi o n. 
7. 2. 2  
S af et y a n d t ol er a bilit y a s s e s s m e nt s 
Safet y will be m o nit ore d b y c ollecti n g a n d assessi n g all a d vers e e ve nts, i ncl u di n g seri o us 
a d verse e ve nts, t he re g ular m o nit ori n g of he mat ol o g y, bl o o d c he mistr y, vital si g ns, p h ysical 

N o v arti s 
C o nfi d e nti al 
P a g e 7 5 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
c o n diti o n a n d E C G. T hese assess me nts s h o ul d be perf or me d ± 3 da ys of t he sc he d ule d da y 
of  assess me nt  e xce pt  f or  a d verse  e ve nts  t hat  will  be  e val uate d c o nti n u o usl y  t hr o u g h  t he 
st u d y, starti n g after t he patie nt has pr o vi de d i nf or me d c o nse nt ( Refer t o Ta ble 7- 1 ). 
T o xicit y  will  be  assesse d  usi n g t he  N CI- C T C A E  C o m m o n  Ter mi n ol o gy  Criteria  f or 
A d verse E ve nts, versi o n 4. 0 3 ( C T C A E v 4. 0 3). 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. 
7. 2. 2. 1  P h y si c al e x a mi n ati o n 
P h ysical e xa mi nati o n s h o ul d i ncl u de a t otal b o d y e xa mi nati o n ( g e neral a p peara nce, s ki n, 
nec k, i ncl u 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 y m p h n o des 
a n d e xtre mities).  
P h ysical  e xa mi nati o n  will  be  perf or me d  at  scree ni n g,  o n  treat me nt Da y 1 ( pri or t o 
a d mi nistrati o n of t he st u d y dr u g, u nless p h ysical e xa mi nati o n i n scree ni n g was d o ne less 
t ha n 7 da ys bef ore Da y 1), o n Da y 1 of c ycle 1- 1 3, e ver y 1 2 wee ks t hereafter, a n d at t he E n d 
of treat me nt.  
I nf or mati o n f or all p h ysical e xa mi nati o ns m ust be i ncl u de d i n t he s o urce d oc u me ntati o n at 
t he st u d y site. Si g nifica nt fi n din gs t hat were prese nt pri or t o  t he si g ni n g of t he i nf or me d 
c o nse nt m ust be d oc u me nte d o n t he Me dical Hist or y / C urre nt Me d ical C o n diti o ns e 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 e C R F. 
Hei gt h will be meas ure d at scree ni n g o nl y.  
Wei g ht will be meas ure d at scree ni n g a n d w he n cli nicall y i n dica te d. 
Si g nifica nt  fi n di n gs  t hat  were  pre se 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 will be rec or de d o n t he a p pr o priate e C R F pa ges. Vit al Si g ns s h o ul d be rec or de d 
at scree ni n g, o n Da y 1 of c ycle  1- 1 3, e ver y 1 2 wee ks t hereafter, a n d at t he E n d of treat me nt. 
Heart rate, te m perat ure a n d bl o o d press ure will be meas ure d acc or di n g t o n or mal me dical 
practice. 
T he partic ular cli nical fi n di n gs t hat were prese nt pri or t o t he  si g ni n g of t he i nf or me d c o nse nt 
m ust  be  d oc u me nte d  i n  t he  Rele va nt  Me dical  Hist or y  e C R F.  T he  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 d oc u me nte d i n t he A d verse  E ve nt e C R F. 
7. 2. 2. 3  P erf or m a n c e st at u s 
T he perf or ma nce stat us will be s c ore d usi n g t he E C O G Perf or ma nce Stat us Scale. 
E C O G Perf or ma nce Stat us will be assesse d a n d rec or de d at scree n i n g, o n Da y 1 of c ycle 1-
1 3, e ver y 1 2 wee ks t hereafter, a n d at t he E n d of treat me nt..  
Assess me nt of E C O G Perf or ma nce Stat us will be perf or me d o n t he sc he d ule d da y, e ve n if 
st u d y me dicati o n is bei n g hel d. T he E C O G Perf or ma nce Stat us Scale I n de x ( O ke n, 1 9 8 2) 
all o ws patie nts t o be classifie d as t o t heir f u ncti o nal i m pair m e nt; t he defi niti o n of sc ores i n 
relati o n t o t he Perf or ma nce Stat us is gi ve n i n Ta ble 7- 2. 

N o v arti s 
C o nfi d e nti al 
P a g e 7 6 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
T a bl e 7- 2  
E C O G P erf or m a n c e St at u s S c al e 
Sc ore 
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 a ll pr e- di s e a s e p erf or m a n c e wit ho ut r e stri cti o n. 
1 
R e stri ct e d i n p h y si c all y str e n u o u s a cti 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 nt ar y n at ur e, e. g ., li g ht h o u s e w or k, offi c e w or k. 
2 
A m b ul at or y a n d c a p a bl e of all s e lf- c ar e b ut u n a ble t o c arr y o ut  a n y w or k a cti viti e s. U p 
a n d a b o ut m or e t h a n 5 0 % of w a ki n g h o ur s. 
3 
C a p a bl e of o nl y li mit e d s elf- c ar e, c o nfi n e d t o b e d or c h air m or e t h a n 5 0 % of w a ki n g 
h o ur s. 
4 
C o m pl et el y di s a bl e d. C a n n ot c arr y  o n a n y s elf- 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. 4  L a b or at or y e v al u ati o n s 
La b orat or y e val uati o ns s h o ul d be perf or me d l ocall y at e ver y pr o t oc ol re q uire d visit (Ta ble 
7- 1 ) or as fre q ue ntl y as cli nicall y i n dicate d.  
T he  fre q ue nc y  of  t he  assess me nts  is  i n dicate d  i n T a ble  7- 1 .  All  sc he d ule d  la b orat or y 
e val uati o ns m ust be o btai ne d ≤ 7 da ys of t he s pecifie d ti me per i o ds, w het her or n ot st u d y 
treat me nt is a d mi nistere d. Scree ni n g e xa mi nati o ns perf or me d ≤ 7 da ys 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. 
La b orat or y val ues will n ot be d oc u me nte d i n t he e C R F u nless cli nicall y si g nifica nt.  
A n y partic ular cli nicall y si g ni fica nt fi n di n gs prese nt at screeni n g at t he ti me of i nf or me d 
c o nse nt m ust be d oc u me nte d i n t he Rele va nt Me dical Hist or y/ C urr e nt Me dical C o n diti o ns 
e C R F.  A b n or mal  la b orat or y  para meters  t hat  i n d uce  cli nical  si g ns   or  s y m pt o ms,  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 dr u g(s) c o nstit ute a n a d verse e ve nt ( Secti o n 8. 1. 2), 
m ust be rec or de d o n t he A d verse E ve nt e C R F. 
La b orat or y certificates will be  c ollecte d f or t his st u d y. 
T a bl e 7- 3  
L o c al Cli 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 
W hit e bl o o d c ell c o u nt ( W B C) w it h diff er e nti al ( n e utr o p hil s, l ym p h o c yt e s, m o n o c yt e s, 
e o si n o p hil s, a n d b a s o p hil s), h e m o gl o bi n ( H g b) a n d pl at el et c o u n t.  
Bi o c h e mi str y wit h 
f a sti n g gl u c o s e 
S o di u m,  p ot a s si u m,  c al ci u m,  c o rr e ct e d  c al ci u m,  m a g n e si u m,  t ot al pr ot ei n a n d 
al b u mi n. 
A S T  ( S G O T),  A L T  ( S G P T ),  t ot al  bilir u bi n,  dir e ct  bilir u bi n,  G G T a n d  al k ali n e 
p h o s p h at a s e, a n d L D H.  
At B a s eli n e a n d if cli ni c all y i n di c at e d: ur e a, cr e ati ni n e, f a st i n g gl u c o s e 
C o a g ul ati o n  
At B a s eli n e a n d if cli ni c all y i n di c at e d: I N R 
F a sti n g Li pi d P a n el 
At  B a s eli n e  a n d  if  cli ni c all y  i n di c at e d:  T ot al  c h ol e st er ol,  L D L - c h ol e st er ol,  H D L-
c h ol e st er ol a n d tri gl y c eri d e s 
7. 2. 2. 4. 1 H e m at ol o g y 
He mat ol o g y tests are t o be perf or me d acc or di n g t o t he Visit Sc h e d ules o utli ne d i n Ta ble 7-
1.  F or  details  of  t he  He mat ol o g y  pa nel  refer  t o Ta ble  7- 3   He mat ol o gical  tests  will  be 
perf or me d at scree ni n g, o n treat me nt Da y 1 (re peate d pri or t o a d mi nistrati o n of t he st u d y 
dr u g, if greater t ha n 7 da ys pri or t o Da y 1), C y cle 1 Da y 1 5, C ycle 2 Da y 1 a n d 1 5 a n d Da y 
1 of eac h s u bse q ue nt c ycle a n d at E n d of treat me nt. 

N o v arti s 
C o nfi d e nti al 
P a g e 7 7 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
I n t he e ve nt of Gra de 2, Gra de 3 or Gra de 4 he mat ol o gical t o xicities t hat re q uire st u d y dr u g 
d ose  m o dificati o ns  or  i nterr u pti o ns,  he mat ol o gical  tests  s h o ul d   be  re peate d  wee kl y  u ntil 
rec o ver y t o t he baseline val ue or Gra de 1. 
7. 2. 2. 4. 2 Cli ni c al c h e mi str y 
Ser u m c he mistr y tests are t o be perf or me d acc or di n g t o t he Visit Sc he d ules o utli ne d i n Ta ble 
7- 1 . F or details of t he bi oc he mistr y pa nel refer t o Ta ble 7- 3 . 
Ser u m c he mistr y s h o ul d be perf or me d at scree ni n g, o n treat me nt Da y 1 (re peate d pri or t o 
a d mi nistrati o n of t he st u d y dr u g, if greater t ha n 7 da ys pri or t o Da y 1), C ycle 1 Da y 1 5, 
C ycle 2 Da y 1 a n d Da y 1 5 a n d Da y 1 of eac h s u bse q ue nt c ycle a n d  at E n d of treat me nt. 
I n t he e ve nt of Gra de 2, Gra de 3 or Gra de 4 n o n- he mat ol o gical to xicities t hat re q uire st u d y 
dr u g d ose m o dificati o ns or i nterr u pti o ns, bi oc he mistr y tests s h o ul d be re peate d wee kl y u ntil 
rec o ver y t o t he baseline val ue or Gra de 1. 
N ote: I n t he p hase III st u d y M o na L E Esa- 2 t he maj orit y ( 8 3. 8 %; 3 1/ 3 7) of t he gra de 3/ 4 
A L T a n d A S T i ncreases wit h t he c o m bi nati o n t hera p y occ urre d d ur i n g t he first 6 m o nt hs of 
treat me nt. T he me dia n ti me-t o- o nset of gra de ≥ 3 A L T/ A S T ele vatio n was 5 7 da ys a n d 6 2 
da ys,  res pecti vel y  ( base d  u p o n  me dia ns  of  patie nts  wit h  e ve nts) .  T he  me dia n  ti me  t o 
res ol uti o n (t o n or malizati o n or gra de < 3) (a gai n base d u p o n me dia ns of patie nts wit h e ve nts) 
was 2 4 da ys i n t he ri b ocicli b pl us letr oz ole treat me nt gr o u p vs. 1 9 da ys f or t he place b o pl us 
letr oz ole gr o u p. 
I n t his st u d y, la b orat or y val ues will be perf or me d at t he be gi n ni n g of eac h c ycle t o ass ure 
t hat L F T a b n or malities will be a p pr o priatel y ca pt ure d wit h t his m o nit ori n g sc he d ule. 
7. 2. 2. 4. 3 S er u m li pi d pr ofil e 
Ser u m li pi d tests are t o be perf or me d acc or di n g t o t he Visit Sc he d ules o utli ne d i n Ta ble 7-
1 . F or details of t he li pi d pa nel refer t o Ta ble 7- 3.  
A  ser u m  li pi d  pr ofile  assess me nt  acc or di n g  t o  l ocal  sta n dar d  s h o ul d  be  perf or me d  at 
scree ni n g a n d as cli nicall y i n dicate d. 
I n t he e ve nt of Gra de 2, Gra de 3 or Gra de 4 t o xicities ser u m lipi d tests s h o ul d be re peate d 
wee kl y u ntil rec o ver y t o t he  baseli ne val ue or Gra de 1.  
7. 2. 2. 4. 4 Uri n al y si s 
Uri nal ysis  is  t o  be  perf or me d  at  Scree ni n g/ Baseli ne  acc or di n g  t o  l ocal  sta n dar d  a n d  as 
cli nicall y i n dicate d ( di pstic k a nal ysis is s ufficie nt).  
7. 2. 2. 4. 5 Pr e g n a n c y a n d a s s e s s m e nt s of f ertilit y 
F or pre- or peri me n o pa usal patie nts, a ser u m or uri ne pre g na nc y  tests ( patie nts w h o ha ve 
u n der g o ne  a  h ysterect o m y  d o  n ot  nee d  pre g na nc y  tests  perf or me d)  are t o be perf or me d 
acc or di n g t o t he Visit Sc he d ules o utli ne d i n Ta ble 7- 1 . At scree ni n g, a ser u m pre g na nc y test 
s h o ul d  be  perf or me d  f or  pre-  a n d  peri me n o pa usal  patie nts,  re gardless of t he a ge of t he 
patie nts, w hile at baseli ne, d uri n g t he st u d y, a n d at t he e n d o f trial, uri nar y pre g na nc y tests 
are  s ufficie nt.  Si m ulta ne o usl y,  F S H  a n d/ or  estra di ol  s h o ul d  be meas ure d  t o  e ns ure 
p ost me n o pa usal stat us. 

N o v arti s 
C o nfi d e nti al 
P a g e 7 8 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
7. 2. 2. 5  
C ar di a c a s s e s s m e nt s  
7. 2. 2. 5. 1 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 after t he patie nt has bee n resti n g f or 5- 1 0 mi n 
pri or t o eac h ti me p oi nt i n dicate d i n Ta ble 7- 4  bel o w. Traci n gs m ust be date d a n d si g ne d b y 
t he i n vesti gat or ( or his/ her desi g nee) a n d file d wit h t he patient’s s o urce d oc u me ntati o n. Q Tc 
i nter vals s h o ul d be calc ulate d acc or di n g t o Fri dericia. Eac h E CG 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 n 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 E C G a b n or malities prese nt at screeni n g 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 e C R F pa ge. Ne w or w orse ne d 
cli nicall y  si g nifica nt  fi n di n gs  occ urri n g  after  i nf or me d  c o nse n t  m ust  be  rec or de d  o n  t he 
A d verse E ve nts e C R F pa ge E C G ma 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 a n d as cli nicall y i n dicate d; a n y cli nicall y rele va nt fi n di n gs s h o ul d be 
a d de d t o t he A d verse E ve nts e C R F. 
T a bl e 7- 4  
E C G c oll e cti o n pl a n 
C y cl e 
P ati e nt s  
D a y  
Ti m e 
S cr e e ni n g  
All 
- 7 t o - 1  
A n yti m e 
1 
All 
D a y 1 5  
A n yti m e 
2 
All 
D a y 1  
A n yti m e 
A ll 
D a y 1 5 
A n yti m e 
3- 6 
All 
D a y 1  
A n yti m e 
All ot h er c y cl e s 
P ati e nt s  wit h  Q T c F  ≥ 
4 8 1  m s  at  a n y  ti m e 
pri or t o c y cl e 7 
D a y 1  
A n yti m e 
E O T 
A n yti m e 
U n s c h e d ul e d E C G 
A n yti m e 
 
If a n y of t he rea di n gs i ncl u de a n a b n or mal E C G or a n a vera ge Q Tc F val ue of ≥ 4 8 1 ms is 
o btai ne d at a n y ti me after e nr oll me nt i n t he st u d y, treat me nt m ust be i nterr u pte d, re peat E C G 
a n d f oll o w ma na ge me nt g ui deli nes detaile d i n Ta ble 6- 5.  
 
7. 2. 3  
Bi o m ar k er s 
T his  cli nical  st u d y  i ncl u des  ma n dat or y  bi o mar ker  c o m p o ne nts  t ha t  are  s u p p orte d  b y  a n 
e x pl orat or y  o bjecti ve. 
 
 
 
 
 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 7 9 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
T a bl e 7- 5  
Bi o m ar k er s a m pl e c oll e cti o n pl a n  
S a m pl e T y p e 
V ol u m e 
Vi sit 
Ti m e p oi nt 
T u m or s a m ples 
t u m or bl oc k of t he pri mar y 
t u m or a n d t he re- bi o ps y u p o n 
metastatic pr o gressi o n/ 
rec urre nce, if a vaila ble  
N/ A  
 
Scree ni n g 
 
 
Da y - 2 1 t o Da y 1 
Bl o o d s a m ples  
Bl o o d  f or  bi o mar ker  a nal ysis 
( ma n dat or y) 
6 0 m L  
C ycle 1 Da y 1 
Pre- d ose 
6 0 m L  
C ycle 1 Da y 1 5 
A n yti me 
6 0 m L  
C ycle 4 Da y 1 
Pre- d ose 
6 0 m L  
E n d of treat me nt  
A n yti me 
 
 
 
 
 
 
T u m or tiss ue  
T u m or tiss ue sa m ples will be c ollecte d i n t his trial f or i de nti f yi n g bi o mar kers  
 
. It is hi g hl y rec o m me n de d t hat a n arc hi val F F P E bl oc k 
of t he i nitial t u m or a n d of a metastatic lesi o n (if a vaila ble, preferre d) is pr o vi de d. Recei pt 
of t u m or tiss ue will n ot dela y e nr oll me nt. All s peci me ns will b e se nt t o a N o vartis desi g nate d 
la b orat or y f or a nal ysis. F urt her details o n pre parati o n of t he t u m or bi o psies a n d bi o mar ker 
a nal ysis will be pr o vi de d i n t he  La b orat or y Ma n ual.
 
 
 
 
 
 
P h ar m ac o ge netics  
P har mac o ge netics  is  a ble  t o  pr o vi de  ge netic  mar kers  t hat  c o ul d pre dict  t he  pr o g n osis  of 
breast ca ncer patie nts ( Azzat o et al., 2 0 1 0; Fa ger h ol m et al., 2 0 0 8; Sc hr ot h et al., 2 0 0 9), b ut 
als o  t he  t o xicit y  of  treat me nts  s uc h  as  ar o matase  i n hi bit or  t hera p y  (I n gle  et  al.,  2 0 1 0). 
F urt her m ore,  t here  is  e vi de nce  t hat  -  wit hi n  a n  i n di vi d ual  -  a t u m or  will  e x hi bit  disti nct 
m olec ular  patter ns  base d  o n  its  ger mli ne  ge netic  ma ke u p.  ( Garci a- Cl osas  et  al.,  2 0 0 8; 
Ree ves at al., 2 0 1 0) 
T he direct i n v ol ve me nt of ge netic mar kers i n t he meta b olis m a n d  t he p har mac o ki netics of a 
dr u g, t he i nfl ue nce of t he i n herite d ge netic trait o n t he m olec ular pr ofile of t he t u m or a n d 
t he ac q uire d t u m or m utati o ns c o ul d ha ve a n i nfl ue nce o n a n i n divi d ual’s pr o g n osis.  
 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 8 0 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 

N o v arti s 
C o nfi d e nti al 
P a g e 8 1 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
D et ail s r e g ar di n g a d dr e s s e s of s hi p m e nt s, c arri er r e c o m m e n d ati o n s, 
l a b eli n g of t h e p ar c el s, d a ys of s hi p m e nt s, c o nt a ct d et ail s a n d  ot h er 
s a m pl e s l o gi sti c s will b e pr o vi d e d i n a s e p ar at e d l a b or at or y m a n u al. 
 
  
 
 
 
e 
 
 
  
 
 
 
 
 
7. 2. 3. 1. 2 Ot h er a s s e s s m e nt s 
N o a d diti o nal tests will be perf or me d o n patie nts e ntere d i nt o t his st u d y. 
7. 2. 4  
P ati e nt r e p ort e d o ut c o m e s 
T he f oll o wi n g q uesti o n naires will be use d t o assess t he healt h relate d q ualit y of life: E O R T C 
Q L Q- C 3 0 a n d t he breast m o d ule B R 2 3.  
All q uesti o n naires will be c o m plete d o n Da y 1 at e ver y c ycle u n til C 1 3 a n d e ver y 1 2 wee ks 
t hereafter u ntil safet y f oll o w u p. 
C o m plete d  q uesti o n naires,  i ncl u di n g  b ot h  res p o nses  t o t he  q uest i o ns  a n d  a n y  u ns olicite d 
c o m me nts  writte n  b y  t he  patie nt,  m ust  be  re vie we d  a n d  assesse d b y  t he  i n vesti gat or  f or 
res p o nses w hic h ma y i n dicate p ote ntial A Es or S A Es. T his re vie w s h o ul d be d oc u me nte d 
i n t he st u d y s o urces.  

N o v arti s 
C o nfi d e nti al 
P a g e 8 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
If a n A E or S A E is c o nfir me d t he n t he i n vesti gat or s h o ul d rec or d t he e ve nt as i nstr ucte d i n 
Secti o n 8 of t his pr ot oc ol. I n vesti gat or s h o ul d n ot e nc o ura ge t he patie nts t o c ha n ge res p o nses 
re p orte d i n q uesti o n naires.   
U p o n ra di ol o gic pr o gressi o n acc or di n g t o R E CI S T 1. 1 treat me nt wit h st u d y dr u g ma y be 
c o nti n ue d at t he discreti o n of t he i n vesti gat or u ntil a cli nica ll y s y m pt o matic pr o gress occ urs. 
I n t his case, t he q ualit y of life q uesti o n naires m ust be c o m plete d acc or di n g t o Visit sc he d ule. 
If ra di ol o gic pr o gressi o n occ urs, bef ore C ycle 1 3 m o nt hl y a n d after C ycle 1 3 e ver y 1 2 wee ks 
u ntil s y m pt o matic pr o gressi o n or E n d of st u d y as well as u p o n s y m pt o matic pr o gressi o n.  
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 y m pt o m(s), or me dical c o n diti o n(s) t hat o cc 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  i n d uce  cli nical  si g ns  or  s y m pt o ms, are  c o nsi dere d  cli nicall y 
si g nifica 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 or se 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  t he  Me dical  Hist or y  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 ys ( or 5 half-li ves, w hic he ver is l o n ger) 
f oll o wi n g t he last d ose of 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 yi n g  si g ns  a n d  s y m 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 y m pt o m s h o ul d be re p orte d as a se parate A d verse E ve nt. 
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. If C T C A E gra di n g d oes n ot e xist 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, c orres p o n di n g t o Gra des 
1 - 4, will be use d. C T C A E Gra de 5 ( deat h) will n ot be use d i n t his st u d y If deat h is n ot 
ca use d b y pr o gressi o n of t he disease, it has t o be re p orte d as S A E o n t he S A E re p ort f or m. 
A d verse e ve nts wit h deat h as o utc o me m ust be d oc u me nte d as S A E o n t he S A E re p ort f or m. 
T he  occ urre nce  of  a d verse  e ve n ts  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 uri n g t he scr ee ni n g pr ocess after si g ni n g i n f 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 ma y be detecte d w he n t he y are v ol u nteere d b y 
t he  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: 
 T he se verit y gra de ( C T C A E Gra de 1- 4). 
 Its d urati o n ( Start a n d e n d dates). 
 Its relati o ns hi p t o t he st u d y dr u g ( Yes or N o).   

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 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 ( n o ne, d ose a dj uste d, 
te m p oraril y i nterr u pte d, per ma ne ntl y disc o nti n ue d, u n k n o w n, n ot  a p plica ble). 
 W het her  dia g n ostics,  me dicati o n  wit h  w hic h  d osa ges  or  t hera p y  t a ke 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). 
 Setti n g: i n or o ut patie nt treat me nt. 
 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 ve ri 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). 
 W het her it is seri o us, w here a seri o us a d verse e ve nt ( S A E) is d efi ne d as i n Secti o n 
8. 2. 
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 m ita nt me dicati o n or n o n- dr u g 
t hera p y 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 verit y, t he s us pecte d relati ons 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. 
Pr o gressi o n of mali g na nc y (i ncl u di n g fatal o utc o mes), , s h o ul d n ot be re p orte d as a seri o us 
a d verse e ve nt. 
A d verse  e ve nts  se parate  fr o m  t he  pr o gressi o n  of  mali g na nc y  (e xa m ple,  dee p  vei n 
t hr o m b osis  at  t he  ti me  of  pr o gressi o n  or  he m o pt ysis  c o nc urre nt wit h  fi n di n g  of  disease 
pr o gressi o n)  will  be  re p orte d  as  per  us ual  g ui deli nes  use d  f or s uc h  e ve nts  wit h  pr o per 
attri b uti o n re gar di n g re late d ness t o t he dr u g. 
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 a b n or malities t hat c o nstit ute a n A d verse e ve nt i n t h eir o w n ri g ht (are c o nsi dere d 
cli nicall y  si g nifica nt,  i n d uce  cli nical  si g ns  or  s y m pt o ms,  re q u ire  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 y m 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).  La b orat or y  a b 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 
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 y m pt o m of a n alrea 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 a b 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 (se vere) or 4 (life-t hreate ni n g) e ve nt as per C T C A E 
d oes n ot a ut o maticall y i n dicate a S A E u nless it meets t he defi n iti o n of seri o us as defi ne d 
bel o w  a n d/ or  as  per  i n vesti gat o r’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 t he pr ot oc ol i n w hic h case t he la b a b n or malit y w o 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: 

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O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 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 dicall y 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 : H os pitalizati o ns f or t he foll o wi n g reas o ns s h o ul d n ot be re p o rte 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 ng 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 : 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 n iti o ns of a S A E 
gi ve n a b o ve is n ot a ser i o us a d verse e ve nt. 
Pr ot oc ol e xe m pt S A Es 
S A Es s pecificall y defi ne d i n t he pr ot oc ol a n d w here t here has b ee n a clear a gree me nt wit h 
re g ulat ors  n ot  t o  c ollect  t hese  S A Es  i n  t he  safet y  data base,  pro vi de d  t he  i nf or mati o n  is 
c ollecte d  else w here.  I n  t his  e x isti n g  pr ot oc ol,  pr o gressi o n  of mali g na nc y  (i ncl u di n g 
pr o gressi o n of mali g na nc y wit h fatal o utc o me). 
8. 2. 2  
R e p orti n g 
T o e ns ure patie nt safet y, e ver y S A 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 3 0 da ys after t he patie nt has st o p pe d st u d y 
dr u g m ust be re p orte d t o N o va rtis wit hi n 2 4 h o urs of lear ni n g of its occ urre nce.  
A n y S A Es e x perie nce d after t his 3 0- da y 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 (ri b ocicli b, letr oz ole a n d/ or 
g osereli n).   
Rec urre nt e pis o des, c o m plicati o ns , or pr o gressi o n of t he i nitial S A E 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, re gar dless of w he n t he e ve nt occ urs.  T his re p ort m ust be 
s u b mitte d 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 
t hat  is  c o nsi dere d  c o m pletel y  u nrelate d  t o  a  pre vi o usl y  re p orted  o ne  s h o ul d  be  re p orte d 
se paratel y as a ne w e ve 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 must assess a n d rec or d t he re lati 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 se n d t he c o m plete d, si g ne d f or m b y fa x wit hi n 2 4 h o urs t o t he 
o nc ol o g y N o vartis Patie nt  Safet y de part me nt. 
T he tele p h o ne a n d telefa x n u m ber of t he c o ntact pers o ns i n t he l ocal de part me nt of N o vartis 
Patie nt Safet y, s pecific t o t he s ite, are liste d i n t he i n vestigat or f ol der pr o vi de d t o eac h site. 

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Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
T he ori gi nal c o p y of t he S A E Re p ort F or m a n d t he fa x c o nfir mati o n s heet m ust be ke pt wit h 
t he case re p ort f or m d oc u me ntati o n at t he st u d y site. 
F oll o w- u p i nf or mati o n is se nt t o t he sa me c o ntact(s) t o w h o m t h e ori gi nal S A E Re p ort F or m 
was se nt, usi n g a ne w S A E Re p ort F or m stati n g t hat t his is a f o ll o w- u p t o t he pre vi o usl y 
re p orte d S A E a n d gi vi n g t he date of t he ori gi nal re p ort. Eac h r e- 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 o ll 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 h et 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, a n d w het her t he patie n t c o nti n ue d or wit h dre w fr o m 
st u d y partici pati o n. 
A n  S A E  t hat  is  c o nsi dere d  c o m plet el y  u nrelate 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. 
If t he S A E is n ot pre vi o usl y d oc 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 
N o vartis Patie nt Safet y de part me nt ass ociate ma y ur ge ntl y re q ui re 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 orit y 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 u lat or y  re q uire me nts  i n 
partici pati n g c o u ntries. 
8. 3  
Pr e g n a n ci e s 
T o e ns ure patie nt safet y, eac h pre g na nc y occ urri n g w hile t he pa tie nt is o n st u d y treat me nt 
m ust be re p orte d t o N o vartis w it hi n 2 4 h o urs of lear ni n g of its occ urre nce. T he pre g na nc y 
s h o ul d  be  f oll o we d  u p  t o  deter mi ne  o utc o me,  i ncl u di n g  s p o nta ne o us  or  v ol u ntar y 
ter mi nati o n, details of t he birt h, a n d t he prese nce or a bse nce of a n y birt h defects, c o n ge nital 
a b n or malities, or mater nal a n d/ or ne w b or n c o m plicati o ns. 
Pre g na nc y  s h o ul d  be  rec or de d  o n a  Cli nical  Trial  Pre g na nc y  F or m   a n d  re p orte d  b y  t he 
i n vesti gat or  t o  t he  o nc ol o g y  N o vartis  Patie nt  Safet y.  Pre g na nc y  f oll o w- u p  s h o ul d  be 
rec or de d o n t he sa me f or m a n d sh o ul d i ncl u de a n assess me nt of t he p ossi ble relati o ns hi p t o 
t he st u d y treat me nt a n y pre g na ncy o utc o me. A n y S A E e x perie nce d d uri n g pre g na nc y m ust 
be re p orte d o n t he S A E Re p ort F or m. 
8. 4  
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 n vesti gat or Br oc h ure. A d diti o nal safet y i nf 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 n vesti gat or N otificati o ns. T his i n f 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 h e patie nt d uri n g t he st u d y as 
nee de d. 
8. 5  
St e eri n g C o m mitt e e 
A St u d y Steeri n g C o m mittee ( S S C) will be c o nstit ute d t o o versee  t he c o n d uct of t he st u d y 
a n d  ma ki n g  a n y  necessar y  rec o m me n dati o ns  as  nee de d.  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 

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Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
a p pr o priate. 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. 
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 s u bjects 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 use 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 ollected  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 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 safet y i nf or mati o n (e. g. 
has t he s u bject e x perie nce d a n y 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 y pt 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  ac cess  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. 
9. 2  
Sit e m o nit ori n g 
Bef ore  st u d y  i nitiati o n,  at  a  site   i nitiati o n  visit  or  at  a n  i nvesti 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  Practi ce,  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 din g  t o  s pecificati o ns.  Ke y 
st u d y pers o n nel m ust be a vaila ble t o assist t he fiel d m o nit or duri 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 n t 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 d ata, 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 p y is gi ve n t o t he patie nt). 
T he i n vesti gat or m ust gi ve t he  m o nit or access t o all rele va nt so 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  entries.  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 me 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 n it ori n g pla n. 

N o v arti s 
C o nfi d e nti al 
P a g e 8 7 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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  t he  pr ot oc ol  i nt o  t he 
Electr 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 ull y  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 quire me nts, I n vesti 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. 
T he  Pri nci pal  I n vesti gat or  is  re s 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. 
A ut o matic vali dati o n pr oce d ures wit hi n t he s yste m c hec k f or dat a discre pa ncies d uri n g a n d 
after  data  e ntr y  a n d,  b y  ge nerati n g  a p pr o priate  err or  messa ges,   all o w  t he  data  t o  be 
c o nfir me d or c orrecte d o nli ne b y  t he desi g nate d i n vesti gat or site staff. T he I n vesti gat or m ust 
certif y t hat t he data e ntere d i nt o t he electr o nic Case Re p ort F or ms are c o m plete a n d acc urate. 
After data base l oc k, t he i n vesti gat or will recei ve c o pies of t h e patie nt data f or arc hi vi n g at 
t he i n vesti gati o nal site. 
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 nt ere d b y i n 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 staff 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 to 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 d ata 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 herape 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 ( M e d D R A) ter mi n ol o g y. 
T he occ urre nce of rele va nt pr ot oc ol de viati o ns will be deter mi n e d. After t hese acti o ns ha ve 
bee n c o m plete d a n d t he data base has bee n declare d t o be c o m plet e a n d acc urate, it will be 
l oc ke d a n d ma de a vaila ble f or data a nal ysis. A n y c ha n ges t o t he data base after t hat ti me ca n 
o nl y be ma de b y j oi nt writte n a gree me nt bet wee n t he Trial Statisticia n a n d t he T hera pe utic 
Area Hea d. 
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 
T he st u d y is desi g ne d as a n o pe n- la bel, si n gle-ar m, p hase III B trial t o assess t he efficac y 
a n d safet y of ri b ocicli b pl us letr oz ole i n w o me n wit h h or m o ne r ece pt or p ositi ve a d va nce d 
breast ca ncer. 
T he data will be a nal yze d b y N o vartis a n d/ or desi g nate d C R O. A n y data a nal ysis carrie d 
o ut i n de pe n de ntl y b y t he 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. It is pla n ne d t hat  t he data fr o m partici pati n g centers i n t his pr ot oc ol 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 will be a vaila ble f or a nal ysis. 
T he  data  will  be  s u m marize d  wit h  res pect  t o  de m o gra p hic  a n d  bas eli ne  c haracteristics, 
efficac y  o bser vati o ns  a n d  meas ure me nts,  safet y  o bser vati o ns.  T h e  pri mar y  efficac y  a n d 
safet y  a nal ysis  will  be  c o n d ucte d o n  all  patie nt data  at t he  ti me all patie nts w h o are still 
recei vi n g st u d y dr u g will ha ve c o m plete d at least 2 4 wee ks of treat me nt ( or disc o nti n ue d 
pre mat urel y). T he a d diti o nal data f or a n y patie nts c o nti n ui n g t o recei ve st u d y dr u g past t hese 

N o v arti s 
C o nfi d e nti al 
P a g e 8 8 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
ti mes, as all o we d b y t he pr ot oc ol, will be f urt her s u m marize d in a re p ort o nce t hese patie nts 
c o m plete t he st u d y. 
I n ge neral, cate g orical varia bles will be s u m marize d b y a bs ol ute a n d relati ve fre q ue ncies. 
C o nti n u o us  varia bles  will  be  s u m marize d  b y  descri pti ve  statisti cs  ( n u m ber  of  vali d  a n d 
missi n g o bser vati o ns, mea n, sta n dar d de viati o n, mi ni m u m, me dia n  a n d ma xi m u m). Ti me-
t o-e ve nt data i ncl u di n g rates of affecte d patie nts will be assesse d usi n g t he Ka pla n- Meier 
met h o d.  T he  pri mar y  ai m  of  t his  trial  is  i n  esti mati o n  rat her  t ha n  si g nifica nce  testi n g  of 
statistical h y p ot heses. T h us, mainl y statistical esti mat ors al o n g wit h a p pr o priate t w o-si de d 
9 5 % c o nfi de nce i nter vals will be use d. H o we ver, c ha n ges fr o m baseli ne ma y be e x pl ore d 
usi n g s uita ble statis tical tests f or paired sa m ples. N o a dj ust m e nt f or m ulti plicit y is f oresee n 
d ue t o t he e x pl orat or y n at ure of t he trial. 
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 ysis  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. Patie nts will be a nal yze d acc or di n g t o t he treat me nt t he y ha ve bee n assi g ne d t o. 
1 0. 1. 2  
S af et y S et 
T he  Safet y  Set  i ncl u des  all  patie nts  w h o  recei ve d  at  least  o ne d ose  of  st u d y  me dicati o n. 
Patie nts will be a nal yze d acc or di n g t o t he st u d y treat me nt (re g i me n) t he y act uall y recei ve d. 
A precise defi niti o n of “act uall y recei ve d” will be a d de d i n t h e R A P. 
1 0. 1. 3  
P er- Pr ot o c ol S et 
T he Per- Pr ot oc ol Set ( P P S) c o nsists of a s u bset of t he patie nts  i n t he F A S w h o are c o m plia nt 
wit h re q uire me nts of t he C S P. T he P P S ma y be a nal yse d i n case a  s u bsta ntial n u m ber of 
patie nts was n ot c o m plia nt wit h re q uire me nts of t he C S P. 
O nc ol o g y sta n dar ds f or pr ot oc ol de viati o ns p ote nti all y  lea di n g t o e xcl usi o n fr o m t he P P S 
are  
 t y pe of i n dicati o n differe nt fr o m t h ose re q uire d b y t he C S P (e.g., i nc orrect 
hist ol o g y/c yt ol o g y, n ot refract or y, n ot metastatic, differe nt g ra de of ca ncer, etc.) 
 if pri or t hera p y d oes n ot matc h wit h C S P re q uire me nts i n ter ms of n u m ber a n d t y pes of 
pre vi o us t hera p y re gi me ns 
 missi n g or i nc o m plete d oc u me ntati o n of sta ge of disease (as re q uire d i n t he C S P) 
 if E C O G perf or ma nce stat us at least 1 cate g or y w orse t ha n pr ot o c ol- defi ne d i ncl usi o n 
criteria 
 a n ot her a nti- ne o plastic t hera p y a d mi nistere d after start of st u d y treat me nt a n d pri or t o 
first t u m or assess me nt 
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 
De m o gra p hic a n d ot her baseli ne c haracteristics will be s u m mariz e d f or t he F ull A nal ysis 
Set  ( F A S).  Baseli ne  c haracteristics  i ncl u de  pri or  me dicati o n,  p ast/c urre nt  me dical 
c o n diti o ns a n d disease hist or y. C ate g orical varia bles will be s u m marize d b y a bs ol ute a n d 
relati ve  fre q ue ncies.  C o nti n u o us  varia bles  will  be  s u m marize d  by  descri pti ve  statistics 
( n u m ber of  vali d a n d missi n g o bser vati o ns, mea n, sta n dar d de viati o n, mi ni m u m,  me dia n 

N o v arti s 
C o nfi d e nti al 
P a g e 8 9 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
a n d  ma xi m u m,  2 5 t h a n d 7 5t h  perce ntiles).  Ti me-t o-e ve nt  data  i ncl u di n g  rates  of  affecte d 
patie nts will be assesse d usi n g t he Ka pla n- Meier met h o d. 
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) 
D urati o n ( da ys) of dr u g e x p os ure will be s u m marize d usi n g descr i pti ve statistics se paratel y 
f or  ri b ocicli b,  letr oz ole  ( or  g osereli n),  res pecti vel y.  D urati o n  of  dr u g  e x p os ure  will  be 
calc ulate d as t he differe nce bet wee n t he last a n d first da y of dr u g a p plicati o n + 1. D osa ge 
a vera ges  will  be calc ulate d  i ncl u di n g  a n d  e xcl u di n g  zer o  d oses f or  peri o ds  of  te m p orar y 
i nterr u pti o n of treat me nt re gar dless of w het her t his was d ue t o  safet y reas o ns or patie nts’ 
n o n-c o m plia nce. A vera ge dail y d ose le vels will be s u m marize d de scri pti vel y. Fre q ue ncies 
of t he n u m ber of patie nts wit h a n y d ose re d ucti o n (i ncl u di n g te m p orar y d ose i nterr u pti o n) 
as well as t he n u m ber of d ose re d ucti o ns b y reas o n will be gi ve n. T hese a nal yses will be 
perf or me d f or t he safet y set. 
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 o r t o a n d after t he start of 
t he st u d y dr u g will be c o de d acc or di n g t o t he W H O Dr u g Refere nce List a n d s u m marize d 
b y A T C class a n d preferre d ter m us i n g fre q ue nc y distri b uti o ns. 
1 0. 4  
Pri m ar y o bj e cti v e 
T he pri mar y o bjecti ve of t his st u d y is t he assess me nt of t he cl i nical be nefit rate f or t he t otal 
p o p ulati o n a n d f or c o h orts A a n d B se paratel y: 
 T o  assess  t he  cli nical  be nefit  rate  ( C B R)  after  2 4  wee ks  f or  ri b ocicli b  ( L E E 0 1 1)  i n 
c o m bi nati o n  wit h  letr oz ole  a m o n g  p ost me n o pa usal  w o me n  a n d  me n  w it h  h or m o ne 
rece pt or  p ositi ve,  H E R 2-  ne gati ve,  a d va nce d  breast  ca ncer  w h o  recei ve d  n o  pri or 
treat me nt f or a d va nce d disease( C o h ort A). 
 T o  assess  t he  cli nical  be nefit  rate  ( C B R)  after  2 4  wee ks  f or  ri b ocicli b  ( L E E 0 1 1)  i n 
c o m bi nati o n wit h letr oz ole a n d g osereli n a m o n g pre-, a n d peri me n o pa usal w o me n w h o 
recei ve d  n o  pri or  treat me nt  f or  a d va nce d  disease  as  well  as  pre-, peri- a n d 
p ost me n o pa usal  w o me n  a n d  me n  wit h  h or m o ne  rece pt or  p ositi ve,  H E R 2-  ne gati ve, 
a d va nce d breast ca ncer w h o recei ve d n o m ore t ha n 1 pri or c he m ot hera p y a n d 2 pri or 
li nes of e n d ocri ne t hera p y f or a d va nce d disease ( C o h ort B). 
1 0. 4. 1  
V ari a bl e 
T he 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 o nfir me d c o m plete ( C R) or partial ( P R) res p o nse or sta ble d isease ( S D) or n o n-c o m plete 
res p o nse, n o n- pr o gressi ve disease ( N C R N P D) b y Wee k 2 4. 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  i n vesti gat or  o v erall  lesi o n  res p o nses 
acc or di n g  t o  R E CI S T  1. 1.  T o  be  assi g ne d  a  best  o verall  res p o nse   of  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 are re q uire d. T o be assi g ne d 
a best o verall res p o nse of 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 ualif yi n g f or a C R) are re q uire d. T o be assi g ne d a sta ble 
disease, t w o deter mi nati o ns of S D at least 1 2 wee ks a part (a n d n ot q ualif yi n g f or P R or P D) 
are re q uire d.  
F or  f urt her  details,  please  refer  t o  A p pe n di x  1 4- 2:  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 vera ll  S ur vi val  ( base d  o n 
R E CI S T 1. 1). 

N o v arti s 
C o nfi d e nti al 
P a g e 9 0 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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 
I n t his si n gle-ar m trial, t he pri mar y o bjecti ve is t o esti mate t he C B R. T heref ore, n o statistical 
h y p ot hesis or m o del is u n de rl yi n g t he a nal ysis. 
T he  C B R  ( best  o verall  res p o nse  of  C R  or  P R  or  S D  or  N C R N P D)  as  well  as  i n di vi d ual 
res p o nse cate g ories ( C R, P R, S D, P D, N C R N P D or u n k n o w n) will be s u m marize d usi n g 
fre q ue nc y ta bles t o get her wit h t heir ass ociate d t w o-si de d e xact 9 5 % c o nfi de nce i nter vals 
( Cl o p per- Pears o n  met h o d).  T he  F ull  A nal ysis  Set  will  be  use d  f or  t he  pri mar y  efficac y 
a nal ysis. 
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 
Si nce t he defi niti o n of t he pri mar y  varia ble is deri ve d fr o m t u m or assess me nts base d o n 
R E CI S T  1. 1  criteria,  t hese  criteria  a p pl y  f or  t he  ha n dli n g  of  m issi n g  val ues  i n  t u m or 
assess me nts. 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 (see P ost-
te xt s u p ple me nt 1). If t he e val uati o n of a n y of t he tar get or n o n-tar get lesi o ns i de ntifie d at 
baseli ne c o ul d n ot be ma de d uri n g f oll o w- u p, t he o verall stat us m ust be ‘ u n k n o w n’ u nless 
pr o gressi o n was see n. Patie nts w it 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 de rs’  b ut  will  be  i ncl u de d  i n  t he  de n o mi nat or  f or  t he 
calc ulati o n of t he O R R f or t he F A S. 
1 0. 4. 4  
S u p p orti v e a n al y s e s 
C B R b y Wee k 2 4 will be a d diti o nall y prese nte d f or t he Per- pr ot o c ol Set. F urt her m ore, t he 
C B R ma y be s u m marize d b y s u b gr o u ps f or t he F A S a n d P P set, res p ecti vel y. 
1 0. 5  
S e c o n d ar y o bj e cti v e s 
1 0. 5. 1  
Effi c a c y ( s e c o n d ar y) 
T he f oll o wi n g sec o n dar y efficac y varia bles will be a nal yze d i n a n e x pl orati ve ma n ner f or 
t he f ull a nal ysis set ( F A S): C B R s u b gr o u ps, O R R b y Wee k 2 4, Pr ogressi o n-free s ur vi val 
( P F S) a n d o verall sur vi val ( O S). 
C B R S u b gr o u p s 
 T o  assess  t he  cli nical  be nefit  rate  ( C B R)  after  2 4  wee ks  f or  ri b ocicli b  ( L E E 0 1 1)  i n 
c o m bi nati o n wit h letr oz ole a n d g osereli n a m o n g pre- a n d peri me n o pa usal w o me n w h o 
recei ve d n o pri or treat me nt f or a d va nce d disease. 
 T o  assess  t he  cli nical  be nefit  rate  ( C B R)  after  2 4  wee ks  f or  ri b ocicli b  ( L E E 0 1 1)  i n 
c o m bi nati o n  wit h  letr oz ole  (a n d  g osereli n)  a m o n g  pre-,  peri-  a n d  p ost me n o pa usal 
w o me n a n d me n w h o recei ve d pri or t reat me nt f or a d va nce d disease.  
O R R b y W e e k 2 4 
T he  O R R  b y  Wee k 2 4  will  be  deri ve d  fr o m  t he  se q ue nce  of  o verall   lesi o n  res p o nses  as 
descri be d f or t he pri mar y efficac y varia ble. T he O R R b y Wee k 2 4  will be s u m marize d usi n g 
fre q ue nc y  ta bles  prese nti n g  a bs ol ute  a n d  relati ve  fre q ue ncies  to get her  wit h  a p pr o priate 
c o nfi de nce i nter vals. 

N o v arti s 
C o nfi d e nti al 
P a g e 9 1 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Pr o gr e s si o n-fr e e s ur vi v al 
Pr o gressi o n-free s ur vi val ( P F S) is t he ti me fr o m date of 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. Disease pr o gressi o n f or pri mar y efficac y e n d p oi nt d eri 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. P F S will be 
s u m marize d usi n g t he Ka pla n- Meier met h o d. Perce ntiles ( 2 5 %, me dia n, 7 5 %) of t he e ve nt 
ti me  distri b uti o n  will  be  prese nte d  al o n g  wit h  t heir  t w o-si de d 9 5 %  c o nfi de nce  i nter val. 
A d diti o nall y,  Ka pla n- M eier  esti mates  f or  t he  pr o p orti o ns  of  pat ie nts  pr o gressi o n-free  b y 
Wee k 4 8  a n d  Wee k 7 2  will  be  prese nte d.  T he  Ka pla n- Meier  c ur ve  w ill  be  dis pla ye d 
gra p hicall y. 
O v er all s ur vi v al 
O verall s ur vi val ( O S) is defi ne d as t he ti me fr o m date of 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 ve die d, s ur vi val will be ce ns ore d at t he date 
of last c o ntact. O S will be s u m marize d usi n g t he Ka pla n- Meier m et h o d as descri be d a b o ve. 
T he  Ka pla n- Meier  c ur ve  will  be  dis pla ye d  gra p hicall y.  A d diti o na ll y,  t he  pr o p orti o n  of 
patie nts ali ve at 4 8 a n d 9 6 w ee ks will be prese nte d 
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 
T he assess me nt of safet y will be base d mai nl y o n 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 that fall o utsi de of pre- deter m i ne d ra n ges. Ot her safet y data 
(e. g. vital si g ns, a n d s pecial tests) will be c o nsi dere d as a p pr o priate. F or all safet y a nal yses, 
t he safet y set will be use d. 
All  listi n gs a n d  ta bles will  be  prese nte d  b y  pretreat me nt  gr o u p   ( p ost me n o pa usal  patie nts 
wit h o ut pri or treat me nt f or a d va nce d disease, pre- a n d peri me n o pa usal patie nts wit h o ut pri or 
treat me nt  f or  a d va nce d  disease  a n d  pre-,  peri  a n d  p ost me n o pa usal  patie nts  wit h  pri or 
treat me nt f or a d va nce d disease). 
T he o verall o bser vati o n peri o d wi ll 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 me dicati o n 
2.  o n-treat me nt peri o d: fr o m da y of  first d ose of st u d y me dicati o n t o 3 0 da ys after last 
d ose of st u d y me dicati o n 
3.  p ost-treat me nt peri o d: starti n g at da y 3 0 + 1 after last d ose of st u d y me dicati o n. 
1 0. 5. 2. 2  A d v er s e e v e nt s ( A E s) 
S u m mar y ta bles f or a d verse e ve nt s ( A Es) ha ve t o i ncl u de o nl y A Es t hat starte d or w orse ne d 
d uri n g  t he  o n-treat me nt  peri o d,  t he tre at me nt-e mer ge nt  A Es.  H o we ver,  all  safet y  data 
(i ncl u di n g t h ose fr o m t he pre an 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. 
T he i nci de nce of treat me nt-e mer ge nt a d verse e ve nts ( ne w or w ors e ni n g fr o 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 ter m, se ve rit y  ( base d  o n  C T C A E 
gra des), t y pe of a d verse e ve nt, relati o n t o st u d y treat me nt b y pretreat me nt gr o u p. 

N o v arti s 
C o nfi d e nti al 
P a g e 9 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Deat hs re p orta ble as S A Es a n d n o n-fatal seri o us a d verse e ve nts will be liste d b y patie nt a n d 
ta b ulate d b y t y pe of a d verse e ve nt. 
Data c ollecte d b y A E C R Fs will be c o de d usi n g t he Me d D R A dicti o nar y. T he i nci de nce of 
treat me nt-e mer ge nt a d verse e ve nts ( ne w or w orse ni n g fr o m baseline) will be s u m marize d 
b y  Me d D R A  s yste m  or ga n  class  a n d  preferre d  ter m  usi n g  fre q ue nc y   distri b uti o ns. 
A d diti o nall y, A E will be s u m marize d b y ma xi m u m se verit y ( base d o n C T C A E gra des), a n d 
f or  A E  wit h  s us pecte d  dr u g  relati o n,  seri o us  A E  ( S A E),  a n d  A E  lea di n g  t o  per ma ne nt 
disc o nti n uati o n of st u d y dr u g. All i nf or mati o n pertai ni n g t o A E n ote d d uri n g t he st u d y will 
be  liste d  b y  patie nt,  detaili n g  t he  ver bati m  ter m  gi ve n  b y  t he  i n vesti gat or,  Me d D R A 
preferre d ter m a n d s yste m or ga n  class, start/en d dates, se verit y, seri o us ness, relati o ns hi p t o 
st u d y dr u g a n d acti o n ta ke n. T he A E o nset will als o be s h o w n relati ve (i n n u m ber of da ys) 
t o t he date of i nitial d ose. 
1 0. 5. 2. 3  L a b or at or y a b n or m aliti e s 
N or mal  la b orat or y  val ues  will  n ot  be  d oc u me nte d  i n  t he  C R F.  A b n or mal  la b orat or y 
para meters  t hat  i n d uce  cli nical  si g ns  or  s y m pt o ms,  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 cel l s u p p ort), or re q uire c ha n ges 
i n st u d y dr u g(s) c o nstit ute a n a d verse e ve nt ( Secti o n 8. 1. 2), must be rec or de d o n t he A d verse 
E ve nts C R F a n d are c o de d a n d s u m marize d acc or di n gl y as descri be d i n 1 0. 5. 2. 2. 
F or  la b orat or y  tests  c o vere d  b y  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, t he st u d y’s bi ostatistical a n d re p orti n g tea m will gra de la b orat or y 
data acc or di n gl y. F or la b orat or y  tests c o vere d b y C T C A E, a Gra 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, results will be gra de d b y t he 
l o w/ n or mal/ hi g h classificati o ns base d o n la b orat or y n or mal ra n ges. 
1 0. 5. 2. 4  Ot h er s af et y d at a 
Data  fr o m  ot her  tests  (e. g.,  electr ocar di o gra m  or  vital  si g ns) 
will  be  s u m marize d 
descri pti vel y  as  a p pr o priate.  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. 
E C G 
E C G res ults will be re p orte d o nl y if  t he criteria f or S A E are met. 
Vit al si g n s 
Defi niti o ns of n ota bl y a b n or mal res ults ha ve t o part of t he C D P, M A P, C S P a n d R A P. 
 s hift ta ble baseli ne t o w orst o n-treat me nt res ult 
 ta ble wit h descri pti ve statistics at baseli ne, o ne or se veral p ost- baseli ne ti me p oi nts a n d 
c ha n ge fr o m baseli ne t o t his/t h ese p ost- baseli ne ti me p oi nts. 
E C O G P erf or m a n c e St at u s 
T he E C O G Perf or ma nce Stat us will be s u m marize d usi n g fre q ue nc y distri b uti o ns b y visit. 
S hifts fr o m baseli ne val ue t o w orst p ost- baseli ne val ue will be  s u m marize d usi n g fre q ue nc y 
distri b uti o ns. 
 

N o v arti s 
C o nfi d e nti al 
P a g e 9 3 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
1 0. 5. 3  
Bi o m ar k er s 
Si nce t his cli nical trial was n ot desi g ne d t o a d dress s pecific bi o mar kers-relate d h y p ot heses, 
t he a nal ysis of t his data s h o ul d be vie we d as e x pl orat or y a n d hy p ot heses ge nerati n g.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
e 
 
 
 
1 0. 5. 3. 1  O utli n e of t h e d at a a n al y si s 
A d diti o nal a nal yses t hat ma y be perf or me d after t he c o m pleti o n of t he e n d- of-st u d y C S R 
will be d oc u me nte d i n se parate re p orts. T hese a nal yses ma y i ncl u de b ut are n ot li mite d t o 
t he  meta-a nal ysis  of  data  fr o m  t his  st u d y  c o m bi ne d  wit h  data  fro m ot her st u dies or t he 
a nal ysis of bi o mar kers ge nerate d fr o m sa m ples c ollecte d d uri n g t he st u d y b ut a nal yze d after 
t he  data base  l oc k  a n d  c o m pleti o n of  t he  C S R.  T he  data  a nal ysis  will  be  descri be d  i n  a n 
a d de n d u m of t he a nal ysis pla n or i n a sta n d-al o ne a nal ysis pla n  d oc u me nt, as a p pr o priate. 
1 0. 5. 3. 2  D at a h a n dli n g pri n ci pl e s 
I m m u n o hist oc he mistr y (I H C) data re p orte d fr o m t he la b will i nclu de q ua ntitati v e data s uc h 
as  perce nt  t u m or  a n d  perce nt  p ositi ve  cells  or  a  se mi  q ua ntitat i ve  meas ure  of  pr otei n 
e x pressi o n i n cell ular c o m part me nts (i.e. c yt o plas m, n ucle us, m e m bra ne). T he pat h ol o gist 
deter mi nes  w het her  t he  stai ni n g  i n  a  cell ular  c o m part me nt  is  a b se nt  ( 0 +),  sli g ht  ( 1 +), 
m o derate ( 2 +), or str o n g ( 3 +).  
1 0. 5. 3. 3  D at a a n al y si s pri n ci pl e s 
1 0. 5. 3. 3. 1  
A n al y si s s et s 
T he sta n dar d a nal ysis sets will be use d acc or di n g t o t he p ur p os e of a gi ve n a nal ysis (e. g. 
F A S  t o  descri be  bi o mar kers,  safet y/ per- pr ot oc ol  set  t o  assess  t he  relati o ns hi p  bet wee n 
bi o mar kers a n d selecte d safet y/ efficac y e n d p oi nts). T he n u m ber of patie nts i ncl u de d i n a 

N o v arti s 
C o nfi d e nti al 
P a g e 9 4 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
gi ve n a nal ysis will reflect t he n u m ber of patie nts i n t he c h ose n a nal ysis set w hic h ha ve a 
vali d bi o mar ker assess me nt. 
1 0. 5. 3. 3. 2  
A n al y si s m et h o d s 
T u m or  tiss ue  sa m ples  a n d  bl o o d  sa m ples  will  be  c ollecte d  i n  t hi s  trial 
 
 
 
 
 
 
 
 
 
 
  
1 0. 5. 4  
P ati e nt-r e p ort e d o ut c o m e s 
Healt h-relate d q ualit y of life ( H R Q o L) will be assesse d usi n g the E O R T C Q L Q- C 3 0 a n d 
B R 2 3 q uesti o n naires. Sc ori n g will f oll o w t he i nstr ucti o ns of t h e res pecti ve ma n uals. 
Descri pti ve statistics will be use d t o s u m marize t he i n di vi d ual  ite m a n d sc ore d s u b-scale 
sc ores of Q o L data at eac h sc he d ule d assess me nt ti me p oi nt. Patie nts will be i ncl u de d if t he y 
c o m plete d at least o ne q uesti o n n aire ite m. A d diti o nall y, c ha n ge  fr o m baseli ne i n t he d o mai n 
sc ores  at  t he  ti me  of  eac h  assess me nt  will  be  s u m marize d.  Patients  wit h  a n  e val ua ble 
baseli ne sc ore a n d at least o ne e val ua ble p ost- baseli ne sc ore d uri n g t he treat me nt peri o d will 
be i ncl u de d i n t he c ha n ge fr o m baseli ne a nal yses (assess me nts a fter disease pr o gressi o n will 
be e xcl u de d). 
1 0. 6  
E x pl or at or y o bj e cti v e s 
 
 
1 0. 7  
I nt eri m a n al y si s 
T hree  i nteri m  a nal yses  are  pla n ne d  d uri n g  t he  st u d y.  T he  first i nteri m  a nal ysis  will  be 
c o n d ucte d  o ne  year  after  t he  first  patie nt  has  bee n  e nr olle d  a n d  i ncl u de  a  preli mi nar y 
a nal ysis o n safet y. T he sec o n d i n teri m a nal ysis will be c o n d ucte d 1 2 m o nt hs after L P F V i n 
t he 3 0 % pretreate d a n d pre me n o pausal c o h ort a n d will i ncl u de a preli mi nar y a nal ysis o n 
safet y, efficac y a n d q ualit y of life. T he t hir d i nteri m a nal ysis will ta ke place 6 m o nt hs after 
t he  last  patie nt  has  bee n  recr uite d  a n d  will  i ncl u de  a  preli mi nar y  a nal ysis  o n  safet y  a n d 
efficac y. 
1 0. 8  
S a m pl e si z e c al c ul ati o n 
Sa m ple size ass u m pti o ns i n t his st u d y f or p ost me n o pa usal patie n ts wit h o ut pri or treat me nt 
f or a d va nce d disease are base d o n t he data fr o m t he C L E E 0 1 1 X 2 1 07 st u d y (J uric, p oster 
prese nte d at A S C O 2 0 1 6), w hic h e nr olle d a si milar patie nt p o p ul ati o n. 
 
Re gar di n g  patie nts  i n  later  t ha n first  li nes  a n d  pretreate d  preme n o pa usal  patie nts, 
ass u m pti o ns are base d o n Crist of a nilli et al 2 0 1 6 - P A L O M A- 3 fi nal a nal ysis. 

N o v arti s 
C o nfi d e nti al 
P a g e 9 5 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
It is e x pecte d t hat t he C B R ( base d o n l ocal assess me nt) b y wee k 2 4 is i n a ra n ge as re p orte d 
f or  t he  C L E E 0 1 1 X 2 1 0 7st u d y  f or  t he  ri b ocicli b  +  letr oz ole  gr o u p ( C B R  =  7 9 %,  9 5 % 
c o nfi de nce i nter val [ 5 9 % t o 9 2 %]). 
Usi n g t he l o wer li mit of t he CI ( 5 9 %) as a pessi mistic esti mate  f or t he C B R b y wee k 2 4, a 
sa m ple size of 5 0 0 pr o d uces a t w o-si de d 9 5 % c o nfi de nce i nter val wit h a wi dt h e q ual t o 8. 6 
perce nta ge p oi nts (t he ass ocia te d 9 5 % CI is [5 4. 7 % t o 6 3. 3 %]). W he n usi n g t he sa me C B R 
as o bser ve d ( C B R 7 9 %), a sa m ple size of 5 0 0 pr o d uces a t w o-si de d 9 5 % c o nfi de nce i nter val 
wit h a wi dt h e q ual t o 7. 2 perce nta ge p oi nts (t he 9 5 % CI is [ 7 5. 4 % t o 8 2. 6 %]). Usi n g t he 
u p per li mit of t he CI ( 9 2 %) as a n o pti mistic esti mate f or t he C B R, a sa m ple size of 5 0 0 
pr o d uces a t w o-si de d 9 5 % c o nfi de nce i nter val wit h a wi dt h e q ual  t o 4. 8 perce nta ge p oi nts 
(t he 9 5 % CI is 8 9. 6 % t o 9 4. 4 %]). Ass u mi n g a n esti mate d rate of 7 0 % t o be recr uite d i n t he 
s u b gr o u p of p ost me n o pa usal first li ne patie nts res ulti n g i n a sa m ple size of 3 5 0 patie nts, t he 
wi dt h  of  t he  c o nfi de nce  i nter val  will  be  bet wee n  1 0. 4  perce nta g e  p oi nts  ( pessi mistic 
sce nari o) a n d 5. 6 perce nta ge p oi nts ( o pti mistic sce nari o). 
 
Re gar di n g t he s u b gr o u p of sec o n d or f urt her treat me nt li nes a n d  pre me n o pa usal patie nts, 
ass u mi n g a n esti mate d rate of 3 0 % t o be recr uite d, a n d f urt her base d o n t he data as prese nte d 
b y Crist ofa nili et al. ( C B R 6 7 % , 9 5 % CI [ 6 1. 3 % t o 7 1. 5 %]), t he res ulti n g precisi o n base d 
o n  1 5 0  patie nts  lea ds  t o  a  wi dt h  of  t he  res ulti n g  9 5 %  c o nfi de nce  i nter val  bet wee n  1 5. 6 
perce nta ge p oi nts ( pessi mis tic sce nari o) a n d 1 4. 4 perce nta ge p oi nts ( o pti mistic sce nari o). 
T h us, a sa m ple size of 5 0 0 patie nts all o ws esti mati n g t he C B R i n t his patie nt p o p ulati o n 
wit h reas o na ble precisi o n. 
1 0. 9  
P o w er f or a n al y si s of k e y s e c o n d ar y v ari a bl e s 
N ot a p plica ble. P o wer f or a nal y sis of sec o n dar y varia bles was not i n vesti gate d. 
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,  wit 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 Dec larati 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 v ie 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 h ics  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  s tart,  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 vartis 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 R Bs/I E Cs/ R E Bs a n d re g ulat ory 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 o nl 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 b y la w or re g ulati o n), IR B/I E C/ R E B-a p pr o ve d i nf or me d c o nse nt. 

N o v arti s 
C o nfi d e nti al 
P a g e 9 6 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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-specific 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 b tai 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 wil l 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 g at ors, i n a se parate d oc u me nt, a pr o p ose d i nf or me d c o nse nt 
f or m (I C F) t hat is c o nsi dere d a ppr o priate f or t his st u d y a n d c o m plies wit h t he I C H 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 C F s u g geste d  b y  t he 
i n vesti gat or m ust be a gree d t o b y N o vartis bef ore s u b missi o n t o t he I R B/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. 
W o me n of c hil d beari n g p ote ntial s h o ul d be i nf or me d t hat ta ki n g  t he st u d y me dicati o n ma y 
i n v ol ve u n k n o w n ris ks t o t he fet us if pre g na nc y were t o occ ur d uri n g t he st u d y a n d a gree 
t hat i n or der t o partici pate i n t he st u d y t he y m ust a d here t o the c o ntrace pti o n re q uire me nt 
f or t he d urati o n of t he st u d y. If t here is a n y q uesti o n t hat t he patie nt will n ot relia bl y c o m pl y, 
t he y s h o ul d n ot be e ntere d i n t he st u d y. 
A d diti o n al c o n s e nt f or m  
S u b-st u dies  a n d  st u dies  wit h  a n  o pt i o nal  E x pl orat or y  Bi o mar ker c o m p o ne nt  will  ha ve  a 
se parate c o nse nt f or m c o veri n g th ose st u dies. T his i nf or me d c o n se nt f or m will be s u b mitte d 
f or et hical a p pr o val t o get her wit h t he St u d y Pr ot oc ol a n d t he mai n i nf or me d c o nse nt f or m 
of t he St u d y. If a s u bject o pts n ot t o partici pate i n t he o pti o nal assess me nts, t his i n n o wa y 
affects t he s u bject’s a bilit y t o partici pate i n t he mai n resear c h st u d y. 
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 d isc o nti n ue t his st u d y u n der t he c o n diti o ns s pecifie d i n t he 
cli nical  st u d y  a gree 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 ke y de si 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  c o m pleti o n  a n d 
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 bl icl 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 r esearc 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 C H  E 6  G C P,  a n d  re g ulat ory  a n d  i nstit uti o nal 
re q uire me nts f or t he pr otectio 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 pr ese ntati ves of t he s p o ns or(s) 
a n d re g ulat or y a ge ncies t o e xa mi ne (a n d w he n re q uire d b y a p plic a 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 an d e val uati o n of t he st u d y 
safet y a n d pr o gress. 
S o urce data are all i nf or mati o n, ori gi nal rec or d s 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  f or  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 

N o v arti s 
C o nfi d e nti al 
P a g e 9 7 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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 b ilit 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  I n 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 n s 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 fro 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 e x 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 t he s yste m. T he i n vesti gat or s h o ul d retai n rec or ds of t he c h a 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 nt s  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  (I C 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 nst it uti o n s h o ul d ta ke meas ures 
t o pre ve nt acci de ntal or pre mature destr ucti o n of t hese d oc u me n ts. 
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) years fr o m t he c o m pleti o n of t he Cli nical Trial u n less 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. 
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 r e c or d s 
T he i n vesti gat or m ust e ns ure pse u d o ni mit y of t he patie nts; pati e 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 n a 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 N o var tis or desi g nee or Healt h 
A ut h orities. 
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 d ue 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 t his 
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 t he I R B/I E C/ R E B it ca n n ot be i m ple m e nte d. All si g nifica nt 
pr ot oc ol de viati o ns will be rec o r de d a n d re p orte d i n t he C S R. 

N o v arti s 
C o nfi d e nti al 
P a g e 9 8 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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 nl y be ma de i n a wr itte n pr ot oc ol a me n d me nt 
t hat  m ust  be  a p pr o ve d  b y  N o vartis,  Healt h  A ut h orities  w here  re quire d,  a n d  t he 
I R B/I E C/ R E B. O nl y a me 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 R B/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 p r 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  i m me diate acti o n  re q uire d  f or  t he 
safet y 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, No 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 b u t n ot later t ha 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 9 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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) 
 
Ba ker DJ, Wijs ha ke T, Tc h k o nia T, Le Brasse ur N K, C hil ds B G, va n  de Sl uis B, Kir kla n d 
J L, va n De urse n J M. ( 2 0 1 1) Cleara nce of p 1 6I n k 4a- p ositi ve se nes ce nt cells dela ys a gei n g-
ass ociate d dis or ders. Nat ure. 2 0 1 1 N o v 2; 4 7 9( 7 3 7 2): 2 3 2- 6. d oi: 1 0. 1 0 3 8/ nat ure 1 0 6 0 0. 
Bart k o va J, L u kas J, M üller H, L ütz h øft D, Stra uss M, Barte k J.  ( 1 9 9 4). C ycli n D 1 pr otei n 
e x pressi o n a n d f u ncti o n i n h u ma n breas t ca ncer. I nt J Ca ncer. 1 9 9 4 Ma y 1; 5 7( 3): 3 5 3- 6 1. 
Ber o u k hi m R, Mer mel C H, P orter D, et al ( 2 0 1 0) T he la n dsca pe of  s o matic c o p y- n u m ber 
alterati o n acr oss h u ma n ca ncers. Nat ure. 4 6 3( 7 2 8 3): 8 9 9- 9 0 5.  
Berr y D A, Cirri nci o ne C, He n ders o n I C, Citr o n M L, B u d ma n D R, G o l dstei n LJ, Marti n o S, 
Perez E A, M uss H B, N ort o n L, H u dis C, Wi ner E P. ( 2 0 0 6) Estr o ge n-rece pt or stat us a n d 
o utc o mes of m o der n c he m ot hera p y f or patie nts wit h n o de- p ositi ve  breast ca ncer. J A M A. 
2 0 0 6 A pr 1 2; 2 9 5( 1 4): 1 6 5 8- 6 7. 
Beslija S, B o n neterre J, B urstei n HJ, C oc q u yt V, G na nt M, Hei ne ma n n V, Jasse m J, K östler 
WJ, Krai ner M, Me nar d S, Petit T, Petr uzel ka L, P ossi n ger K, Sc h mi d P, Sta dt ma uer E, 
St oc kler M, Va n Belle S, V o gel C, Wilc ke n N, Wiltsc h ke C, Zieli ns ki C C, Z wierzi na H; 
Ce ntral  E ur o pea n  C o o perati ve  O nc ol o g y  Gr o u p  ( C E C O G).  ( 2 0 0 9).  T h ir 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. d oi: 
1 0. 1 0 9 3/a n n o nc/ m d p 2 6 1. E p u b 2 0 0 9 J ul 1 6. 
B or g A, Z ha n g Q X, Al m P, et al ( 1 9 9 2) T he reti n o blast o ma ge ne i n breast ca ncer: allele l oss 
is n ot c orrelate d wit h l oss of gene pr otei n e x pressi o n. Ca ncer Res; 5 2: 2 9 9 1- 4 
B osc o E E, Wa n g Y, X u H, Zilf o u J T, K n u dse n K E, Ar o n o w BJ, L o we S W, K n u dse n E S 
( 2 0 0 7). T he reti n o blast o ma t u m or s u p press or m o difies t he t hera pe utic res p o nse of breast 
ca ncer. J Cli n I n vest. 2 0 0 7 Ja n; 1 1 7( 1): 2 1 8- 2 8. E p u b 2 0 0 6 Dec 7.  
B uc kle y M F, S wee ne y KJ, Ha milt o n J A, Si ni R L, Ma n ni n g D L, Nic h o ls o n RI, de Fazi o A, 
Watts  C K, M us gr o ve  E A,  S ut herla n d  R L  ( 1 9 9 3).  E x pressi o n  a n d  a m p lificati o n of c ycli n 
ge nes i n h u ma n breast ca ncer. O nc o ge ne. 1 9 9 3 A u g; 8( 8): 2 1 2 7- 3 3. 
Car d os o F, Har bec k N, Fall o wfiel d L, K yria ki des S, Se n k us E; E S M O G ui deli nes W or ki n g 
Gr o u p  ( 2 0 1 2).  L ocall y  rec urre nt  or  metastatic  breast  ca ncer:  E S M O  Cli nical  Practice 
G ui deli nes f or dia g n osis, treat me nt a n d f oll o w- u p. A n n O nc ol. 2 0 1 2 Oct; 2 3 S u p pl 7: vii 1 1-
9. 
C ha n o T, K o nta ni K, Tera m ot o K, e t al ( 2 0 0 2) Tr u ncati n g m utati o ns of R B 1 C C 1 i n h u ma n 
breast ca ncer. Nat Ge net; 3 1: 2 8 5- 8 
Dic ks o n C, Fa ntl V, Gillett C, Br o o kes S, Barte k J, S mit h R, Fi s her C, Bar nes D, Peters G. 
( 1 9 9 5). A m plificati o n of c hr o m os o me ba n d 1 1 q 1 3 a n d a r ole f or cycli n D 1 i n h u ma n breast 
ca ncer. Ca ncer Lett. 1 9 9 5 M ar 2 3; 9 0( 1): 4 3- 5 0. 
Ellis MJ, C o o p A, Si n g h B, Ma uriac L, Ll o m bert- C ussac A, Jä nic k e F, Miller W R, E va ns 
D B, D u ga n M, Bra d y C, Q ue be- Fe hli n g E, B or gs M. ( 2 0 0 1). Letr oz o le is m ore effecti ve 
ne oa dj u va nt e n d ocri ne t hera p y t ha n  ta m o xife n f or Er b B- 1- a n d/ or Er b B- 2- p ositi ve, estr o ge n 
rece pt or- p ositi ve pri mar y breast ca ncer: e vi de nce fr o m a p hase III ra n d o mize d trial. J Cli n 
O nc ol. 2 0 0 1 Se p 1 5; 1 9( 1 8): 3 8 0 8- 1 6. 
Fi n n R S, Deri n g J, C o n kli n D, Kal o us O, C o he n DJ, Desai AJ, Gi nt her C, Atefi M, C he n I, 
F o wst C, L os G, Sla m o n DJ. ( 2 0 0 9). P D 0 3 3 2 9 9 1, a selecti ve c ycl i n D ki nase 4/ 6 i n hi bit or, 

N o v arti s 
C o nfi d e nti al 
P a g e 1 0 0 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
prefere ntiall y  i n hi bits  pr olifera ti o n  of  l u mi nal  estr o ge n  rece pt or- p ositi ve  h u ma n  breast 
ca ncer cell li nes i n vitr o. Breas t Ca ncer Res. 2 0 0 9; 1 1( 5): R 7 7. d oi: 1 0. 1 1 8 6/ bcr 2 4 1 9. 
Fi n n R S, Cr o w n J P, La n g I, B oer K, B o n dare n k o I M, K ul y k S O, Ett l J, Patel R, Pi nter T, 
Sc h mi dt M, S h par y k Y, T h u m mala A R, V o yt k o N L, F o wst C, H ua n g X, Ki m S T, Ra n d ol p h 
S, Sla m o n DJ. ( 2 0 1 4). T he c ycli n- de pe n de nt ki nase 4/ 6 i n hi bit or  pal b ocicli b i n c o m bi nati o n 
wit h letr oz ole vers us letr oz ole al o ne as first-li ne treat me nt o f oestr o ge n rece pt or- p ositi ve, 
H E R 2- ne gati ve,  a d va nce d  breast  ca ncer  ( P A L O M A- 1/ T RI O- 1 8):  a  ra n d o mise d  p hase  2 
st u d y.  La ncet  O nc ol.  2 0 1 5  Jan; 1 6( 1): 2 5- 3 5.  d oi:  1 0. 1 0 1 6/ S 1 4 7 0- 2 0 4 5( 1 4) 7 1 1 5 9- 3.  E p u b 
2 0 1 4 Dec 1 6. 
Gia n ni L, Basel ga J, Eier ma n n W, G uille m P orta V, Se mi glaz o v V,  Ll uc h A, Za m betti M, 
Sa ba dell D, Raa b G, Ll o m bart C ussac A, B oz h o k A, Marti nez- A g ull ó A, Grec o M, B ya k h o v 
M, L o pez L o pez JJ, Ma ns utti M, Vala g ussa P, B o na d o n na G; E ur o pe a n C o o perati ve Trial 
i n  O pera ble  Breast  Ca ncer  St u d y  Gr o u p.  ( 2 0 0 5)  Feasi bilit y  a n d  tolera bilit y  of  se q ue ntial 
d o x or u bici n/ paclita xel f oll o we d b y c ycl o p h os p ha mi de, met h otre xa te, a n d fl u or o uracil a n d 
its effects o n t u m or res p o nse as pre o perati ve t hera p y. Cli n Ca ncer Res. 2 0 0 5 Dec 1 5; 1 1( 2 4 
Pt 1): 8 7 1 5- 2 1. 
Gillett C, Fa ntl V, S mit h R, Fis her C, Barte k J, Dic ks o n C, Bar nes D, Peters G. A m plificati o n 
a n d o vere x pressi o n of c ycli n D 1 i n breast ca ncer detecte d b y i m m u n o hist oc he mical stai ni n g. 
Ca ncer Res. 1 9 9 4 A pr 1; 5 4( 7): 1 8 1 2- 7. 
Gillett C, S mit h P, Gre g or y W, Ric har ds M, Millis R, Peters G, Bar nes D. C ycli n D 1 a n d 
pr o g n osis i n h u ma n breast ca ncer . I nt J Ca ncer. 1 9 9 6 A pr 2 2; 6 9( 2): 9 2- 9. 
Jeffre y R. I nfa nte A p hase I st u d y of t he si n gle-a ge nt C D K 4/ 6 in hi bit or L E E 0 1 1 i n pts wit h 
a d va nce d s oli d t u m ors a n d l y m p h o mas. A S C O 2 0 1 4; a bstract 2 5 2 8 
Je o n g  S,  W o o  M M,  Fl oc k hart  D A,  Desta  Z;  I n hi biti o n  of  dr u g  metab olizi n g  c yt oc hr o me 
P 4 5 0s  b y  t he  ar o matase  i n hi bit or  dr u g  letr oz ole  a n d  its  maj or  o xi dati ve  meta b olite  4, 4'-
met ha n ol- bis be nz o nitrile  i n  vitr o.  Ca ncer  C he m ot her  P har mac ol. 2 0 0 9  Oct; 6 4( 5): 8 6 7- 7 5. 
d oi: 1 0. 1 0 0 7/s 0 0 2 8 0- 0 0 9- 0 9 3 5- 7. E p u b 2 0 0 9 Fe b 7. 
J uric et al. Ri b ocicli b ( L E E 0 1 1) a n d letr oz ole i n estr o ge n recept or- p ositi ve ( E R +), H E R 2-
ne gati ve ( H E R 2 –) a d va nce d breast ca ncer (a B C): P hase I b safet y, preli mi nar y efficac y a n d 
m olec ular a nal ysis. J Cli n O nc ol 3 4, 2 0 1 6 (s u p pl; a bstr 5 6 8) 
La n ge  C A,  Yee  D.;  Killi n g  t he  s ec o n d  messe n ger:  tar geti n g  l oss of  cell  c ycle  c o ntr ol  i n 
e n d ocri ne-resista nt  breast  ca ncer.  E n d ocr  Relat  Ca ncer.  2 0 1 1  J u l  4; 1 8( 4): C 1 9- 2 4.  d oi: 
1 0. 1 5 3 0/ E R C- 1 1- 0 1 1 2 
Li pt o n A, De mers L M, Har ve y H A, Ka m bic K B, Gr oss ber g H, Bra d y C , A dlercr uetz H, 
Tr u net  P F,  Sa nte n  RJ.;  Letr oz ole  ( C G S  2 0 2 6 7).  A  p hase  I  st u d y  o f  a  ne w  p ote nt  oral 
ar o matase i n hi bit or of breast ca ncer. Ca ncer. 1 9 9 5 A pr 1 5; 7 5( 8) : 2 1 3 2- 8. 
L u n d gre n K, Br o w n M, Pi ne da S, C uzic k J, Salter J, Za ba gl o L, H o well A, D o wsett M, 
La n d ber g G; Tra ns A T A C i n vesti gat ors. Effects of c ycli n D 1 ge ne a m plificati o n a n d pr otei n 
e x pressi o n  o n  ti me  t o  rec urre nce  i n  p ost me n o pa usal  breast  ca nce r  patie nts  treate d  wit h 
a nastr oz ole or ta m o xife n: a Tra ns A T A C st u d y. Breast Ca ncer Res.  2 0 1 2 A pr 4; 1 4( 2): R 5 7. 
McI nt os h G G, A n ders o n JJ, Milt o n I, Ste war d M, Parr A H, T h o mas M D, He nr y J A, A n g us 
B,  Le n nar d  T W,  H or ne  C H.;  Deter mi nati o n  of  t he  pr o g n ostic  val ue  of c ycli n D 1 
o vere x pressi o n i n breast ca ncer . O nc o ge ne. 1 9 9 5 Se p 7; 1 1( 5): 8 8 5- 9 1. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 0 1 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Miller  T W,  Bal k o  J M,  Artea ga  C L .:  P h os p hati d yli n osit ol  3- ki nase  a n d  a ntiestr o ge n 
resista nce  i n  breast  ca ncer.  J  Cli n  O nc ol.  2 0 1 1  N o v  2 0; 2 9( 3 3): 4 4 5 2- 6 1.  d oi: 
1 0. 1 2 0 0/J C O. 2 0 1 0. 3 4. 4 8 7 9. E p u b 2 0 1 1 Oct 1 7.  
Miller T W, Bal k o J M, F o x E M, G haz o ui Z, D u n bier A, A n ders o n H, D o wsett M, Jia n g A, 
S mit h  R A,  Maira  S M,  Ma n ni n g  H C,  G o nzález- A n g ul o  A M,  Mills  G B,  Hi g ha m  C, 
C ha nt ha p ha yc hit h  S,  K u ba  M G,  Miller  W R,  S h yr  Y,  Artea ga  C L.  E R α - de pe n de nt  E 2 F 
tra nscri pti o n ca n me diate resista nce t o estr o ge n de pri vati o n i n h u ma n breast ca ncer. Ca ncer 
Disc o v. 2 0 1 1 Se p; 1( 4): 3 3 8- 5 1. d oi: 1 0. 1 1 5 8/ 2 1 5 9- 8 2 9 0. C D- 1 1- 0 1 0 1 . E p u b 2 0 1 1 J ul 2 0. 
M o uri dse n H 1, Gers ha n o vic h M, S u n Y, Pérez- Carri ó n R, B o ni C, M o n nier A, A pffelstae dt 
J,  S mit h  R,  Slee b o o m  H P,  Jä nic ke  F,  Pl uza ns ka  A,  Da n k  M,  Bec q uart  D,  Ba ps y  P P, 
Sal mi ne n E, S n y der R, Lass us M, Ver bee k J A, Staffler B, C ha u dri - R oss H A, D u ga n M.; 
S u peri or  efficac y  of  letr oz ole  vers us  ta m o xife n  as  first-li ne  t hera p y  f or  p ost me n o pa usal 
w o me n  wit h  a d va nce d  breast  ca ncer:  res ults  of  a  p hase  III  st u d y   of  t he  I nter nati o nal 
Letr oz ole Breast Ca ncer Gr o u p. J Cli n O nc ol. 2 0 0 1 Ma y 1 5; 1 9( 1 0) : 2 5 9 6- 6 0 6. 
M ur p hree A L, Be ne dict W F ( 1 9 8 4) R eti n o blast o ma: cl ues t o h u ma n o nc o ge nesis. Scie nce; 
2 2 3: 1 0 2 8- 3 3 
M us gr o ve E A, Cal d o n C E, Barracl o u g h J, et al ( 2 0 1 1) C ycli n D as  a t hera pe utic tar get i n 
ca ncer. Nat Re v Ca ncer 1 1: 5 5 8- 7 2. 
T heria ult  R L,  Carls o n  R W,  Allre d  C,  A n ders o n  B O,  B urstei n  HJ,  E d ge  S B,  Farrar  W B, 
F orer o  A,  Gi or da n o  S H,  G ol dstei n  LJ,  Gra dis har  WJ,  Ha yes  D F,  H u dis  C A,  Isa k off  SJ, 
Lj u n g  B M,  Ma n k off  D A,  Marc o m  P K,  Ma yer  I A,  Mc C or mic k  B,  Pierce LJ,  Ree d  E C, 
Sc h wartz ber g L S, S mit h M L, S oli ma n H, S o ml o G, War d J H, W olff A C, Zellars R, S hea d 
D A, K u mar R; Nati o nal C o m pre he nsi ve Ca ncer Net w or k.: Breast ca n cer, versi o n 3. 2 0 1 3: 
feat ure d u p dates t o t he N C C N g ui deli nes. J Natl C o m pr Ca nc Net w. 2 0 1 3 J ul; 1 1( 7): 7 5 3- 6 0; 
q uiz 7 6 1. 
Oesterreic h S, F u q ua S A W ( 1 9 9 9) T u m or s u p press or ge nes i n breast ca ncer. E n d ocr Relat 
Ca ncer; 6: 4 0 5- 1 9 
O ke n M M, Creec h R H, T or me y D C et al. ( 1 9 8 2) T o xicit y A n d Res p o n se Criteria Of T he 
Easter n C o o perati ve O nc ol o g y Gr o u p. A m J Cli n O nc ol; 5: 6 4 9- 6 5 5.  
Ols o n J A Jr, B u d d G T, Car e y L A, Harris L A, Esser ma n LJ, Fle mi n g   G F,  Marc o m  P K, 
Lei g ht G S Jr, Gi u nt oli T, C o m mea n P, Bae K, L u o J, Ellis MJ.: I m pr o ve d s ur gical o utc o mes 
f or br east ca ncer pati e nts r eceivi n g ne oa dj u va nt ar o matase i n hi bit or t hera p y: res ults fr o m 
a m ultice nter p hase II trial. J A m C oll S ur g. 2 0 0 9 Ma y; 2 0 8( 5): 9 0 6- 1 4; 
Pietilai ne n  T,  Li p p o ne n  P,  Aalt o maa  S,  et  al  ( 1 9 9 5)  E x pressi o n of  reti n o blast o ma  ge ne 
pr otei n ( R b) i n breast ca ncer as relate d t o  esta blis he d pr o g n ostic fact ors a n d s ur vi val. E ur J 
Ca ncer; 3 1 A: 3 2 9- 3 3 
Se mi glaz o v  V F,  Se mi glaz o v  V V,  Das h ya n  G A,  Zilts o va  E K,  I va n o v  V G,  B oz h o k  A A, 
Mel ni k o va O A, Palt ue v R M, Kletzel  A, Berstei n L M.: P hase 2 ra n do mize d trial of pri mar y 
e n d ocri ne t hera p y vers us c he m ot h era p y i n p ost me n o pa usal patie nt s wit h estr o ge n rece pt or-
p ositi ve breast ca ncer. Ca ncer. 2 0 0 7 J ul 1 5; 1 1 0( 2): 2 4 4- 5 4. 
S mit h TJ, K hatc heressia n J, L y ma n G H, et al. 2 0 0 6 u p date of rec o m me n dati o ns f or t he use 
of  w hite  bl o o d  cell  gr o wt h  fact ors:  a n  e vi de nce- base d  cli nical practice  g ui deli ne.  J  Cli n 
O nc ol 2 0 0 6; 2 4: 3 1 8 7 – 3 2 0 5. d oi: 1 0. 1 2 0 0/J C O. 2 0 0 6. 0 6. 4 4 5 1 

N o v arti s 
C o nfi d e nti al 
P a g e 1 0 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Tr u net P F, B hat na gar A S, C ha u dri H A, H or n ber ger U.; Letr oz ole ( C G S 2 0 2 6 7), a ne w oral 
ar o matase i n hi bit or f or t he treat me nt of a d va nce d breast ca ncer  i n p ost me n o pa usal patie nts. 
Acta O nc ol. 1 9 9 6; 3 5 S u p pl 5: 1 5- 8. 
T ur ner N C, et al ( 2 0 1 5) Pal b ocicli b i n h or m o ne-rece pt or- p ositi v e a d va nce d breast ca ncer. 
N E n gl J Me d; 3 7 3( 3): 2 0 9- 2 1 9 
T he Ca ncer Ge n o me Atl as Net w or k: C o m pre he nsi ve m olec ular p ortra its of h u ma n breast 
t u m o urs Nat ure 2 0 1 2 Oct. 0 4; 4 9 0:6 1 – 7 0; D OI: d oi: 1 0. 1 0 3 8/ nat ure 1 1 4 1 2 
Y u Q, Sici ns ka E, Ge n g Y, A h ns tr ö m M, Za g oz dz o n A, K o n g Y, Gar dner H, Ki y o ka wa H, 
Harris  L N,  Stål  O,  Sici ns ki  P.:  Re q uire me nt  f or  C D K 4  ki nase  f u n cti o n  i n  breast  ca ncer. 
Ca ncer Cell. 2 0 0 6 Ja n; 9( 1): 2 3- 3 2. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 0 3 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
1 4  
A p p e n di c e s 
1 4. 1  
A p p e n di x 1 – C o n c o mit a nt M e di c ati o n s 
I n  ge neral,  t he  use  of  a n y  c o nc o mita nt  me dicati o n  dee me d  necessar y  f or  t he  care  of  t he 
patie nt  is  per mitte d  i n  t his  st u d y,  e xce pt  as  s pecificall y  pr o h i bite d  bel o w.  C o m bi nati o n 
a d mi nistrati o n  of  st u d y  dr u gs  c o ul d  res ult  i n  dr u g- dr u g  i nterac ti o ns  ( D DI)  t hat  c o ul d 
p ote ntiall y  lea d  t o  re d uce d  acti vit y  or  e n ha nce d  t o xicit y  of  t h e  c o nc o mita nt  me dicati o n 
a n d/ or ri b ocicli b. 
T he f oll o wi n g lists are n ot c o m pre he nsi ve a n d are o nl y mea nt t o  be use d as a g ui de. T he 
lists are base d o n O nc ol o g y Cli nical P har mac ol o g y g ui da nce, Dr ug- Dr u g I nteracti o n a n d 
C o- Me dicati o n C o nsi derati o ns  ( v 0 7, release date: Ja n 2 0 1 8), w hic h was c o m pile d fr o m t he 
I n dia na  
U ni versit y  
Sc h o ol  
of  
Me dici ne’s  
P 4 5 0  
Dr u g  
I nteracti o n  
Ta ble 
(htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ mai n-ta ble/ )  a n d  s u p ple me nte d  wit h  t he  F D A 
Draft G ui da nce f or I n d ustr y, Dr u g I nteracti o n St u dies – St u d y D esi g n, Data A nal ysis, a n d 
I m plicati o ns  
f or  
D osi n g  
a n d  
La beli n g  
( Fe br uar y  
2 0 1 2) 
(htt p:// w w w.f da. g o v/ d o w nl oa ds/ dr u gs / g ui da ncec o m plia ncere g ulat or yi nf or mati o n/ g ui da nc
es/ uc m 2 9 2 3 6 2. p df ),  a n d  t he  U ni versit y  of  Was hi n gt o n’s  Dr u g  I nteracti o n  Data base 
(htt p:// w w w. dr u gi nteracti o ni nf o. or g/ ). F or c urre nt lists of me dicati o ns t hat ma y ca use Q T 
pr ol o n gati o n  a n d/ or  t orsa des  de  p oi ntes  ( T d P),  refer  t o  t he  Cre di ble Me ds ®  we bsite 
(w w w. qt dr u gs. or g/ ). Please c o ntact t he me dical m o nit or wit h a n y q uesti o ns. 
T a bl e 1 4- 1  
Li st of pr o hi bit e d m e di c ati o n s d uri n g st u d y dr u g tr e at m e nt 
C at e g or y 
Dr u g N a m e 
Str o n g C Y P 3 A 4/ 5 i n hi bit or s 
At a z a n a vir/rit o n a vir,  b o c e pr e vir, cl arit hr o m y cin, c o bi ci st at, c o ni v a pt a n, 
d a n o pr e vir/rit o n a vir, d ar u n a vir/rit o n a vir,  el vit e gr a vir/rit o n a vir, gr a p efr uit j ui c e, 
i d el ali si b, 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, k et o c o n a z ol e, 
l o pi n a vir/rit o n a vir, mi b efr a dil, n ef a z o d o n e, n elfi n a vir, 
o m bit a s vir/ p arit a pr e vir/ d a s a b u v ir/rit o n a vir ( VI E KI R A P A K), p o s ac o n a z ol e, 
rit o n a vir, s a q ui n a vir/rit o n a vir, t el a pr e vir, t elit hr o m y ci n, ti pr a n a vir/rit o n a vir, 
tr ol e a n d o m y ci n, v ori c o n a z ol e 
Str o n g C Y P 3 A 4/ 5 i n d u c er s 
A v a si mi b e 2, 3 , c ar b a m a z e pi n e, e n z al ut a mi de, l u m a c aft or, mit ot a n e, 
p h e n o b ar bit al, p h e n yt oi n 3 , rif a b uti n, rif a m pi n (rif a m pi ci n)3 , St. J o h n' s w ort 
( h y p eri c u m p erf or at u m)2, 3  
C Y P 3 A 4/ 5 s u b str at e s wit h 
N TI 1  
Alf e nt a nil, a st e mi z ol e, ci s a pri d e , c y cl o s p ori n e, di er g ot a mi n e, di h y dr o er g ot a mi n e, 
er g ot a mi n e, f e nt a n yl, l o mit a pi d e 5 , l o v a st ati n, ni c ar di pi n e, ni s ol di pi n e, pi m o zi d e, 
q ui ni di n e, si m v a st ati n , sir oli m u s, t a cr oli m u s 
M e di c ati o n s wit h a k n o w n ri s k 
f or Q T pr ol o n g ati o n4  
A mi o d ar o n e, a n a gr eli d e, ar s e ni c tri o xi d e, a st e mi z ol e, a zit hr o m y ci n, b e pri dil, 
c hl or o q ui n e, c o c ai n e, c hl or pr o m a zi n e, cil o st a z ol, ci pr ofl o x a ci n, ci s a pri d e, 
cit al o pr a m, cl arit hr o m y ci n, di s o p yr a mi d e, d of etili d e, d o m p eri d o n e, d o n e p e zil, 
dr o n e d ar o n e, dr o p eri d ol, er yt hr o m y ci n, e s cit al o pr a m, fl e c ai ni d e , fl u c o n a z ol e, 
g atifl o x a ci n, gr e p afl o x a ci n, h al of a ntri n e, h al o p eri d ol, i b utili d e, l e v ofl o x a ci n, 
l e v o m e pr o m a zi n e, l e v o s ul piri d e, l e v o m et h a d yl, m e s ori d a zi n e, m et h a d o n e, 
m o xifl o x a ci n, o n d a n s etr o n, o x ali pl ati n, p a p a v eri n e H Cl (i ntr a c o r o n ar y), 
p e nt a mi di n e, pi m o zi d e, pr o b u c ol, p r o c ai n a mi d e, pr o p of ol, q ui ni di n er, 
ro xit hr o m y ci n, s e v ofl ur a n e, s ot al ol, s p arfl o x a c i n, s ul piri d e, sult o pri d e, t erl i pr e s si n, 
t er o dili n e, t erf e n a di n e, t hi ori d a zi n e, v a n d et a ni b 
H er b al pr e p ar ati o n s/ 
m e di c ati o n s 
H er b al pr e p ar ati o n s/ m e di c ati o n s  k n o w n a s str o n g i n d u c er s or i n hi bit or s of 
C Y P 3 A 4/ 5 or t h o s e wit h a k n o w n r i s k of Q T pr ol o n gati o n ar e pr o h i bit e d 
t hr o u g h o ut t h e st u d y. T h e s e h er b al m e di c ati o n s i n cl u d e, b ut ar e n ot li mit e d t o: 
St. J o h n’ s w ort, K a v a, e p h e dr a ( m a h u a n g), gi n g k o bil o b a, 
d e h y dr o e pi a n dr o st er o n e ( D H E A), y o hi m b e, s a w p al m ett o, a n d gi n s e n g. P ati e nt s 
s h o ul d st o p u si n g t h e s e h er b al m e di c ati o n s 7 d a y s pri or t o fir s t d o s e of st u d y 
dr u g. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 0 4 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
C at e g or y 
Dr u g N a m e 
Ot h er i n v e sti g ati o n al a n d 
a nti n e o pl a sti c t h er a pi e s 
Ot h er i n v e sti g ati o n al t h er a pi e s m u st n ot b e u s e d w hil e t h e p ati e nt i s o n t h e 
st u d y. A nti c a n c er t h er a p y ( c h e m ot h er a p y, bi ol o gi c or r a di ati o n t h er a p y, e x c e pt 
f or p alli ati v e r a di ot h er a p y a s o utli n e d i n t h e pr ot o c ol, a n d s ur g er y) ot h er t h a n t h e 
st u d y tr e at m e nt s m u st n ot b e gi v e n w hil e t h e p ati e nt i s o n t h e st u d y m e di c ati o n. 
If s u c h a g e nt s ar e r e q uir e d t h e n th e p ati e nt m u st di s c o nti n u e s t u d y dr u g. 
1  N TI = n arr o w t h er a p e uti c i n d e x dr u g s w h o s e e x p o s ur e-r e s p o n s e in di c at e s t h at i n cr e a s e s i n t h eir e x p o s ur e l e v el s 
b y t h e c o n c o mit a nt u s e of p ot e nt i n hi bit or s m a y l e a d t o s eri o u s  s af et y c o n c er n s ( e. g., T or s a d e s d e P oi nt e s) or 
dr u g s w hi c h h a v e < 2-f ol d diff er e n c e i n t h e mi ni m u m t o xi c c o n c e n tr ati o n s a n d mi ni m u m eff ecti v e c o n c e ntr ati o n s i n 
t h e bl o o d... 
2  H er b al pr o d u ct 
3  P- g p i n d u c er 
4  S o ur c e: w w w. qt dr u g s. or g ( a s of A pr 7, 2 0 1 5) 
5  Dr u g h a s w ar ni n g f or ris k of h e p at ot o xi cit y. 
A s f ar a s p o s si bl e, a v oi d c o- a d mi ni str ati o n of Q T pr ol o n gi n g dr u g s or a n y ot h er dr u g s w it h t h e p ot e nti al t o 
i n cr e a s e t h e ri s k of dr u g-r el at e d Q T pr olo n g ati o n ( e. g., vi a a p ot e nti al D DI t h at i n cr e a s e s t h e e x p o s ur e of ri b o ci cli b 
or t h e e x p o s ur e of t h e Q T pr ol o n g i n g dr u g). A d efi niti v e li st of dr u g s wit h a k n o w n ri s k, p os si bl e ri s k, or c o n diti o n al 
ri s k of Q T pr ol o n g ati o n a n d/ or T ors a d e s d e P oi nt e s ( T d P) i s a v ail a bl e o nli n e at qt dr u g s. or g. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 0 5 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
T a bl e 1 4- 2  
Li st of m e di c ati o n s t o b e u s e d wit h c a uti o n d uri n g s t u d y dr u g 
tr e at m e nt 
C at e g or y 
Dr u g N a m e 
M o d er at e C Y P 3 A 4/ 5 
i n hi bit or s 
A pr e pit a nt, a m pr e n a vir, a s af o eti d a r e si n ( F er ul a a s af o eti d a), ci m eti di n e, cri z oti ni b, 
dilti a z e m, f al d a pr e vir, i m ati ni b, 
i s a v u c o n a z ol ef, n et u pit a nt, nil oti ni b, t ofi s o p am, S c hi s a n dr a s p h e n a nt h er a ( n a n w u 
w ei zi), v er a p a mil  
M o d er at e C Y P 3 A 4/ 5 
i n d u c er s 
B o s e nt a n, d a br af e ni b, ef a vir e n z, etr a viri n e, g e ni st ei n, l er si vi ri n e, l o pi n a vir5 , 
m o d afi nil, n af cilli n, t el otri st at 
S e n siti v e C Y P 3 A 4/ 5 
s u b str at e s 1  
Al p h a- di h y dr o er g o cr y pt i n e, a pi x a b a n, a pr e pit a nt, at or v a st ati n, a v a n afil, b o s uti ni b, 
br oti z ol a m, b u d e s o ni d e, b u s pir o n e, c o bi m eti ni n b, d arif e n a ci n, d a s ati ni b, e b a sti n e, 
el etri pt a n, e pl er e n o n e, e v er oli m u s, gr a z o pr e vir, i br ut ni b, i s a v u c o n a z ol e, 
i v a br a di n e, i v a c aft or,  lu m ef a ntri n e, l ur a si d o n e, m ar a vir o c, mi d a z ol a m, 
p er o s pir o n e, q u eti a pi n e, ri d af or oli m u s, ri v ar o x a b a n, sil d e n afil , si m e pr e vir, 
ti c a gr el or, tili di n e, t ol v a pt a n, tri a z ol a m, uli pri st al, v ar d e n afil, v e n et o cl a x, vi cri vir o c, 
v o cl o s p ori n  
B S E P i n hi bit or s 
Al e cti ni b, at or v a st ati n, br o m o cri pti n e, c a n d e s art a n, cl o b et a s ol , cl of a zi mi ni e, 
d a bi g atr a n, di p yri d a m ol e, gl y b uri d e, gr a z o pr e vir, l e di p a s vir, m if e pri st o n e, 
pi o glit a z o n e, r e s er pi n e,rif a m y ci n, si m e pr e vir, t el mi s art a n,ti m c o d ar, tr o glit a z o n e, 
v ali n o m y ci n, v el p at a s vir  
M e di c ati o n s t h at c arr y a 
p o s si bl e ri s k f or Q T 
pr ol o n g ati o n 2  
Alf u z o si n, a p o m or p hi n e, ari pi pr a z ol e, art e ni m ol + pi p er a q ui n e, a s e n a pi n e, 
at a z a n a vir, at o m o x eti n e, b e d a q uili n e, b e n d a m u sti n e, b ort e z o mi b,  b o s uti ni b, 
b u pr e n or p hi n e, c a b o z a nti ni b, c a p e cit a bi n e, c eriti ni b, cl o mi pr a m i n e, cri z oti ni b, 
cl o z a pi n e, c y a m e m a zi n e ( c y a m e pr o m a zi n e), d a br af e ni b, d a s ati ni b,  d e g arili x, 
d el a m a ni d, d e si pr a mi n e, d e x m e d et o m i di n e, d ol a s etr o n, ef a vir e n z, eli gl u st at, 
e pir u bi ci n, eri b uli n m e s yl at e, e z o g a bi n e(r eti g a bi n e), f a m oti di n e, f el b a m at e, 
fi n g oli m o d, fl u p e nti x ol, g e mifl o x a ci n, gr a ni s etro n, h y dr o c o d o n e - E R, il o p eri d o n e, 
i mi pr a mi n e ( m eli pr a mi n e), i sr a di pi n e, k et a n s eri n, 
l a p ati ni b, l e n v ati ni b, l e u pr oli d e, l o p er a mi d e, lit hi u m, m el p er on e, mi d o st a uri n, 
mif e pri st o n e, mir a b e gr o n, mirt a z a pi n e, m o e xi pril/ H C T Z, n e cit u m u m a b, nil oti ni b, 
n orfl o x a ci n, n ortri pt yli n e, n u si n er s e n, ofl o x a ci n, ol a n z a pi n e, o si m erti ni b, o x yt o ci n, 
p ali p eri d o n e, p al o n o s etr o n, p a n o bi n o st at, p a sir e oti d e, p a z o p a ni b, 
p erfl utr e n li pi d mi cr o s p h er e s, p er p h e n a zi n e, pil si c ai ni d e, pi m a v a n s eri n, 
pi p a m p er o n e, pr o m et h a zi n e, pr ot hi p e n d yl, q u eti a pi n e, r a n ol a zi n e , ril pi viri n e, 
ri s p eri d o n e, r o mi d e p si n, s ertin d ol e, s or af e ni b, s u niti ni b, t a m o xif e n, t el a v a n ci n, 
t etr a b e n a zi n e, ti pir a cil/trifl uri di n e, ti z a ni di n e, t olt er o di n e, t or e mif e n e, tri mi pr a mi n e, 
tr o pi s etr o n, v ar d e n afil, v e m ur af e ni b, v e nl af a xi n e, v ar d e n afil, zi pr a si d o n e  
M A T E 1/ 2 s u b str at e s
3 
A c y cl o vir, c e p h al e xi n, ci m eti d i n e, f e x of e n a di n e, g a n ci cl o vir, gl y c o p yrr o ni u m, 
m etf or mi n, pi n d ol ol,  pli si c ai ni d e, r a niti di n e, t o p ot e c a n a n d v ar e n ci cli n e  
O C T 1/ 2 s u b str at e s 4  
A m a nt a di n e, 6- b et a- h y dr o x y c orti s ol, c ar b o pl ati n, ci s pl ati n, c e p h al e xi n, 
c e p hr a di n e, i pr atr o pi u m, l a mi v u di n e, li n a gli pti n, m etf or mi n, o x y pl ati n, o x y b ut y ni n, 
p h e nf or mi n, pi c o pl ati n, pil si c ai ni d e, pi n d ol ol, r a niti di n e, s or af e ni b, tr o pi s etr o n, 
tr o s pi u m, u m e cli di ni u m, a n d zi d o v u di n e 
B C R P s u b str at e s 
D a u n or u bi ci n, d ol ut e gr a vir, d o x or u bi ci n, h e m at o p or p h yri n, i m ati ni b, m et h otr e x at e, 
mit o x a ntr o n e, pit a v a st ati n, r o s u v a st ati n, iri n ot e c a n, et hi n yl e str a di ol, a n d 
s ulf a s al a zi n e , s of o s b u vir, t e n of o vir, t o p ot e c a n, v e n et o cl a x 
1  S e n siti v e s u b str at e si n cl u d e s dru g s w h o s e pl a s m a A U C v al u e s h a v e b e e n s h o w n t o i n cr e a s e 5-f ol d or hi g h er 
w h e n c o- a d mi ni st er e d wit h a p ot e nt i n hi bit or. 
2 T h e li st pr o vi d e d i s a s of J a n u ar y 2 0 1 8. C h e c k cr e di bl e m e d s. or g / h e alt h c ar e- pro vi d er s/ dr u g-li st f or t h e m o st 
u p d at e d li st. 3 M A T E 1 a n d M A T E 2 s h ar e c o n si d er a bl e s u b str at e s p e cifi cit y. 
4 O C T 1 a n d O C T 2 s h ar e c o n si d er a bl e s u b str at e s p e cifi cit y. 
5 L o pi n a vir i s pr o hi bit e d w h e n c o m bi n e d wit h rit o n a vir ( s e e T a bl e 1 4- 1) 
 S o ur c e: N o v arti s P K S ci e n c e s M e m or a n d u m: Dr u g- Dr u g I nt er a cti o n s  ( D DI) a n d C o- m e di c ati o n C o n si d er ati o n s f or 
N o v arti s Cli ni c al Tri al s ( J a n u ar y 2 0 1 8), w hi c h i s c o m pil e d fr o m I n di a n a U ni v er sit y “ Cli ni c all y R el e v a nt” Fl o c k h art 
T a bl e ™, U ni v er sit y of W a s hi n gt o n Dr u g I nt er a cti o n D at a b a s e, a n d  F D A Dr u g D e v el o p m e nt a n d Dr u g I nt er a cti o n s: 
T a bl e of S u b str at e s, I n hi bit or s a n d I n d u c er s  

N o v arti s 
C o nfi d e nti al 
P a g e 1 0 6 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
1 4. 2  
A p p e n di x 2: 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 sio n-fr e e s ur vi v al a n d o v er all 
s ur vi v al ( b a s e d o n R E CI S T 1. 1) 
D o c u m e nt t y p e:  
T A S p e cifi c G ui d eli n e 
D o c u m e nt st at u s:  
V er si o n 3. 1:  2 9- N o v- 2 0 1 1 
V er si o n 3: 0:  1 9- O ct- 2 0 0 9 
V er si o n 2: 0:  1 8- J a n- 2 0 0 7 
V er si o n 1: 0:  1 3- D e c- 2 0 0 2 
R el e a s e d at e:  
2 9- N o v- 2 0 1 1 
Li st of c o ntri b ut or s 
A ut h or s ( V er si o n 3. 1) : 
 
 
A ut h or s ( V er si o n 3): 
 
 
 
A ut h or s ( V er si o n 2): 
 
 
A ut h or s ( V er si o n 1): 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 1 0 7 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 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 8 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
1  
I ntr o d u cti o n 
T he p ur p ose of t his d oc u me nt is t o pr o vi de t he w or ki n g defi niti o ns a n d r ules necessar y f or 
a  c o nsiste nt  a n d  efficie nt  a nal ysis  of  efficac y  f or  o nc ol o g y  st u dies  i n  s oli d  t u m ors.  T his 
d oc u me nt is base d o n t he R E CI S T criteria f or t u m or res p o nses ( T herasse et al 2 0 0 0 ) a n d t he 
re vise d R E CI S T 1. 1 g ui deli nes (Eise n ha uer et al 2 0 0 9 ). 
T he  efficac y  assess me nts  descri be d  i n Secti o n  2   a n d  t he  defi niti o n  of  best  res p o nse  i n 
Secti o n 3. 1  are base d o n t he R E CI S T 1. 1 criteria b ut als o gi ve m ore detaile d i nstr ucti o ns 
a n d r ules f or deter mi nati o n of best res p o nse. Secti o n 3. 2  is s u m marizi n g t he “ti me t o e ve nt” 
varia bles  a n d  r ules  w hic h  are  mai nl y  deri ve d  fr o m  i nter nal  disc ussi o ns  a n d  re g ulat or y 
c o ns ultati o ns, as t he R E CI S T criteria d o n ot defi ne t hese varia bles i n detail. Secti o n 4  of 
t his g ui deli ne descri bes data ha n dli n g a n d pr o g ra m mi n g r ules. This secti o n is t o be referre d 
t o  i n  t he  R A P  ( Re p orti n g  a n d  A nalysis  Pla n)  t o  pr o vi de  f urt her details  nee de d  f or 
pr o gra m mi n g. 
2  
Effi c a c y a s s e s s m e nt s 
T u m or  e val uati o ns  are  ma de  base d  o n  R E CI S T  criteria  ( T herasse  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 or s,  J o ur nal  of  Nati o nal 
Ca ncer I nstit ute, V ol. 9 2; 2 0 5- 1 6 a n d re vise d R E CI S T g ui deli nes  ( versi o n 1. 1) (Eise n ha uer 
et al 2 0 0 9) E ur o pea n J o ur nal of Ca ncer; 4 5: 2 2 8- 2 4 7. 
2. 1  
D efi niti o n s 
2. 1. 1  Di s e a s e m e a s ur a bilit y 
I n or der t o e val uate t u m ors t hr o u g h o ut a st u d y, defi niti o ns of meas ura bilit y are re q uire d i n 
or der t o classif y lesi o ns a p pr o priatel y at baseli ne. I n defi ni n g meas ura bilit y, a disti ncti o n 
als o  nee ds  t o  be  ma de  bet wee n  n o dal  lesi o ns  ( pat h ol o gical  l y m p h   n o des)  a n d  n o n- n o dal 
lesi o ns. 
 Me as ur a ble dise ase  - t he prese nce of at least o ne meas ura ble n o dal or n o n- n o dal lesi o n. 
If t he meas ura ble disease is restricte d t o a s olitar y lesi o n, its ne o plastic nat ure s h o ul d be 
c o nfir me d b y c yt ol o g y/ hist ol o g y. 
F or patie nts wit h o ut meas ura ble disease see Secti o n 3. 2. 8 . 
Me as ur a ble lesi o ns  ( b ot h n o dal a n d n o n- n o dal) 
 Meas ura ble n o n- n o dal - As a r ule of t h u m b, t he mi ni m u m size of a meas ura ble n o n-
n o dal tar get lesi o n at baseli ne s h o ul d be n o less t ha n d o u ble t he slice t hic k ness or 1 0 m m 
w hic he ver is greater - e. g. t he mi ni m u m n o n- n o dal lesi o n size f or C T/ M RI wit h 5 m m 
c uts will be 1 0 m m, f or 8 m m c o nti g u o us c uts t he mi ni m u m size will be 1 6 m m. 
 L ytic b o ne lesi o ns or mi xe d l ytic- blastic lesi o ns wit h i de ntifia ble s oft tiss ue c o m p o ne nts, 
t hat ca n be e val uate d b y C T/ M RI, ca n be c o nsi dere d as meas ura ble lesi o ns, if t he s oft 
tiss ue c o m p o ne nt meets t he defi niti o n of meas ura bilit y. 
 Meas ura ble n o dal lesi o ns (i.e. l y m p h n o des) - L y m p h n o des 1 5 m m i n s h ort a xis ca n 
be c o nsi dere d f or selecti o n as t ar get lesi o ns. L y m p h n o des meas uri n g 1 0 m m a n d < 1 5 
m m are c o nsi dere d n o n- meas ura ble. L y m p h n o des s maller t ha n 1 0 m m i n s h ort a xis at 
baseli ne, re gar dless of t he slice t hic k ness, are n or mal a n d n ot c o nsi dere d i n dicati ve of 
disease. 
 C ystic lesi o ns: 

N o v arti s 
C o nfi d e nti al 
P a g e 1 0 9 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 Lesi o ns  t hat  meet  t he  criteria f or  ra di o gra p hicall y  defi ne d  si mple  c ysts  (i.e., 
s p herical str uct ure wit h a thi 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 ysts. 
 ‘ 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 bility  descri be d  a b o ve. 
H o we ver, if n o nc ystic 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  lesi o ns  -  all  ot her  lesi o ns  are  c o nsi dere d  n o n- m eas 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 hol o gical l y m 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 o me ni n geal disease, ascites, ple ural/ pericar d ial eff usi o n, i nfla m mat or y 
breast  
disease,  l y m 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 ysical  e xa m  t hat  is  n ot  meas ura ble   b y  re pr o d uci ble 
i ma gi n g tec h ni q ues. 
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 dentifie d at baseli ne, t he patie n t ma y be all o we d t o e nter t he 
st u d y  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 trial s w here 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 wi t 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 nal yses 
is gi ve n i n Secti o n 3. 2. 8 . 
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: 
 All 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 on ( 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  2 8  da ys  bef ore  t he  b e gi n ni n g  of  t he 
treat me nt. E xisti n g b o ne sca ns ca n be use d if assess u p t o 5 6 d a ys pri or t o C 1 D 1. 
 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 trea t 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 m e 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 ho ul d  prefera bl y  be 
perf or me d  usi n g  a  5  m m  slice  t h ic 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 ow 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 u s  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 1 0 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 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 ustifi cati o n f or t he c ha n ge) or a 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 d alit y.  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. 
H o we ver, a n ot her res p o nse assess me nt t ha n t he N o vartis calc ulat e 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 w er 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 . 
 C hest x-ra y: Lesi o ns o n c hest x-ra y are acce pta ble as meas ura bl e 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. 
 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. 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 l y m p h n o des, s u bc uta ne o us 
lesi o ns  a n d  t h yr 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 nce of s u perficial le si 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 u tilizati 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 yet 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 p ertise t hat ma y o nl y be 
a vaila ble  i n  s o me  ce nters.  T heref ore,  t he  utilizati o n  of  s uc h  t ec 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 uc h tec h ni q ues ca n be usef ul i n c o nfir mi n g c o m plete p at h ol o gical res p o nse 
w he n bi o psies are o btai ne d. 
 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 varia 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 u lar  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 res p o nse w he n 
all lesi o ns ha ve disa p peare d. 
 C yt 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  t u m or  t y pes  s uc h  as  ger m  cell  t u m ors). 
C yt ol o gic  c o nfir mati o n  of  ne o plastic  nat ure  of  a n y  eff usi o n  t ha t  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 m i 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 nic al e x a mi n ati 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 ul es 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 h y, i ncl u di n g a r uler t o esti ma te t he size of t he lesi o n, 
is rec o m me n de d. 
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 or t he e val uati o n of lesi o ns a t baseli ne a n d t hr o u g h o ut t he stu d y, t he lesi o ns are classifie d 
at baseli ne as eit her tar ge t or n o n-tar get lesi o ns: 

N o v arti s 
C o nfi d e nti al 
P a g e 1 1 1 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 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 res i des i n t he sa me or ga 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 h y) s h o ul d be at least 1 0 
m m i n l o n gest dia meter. See Secti o n 2. 1. 1 . 
 N o d al t ar get:  See Secti o n 2. 1. 1 . 
A  s u m  of  dia meters  (l o n g  a xis  f or  n o n- n o dal  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 rep orte d as t he baseli ne s u m of dia meters ( S O D). T he baseli ne 
s u m of dia meters will be 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. lesio 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  asse sse 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 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 pl e li ver metastases). Eac h 
n o n-tar get lesi o n i de ntifie d at b aseli 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. 
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 l esi o ns will be calc ulate d (at 
baseli ne a n d t hr o u 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 2- 1 ) a n d n o n-tar get lesi o ns (Ta ble 2- 2 ) i de ntifie d 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 2- 3 ) as well as t he prese nce or a bse nce of ne w lesi o ns. 
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 eac h visit a n d f or eac h lesi o n t he act ual date of t he sca n o r pr oce d ure w hic h was use d f or 
t he e val uati o n of eac h s pecific lesi o n s h o ul d be rec or de d. T his a p plies t o tar get a n d 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 u lar visit s h o ul d be ass ociate d 
wit h t he sa me assess me nt n u m ber. 
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 m e 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 bsta ntial “ 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 r e mai n t he sa me size). 

N o v arti s 
C o nfi d e nti al 
P a g e 1 1 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
If t he lesi o n has c o m pletel y disa p peare d, t he lesi o n size s h o uld 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 le ss i n l o n gest dia meter are 
li kel y t o be 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 de ri ve d fr o m t he 5 m m C T 
slice  t hic k ness  ( b ut  sh o ul d  n ot  be  c ha n ge d  wit h  var yi n g  C T  slic e  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 nato mical  str uct ures),  n o 
meas ure me nt s h o ul d be e ntere d a n d t he lesi o n ca n n ot be e val uate d. 
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 de re 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 pl etel 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 kel y t o be 
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 s h o ul d n ot be c ha n ge d wit h var yi 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 s h ort a xis irres pe cti 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 hri n 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 y m 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 su bse q ue ntl y f or res p o nse deter m i nati o n. 
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 2- 1  
R e s p o n s e crit er i 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 s t 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 a t 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 u ffi 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 o r 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 wh 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 a r e < 1 0 m m i n si z e. I n t hi s c a s e, t h e t arg et l e si o n r e s p o n s e i s C R 
3.   
M et h o d ol o g y c h a n g e S e e S e cti o n 2. 2 . 

N o v arti s 
C o nfi d e nti al 
P a g e 1 1 3 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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  of 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” r ec or di n g) be re-e val uate d t o m a ke s ure t hat t he lesi o n was 
n ot act uall y prese 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 the  0  val ue,  t he n  t he  i n vesti ga t or/ra di ol o gist  has t o deci de 
bet wee n t he f oll o wi n g t hree 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 ass ess me nt will be c o nsi dere d 
as pr o gressi ve disease 
 T he lesi o n is clearl y a rea p peara n ce of a pre vi o usl y disa p peare d lesi 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 mor 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 2- 1  a b o ve (i.e., a P D 
will  be  deter 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 o f 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 pp ort t his decisi o n. T his 
a p plies t o patie nts w h o 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 las t 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 usl y, 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 f or 5 tar get lesi o ns at baseli ne 
is 1 0 0 m m at baseli ne a nd t he s u m of dia meters f or 3 of t h ose l esi o ns at a p ost- 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 u te 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 nc l 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 sti ll 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 hen  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:  I n  s o me  circ u msta nces,  disease  t hat  is  meas ura bl e  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 r ec 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 lesi o 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 not a ut o maticall y tri g ger a 
P D desi g nati o n. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 1 4 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 Lesi o ns c oalesce d: C o n versel y, 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 bec o 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 u l 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 be 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 orm,  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 o ri 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 t ar 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 lesi 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 gressio n of tar get le si 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 least 2 0 % i ncrease i n s u m of t he dia meters o f all n o dal tar get lesi o ns 
relati ve t o na dir with at least 5 m m i ncrease i n t he a bs ol ute s u m of t he dia meters. 
2. 4. 3  D et er mi n ati o n of n o n-t ar g et l e si o n r e s p o n s e 
T a bl e 2- 2  
R e s p o n s e crit er i 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 o r 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. 
1.   
Alt h o u g h a cl e ar pr o gr e s si o n of n o n-t ar g et l e si o n s o nl y i s e x ce 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 tr e ati n g p h y si ci a n d o e s pr e v ail a n d t h e pr o gr e s s i o n st at u s s h o ul d b e c o nfir m e d l at er 
o n b y t h e r e vi e w p a n el ( or st u d y c h air). 
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 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 a n y of t he n o n-tar get lesi o ns are still prese nt, 
or t here are a n 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 nl y be ‘N o n-
C R/ N o n- P D ’  u nless  a n y  of  t he  lesi o ns  was  n ot  assesse d  (i n  w hic h  case  resp o nse  is 
U N K )  or  t here  is  u ne q ui v ocal  pr o gressi o n  of  t he  n o n-tar get  lesi o ns (i n w hic h case 
res p o nse is P D ). 

N o v arti s 
C o nfi d e nti al 
P a g e 1 1 5 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 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 o rse ni n g  i n  n o n-tar get 
disease s uc h t hat, e ve n i n prese n ce of C R, P R or S D i n tar get d isease, t he o verall t u m or 
b ur de n has i ncrease d s ufficie ntl y t o merit disc o nti n uati o n of t hera p y. A m o dest “i ncrease” 
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 g ressi o n  s olel y  o n  t he 
basis of c ha n ge i n 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 vocal 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 must be assi g ne d a stat us of 
“ W orse ne d”.  W here  p ossi ble,  si mil ar  r ules  t o  t h ose  descri be d  i n Secti o n  2. 4. 2  f or 
assi g ni n g P D f oll o 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. 
2. 4. 4  N e w l e si o n s 
T he a p peara nce of a ne w lesi o n is al wa ys ass ociate d wit h Pr o gre ssi 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 hera p y 
a n d f oll o w- u p e val uati o n will cla rif y if it re prese nts tr ul y new disease. If re peat sca ns 
c o nfir m t here is defi nitel y a ne w lesi o n, t he n pr o gressi o n s h o u l 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 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. 
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 lesio 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 2- 3 . 

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C o nfi d e nti al 
P a g e 1 1 6 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
T a bl e 2- 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 ed, 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 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). 
If t he e val uati o n of a n y of t he tar get or n o n-tar get lesi o ns i de ntifie d at baseli ne c o ul d n ot be 
ma de d uri n g f oll o w- u p, t he o verall stat us m ust be ‘ u n k n o w n’ u nl ess pr o gressi o n was see n. 
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 m i 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. 
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 nts  w h o  ha ve   meas ura ble  disease  at 
baseli ne. Secti o n 3. 2. 8  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 bas eli ne i n or der t o a p pl y t he sa me c o nce pts. 
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 h e 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 verall 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  tre at me nt  wit h dra wal  t he 
pr ot oc ol s h o ul d s pecificall y descr i be if t hese will 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 wi ll be re q uire d f or se nsiti vit y 
or s u p p orti ve a nal yses. As a defa ult, a n y assess me nts ta ke n m or e t ha n 3 0 da ys a fter t he last 
d ose of st u d y treat me nt will n ot be i ncl u de d i n t he best o veral l res p 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 d y  a n y  s u bse q ue nt  assess me nts  w o ul d 
or di naril y be e xcl u de d fr o m t he best o verall res p o nse deter mi na ti o n. If res p o nse assess me nts 
ta ke n after wit h dra wal fr o m st u d y treat me nt a n d/ or alter nati ve t hera p y are 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. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 1 7 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
W here  a  st u d y  re q uires  c o nfir mati o n  of  res p o nse  ( P R  or  C R),  c ha n ges  i n  t u m or 
meas ure me nts m ust be c o nfir me d b y re peat assess me nts t hat s h o ul d be perf or me d n ot less 
t ha n 4 wee ks after t he criteria f or res p o nse are first met. 
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  clearl y state d i n t he 
pr ot oc ol. T he mai n g oal of c o nfir mati o n of o bjecti ve res p o nse i s 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 here c o nfir mati o n of res p o nse is n ot feasi ble, it s h o ul d be 
ma de 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 ot 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 n t,  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 the 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 b ef 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 gr essi o n  w here 
c o nfir mati 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 ualif yi 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  least  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 yi n g 
f or C R, P R or S D). 
 U N K = all ot her cases (i.e. n ot q ualif yi 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 gr essi o n wit hi n t he first 1 2 wee k s). 
O verall  lesi o n  res p o nses  of  C R  m ust  sta y  t he  sa me  u ntil  pr o gres si 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 ntl y 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 pl y a pr 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 nce a n o verall lesi o n res p o nse of  P R is o bser ve d ( w hic h ma y have 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  sta y  t he  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 v er,  i n  st u dies  w here 
c o nfir mati o n of res p o nse is re q ui re 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 we d  b y  a  < 3 0 %  re d ucti o n  fr o m 
baseli ne at t he ne xt 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 otall y  disa p pear  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 here 
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  c o nsi dere d  P R  ( or  U N K)  until  pr o gressi o n  is  d oc u me nte d   or  t he  lesi o n  t otall y 
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 of 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-tar get  lesi o ns  di d  n ot  pr ogress,  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 

N o v arti s 
C o nfi d e nti al 
P a g e 1 1 8 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
meas ure me nts  decrease  o nl y  b y  2 0 %  c o m pare 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  co nti n ues  st u d y  treat me nt,  f urt he r  assess me nts  are  n ot 
c o nsi dere d f or t he deter mi na ti o n of best o verall res p o nse. 
N ote: T hese cases ma y be 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 dise ase 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, b ase d o n t he se q ue nce of o verall 
lesi o n  res p o nses.  H o we ver,  t he  o verall  lesi o n  res p o nse  at  a  gi ve n  assess me nt  ma y  be 
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 mar y a nal ysis of t he best o verall res p o nse will be base d  o n t he i n vesti gat or re vie w 
of o verall lesi o n res p o nses. 
Base d o n t he patie nts’ best o ve rall res p o nse d uri n g t he st u d y, t he f oll o wi n 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 of C R 
or P R or S D. 
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 cert ai 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 ate ( E P 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. 
T he pr ot oc ol s h o ul d defi ne p o p ulat i 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 d y s pecific. E P R is use d f or t he m ulti n o mial desig 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 hi s  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 ysis 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 ysis 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 po 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 ma 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 ysis 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). 
3. 2  
Ti m e t o e v e nt v ari a bl e s 
3. 2. 1  Pr o gr e s si o n-fr e e s ur vi v al 
Us uall y  i n  all  O nc ol o g y  st u dies,  patie nts  are  f oll o we d  f or  t u m o r  pr o gressi o n  after 
disc o nti n uati o n of st u d y me dica ti o n f or reas o ns ot her t ha n pr o gressi 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 h is s h o ul d be clearl y state d i n t he pr ot oc ol. N ote t hat 

N o v arti s 
C o nfi d e nti al 
P a g e 1 1 9 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
ra n d o mize d trials ( prefera bl y bli n de d) are rec o m me n de d w here P FS 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 on 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. 
3. 2. 2  O v er all s ur vi v al 
All patie nts s h o ul d be f oll o we d u ntil deat h or u n til patie nt has ha d a de q uate f oll o w- u p 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 o w- u p data s h o ul d 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 ve 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 ve. 
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 n si der  o nl y  deat h  relate d  t o  u n derl yi n g  cancer  as  a n  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 be 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 yi n g ca ncer. 
Ti 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 the 
date of e ve nt defi ne d as t he first d oc u me nte d pr o gressi o n or de at h d ue t o u n derl yi n g ca ncer. 
If a patie nt has n ot ha d a n e vent, ti me t o pr o gressi o n is ce ns o re d at t he date of last a de q uate 
t u m or assess me nt. 
3. 2. 4  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  disea se 
w here earl y 
disc o nti n uati o n is t y picall y rel ate d t o i nt olera nce of t he st u d y dr 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 o m date of ra n d o mizati o n/start of treat me nt 
t o  t he  earliest  of  date  of  pr o gressi o n,  date  of  deat h  d ue  t o  a ny  ca use,  or  date  of 
disc o nti n uati o n d ue t o reas o ns ot h er t ha n ‘ Pr ot oc ol vi olati o n’ or ‘ A d mi nistrati ve pr o ble ms’. 
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 n ce treat me nt fail ure will be 
ce ns ore d at last a de q uate t u m or assess me nt. 
3. 2. 5  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 ul d  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 intr 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 ntl y 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 here  t h is  pr o ba bl y  pri maril y  reflected  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 p s 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 get i nt o res p o nse rea dil y (a n d relati vel y 
q uic kl y) a n d te n d t o re mai n i n res p o nse after t he y 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 resp o nse, ma y ha ve 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 he y 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 2 0 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
ris k patie nts. Less p ote nt a ge nts i n d uce a res p o nse mai nl y i n go o d ris k patie nts o nl y. T his is 
descri 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 ysis of all patie nts ( b ot h res p o nders a n d n o n-res p o n ders) be 
perf or me d w het her or n ot a “re s p o n ders o nl y” descri pti ve a nal ysis is prese nte d. A n a nal ysis 
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  s tatistics  a n d  e ve n  t he n 
i nter prete d wit h ca uti o n b y e valuati 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  be 
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 s h 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 or  s u m mar y  statistics  o n  “res p o n ders”  o nl y  t he  f oll o wi n g  defi n iti o ns  are  a p pr o priate. 
( S pecific defi niti o ns f or a n all- patie nt a nal ysis of t hese e n d poi nts are n ot 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 ( C R or P R):  F or patie nts wit h a C R or P R ( w hic h ma y ha ve 
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 w o 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 d y 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 or patie nts wit h a C R ( w hic h ma y ha ve 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  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. 
D ur ati o n of st a ble dise ase ( C R/ P R/ S D):  F or patie nts wit h a C R or P R ( w hic h ma y ha ve 
t o be c o nfir me d) or S D t he start a n d e n d date as well 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. 
3. 2. 6  Ti m e t o r e s p o n s e 
Ti me t o o ver all res p o nse ( C R 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  ( C R  or  P R).  T he  res p onse  ma y  nee d  t o  be 
c o nfir me d de pe n di n g o n t he t y pe of st u d y a n d its i m p orta nce. W h ere t he res p o nse nee ds 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 ysis  o n  t he  f ull  p o p ulati o n  is  preferre d  a  desc ri pti ve  a nal ysis  ma y  be 
perf or me d o n t he “res p o n ders” s u bs et o nl y, i n w hic h case t he re s ults s h o ul d 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  3. 2. 5 .  It  is 
rec o m me n de d  t hat  a n  a nal ysis  of  all  patie nts  ( b ot h  res p o n ders  an 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 ysis  i ncl u di n g all  patie nts, 
patie nts w h o di d n ot ac hie ve a r es 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: 

N o v arti s 
C o nfi d e nti al 
P a g e 1 2 1 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 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 nal ysis) f or patie nts w h o ha d 
a P F S e ve nt (i.e. pr o gresse d or di e 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 
w orst p ossi ble o utc 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 nal ysis 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 o w- 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 m e nt date, ot her wise. I n t his case patie nts ha ve n ot yet 
pr o gresse d s o t he y t he oreticall y s till ha ve a c hance of res p o n d i n g 
Ti me t o o ver all c o m plete res p o nse ( C R)  is t he ti me bet wee n dates of 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 nal ysis  c o nsi d erati 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. 
3. 2. 7  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 or 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-ra y,  C T-sca n)  if  t he  o verall  l esi 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 u re me nt dates at t hat e val uati o n 
n u m ber. 
St art d at e s 
F or all “ti me t o e ve nt” varia ble s, ot her t ha n d urati o n of res p onse, 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  of  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 pecti vel y, w he n t his stat us is later c o nfi r me d. 
E n d d at e s 
T he e n d dates w hic h are use d t o cal c ulate ‘ti me t o e ve nt’ varia bles 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 o w- 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 ( bef ore a n e ve nt or a ce ns or i n g reas o n occ urre d) t he 
date of ra n d o mizati o n/star t of treat me nt is use d. 
 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 be y o n d t he acce pta ble ti me wi n d o w for t he ne xt 
t u m or assess me nt as per pr ot oc ol (see Secti o n 3. 2. 8 ). 

N o v arti s 
C o nfi d e nti al 
P a g e 1 2 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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 mor assess me nts at 
baseli ne - 3 m o nt hs - 6 m o nt hs - missi n g - missi n g - P D. Date o f 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 da te 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 wa s 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  s a 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 v e fr o m t he s ur vi val f oll 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 dat e 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 he ra p y  is  defi ne d  as  t he  start  date  of  a n y  a d diti o nal 
(sec o n dar y) a nti ne o plastic t hera p y or s ur ger y. 
3. 2. 8  H a n dli n g of p ati e nt s wi t 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 d y, 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 t he pri mar y e n d p oi nt). I n s uc h cases t he ha n dli n g o f 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 a nal 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 patie 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  wit 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 
meas ura ble disease is deri ve d sli g htl y differe ntl y acc or di n g t o  Ta ble 3- 1 . 
T a bl e 3- 1  
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 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 nts is c o nsi dere d 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 s u m mar y ta bles f or be st o verall res p o nse patie nts 
wit h  o nl y  n o n- meas ura ble  disease  ma 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 yi n g t he s p ecific n u m bers wit h t he n o n- C R/ n o n- P D cate g or y. 
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 ysis t he i m p orta nce 
t o eac h e n d p oi nt of bei n g a ble to 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 nee ds 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 ysis 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”. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 2 3 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
F or P F S , it is a gai n rec o m me n de d t hat t he mai n I T T a nal yses o n t hese en 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 a nal 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  ca n  i nc or p orate  data  fr o m  patie nts  wit h  o nl y 
n o n- meas ura ble disease. 
3. 2. 9  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 o r  pr o gressi o n,  as  well  as 
a d dresses 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 n t, 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 n ore d if it occ urre d after 
a l o n g peri o d of a patie nt bei n g l o st t o f oll o w- u p? It is i m p orta nt t hat t he prot 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 definiti o n of e ve nt a n d ce ns ori n g 
dates a n d als o i ncl u de a descr i 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  3. 2. 7 ,  a n d  usi n g  t he  draft  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 nal yses ca n be c o nsi dere d:  
T a bl e 3- 2  
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 nt 3   
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 or 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 la st a d e q u at e a s s e s s m e nt  
C e n s or e d 
E 
Tr e at m e nt di s c o nti n u at i 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) N/ A 
( 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) 
I g n or e d 
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) D at e of l a st a d e q u at e a s s e s sm e nt 
( 2) 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 
( 3) 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 
( 4) N/ A 
C e n s or e d 
C e n s or e d 
E v e nt 
I g n or e d 
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 3. 2. 7 . 
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 dul 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 3. 2. 7 . 
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 ha 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 nal ysis a n d t he se n siti vit y a nal yses m ust be s pecifie d i n t he pr otoc ol. Clearl y 
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. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 2 4 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
Sit uati o n s C ( C 1 a n d C 2): Pr o gressi o n or deat h after o ne or m ore missi n g assess me nts: The 
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 gressio n  or  deat h  date,  i n  t he  case  o f  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 w o  or  missi n g  assess me nts  (sit uati o n  C 2),  o pti on  ( 3)  ma y  be  c o nsi dere d 
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  s c 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. 
Sit u ati o n  E:  Tre at me nt  disc o nti n u a ti 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 defa 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 ul d  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 nstea d of t u m or assess me nt b y e. g. C T-s ca n, o pti o n ( 2) ma y be use d 
f or  i n dicati o ns  wit h  hi g h  earl y  pr 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.e. ce ns ori n g at last a de q uate assess me nt ma y 
be use d as a defa ult i n t his case. 
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 nal yses  t o  c hec k  f or 
p ote ntial bias i n f oll o w- u p sc he d ules f or t u m or assess me nts, e. g. b y assi 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 h e d 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  3- 2   t he  “ Date  of  last  a de q uate  assess me nt”  b y  t he  “ 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 s c 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 h e last a de q uate t u m or 
assess me nt. 
I n  a d diti o n,  a nal yses  c o ul d  be  re peate d  usi n g  t he  I n vesti 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 y pes  of  se nsiti vit y  a nal yses  will 
de pe n d o n 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. 
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 nce  f or  de vel o p me n t  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 p lete dates). 
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 AP d oc u me ntati o n. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 2 5 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
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 yse s s h o ul d 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). 
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 m a y  v ol u ntaril y wit h dra w fr o m t he st u d y treat me nt or ma y be 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 or patie nts w h o are l ost t o f oll o w-
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 te le 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 uld occ ur 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 tre at me nt f or a n 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 ysicia 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 decisi o n 
 Deat h 
 Pr o gressi ve 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 pe r 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) 
4. 3  
E n d of p o st-tr e at m e nt f oll o w- 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 o w- u p  visit  will  be  c o m plete d  after  d isc 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 o w- u p. 
Patie nts ma y pr o vi de st u d y p hase 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 verse e ve nt 
 L ost t o f oll o w- u p 
 P h ysicia 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 decisi o n 
 Deat h 
 Ne w t hera p y f or st u d y i n dicati o n 
 Pr o gressi ve disease 
 St u d y ter mi nate d b y t he s p o ns or 

N o v arti s 
C o nfi d e nti al 
P a g e 1 2 6 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 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 
As R E CI S T 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  qualifie d  f or  P D),  t hese 
U N K  assess me nts  ma y  be  re-e val uate d  b y  cli nicia ns  at  N o vartis  o r  e xter nal  e x perts.  I n 
a d diti o n,  data  re vie w  re p orts  wil l  be  a vaila ble  t o  i de ntif y  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 CI S 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 ver  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 x ter 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 ‘ Dis ease 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 CI S T criteria s h o ul d be caref ull y re vie we d. O nl y patie nts wit h d oc u me nte d deteri orati o n 
of s y m pt o ms i n dicati ve of pr o gr essi o n of disease s h o ul d ha ve t his reas o n f or disc o nti n uati o n 
of treat me nt or st u d y e val uati o n. 
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 ult s: 
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 - s tart date + 1 (i n da ys). 
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 da y) w he n ti me is t o be ce ns ore d at last 
t u m or assess me nt, i.e. ti me t o eve nt varia bles ca n ne ver be ne g ati ve. 
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 da tes (e. g. X-ra y, C T sca n) m ust be c o m plete d wit h da y, m o nt h a n d year. 
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 f or calc ulati on 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 3. 2. 7 ). If all meas ure me nt dates ha ve n o 
da y rec or de d, t he 1 st 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, the 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 bet 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 ot be use d f or 
a n y calc ulati o n. 
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 a t h 
All dates m ust be c o m plete d w it h da y, m o nt h a n d year. If t he day 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. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 2 7 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 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 herefore 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)’. 
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 nal ysis pr o gra ms  nee d t o be a da pte d f or eac h st u dy/ pr oject. 
4. 5. 6  C e n s ori n g r e a s o n 
I n or der t o s u m marize t he vario us reas o ns f or ce ns ori n g, t he f o ll 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 n s ori n g reas o ns are p ossi ble: 
 Ali ve 
 L ost t o f oll o w- u p 
F or P F S a n d T T P (a n d t h eref ore d urati o n of r es p o nses) t he f oll owi n g ce ns ori n g reas o ns are 
p ossi ble: 
 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 afte r t w o or m ore missi n g t u m or assess me nts ( o pti o nal, see Ta ble 3-
2 ) 
 Deat h d ue t o reas o n ot her  t ha n u n derl yi 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 3. 2. 7 . 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 u t- 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 n g  clarificat i 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 va l uati o n  (e. g. 
reas o n =“ S p o ns or decisi o n” o n stu 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 o r 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 va ils i n sit uati o ns w he n 
a n ot her ce ns ori n g reas o n (e. g. w it h dra wal of c o nse nt, l oss t o foll o w- u p or alter nati ve 
a nti-ca ncer  t hera p 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. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 2 8 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 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, Zee ( 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 n d 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 r es p o nse e val uati o n criteria i n s oli d t u m ors: re vise d 
R E CI S 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 
F D A G ui deli nes: 2 0 0 5 Cli nical Tri al 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 ui deli nes: 2 0 0 7 Cli nical Tri al 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, Ma y 2 0 0 7 
M or ga n T M ( 1 9 8 8) A nal ysis of d ur ati o n of res p o nse: a pr o ble m of  o nc ol o g y 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 0 5- 1 6 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 1 2 9 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
1 4. 3  
A p p e n di x 3: P ati e nt r e p ort e d o ut c o m e s 
 
Fi g ure 1 4- 1 E O R T C- Q L Q- C 3 0  

N o v arti s 
C o nfi d e nti al 
P a g e 1 3 0 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 1 3 1 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1 
 
 
Fi g ure 1 4- 2:  E O R T C- Q L Q- B R 2 3  

N o v arti s 
C o nfi d e nti al 
P a g e 1 3 2 
O n c ol o g y Cli ni c al Tri al Pr ot o c ol ( V er si o n 0 4)  
 
Pr ot o c ol N o. C L E E 0 1 1 X D E 0 1