Conditions: Advanced Metastatic Breast Cancer
Keywords: ribociclib LEE011 RIBECCA breast cancer breast carcinoma HR-positive HER2-negative advanced breast cancer Letrozole CDK4/6 breast lump HER2 positive metastatic breast cancer breast cancer positive for human epidermal growth factor receptor 2 (HER2) HER2 positive metastatic breast cancer breast cancer progression estrogen-receptor (ER) positive(+) breast cancer Paget's disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 502
Healthy volunteers: no

Brief summary:
This was a national, multi-center, open-label, phase IIIb trial to determine the efficacy and safety of treatment with ribociclib (LEE011) plus letrozole in patients with HR+, HER2-negative advanced (recurrent or metastatic) breast cancer. Patients were treated with daily doses of 600 mg ribociclib (3-weeks-on/1-week-off schedule) in combination with 2.5 mg letrozole daily (continuous dosing). Dose adjustments (dose reduction or interruption) according to safety findings were allowed.

Detailed description:
The main purpose of this study was to collect additional efficacy and safety data for the combination of ribociclib and letrozole in a patient population broader than the MONALEESA-2 study (NCT01958021 / CLEE011A2301), and to provide access to ribociclib to patients for which available treatment options are unsatisfactory treatment alternatives until the drug is approved for this indication. Furthermore, this trial aimed to collect data for the combination of ribociclib and letrozole in the context of current local routine therapy algorithms for the treatment of metastatic and advanced breast cancer.

This multi-center, open-label, single-arm study aimed to evaluate the efficacy, safety, and quality of life for the combination of ribociclib and letrozole in a patient population than in the MONALEESA-2 study, i.e. in patients pretreated with one line of chemotherapy and/or a maximum of two lines of endocrine therapy as well as premenopausal patients, without limitations regarding the disease free interval after adjuvant therapy.

For ethical reasons no endocrine comparator drugs were investigated in this study. The duration of study treatment of 80 weeks was adequate to determine the primary, secondary and exploratory study parameters. The sample size was suitable to estimate the clinical benefit rate (CBR) in this patient population with reasonable precision.

Goserelin was used in premenopausal patients, since it was shown that ovarian suppression of estrogen release with luteinizing hormone-releasing hormone agonists (LHRHa) (such as goserelin) is effective in preventing relapse in premenopausal women with early stage ER+ breast cancer (Klijn et al. 2001).

The efficacy and safety of ribociclib in combination with letrozole for the treatment of postmenopausal women with advanced or metastatic breast cancer vs. placebo (i.e., letrozole alone) was already demonstrated in the preceding, pivotal MONALESSA-2 study. Thus, for ethical reasons no endocrine comparator drugs were investigated in the present RIBECCA study.

Generally, the single-arm, open-label design and the broadening of the study population (compared to the pivotal MONALESSA-2 study) in the RIBECCA study was deemed appropriate to further evaluate the efficacy and safety of ribociclib plus letrozole among breast cancer patients in a treatment setting closer to routine care. The duration of study treatment of up to 80 weeks was considered adequate to determine the primary, secondary and exploratory study parameters. Moreover, the sample size was suitable to estimate the CBR in this patient population with reasonable precision.

Arms:
arm 1: ribociclib + letrozole cohort A - postmenopausal women, or men; naïve.

All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. arm 2: ribociclib + letrozole cohort B1 - premenopausal women or perimenopausal women; naïve

All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily.

Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly arm 3: ribociclib + letrozole cohort B2 - premenopausal women or perimenopausal women or postmenopausal women, or men; pre-treated.

All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily.

Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly

Interventions: intervention 1: ribociclib intervention 2: letrozole intervention 3: goserelin
Intervention descriptions: intervention 1: All patients with oestrogen receptor positive advanced or metastatic breast cancer were treated with oral ribociclib at a dose of 600mg daily and oral letrozole 2.5mg daily. The study treatment for an individual patient began on Study Day 1 and continued until 80 weeks after the last patient enrolled the study or until disease progression, unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occured first. intervention 2: All patients with oestrogen receptor positive advanced or metastatic breast cancer were treated with oral ribociclib at a dose of 600mg daily and oral letrozole 2.5mg daily. The study treatment for an individual patient began on Study Day 1 and continued until 80 weeks after the last patient enrolled the study or until disease progression, unacceptable toxicity, death or early discontinuation from the study for any other reason, whichever occured first. intervention 3: Premenopausal patients additionally received goserelin 3.6mg as monthly implant

Protocol document:
Prot_000.pdf: 
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 
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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 
 
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 
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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 
 
 


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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C o nfi d e nti al 
P a g e 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 
 
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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C o nfi d e nti al 
P a g e 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 
 
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 


N o v arti s 
C o nfi d e nti al 
P a g e 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 
 
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 


N o v arti s 
C o nfi d e nti al 
P a g e 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 
 
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; 


N o v arti s 
C o nfi d e nti al 
P a g e 3 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 
 
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, 


N o v arti s 
C o nfi d e nti al 
P a g e 3 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 
 
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 


N o v arti s 
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.  


N o v arti s 
C o nfi d e nti al 
P a g e 4 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.  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) 


N o v arti s 
C o nfi d e nti al 
P a g e 4 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 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, 


N o v arti s 
C o nfi d e nti al 
P a g e 4 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 
 
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: 


N o v arti s 
C o nfi d e nti al 
P a g e 5 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 
 
 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. 


N o v arti s 
C o nfi d e nti al 
P a g e 5 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 
 
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).   


N o v arti s 
C o nfi d e nti al 
P a g e 8 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 
 
 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: 


N o v arti s 
C o nfi d e nti al 
P a g e 8 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 
 
 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. 


N o v arti s 
C o nfi d e nti al 
P a g e 8 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 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 


N o v arti s 
C o nfi d e nti al 
P a g e 8 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 
 
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 
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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 
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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 
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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 
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9. 
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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. 
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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 
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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 . 


N o v arti s 
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 
 
 

SAP_001.pdf: 
Clinical Development 
LEE011/Ribociclib/Kisquali® 
   CLEE011XDE01 / NCT03096847
A national phase IIIb, multi-center, open label study for 
women and men with hormone-receptor positive, HER2-
negative locally advanced or metastatic breast cancer treated 
with ribociclib (LEE011) in combination with letrozole  
RIBECCA 
Statistical Analysis Plan (SAP) 
Author: 
: 
 (TS) 
Document type: 
SAP Documentation 
Document status: 
Final Version 3.0 
Release date: 
22-Apr-2020
Number of pages: 
27 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Signature Page 
 
 
 
 
Dr. 
 
_________________________ 
____________ 
(
) 
Signature 
Date 
 
 
 
 
Dr. 
  
_________________________ 
____________ 
(Trial Statistican) 
Signature 
Date 
 
 
 
 
  
_________________________ 
____________ 
(
) 
Signature 
Date 
 
 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for update 
Outcome for update 
Section and title 
impacted 
(Current) 
25-SEP-
2017 
Prior 
to 
1st 
interim analysis 
Creation of draft version for 
review by Novartis TS/ML 
N/A – First version 
NA 
06-NOV-
2017 
After 
RAMP-
Meeting 
for 
IA1 
Revision of draft version 
Draft 02 
 
14-DEC-
2017 
Before 
1st 
Interim analysis  
Revised after review TS Dr. 
 
Draft 03 
 
14-DEC-
2017 
Before 
1st 
Interim analysis 
Prefinal version for IA1 
Prefinal 01 
 
20-DEC-
2017 
Before 
1st 
Interim analysis 
Revised after review by 
 Dr. 
 
Prefinal 02 
Final version 1.0  
(21-DEC-2021) 
Signature 
page 
included 
30-OCT-
2019 
After 3rd 
interim 
analysis, before 
final analysis 
 
post-hoc multivariate 
analysis for neutropenia 
and AST/ALT 
elevations included,  
 
programming details 
added 
Sensitivity 
analyses 
added 
(in-/excluding 
centers 
with 
relevant 
inspection finding) 
 
Final Version 2.0 
 2.13 Other 
exploratory 
analyses 
 Several 
 
 
22-Apr-
2020 
After Data 
Review 
Meeting 
Final decision rules for 
Populations 
Final version 3.0 (22-Apr-
2020) 
Section 5.8:  
Table 1,  
Table 2 
 


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Table of contents 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design............................................................................................................. 8 
1.2 
Study objectives and endpoints ............................................................................... 8 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................................... 11 
2.2.1 
Subgroup of interest .............................................................................. 11 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 12 
2.3.1 
Patient disposition ................................................................................. 12 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 12 
2.4.1 
Study treatment / compliance ................................................................ 12 
2.4.2 
Prior, concomitant and post therapies ................................................... 13 
2.5 
Analysis of the primary objective .......................................................................... 13 
2.5.1 
Primary endpoint ................................................................................... 13 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 15 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 15 
2.5.4 
Supportive analyses ............................................................................... 15 
2.6 
Analysis of the key secondary objective ............................................................... 16 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 16 
2.7.1 
Secondary endpoints ............................................................................. 16 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 17 
2.8 
Safety analyses ....................................................................................................... 17 
2.8.1 
Adverse events (AEs) ............................................................................ 17 
2.8.2 
Deaths .................................................................................................... 19 
2.8.3 
Laboratory data ..................................................................................... 19 
2.8.4 
Other safety data ................................................................................... 19 
2.9 
Pharmacokinetic endpoints .................................................................................... 19 
2.10 
PD and PK/PD analyses......................................................................................... 20 
2.11 
Patient-reported outcomes ..................................................................................... 20 
2.12 
Biomarkers ............................................................................................................. 20 
2.13 
Other Exploratory analyses .................................................................................... 20 
2.14 
Interim analysis ...................................................................................................... 21 


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3 
Sample size calculation ..................................................................................................... 21 
4 
Change to protocol specified analyses .............................................................................. 21 
5 
Appendix ........................................................................................................................... 22 
5.1 
Definition of efficacy variables ............................................................................. 22 
5.1.1 
Clinical Benefit Rate (CBR) until week 24 ........................................... 22 
5.1.2 
Overall response rate (ORR) by week 24 ............................................. 23 
5.1.3 
Progression-free survival ...................................................................... 23 
5.1.4 
Overall survival (OS) ............................................................................ 23 
5.2 
Definiton of safety variables .................................................................................. 23 
5.2.1 
Duration of study treatment exposure ................................................... 23 
5.2.2 
Cumulative dose .................................................................................... 24 
5.2.3 
Dose intensity (DI) ................................................................................ 24 
5.2.4 
Planned dose intensity (PDI) ................................................................. 24 
5.2.5 
Relative dose intensity (RDI) ................................................................ 24 
5.2.6 
Mean relative dose intensity (mean RDI) ............................................. 24 
5.2.7 
Adverse events of special interest ......................................................... 24 
5.3 
Programming rules ................................................................................................. 24 
5.3.1 
Calculation of ‘time to event’ variables ................................................ 24 
5.4 
Imputation rules ..................................................................................................... 25 
5.4.1 
Incomplete assessment dates ................................................................. 25 
5.4.2 
Incomplete dates for last known date patient alive or death ................. 25 
5.4.3 
Non-target lesion response .................................................................... 25 
5.4.4 
Censoring reason ................................................................................... 25 
5.4.5 
Study treatment ..................................................................................... 26 
5.4.6 
AE date imputation ............................................................................... 26 
5.4.7 
Concomitant medication date imputation ............................................. 26 
5.5 
AEs coding/grading ............................................................................................... 27 
5.6 
Laboratory parameters derivations ........................................................................ 27 
5.7 
Statistical models ................................................................................................... 27 
5.7.1 
Primary analysis .................................................................................... 27 
5.8 
Rule of exclusion criteria of analysis sets.............................................................. 27 
6 
Reference ........................................................................................................................... 29 


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List of abbreviations 
 
aBC  
AE  
Advanced Breast Cancer  
Adverse Event  
ALT  
Alanine aminotransferase/glutamic pyruvic 
transaminase/GPT  
AST  
Aspartate aminotransferase/glutamic 
oxaloacetic transaminase/GOT  
β-hCG  
β-subunit of hCG gonadotropin – free hCG 
gonadotropin  
BLRM  
Bayesian Logistic Regression Model  
CBR  
CISH  
Clinical benefit rate  
Chromogen-in situ-Hybridisierung  
CNS  
Central nervous system  
CR  
Complete response  
CRF  
Case Report/Record Form; the term CRF can 
be applied to either EDC or Paper  
CRO  
Contract Research Organization  
CSR  
Clinical study report  
CSR addendum  
  
An addendum to Clinical Study Report (CSR) 
that captures all the additional information that 
is not included in the CSR  
CT  
DDI  
DFS 
Computed tomography  
Drug-Drug-Interaction  
Disease-free survival 
DLT  
Dose Limiting Toxicity  
DS&E  
Drug Safety and Epidemiology  
ECG  
Electrocardiogram  
ECOG  
Eastern cooperative oncology group  
ER  
FAS 
FISH  
FSH  
GBM  
Estrogen receptor  
Full Analysis Set 
Fluoreszenz-in-situ-Hybridization  
follikelstimulierendes Hormon  
Glioblastoma multiforme  
i.v.  
intravenous(ly)  
ICH  
International Conference on Harmonization  
IEC  
Independent Ethics Committee  
IRB  
Institutional Review Board  
LPFV  
LPLV  
Last Patient First Visit  
Last Patient Last Visit  
MAP  
Master Analysis Plan documents project 
standards in the statistical methods which will 
be used within the individual clinical trial RAP 
documentation  
MTD  
Maximum Tolerated Dose  
NCI-CTCAE  
National cancer institute – common terminolgy 
criteria for adverse events  
NCRNPD  
neither complete response nor progressive 
disease  
PD  
PFS  
Progressive disease  
Progression Free Survival  
p.o.  
per os/by mouth/orally  
PHI  
Protected Health Information  


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PgR  
PR  
QTcF  
Progesterone receptor  
Partial Response  
QT corrected for HR using Fridericia's 
method  
ORR  
Overall response rate  
OS  
Overall survival  
RAP  
The Report and Analysis Plan (RAP) is a 
regulatory document which provides 
evidence of preplanned analyses  
REB  
Research Ethics Board  
RECIST  
Response Evaluation Criteria in Solid 
Tumors  
SAE  
SAF 
Serious Adverse Event  
Safety Analysis Set 
SD  
SISH  
SmPC  
SOD  
Stable disease  
silver-in situ-Hybridisation  
Summaries of Product Characteristics  
Sum of Diameter  
SOP  
TTF  
TTP  
UNK  
Standard Operating Procedure  
Time to treatment failure  
Time to Progression  
Unknown  
 
 
 


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1 
Introduction 
This statistical analysis plan describes the final and the three pre-planned interim analyses. 
It is based on the 4th amendment of the study protocol, dated 05-JUN-2019. 
1.1 
Study design 
This was a national, multi-center, open-label, phase IIIb trial to determine the efficacy and 
safety of treatment with ribociclib (LEE011) plus letrozole in patients with HR+, HER2-
negative advanced (recurrent or metastatic) breast cancer.  
In this trial a total of 500 patients from 100 centers were planned to be recruited. 
The study was designed as an open-label, single-arm trial, hence no randomization took place. 
The primary efficacy and safety analysis was conducted on all patient data at the time all 
patients who are still receiving study drug will have completed at least 24 weeks of treatment 
(or discontinued prematurely). The additional data for any patients continuing to receive study 
drug past these times, as allowed by the protocol, was further summarized in a report once these 
patients completed the study. 
Three interim analyses were planned during the study. The first interim analysis was conducted 
one year after the first patient has been enrolled and included a preliminary analysis on safety. 
The second interim analysis was conducted 12 months after LPFV in the 30% pretreated and 
premenopausal cohort (=Cohort B, see section 2.2.1 Subgroup of interest) and included a 
preliminary analysis on safety, efficacy and quality of life. The third interim analysis took place 
6 months after the last patient had been recruited into cohort A (see section 2.2.1 Subgroup of 
interest) and included a preliminary analysis on safety and efficacy. 
1.2 
Study objectives and endpoints 
Objectives and related endpoints are described in the table below (in accordance with Table 3-1 
from the protocol). 
 
Primary Objective  
Endpoint  
The primary objective of this study is the assessment of 
the clinical benefit rate after 24 weeks for the total 
population and for cohorts A and B separately:  
1. Cohort A: postmenopausal women and men who 
received no prior treatment for advanced disease. 
(70% group)  
2. Cohort B: pre-, and perimenopausal women who 
received no prior treatment for advanced disease 
as well as pre-, peri- and postmenopausal women 
and men who received no more than 1 prior 
chemotherapy and 2 prior lines of endocrine 
therapy for advanced disease (30% group) 
Clinical Benefit Rate (CBR) after 
24 weeks of treatment as defined 
by RECIST 1.1 as percentage of 
patients with CR, PR or SD until 
week 24 or longer as well as 
patients with NCRNPD >24 
weeks for patients with non-
measurable disease  
 


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Secondary Objectives  
Endpoint  
To assess the clinical benefit rate (CBR) after 24 weeks 
among Cohort B1 and B2: 
 
- Cohort B1: pre- and perimenopausal women 
without prior therapy for advanced disease  
 
- Cohort B2: pre-, peri- and postmenopausal women 
and men who were pretreated for advanced disease 
Clinical Benefit Rate (CBR) after 
24 weeks of treatment as defined 
by RECIST 1.1 as percentage of 
patients with CR, PR or SD  until 
week 24 or longer as well as 
patients with NCRNPD >24 
weeks for patients with non-
measurable disease  
Progression-free survival (PFS) for the three different 
populations: 
Cohort A, Cohort B1, Cohort B2  
PFS 
based 
on 
radiologic 
assessment by investigator using 
RECIST 1.1 criteria (e.g. median 
PFS, PFS rate at 12 and 18 
months)  
Overall survival (OS) for the three different populations, 
defined as the time from date of start of treatment to date 
of death due to any cause. 
Overall survival (OS) (e.g. OS 
rate at 12 and 24 months)  
Overall response rate (ORR) for the three different 
populations, defined as complete response or partial 
response as defined by RECIST 1.1 
Overall Response Rate (ORR) 
after 24 weeks 
To evaluate the safety and tolerability of ribociclib in 
combination with letrozole (and goserelin in 
premenopausal patients) 
Frequency/severity of AEs 
AEs of special interest: 
Frequency, severity, frequency 
per patient, time to Event, 
duration of Event and recurrence  
Laboratory values 
To evaluate patient reported outcomes for health 
related quality of life 
Time to 10% deterioration in the 
global health status/QOL scale 
score of the EORTC QLQ-C30 
 
Change from baseline in the 
global health status/QOL scale 
score of the EORTC QLQ-C30 
 


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Exploratory Objectives  
(out of scope of this statistical analysis plan)  
Endpoint 
 
 
 
 
  
 
 
 
  
 
 
 
 
Analysis methods and endpoints 
will be used that resemble the 
current scientific standard at the 
time of analysis.  
 
Such analyses will be described 
in a separate analysis plan  
 
2 
Statistical methods 
2.1 
Data analysis general information 
The data were analyzed by 
. Analysis was carried out using the SAS 
(Statistial Analysis System) software, version 9.2, 2009, SAS Institute Inc., Cary, North 
Carolina, USA. 
Interim analyses were carried out by 
 as well. The analyses were 
based on definitions within this SAP and RAP 7.1 and the tables generated for the particular 
interim analyses were marked in RAP 7.2. 
The first interim analysis included a preliminary analysis of safety (as well as baseline 
characteristics). The second interim analysis included a preliminary analysis of safety, efficacy 
and quality of life. The third interim analysis included a preliminary analysis of safety and 
efficacy. The primary efficacy and safety analysis was conducted on all patient data at the time 
all patients who are still receiving study drug had completed at least 24 weeks of treatment (or 
discontinued prematurely). The additional data for any patients continuing to receive study drug 
past these times, as allowed by the protocol, were further summarized in a report once these 
patients completed the study. 
In general, categorical variables were summarized by absolute and relative frequencies. 
Continuous variables were summarized by descriptive statistics (number of non-missing 
observations, mean, standard deviation, minimum, median and maximum). Time-to-event data 
including rates of affected patients were assessed using the Kaplan-Meier method. The primary 
aim of this trial was in estimation rather than significance testing of statistical hypotheses. Thus, 
mainly statistical estimators along with appropriate two-sided 95% confidence intervals were 
used. However, changes from baseline were explored using suitable statistical tests for paired 
samples. No adjustment for multiplicity was done due to the exploratory nature of the trial. 
The data from all participating centers were combined, so that an adequate number of patients 
was available for analysis and the factor center was included in the analysis of the primary 
endpoint. 


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2.1.1 
General definitions  
Study treatment: 
The combination of drugs including investigational drug 
ribociclib as well as letrozole and goserelin acetate. 
 
On-treatment period: 
Period the patient was exposed to any study treatment, i.e from 
the first administration of any study treatment at or after C1/D1 to 
the last administration of any study treatment (for ribociclib and 
letrozole documented on the Treatment Completion CRF and for 
Goserelin documented on the Dosage Administration record but 
not later than the End-of-study visit (see 5.2.1) 
 
 
2.2 
Analysis sets 
The Enrolled Patient Population (ENR) includes all patients who signed an informed 
consent regardless whether they received study treatment or not. 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned. 
Patients with critical findings by an inspection were excluded. 
The Safety Set (SAF) includes all patients who received at least one dose of study treatment. 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the CSP. During the data review meeting the violations against the CSP 
were identified and assessed as relevant for analysis (called “major”) or not (“minor”). The PPS 
may be analyzed if a substantial number of patients was not compliant with the requirements of 
CSP. This decision will be done during a data review meeting before analysis. 
2.2.1 
Subgroup of interest 
All results of this study were displayed for the total population and for cohorts A, B, B1 and 
B2 separately (each cohort is displayed in a separate column):  
 Cohort A: Postmenopausal women and men who received no prior treatment for 
advanced disease. 
 Cohort B: Pre-, and perimenopausal women who received no prior treatment for 
advanced disease (B1) as well as pre-, peri- and postmenopausal women and men who 
received prior therapy (B2). According to exclusion criteria only patients with no more 
than 1 prior chemotherapy and 2 prior lines of endocrine therapy for advanced disease 
were included. 
 


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Cohorts: 
Postmenopausal 
women or men 
Pre- or perimenopausal 
women 
Treatment naive 
A 
B1 
Pre-treated 
B2 
B2 
 
Further subgroups of interest may be analyzed for selected endpoints. These subgroups were: 
 Men 
 Pre- and perimenopausal women 
across all cohorts. 
During review of analysis tables it will be defined which tables will be additionally produced 
for the further subgroups. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographic and other baseline characteristics were summarized for the Full Analysis Set 
(FAS). Baseline characteristics include prior medication, past/current medical conditions and 
disease history. 
2.3.1 
Patient disposition 
Patient disposition was summarized for all patients by absolute and relative frequency of 
patients completing the study phases screening, treatment and study completion. Reasons for 
discontinuation were shown for the Enrolled Patient Population (ENR) for screening resp. the 
Full Analysis Set (FAS). 
The number of patients per visit and the number of on-treatment visits were given for the 
FAS. 
Frequencies of major (=leading to exclusion from per-protocol population) and minor protocol 
violations were reported. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Duration (days) of study treatment exposure for patients who took at least one dose of any of 
the components of the study treatment was calculated as the difference between the last and 
first day of drug application +1 day. For details see 5.2.1. 
The duration includes the periods of temporary interruptions for any reason. Additionally, 
duration of drug exposure was summarized using descriptive statistics separately for 
ribociclib, letrozole and goserelin, respectively.  


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The cumulative dose, dose intensity (DI) and relative dose intensity (RDI) were summarized 
by cohort. Cumulative dose is defined as the total dose given during the study treatment 
exposure. For patients who did not receive the respective drug the cumulative dose was set to 
zero (in case of goselerin for pre- and perimenopausal patients only). The dose intensity (DI) 
for patients with non-zero duration of exposure is defined as cumulative dose / duration of 
exposure. For patients who did not receive any drug, the DI was set to zero. Planned dose 
intensity (PDI) is the assigned dose in mg/day prescribed by the investigator to be given to 
patients. Relative dose intensity (RDI) is defined as DI divided by PDI. The DI and RDI were 
summarized separately for each of the study treatment components, but using the duration of 
the whole study treatment exposure, not the duration of each of the components. In addition, 
for combinations, the RDI was calculated as mean RDI of each of the study treatment 
components on a per-patient basis. 
 
Ribociclib interruptions (defined as null doses for any reason except “as per protocol”) were 
displayed by the number of affected patients, the total duration and frequencies of study drug 
interruptions. The total duration was calculated by end date – start date of interruption (for 
any reason except “as per-protocol”) + 1 day. All interruptions of a patient are summed up to 
the total duration (for any reason except “as per protocol”) 
Frequencies of the number of patients with ribociclib dose reduction (defined as dose > 0 mg 
but lower than the previous dose) as well as the number of dose reductions by reason were 
given. Additionally, dose reductions and dose interruptions were tabulated in combined 
fashion. In the combined summary, the dose interruptions were considered as dose reductions 
to 0 mg and therefore all reductions/interruptions were labeled as reductions and tabulated in 
one table. 
These analyses were performed for the Safety Set (SAF).  
2.4.2 
Prior, concomitant and post therapies 
Regarding the prior treatment for advanced breast cancer, the number, type, setting and best 
response of regimes before study were evaluated. The type was classified by WHO ATC level 2 
and preferred name. Radiotherapies and surgeries were analysed similarily. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be coded according to the WHO Drug Reference List and summarized by ATC 
class and preferred term using frequency distributions. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary objective of this study was the assessment of the clinical benefit rate after 24 
weeks. 
The Clinical Benefit Rate (CBR) is the proportion of patients with a best overall response of 
confirmed complete (CR) or partial (PR) response or stable disease (SD) or non-complete 
response, non-progressive disease (NCRNPD) within Week 24. The best overall response for 


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each patient is determined from the sequence of investigator overall lesion responses until week 
24 according to RECIST 1.1. To be assigned a best overall response of CR at least two 
determinations of CR at least 4 weeks apart before progression are required. To be assigned a 
best overall response of PR at least two determinations of PR or better at least 4 weeks apart 
before progression (and not qualifying for a CR) are required. To be assigned a stable disease, 
two determinations of SD at least 12 weeks apart (and not qualifying for PR or CR) are required.  
Patients with best overall response “unknown” will be summarized by reason for having 
unknown status. The following reasons will be used: 
 No valid post-baseline assessment 
 All post-baseline assessments have overall response UNK 
 New anti-neoplastic therapy started before first post-baseline assessment 
 SD too early (≤6 weeks after randomization) 
 PD too late (>12 weeks after randomization and not qualifying for CR, PR, or SD) 
Special (and rare) cases where BOR is unknown due to both early SD and late PD 
will be classified as “SD too early” 
During data review. i.e. before analysis, the number and reasons for best responses falling into 
the category “unknown” according to RECIST 1.1 criteria are investigated. In addition, the 
impact of confirmation of response on the outcome in the context of the visit schedule and 
assessment timepoints will be assessed. If necessary, further sensitivity analyses were defined 
to adjust for this uninformative category. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria will be carefully reviewed during the data review meeting. Only patients with 
documented deterioration of symptoms indicative of progression of disease should have this 
reason for discontinuation of treatment or study evaluation. 
 
Per RECIST 1.1, a change in methodology can be defined as either a change in contrast use (e.g. 
keeping the same technique, like CT, but switching from with to without contrast use or vice-
versa, regardless of the justification for the change) or a change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology will 
result by default in an UNK (unknown) overall lesion response assessment. However, another 
response assessment than the Novartis calculated UNK response may be accepted from the 
investigator or the central blinded reviewer if a definitive response assessment can be justified 
based on the available information. Potential discrepancies between the modality used and 
overall lesion response (e.g. change in modality but response is different from ‘Unknown’) will 
be queried during the data validation process.” 
Additionally, the CBR at EOT was determined. 


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2.5.2 
Statistical hypothesis, model, and method of analysis 
In this single-arm trial, the primary objective is to estimate the CBR. Therefore, no statistical 
hypothesis or model is underlying the analysis.  
The CBR (best overall response of CR or PR or SD or NCRNPD) as well as individual response 
categories (CR, PR, SD, PD, NCRNPD or unknown) will be summarized using frequency tables 
together with their associated two-sided exact 95% confidence intervals (Clopper-Pearson 
method).  
The Full Analysis Set will be used for the primary efficacy analysis, the per-protocol set will 
serve as sensitivity analysis. Further, selected analysis tables (see RAP module 7.1) were 
desplayed as sensitivity analysis for a modified FAS population which inexcludes patients from 
centers with a relevant inspection finding. 
 
2.5.3 
Handling of missing values/censoring/discontinuations 
Since the definition of the primary variable was derived from tumor assessments based on 
RECIST 1.1 criteria, these criteria apply for the handling of missing values in tumor 
assessments. The evaluation of overall lesion response at each assessment is a composite of the 
target lesion response, non-target lesion response and presence of new lesions (see protocol, 
Post-text supplement 1). If the evaluation of any of the target or non-target lesions identified at 
baseline could not be made during follow-up, the overall status must be ‘unknown’ unless 
progression was seen. Patients with a best overall response assessment of unknown (UNK) were 
not be regarded as ‘responders’ but were included in the denominator for the calculation of the 
ORR for the FAS. 
 
For patients who took other anti-neoplastic drugs their efficacy data will be censored so that the 
tumor assessments made after the administration of the other anti-neoplastic drugs are not included 
in the primary efficacy analyses. Sensitivity analysis including these observations may be performed 
if decided during data review meeting. 
2.5.4 
Supportive analyses 
CBR until Week 24 were additionally presented for the Per-protocol Set (PPS). Furthermore, the 
CBR were summarized by subgroups (cohorts A, B, B1 and B2) for the FAS and PPS, respectively. 
2.5.4.1 
Time to reponse (CR or PR) 
Furthermore, the time to overall response (CR or PR) were analyzed by Kaplan Meier curve and 
Kaplan meier statistics for the total population and for cohorts. The time to overall response is the 
time between date of start of treatment until first documented response (CR od PR). Patients who 
did not achieve a confirmed PR or CR will be censored: 
- 
At maximum follow-up (i.e. FPFV to LPLV used for analysis) for patients who had a PFS 
event (i.e. either progressed or died due to any cause) 


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2.5.4.2 
At last adequate tumor assessment date otherwise Duration of response 
(DoR) 
DoR applies only to patients whose best overall response was CR or PR. The start date is the date 
of first documented response (CR or PR) and the end date is the date of event defined as the first 
documented progression or death due to underlying cancer. In other words, the start date will be 
determined using the time the response was first determined and not using the time the response 
was confirmed. If a patient has not had an event, duration is censored at the date of last adequate 
tumor assessment. DoR will be summarized for the total population and the cohorts separately. 
Distribution of duration of response will be estimated using the Kaplan-Meier method and the 
median response duration will be presented along with 95% confidence interval only if there are 
sufficient numbers of events.  
 
2.6 
Analysis of the key secondary objective 
No ‘key’ secondary objective was defined. 
2.7 
Analysis of secondary efficacy objective(s) 
2.7.1 
Secondary endpoints 
2.7.2 
Statistical hypothesis, model, and method of analysis 
The following secondary efficacy variables were analyzed in an explorative manner for the full 
analysis set (FAS): overall response rate (ORR) by Week 24, progression-free survival (PFS) 
and overall survival (OS).  
 
ORR within Week 24  
The ORR within Week 24 was derived from the sequence of overall lesion responses as 
described for the primary efficacy variable. The ORR by Week 24 was summarized using 
frequency tables presenting absolute and relative frequencies together with appropriate 
confidence intervals. Furthermore, the ORR at EOT was analyzed. 
 
Progression-free survival  
Progression-free survival (PFS) is the time from date of start of treatment to the date of event 
defined as the first documented progression or death due to any cause. If a patient had not had 
an event, progression-free survival was censored at the date of last adequate tumor assessment. 
Disease progression for primary efficacy endpoint derivation was assessed using the local 
investigator’s tumor assessment (treating center’s radiologist). PFS was summarized using the 
Kaplan-Meier method. Percentiles (25%, median, 75%) of the event time distribution were 
presented along with their two-sided 95% confidence interval. Additionally, Kaplan-Meier 
estimates for the proportions of patients progression-free by Week 48 and Week 72 were 
presented. The Kaplan-Meier curve (with censored patients at number of patients at risk) was 
displayed graphically. 
 
Overall survival  
Overall survival (OS) is defined as the time from date of start of treatment to date of death due 
to any cause. If a patient was not known to have died, survival was censored at the date of last 


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contact. OS was summarized using the Kaplan-Meier method as described above. The Kaplan-
Meier curve was displayed graphically. Additionally, the proportion of patients alive at 48 and 
96 weeks were presented 
2.7.3 
Handling of missing values/censoring/discontinuations 
Same instructions as for primary analysis 
2.8 
Safety analyses 
The analysis of safety objectives was described in section 10.5.2.1. of the study protocol. All 
listings and tables are presented for the Safety Analysis Set by pretreatment group and total, i.e. 
cohorts A, B1, B2, B and total: 
 postmenopausal women or men without prior treatment for advanced disease (cohort A) 
 pre- and perimenopausal women without prior treatment for advanced disease 
(cohort B1) 
 pre-, peri and postmenopausal women with prior treatment for advanced disease 
(cohort B2) 
The overall observation period will be divided into three mutually exclusive segments: 
1. 
pre-treatment period: from day of patient’s informed consent to the day before first 
dose of study treatment 
2. 
on-treatment period plus 30 days: from day of first dose of study medication to 30 
days after last dose of study treatment 
3. 
post-treatment period: starting at day 30+1 after last dose of study treatment. 
Goserelin and letrozole after end of treatment were not considered as study treatment, see 
5.2.1. 
As a sensitivity analysis selected analysis tables (see RAP module 7.1) were desplayed for a 
modified SAF population which excludes patients from centers with a relevant inspection finding. 
 
2.8.1 
Adverse events (AEs) 
Summary tables for adverse events (AEs) include only AEs that started or worsened during the 
on-treatment period plus 30 days, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed in CSR section 16.2. 
Absolute and relative frequencies for patients with AEs collected during the pre-treatment and 
post-treatment period are presented. 
The following analyses are presented for the different types of AEs: 


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Incidence 
(frequency 
table) 
Two-level 
frequency 
table  
SOC x PT 
(MedDRA) 
Patient 
data 
Listing 
(section 
14.3.1) 
Maximum 
severity 
(frequency 
table) 
Time 
to 
event 
Dur-
ation of 
event 
Recurrence/
frequency of 
events per 
patient 
Treatment 
emergent AEs 
X 
X 
 
X 
 
 
 
Treatment 
emergent 
serious AEs 
X 
X 
X 
X 
X 
X 
X 
Treatment 
emergent non-
serious AEs 
X 
X 
 
 
 
 
 
TEAE 
with 
suspected drug 
relation 
to 
ribociclib  
X 
X 
 
 
 
 
 
TEAE leading 
to 
permanent 
discontinuation 
of study drug 
X 
X 
 
 
 
 
 
TEAE of 
special interest 
X 
x 
x 
 
X 
X 
X 
Death (in pre-
/on-/post-
treatment 
period) 
X 
 
X 
 
 
 
 
The incidence frequency table presents the number, percentage and 95% confidence for 
occurrence of at least one event of the respective AE type. This table is separated by each of the 
observation period (pre-/on-/post-treatment) and total. Denominator (for each period) is the 
number of patients in the Safety Analysis Set (SAF). 
The two-level frequency table calculates absolute and relative frequencies for MedDRA 
System Organ Classes (SOC) and Preferred Terms (PT) within SOCs. Again, the number of 
patients in SAF is used as denominator and each event is counted only once in the respective 
category. The MedDRA version currently available at time point of analysis is used for 
decoding. 
The frequency table for maximum severity analyses the maximum CTC-AE grade and 
display n and % for each category (total, SOC, and PT). Again, the number of patients in SAF 
is used as denominator and each maximum severity is counted only once in the respective 
category. 
All patient data are listed in CSR section 16.2. Additionally data listings relevant for safety 
assessment are presented in section 14.3.2. Here, the patient identification, the verbatim term 
given by the investigator, MedDRA preferred term and system organ class, start/end dates, 


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severity, seriousness, relationship to study drug and action taken are listed. The AE onset will 
also be shown relative (in number of days) to the date of initial dose. 
 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
 
The following (S)AEs of special interest were defined: 
 Neutropenia (MedDRA Code 10029354) 
 Hepatobiliary toxicity, defined as grade 3 or 4 increases in ALT or/and AST 
(MedDRA Codes: 10001551, 10003481) 
 QT prolongation (MedDRA Code 10014387) 
In addition, the time to occurrence from start of study drug to the (first) onset of a TEAE of 
special interest (TEAESI) is analysed by sample statistics as well as the duration (start – end + 
1 day). Further the number of TEAESI occurring in one patients during on-treatment period is 
displayed. 
 
2.8.2 
Deaths 
The number of deaths in the pre-, on- and post-treatment period plus 30 days were displayed as 
absolute and relative frequencies with 95% confidence intervals. Deaths are listed by patient. 
2.8.3 
Laboratory data 
Normal laboratory values were not documented in the CRF. Abnormal laboratory parameters 
that induced clinical signs or symptoms, required therapy or required changes in study drug(s) 
constituted an adverse event and were recorded on the Adverse Events CRF. These relevant 
laboratory values associated with an adverse event were listed only. 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
ECG results were summarized using frequency distributions by visit.  
2.8.4.2 
Vital signs 
Vital signs were summarized descriptively by visit for baseline and all post-baseline time 
points and change from baseline to these time points.  
2.8.4.3 
ECOG Performance Status 
The ECOG Performance Status was summarized using frequency distributions by visit. Shifts 
from baseline value to worst (i.e. the highest) post-baseline value were summarized using 
frequency distributions. 
2.9 
Pharmacokinetic endpoints   
Not applicable 


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2.10 
PD and PK/PD analyses 
Not applicable 
2.11 
Patient-reported outcomes 
Health-related quality of life (HRQoL) was assessed using the EORTC QLQ-C30 and BR23 
questionnaires. 
Descriptive statistics was used to summarize the individual item and scored sub-scale scores of 
QoL data at each scheduled assessment time point. Patients were included if they completed at 
least one questionnaire item. Additionally, change from baseline in the domain scores at the 
time of each assessment was summarized. Patients with an evaluable baseline score and at least 
one evaluable post-baseline score during the treatment period were included in the change from 
baseline analyses (assessments after disease progression were excluded). 
The time (from start of study drug) to 10% deterioration in EORTC QLQ-C30 was analysed by 
sample statistics. 
2.12 
Biomarkers 
Analysis of Biomarker was described in a stand-alone analysis plan document. 
2.13 
Other Exploratory analyses 
Multivariate regression analysis to identify prognostic factors for Neutropenia 
respectively AST/ALT increase. 
This analysis was not foreseen in the study protocol but included on request of the principal 
investigator for the presentation of interim and final results. 
 Two separate multivariate regression analyses were calculated for these interesting events 
(dependent variables): 
1. 
Neutropenia, selected from AE data set via PTs “neutropenia” and/or “neutrophil 
count decreased” 
2. 
Increase in ALT or AST: Selected from AE dataset via PTs “ALANINE 
AMINOTRANSFERASE 
INCREASED” 
and/or 
“ASPARTATE 
AMINOTRANSFERASE INCREASED” 
The following effects (without interactions) were investigated by Type 3 estimates and Wald’s 
confidence intervals for Odds ratios: 
 Age at baseline (categorical): <60 years, 60-70 years, and >= 70 years 
 BMI at baseline (categorical, rounded to integers): < 20, 20-25, 26-29, and >30 kg/m² 
 Presence (no vs. yes) of bone metastases at study start 
 Use of chemo therapy as prior antineoplastic medication (no vs. yes) 
 Therapy line: 1st, 2nd, and >= 3rd 


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2.14 
Interim analysis 
Three interim analyses were planned during the study. The first interim analysis was conducted 
one year after the first patient has been enrolled and included a preliminary analysis on safety. 
The second interim analysis was conducted 12 months after LPFV in the 30% pretreated and 
premenopausal cohort and included a preliminary analysis on safety, efficacy and quality of life. 
The third interim analysis took place 6 months after the last patient had been recruited and 
included a preliminary analysis on safety and efficacy. 
3 
Sample size calculation 
Sample size assumptions in this study for postmenopausal patients without prior treatment for 
advanced disease are based on the data from the CLEE011X2107 study (Juric, poster presented 
at ASCO 2016), which enrolled a similar patient population. 
Regarding patients in later than first lines and pretreated premenopausal patients, assumptions 
are based on Cristofanilli et al 2016 - PALOMA-3 final analysis.  
It is expected that the CBR (based on local assessment) by week 24 is in a range as reported for 
the CLEE011X2107study for the ribociclib + letrozole group (CBR = 79%, 95% confidence 
interval [59% to 92%]).  
Using the lower limit of the CI (59%) as a pessimistic estimate for the CBR by week 24, a 
sample size of 500 produces a two-sided 95% confidence interval with a width equal to 8.6 
percentage points (the associated 95% CI is [54.7% to 63.3%]). When using the same CBR as 
observed (CBR 79%), a sample size of 500 produces a two-sided 95% confidence interval with 
a width equal to 7.2 percentage points (the 95% CI is [75.4% to 82.6%]). Using the upper limit 
of the CI (92%) as an optimistic estimate for the CBR, a sample size of 500 produces a two-
sided 95% confidence interval with a width equal to 4.8 percentage points (the 95% CI is 89.6% 
to 94.4%]). Assuming an estimated rate of 70% to be recruited in the subgroup of 
postmenopausal first line patients resulting in a sample size of 350 patients, the width of the 
confidence interval will be between 10.4 percentage points (pessimistic scenario) and 5.6 
percentage points (optimistic scenario).  
Regarding the subgroup of second or further treatment lines and premenopausal patients, 
assuming an estimated rate of 30% to be recruited, and further based on the data as presented 
by Cristofanili et al. (CBR 67%, 95% CI [61.3% to 71.5%]), the resulting precision based on 
150 patients leads to a width of the resulting 95% confidence interval between 15.6 percentage 
points (pessimistic scenario) and 14.4 percentage points (optimistic scenario).  
Thus, a sample size of 500 patients allows estimating the CBR in this patient population with 
reasonable precision. 
4 
Change to protocol specified analyses 
Additionally to protocol specified analyses, the time to and duration of RECIST response was 
analysed for the full analysis set (FAS). 


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5 
Appendix 
5.1 
Definition of efficacy variables 
Progression:  
1. 
ds.eotdreasn = 4 (Main reason for ribociclib discontinuation = progressive disease) 
2. 
ds.eotprdi1n = 1 (Radiologic progression according to RECIST 1.1) OR  
3. 
ds.eotprdi3n = 1 (Clinically symptomatic progress) OR 
4. 
zr.recoveran = 4 (Overall lesion response = Progressive Disease) OR 
5. 
zr.recnewln=1 (New Lesion) 
Progression date:  
1. 
ds.eotcprdt (date of clinically symptomatic progress) OR 
2. 
Date of Evaluation where zr.recoveran = 4 or zr.recnewln = 1 
Response: 
3. 
zr.recoveran (Overall lesion response) 
Assessment Date: 
4. 
zr.tlesdt (Date of image or examination, Target Lesion Assessment) 
5. 
zr.ntlesdt (Date of image or examination, Non-Target Lesion Assessment) 
6. 
zr.nlesdt (Date of image or examination at which new lesion appeared) 
Date of Death: 
7. 
sc.deathdt 
Date of last contact: 
8. 
sc.eoslcdt 
Start of treatment = first administration of Ribociclib or Letrozole: 
9. 
min(min(zq.ribostdt), min(zq.letrstdt)) 
 
5.1.1 
Clinical Benefit Rate (CBR) until week 24 
Best overall response in (CR, PR, SD, NCRNPD): 
1. 
zr.recoveran = 1; at least two determinations of CR at least 4 weeks apart before progression 
OR 
2. 
zr.recoveran = 2; at least two determinations of PR or better at least 4 weeks apart before 
progression (and not qualifying for a CR) 
3. 
zr.recoveran = 3; two determinations of SD at least 12 weeks apart (and not qualifying for 
PR or PD) 


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4. 
zr.recoveran = 5 
Tumor evaluations are scheduled for baseline, Cycle 4 and cycle 7 etc. (every 12 weeks). Thus, 
to assess the CBR at week 24 the first two post-baseline evaluations have to be considered. 
Additionally it has to be checked that no progression occurred during the following 4 weeks. 
Deviations against the time schedule is investigated and assessed during the data review 
meeting. 
5.1.2 
Overall response rate (ORR) by week 24 
Similar to 5.1.1, but the best overall response must be in in (CR, PR) 
5.1.3 
Progression-free survival  
Start date = Start of treatment (first administration of Ribociclib or Letrozole) 
End date = First date of progress or date of death or (if no event) date of last tumor assessment 
5.1.4 
Overall survival (OS) 
Start date = Start of treatment (first administration of Ribociclib or Letrozole) 
End date = Date of death or (if no event) date of last contact 
5.2 
Definiton of safety variables 
5.2.1 
Duration of study treatment exposure 
For ribociclib and letrozole the duration of exposure (days) = date of last administration of 
ribociclib resp. letrozole – date of first administraton of ribociclib resp. letrozole + 1 day. The 
first administration of the study treatments ribociclib and letrozole are taken from the respective 
Dosage Administration Record, i.e. the date of first dose > 0 at/after C1/D1. The date of last 
administration of the study treatments ribociclib and letrozole are taken from the Treatment 
Completion CRF. In case of ongoing treatment, resulting in missing end days on Treatment 
Completion CRF, the end date is substituted hierarchy by: 
- 
End date of last administration with dose >0 of ribociclib resp. letrozole on the Dosage 
Administration record before End-of-Treatment-visit  
- 
If the end date of the last administration with dose >0 of ribociclib resp. letrozole on the 
Dosage Administration is missing (normally because “ongoing” is ticked) the date of 
the last visit during the on-treatment period (C1/D1 to End-of-treatment) is used to 
substitute the end date. 
For goselerin the duration of exposure (days) = date of last administration of goselerin – date 
of first administraton of goselerin + 1 day. The first administration of the study treatment 
goselerin is taken from the respective Dosage Administration Record, i.e. the first dose > 0 
at/after C1/D1. The end of the third component goselerin is not asked at the Treatment 
Completion CRF and must be derived from the Dosage Administration record therefore. 
Goselerin may be continued in combination with a follow-up therapy and may be documented 
on the Dosage Administration Record, although it is no longer a study treatment. For this reason 


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the date of last goselerin administration is the last dose > 0 administered until the End-of-
treatment visit. 
The exposure to study treatment is displayed for each of the third components separately, and 
in combination. For combination, called “exposure to any of the study treatments”, the first start 
date and the last end date of the study treatments is used for calculation. 
The duration of exposure includes the periods of temporary interruption (of any component of 
the study treatment for any reason). 
 
5.2.2 
Cumulative dose 
Cumulative dose (mg) = total dose given during study treatment exposure 
For patients who do not receive any drug the cumulative dose is set to zero. 
5.2.3 
Dose intensity (DI) 
Dose intensity (mg/day) = cumulative dose (mg) / duration of exposure of study treatment (days) 
For patients who do not receive any drug the dose intensity is set to zero. 
5.2.4 
Planned dose intensity (PDI) 
Planned dose intensity (mg/day) = total daily dose pescribed 
5.2.5 
Relative dose intensity (RDI) 
Relative dose intensity (mg/day) = dose intensity (mg/day) / planned dose intensity (mg/day) 
5.2.6 
Mean relative dose intensity (mean RDI) 
Mean relative dose intensity (mg/day) = mean of the relative dose intensity per patient by study 
treatment component 
5.2.7 
Adverse events of special interest 
 Neutropenia = AE term: MedDRA Preferred Term “Neutropenia” (10029354) 
 Hepatobiliary toxicity = AE term: MedDRA Preferred Term “Alanine aminotransferase 
increased” (10001551) or “Aspartate aminotransferase increased” (10003481), Toxicity 
grade “Grade 3” or “Grade 4” 
 QT prolongation = AE term: MedDRA Preferred Term “Electrocardiogram QT 
prolonged” (10014387) 
5.3 
Programming rules 
5.3.1 
Calculation of ‘time to event’ variables 
Time to event = end date - start date + 1 (in days). 


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When no post-baseline tumor assessments was available, the date of first application of 
treatment was used as end date (duration = 1 day) when time was to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
 
5.4 
Imputation rules 
5.4.1 
Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must have been completed with day, month and 
year.  
If one or more investigation dates was incomplete but other investigation dates were available, 
this/these incomplete date(s) was/were not considered for calculation of the assessment date 
(and assessment date was calculated as outlined in Section 3.2.7). If all measurement dates had 
no day recorded, the 1st of the month is used.  
If the month was not completed, for any of the investigations, the respective assessment was 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment was not available, this assessment was not used for any 
calculation. 
5.4.2 
Incomplete dates for last known date patient alive or death 
All dates must have been completed with day, month and year. If the day was missing, the 15th 
of the month was used for incomplete death dates or dates of last contact. 
5.4.3 
Non-target lesion response 
If no non-target lesions were identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment was considered ‘not applicable (NA)’. 
5.4.4 
Censoring reason 
In order to summarize the various reasons for censoring, the following categories were 
calculated for each time to event variable based on the treatment completion page, the end of 
study page and the survival follow-up page.  
 
For survival the following censoring reasons are possible:  
 Alive 
 Unknown/Lost to follow-up 
 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:  
 Ongoing without event 
 Lost to follow-up 
 Withdrew consent 
 Adequate assessment no longer available* 
 Event documented after two or more missing tumor assessments (optional, see Table 
3-2)  


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 Death due to reason other than underlying cancer (only used for TTP and duration of 
response)  
 Initiation of new anti-cancer therapy 
*Adequate assessment is defined in Section 3.2.7. This reason was applicable when adequate 
evaluations were missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:  
 This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).  
 The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative 
anti-cancer therapy) has occurred more than the specified period following the last 
adequate assessment.  
 This reason will also be used to censor in case of no baseline assessment.  
 
5.4.5 
Study treatment 
In case of missing or partial start date, the start date should be shifted to the earliest possible 
date, but not earlier than the C1/D1 visit, i.e. the beginning of the on-treatment period, 
respectively not earlier than the previous administration. Missing or partial end dates (which 
result often from “ongoing” answers)  should be shifted forward as far as possible: At maximum 
to the last documented on-treatment visit, i.e. C1/D1 to End-of-treatment-visit and not later than 
the following administration.  
5.4.6 
AE date imputation 
In case of missing or partial start date or end date of an AE, the start date should be shifted to 
the earliest possible date, but not ealier than the first intake of study drug while the end date 
should be shifted forward as far as possible. 
5.4.7 
Concomitant medication date imputation 
In case of missing or partial start date or end date of a concomitant medication, the start date 
should be shifted to the earliest possible date, but not earlier than the first intake of study drug 
while the end date should be shifted forward as far as possible. 
5.4.7.1 
Prior antineoplastic therapies date imputation 
In case of missing or partial start date or end date of a prior therapy, the start date should be 
shifted to the earliest possible date, but not earlier than the initial diagnosis while the end date 
should be shifted as far back as possible, but not later than the first intake of study drug. 


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5.4.7.2 
Post antineoplastic therapies date imputation 
In case of missing or partial start date or end date of a post therapy, the start date should be 
shifted to the earliest possible date, but not earlier than the first intake of study drug while the 
end date should be shifted forward as far as possible. 
5.4.7.3 
Other imputations 
5.5 
AEs coding/grading 
Adverse events were assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading did not exist for an adverse event, the severity 
of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, was used. 
CTCAE Grade 5 (death) was not used in this study. 
5.6 
Laboratory parameters derivations 
Not applicable. 
5.7 
Statistical models 
5.7.1 
Primary analysis 
No statistical hypothesis or model was underlying the analysis. 
5.8 
Rule of exclusion criteria of analysis sets  
Table 1 
Protocol deviations that cause subjects to be excluded 
Deviation 
ID 
Description of Deviation 
Exclusion in Analyses 
I_06 
No positive hormone receptor status 
Excluded form PP analysis 
I_07 
positive HER2 receptor status 
Excluded form PP analysis 
I_08 
No negative HER2 receptor status 
Excluded form PP analysis 
E_04 
Patient received any non-permitted prior 
medication or therapy  
 
Excluded form PP analysis, only 
if medication/therapy is assessed 
as influencing the primary 
parameter in Data Review 
Meeting (DRM) 
 
E_12 
History or clinical evidence of central 
nervous system metastases not meeting 
the specific criteria for eligibility 
Excluded form PP analysis 
D_01 
Patient continued with trial treatment in 
spite of IMP Ribociclib was interrupted 
for > 28 days. 
Excluded form PP analysis 
M_01 
Non-permitted concomitant medication 
Excluded form PP analysis  


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Table 2 
Subject Classification 
Analysis Set 
PD ID that 
    
cause subjects to be excluded 
Non-PD criteria that cause  
subjects to be excluded 
ENR 
NA 
Not having informed consent; 
SAF 
NA 
Not having informed consent; Screening failure, 
not treated with any dose of study treatment 
SAF 2 (for 
sensitivity 
analysis of 
AE) 
NA 
Not having informed consent; Screening failure, 
not treated with any dose of study treatment; 
Centers with a critical finding by audit / 
inspection 
(as 
assessed 
by 
Novartis 
“Massnahmenausschuss”) 
FAS 
NA 
Not having informed consent; Screening failure; 
not intended to be treated with any dose of study 
treatment; Centers with a critical finding by 
 
(only if during DRM 
medication/therapy is assessed 
as influencing the primary 
parameter) 
S_03 
IMP (Ribociclib and letrozole) intake is 
not 80-120% 
Excluded from PPS if leading to 
invalid primary enpoint 
(assessed additionally during 
DRM, although not specified in 
VAP Module 3) 
O_03 
Tumor evaluation omitted 
if assessed during DRM as relevant 
(timepoint, frequency) 
 
O_05 
Tumor assessment method invalid or 
changed during course of study 
 
Excluded form PP analysis if 
leading to invalid primary 
endpoint (assessed during DRM) 
 
O_09 
Any data for evaluating the primary 
endpoint is missing 
 
 
Excluded form PP analysis, if 
leading in invalid assessment of 
primary endpoint (assessed in 
DRM) 
 
O_10 
Complete patient’s study visit was 
omitted 
 
Excluded form PP analysis, if 
leading in invalid assessment of 
primary endpoint (assessed in 
DRM) 
 


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SAP, Version 3.0 
 
CLEE011XDE01 
 
Analysis Set 
PD ID that 
    
cause subjects to be excluded 
Non-PD criteria that cause  
subjects to be excluded 
audit / inspection (as assessed by Novartis 
“Massnahmenausschuss”) 
FAS 2 (for 
sensitivity 
analysis of 
primary 
parameter)  
NA 
Not having informed consent; Screening failure; 
not intended to be treated with any dose of study 
treatment 
PPS 
I_01 – I_08 
E_04, E_12, 
D_01, M_01, 
O_03, O_05, O_09, O_10 
Not in FAS; not treated with any dose of study 
treatment 
 
 
6 
Reference 
None.