A Phase 2, Multi-center, Open-label, Randomized Study of Oral Asciminib Added to Imatinib Versus Continued Imatinib Versus Switch to Nilotinib in Patients With CML-CP Who Have Been Previously Treated With Imatinib and Have Not Achieved Deep Molecular Response
Phase: PHASE2
Conditions: CML, Chronic Myelogenous Leukemia, Leukemia, Myeloid Chronic, Hematologic Diseases
Sponsor: Novartis Pharmaceuticals

N o v arti s R e s e ar c h a n d D e v el o p m e nt 
A B L 0 0 1 
Cli ni c al Tri al Pr ot o c ol C A B L 0 0 1 E 2 2 0 1 / N C T 0 3 5 7 8 3 6 7 
A p h a s e 2, m ulti- c e nt er, o p e n-l a b el, r a n d o mi z e d st u d y of 
or al a s ci mi ni b a d d e d t o i m ati ni b v er s u s c o nti n u e d im ati ni b 
v er s u s s wit c h t o nil oti ni b i n p ati e nt s wit h C M L- C P w h o 
h a v e b e e n pr e vi o u sl y tr e at ed wit h im ati ni b a n d h a v e n ot 
a c hi e v e d d e e p m ol e c ul ar r e s p o n s e  
Cli ni c al Tri al P r ot o c ol N u m b e r: C A B L 0 0 1 E 2 2 0 1 
V er s i o n N u m b er: 0 5 A m e n d e d G l o b al P r ot o c ol V er si o n (Cl e a n)  
C o m p o u n d : A B L 0 0 1 
Bri ef Titl e : St u d y o f effi c a c y a n d s a f et y o f a s ci mi ni b i n co m bi n ati o n wit h i mati n i b i n 
C M L- C P p ati e nt s
St u d y P h a s e : II 
S p o n s or N a m e : N o v arti s P h ar m a A G o r it s affili at e s o ut si d e of t h e E E A ( wh er e 
a p pli c a bl e) 
S p o n s or a d dr e s s in t h e E E A: N o v arti s P h ar m a A G, Li c ht str a s s e 3 5 , 4 0 5 6 B a s el 
T o w n, S wit z erl a n d 
R e g ul at or y A g e n c y Id e ntifi er N u m b er( s):  2 0 1 8- 0 0 1 5 9 4- 2 4 ( E U DR A C T n u m b er), 
2 0 2 4- 5 1 5 0 4 0- 2 3 -0 0  ( E U C T n u m b er) , 1 1 9 2 5 7 (I N D n u m b er) 
C o nt e nt fi n al D at e : 2 1- A u g- 2 0 2 4 
Pr o p ert y o f N o v arti s  
C o nfi d e nti al 
M a y n o t 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 n t of N o v arti s  
Cli ni c al Tr i al Pr ot o c ol T e m pl at e V er si o n 5. 0 d at e d, eff e cti v e 1 4- J a n- 2 0 2 2 

N o v arti s  
C o nfi d e nti al  
P a g e 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
T a bl e of c o nt e nt s  
Ta ble of c o nt e nts  ................................................................................................................. 2  
List of ta bles  ........................................................................................................................ 6  
List of fi g ures  ...................................................................................................................... 7  
List of a b bre viati o ns  ............................................................................................................ 8  
Gl ossar y of ter ms  ............................................................................................................... 1 3  
A me n d me nt 5 ( 2 1 -A u g -2 0 2 4)  ........................................................................................... 1 5  
A me n d me nt 4 ( 2 4 -A u g -2 0 2 3)  ........................................................................................... 1 7  
A me n d me nt 3 ( 1 2 -J ul-2 0 2 2)  ............................................................................................. 1 9  
A me n d me nt 2 ( 1 0 -A u g -2 0 2 0)  ........................................................................................... 2 4  
L ocal versi o n  A me n d m e nt 0 2 -U S. 0 1 ( 1 0 -A u g -2 0 2 0) f or U S A  ........................................ 2 6  
A me n d me nt 1 ( 1 8 -J ul-2 0 1 9)  ............................................................................................. 2 7  
Pr ot oc ol s u m mar y  .............................................................................................................. 3 3  
1  
I ntr o d u cti o n ....................................................................................................................... 3 8  
1. 1  
Bac k gr o u n d  ............................................................................................................ 3 8  
1. 1. 1  
I ntr o d u cti 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) ........................................................................................... 3 8  
1. 2  
P ur p ose  .................................................................................................................. 5 1  
2  
O bjecti ves a n d e n d p oi nts  ................................................................................................... 5 3  
3  
St u d y desi g n  ...................................................................................................................... 5 5  
4  
Rati o nale  ............................................................................................................................ 5 7  
4. 1  
Rati o nale f or st u d y desi g n  ..................................................................................... 5 7  
4. 1. 1  
Rati o nale f or a d diti o n of asci mi ni b si n gle a ge nt c o h ort  ....................... 5 8  
4. 2  
Rati o nale f or d ose/r e gi me n a n d d urati o n of tr eat m e nt  .......................................... 5 9  
4. 3  
Rati o nale f or c h oic e of c o m parat or a n d c o m bi nati o n dr u gs  .................................. 6 0  
4. 4  
P ur p ose a n d ti mi n g of i nteri m a nal yses/ desi g n a da ptati o ns  .................................. 6 0  
4. 5  
Ris ks a n d be nefits  .................................................................................................. 6 1  
4. 6  
Rati o nale f or p u blic healt h e mer ge n c y miti gati o n pr oce d ures  .............................. 6 3  
5  
P o p ulati o n  .......................................................................................................................... 6 3  
5. 1  
I n cl usi o n criteria .................................................................................................... 6 3  
5. 2  
E xcl usi o n criteria  ................................................................................................... 6 4  
6  
Treat me nt  ........................................................................................................................... 6 7  
6. 1  
St u d y treat me nt  ...................................................................................................... 6 7  
6. 1. 1  
St u d y dr u gs ............................................................................................ 6 7  
6. 1. 2  
A d diti o nal st u d y treat me nts  .................................................................. 6 7  
6. 1. 3  
Treat me nt ar ms/ gr o u p  ........................................................................... 6 8  

N o v arti s  
C o nfi d e nti al  
P a g e 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
6. 1. 4  
G ui deli nes f or c o nti n uati o n of treat me nt  .............................................. 6 8  
6. 1. 5  
Treat me nt d ur ati o n  ................................................................................ 6 8  
6. 2  
Ot her treat me nt(s)  .................................................................................................. 6 9  
6. 2. 1  
C o nc o mita nt t hera p y  ............................................................................. 6 9  
6. 2. 2  
Pr o hi bite d me dicati o n  ........................................................................... 7 1  
6. 3  
S u bject n u m beri n g, treat me nt assi g n me nt, ra n d o mizati o n  .................................... 7 2  
6. 3. 1  
S u bject n u m beri n g  ................................................................................ 7 2  
6. 3. 2  
Treat me nt assi g n me nt, r a n d o mizati o n  .................................................. 7 2  
6. 3. 3  
Treat me nt assi g n me nt f or asci mi ni b si n gle a ge nt c o h ort  ...................... 7 3  
6. 4  
Treat me nt bli n di n g  ................................................................................................. 7 3  
6. 5  
D ose escalati o n a n d d ose m o dificati o n  .................................................................. 7 3  
6. 5. 1  
D ose m o dificati o ns  ................................................................................ 7 3  
6. 5. 2  
F oll o w -u p f or t o xicities  ......................................................................... 7 9  
6. 6  
A d diti o nal treat me nt g ui da nce  ............................................................................... 8 0  
6. 6. 1  
Treat me nt c o m plia nce  ........................................................................... 8 0  
6. 6. 2  
E mer ge nc y brea ki n g of assi g ne d treat me nt c o de  .................................. 8 1  
6. 7  
Pre parati o n a n d dis pe ns ati o n  ................................................................................. 8 1  
6. 7. 1  
Ha n dli n g of st u d y treat m e nt a n d a d diti o nal treat m e nt  .......................... 8 1  
6. 7. 2  
I nstr u cti o n f or prescri bi n g a n d ta ki n g st u d y treat m e nt ......................... 8 2  
6. 7. 3  
Asci mi ni b si n gle a ge nt c o h ort - I nstr ucti o n f or prescri bi n g a n d 
ta ki n g st u d y treat me nt ........................................................................... 8 4  
7  
I nf or me d c o ns e nt pr oce d ures ............................................................................................ 8 5  
8  
Visit sc he d ule a n d assess me nts  ......................................................................................... 8 6  
8. 1  
Scree ni n g  ............................................................................................................... 9 3  
8. 1. 1  
Eli gi bilit y scree ni n g  .............................................................................. 9 3  
8. 1. 2  
I nf or mati o n t o be c ollecte d o n scree ni n g fail ures ................................. 9 4  
8. 2  
S u bject de m o gra p hics/ ot her baseli ne c haracteristics  ............................................. 9 4  
8. 3  
Efficac y  .................................................................................................................. 9 4  
8. 3. 1  
M olec ular res p o nse a n d B C R:: A B L 1 R T -q P C R  .................................. 9 4  
8. 3. 2  
B o ne marr o w a nal ysis a n d c yt o ge netics  ............................................... 9 6  
8. 3. 3  
A p pr o priate n ess of efficac y assess me nts  .............................................. 9 6  
8. 4  
Safet y a n d  t olera bilit y  ........................................................................................... 9 6  
8. 4. 1  
La b orat or y e val uati o ns  .......................................................................... 9 7  
8. 4. 2  
Electr ocar di o gra m ( E C G)  ..................................................................... 9 9  
8. 4. 3  
Pre g na nc y a n d assess me nts of fertilit y  ............................................... 1 0 1  
8. 4. 4  
A p pr o priate n ess of safet y meas ure me nts  ............................................ 1 0 2  

N o v arti s  
C o nfi d e nti al  
P a g e 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
8. 5  
A d diti o nal assess me nts  ........................................................................................ 1 0 2  
8. 5. 1  
Cli nical O utc o me Assess me nts ( C O As)  ............................................. 1 0 2  
8. 5. 2  
P har mac o ki netics  ................................................................................ 1 0 4  
8. 5. 3  
Bi o mar kers  .......................................................................................... 1 0 6  
9  
St u d y disc o nti n uati o n a n d c o m pleti o n  ............................................................................ 1 0 7  
9. 1  
Disc o nti n uati o n  .................................................................................................... 1 0 7  
9. 1. 1  
Disc o nti n uati o n of st u d y treat me nt  ..................................................... 1 0 7  
9. 1. 2  
Wit h dra wal of i nf or me d c o nse nt  ......................................................... 1 0 9  
9. 1. 3  
L ost t o f oll o w-u p  ................................................................................. 1 0 9  
9. 1. 4  
Earl y st u d y ter mi nati o n b y t he s p o ns or  ............................................... 1 0 9  
9. 2  
St u d y c o m pleti o n a n d p ost -st u d y treat me nt ........................................................ 1 1 0  
1 0  Safet y m o nit ori n g a n d re p orti n g  ...................................................................................... 1 1 0  
1 0. 1  
Defi niti o n of a d vers e e v e nts a n d re p orti n g re q uir e me nts  .................................... 1 1 0  
1 0. 1. 1  
A d verse e ve nts  .................................................................................... 1 1 0  
1 0. 1. 2  
Seri o us a d verse e ve nts  ........................................................................ 1 1 2  
1 0. 1. 3  
S A E re p orti n g ...................................................................................... 1 1 3  
1 0. 1. 4  
Pre g na nc y re p orti n g  ............................................................................ 1 1 5  
1 0. 1. 5  
Re p orti n g of st u d y treat me nt err ors i ncl u di n g mis use/a b use  .............. 1 1 5  
1 0. 2  
A d diti o nal Safet y M o nit ori n g  .............................................................................. 1 1 6  
1 0. 2. 1  
Li ver safet y m o nit ori n g  ....................................................................... 1 1 6  
1 0. 2. 2  
Re nal safet y m o nit ori n g  ...................................................................... 1 1 7  
1 0. 2. 3  
Steeri n g C o m mittee  ............................................................................. 1 1 7  
1 1  Data C ollecti o n a n d Dat a base ma na g e me nt  .................................................................... 1 1 7  
1 1. 1  
Data c ollecti o n  ..................................................................................................... 1 1 7  
1 1. 2  
Data base m a na ge m e nt a n d q ualit y c o ntr ol  .......................................................... 1 1 7  
1 1. 3  
Site m o nit ori n g  .................................................................................................... 1 1 8  
1 2  Data a n al ysis a n d statistical met h o ds  .............................................................................. 1 1 9  
1 2. 1  
A nal ysis sets  ........................................................................................................ 1 1 9  
1 2. 2  
S u bject de m o gra p hics a n d ot her baseli ne c haracteristics  .................................... 1 2 0  
1 2. 3  
Treat me nts  ........................................................................................................... 1 2 0  
1 2. 4  
A nal ysis of t he pri mar y e n d p oi nt(s)  .................................................................... 1 2 1  
1 2. 4. 1  
Defi niti o n of pri mar y e n d p oi nt(s)  ....................................................... 1 2 1  
1 2. 4. 2  
Statistical m o del, h y p ot hesis, a n d met h o d of a nal ysis  ........................ 1 2 1  
1 2. 4. 3  
Ha n dli n g of missi n g val ues/ce ns ori n g/ disc o nti n uati o ns  ..................... 1 2 1  
1 2. 4. 4  
S u p p orti ve a nal yses  ............................................................................. 1 2 2  

N o v arti s  
C o nfi d e nti al  
P a g e 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
1 2. 5  
A nal ysis of sec o n dar y e n d p oi nts  ......................................................................... 1 2 2  
1 2. 5. 1  
Efficac y a n d/ or P har m ac o d y na mic e n d p oi nt(s)  .................................. 1 2 2  
1 2. 5. 2  
Safet y e n d p oi nts  .................................................................................. 1 2 5  
1 2. 5. 3  
P har mac o ki netics  ................................................................................ 1 2 7  
1 2. 6  
A nal ysis of e x pl orat or y e n d p oi nts  ....................................................................... 1 2 8  
1 2. 6. 1  
Efficac y e x pl or at or y e n d p oi nts  ........................................................... 1 2 8  
1 2. 6. 2  
Ot her e x pl or at or y e n d p oi nts  ................................................................ 1 2 8  
1 2. 6. 3  
Bi o mar kers  .......................................................................................... 1 2 8  
1 2. 6. 4  
Patie nt Re p orte d O utc o m es  ................................................................. 1 2 9  
1 2. 7  
I nteri m a nal yses ................................................................................................... 1 2 9  
1 2. 8  
Sa m ple size calc ul ati o n  ........................................................................................ 1 3 0  
1 2. 8. 1  
Pri mar y e n d p oi nt(s)  ............................................................................. 1 3 0  
1 2. 8. 2  
Sec o n dar y e n d p oi nt(s)  ......................................................................... 1 3 0  
1 3  Et hical c o nsi derati o ns a n d a d mi nistrati ve pr oce d ures  .................................................... 1 3 1  
1 3. 1  
Re g ulat or y a n d et hical c o m plia nce  ...................................................................... 1 3 1  
1 3. 2  
Res p o nsi bilities of t he i n vesti gat or a n d I R B/I E C  ................................................ 1 3 1  
1 3. 3  
P u blicati o n of st u d y pr ot oc ol a n d res ults ............................................................. 1 3 2  
1 3. 4  
Q ualit y C o ntr ol a n d Q ualit y Ass ura nce  ............................................................... 1 3 2  
1 3. 5  
Partici pa nt e n ga ge m e nt  ........................................................................................ 1 3 2  
1 4  Pr ot oc ol a d here n ce  .......................................................................................................... 1 3 3  
1 4. 1  
Pr ot oc ol A me n d me nts  ......................................................................................... 1 3 3  
1 5  Refere n ces  ....................................................................................................................... 1 3 4  
1 6  A p pe n dices  ...................................................................................................................... 1 3 7  
1 6. 1  
A p pe n di x 1: Li ver e v e nt a n d La b orat or y tri g ger Defi niti o ns a n d F oll o w -u p 
Re q uire me nts  ....................................................................................................... 1 3 7  
1 6. 2  
A p pe n di x 2: S pecific Re nal Alert Criteria a n d Acti o ns a n d E ve nt F oll o w -u p  .... 1 4 0  
1 6. 3  
A p pe n di x 3: List of c o nc o mita nt me dicati o ns w hic h are pr o hi bite d or t o be 
use d wit h ca uti o n  ................................................................................................. 1 4 1  
1 6. 3. 1  
C o nc o mita nt me dicati o ns t o be use d wit h ca uti o n f or asci mi ni b + 
i mati ni b ar ms ....................................................................................... 1 4 1  
1 6. 3. 2  
Pr o hi bite d c o me dicati o ns f or asci mi ni b + i mati ni b ar ms  ................... 1 4 2  
1 6. 3. 3  
C o nc o mita nt me dicati o ns t o be use d wit h ca uti o n f or asci mi ni b 
si n gle a ge nt c o h ort .............................................................................. 1 4 2  

N o v arti s  
C o nfi d e nti al  
P a g e 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
Li st of t a bl e s  
Ta ble 2 -1  
O bjecti ves a n d relate d e n d p oi nts  .......................................................... 5 3  
Ta ble 6 -1  
St u d y dr u g  ............................................................................................. 6 7  
Ta ble 6 -2  
Criteria f or d ose re d ucti o n/i nterr u pti o n a n d re -i nitiati o n of 
asci mi ni b + i mati ni b, or asci mi ni b si n gle a ge nt treat me nt f or 
a d verse dr u g reacti o ns  ........................................................................... 7 4  
Ta ble 6 -3  
D ose re d u cti o n f or as ci mi ni b a n d i mati ni b  ........................................... 7 8  
Ta ble 6 -4  
D ose re d u cti o n f or as ci mi ni b si n gle a ge nt c o h ort  ................................. 7 8  
Ta ble 6 -5  
D ose a n d treat me nt sc he d ule  ................................................................. 8 2  
Ta ble 8 -1  
Assess me nt Sc he d ule, ra n d o mize d treat me nt ar ms 1 –  4 a n d 
asci mi ni b si n gle a ge nt c o h ort  ................................................................ 8 7  
Ta ble 8 -2  
Assess me nt Sc he d ule, patie nts ra n d o mize d t o t he c o nti n ue d 
i mati ni b ar m w h o cr oss-o ver t o recei ve asci mi ni b 6 0 m g + i mati ni b  ... 9 1  
Ta ble 8 -3  
Bl o o d sa m ples f or P C R ( pri mar y a n d sec o n dar y efficac y 
e n d p oi nts) i n all ra n d o mize d treat me nt ar ms 1 - 4, a n d asci mi ni b 
si n gle a ge nt c o h ort ................................................................................ 9 5  
Ta ble 8 -4  
Bl o o d sa m ples f or P C R i n cr oss -o ver  ................................................... 9 5  
Ta ble 8 -5  
Safet y a n d t olera bilit y assess me nts  ....................................................... 9 6  
Ta ble 8 -6  
La b orat or y assess me nts  ......................................................................... 9 8  
Ta ble 8 -7  
Ce ntral E C G c ollecti o n pla n i n all ra n d o mize d treat me nt ar ms 1 - 4, 
a n d asci mi ni b si n gle a ge nt c o h ort  ....................................................... 1 0 0  
Ta ble 8 -8  
Ce ntral E C G c ollecti o n pla n i n cr oss -o ver .......................................... 1 0 0  
Ta ble 8 -9  
P har mac o ki netic bl o o d c ollecti o n l o g  ................................................. 1 0 5  
Ta ble 8 -1 0  
Bi o mar ker sa m ple c ollecti o n pla n  ....................................................... 1 0 7  
Ta ble 1 2 -1  
N o n -c o m part me nt al p har mac o ki netic para meters  .............................. 1 2 7  
Ta ble 1 2 -2  
9 0 % C o nfi de nce i nter vals f or 3 0 % differe n ce rate bet wee n t he 
ar ms ..................................................................................................... 1 3 0  
Ta ble 1 6 -1  
Li ver E ve nt a n d La b orat or y Tri g ger Defi niti o ns  ................................ 1 3 7  
Ta ble 1 6 -2  
F oll o w U p Re q uire me nts f or Li ver E v e nts a n d La b orat or y Tri g gers  . 1 3 7  
Ta ble 1 6 -3  
S pecific Re nal Alert Criteria a n d Acti o ns  ........................................... 1 4 0  
Ta ble 1 6 -4  
C o nc o mita nt me dicati o ns t o be use d wit h ca uti o n f or asci mi ni b + 
i mati ni b ar ms ....................................................................................... 1 4 1  
Ta ble 1 6 -5  
Pr o hi bite d c o me dicati o n f or asci mi ni b + i mati ni b ar ms  ..................... 1 4 2  
Ta ble 1 6 -6  
C o nc o mita nt me dicati o ns t o be use d wit h ca uti o n f or asci mi ni b 
si n gle a ge nt c o h ort .............................................................................. 1 4 2  

N o v arti s  
C o nfi d e nti al  
P a g e 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
Li st of fi g ur e s  
Fi g ure 1 -1  
C u m ulati ve i nci de nce of M R 4. 5 acc or di n g t o res p o nse le vel at 2 4 
m o nt hs of i mati ni b treat me nt  ................................................................ 5 2  
Fi g ure 3 -1  
St u d y desi g n  .......................................................................................... 5 6  

N o v arti s  
C o nfi d e nti al  
P a g e 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
Li st of a b br e vi ati o n s  
( e) C R F 
(El e ctr o ni c) C a s e R e p ort F or m  
A B L  
A b el s o n pr ot o -o n c o g e n e  
A D M E  
A b s or pti o n, Di stri b uti o n, M et a b oli s m, a n d E x cr eti o n  
A E  
A d v er s e E v e nt  
A E SI  
A d v er s e E v e nt s of S p e ci al I nt er e st  
Al b  
Al b u mi n  
A L L  
A c ut e L y m p h o bl a sti c L e u k e mi a  
A L P  
Al k ali n e P h o s p h at a s e  
A L T  
Al a ni n e A mi n otr a n sf er a s e  
A P  
A c c el er at e d P h a s e   
A S T  
A s p art at e A mi n otr a n sf er a s e  
A S A C  
A s ci mi ni b si n gl e a g e nt c o h ort  
A T C  
A n at o mi c al T h er a p e uti c C h e mi c al  
A T P  
A d e n o si n e Tri p h o s p h at e -bi n di n g  
A U C  
Ar e a U n d er t h e C ur v e  
A U C 0 -1 2 h o ur s  
Ar e a U n d er t h e pl a s m a c o n c e ntr ati o n -ti m e C ur v e fr o m ti m e z er o t o 1 2 h o ur s 
A U C 0 -2 4 h o ur s  
Ar e a U n d er t h e pl a s m a c o n c e ntr ati o n -ti m e C ur v e fr o m ti m e z er o t o 2 4 h o ur s 
A U Ci nf  
Ar e a U n d er t h e pl a s m a dr u g c o n c e ntr ati o n -ti m e C ur v e fr o m ti m e z er o t o i nfi nit y 
A U Cl a st  
T h e A U C fr o m ti m e z er o t o t h e l a st m e a s ur a bl e c o n c e ntr ati o n s a m pli n g ti m e ( T l a st) ( m a s s x 
ti m e x v ol u m e-1)  
A U C R  
Ar e a U n d er t h e C ur v e R ati o  
A U Ct a u  
T h e A U C c al c ul at e d t o t h e e n d of a d o si n g i nt er v al (t a u) at st e a d y -st at e ( a m o u nt x ti m e x 
v ol u m e -1)  
A V  
Atri o v e ntri c ul ar  
B C  
Bl a st Cri si s  
B C R  
Br e a k p oi nt Cl u st er R e gi o n  
B C R:: A B L 1  
B C R -A B L 1 f u si o n pr ot ei n  
B C R:: A B L 1  
B C R -A B L 1 f u si o n g e n e  
B C R P  
Br e a st C a n c er R e si st a nt Pr ot ei n  
B C S  
Bi o p h ar m a c e uti c al Cl a s sifi c ati o n S y st e m  
BI D  
Bi s I n Di e m  (t wi c e a d a y) 
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  
B P  
Bl a st P h a s e  
C A B G  
C or o n ar y Art er y B y p a s s Gr aft  
C C A  
Cl o n al C hr o m o s o m al A b n or m aliti e s   
C C y R  
C o m pl et e C yt o g e n eti c R e s p o n s e  
C D S  
C or e D at a S h e et (f or m ar k et e d dr u g s)  
C F R  
C o d e of F e d er al R e g ul ati o n  
C H R  
C o m pl et e H e m at ol o gi c R e s p o n s e  
CI  
C o nfi d e n c e I nt er v al  
C m a x  
T h e m a xi m u m ( p e a k) o b s er v e d pl a s m a dr u g c o n c e ntr ati o n aft er or al d o s e a d mi ni str ati o n 
( m a s s x v ol u m e-1)  
C mi n  
Mi ni m u m dr u g pl a s m a ( s er u m/ bl o o d) c o n c e ntr ati o n  
C M L  
C hr o ni c M y el oi d L e u k e mi a  

N o v arti s  
C o nfi d e nti al  
P a g e 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
C M L -A P  
C hr o ni c M y el oi d L e u k e mi a - A c c el er at e d P h a s e  
C M L -B C  
C hr o ni c M y el oi d L e u k e mi a - Bl a st Cri si s  
C M L -C P  
C hr o ni c M y el oi d L e u k e mi a - C hr o ni c P h a s e  
C M O & P S  
N o v arti s C hi ef M e di c al Offi c e a n d P ati e nt S af et y  
C M V  
C yt o m e g al o vir u s  
C N S  
C e ntr al N er v o u s S y st e m  
C O  
Cr o s s -O v er  
C O A( s)  
Cli ni c al O ut c o m e A s s e s s m e nt s  
C R A  
Cli ni c al R e s e ar c h A s s o ci at e  
C R F  
C a s e R e p ort/ R e c or d F or m ( p a p er or el e ctr o ni c)  
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 F  
Cli ni c al S er vi c e F or m  
C S R  
Cli ni c al St u d y R e p ort  
C T C  
C o m m o n T o xi cit y Crit eri a  
C TI S  
Cli ni c al Tri al I nf or m ati o n S y st e m  
C T R  
Cli ni c al Tri al R e g ul ati o n  
Ctr o u g h  
Mi ni m al c o n c e ntr ati o n  b ef or e t h e n e xt d o s e i s a d mi ni st er e d  
C V  
C o effi ci e nt of V ari ati o n  
C Y P  
C yt o c hr o m e P 4 5 0  
D A R  
D o s e A d mi ni str ati o n R e c or d  
D DI  
Dr u g -Dr u g I nt er a cti o n s  
D H E A  
D e h y dr o e pi a n dr o st er o n e  
DI LI  
Dr u g -I n d u c e d Li v er I nj ur y 
D L T s  
D o s e  Li miti n g  T o xi citi e s  
D M R  
D e e p M ol e c ul ar R e s p o n s e  
D S & E  
O n c ol o g y N o v arti s Dr u g S af et y a n d E pi d e mi ol o g y D e p art m e nt  
D TI  
Dir e ct T hr o m bi n i n hi bit or  
E B V  
E p st ei n – B arr vir u s  
E C G  
El e ctr o c ar di o gr a m  
E D C  
El e ctr o ni c D at a C a pt ur e  
E L N  
E ur o p e a n L e u k e mi a N et w or k  
E M A  
E ur o p e a n M e di ci n e s A g e n c y  
E O R T C  
E ur o p e a n Or g a ni z ati o n f or R e s e ar c h a n d Tr e at m e nt of C a n c er  
E O T  
E n d of Tr e at m e nt  
e R T  
e R e s e ar c h T e c h n ol o g y  
E U  
E ur o p e a n U ni o n  
E u dr a C T  
E ur o p e a n U ni o n Dr u g R e g ul at ori n g A ut h oriti e s Cli ni c al Tri al s  
F A CI T  
F u n cti o n al A s s e s s m e nt of C hr o ni c Ill n e s s T h er a p y  
F A S  
F ull A n al y si s S et  
F D A  
F o o d a n d Dr u g A d mi ni str ati o n  
FI H  
Fir st -I n-H u m a n  
FI S H  
Fl u or e s c e nt I n -sit u h y bri di z ati o n  
F MI  
Fi n al M ar k et I m a g e  
F S H  
F olli cl e -sti m ul ati n g h or m o n e  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
G C P  
G o o d Cli ni c al Pr a cti c e  
G G T or γ G T  
G a m m a -gl ut a m yl -tr a n sf er a s e 
G P  
G e n er al P o p ul ati o n  
G U S B  
Gl u c ur o ni d a s e B et a  
H b A 1 c  
H e m o gl o bi n A 1 c  
H B c A b  
H e p atiti s B c or e a nti b o d y  
H B s A g  
H e p atiti s B s urf a c e a nti g e n  
H B V  
H e p atiti s B  
H C V  
H e p atiti s C  
h E R G  
H u m a n Et h er -a -g o -g o -r el at e d G e n e 
HI V  
H u m a n I m m u n o d efi ci e n c y Vir u s  
H S V  
H er p e s si m pl e x vir u s  
I B 
I n v e sti g at or' s Br o c h ur e 
I C 5 0 
I n hi bit or y C o n c e ntr ati o n (I C5 0 , t h e h alf m a xi m al) 
I C F 
I nf or m e d C o n s e nt F or m 
I C H 
I nt er n ati o n al C o u n cil f or H ar m o ni z ati o n of T e c h ni c al R e q uir e m e nt s f or R e gi str ati o n of 
P h ar m a c e uti c al s f or H u m a n U s e  
I D 
I d e ntifi c ati o n N u m b er 
I E C 
I n d e p e n d e nt Et hi c s C o m mitt e e 
I N 
I n v e sti g at or N otifi c ati o n 
I N R 
I nt er n ati o n al N or m ali z e d R ati o 
I R B 
I n stit uti o n al R e vi e w B o ar d 
I RI S 
I nt er n ati o n al R a n d o mi z e d St u d y of I nt erf er o n a n d S TI 5 7 1 
I R T 
I nt er a cti v e R e s p o n s e T e c h n ol o g y 
I S 
I nt er n ati o n al S c al e 
I T T 
I nt e nt t o tr e at 
I U D 
I ntr a ut eri n e d e vi c e 
I U S 
I ntr a ut eri n e s y st e m 
L C -M S/ M S  
Li q ui d c hr o m at o gr a p h y/t a n d e m m a s s s p e ctr o m etr y  
L D L  
L o w D e n sit y Li p o pr ot ei n  
L L N  
l o w er li mit of n or m al 
L L O Q  
L o w er li mit of q u a ntifi c ati o n  
L P L V  
L a st P ati e nt L a st Vi sit  
L S C  
l e u k e mi c st e m c ell 
M C R or M C y R  
M aj or C yt o g e n eti c R e s p o n s e  
M C V  
M e a n c or p u s c ul ar v ol u m e  
m C y R  
mi n or C yt o g e n eti c R e s p o n s e  
M e d D R A  
M e di c al di cti o n ar y f or r e g ul at or y a cti viti e s  
MI  
M y o c ar di al I nf ar cti o n  
M M R  
M aj or M ol e c ul ar R e s p o n s e  
M N T  
Mi cr o n u cl e u s t e st  
M R  
M ol e c ul ar R e s p o n s e  
M R D  
Mi ni m al R e si d u al Di s e a s e  
M RI  
M a g n eti c R e s o n a n c e I m a gi n g  
N C C N  
N ati o n al C o m pr e h e n si v e C a n c er N et w or k  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
N CI  
N ati o n al C a n c er I n stit ut e  
 
 
n M  
n a n o M ol ar  
N O A E L  
N o o b s er v e d a d v er s e eff e ct l e v el   
N T C P  
s o di u m -d e p e n d e nt t a ur o c h ol at e c o -tr a n s p ort pr ot ei n 
O A T P  
Or g a ni c a ni o n -tr a n s p orti n g p ol y p e pti d e 
O C T  
Or g a ni c C ati o n Tr a n s p ort er  
O S  
O v er all S ur vi v al  
P -g p  
P er m e a bilit y gl y c o pr ot ei n  
P A S  
P h ar m a c o ki n eti c a n al y si s s et  
P B P K  
P h y si ol o gi c all y -B a s e d P h ar m a c o ki n eti c  
P C R  
P ol y m er a s e C h ai n R e a cti o n  
P D  
p h ar m a c o d y n a mi c( s)  
P h +  
P h + P hil a d el p hi a c hr o m o s o m e p o siti v e  
P K  
p h ar m a c o ki n eti c( s)  
P R O  
P ati e nt R e p ort e d O ut c o m e( s)  
P T  
Pr ot hr o m bi n Ti m e  
P T A  
P o st -tri al a c c e s s 
Q D  
Q u a q u e Di e ( o n c e d ail y)  
Q L Q  
Q u alit y of Lif e Q u e sti o n n air e  
Q M S  
Q u alit y M a n a g e m e nt S y st e m  
Q T  
Q T i nt er v al  
Q T c  
Q T i nt er v al c orr e ct e d f or h e art r at e  
Q T c F  
Q T i nt er v al c orr e ct e d a c c or di n g t o Fri d eri ci a' s F or m ul a  
R N A  
Ri b o n u cl ei c a ci d  
R o W  
R e st of t h e W orl d  
R P 2 D  
R e c o m m e n d e d p h a s e ( P h) II d o s e  
R T -q P C R  
r e al-ti m e q u a ntit ati v e r e v er s e tr a n s cri pt a s e - P ol y m er a s e C h ai n R e a cti o n  
S A E  
s eri o u s a d v er s e e v e nt  
S A P  
St ati sti c al A n al y si s Pl a n  
S A S  
st ati sti c al a n al y si s s y st e m  
S C  
st e eri n g c o m mitt e e  
s Cr  
s er u m cr e ati ni n e  
S D  
st a n d ar d d e vi ati o n  
S O C s  
S y st e m Or g a n Cl a s s e s  
S O P  
St a n d ar d O p er ati n g Pr o c e d ur e  
S T A T 5  
Si g n al tr a n s d u c er a n d a cti v at or of tr a n s cri pti o n 5  
S U S A R  
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n  
T B L  
t ot al bilir u bi n 
T d P  
T or s a d e d e P oi nt e  
T F R  
Tr e at m e nt Fr e e R e mi s si o n  
T KI  
T yr o si n e Ki n a s e I n hi bit or  
Tl a st  
Ti m e of l a st m e a s ur e m e nt (ti m e)  
T m a x  
T h e ti m e t o r e a c h m a xi m u m ( C m a x) pl a s m a dr u g c o n c e ntr ati o n aft er or al d o s e a d mi ni str ati o n 
(ti m e) 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
T S Q M  
Tr e at m e nt S ati sf a cti o n Q u e sti o n n air e f or M e di c ati o n  
U G T  
U D P -Gl u c ur o n o s yltr a n sf er a s e   
U L N  
u p p er li mit of n or m al  
U L Q  
u p p er li mit of q u a ntifi c ati o n  
U S  
U nit e d St at e s  
U V -L L N A  
Ultr a vi ol et r a di ati o n - L o c al L y m p h N o d e A s s a y  
W B C  
w hit e bl o o d c ell( s)  
W H O  
W orl d H e alt h Or g a ni z ati o n  
ß -H C G  
B et a fr a cti o n of h u m a n c h ori o ni c g o n a d otr o pi n  

N o v arti s  
C o nfi d e nti al  
P a g e 1 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 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 st u d y  
Bi ol o gi c S a m pl e s  
A bi ol o gi c al s p e ci m e n i n cl u di n g, f or e x a m pl e, bl o o d ( pl a s m a, s er u m), ti s s u e, uri n e et c. 
t a k e n fr o m a st u d y s u bj e ct or p ati e nt  
C y cl e  
N u m b er a n d ti mi n g or r e c o m m e n d e d r e p etiti o n s of t h er a p y ar e u s u all y e x pr e s s e d a s 
n u m b er of d a y s ( e. g.  q 2 8 d a y s)  
D M R  
D e e p M ol e c ul ar R e s p o n s e i s c o n si d er e d a s a r e s p o n s e l e v el of at l e a st M R 4. 0  I S ( eit h er 
d et e ct a bl e di s e a s e ≤ 0. 0 1 % B C R:: A B L 1 I S or u n d et e ct a bl e di s e a s e i n c D N A wit h ≥ 1 0 
0 0 0 A B L 1 (l o g 1 0  4. 0) or ≥ 2 4 0 0 0 G U S B ( gl u c ur o ni d a s e b et a) tr a n s cri pt s)   
D o s a g e  
D o s e of t h e st u d y tr e at m e nt gi v e n t o t h e s u bj e ct i n a ti m e u nit ( e. g. 1 0 0 m g o n c e a d a y, 
7 5 m g t wi c e a d a y)  
E nr oll m e nt  
P oi nt/ti m e of s u bj e ct e ntr y i nt o t h e st u d y; t h e p oi nt at w hi c h i nf or m e d c o n s e nt m u st b e 
o bt ai n e d (i. e. pri or t o st arti n g a n y of t h e pr o c e d ur e s d e s cri b e d i n t h e pr ot o c ol).  
I n v e sti g ati o n al 
dr u g  
T h e st u d y dr u g w h o s e pr o p erti e s ar e b ei n g t e st e d i n t h e st u d y; 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” or “i n v e sti g ati o n al m e di ci n al pr o d u ct”.  
I n v e sti g ati o n al 
tr e at m e nt 
All i n v e sti g ati o n al dr u g( s) w h o s e pr o p erti e s ar e b ei n g t e st e d i n t h e st u d y a s w ell a s t h eir 
a s s o ci at e d tr e at m e nt c o ntr ol s. T hi s i n cl u d e s a n y pl a c e b o s, a n y a cti v e c o ntr ol s, a s w ell a 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 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 tr e at m e nt s 
a d mi ni st er e d a s c o n c o mit a nt b a c k gr o u n d t h er a p y r e q uir e d or all o w e d b y t h e pr ot o c ol 
w h e n u s e d 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 dr u g p a c k a g e i n st u di e s t h at di s p e n s e st u d y 
dr u g u si n g a n I R T s y st e m.  
P ati e nt  
A n i n di vi d u al wit h t h e c o n diti o n of i nt er e st  
P eri o d  
A mi n or s u b di vi si o n of t h e st u d y ti m eli n e; di vi d e s p h a s e s i nt o s m all er f u n cti o n al 
s e g m e nt s s u c h a s s cr e e ni n g, b a s eli n e, titr ati o n, w a s h o ut, et c.  
P er s o n al D at a  
S u bj e ct i nf or m ati o n c oll e ct e d b y t h e I n v e sti g at or t h at i s tr a n sf err e d t o N o v arti s f or t h e 
p ur p o s e of t h e cli ni c al tri al. T hi s d at a i n cl u d e s s u bj e ct i d e ntifi er i nf or m ati o n, st u d y 
i nf or m ati o n a n d bi ol o gi c al s a m pl e s.  
Pr e m at ur e s u bj e ct 
wit h dr a w al  
P oi nt/ti m e w h e n t h e s u bj e ct 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 dr u g a d mi ni str ati o n a n d a s s e s s m e nt s; at t hi s ti m e all st u d y dr u g 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.  
R a n d o mi z ati o n 
n u m b er  
A u ni q u e i d e ntifi er a s si g n e d t o e a c h r a n d o mi z e d s u bj e ct, c orr e s p o n di n g t o a s p e cifi c 
tr e at m e nt ar m a s si g n m e nt 
S cr e e n F ail ur e  
A s u bj e ct w h o i s s cr e e n e d b ut i s n ot tr e at e d or r a n d o mi z e d  
St u d y c o m pl eti o n  
P oi nt/ti m e at w hi c h t h e s u bj e ct 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 dr u g 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 dr u g 
di s c o nti n u ati o n  
P oi nt/ti m e w h e n s u bj e ct p er m a n e ntl y st o p s t a ki n g st u d y dr u g 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 at ur e s u bj e ct wit h dr a w al.  
St u d y 
dr u g/tr e at m e nt  
A n y dr u g ( or c o m bi n ati o n of dr u g s) a d mi ni st er e d t o t h e s u bj e ct a s p art of t h e r e q uir e d 
st u d y pr o c e d ur e s; i n cl u d e s i n v e sti g ati o n al dr u g, a cti v e dr u g r u n -i n s or b a c k gr o u n d 
t h er a p y. 
St u d y tr e at m e nt 
di s c o nti n u ati o n  
W h e n t h e s u bj e ct p er m a n e ntl y st o p s t a ki n g st u d y tr e at m e nt pri or t o t h e d efi n e d st u d y 
tr e at m e nt c o m pl eti o n d at e 
S u bj e ct  
A n i n di vi d u al w h o h a s c o n s e nt e d t o p arti ci p at e i n t hi s st u d y.  
S u bj e ct N u m b er  
A u ni q u e i d e ntif yi n g n u m b er a s si g n e d t o e a c h s u bj e ct w h o e nr oll s i n t h e st u d y  
S u st ai n e d Mi ni m al 
R e si d u al Di s e a s e  
S u st ai n e d M R D ( Mi ni m al R e si d u al Di s e a s e) i s b a s e d o n t h e l a st 5 q u art erl y p erf or m e d 
P C R a s s e s s m e nt s, i. e ( 1) t h e fir st a n d t h e l a st a s s e s s m e nt s ar e M R 4. 5 (l o g1 0  4. 5 
r e d u cti o n i n tr a n s cri pt s), ( 2) n o a s s e s s m e nt i s w or s e t h a n M R4 , a n d ( 3) n o m or e t h a n t w o 
a s s e s s m e nt s ar e b et w e e n M R 4  a n d M R 4. 5  

N o v arti s  
C o nfi d e nti al  
P a g e 1 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
Tr e at m e nt n u m b er  
A u ni q u e i d e ntifi er a s si g n e d i n n o n -r a n d o mi z e d st u di e s t o e a c h d o s e d s u bj e ct, 
c orr e s p o n di n g t o a s p e cifi c tr e at m e nt ar m  
V ari a bl e  
I nf or m ati o n u s e d i n t h e d at a a n al y si s; d eri v e d dir e ctl y or i n dir e ctl y fr o m d at a c oll e ct e d 
u si n g s p e cifi e d a s s e s s m e nt s at s p e cifi e d ti m e p oi nt s  
Wit h dr a w al of 
st u d y c o n s e nt  
Wit h dr a w al of c o n s e nt fr o m t h e st u d y o c c ur s o nl y w h e n a s u bj e ct d o e s n ot w a nt t o 
p arti ci p at e i n t h e st u d y a n y l o n g er, a n d d o e s n ot all o w a n y f urt h er c oll e cti o n of p er s o n al 
d at a  
 

N o v arti s  
C o nfi d e nti al  
P a g e 1 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
A m e n d m e nt 5  (2 1 -A u g -2 0 2 4 ) 
A m e n d m e nt r ati o n al e  
T he st u d y is c urre ntl y o n g oi n g i n t he asci mi ni b si n gle a ge nt c o h ort, 2 0 p atie nts are e nr olle d. 
T he 8 4 patie nts e nr olle d i n treat me nt ar ms 1–  4 ha ve c o m plete d or disc o nti n ue d t he trial. 
Recr uit me nt is n o w c o m plete.  
T he pri mar y p ur p os e of t his a me n d me nt is t o u p date t he pr ot oc ol b ase d o n  t he versi o n 1 1. 0 of 
Asci mi ni b I B w hic h i ncl u des t he  2 -year carci n o ge nicit y st u d y c o n d ucte d i n rats, i nteracti o ns of 
asci mi ni b wit h O A T P 1 B a n d B C R P s u bstrates, a n d wit h P -g p s u bstrates of narr o w t hera p e utic 
i n de x [I n vesti gat or’s Br oc h ure E diti o n 1 1. 0 date d 0 1-Mar -2 0 2 4 ].  
T he H y’s La w la n g ua ge has bee n u p date d  i n or der t o pr o vi de a d diti o nal g ui da nce t o t he 
i n vesti gat ors f or a p pr o pri ate re p orti n g of b ot h p ote ntial a n d c o nfir me d DI LI cases. Of n ote, n o 
A Es relat e d t o li ver f u ncti o n a b n or malit y  i n t he c o nte xt of DI LI h a ve b ee n re p orte d i n t h e st u d y 
till date.  
It w as als o clarifi e d t hat f or t he cli nical o utc o mes assess me nts, pa per P R O c ollecti o n will n ot  
be all o we d. T he statistical met h o ds were u p dat e d t o i ncl u de data a nal ysis pla n f or asci mi ni b 
si n gle a ge nt c o h ort.  
C orrecti o ns of discre p a n cies, clarificati o ns a n d s pelli n g c orrecti o ns ha v e als o bee n ma de i n 
se veral se cti o ns of t he pr ot oc ol.  
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N o v arti s  
C o nfi d e nti al  
P a g e 1 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
I R B s/I E C s 
A c o p y of t his a me n de d pr ot oc ol 
will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n d e pe n d e nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c ha n g es descri b e d i n t his a me n de d pr ot oc ol re q uire I R B/I E C a p pr o val pri or t o 
i m ple me ntati o n. T he c ha n ges herei n affect t he I nf or me d C o nse nt. Sites are re q uire d t o u p dat e 
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N o v arti s  
C o nfi d e nti al  
P a g e 1 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
a n d s u b mit f or a p pr o val a re vise d I nf or me d C o nse nt t hat ta kes i nt o acc o u nt t he c h a n ges 
descri be d i n t his pr ot oc ol a me n d me nt.  
A m e n d m e nt 4 ( 2 4 -A u g -2 0 2 3)  
A m e n d m e nt r ati o n al e  
T he st u d y is c urre ntl y o n g oi n g 8 4 patie nts i n treat me nt ar ms 1 –  4 ha ve c o m plete d or 
disc o nti n ue d t he trial, a n d i n t he asci mi ni b si n gle a ge nt c o h ort, 1 7 patie nts ha ve bee n scree ne d 
a n d 1 2/ 2 0 patie nts ha ve b ee n e nr olle d.  
T his pr ot oc ol a me n d m e nt ai ms t o u p date c o nc o mita nt me dicati o ns t hat s h o ul d be use d wit h 
ca uti o n. O A T P 1 B  a n d B C R P s u bstrates ha ve bee n a d de d t o t his list. T his is base d o n t he res ults 
of a P B P K si m ulati o n st u d y d o ne as part of p ost -mar keti n g re q uir e me nts re q uest per F D A 
( A B L 0 0 1 I B E d. 1 0 –  Secti o n 1. 4. 2).  
Base d o n i n vesti gat ors fee d bac k, t he i ncl usi o n criteri o n 3 has bee n u p date d t o all o w e nr oll me nt 
of patie nts w h o were treate d wit h i mati ni b at a d ose of 3 0 0 m g Q D or hi g her f or at least o ne 
year a n d ha v e n ot ac hie ve d D M R. T he le vel of res p o nse f or e nteri n g t he trial re m ai ns 
u nc ha n ge d, B C R:: A B L 1 le vels > 0. 0 1 % I S a n d ≤ 1 % I S at t he ti me of ra n d o mizati o n.)  
I mati ni b 4 0 0 m g Q D is t he a p pr o ve d d os e f or ne wl y dia g n ose d patie nts wit h C M L. H o we ver, 
s o me patie nts re q uire a l o wer d osa ge of i mati ni b t o ma na ge t o xicit y or i m pact o n q ualit y of life. 
F or p atie nts wit h B C R:: A B L 1 le vels > 0. 0 1 % I S a n d ≤ 1 % I S, sta ble o n a 3 0 0 m g Q D d os e of 
i mati ni b, a s witc h t o asci mi ni b pr o vi des a n o p p ort u nit y t o all o w patie nts t o re mai n o n treat me nt 
at a n o pti mal d ose f or l o n ger i n or der t o ac hie ve dee p res p o nses. As t he B C R:: A B L 1 le vels 
re q uire d at t he ti me of st u d y e ntr y are u nc ha n g e d, n o i m pact o n t h e efficac y e n d p oi nts is 
e x pecte d wit h t his c ha n g e i n t he i ncl usi o n criteri a. B C R:: A B L 1 le vels re q uire d at t he ti me of 
st u d y e ntr y are u nc ha n g e d, n o i m pact o n t he efficac y e n d p oi nts is e x pecte d wit h t his c ha n ge i n 
t he i ncl usi o n criteria. 
T he e x pl orat or y  bi o mar ker assess me nts of 
 via  
 h as 
bee n re m o ve d f or patie nts e nteri n g t he st u d y i n t he asci mi ni b si n gle a ge nt c o h ort. Sa m ple 
c ollecti o n a n d a n al ysis will be c o m plete d f or p atie nts i n treat me nt ar ms 1 -4 a n d disc o nti n ue d 
t here-after d ue t o l o w n u m ber of s a m ples 
meeti n g assa y eli gi bilit y criteria( 
 
 detecte d i n sa m ples a nal yze d t o date. 
P K sa m ple l o g s pecific f or t he asci mi ni b si n gle a ge nt c o h ort is re m o ve d t o har m o nize it o ver 
all treat me nt ar ms ( usi n g t he sa me f or all ar ms).  
U p dates base d  o n N o v artis te m plate versi o n i m ple me ntati o n pla n a n d g ui da nce f or pr ot o c ols i n 
t he c o nte xt of t he u pc o mi n g tra nsiti o n f or t he E ur o pea n Cli nical Trial Directi ve ( E U C T D) 
2 0 1 1/ C 1 7 2/ 0 1 t o t he E ur o pea n U ni o n Cli nical Tri al Re g ulati o n ( E U C T R) 5 3 6/ 2 0 1 4    
C h a n g e s t o t h e pr ot o c ol  
C ha n ges t o s pecific s ecti 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 d eleti o ns a n d re d u n derli ne f or i ns erti o ns. 
T he f oll o wi n g secti o ns h a ve bee n u p date d :  
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N o v arti s  
C o nfi d e nti al  
P a g e 1 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
•  
Secti o n 1. 1. 1. 1 U p date f or t he C A B L 0 0 1 A 2 3 0 1 is d o ne t o reflect c urre nt stat us of t he trial 
al o n g wit h A B L 0 0 1 I B E d. 1 0 u p dates.  
•  
Secti o n 4. 6 is u p date d t o reflect c ha n g es i n t he pr ot oc ol te m plate.  
•  
Secti o n 5. 1 i ncl usi o n criteri o n a 3 is u p date d base d o n i n vesti gat or’s fee d b ac k. T he 
i ncl usi o n criteri o n n u m ber 3 is c ha n g e d fr o m 3a. t o 3 b. f or reflecti n g t he c h a n ge i n t he 
pr ot oc ol.  
•  
Secti o n 6. 1. 1 St u d y dr u gs ta ble is u p date d t o refl ect u p date d pr ot oc ol te m plate.  
•  
Secti o n 6. 2. 1. 1 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 :  O A T P 1 B, 
B C R P s u bstrates a d de d as per mitte d c o nc o mita nt me dicati o n re q uiri n g ca uti o n.  
•  
Secti o n 7 is u p date d t o re m o ve t he o pti o nal p h o ne call i nter vie w.  
•  
Ta ble 8 -1 Assess me nt Sc he d ule, ra n d o mize d treat me nt: asci mi ni b si n gle a ge nt c o h ort 
a d de d; s u bject i nter vie w re m o ve d; n ote a d d e d t hat sa m ple c ollecti o n f or 
 
 is o nl y f or treat me nt ar ms 1-4.  
•  
Secti o n 8. 5. 2. 1 Ta ble 8 -1 0 P K sa m ple l o g s pecific f or t he asci mi ni b si n gle a ge nt c o h ort is 
re m o ve d t o har m o nize it o ver all treat me nt ar ms ( usi n g t he sa me f or all ar ms). 
•  
Secti o n 8. 5. 3 a n d Ta ble 8 -1 1 ( na me d as Ta ble 8 -1 0 i n P A 4): 
 
sa m ple c ollecti o n a n d e x pl orat or y bi o mar ker a nal ysis was li mite d t o treat me nt ar ms 1 -4.  
•  
1 0. 1. 2 Seri o us a d verse e ve nts a n d 1 0. 1. 3 S A E re p orti n g secti o ns are u p d ate d t o reflect 
ne w pr ot oc ol te m plate.  
•  
1 0. 1. 5 is u p date d a n d Ta ble 1 0 -1 is re m o ve d t o reflect ne w pr ot oc ol te m plate a n d E U -
C T R la n g ua ge.  
•  
1 3. 3 is u p d at e d  t o reflect ne w pr ot oc ol te m plate a n d E U-C T R la n g ua ge.  
•  
1 6. 3. 3 S e cti o n  A p p e n di x 3 List of c o nc o mita nt me dicati o ns w hic h are pr o hi bite d or t o be 
use d wit h ca uti o n: u p date d base d o n re visi o ns i n Secti o n 6. 2 a n d c urre nt k n o wle d ge. 
O A T P 1 B a n d B C R P s u bstrates u p date d as p er A B L 0 0 1 I B E d. 1 0.  
I n a d diti o n, s o me mi n or c ha n ges i ncl u di n g i nc o nsiste ncies ( discre p a ncies bet wee n secti o ns, 
t y p os) ha ve bee n c orrect e d. 
I R B s/I E C s 
A c o p y of t his a me n de d pr ot oc ol 
will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n d e pe n d e nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c ha n g es descri b e d i n t his a me n de d pr ot oc ol re q uire I R B/I E C a p pr o val pri or t o 
i m ple me ntati o n. 
T he c h a n ges h ere  i n affect t he I nf or me d C o nse nt. Sites are re q uir e d t o u p date a n d s u b mit f or 
a p pr o val a re vise d I nf or me d C o nse nt t hat ta kes i nt o acc o u nt t he c ha n ges descri be d i n t his 
pr ot oc ol a me n d me nt.  
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N o v arti s  
C o nfi d e nti al  
P a g e 1 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
A m e n d m e nt 3 ( 1 2 -J ul -2 0 2 2)  
A m e n d m e nt r ati o n al e  
A n i nteri m a nal ysis was perf or me d t o gai n a n earl y i nsi g ht i nt o t he safet y a n d efficac y of t he 
asci mi ni b a d d -o n c o m bi nati o n. T he i nteri m a nal ysis was pla n ne d t o be perf or me d w he n at least 
4 0 ( 5 0 %) patie nts h a ve bee n ra n d o mize d a n d h a ve bee n f oll o we d f or t h eir 2 4 wee ks visit 
assess me nt or ha ve disc o nti n ue d treat me nt. T he i nteri m a nal ysis c ut -off was o n 2 2 -J ul y-2 0 2 0. 
T he res ults s h o we d n o e x cess of ris k a n d/ or re d uce d effi cac y i n t he asci mi ni b a d d -o n ar ms. N o 
c ha n ge i n st u d y c o n d uct were p erf or me d base d o n t h e be nefit/ris k bala nce.  
T his a me n d me nt ai ms t o a d d a n asci mi ni b si n gle a ge nt c o h ort t o assess w het her asci mi ni b si n gle 
a ge nt at t he rec o m me n de d d ose of 8 0 m g Q D lea ds t o si milar efficac y a n d safet y as o bser ve d 
i n t he a d d-o n ar ms of as ci mi ni b a n d i mati ni b. T his a d diti o nal c o h ort w ill hel p t o e val uate if t he 
c o m bi nati o n of asci mi ni b wit h i mati ni b is nee de d t o i ncrease t he li keli h o o d of ac hie vi n g D M R, 
or if t his ca n be ac hie ve d b y asci mi ni b al o ne. T he pri mar y a nal ysis c ut -off was o n 1 0 -Ja n-2 0 2 2. 
Ei g ht y -f o ur patie nts ha v e bee n ra n d o mize d i n t h e st u d y. T he pri mar y a n al ysis res ults s h o w 
acti vit y of asci mi ni b as a n a d d -o n t hera p y t o i mati ni b, assesse d b y M R 4. 5 rate at Wee k 4 8. T he 
M R
 4. 5 rate at Wee k 4 8 was 1 9 %, 2 8. 6 %, 0 % a n d 4. 8 % i n t he asci mi ni b 4 0 m g + i mati ni b, 
asci mi ni b 6 0 m g + i mati ni b, c o nti n ue d i mati ni b a n d s witc h t o nil oti ni b ar m. Asci mi ni b 4 0 m g 
Q D or 6 0 m g Q D a d d e d o n t o i mati ni b was well t olerate d wit h n o ne w or w orse ni n g e v e nt s as 
c o m pare d t o t he k n o w n s afet y pr ofile of si n gle a g e nt asci mi ni b a n d i mati ni b.  
Data f or 
m olec ular 
res p o nse 
wit h si n gle a g e nt asci mi ni b is a v aila ble fr o m st u dies 
C A B L 0 0 1 A 2 3 0 1 ( calle d A 2 3 0 1 h e ncef ort h)  a n d C A B L 0 0 1 X 2 1 0 1 ( calle d X 2 1 0 1 h e ncef ort h)  
t hat i ncl u de d hea vil y pre-treate d C M L-C P patie nts wit h pri or treat me nt wit h at least 2 or m ore 
T KIs. T he M R 4. 5 rate i n st u d y A 2 3 0 1, i n t he s u b gr o u p of patie nts treate d wit h asci mi ni b si n gle 
a ge nt wit h b aseli ne B C R:: A B L 1 le vels t he s a me as t hat of patie nts e nr olle d i n st u d y 
C A B L 0 0 1 E 2 2 0 1 ( calle d E 2 2 0 1 he ncef ort h)  (i. e., > 0. 0 1 ≤1 %), was ver y si milar (1 8. 8 %, 3 
res p o n ders a m o n g 1 6 patie nts ) t o t hat see n wit h t he asci mi ni b as a d d-o n t o i mati ni b i n st u d y 
E 2 2 0 1.  
T he list of c o nc o mita nt me dicati o ns per mitte d t o be use d wit h ca uti o n a n d pr o hi bite d f or t he 
asci mi ni b c o m bi nati o n ar ms has bee n u p date d. Base d o n e mer gi n g data fr o m p har mac o ki neti c 
st u dies [ Asci mi ni b I n vesti gat or Br oc h ure], pr o hi biti o n f or str o n g C Y P 3 A 4/ 5 i n hi bit ors has bee n 
re m o ve d a n d ca uti o n state me nt f or asci mi ni b c o m bi nati o n ar m are a d de d. A d diti o nall y, 
i nstr ucti o ns are a d de d f or str o n g C Y P 3 A 4 i n d ucers t o be us e d wit h ca uti o n f or asci mi ni b si n gle 
a ge nt a n d pr o hi bite d f or t he c o m bi nati o n ar ms.  
A ge nts ca usi n g Q T pr ol o n gati o n or wit h  a " k n o w n", ris k of T orsa des de P oi ntes ( T d P) are n o 
l o n ger pr o hi bite d b ut s h o ul d be use d wit h ca uti o n. Of n ote t here is n o nee d f or ca uti o n or 
pr o hi biti o n f or dr u gs wit h “ p ossi ble” or “c o n diti o nal” ris k of T d P a n d t his state me nt is m o difie d 
acc or di n gl y.  Asci mi ni b is n ot rele va ntl y affecte d b y U G T 1 A/ 2 B i n d ucers, or B C R P a n d P -g p 
i n hi bit ors, t h us t here is n o l o n ger a li mitati o n t o use of t hese a ge nts f or p atie nts bei n g treate d 
wit h asci mi ni b. N o rele va nt i nteracti o n wit h se nsiti ve s u bstrates of C Y P 2 C 8 has bee n o bser ve d. 
A d diti o nall y, t he a me n d me nt clari fies t he e x pl orat or y bi o mar ker o bjecti ve st u d yi n g t he 
 a n d re m o ves a n e x pl orat or y o bjecti ve base d o n s u bject q ualitati ve 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
i nter vie ws d ue t o l o gistical iss ues t o i m ple me nt t he pr ocess t o c o m plete t hese i nter vie ws. T h e 
i nter vie ws i nte n de d t o descri be c o nce pts i m p orta nt t o st u d y patie nts  n ot ca pt ure d b y sta n dar d 
P R O i nstr u me nts t hat c o ul d i nf or m f ut ure cli nical trial desi g ns were re m o v e d.  
As t he T F R st u d y has n ot bee n i nitiate d a n d will n ot be a vaila ble f or patie nts c o m pleti n g t he 
st u d y E 2 2 0 1, t he o pti o n f or T F R st u d y as a p ost-trial access mec ha nis m f or patie nts has b ee n 
re m o ve d. 
T he c o nte nt of t he l ocal a me n d me nt f or t he U S A A me n d me nt 0 2 -U S. 0 1 ( 1 0 -A u g -2 0 2 0) is 
s u perse de d b y t his gl o bal a me n d me nt 0 3 as male c o ntrace pti o n f or t he U S patie nts  o n asci mi ni b 
was re m o ve d bas e d o n t he latest [I n vesti gat or’s Br oc h ure] a n d a p pr o ve d U S prescri bi n g 
i nf or mati o n ( U S PI), w here n o male c o ntrace pti o n is re q uire d. 
C h a n g e s t o t h e pr ot o c ol  
C ha n ges t o s pecific s ecti 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 d eleti o ns a n d re d u n derli ne f or i ns erti o ns.  
T he f oll o wi n g secti o ns h a ve bee n u p date d t o i ncl u de t he asci mi ni b si n gle a ge nt c o h ort:  
•  Pr ot oc ol S u m mar y u p date d base d o n Pr ot oc ol A m e n d me nt c ha n g es  
•  Secti o n 1. 1. 1 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): 
u p date d f or as ci mi ni b wit h c urre nt a vaila bl e i nf or mati o n fr o m n o n -cli nical st u dies f or 
p h ot ot o xicit y a n d fr o m o n g oi n g cli nical st u dies as reflect e d i n t he c urre nt [ Asc i mi ni b 
I n v esti gat or’s Br oc h ure] 
•  Secti o n 1. 2  P ur p ose: a d de d sec o n dar y o bjecti ve t o esti mate t he efficac y of asci mi ni b si n gle 
a ge nt. Secti o n 2  O bjecti v es a n d rel ate d e n d p oi nts:  
•  D urati o n of M R 4. 5 a d de d t o sec o n dar y o bjecti ve (t o assess a d diti o nal para meters of t he 
effic ac y of asci mi ni b 6 0 m g / 4 0 m g a d de d t o i mati ni b vs c o nti n ue d i mati ni b or s witc h 
t o nil oti ni b) t o assess if patie nts  i n t he a d d-o n ar ms ha ve a l o n ger res p o ns e t o treat me nt  
•  Sec o n dar y o bj ecti ves a n d t he c orres p o n di n g e n d p oi nts a d de d f or asci mi ni b si n gle a ge nt  
•  D urati o n of M R 4. 5 a d de d t o e x pl orat or y o bjecti ve (t o descri be t he efficac y a n d safet y of 
asci mi ni b 6 0 
m g + i mati ni b i n patie nts  ra n d o mize d t o c o nti n ue d i m ati ni b w h o 
cr oss-o ver t o recei ve as ci mi ni b 6 0 m g + i mati ni b) t o assess if patie nts  i n t he a d d-o n 
ar ms ha ve a l o n ger res p o nse t o treat me nt  
•  E x pl orat or y bi o mar ker o bjecti ve 
was re w or d e d t o a d d clarit y, n o c ha n ges t o 
assess me nts  
•  E x pl orat or y o bjecti ve t o descri be c o n ce pts n ot ca pt ure d b y sta n dar d P R O i nstr u me nts 
t o i nf or m f ut ure cli nical trial desi g ns was re m o ve d d ue t o u na v aila bilit y of v e n d or 
c o ntract  
•  Secti o n 3  St u d y desi g n:  
•  Asci mi ni b si n gle a ge nt c o h ort a d de d  
•  F o ur ra n d o mize d treat me nt ar ms were l a bele d treat me nt ar m 1 -4 f or clarit y  
•  E n d of treat me nt peri o d a d de d f or as ci mi ni b si n gle a ge nt c o h ort  

N o v arti s  
C o nfi d e nti al  
P a g e 2 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
•  E n d of St u d y Treat me nt peri o d a d de d f or asci mi ni b si n gle a ge nt c o h ort, a n d re w or de d 
f or clarit y 
•  P ost trial access o pti o ns were u p d ate d t o ali g n wit h cli nical de vel o p me nt strate g y  
•  Fi g ure 1 -1 was u p dat e d t o reflect t he a d diti o n of t he asci mi ni b si n gle a ge nt c o h ort  
•  Secti o n 4. 1. 1  Rati o nale f or a d diti o n of asci mi ni b si n gle a ge nt c o h ort se cti o n a d de d  
•  Secti o n 4. 2  Rati o nale f or d ose/re gi me n a n d d urati o n of treat me nt: asci mi ni b si n gle a ge nt 
c o h ort a d de d  
•  Secti o n 4. 5  Ris ks a n d be nefits: ris k -be nefit e val uati o n u p date d base d o n ne w a vaila ble data  
•  Secti o n 4. 6  Rati o nale f or p u blic healt h e mer ge n c y miti gati o n pr oce d ures: secti o n a d de d 
base d o n ne w sta n d ar d pr oce d ures i n t he e ve nt of a p u blic healt h e mer ge nc y  
•  Secti o n 5: P o p ulati o n: asci mi ni b si n gle a ge nt c o h ort a d de d  
•  Secti o n 5. 2  E xcl usi o n criteri o n # 1 5: C o ntrace pti o n d urati o n re vise d t o ali g n wit h U S PI; te xt 
u p date d f or clarit y  
•  Criteri o n fr o m l ocal a me n d me nt 0 2 -U S. 0 1: 
male c o ntrace pti o n f or 
patie nts  o n 
asci mi ni b re m o ve d base d o n N o vartis assess me nt of t he  ris k f or mal e-me diate d 
e m br y o/fetal h ar m t hr o u g h se me n tr a ns missi o n  acc or di n g t o [ I nvesti g at or’s Br oc h ure] 
•  Secti o n 6. 1. 3  Treat me nt ar m/ gr o u p: asci mi ni b si n gle a ge nt c o h ort a d de d  
•  Secti o n 6. 1. 5  Treat me nt d urati o n: asci mi ni b si n gle a ge nt c o h ort a d de d  
•  Secti o n 6. 2  C o nc o mita nt t hera p y a n d pr o hi bite d m e dicati o ns u p date d t o ali g n wit h t he latest 
I n v esti gat or Br oc h ure Secti o n 6. 3. 3 Treat me nt assi g n me nt f or asci mi ni b si n gle a ge nt c o h ort 
secti o n a d de d 
•  Ta ble 6 -2: Criteria f or d ose re d u cti o n/i nterr u pti o n a n d re -i nitiati o n of asci mi ni b + i mati ni b: 
asci mi ni b si n gle a ge nt c o h ort a d de d. Ta bl e u p dat e d, t he rati o nale f or t he c ha n ge is d ue t o 
u p dates t o i nter nal N V S g ui da nce o n ma na ge me nt of L F T d era n g e me nts a n d  clarificati o n 
of g ui da nce a p plica ble t o patie nts  i n t he trial 
•  Ta ble 6 -4  D os e re d u cti o n g ui da nce f or asci mi ni b si n gle a ge nt c o h ort ta ble a d de d  
•  Secti o n 6. 6. 1 Treat me nt c o m plia nce: asci mi ni b si n gle a ge nt c o h ort a d de d  
•  Secti o n 6. 7. 1. 1 Ha n dli n g of st u d y treat me nt: Refere n ce t o p u blic healt h e mer ge nc y 
miti gati o n pr oce d ures  a d de d 
•  Secti o n 6. 7. 3 Asci mi ni b si n gle a ge nt c o h ort - I nstr ucti o n f or pres cri bi n g a n d ta ki n g st u d y 
treat me nt secti o n a d d e d 
•  Secti o n 7 I nf or me d c o ns e nt pr oce d ures te xt u p dat e d f or cl arit y  
•  Secti o n 8  Visit sc he d ule a n d assess me nts: Refere n ce t o p u blic healt h e mer ge nc y miti gati o n 
pr oce d ures  a d de d  
•  Ta ble 8 -1 Assess me nt Sc he d ule, ra n d o mize d tr eat me nt: asci mi ni b si n gle a ge nt c o h ort 
a d de d; s u bject i nter vie w re m o ve d  
•  Secti o n 8. 1. 2 I nf or m ati o n t o be c ollecte d o n scree ni n g fail ures: asci mi ni b si n gle a ge nt 
c o h ort a d de d  
•  Ta ble 8 -3 Bl o o d sa m ples f or P C R: asci mi ni b si n gle a ge nt c o h ort a d de d  

N o v arti s  
C o nfi d e nti al  
P a g e 2 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
•  Secti o n 8. 4 Safet y a n d T olera bilit y: Refere nce t o p u blic healt h e mer g e nc y miti gati o n 
pr oce d ures  a d de d  
•  Secti o n 8. 4. 1  La b orat or y e val uati o ns: Refere n ce t o p u blic healt h e mer ge nc y miti gati o n 
pr oce d ures  a d de d  
•  Ta ble 8 -7 Ce ntr al E C G c ollecti o n pla n: asci mi ni b si n gle a ge nt c o h ort a d de d  
•  Secti o n 8. 4. 3 Pre g na nc y a n d assess me nts of fertilit y: Refere nce t o p u blic h ealt h 
e mer ge n c y miti gati o n pr oce d ures  a d de d. Defi niti o n of p ost -me n o pa usal a n d c hil d -
beari n g p ote ntial r e w or d e d t o a d d m ore cl arit y  
•  Secti o n 8. 5. 1. 4  S u bject i nter vie w: secti o n re m o ve d as e x pl orat or y o bjecti ve was 
re m o ve d 
•  Secti o n 8. 5. 2. 1 P har mac o ki netic  bl o o d c ollecti o n a n d ha n dli n g: asci mi ni b si n gle 
a ge nt c o h ort a d d e d  
•  Secti o n 9. 2 St u d y c o m pleti o n a n d p ost -st u d y treat me nt: Secti o n u p date d t o clarif y e n d 
of st u d y, Wee k 9 6 , a n d fi nal a nal ysis 
•  Secti o n 1 0. 1. 3 S A E  re p orti n g: re p orti n g i nstr ucti o ns re w or d e d t o c o ver re q uire me nts 
fr o m a ut h orities 
•  Secti o n 1 2. 1  A nal ysis sets: asci mi ni b si n gle a ge nt c o h ort a d de d. T h e a n al ysis of t he 
d urati o n of M R 4. 5 was a d de d t o t he M R 4. 5 Res p o n der set  
•  Secti o n 1 2. 2  S u bject de m o gra p hics a n d ot her baseli ne c haracteristics: asci mi ni b 
si n gle a ge nt c o h ort a d d e d 
•  Secti o n 1 2. 3  Treat me nts: asci mi ni b si n gle a ge nt c o h ort a d de d  
•  Secti o n 1 2. 5  A nal ysis of sec o n dar y e n d p oi nts: sec o n dar y e n d p oi nt a nal ysis a d de d t o ali g n 
wit h t he o bjecti ves. Asci mi ni b si n gle a ge nt sec o n dar y e n d p oi nt a nal ysis a d de d  
•  Secti o n 1 2. 5. 1  Efficac y a n d/ or P har mac o d y na mic e n d p oi nt(s): asci mi ni b si n gle a ge nt 
a d de d, te xt u p date d f or cl arit y  
•  Secti o n 1 2. 5. 1. 1  Rate of M R 4. 5 at 4 8 wee ks: asci mi ni b si n gle a ge nt a d de d, t e xt 
u p date d f or clarit y  
•  Secti o n 1 2. 5. 1. 2  Rate of s ustai ne d M R 4. 5 at 9 6 wee ks a n d secti o n 1 2. 5. 1. 3. Rate of 
M R
4. 5 at 9 6 wee ks a n d secti o n 1 2. 5. 1. 4 Rate of M R 4. 5 b y 4 8 a n d 9 6 wee ks: te xt 
u p date d f or clarit y  
•  Secti o n 1 2. 5. 1. 6  D urati o n of M R 4. 5: Ne wl y a d de d secti o n t o descri be t he a nal ysis of 
t he d urati o n of M R4. 5 
•  Secti o n 1 2. 5. 2 te xt u p date d f or cl arit y  
•  Secti o n 1 2. 5. 3 P har mac o ki netics: asci mi ni b si n gle a ge nt c o h ort a d de d  
•  Ta ble 1 2 -1 N o n -c o m part me ntal p har mac o ki n etic para meters: T he C tr o u g h was re m o ve d 
fr o m t he list of p har mac o ki netic para met ers c o mi n g fr o m n o n-c o m part me ntal a nal ysis 
as it will be deri ve d fr o m t he descri pti ve stats of t he differe nt pre -d ose (tr o u g h) 
assess me nts  
•  Secti o n 1 2. 7  I nteri m a nal yses: clarifie d t hat pri mar y a nal ysis was perf or m e d i n 
treat me nt ar ms 1-4  

N o v arti s  
C o nfi d e nti al  
P a g e 2 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
•  Secti o n 1 2. 8  Sa m ple size calc ulati o n: u p date d f or asci mi ni b si n gle a ge nt c o h ort  
•  Secti o n 1 3. 5  S u bject e n ga ge me nt: secti o n a d d e d p er ne w pr ot oc ol te m plate  
•  Secti o n 1 5  Refere n ces: n e wl y cite d refere nces a d d e d  
•  Secti o n 1 6. 3 A p pe n di x 3 List of c o nc o mita nt me dicati o ns w hic h are pr o hi bite d or t o 
be use d wit h ca uti o n: u p date d base d o n re visi o ns i n Secti o n 6. 2 a n d c urre nt 
k n o wle d ge.  
I n a d diti o n, s o me mi n or c ha n ges i ncl u di n g i nc o nsiste ncies ( discre p a ncies bet wee n secti o ns, 
t y p os) ha ve bee n c orrect e d. 
I R B s/I E C s 
A c o p y of t his a me n de d pr ot oc ol 
will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n d e pe n d e nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c ha n g es descri b e d i n t his a me n de d pr ot oc ol re q uire I R B/I E C a p pr o val pri or t o 
i m ple me ntati o n.  
T he c ha n ges herei n affect t he I nf or me d C o nse nt. Sites are re q uire d t o u p date a n d s u b mit f or 
a p pr o val a re vise d I nf or me d C o nse nt t hat ta kes i nt o acc o u nt t he c ha n ges descri be d i n t his 
pr ot oc ol a me n d me nt.  

N o v arti s  
C o nfi d e nti al  
P a g e 2 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
A m e n d m e nt 2 ( 1 0 -A u g -2 0 2 0)  
A m e n d m e nt r ati o n al e  
As of 2 2 -J ul-2 0 2 0, 9 1 patie nts ha ve bee n scree ne d a n d 6 2 patie nts ha ve bee n ra n d o mize d i n t he 
st u d y. T he st u d y is c urre ntl y o n g oi n g a n d n o a nal ysis has bee n c o n d u cte d s o far.  
Pri mar y p ur p ose of t he a me n d me nt is:  
T o all o w f or m o dificati o n of st u d y c o n d uct b ase d o n i nteri m a nal ysis res ults i n case of 
o bser vati o n of  a n i m bal a nce i n t h e be n efit ris k pr ofile of o ne of t he i n vesti gati o nal ar ms 
(asci mi ni b a d d-o n tr eat m e nt ar ms) , s p ecificall y fi n di n gs relate d t o e x cessi ve t o xicit y wit h o ut 
a d de d b e nefit. T h e i nteri m a nal ysis is pla n ne d t o pr o vi de earl y i nsi g hts i nt o t he safet y a n d 
effic ac y para meters t o i nf or m t he be nefit ris k assess me nt of asci mi ni b as a n a d d -o n t hera p y t o 
i mati ni b. If e xcessi ve t o xicit y wit h o ut a d de d be n efit is o bser ve d i n o n e of t he i n vesti gati o nal 
ar ms, disc o nti n uati o n of t hat treat me nt ar m will be c o nsi dere d. T he decisi o n of disc o nti n uati o n 
of a n i n vesti gati o nal ar m i n t he st u d y will be ta ke n base d o n t he ris k be nefit bala nce of t he t w o 
i n vesti gati o nal ar ms, a n d i n c o nte xt of t he ot her t w o treat me nt o pti o ns a vaila ble f or t he patie nts 
i n t he st u d y, na mel y, c o nti n ue o n i mati ni b wit h n o p ote ntial i m pr o ve me nt of efficac y, or s witc h 
t o nil oti ni b wit h a p ote ntial t o i m pr o ve efficac y h o we ver wit h a relati vel y ad verse safet y pr ofile 
as c o m pare d t o i mati ni b.  T he i nteri m a nal ysis is pl a n ne d t o b e p erf or me d w he n at l east 4 0 ( 5 0 %) 
patie nts ha ve bee n ra n d o mize d a n d h a ve bee n f oll o we d f or t heir 2 4 wee ks visit assess me nt or 
ha ve disc o nti n ue d treat me nt.  
I n a d diti o n, d ose m o difi cati o n re q uire me nts h a v e bee n u p d ate d t o f urt h er clarif y t he d os e 
m o dificati o ns f or rec urre nt Gra de 3/ 4 c yt o pe ni as.  
•  If, aft er a 1st e v e nt of Gra de 1/ 2 c yt o pe nia, rec urre nt c yt o pe nia of a n y gra de occ urs, it is 
rec o m me n de d t hat t he st u d y treat me nt be hel d u ntil t here is res ol uti o n t o ≤ Gra de 2, a n d 
t hereafter c urre nt d os e le vel ca n be m ai ntai ne d.  
•  After a 1 st e ve nt of Gra d e 3/ 4 c yt o pe nia, if t here is rec urre nce of Gra d e 3/ 4 c yt o pe nia, t he 
d ose le vel s h o ul d be mai ntai ne d o nl y if it res ol ves t o ≤ Gra de 2 i n ≤ 1 4 da ys.  
•  I n case of rec urre nt Gra d e 3/ 4 c yt o pe nias of d urati o n > 1 4 da ys asci mi ni b a n d i mati ni b d oses 
are rec o m me n d e d t o be re d uce d b y 1 d os e le vel.  
I nf or mati o n f or C Y P 3 A s u bstrates a n d i n hi bit ors i n t he A p pe n di x 3 has b ee n u p date d i n or der 
t o reflect u p d ates i ntr o d uce d wit h pr ot oc ol a m e n d me nt 0 1 base d o n a m ost u p date d P B P K 
m o deli n g.  
C h a n g e s t o t h e pr ot o c ol  
C ha n ges t o s pecific s ecti 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 d eleti o ns a n d re d u n derli ne f or i ns erti o ns.  
1.  Pr ot oc ol S u m mar y : St u d y desi g n a n d Data a n al ysis secti o ns u p date d i n or der t o matc h wit h 
t he u p dates ma de i n t he res pecti ve pr ot o c ol secti o ns.  
2.  Secti o n 1. 1. 1. 1 - O ver vie w of asci mi ni b : Narr o w t hera pe utic i n de x s pecifi e d f or s u bstrat es 
of C Y P 3 A 4/ 5, C Y P 2 C 8 a n d C Y P 2 C 9.  

N o v arti s  
C o nfi d e nti al  
P a g e 2 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
3.  Secti o n 2 - O bjecti ves a n d e n d p oi nts:  U p date of t he e n d p oi nt f or e x pl orat or y o bjecti ve 
 
 w as re m o ve d. 
4.  Secti o n 3 - St u d y Desi g n: U p date d f or p ossi bilit y of m o dificati o n of cr oss -o ver ar m if 
si g nals of t o xicit y are see n i n o ne or m ore treat me nt ar ms, at t he ti me of i nteri m a nal ysis. If 
a decisi o n is ta k e n t o disc o nti n ue asci mi ni b 6 0 m g + i mati ni b treat me nt ar m at i nteri m 
a nal ysis or u p o n e mer gi n g data, cr oss -o ver ma y be c ha n ge d t o asci mi ni b 4 0 m g + i mati ni b 
treat me nt ar m. Fi g ur e 3 -1 s u b hea di n g h as bee n a me n de d t o mat c h t he u p d ates i n Secti o n 3.  
5.  Secti o n 4. 4 - P ur p ose a n d ti mi n g of i nteri m a n al yses/ desi g n a d a pt ati o ns: U p date t o 
all o w p ossi bilit y of m o dificati o n of st u d y c o n d uct if e xcessi ve t o xicit y wit h o ut a d de d 
be nefit is o bser ve d i n o n e or m ore tr eat me nt ar ms, at t he ti me of i nteri m a n al ysis.  
6.  Secti o n 6. 5. 1 - D ose m o dific ati o n : Ta ble 6-2 has bee n u p date d t o clarif y rec o m me n dati o ns 
f or rec urre nt c yt o pe nias. 
7.  Secti o n 8 - Visit sc he d ule a n d assess me nts: U p date f or 
 
 
 was r e m o ve d.  
8.  Secti o n 1 2. 5. 2 - S afet y e n d p oi nts: U p date d f or p ossi bilit y of c ha n ge of cr oss -o ver treat me nt 
base d o n res ults of t he i nteri m a nal ysis.  
9.  Secti o n 1 2. 6. 2 - Ot her e x pl or at or y e n d p oi nts: U p date d f or  p ossi bilit y of c ha n ge of 
cr oss-o ver treat me nt b ase d o n res ults of t he i nteri m a nal ysis.  
1 0.  Secti o n 1 2. 7 - I nteri m A n al yses: U p date t o all o w p ossi bilit y of st u d y m o dificati o n if si g nals 
of t o xicit y are see n i n o ne or m ore tr eat me nt ar ms, at t he ti me of i nteri m a n al ysis.  
1 1.  Secti o n 1 6. 3. 3 - C o nc o mit a nt me dic ati o ns t o be use d wit h c a uti o n f or asci mi ni b + 
i m ati ni b ar ms: I nf or m ati o n i n A p pe n di x 3, Ta ble 1 6-6 f or C Y P 3 A s u bstrat es a n d i n hi bit ors 
u p date d i n li ne wit h i nf or mati o n i n Secti o n 6. 2.  
T he ass ess me nt of t h e Be nefit/ Ris k c o ncl u de d t he a bse nce of a d diti o nal ris ks relate d t o C O VI D -
1 9.  
I n a d diti o n s o me mi n or c ha n ges i ncl u di n g i nc o nsiste ncies ( discre pa n cies bet wee n secti o ns, 
t y p os) ha ve bee n c orrect e d. 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 2 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
L o c al v er si o n  A m e n d m e nt 0 2 -U S. 0 1 ( 1 0 -A u g -2 0 2 0) f or U S A  
A d diti o nal c ha n ges o nl y a p plica ble f or t he U S A:  
A m e n d m e nt r ati o n al e  
Base d o n F D A re q uest, r e q uire me nt f or male c o ntrace pti o n has bee n rei ntr o d uce d i n t he st u d y.  
C h a n g e s t o t h e pr ot o c ol  
Secti o n 5. 2 E xcl usi o n criteri o n # 1 5: 
Male c o ntrace pti o n re q uire m e nts a d de d i n e x cl usi o n 
criteria 1 5. Criteri a n u m beri n g re vise d t o 1 5 b.  
Secti o n 8. 4. 3 Pre g n a nc y a n d assess me nts of fertilit y:  a d de d fe male part ners of male t o b e 
rec or de d o n Cli nical trial pre g na n c y f or m a n d t o i ncl u de g ui da nce f or se x uall y acti ve male. 
A d diti o nall y a d de d, se x u all y acti ve m ales o n asci mi ni b treat me nt m ust use a c o n d o m d uri n g 
i nterc o urse w hile ta ki n g t he dr u g a n d f or at least 3 da ys after st o p pi n g treat me nt a n d s h o ul d n ot 
fat her a c hil d i n t his peri o d. 
I R B s/I E C s 
A c o p y of t his a me n de d pr ot oc ol 
will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n d e pe n d e nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c ha n g es descri b e d i n t his a me n de d pr ot oc ol re q uire I R B/I E C a p pr o val pri or t o 
i m ple me ntati o n.  
T he c ha n ges herei n affect t he I nf or me d C o nse nt. Sites are re q uire d t o u p date a n d s u b mit f or 
a p pr o val a re vise d I nf or me d C o nse nt t hat ta kes i nt o acc o u nt t he c ha n ges descri be d i n t his 
pr ot oc ol a me n d me nt.  

N o v arti s  
C o nfi d e nti al  
P a g e 2 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
A m e n d m e nt 1 ( 1 8 -J ul -2 0 1 9)  
A m e n d m e nt r ati o n al e  
As of 1 8 -J ul-2 0 1 9, 3 2 p atie nts were scree ne d a n d 2 3 patie nts were ra n d o mize d i n t he st u d y. 
T he st u d y is c urre ntl y o n g oi n g.  
Pri mar y p ur p ose of t he a me n d me nt is:  
M o dificati o n of t h e i ncl usi o n criteria # 3 re gar di n g i mati ni b pretreat me nt d urati o n, fr o m  “ at 
le ast 2 4 m o nt hs ” t o “ at le ast 1 2 m o nt hs ”  i n patie nts wit h B C R:: A B L 1 le vel bet wee n > 0. 0 1 % 
I S a n d ≤ 1 % I S t o fr o ntli n e i mati ni b. T he rati o nale of t his c ha n ge is base d o n e v ol vi n g treat me nt 
g oals i n C hr o nic M yel oi d Le u ke mia ( C M L) t o war ds t he ac hi e ve me nt of faster dee p m olec ular 
res p o nse ( D M R) t o e na ble treat me nt free re missi o n ( N C C N 2 0 1 8, Rea a n d Ca y uela 2 0 1 7, 
Ma h o n  2 0 1 6). A s ustai ne d D M R f or at least 2 years is rec o g nize d as a n ess e ntial re q uire m e nt 
t o atte m pt disc o nti n uati o n of T yr osi ne 
Ki nase I n hi bit or ( T KI) t hera p y i n P h + C M L 
( N C C N 2 0 1 8, Baccara ni  et al 2 0 1 3, H oc h ha us  et al 2 0 1 7). I n a d diti o n, D M R is ass ociate d wit h 
i m pr o ve d s ur vi val rates a n d a v oi da nce of diseas e pr o gressi o n ( C ortes 2 0 1 8, D ul uc q a n d Ma h o n 
2 0 1 6, Bra nf or d 2 0 1 6, 
Ye u n g et al 2 0 1 5, He hl ma n n et al 2 0 1 4; Etie n ne et al 2 0 1 4; 
Falc hi  et al 2 0 1 3). I n C M L St u d y I V wit h fr o ntli ne i mati ni b, patie nts wit h M R 4. 5 at 4 years h a d 
a hi g her pr o ba bilit y of s ur vi val at 8 years v ers us patie nts wit h B C R:: A B L 1 I S of 0. 1 -1 % a n d 
n o patie nt w h o ac hi e ve d M R 4. 5 ha d e x perie nce d pr o gressi o n t o accelerat e d p hase/ blast crisis b y 
t he data c ut off ( He hl ma n n et al 2 0 1 4). A retr os pecti ve a nal ysis of patie nts treate d wit h fr o ntli n e 
i mati ni b f o u n d t hat patie nts wit h c o nfir me d M R4. 5 at a n y ti me ha d a hi g her e ve nt -free s ur vi v al 
rate ( 9 5. 2 %) c o m p are d t o t h ose wit h Maj or M olec ular Res p o nse ( M M R), b ut n ot M R4. 5 ( 6 4. 7 %), 
a n d t h ose w h o ac hie ve d C o m plete C yt o ge netic Res p o nse ( C C y R), b ut n ot M M R ( 2 7. 7 %) 
( Etie n ne et al 2 0 1 4). 
A n ot her retr os p ecti ve st u d y f o u n d a l o wer ris k of l osi n g C C y R, 
pr o gressi o n t o Accelerat e d P hase ( A P) or Blast P hase ( B P), or deat h i n patie nts ac hie vi n g 
dee per M R ( Fal c hi  et al 2 0 1 3). F or p atie nts wit h B C R:: A B L 1 le vel bet wee n > 0. 0 1 % I S a n d ≤1 % 
I S b ut n o D M R o n fr o ntli ne i mati ni b f or at least 1 2 m o nt hs, a n earl y treat me nt s witc h pr o vi des 
a n o p p ort u nit y t o ac hie ve a faster D M R wit h a better disease c o ntr ol. T his is i n li ne wit h c ur re nt 
treat me nt g ui deli nes. 
T he E ur o pea n Le u k e mia Net w or k ( E L N) criteri a s u g gest t hat ( Baccara ni et al 2 0 1 3), patie nts 
wit h B C R:: A B L 1 le vels > 0. 1 -1 % at 1 2 m o nt hs are c o nsi dere d t o be at a war ni n g le vel re q uiri n g 
m ore fre q ue nt m o nit ori n g. Base d o n E L N g ui deli nes patie nts at a war ni n g le vel ma y be treat e d 
wit h alter nati ve treat me nts t o i m pr o ve t he le vel of r es p o nse ( B accara ni  et al 2 0 1 3). Si milarl y, 
t he E S M O treat me nt g ui deli nes f or C M L als o c o nsi der B C R le vels bet wee n 0. 1-1 % at 1 2 
m o nt hs a n d be y o n d t o be war ni n g le vels a n d rec o m me n d t hat patie nts wit h war ni n g le vels ma y 
be eli gi ble f or p ote ntiall y better treat me nts. A d diti o nall y, t he N C C N C M L treat me nt g ui deli nes 
rec o m me n d a s witc h of T KI treat me nt at ≥ 1 2 m o nt hs f or patie nts wit h B C R:: A B L 1 le vels 
bet wee n 0. 1 -1 % a n d si milarl y e m p hasizes t hat t he ac hie ve me nt of res p o nse milest o nes  b y 
s pecific 
m o nt h 
m ust b e i nter prete d wit hi n t he c o nte xt of cli nical a n d treat me nt g oals 
( N C C N 2 0 1 8).  
Wit h t his c ha n ge i n i ncl usi o n criteri o n, patie nts wit h o pti mal res p o nse ( B C R:: A B L le vels > 
0. 0 1 a n d ≤ 0. 1 % I S) pretreate d wit h at least 1 2 m o nt hs o n fr o nt li ne i mati ni b will ha ve t he 

N o v arti s  
C o nfi d e nti al  
P a g e 2 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
o p p ort u nit y t o ac hie ve a dee per res p o nse a n d will eit her c o nti n ue t o recei ve i mati ni b, or recei ve 
nil oti ni b, a n a p pr o ve d treat me nt i n fr o ntli ne, or recei ve asci mi ni b as a n a d d -o n t o t he bac k b o ne 
i mati ni b treat me nt. 
I n vie w of t he e v ol vi n g u n dersta n di n g of t he treat me nt la n dsca pe a n d t o gai n a n earl y i nsi g ht 
i nt o t he safet y a n d effic ac y of t he asci mi ni b c o m bi nati o n, t he statistical a nal ysis f or t he pri mar y 
o bjecti ve has bee n u p date d t o esti mate t he efficac y of  as ci mi ni b 4 0 m g o nce dail y ( Q D) + 
i mati ni b 4 0 0 m g Q D or asci mi ni b 6 0 m g Q D + i mati ni b 4 0 0 m g Q D as a gai nst c o nti n ue d 
i mati ni b. N o f or mal c o m paris o ns bet wee n t he treat me nt ar ms will be perf or me d. C o nse q ue ntl y, 
base d o n t his u p date i n t he statistical a n al ysi s of t he pri mar y o bjecti ve, t he sa m ple si ze was 
reassess e d usi n g t he esti mati o n-precisi o n fra me w or k. T he s a m ple size of t he st u d y has bee n 
a dj uste d fr o m 1 2 0 ( 3 0 p atie nts per ar m) t o ~ 8 0 ( 2 0 patie nts per ar m) patie nts base d o n t he 
e val uati o n of t he o perati n g c hara ct eristics f or t he esti mati o n of t he efficac y i n a n e x pl orat or y 
fra me w or k w hile c o nsi d eri n g cli nicall y rele va nt effect sizes a n d e m er gi n g cli nical data. A 
sa m ple size of ~ 8 0 patie nts will pr o vi de desire d precisi o n base d o n t he e x pecte d tr ue effect siz e. 
Wi t h 2 0 patie nts  e nr olle d per ar m, t he l o wer b o u n d of t he t w o -si de d 9 0 % c o nfi de n ce i nter val 
of t he differe n ce bet w ee n eac h asci mi ni b + i mati ni b ar ms a n d t he c o nti n ue d i mati ni b ar m will 
e xcl u de 0 ass u mi n g a tr u e 3 0 % differe n ce i n t he M R 4. 5 rate at 4 8 wee ks. 
F urt her, a n i nteri m a n al ysis will be perf or m e d i n or der t o gai n a n earl y i nsi g ht i nt o t he safet y 
a n d effi cac y of t he as ci mi ni b a d d -o n c o m bi nati o n w hic h will hel p i n pla n ni n g t he f ut ure 
de vel o p me nt of t he asci mi ni b c o m bi nati o n. T he i nteri m a nal ysis will be perf or me d w he n at 
least 4 0 ( 5 0 %) p atie nts h a ve bee n ra n d o mize d a n d ha ve bee n f oll o we d f or t heir 2 4 wee ks visit 
assess me nt or ha ve disc o nti n ue d treat me nt. T he e nr oll me nt will c o nti n ue d uri n g t his 2 4 wee ks 
f oll o w-u p. T he i nteri m a nal ysis will i ncl u de all ra n d o mize d patie nts u ntil t he date of data c ut -
off, a n d i ncl u de b ot h effi cac y (e. g. B C R:: A B L 1 assess me nt o verti me, M R 4 a n d M R 4. 5 rate at 
differe nt ti me -p oi nts) a n d safet y (e. g. A d verse E ve nts a n d la b orat or y val ues) s u m maries, w hic h 
will be detaile d i n t he Statistical A nal ysis Pla n f or t he i nteri m a nal ysis. T here will be n o c ha n ge 
i n t he st u d y c o n d uct base d o n t his i nteri m a nal ysis a n d t he st u d y will c o nti n ue as pla n n e d aft er 
t he i nteri m a nal ysis. It is n ot pla n ne d t o write a n i nteri m C S R base d o n t his i nteri m a nal ysis.   
A d diti o nall y, t he bel o w c ha n ges t o i ncl usi o n a n d e xcl usi o n criteria of t h e st u d y ha ve bee n ma de 
base d o n e mer gi n g pre -cli nical data a n d fee d bac k recei ve d fr o m i n vesti gat ors scree ni n g patie nts 
f or t his st u d y: 
•  C ha n ge i n pri or dee p m olec ular res p o nse criteria (i ncl usi o n criteria # 4) fr o m “ m ust n ot ha ve 
ac hie ve d d ee p m olec ular res p o nse ( M R 4 I S) at a n y ti me d uri n g pri or i mati ni b treat me nt" t o 
" m ust n ot ha ve ac hie ve d dee p m olec ular res p o nse ( M R 4 I S) c o nfir me d b y 2 c o nsec uti ve 
tests at a n y ti me d uri n g pri or i mati ni b treat me nt. A n is olate d, si n gle test res ult wit h 
B C R:: A B L 1 le vels < 0. 0 1 % ( M R 4 I S) is all o we d, h o we ver, it s h o ul d n ot ha ve bee n 
o bser ve d wit hi n t he 9 m o nt hs pri or t o ra n d o mizati o n". A d diti o nall y, a n e xcl u si o n criteri a 
( # 1 6) t o rei nf orce t his crit eria has b ee n a d de d t o e x cl u de a n y p atie nt wit h “a dee p m olec ular 
res p o nse ( M R4 I S) c o nfir me d b y 2 c o nsec uti ve tests at a n y ti me d uri n g pri or i mati ni b 
treat me nt”. T h ese c ha n g es ha ve bee n ma de t o e ns ure t h at patie nts wit h u nc o nfir me d, 
is olate d B C R:: A B L 1 le vels of < 0. 0 1 % are n ot e xcl u de d fr o m t he st u d y. 

N o v arti s  
C o nfi d e nti al  
P a g e 2 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
•  Patie nts wit h hist or y of ac ute pa n creatitis wit hi n 1 year pri or t o ra n d o mizati o n or me dical 
hist or y of c hr o nic p a ncreatitis are alr ea d y e x cl u de d fr o m t he st u d y as per e xcl usi o n criteria 
# 6. I n a d diti o n t o t hat, ser u m li pase re q uire me nt f or i ncl usi o n criter ia # 5, as a f urt her det ail 
f or t his criteria, were a d de d. Ser u m li pase is t he preferre d test f or p a ncreatitis d ue t o its 
i m pr o ve d se nsiti vit y, a n d a t hres h ol d c o nce ntrati o n of 2-3 x U L N is rec o m me n de d f or t he 
dia g n osis of pa n creatitis. T here are a n u m ber o f ot her c o n diti o ns t hat ca n ele vat e li pase, 
i ncl u di n g T KI pretreat me nt, t h us t he scree ni n g t hres h ol d f or li pase is ≤ 1. 5 x U L N ( C T C A E 
v 4. 0 3 gra de 1) as patie nts wit h hist or y of ac ute pa ncreatitis wit hi n 1 year of st u d y a n d hist or y 
of c hr o nic p a ncreatitis a re e xcl u de d. A m ylase is n ot a s pecific m ar ker f or p a ncreatitis, as u p 
t o 6 0 % of t otal s er u m a m ylase ori gi nates fr o m n o n-pa ncreatic s o urces. Its s h ort half -life 
re d uces its val ue as a dia g n ostic test i n t he earl y cli nical c o urse. Li pase has re place d a m ylas e 
as t he bi o c he mical t est of c h oice f or ac ut e p a ncreatitis d ue t o its hi g her s pecificit y 
( Bas na ya ke a n d Rat na m  2 0 1 5), t heref ore t he re q uire me nt of a m ylas e test at scree ni n g is n ot 
a d de d.  
•  T he re q uire me nt f or ele ctr ol yte le vels pri or t o ra n d o mizati o n ha ve bee n m o difie d (i ncl usi o n 
criteria # 6). I n crease i n p otassi u m of u p t o 6. 0 m m ol/ L ( gra de 2) is acce pta ble at st u d y e ntr y 
if ass ociate d wit h creati ni ne cleara nce wit hi n n or mal li mits. Patie nts wit h C M L ofte n 
prese nt wit h h y per kale mi a. T he releas e of p otassi u m fr o m platelets is a well -k n o w n reas o n 
f or pse u d o h y per kale mia i n t hr o m b oc yt he mic states i ncl u di n g m yel o pr oliferati ve dis or ders. 
( Ki m et al 1 9 9 0). T h us, gra de 2 i ncreas e of p ot assi u m is acc e pta bl e i n case of n or mal 
creati ni ne cleara nce as t his is n ot c o nsi dere d t o be a ris k fact or f or Q Tc pr ol o n gati o n. I n 
a d diti o n, t otal calci u m (c orrect e d f or ser u m al b u mi n) i ncrease of u p t o 1 2. 5 m g/ dl or 3. 1 
m m ol/ L ( gra de 2) is acce pta bl e pri or t o ra n d o miz ati o n if ass ociate d wit h creati ni ne 
cleara nce wit hi n n or mal li mits. Gra de 1 i ncreas e of ma g nesi u m  is acce pta ble i n case of 
n or mal creati ni ne cle ara n ce as t his is n ot c o nsi dere d t o be a ris k fact or f or Q Tc pr ol o n gati o n.  
•  Base d o n m ost u p date d P B P K m o deli n g pre dicti n g a ne gli gi ble ris k f or se nsiti ve C Y P 3 A 4/ 5, 
C Y P 2 C 8, or C Y P 2 C 9 s u bstrates is pre dicte d. T h us, t he pr o hi biti o n of n arr o w t hera pe utic 
i n de x C Y P 3 A 4/ 5 s u bstrates at st u d y e ntr y has bee n re m o ve d a n d is n o l o n g er a n e xcl usi o n 
criteri o n f or t he st u d y (e xcl usi o n criteria # 1 1 m o difie d). T he i n vi v o p ote ntial of asci mi ni b 
t o i nteract wit h se nsiti ve C Y P 3 A 4/ 5, C Y P 2 C 8 a n d C Y P 2 C 9 s u bstrates is bei n g e val uate d. 
Preli mi nar y res ults c o nfir m t he P B P K pre dicti o ns wit h n o or wea k dr u g -dr u g i nteracti o n.  
•  Base d o n e mer gi n g n o n -cli nical data ( Asci mi ni b I n v esti gat or Br oc h ure e diti o n 6), t he 
e xcl usi o n criteri a # 1 5 f or se x uall y acti ve males has bee n u p d ate d t o re m o ve t he re q uir e me nt 
of 
male c o ntrace pti o n. I n e m br y ofetal d e vel o p me nt st u dies 
wit h asci mi ni b, fetal  
malf or mati o ns (car diac malf or mati o ns) a n d i ncrease d visceral a n d s kelet al varia nts were 
o bser ve d i n rats a n d i ncrease d i nci de nce of res or pti o ns i n dicati ve of e m br y ofetal m ortalit y 
a n d a l o w i nci de nce of car di ac malf or mati o ns i n dicati ve of d ys m or p h o ge nesis  were 
o bser ve d i n ra b bits. As ci mi ni b is n ot ge n ot o xic. As p u blis he d i n t he literat ure, s mall 
m olec ules ca n distri b ute t o se mi nal fl ui d a n d t he se mi nal acc u m ulati o n s u g geste d is 
se me n/ plas ma rati os u p t o 1 1. 3 ( Kle m mt a n d Scialli  2 0 0 5 ). Acc or di n g t o t h e F D A g ui da nce, 
i n ge neral, t h ere is i ncrease d c o ncer n f or re pr o d ucti ve or de v el o p me ntal t o xicit y i n h u ma ns 
f or relati ve e x p os ure rati os (a ni mal: h u ma n) t hat are < 1 0 a n d d ecreas e d c o ncer n f or 
e x p os ure rati os > 2 5, ( F D A  G ui da nce  f or I n d ustr y 2 0 1 1). T he calc ulati o n s f or t he as ci mi ni b 
safet y mar gi n were d o ne base d o n C ma x ( plas ma) see n i n patie nts at a d ose of 2 0 0 m g BI D 

N o v arti s  
C o nfi d e nti al  
P a g e 3 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
( C ma x 6 9 8 5 n g/ ml) a n d t he C ma x at t he n o o bser ve d a d verse effect le vel ( N O A E L) i n t he 
rat a n d ra b bit e m br y ofet al de vel o p me nt st u dies. He nce t he safet y mar gi ns were 4 8 2- a n d 
5 6 1 -f ol d i n rats a n d ra b bits, res pecti vel y. I n c o ncl usi o n, f or asci mi ni b, as o utli ned a b o ve, 
t he safet y mar gi ns are w ell a b o ve 2 5 a n d t heref ore n o e m br y o- a n d fet o -t o xi cit y effects ca n 
be a ntici pate d via s e mi nal fl ui d.  
I n a d diti o n s o me mi n or i nc o nsiste ncies ( discre p a ncies bet w ee n secti o ns, t y p os) ha ve bee n 
c orrecte d.  
C h a n g e s t o t h e pr ot o c ol  
1.  Secti o n 1: I ntr o d ucti o n:  U p dates t o cli nical e x perie nce of asci mi ni b base d o n e diti o n 6 of 
t he I n vesti gat or's Br oc h ure (I B) ha ve bee n ma de. Secti o n m o difie d t o u p date use of Narr o w 
t hera pe utic I n de x C Y P 3 A 4/ 5 s u bstrates, N TI C Y P 3 A 4/ 5 t o be use d wit h ca uti o n a n d 
e m br y ofetal de v el o p me nt u p date. P ur p ose of st u d y u p date d t o reflect c ha n ge i n re q uire me nt 
of pri or i mati ni b treat me nt fr o m 2 4 m o nt hs t o 1 2 m o nt hs.  
2.  Secti o n 3: St u d y desi g n:  U p date d t o reflect c h a n ge i n i ncl usi o n criteria a n d sa m ple size. 
Fi g ure 1 -1 h as bee n re pla ce d.  
3.  Secti o n 4. 1:  R ati o n ale f or st u d y desi g n:  U p date d  statistical details f or pri mar y a nal ysis. 
4.  Secti o n 4. 2:  R ati o n ale f or D ose/ Re gi m e n:  Dat a err or c orrecte d i n re p orti n g of D L Ts.  
5.  Secti o n 4. 4:  P ur p ose a n d ti mi n g of i nteri m a n al yses/ desi g n a d a pt ati o ns: I n cl usi o n of 
t he rati o nale f or t he i nteri m a nal ysis. 
6.  Secti o n:  4. 5:  Ris k a n d Be nefit:  “ Se x u all y acti ve males” re m o v e d.  
7.  Secti o n 5: P o p ul ati o n:  N u m ber of patie nts u p dat e d t o ei g ht y ( 8 0) fr o m 1 2 0.  
8.  Secti o n 5. 1 - I ncl usi o n Criteri o n # 3: D urati o n of pri or i mati ni b treat me nt c ha n ge d fr o m 2 4 
m o nt hs t o 1 2 m o nt hs.  
9.  Secti o n 5. 1 - I ncl usi o n Criteri o n # 4: pri or D M R c ha n ge d fr o m “ n o D M R at a n y ti me” 
t o “ n o D M R ac hie ve d c o nfir me d b y 2 c o nsec uti ve tests at a n y ti me d uri n g pri or i mati ni b 
treat me nt. A n is olate d, si n gle test res ult wit h B C R:: A B L 1 le vels < 0. 0 1 % ( M R4 I S) is 
all o we d, h o we ver it s h o ul d n ot ha ve bee n o bser ve d wit hi n t he 9 m o nt hs pri or ra n d o mizati o n.  
1 0.  Secti o n 5. 1 - I ncl usi o n 
Criteri o n # 5: la b orat or y criteria f or Ser u m li pase bef ore 
ra n d o mizati o n a d de d. 
1 1.  Secti o n 5. 1 - I ncl usi o n Criteri o n # 6:  Criteria m o difie d t o defi ne la b orat or y refere nce ra n ge 
f or ele ctr ol ytes: 
•  P otassi u m i ncrease of u p t o 6. 0 m m ol/ L is acce pte d if ass ociate d wit h n or mal creati ni n e 
cleara nce  
•  T otal calci u m (c orrecte d f or ser u m al b u mi n) i ncrease of u p t o 1 2. 5 m g/ dl or 3. 1 m m ol/ L 
is acce pta bl e if ass ociat e d wit h creati ni ne cl eara n ce wit hi n n or mal li mits 
•  Ma g nesi u m i ncrease u p t o 3. 0 m g/ d L or 1. 2 3 m m ol/ L is acce pta ble if ass ociate d wit h 
creati ni ne cleara nce wit hi n n or mal li mits  
•  Criteria f or p h os p h or us were re m o ve d  
1 2.  Secti o n 5. 2 - E xcl usi o n criteri o n # 1:  F o ot n ote t o defi ne “c o nfir m e d l oss of M M R” as i n 
t he E L N criteria a d de d 

N o v arti s  
C o nfi d e nti al  
P a g e 3 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
1 3.  Secti o n 5. 2 - E xcl usi o n Criteri o n # 7:  re w or d e d t o clarif y o n g oi n g ac ute li ver disease. 
1 4.  Secti o n 5. 2 - E xcl usi o n Criteri o n # 9:  He patitis scree n re q uire me nt clarifie d wit h a d diti o nal 
tests (a nti-H Bs a n d H B V -D N A) t hat ca n be d o n e if nee de d.  
1 5.  Secti o n 5. 2 - E xcl usi o n criteri o n # 1 1:  Re m o val of s u bstrates of C Y P 3 A 4/ 5 wit h narr o w 
t hera pe utic i n de x as a n e xcl usi o n, base d o n m ost u p date d P B P K m o deli n g pre dicti n g a 
ne gli gi ble ris k f or se nsiti ve C Y P 3 A 4/ 5 s u bstrates.  
1 6.  Secti o n 5. 2 - E xcl usi o n criteri o n  # 1 5: Male c o ntrace pti o n re q uire me nts delete d o n t he 
basis of data a v aila ble fr o m e m br y ofetal de v el o p me nt st u dies.  
1 7.  Secti o n 5. 2 - E xcl usi o n criteri o n # 1 6:  ne w criteri o n has bee n a d d e d t o defi ne D M R criteria 
o n pri or i mati ni b treat me nt.  
1 8.  Secti o n 6. 2 - Ot her tre at me nt ( C o nc o mit a nt Me dic ati o n a n d Pr o hi bite d Me dic ati o n) 
secti o n: Secti o n o n N TI s u bstrates of C Y P 3 A 4/ 5 re m o ve d bas e d o n a m ost u p date d P B P K 
m o deli n g pre dicti n g a ne gli gi ble ris k f or se nsiti ve C Y P 3 A 4/ 5 s u bstrates a n d m o ve d u n der 
re q uiri n g ca uti o n secti o n. Ot her C Y P 3 A 4 s u bstrates (se nsiti ve a n d m o derate C Y P 3 A 4 
s u bstrates) ha v e bee n re m o ve d fr o m t he ca uti o n list. 
1 9.  Secti o n 6. 5. 1 - D ose m o dific ati o n : secti o n has bee n u p date d base d o n I n vesti gat or Br oc h ure 
versi o n 6.  
2 0.  Secti o n 7 - I nf or me d C o nse nt Pr oce d ure: u p d ate o n male c o ntrace pti o n.  
2 1.  Secti o n 8 -Visit sc he d ule a n d assess me nt:  Visit sc he d ule f or p atie nts o n i mati ni b a n d 
nil oti ni b alrea d y prese nt i n Ta ble  8‑ 1 as f o ot n ote, reiterat e d i n te xt.  
2 2.  Secti o n 8. 3. 2 - B o ne M a rr o w a n al ysis a n d c yt o ge netics: "c yt o g e netics" w or d has bee n 
a d de d as cl arific ati o n.  
2 3.  Secti o n 8. 4. 1 - L a b or at or y e v al u ati o ns:  L ocal la b C R F a n d l ocal la b test re p orti n g 
re q uire me nts cl arifie d. Clarificati o n ha ve b ee n ma de i n t he ta ble 8. 6. 
2 4.  Secti o n 8. 4. 3 - Pre g n a nc y a n d assess me nts of fertilit y:  Clarificati o n a d d e d o n Cr oss o ver 
treat me nt C O baseli ne assess me nt a n d u p date o n male c o ntrace pti o n. 
2 5.  Secti o n 8. 5. 1. 1 - E O R T C Q L Q -C 3 0 a n d E O R T C Q L Q -C M L 2 4:  Clarificati o n f or sites 
w here Q L Q -C M L 2 4 n ot a vaila ble d ue t o missi n g la n g ua ge v ali dati o n a d de d.  
2 6.  Secti o n 8. 5. 2. 1 - P h ar m ac o ki netic bl o o d c ollecti o n a n d h a n dli n g:  Ta ble 8 -9 u p date d wit h 
wi n d o w peri o ds f or bl o o d c ollecti o n l o g.  
2 7.  Secti o n 9. 1. 1 - Disc o nti n u ati o n of st u d y tre at me nt:  clarificati o n o n criteria f or treat me nt 
fail ure acc or di n g t o E L N 2 0 1 3 g ui deli nes. 
2 8.  Secti o n 1 0. 2. 1 - Li ver S afet y m o nit ori n g:  u p date d t o delete li ver C R F. Li ver la b orat or y 
para meters will be re p orte d o n sc he d ule d/ u nsc h e d ule d la b orat or y C R F.  
2 9.  Secti o n 1 2. 4 - A n al ysis of pri m ar y e n d p oi nt:  U p date d  pri mar y e n d p oi nt a nal ysis.  
3 0.  Secti o n 1 2. 5. 1 - Effic ac y a n d/ or P h ar m ac o d y n a mic e n d p oi nt(s): C o nfi de nce i nter val of 
rate of M R4. 5c ha n ge d fr o m 9 5 t o 9 0 %.  
3 1.  Secti o n 1 2. 5. 3 - P h ar m ac o ki netics secti o n:  Te xt u p date d f or clarificati o n.  
3 2.  Secti o n 1 2. 7 - I nteri m A n al ysis: I ncl usi o n of i nteri m a nal ysis. 
3 3.  Secti o n 1 2. 8 - S a m ple size c alc ul ati o n:  U p date d base d o n u p d ate d pri mar y e n d p oi nt 
a nal ysis a n d a d diti o n of i nteri m a nal ysis.  
3 4.  Secti o n 1 5 - Refere nces:  U p date d wit h ne wl y a d d e d refere n ces i n pr ot oc ol.  

N o v arti s  
C o nfi d e nti al  
P a g e 3 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
3 5.  A p pe n di x 1 6. 1 a n d T a ble 1 6. 2:  delete d li ver C R F. Li ver la b orat or y para meters will be 
re p orte d o n sc he d ule d/ u nsc he d ule d la b orat or y C R F. 
3 6.  A p pe n di x 1 6. 3:  Secti o n o n N TI s u bstrates of C Y P 3 A 4/ 5 m o ve d u n der re q uiri n g ca uti o n. 
I R B S e cti o n 
A c o p y of t his a me n de d pr ot oc ol 
will be se nt t o t he I nstit uti o nal 
Re vie w 
B oar d 
(I R Bs)/I n d e pe n d e nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he c ha n g es descri b e d i n t his a me n de d pr ot oc ol re q uire I R B/I E C a p pr o val pri or t o 
i m ple me ntati o n. 
T he c ha n ges herei n affect t he I nf or me d C o nse nt. Sites are re q uire d t o u p date a n d s u b mit f or 
a p pr o val a re vise d I nf or me d C o nse nt t hat ta kes i nt o acc o u nt t he c ha n ges descri be d i n t his 
pr ot oc ol a me n d me nt 1.  

N o v arti s  
C o nfi d e nti al  
P a g e 3 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
Pr ot o c ol s u m m ar y  
Pr ot o c ol 
n u m b er  
C A B L 0 0 1 E 2 2 0 1  
F ull Titl e  
A P h a s e 2, m ulti -c e nt er, o p e n -l a b el, r a n d o mi z e d st u d y of or al a s ci mi ni b a d d e d t o i m ati ni b 
v er s u s c o nti n u e d i m ati ni b v er s u s s wit c h t o nil oti ni b i n p ati e nt s wit h C M L -C P w h o h a v e b e e n 
pr e vi o u sl y tr e at e d wit h i m ati ni b a n d h a v e n ot a c hi e v e d d e e p m ol e c ul ar r e s p o n s e  
Bri ef titl e  
St u d y of effi c a c y a n d s af et y of a s ci mi ni b i n c o m bi n ati o n wit h i m ati ni b i n C M L -C P p ati e nt s  
S p o n s or a n d 
Cli ni c al P h a s e  
N o v arti s, St u d y P h a s e II  
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 nt er v e nti o n al 
P ur p o s e a n d 
r ati o n al e  
T h e tri al i s d e si g n e d t o a s s e s s t h e a cti vit y of 2 d o s e s of a s ci mi ni b + i m ati ni b v er s u s  ot h er 
t w o ar m s ( c o nti n u e d i m ati ni b ar m a n d s wit c h t o nil oti ni b ar m), a s s e s s e d b y t h e r at e of 
M ol e c ul ar R e s p o n s e ( M R)
4. 5 at 4 8 w e e k s a s w ell a s a d diti o n al effi c a c y p ar a m et er s, 
p h ar m a c o ki n eti c ( P K), bi o m ar k er s, p ati e nt r e p ort e d o ut c o m e s ( P R O s) a n d s af et y a n d 
t ol er a bilit y. T yr o si n e ki n a s e i n hi bit or s ( T KI s) h a v e r e v ol uti o ni z e d t h e tr e at m e nt of p ati e nt s  
wit h c hr o ni c m y el oi d l e u k e mi a ( C M L), r e s ulti n g i n a n o v er all s ur vi v al ( O S)  t h at i s cl o s e t o 
t h at of t h e g e n er al p o p ul ati o n a n d t h er ef or e a n e ar n or m al lif e e x p e ct a n c y. A n e w e v ol vi n g 
tr e at m e nt g o al i n C M L tr e at m e nt i s tr e at m e nt fr e e r e mi s si o n, w hi c h r e q uir e s p ati e nt s  t o b e 
i n d e e p m ol e c ul ar r e s p o n s e ( D M R), c o n si d er e d a s a r e s p o n s e l e v el of at l e a st M R4. 0 
I nt er n ati o n al S c al e (I S). C urr e ntl y, a n o pti o n f or p ati e nt s  w h o d o n ot a c hi e v e t h e d e sir e d 
l e v el of m ol e c ul ar r e s p o n s e wit h c o nti n u e d i m ati ni b tr e at m e nt i s t o s wit c h t o a m or e p ot e nt 
s e c o n d g e n er ati o n a d e n o si n e tri p h o s p h at e ( A T P) -bi n di n g sit e T KI s. H o w e v er a hi g h 
p er c e nt a g e of p ati e nt s still d o n ot a c hi e v e t h e d e sir e d l e v el of r e s p o n s e. A s ci mi ni b i s a n 
all o st eri c i n hi bit or of Br e a k p oi nt Cl u st er R e gi o n - A b el s o n pr ot o -o n c o g e n e 1 ( B C R:: A B L 1) 
a n d d u e t o it s di sti n ct m o d e of a cti o n s h o w e d pr e cli ni c all y a n a d diti v e a nti -t u m or a cti vit y i n 
c o m bi n ati o n wit h A T P -bi n di n g sit e T KI s.  
T h e a d diti o n of a s ci mi ni b t o i m ati ni b i s e x p e ct e d t o r e s ult i n m or e p ot e nt i n hi biti o n of t h e 
A B L ki n a s e d o m ai n. It i s h y p ot h e si z e d t h at t h e a d diti o n of a s ci mi ni b i n p ati e nt s  w h o h a v e 
n ot a c hi e v e d D M R wit h si n gl e a g e nt i m ati ni b will i n cr e a s e t h eir li k eli h o o d of a c hi e vi n g t hi s 
r e s p o n s e o v er ti m e a n d s u b s e q u e ntl y all o w f or c o n si d er ati o n of T KI di s c o nti n u ati o n. T h e 
p ur p o s e of t hi s tri al i s t o e v al u at e t h e effi c a c y a n d s af et y of t h e c o m bi n ati o n of a s ci mi ni b + 
i m ati ni b tr e at m e nt i n c o m p ari s o n t o c o nti n u e d i m ati nib i n p ati e nt s  w h o h a v e n ot a c hi e v e d 
M R 4  aft er at l e a st o n e y e ar of i m ati ni b fir st -li n e tr e at m e nt. A s a s e c o n d ar y e n d p oi nt, t h e 
diff er e n c e i n effi c a c y b et w e e n t h e c o m bi n ati o n a n d nil oti ni b, a s e c o n d g e n er ati o n T KI, will 
b e e sti m at e d.  
R e s ult s fr o m si n gl e a g e nt st u di e s i n p ati e nt s wit h C M L -C P w h o h a v e b e e n tr e at e d wit h at 
l e a st 2 pri or T KI s h a v e s h o w n a cti vit y of si n gl e a g e nt a s ci mi ni b f or a c hi e v e m e nt of D M R i n 
t hi s h e a vil y pr etr e at e d p o p ul ati o n. I n st u d y A 2 3 0 1, M R4  a n d M R 4. 5  r at e s of 1 0. 8 % a n d 
7. 6 %, r e s p e cti v el y w er e o b s er v e d at W e e k 4 8 ( M a ur o et al, 2 0 2 1). I n t h e s u b gr o u p of 
p ati e nt s wit h b a s eli n e B C R:: A B L 1 l e v el s ( > 0. 0 1 % a n d ≤1 %), t h e M R 4. 5 r at e ( 1 8. 8 %, 3 
r e s p o n d er s a m o n g 1 6 p ati e nt s) w a s si mil ar t o t h at o b s er v e d i n E 2 2 0 1 wit h a s ci mi ni b a s 
a d d -o n t o i m ati ni b at t h e pri m ar y a n al y si s.  
Pri m ar y 
O bj e cti v e( s)  
T h e pri m ar y o bj e cti v e of t hi s st u d y i s t o a s s e s s w h et h er a s ci mi ni b 4 0 m g o n c e d ail y ( Q D) + 
i m ati ni b 4 0 0 m g Q D or a s ci mi ni b 6 0 m g Q D + i m ati ni b 4 0 0 m g Q D i s m or e eff e cti v e t h a n 
c o nti n u e d i m ati ni b b y a s s e s si n g t h e M R 4. 5  r at e s at 4 8 w e e k s. 
S e c o n d ar y 
O bj e cti v e s  
O bj e cti v e 1: t o e sti m at e effi c a c y of s wit c h t o nil oti ni b a s s e s s e d b y t h e M R
4. 5  r at e at 4 8 
w e e k s.  
O bj e cti v e 2: t o e sti m at e diff er e n c e i n effi c a c y b et w e e n a s ci mi ni b 6 0 m g + i m ati ni b a n d 
s wit c h t o nil oti ni b c o n si d eri n g t h e diff er e n c e i n M R 4. 5  r at e at 4 8 w e e k s. 
O bj e cti v e 3: t o e sti m at e diff er e n c e i n effi c a c y b et w e e n a s ci mi ni b 4 0 m g + i m ati ni b a n d 
s wit c h t o nil oti ni b c o n si d eri n g t h e diff er e n c e i n M R 4. 5  r at e at 4 8 w e e k s. 
O bj e cti v e 4: t o a s s e s s a d diti o n al p ar a m et er s of t h e effi c a c y of a s ci mi ni b 6 0 m g or 4 0 m g 
a d d e d t o i m ati ni b v er s u s  c o nti n u e d i m ati ni b or s wit c h t o nil oti ni b i. e. t h e r at e of M R 4. 5  at 9 6 

N o v arti s  
C o nfi d e nti al  
P a g e 3 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
w e e k s, r at e of M R 4. 5  b y 4 8 a n d 9 6 w e e k s, s u st ai n e d M R 4. 5 at 9 6 w e e k s, ti m e t o M R 4. 5 a n d 
d ur ati o n of M R 4. 5 . 
O bj e cti v e 5: t o c h ar a ct eri z e t h e s af et y a n d t ol er a bilit y pr ofil e of a s ci mi ni b 6 0 m g or 4 0 m g + 
i m ati ni b v er s u s  c o nti n u e d i m ati ni b or s wit c h t o nil oti ni b b y c o m p ari n g t h e i n ci d e n c e a n d 
s e v erit y of a d v er s e e v e nt s ( A E s), c h a n g e s i n l a b or at or y v al u e s, cli ni c all y n ot a bl e E C G 
a b n or m aliti e s a n d vit al si g n s.  
O bj e cti v e 6: t o a s s e s s t h e p h ar m a c o ki n eti c pr ofil e of a s ci mi ni b 6 0 m g or 4 0 m g a n d 
i m ati ni b w h e n a d mi ni st er e d i n c o m bi n ati o n. 
O bj e cti v e 7: t o e sti m at e effi c a c y of a s ci mi ni b 8 0 m g Q D  a s s e s s e d b y t h e M R 4. 5  r at e at 4 8 
w e e k s, ti m e t o M R 4. 5 a n d d ur ati o n of M R 4. 5 . 
O bj e cti v e 8: t o c h ar a ct eri z e t h e s af et y a n d t ol er a bilit y pr ofil e of a s ci mi ni b 8 0 m g Q D.  
O bj e cti v e 9: t o a s s e s s t h e p h ar m a c o ki n eti c pr ofil e of a s ci mi ni b 8 0 m g Q D . 
St u d y d e si g n  
T h e st u d y i s a P h a s e 2, m ulti -c e nt er, o p e n -l a b el, r a n d o mi z e d st u d y of a s ci mi ni b i n t w o 
diff er e nt d o s e s ( 4 0 m g or 6 0 m g) i n c o m bi n ati o n wit h i m ati ni b 4 0 0 m g v er s u s  c o nti n u e d 
i m ati ni b v er s u s  s wit c h t o nil oti ni b i n p ati e nt s  wit h c hr o ni c m y el oi d l e u k e mi a i n c hr o ni c p h a s e 
( C M L-C P) w h o h a v e b e e n pr e vi o u sl y tr e at e d wit h i m ati ni b fir st li n e t h er a p y f or at l e a st o n e 
y e ar a n d h a v e n ot a c hi e v e d d e e p m ol e c ul ar r e s p o n s e ( D M R).  
T h e eli gi bl e p ati e nt s  will b e r a n d o mi z e d 1: 1: 1: 1 t o r e c ei v e a s ci mi ni b 6 0 m g Q D a s a d d -o n 
t h er a p y t o i m ati ni b 4 0 0 m g Q D, or 4 0 m g Q D a s a d d-o n t h er a p y t o i m ati ni b 4 0 0 m g Q D, or 
t o c o nti n u e i m ati ni b 4 0 0 m g Q D, or t o s wit c h t o nil oti ni b 3 0 0 m g t wi c e a d a y ( BI D). 
P ati e nt s  o n t h e st u d y will c o nti n u e o n t h e all o c at e d tr e at m e nt u ntil tr e at m e nt f ail ur e, 
i nt ol er a bilit y, or f or u p t o 9 6 w e e k s aft er t h e l a st r a n d o mi z e d s u bj e ct r e c ei v e d t h e fir st d o s e 
of tr e at m e nt. Aft er t h e l a st d o s e r e c ei v e d, e v er y s u bj e ct will b e f oll o w e d u p f o r s af et y f or 3 0 
d a y s.  
A n i nt eri m a n al y si s will b e p erf or m e d w h e n at l e a st 4 0 ( 5 0 %) p ati e nt s h a v e b e e n 
r a n d o mi z e d a n d h a v e b e e n f oll o w e d f or t h eir 2 4 w e e k s vi sit a s s e s s m e nt or h a v e 
di s c o nti n u e d tr e at m e nt. At t h e ti m e of t h e i nt eri m a n al y si s, if e x c e s si v e t o xi cit y wit h o ut 
a d d e d b e n efit i s o b s er v e d i n o n e of t h e i n v e sti g ati o n al ar m s, di s c o nti n u ati o n of t h at 
tr e at m e nt ar m will b e c o n si d er e d. T h e d e ci si o n t o di s c o nti n u e a n i n v e sti g ati o n al ar m i n t h e 
st u d y will b e t a k e n b a s e d o n t h e ri s k b e n efit b al a n c e of t h e t w o i n v e sti g ati o n al ar m s , a n d i n 
c o nt e xt of t h e ot h er t w o tr e at m e nt o pti o n s a v ail a bl e f or t h e p ati e nt s i n t h e st u d y, n a m el y: 
c o nti n u e o n i m ati ni b wit h n o p ot e nti al i m pr o v e m e nt of effi c a c y; or s wit c h t o nil oti ni b wit h a 
p ot e nti al t o i m pr o v e effi c a c y h o w e v er, wit h a r el ati v el y a d v e r s e s af et y pr ofil e a s c o m p ar e d 
t o i m ati ni b. If a d e ci si o n i s t a k e n t o di s c o nti n u e a s ci mi ni b 6 0 m g + i m ati ni b tr e at m e nt ar m at 
i nt eri m a n al y si s, p ati e nt s  o n g oi n g o n t h at tr e at m e nt ar m will b e pr o vi d e d a n o p p ort u nit y t o 
c o nti n u e o n t h e st u d y at a l o w er d o s e ( a s ci mi ni b 4 0 m g + i m ati ni b) if t h e i n v e sti g at or 
c o n si d er s t h at i s i n t h e b e st i nt er e st of t h e p ati e nt.  
P ati e nt s  o n t h e i m ati ni b c o nti n u ati o n ar m w h o h a v e n ot a c hi e v e d M R 4. 5 at 4 8 w e e k s m a y 
cr o s s -o v er ( C O) t o r e c ei v e t h e a d d -o n tr e at m e nt wit hi n 4 w e e k s aft er w e e k 4 8 vi sit. It i s 
pl a n n e d t h at t h e s e p ati e nt s  cr o s s -o v er t o r e c ei v e t h e a s ci mi ni b 6 0 m g a d d -o n tr e at m e nt, a s 
t hi s d o s e pr o vi d e s hi g h er e x p o s ur e. B a s e d o n t h e r e s ult s of t h e i nt eri m a n al y si s or 
e m er gi n g d at a, cr o s s -o v er m a y b e c h a n g e d t o t h e a s ci mi ni b 4 0 m g a d d -o n tr e at m e nt.  T h e 
cr o s s -o v er i s at t h e di s cr eti o n of t h e i n v e sti g at or a n d t h e p ati e nt. A p art fr o m a p ol y m er a s e 
c h ai n r e a cti o n ( P C R) r e s ult of b el o w M R 4. 5  at W e e k 4 8 vi sit, t h er e ar e n o ot h er e ntr y crit eri a 
f or t h e cr o s s-o v er p art. P ati e nt s  o n nil oti ni b ar e n ot all o w e d t o cr o s s -o v er t o r e c ei v e t h e 
a d d -o n tr e at m e nt.  
Aft er t h e pri m ar y a n al y si s, t h e d e ci si o n w a s m a d e t o a d d a n a d diti o n al c o h ort t o t h e st u d y 
( u p o n I R B a n d H e alt h A ut h orit y a p pr o v al) t o i n v e sti g at e t h e effi c a c y a n d s af et y of a s ci mi ni b 
8 0 m g Q D a s c o m p ar e d t o t h e a d d -o n a n d c o nti n u e o n i m ati ni b ar m s. T hi s c o h ort will h a v e 
a p pr o xi m at el y t h e s a m e s a m pl e si z e a s i n tr e at m e nt ar m s 1 -4 ( n = 2 0). A s e nr oll m e nt s ar e 
cl o s e d i n t h e tr e at m e nt ar m s 1 -4, all i n c o mi n g p ati e nt s  will b e i n cl u d e d i n t hi s a d diti o n al 
c o h ort.  
T h e p ati e nt s  e nr oll e d i n t h e a s ci mi ni b si n gl e a g e nt c o h ort will n ot b e all o w e d t o cr o s s -o v er 
t o a n ot h er i n v e sti g ati o n al c o m bi n ati o n ar m if t h e y f ail t o a c hi e v e M R4. 5  at w e e k 4 8.  
P o p ul ati o n  
A p pr o xi m at el y ei g ht y eli gi bl e p ati e nt s  wit h C M L -C P will b e r a n d o mi z e d 1: 1: 1: 1, wit h a 
t ar g et of 2 0 p ati e nt s  i n e a c h ar m (tr e at m e nt ar m s 1-4).  

N o v arti s  
C o nfi d e nti al  
P a g e 3 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
A p pr o xi m at el y n = 2 0 p ati e nt s  will b e i n cl u d e d i n a s ci mi ni b 8 0 m g Q D c o h ort.  
M al e or f e m al e p ati e nt s ≥ 1 8 y e ar s of a g e will b e e nr oll e d.  
K e y I n cl u si o n 
crit eri a  
1.  Si g n e d i nf or m e d c o n s e nt m u st b e o bt ai n e d pri or t o p arti ci p ati o n i n t h e st u d y.  
2.  M al e or f e m al e p ati e nt s ≥ 1 8 y e ar s of a g e wit h a c o nfir m e d di a g n o si s of C M L -C P  
3.  b . Mi ni m u m of o n e y e ar ( 1 2 c al e n d ar m o nt h s) tr e at m e nt wit h i m ati ni b fir st li n e f or C M L-
C P ( p ati e nt s h a v e t o b e o n i m ati ni b 3 0 0 m g Q D or hi g h er ). 
4.  a. B C R:: A B L 1 l e v el s > 0. 0 1 % I S a n d ≤ 1 % I S at t h e ti m e of r a n d o mi z ati o n a s c o nfir m e d 
wit h a c e ntr al a s s e s s m e nt at s cr e e ni n g; p ati e nt s m u st n ot h a v e a c hi e v e d d e e p 
m ol e c ul ar r e s p o n s e ( M R 4 I S) c o nfir m e d b y 2 c o n s e c uti v e t e st s at a n y ti m e d uri n g pri or 
i m ati ni b tr e at m e nt. A n i s ol at e d, si n gl e t e st r e s ult wit h B C R:: A B L 1 l e v el s < 0. 0 1 % 
( M R 4 I S) i s all o w e d, h o w e v er, it s h o ul d n ot h a v e b e e n o b s er v e d wit hi n t h e 9 m o nt h s 
pri or t o r a n d o mi z ati o n.  
5.  a. P ati e nt m u st m e et t h e f oll o wi n g l a b or at or y v al u e s b ef or e r a n d o mi z ati o n:  
•  A b s ol ut e N e utr o p hil C o u nt ≥ 1. 5 x 1 0 9  L  
•  Pl at el et s ≥ 7 5 x 1 0 9/ L  
•  H e m o gl o bi n ≥ 9 g/ d L  
•  S er u m cr e ati ni n e ( s Cr) < 1. 5 m g/ d L  
•  T ot al bilir u bi n ( T B L) ≤ 1. 5 x u p p er li mit of n or m al ( U L N) e x c e pt f or p ati e nt s wit h Gil b ert’ s 
s y n dr o m e w h o m a y o nl y b e i n cl u d e d wit h t ot al bilir u bi n ≤ 3. 0 x U L N  
•  A s p art at e a mi n otr a n s a mi n a s e ( A S T) ≤ 3. 0 x U L N  
•  Al a ni n e a mi n otr a n s a mi n a s e ( A L T) ≤ 3. 0 x U L N  
•  Al k ali n e p h o s p h at a s e ( A L P) ≤ 2. 5 x U L N  
•  S er u m li p a s e ≤ 1. 5 x U L N. F or s er u m li p a s e > U L N - ≤ 1. 5 x U L N, v al u e m u st b e 
c o n si d er e d n ot cli ni c all y si g nifi c a nt a n d n ot a s s o ci at e d wit h ri s k f a ct or s f or a c ut e 
p a n cr e atiti s  
6.  a. P ati e nt s m u st h a v e t h e f oll o wi n g l a b or at or y v al u e s ( ≥ l o w er li mit of n or m al ( L L N)) or 
c orr e ct e d t o wit hi n n or m al li mit s wit h s u p pl e m e nt s pri or t o r a n d o mi z ati o n:  
•  P ot a s si u m ( p ot a s si u m i n cr e a s e of u p t o 6. 0 m m ol/ L i s a c c e pt a bl e if a s s o ci at e d wit h 
cr e ati ni n e cl e ar a n c e* wit hi n n or m al li mit s)  
•  T ot al c al ci u m ( c orr e ct e d f or s er u m al b u mi n); ( c al ci u m i n cr e a s e of u p t o 1 2. 5 m g/ dl or 3. 1 
m m ol/ L i s a c c e pt a bl e if a s s o ci at e d wit h cr e ati ni n e cl e ar a n c e* wit hi n n or m al li mit s)  
•  M a g n e si u m ( m a g n e si u m i n cr e a s e u p t o 3. 0 m g/ d L or 1. 2 3 m m ol/ L if a s s o ci at e d wit h 
cr e ati ni n e cl e ar a n c e* wit hi n n or m al li mit s.  
* Cr e ati ni n e cl e ar a n c e a s c al c ul at e d u si n g C o c k cr oft-G a ult f or m ul a  
K e y E x cl u si o n 
crit eri a  
1.  Tr e at m e nt f ail ur e a c c or di n g t o E L N 2 0 1 3 crit eri a d uri n g i m ati ni b tr e at m e nt.  
2.  K n o w n s e c o n d c hr o ni c p h a s e of C M L aft er pr e vi o u s pr o gr e s si o n t o a c c el er at e d 
p h a s e/ bl a st cri si s ( A P/ B C).  
3.  Pr e vi o u s tr e at m e nt wit h a n y T KI s ot h er t h a n i m ati ni b 
4.  Hi st or y or c urr e nt di a g n o si s of E C G a b n or m aliti e s i n di c ati n g si g nifi c a nt ri s k or s af et y f or 
p ati e nt s  p arti ci p ati n g i n t h e st u d y s u c h a s:  
•  Hi st or y of m y o c ar di al i nf ar cti o n ( MI), a n gi n a p e ct ori s, c or o n ar y art er y b y p a s s gr aft 
( C A B G) wit hi n 6 m o nt h s pri or t o r a n d o mi z ati o n 
•  C o n c o mit a nt cli ni c all y si g nifi c a nt arr h yt h mi a s, e. g. s u st ai n e d v e ntri c ul ar t a c h y c ar di a, a n d 
cli ni c all y si g nifi c a nt s e c o n d or t hir d d e gr e e atri o v e ntri c ul ar  ( A V) bl o c k wit h o ut a 
p a c e m a k er  
•  R e sti n g Q T c F ≥ 4 5 0 m s e c ( m al e) or ≥ 4 6 0 m s e c (f e m al e) pri or t o r a n d o mi z ati o n  
•  L o n g Q T s y n dr o m e, f a mil y hi st or y of i di o p at hi c s u d d e n d e at h or c o n g e nit al l o n g Q T 
s y n dr o m e, or a n y of t h e f oll o wi n g  

N o v arti s  
C o nfi d e nti al  
P a g e 3 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
•  Ri s k f a ct or s f or T or s a d e s d e P oi nt e s i n cl u di n g u n c orr e ct e d h y p o k al e mi a or 
h y p o m a g n e s e mi a, hi st or y of c ar di a c f ail ur e, or hi st or y of cli ni c all y 
si g nifi c a nt/ s y m pt o m ati c br a d y c ar di a  
•  C o n c o mit a nt m e di c ati o n s wit h a " k n o w n" ri s k of T or s a d e s d e P oi nt e s p er 
cr e di bl e m e d s. or g t h at c a n n ot b e di s c o nti n u e d or r e pl a c e d b y s af e alt er n ati v e m e di c ati o n  
•  i n a bilit y t o d et er mi n e t h e Q T c F i nt er v al 
5.  S e v er e a n d/ or u n c o ntr oll e d c o n c urr e nt m e di c al di s e a s e t h at i n t h e o pi ni o n of t h e 
i n v e sti g at or c o ul d c a u s e u n a c c e pt a bl e s af et y ri s k s or c o m pr o mi s e c o m pli a n c e wit h t h e 
pr ot o c ol ( e. g. u n c o ntr oll e d di a b et e s, a cti v e or u n c o ntr oll e d i nf e cti o n, u n c o ntr oll e d 
cli ni c all y si g nifi c a nt h y p erli pi d e mi a a n d  hi g h s er u m a m yl a s e).  
6.  Hi st or y of a c ut e p a n cr e atiti s wit hi n 1 y e ar pri or t o r a n d o mi z ati o n or m e di c al hi st or y of 
c hr o ni c p a n cr e atiti s; o n g oi n g a c ut e li v er di s e a s e or hi st or y of c hr o ni c li v er di s e a s e.  
7.  Hi st or y of ot h er a cti v e m ali g n a n c y wit hi n 3 y e ar s pri or t o r a n d o mi z ati o n wit h t h e 
e x c e pti o n of b a s al c ell s ki n c a n c er, i n d ol e nt pr o st at e c a n c er a n d c ar ci n o m a i n sit u 
tr e at e d c ur ati v el y 
St u d y 
tr e at m e nt 
•  A s ci mi ni b ( A B L 0 0 1) 8 0 m g, 6 0 m g, 4 0 m g Q D  
•  I m ati ni b ( S TI 5 7 1) 4 0 0 m g Q D 
•  Nil oti ni b ( A M N 1 0 7) 3 0 0 m g BI D  
Effi c a c y 
a s s e s s m e nt s  
•  P eri p h er al bl o o d f or B C R:: A B L 1 r e al -ti m e q u a ntit ati v e r e v er s e tr a n s cri pt a s e-P ol y m er a s e 
C h ai n R e a cti o n ( R T -q P C R)  
K e y s af et y 
a s s e s s m e nt s  
•  P h y si c al e x a mi n ati o n  
•  E xtr a m e d ull ar y i n v ol v e m e nt  
•  Vit al si g n s  
•  H e m at ol o g y a n d bi o c h e mi str y ( a n d pr e g n a n c y w h e n a p pli c a bl e)  
•  E C G  
•  A d v er s e E v e nt s  
Ot h er 
a s s e s s m e nt s  
•  P ati e nt R e p ort e d O ut c o m e s: E O R T C Q L Q -C 3 0, E O R T C Q L Q -C M L 2 4, F A CI T G P 5 a n d 
T S Q M  
•  P K s a m pli n g  
•  Bi o m ar k er a s s e s s m e nt s ( c h ar a ct eri z ati o n of 
 
) 
D at a a n al y si s  
T h e pri m ar y effi c a c y e n d p oi nt of t h e st u d y i s t h e r at e of M R 4. 5  at 4 8 w e e k s ( ± a s s e s s m e nt 
wi n d o w), d efi n e d a s t h e pr o p orti o n of p ati e nt s  still tr e at e d wit h t h e r a n d o mi z e d tr e at m e nt at 
4 8 w e e k s a n d ar e i n M R 4. 5  ( B C R:: A B L 1 r ati o of ≤ 0. 0 0 3 2 %) at 4 8 w e e k s. It will b e 
c al c ul at e d b a s e d o n t h e F ull A n al y si s S et ( F A S).  
T h e diff er e n c e i n r at e of M R 4. 5  b et w e e n 1) a s ci mi ni b 6 0 m g + i m ati ni b v er s u s  c o nti n u e d 
i m ati ni b a n d 2) a s ci mi ni b 4 0 m g + i m ati ni b v er s u s  c o nti n u e d i m ati ni b wit h it s 2 -si d e d 9 0 % 
c o nfi d e n c e i nt er v al will b e pr o vi d e d u si n g t h e W al d m et h o d. T h e r at e of M R 4. 5  at 4 8 w e e k s 
a n d it s 2 -si d e d 9 0 % c o nfi d e n c e i nt er v al b a s e d o n t h e Cl o p p er -P e ar s o n m et h o d will b e 
pr e s e nt e d b y tr e at m e nt ar m.  
T o e sti m at e t h e effi c a c y of a s ci mi ni b si n gl e a g e nt, t h e r at e of M R 4. 5 at 4 8 w e e k s a n d it s 2 
si d e d 9 0 % c o nfi d e n c e i nt er v al b a s e d o n t h e Cl o p p er -P e ar s o n m et h o d will b e pr e s e nt e d. N o 
f or m al c o m p ari s o n or e sti m at e of t h e diff er e n c e wit h t h e ot h er tr e at m e nt ar m s will b e 
p erf or m e d f or t hi s a d diti o n al c o h ort.  
I nt eri m A n al y si s: 
A n i nt eri m a n al y si s will b e p erf or m e d w h e n at l e a st 4 0 ( 5 0 %) p ati e nt s h a v e b e e n 
r a n d o mi z e d a n d h a v e b e e n f oll o w e d f or t h eir 2 4 w e e k s vi sit a s s e s s m e nt or h a v e 
di s c o nti n u e d tr e at m e nt. T h e i nt eri m a n al y si s will i n cl u d e all r a n d o mi z e d p ati e nt s u ntil t h e 
d at e of d at a c ut -off, a n d i n cl u d e b ot h effi c a c y ( e. g. B C R:: A B L 1 a s s e s s m e nt o v erti m e, M R 4  
a n d M R 4. 5  r at e at diff er e nt ti m e-p oi nt s) a n d s af et y ( e. g. A d v er s e E v e nt s a n d l a b or at or y 
v al u e s) s u m m ari e s, w hi c h will b e d et ail e d i n t h e St ati sti c al A n al y si s Pl a n f or t h e i nt eri m 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 3 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
a n al y si s. B a s e d o n t h e r e s ult s of t h e i nt eri m a n al y si s a b e n efit ri s k b al a n c e will b e 
a s s e s s e d f or t h e t w o a d d -o n tr e at m e nt ar m s. It i s n ot pl a n n e d t o writ e a n i nt eri m C S R 
b a s e d o n t hi s i nt eri m a n al y si s.  
T h e pri m ar y a n al y si s will b e p erf or m e d aft er all p ati e nt s  i n all 4 ra n d o mi z e d tr e at m e nt ar m s 
h a v e c o m pl et e d W e e k 4 8 or di s c o nti n u e d pri or t o W e e k 4 8. A w e e k 9 6 a n al y si s will b e 
p erf or m e d aft er all p ati e nt s  i n all 4 r a n d o mi z e d tr e at m e nt ar m s h a v e c o m pl et e d W e e k 9 6 
a n d/ or di s c o nti n u e d st u d y pri or t o W e e k 9 6. T h e fi n al a n al y si s will b e p erf or m e d wit h all 
a v ail a bl e d at a fr o m t h e a s ci mi ni b si n gl e a g e nt c o h ort at t h e E n d of t h e St u d y.  
K e y W or d s  
C hr o ni c M y el oi d L e u k e mi a i n C hr o ni c P h a s e ( C M L -C P), T yr o si n e Ki n a s e I n hi bit or ( T KI), 
Gli v e c ®  (i m ati ni b), T a si g n a®  ( nil oti ni b), a s ci mi ni b, M ol e c ul ar R e s p o n s e 

N o v arti s  
C o nfi d e nti al  
P a g e 3 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
1  
I ntr o d u cti o n 
1. 1  
B a c k gr o u n d  
C M L is a cl o nal m yel o pr oliferati ve dis or der of tra nsf or me d, pri miti ve he mat o p oietic pr o ge nit or 
cells. T he hall mar k of C M L is t he P hila del p hia ( P h) c hr o m os o me f o u n d i n u p t o 9 5 % of patie nts . 
It res ults fr o m a reci pr ocal tra nsl ocati o n t( 9; 2 2)( q 3 4; q 1 1) w hic h a d ds a 3' se g me nt of t he A B L 
ge ne o n c hr o m os o me 9 t o t he 5' part of t he brea k p oi nt cl uster re gi o n ( B C R) ge ne o n 
c hr o m os o me 2 2. T he res ulti n g f usi o n ge ne e nc o des f or a c o nstit uti vel y acti ve  t yr osi ne ki nase, 
t he B C R-A bels o n ( A B L) t yr osi ne ki nase ( Fa derl  et al 1 9 9 9 ), w hic h has acti vit y t hat i m parts 
gr o wt h a d va nta ge t o le u ke mic cells, i ncreas es pr oliferati o n a n d c yt o ki ne -i n de pe n de nt gr o wt h, 
i n hi bits 
a p o pt osis, 
a n d 
i n hi bits 
alter nate 
a d hesi o n 
pat h wa ys 
(Sa w yers  1 9 9 9 , 
Dei ni n ger  et al 2 0 0 0 , V a n  Ette n  2 0 0 4 ). 
Wit h a c o nsta nt i nci de nce of 1. 2 -1. 5/ 1 0 0 0 0 0 per year t he pre vale nce of C M L is stea dil y 
i ncreasi n g (H oc h ha us  a n d La  R osée  2 0 1 3 ). Cli nicall y, C M L pr o gresses t hr o u g h t hree disti nct 
p hases of i ncreasi n g refract ori ness t o t hera p y: c hr o nic p hase ( C P), accelerat e d p hase ( A P), a n d 
blast crisis ( B C) ( E nri g ht  H  a n d Mc Gla v e  2 0 0 0 ). M ost patie nts , h o we ver, prese nt i n t he C P, 
c haracteri ze d b y s ple n o m e gal y a n d le u k o c yt osis wit h ge nerall y fe w s y m pt o ms.  
T he g ol d sta n dar d f or t h e treat me nt of C M L was t he t yr osi ne ki nase i n hi bit or ( T KI) Gli vec ®  
(i mati ni b), w hic h was i ntr o d uce d i n 2 0 0 1 a n d re v ol uti o nize d t he C M L treat me nt. Ot her T KI 
a ge nts, i ncl u di n g nil oti ni b, dasati ni b, p o nati ni b, b os uti ni b, are als o mea n w hile a p pr o ve d f or t he 
treat me nt of C M L. P ossi ble o pti o ns f or first-li ne treat me nt i ncl u de i mati ni b, nil oti ni b, dasati ni b 
a n d b os uti ni b, w hile i mati ni b is m ost wi del y use d i n t his setti n g a n d re gar de d as sta n d ar d of 
care.  
C urre nt treat me nt g ui deli nes rec o m me n d c o nti n ui n g t hera p y wit h T KI i n d efi nitel y i n patie nts  
wit h o pti mal res p o nse ( Baccara ni  et al 2 0 1 3, N C C N  2 0 1 8 ). H o we ver, i n selecte d C M L patie nts  
meeti n g certai n criteria, e. g. s ustai ne d dee p 
m olec ular res p o nse (s ustai ne d 
D M R), 
disc o nti n uati o n of T KI t h era p y is p ossi ble ( H oc h h a us  et al 2 0 1 7, N C C N  2 0 1 8 , [ Tasi g na S m P C], 
[ U S PI]). 
1. 1. 1  
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. 1. 1. 1  
O v er vi e w of a s ci mi ni b  
Asci mi ni b ( A B L 0 0 1) is a p ote nt, orall y bi oa vaila ble s pecific B C R:: A B L 1 i n hi bit or wit h a n o vel 
mec ha nis m of acti o n. I n c o ntrast t o i n hi bit ors s uc h as i mati ni b, nil oti ni b a n d dasati ni b t hat bi n d 
wit hi n t he A de n osi ne Tri p h os p hate -bi n di n g ( A T P) site of t he A B L ki nase d o mai n, asci mi ni b 
i n hi bits A B L t yr osi ne ki nase acti vit y b y bi n di n g t o a partic ular all osteric site o n t he ki nase 
d o mai n, w hic h has o nl y bee n i de ntifie d o n A B L 1, A B L 2 a n d B C R:: A B L 1. C o nse q ue ntl y, 
asci mi ni b is s pecific f or t he latter t hree e nz y mes. Asci mi ni b p ote ntl y a n d selecti vel y i n hi bits 
t he pr oliferati o n of cell li nes t hat e x press B C R:: A B L 1. B y virt ue of asci mi ni b n ot i nteracti n g 
wit h t he A T P -bi n di n g site, t he dr u g is acti ve a gai nst cells e x pressi n g cli nicall y o bser ve d A T P -
bi n di n g T KI resista nce  m utati o ns. A c o m bi nati o n of asci mi ni b wit h a n A T P -site i n hi bit or, s uc h 

N o v arti s  
C o nfi d e nti al  
P a g e 3 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
as i mati ni b, has t he p ot e ntial t o pre ve nt t h e e mer ge nce of resista nce d ue t o p oi nt m utati o n(s) 
bei n g ac q uire d i n o n e of t he bi n di n g sites.  
As of 3 0 -J u n-2 0 2 2, as ci mi ni b has bee n a p pr o ve d f or tr eat me nt of C M L pts wit h resista nce or 
i nt olera nce t o pr e vi o us t hera p y i n Al ba nia, C a na da, Ja pa n, K orea, S witzerla n d, U K, a n d U S. 
1. 1. 1. 1. 1  N o n -cli ni c al e x p eri e n c e  
I n vitr o a n d i n vi v o p h ar m a c ol o g y d at a  
Asci mi ni b is a n A B L 1 i n hi bit or t hat bi n ds wit h hi g h affi nit y t o t he all osteric m yristate -bi n di n g 
p oc ket o n t he ki nase S H 1 d o mai n a n d i n hi bits t he A B L 1 ki nase acti vit y of t he B C R:: A B L 1 
f usi o n pr otei n. Asci mi ni b p ote ntl y i n hi bits t he pr oliferati o n of C M L a n d ac ute l y m p h o blastic 
le u ke mia ( A L L) cell li nes t hat e x press B C R:: A B L 1, at d oses > 1 0 0 0-f ol d p ote nt t ha n i n cell 
li nes t hat d o n ot e x press B C R:: A B L 1. 
Asci mi ni b dis pla ys p ote nt a nti -t u m or acti vit y i n viv o wit h a cl ear p har mac o ki netic 
( P K)/ p har mac o d y na mic ( P D)/efficac y relati o ns hi p [ R D-2 0 1 3 -5 0 1 4 5] . I n a K C L-2 2 C M L -B C 
cell li ne m o use s u bc uta n e o us xe n o graft m o del, t u m or re gressi o n was o bser ve d at d oses of 7. 5 
m g/ k g BI D a n d a b o ve w he n asci mi ni b was a d mi nistere d al o ne. Efficac y i n t his B C R:: A B L 1 
de pe n de nt K C L -2 2 x e n o graft m o del c orrelate d wit h c o m plete i n hi biti o n of t he d o w nstrea m P D 
mar k er S T A T 5 (si g nal tra ns d ucer a n d acti vat or of tra nscri pti o n 5), a n d t he mi ni mal t otal plas ma 
c o nce ntr ati o n re q uire d t o ac hie ve t his le vel of P D s u p pressi o n was o bser ve d t o be ar o u n d 5 0 -
1 0 0 n M.  
T he K C L -2 2 xe n o graft m o del was als o use d t o assess t he acti vit y of as ci mi ni b a n d A T P -site 
bi n di n g T KIs ( nil oti ni b) as si n gle a ge nts a n d i n c o m bi nati o n ( W ylie  et al 2 0 1 7 ). I n t hes e 
e x peri me nts, w h e n eac h a ge nt w as a d mi nistere d as m o n ot hera p y i n se q ue n ce, i nitial se nsiti vit y 
of t he t u m or was o bser ve d t o eac h a g e nt, b ut rela pse occ urre d i n eac h case. T he m utati o ns 
o bser ve d were as e x pecte d base d o n cli nical e x perie nce ( T 3 1 5 I f or nil oti ni b) or m o deli n g 
( A 3 3 7 V) f or as ci mi ni b. I n c o ntrast, a ni mals treate d u pfr o nt wit h t he c o m bi nati o n of asci mi ni b 
a n d nil oti ni b ac hie ve d s ustai ne d t u m or re gressi o n wit h n o e vi de nce of disease rela pse d uri n g 
t he 6 8 da ys of treat me nt or f or > 1 0 0 d ays f oll o wi n g disc o nti n uati o n of treat me nt. N ote t hat i n 
t his K C L-2 2 m o del, t he cells ( deri v e d fr o m a blast crisis C M L s u bject) were gr o w n as a s oli d 
t u m or rat her t ha n as disse mi nate d diseas e. Als o, t his m o del is m uc h m ore a g gressi ve t h a n 
c hr o nic p has e C M L i n patie nts . 
Please refer t o t he latest  [ Asci mi ni b I n vesti gat or’s Br oc h ure] f or m or e details.  
S af et y p h ar m a c ol o g y a n d t o xi c ol o g y  
A n e xte nsi ve t o xic ol o g y safet y e v al uati o n pr o gra m (s u bc hr o ni c, c hr o nic, re pr o d ucti ve 
t o xic ol o g y, p h ot ot o xicit y a n d ge n ot o xicit y st u dies) was c o n d u cte d. 
Safet y p har mac ol o g y st u dies i n dicate t hat asci mi ni b is n ot e x pecte d t o ca us e effects o n t he vital 
f u ncti o ns of t he C N S ( Ce ntral Ner v o us S yste m), a n d t he res pirat or y s yste ms. T he h alf ma xi mal 
i n hi bit or y c o nce ntrati o n (I C5 0) f or asci mi ni b i n t he h E R G ( H u ma n Et her-a-g o -g o -relat e d Ge n e) 
patc h cla m p is 1 1. 4 μ M ( 4 4 9 8 n g/ m L). Des pite h E R G i n hi biti o n occ urri n g i n vitr o at l o w 
c o nce ntr ati o n, t his p ote ntial di d n ot tra nslate i nt o car diac r h yt h m dist ur ba nces or Q Tc ( Q T 

N o v arti s  
C o nfi d e nti al  
P a g e 4 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
i nter val c orrecte d f or heart rate) pr ol o n gati o n i n viv o u p t o e x p os ures 1 2 0 -f ol d hi g her t ha n i n 
patie nts  at t he ma xi m u m rec o m me n d e d t hera p e utic d ose of 4 0 m g BI D (free dr u g C ma x  
c o m paris o ns).  
Asci mi ni b d oes n ot s h o w m uta ge nic, clast o ge nic, or a n e u ge nic p ote ntial i n t he i n vitr o assa ys 
or t he M N T ( Micr o n ucle us test) assess me nt i n viv o; t heref ore, n o p ote ntial ris k f or h u ma n is 
percei v e d.  
I n t he 2-year rat c arci n o g e nicit y st u d y, b e ni g n Sert oli cell t u m ors i n t he o varies were o bs er ve d 
i n fe male rats at t he hi g hest d ose of 6 6 m g/ k g/ da y. A U C e x p os ures t o as ci mi ni b i n fe male rats 
at 6 6 m g/ k g/ da y were g e nerall y 8 -f ol d or 5-f ol d hi g her t ha n t h ose ac hi e v e d i n patie nts at t he 
d ose of 4 0 m g  t wi ce d ail y or 8 0 m g o nce dail y, res pecti vel y, a n d e q ui vale nt t o t h ose ac hie ve d 
i n patie nts at t he d ose of 2 0 0 m g t wice dail y. T he cli nical rele va n ce of t hes e fi n di n gs is c urre ntl y 
u n k n o w n . 
Precli nical st u dies s u g geste d t hat asci mi ni b mi g ht ca use p h ot ot o xicit y a n d p h ot ose nsitizati o n. 
Wit hi n t he s u nli g ht ra n ge ( 2 9 0 t o 7 0 0 n m), asci mi ni b s h o we d a bs or pti o n ma xi ma at 3 1 2 n m. A 
p h ot o -i n hi biti o n fact or ( PI F) assa y v al ue of 4 1 was deter mi ne d i n t he 3 T 3 N R U p h ot ot o xicit y 
assa y. As deter mi ne d b y t he res ults of t he p h ot ot o xicit y assess me nt ( i n vitr o a n d i n viv o), 
p h ot ot o xic p ote ntial was i de ntifie d i n t he m o use U V -L L N A ( Ultra vi olet ra diati o n - L ocal 
L y m p h N o de Assa y) at 2 0 0 m g/ k g/ da y. H o we ver, at t he N O A E L i n a ni m al st u dies, e x p os ure 
base d o n C ma x i n plas ma was 1 5 -f ol d hi g her t ha n t he e x p os ure i n patie nts at t he 4 0 m g BI D. 
Gi ve n t he u p date d data, a d ult patie nts  e nr olle d i n t he si n gle a ge nt asci mi ni b c o h ort will n ot 
nee d s u nli g ht pr otecti o n.  
I n 
e m br y ofetal 
de v el o p me nt st u dies 
wit h 
asci mi ni b, fetal 
malf or mati o ns (car diac 
malf or mati o ns) a n d i ncrease d visc eral a n d s k eletal varia nts were o bs er ve d i n rats a n d i ncreas e d 
i nci de nce of res or pti o ns i n dicati ve of e m br y ofet al m ortalit y a n d a l o w i nci de nce of car diac 
malf or mati o ns i n dicati ve of d ys m or p h o ge nesis were o bser ve d i n ra b bits. Asci mi ni b is n ot 
ge n ot o xic. As p u blis he d i n t he literat ure, s mall m olec ules ca n distri b ute t o se mi nal fl ui d a n d 
t he 
se mi nal 
acc u m ulati o n 
s u g geste d 
is 
se me n/ plas ma 
rati os 
u p 
t o 
1 1. 3 
(Kle m mt  a n d Scialli  2 0 0 5 ). Acc or di n g t o t he F D A g ui da nce, i n ge neral, t here is i ncrease d 
c o ncer n f or re pr o d ucti ve or de vel o p me ntal t o xicit y i n h u ma ns f or relati ve e x p os ure rati os 
(a ni mal: 
h u ma n) t hat are 
< 1 0 a n d 
decrease d c o n cer n f or e x p os ure rati os 
> 2 5, 
(F D A  G ui da nce  f or I n d ustr y 2 0 1 1 ). T he calc ulati o ns f or t h e as ci mi ni b safet y mar gi n were d o n e 
base d o n C ma x ( plas ma) see n i n p atie nts at a d os e of 2 0 0 m g BI D ( C ma x 6 9 8 5 n g/ ml)  a n d t he 
C ma x at N O A E L i n t he rat a n d ra b bit e m br y ofetal de vel o p me nt st u dies. He nce t h e safet y 
mar gi ns were 4 8 2 a n d 5 6 1 -f ol d i n rats a n d ra b bits, res pecti vel y. I n c o ncl usi o n, f or asci mi ni b, 
as o utli ne d a b o v e, t he safet y mar gi ns are well a b o ve 2 5 a n d t heref o re n o e m br y o- a n d fet o -
t o xicit y effects c a n be a ntici pate d via se mi nal fl ui d. 
Re peat d ose t o xicit y st u dies i de ntifie d t he p a ncreas, li ver, he mat o p oietic s yste m, a dre n al a n d 
gastr o -i ntesti nal tract as p ote ntial tar get tiss ues. All fi n di n gs s o far ha v e de m o nstrate d a p artial 
t o c o m plete re v ersi bilit y d uri n g a 4-wee k rec o v er y p has e a n d  ca n b e rea dil y m o nit ore d i n 
cli nical setti n gs.  
Please refer t o t he latest [ Asci mi ni b I n vesti gat or’s Br oc h ure] f or m or e details. 

N o v arti s  
C o nfi d e nti al  
P a g e 4 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
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  
T he precli nical p har m ac o ki netic pr ofile of asci mi ni b has bee n i n vesti gate d i n t hree s pecies: 
m o use, rat a n d d o g. I n t hese s pecies, asci mi ni b e x hi bite d l o w t o m o derate cleara nce, a m o derate 
v ol u me of distri b uti o n a n d a s h ort a p pare nt ter mi nal half -life. Bi oa vaila bilit y was f o u n d t o be 
l o w i n r o de nts a n d m o derate t o hi g h i n d o g. 
Asci mi ni b dis pla ye d hi g h plas ma pr otei n bi n di n g acr oss all teste d s p ecies ( 2 % -6 % free fracti o n).  
T he meta b olite pr ofile of asci mi ni b has bee n e x a mi ne d i n vitr o usi n g rat, d o g, m o n ke y a n d 
h u ma n he pat o c ytes. I nters peci es differe n ces were o bser ve d wit h dir ect gl uc ur o ni dati o n 
occ urre d m ost rea dil y i n h u ma n, t o a less er e xt e nt i n d o g a n d m o n ke y, a n d was n oticea bl y 
a bse nt i n rat. Ne v ert hel ess, t he meta b olic t ur n o ver o f asci mi ni b was l o w t o m o derat e acr oss 
s pecies. N o u ni q ue h u m a n meta b olites were detecte d i n t his i n vitr o h e pat oc ytes meta b olis m 
st u d y acr oss s peci es. 
T he meta b olite pr ofile of asci mi ni b has als o bee n e xa mi ne d i n viv o i n rats. F oll o wi n g 
i ntra ve n o us a n d oral a d mi nistrati o n of [1 4C -A B L 0 0 1] t o i ntact rats, as ci mi ni b was f o u n d t o be 
t he pre d o mi na nt c o m p o n e nt of pl as ma, acc o u nti n g f or ~ 8 6 %-9 1 % of ra di oacti vit y fr o m 0 - 8 
h o urs. Asci mi ni b w as e x crete d pri maril y i n t he feces, wit h ~ 9 0 % of ra di o acti vit y detect e d i n 
t he feces fr o m 0 - 4 8 h. Re nal eli mi nati o n re prese nte d a mi n or r o ute, wit h ~ 2. 4 % of ra di oacti vit y 
detecte d i n t he uri ne fr o m 0 - 7 2 h. I n t he feces, ~ 5 8 % (i ntra v e n o us) a n d ~ 7 1 % ( oral) of t he 
d ose was ass ociate d wit h u nc ha n ge d asci mi ni b, wit h se veral o xi dati ve meta b olites acc o u nti n g 
f or t he re mai ni n g ra di oa cti vit y. T he meta b olites f or me d i n viv o were c o nsiste nt wit h t h ose 
o bser ve d i n vitr o. Si milar o bser vati o ns were n ote d i n bile-d uct ca n n ulate d rats. A n  a bs or pti o n, 
distri b uti o n, meta b olis m, a n d e xcreti o n ( A D M E) St u d y was as well c o n d ucte d i n m o n ke y 
[ R 1 5 0 0 8 1 5] a n d s h o w e d t hat asci mi ni b is t he pre d o mi na nt dr u g -relat e d c o m p o ne nt i n plas ma. 
All meta b olites d etecte d i n h u ma n plas ma were als o o bser ve d i n t he A D M E m o n ke y St u d y.  
T o assess f or p ote ntial dr u g -dr u g i nteracti o ns ( D DI), st u dies h a ve b ee n c o n d u cte d wit h 
c yt oc hr o me P 4 5 0 ( C Y P) e nz y mes a n d s e veral tra ns p orters i n vitr o. 
Base d u p o n t he cli nical h u ma n A D M E data a n d ali g n me nt wit h t he i n vitr o h u ma n he pat oc yte 
cleara nce a n d e n z y me reacti o n p he n ot y pi n g st u dies, t he relati ve c o ntri b uti o n of C Y P - a n d U D P -
Gl uc ur o n os yltra nsf eras e ( U G T) -me diat e d asci mi ni b cleara nce was esti mate d t o be 3 6. 6 % a n d 
5 8. 3 %, res p ecti vel y. M ulti ple e nz y mes ( U G T 1 A 3, U G T 1 A 4, U G T 2 B 7, U G T 2 B 1 7, C Y P 3 A 4/ 5, 
C Y P 2 C 8, C Y P 2J 2 a n d C Y P 2 D 6) are i n v ol ve d i n t he meta b olis m of asci mi ni b. C Y P 3 A 4 was 
esti mate d t o c o ntri b ute 3 5 % t o t he t otal cleara n ce of asci mi ni b i n h u ma ns, wit h U G T 2 B 7 
c o ntri b uti n g 2 7. 9 %. T he c o ntri b uti o n of U G T 2 B 1 7 a n d U G T 1 A 3/ U G T 1 A 4 t o asci mi ni b t otal 
cleara nce w as 1 6. 3 % a n d 1 4. 1 %, res pecti vel y. Ot her C Y P e nz y mes: C Y P 2 C 8, C Y P 2 D 6 a n d 
C Y P 2J 2 were esti mate d t o c o ntri b ute t o a mi n or e xte nt (less t ha n 1 %). T he p o te ntial f or cli nical 
D DIs wit h c o -me di cati o ns t hat i n hi bit a si n gle U G T e nz y me is li kel y t o be l o w.  
Str o n g i n d ucers or i n hi bit ors of C Y P 3 A 4/ 5 ha ve t he p ote ntial t o alter asci mi ni b c o nce ntrati o ns.  
Tra ns p orter p he n ot y pi n g st u dies ha ve i de ntifie d asci mi ni b t o be a s u bstrat e of Breast Ca ncer 
Resista nt Pr otei n ( B C R P) ( K m ≈ 4 µ M) a n d Per mea bilit y gl yc o pr otei n ( P -g p) ( K m c o ul d n ot 
be esti mate d d ue t o i ns ufficie nt sat urati o n of effl u x acti vit y). I n hi bit ors  of B C R P a n d P -g p ma y 
i ncreas e asci mi ni b c o nce ntrati o n a n d are t o be use d wit h ca uti o n i n t his st u d y. 

N o v arti s  
C o nfi d e nti al  
P a g e 4 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
T he i n viv o p ote ntial of asci mi ni b t o i nteract wit h se nsiti ve C Y P 3 A 4/ 5, C Y P 2 C 8 a n d C Y P 2 C 9 
s u bstrates has bee n e val u ate d b y P B P K m o deli n g a n d w o ul d i n dicate a mi ni mal or ne gli gi ble 
ris k. At t he d ose of asci mi ni b 8 0 m g q d ( C ma x,ss of ~ 1 2 7 0 n g/ m L), t he P B P K m o del pre dicte d 
a A U C rati o of 1. 2 2, 1. 1 1 a n d 1. 0 8 f or t he se nsiti ve s u bstrate of C Y P 3 A 4 ( mi daz ola m), 
C Y P 2 C 8 (re pa gli ni de) a n d C Y P 2 C 9 ( S -warfari n), res pecti vel y ( R 1 7 0 0 9 1 2)  
T heref ore, s u bstrates of C Y P 3 A 4/ 5, C Y P 2 C 8 a n d C Y P 2 C 9 wit h narr o w t hera pe utic i n de x 
s h o ul d be use d wit h ca uti o n. 
Base d o n P B P K asci mi ni b is a wea k i n hi bit or of i ntesti nal P -g p at 4 0 m g b.i. d., 8 0 m g q. d. a n d 
2 0 0 m g b.i. d.  
F urt her, at d oses of 4 0 m g b.i. d., 8 0 m g q. d., a n d 2 0 0 m g b.i. d. asci mi ni b wea k t o m o derate 
i ncreas es i n O A T P 1 B s u bstrates (e. g., pita v astati n, pra vastati n) a n d B C R P s u bstrates (e. g., 
s ulfasalazi ne) are e x p ect e d w he n a d mi nistere d c o nc o mita ntl y ( D M P K -R 2 2 7 0 3 2 8). At d oses of 
4 0 m g b.i. d. a n d 8 0 m g q. d. asci mi ni b was pre dicte d t o be m o derate i n hi bit or of t he d u al B C R P 
a n d O A T P 1 B s u bstrate r os u vastati n a n d a str o n g i n hi bit or at 2 0 0 m g b.i. d.  
Please refer t o t he latest [ Asci mi ni b I n vesti gat or's Br oc h ure] v ersi o n f or m ore details.  
1. 1. 1. 1. 2  Cli ni c al e x p eri e n c e  
As of 1 5 -Ja n-2 0 2 4 , asci mi ni b is bei n g i n vesti gate d i n 10  o n g oi n g N o vartis s p o ns ore d st u dies i n 
patie nts wit h C M L - C P/ A P or C M L -B C or P h + A L L.  
T he a p pr o val of asci mi ni b m o n ot hera p y i n C M L -C P patie nts wit h P h + C M L i n C P, pre vi o usl y 
treate d wit h 2 or m ore T KIs was base d o n res ults fr o m t he first-i n-h u ma n ( FI H) P hase I cli nical 
St u d y, St u d y [ C A B L 0 0 1 X 2 1 0 1] (calle d X 2 1 0 1 h e ncef ort h), a n d t he o n g oi n g  P hase 3 pi v otal 
St u d y i n 3r d li ne C M L -C P [ C A B L 0 0 1 A 2 3 0 1] (calle d A 2 3 0 1 he ncef ort h).  
St u d y C A B L 0 0 1 A 2 3 0 1  
St u d y A 2 3 0 1 is a n o n g oi n g P hase III, m ulti -ce nter, acti ve -c o ntr olle d, o pe n -la bel, ra n d o mize d 
st u d y of oral as ci mi ni b vers us b os uti ni b i n patie nts wit h C M L -C P, pre vi o usl y treate d wit h at 
least 2 T KIs. O v erall, 2 3 3 patie nts wit h C M L-C P were e nr olle d i n t he s t u d y of w hi c h 1 5 7 were 
ra n d o mize d t o asci mi ni b ar m a n d 7 6 t o b os uti ni b ar m, 8 9 patie nts ( 5 6. 7 %) i n t he asci mi ni b ar m 
a n d 1 7 patie nts ( 2 2. 4 %) i n t he b os uti ni b ar m are still o n g oi n g o n st u d y treat me nt.  
T he st u d y met its pri mar y e n d p oi nt. T he M M R rate at 2 4 wee ks was 2 5. 5 % i n t he asci mi ni b 
ar m c o m pare d t o 1 3. 2 % i n t he b os uti ni b ar m ( 9 5 % CI: 2. 1 9, 2 2. 3 0, p val ue: 0. 0 2 9). At t he Wee k 
9 6 c ut -off, t he cli nical s u peri orit y of asci mi ni b vers us b os uti ni b i ncreas e d c o m pare d t o t he 
pri mar y a nal ysis, t he M M R rate i n t he asci mi ni b ar m 3 7. 5 8 % ( 9 5 % CI: 2 9. 9 9, 4 5. 6 5) c o m pare d 
t o 1 5. 7 9 % ( 9 5 % CI: 8. 4 3, 2 5. 9 6) i n t he b os uti ni b ar m. At t he E O T c ut -off ( 2 2 -Mar -2 0 2 3), 
asci mi ni b mai ntai ne d c o nsiste ntl y hi g her M M R rates vs b os uti ni b ( 3 3. 8 % vs 1 0. 5 % at Wee k 
1 5 6) a n d c o nti n ue d t o b e safe a n d t olera ble e v e n after t he l o n ger d urati o n of e x p os ure. F or 
f urt her det ails refer t he latest [Asci mi ni b I n v esti gat or’s Br oc h ure]. 

N o v arti s  
C o nfi d e nti al  
P a g e 4 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
 St u d y C A B L 0 0 1 X 2 1 0 1  
St u d y X 2 1 0 1 is a c o m plete d first i n h u ma n ( FI H) d ose escalati o n st u d y. A t otal of 3 2 6 patie nts 
wit h C M L -C P/ A P/ B C or P h + A L L ha d bee n treat e d acr oss 5 ar ms i n t he st u d y.  
A s ci mi ni b Si n gl e A g e nt  
Safet y  
As of t he c ut -off d ate of  1 4 -Mar -2 0 2 3 (fi nal a n al ysis) , 2 0 0 patie nts wit h C M L-C P/ A P ha ve 
bee n treate d wit h asci mi ni b si n gle a ge nt wit h d ose le vels fr o m 1 0 m g BI D t o 2 0 0 m g BI D a n d 
d ose le vels fr o m 8 0 m g Q D t o 2 0 0 m g Q D. All 2 0 0 patie nts reac he d e n d of st u d y treat me nt 
eit her t hr o u g h pre m at ure disc o nti n uati o n of st u d y treat me nt or t hr o u g h tra nsiti o n t o p ost -trial 
access (P T A ) o pti o ns or c o m mercial dr u g. B y t he c ut -off date, t he me di a n d urati o n of e x p os ure 
t o asci mi ni b si n gle a ge nt i n 2 0 0 patie nts wit h C M L-C P/ -A P was 2 1 5. 4 wee ks ( mi n -ma x: 0 t o 
4 3 9 wee ks). T he m ost c o m m o n A Es re p orte d i n at least 2 5 % patie nts a m o n g t he 2 0 0 wit h C M L -
C P/ -A P treate d wit h asci m i ni b si n gle a ge nt w he n c o nsi deri n g all d oses a n d all gra des were 
art hral gia a n d hea dac h e, fati g ue, li pase i ncrease, diarr hea a n d  n a usea. N o c ha n ge of t h e safet y 
pr ofile of asci mi ni b has occ urre d t hat re q uir es t he pr ot oc ol t o be m o difie d. F or f urt h er detail s 
refer t he latest [As ci mi ni b I n v esti gat or’s Br oc h ure ]. 
Efficac y  
As per [Asci mi ni b I n v esti gat or's Br oc h ure ] dat a wit h a c ut -off date of  1 4 -Mar -2 0 2 3 ( Fi nal 
a nal ysis), fr o m t he P has e I FI H St u d y [ C A B L 0 0 1 X 2 1 0 1] i n dicate t hat asci mi ni b e x hi bits 
acti vit y as si n gle -a ge nt i n patie nts wit h C M L w h o ha ve faile d at least t w o pri or T KIs or are 
i nt olera nt t o T KIs as w ell as patie nts carr yi n g T 3 1 5I m utati o n w h o h a ve faile d at least o ne pri or 
T KI , as well as i n patie nts wit h C M L har b ori n g t he T 3 1 5I m utati o n w h o ha ve faile d at least o n e 
pri or T KI .  O verall, M M R was ac hi e ve d b y 8 6/ 1 6 4 ( 5 2. 4 %) p atie nts b y a n y ti me p oi nt u p t o t he 
Fi nal A nal ysis data c ut -off. A m o n g 8 6 patie nts w h o ac hie ve d M M R o verall at a n y ti me p oi nt, 
res p o nse was mai ntai ne d i n m ost of t he m ( 7 6; 8 8. 4 %) u p t o t he c ut-off dat e.  
Re vie wi n g t he t otalit y of t he efficac y, safet y, a n d p har mac o ki netic data deri ve d fr o m t he 
[ C A B L 0 0 1 X 2 1 0 1] St u d y, 4 0 m g BI D si n gle a ge nt d ose was rec o m me n d e d f or cli nical st u dies 
i n patie nts  wit h C M L -C P w h o d o n ot carr y T 3 1 5I m utati o ns a n d 2 0 0 m g BI D d os e i n C M L 
patie nts carr yi n g T 3 1 5I  m utati o n.  
A s ci mi ni b i n c o m bi n ati o n wit h i m ati ni b, nil oti ni b or d a s ati ni b  
Safet y  
T we nt y -fi ve p atie nts  ha v e bee n tr eate d wit h a c o m bi nati o n of i mati ni b 4 0 0 m g Q D a n d differe nt 
asci mi ni b d ose le vels ( 4 0 m g BI D/ Q D, 6 0 m g Q D a n d 8 0 m g Q D). As of t he Fi n al A nal ysis 
data c ut -off ( 1 4 -Mar -2 0 2 3), all 2 5 patie nts reac he d e n d of st u d y treat me nt eit her t hr o u g h 
pre mat ure disc o nti n uati o n of st u d y treat me nt or t hr o u g h tra nsiti o n t o P T A o pti o ns or 
c o m mercial dr u g.  T h e m ost fre q ue nt pri mar y reas o n f or disc o nti n uati o n was p h ysicia n’s 
decisi o n d ue t o lac k of efficac y ( 6 0 . 0 %). A d verse e ve nts lea di n g t o tr eat m e nt disc o nti n uati on 
were re p orte d i n 4 p atie nts ( 1 6 . 0 %).  

N o v arti s  
C o nfi d e nti al  
P a g e 4 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
Na usea ( 4 8 %), a b d o mi nal pai n ( 3 6 %) a n d diarr hea ( 3 2 %) were t he t hr ee m ost c o m m o n A Es 
re p orte d i n patie nts  wit h C M L i n C P or A P treate d wit h a c o m bi nati o n of asci mi ni b a n d i mati ni b 
(all c o h orts) re g ar dless of relati o ns hi p t o st u d y dr u g. F o ur of 2 5 p atie nts ( 1 6. 0 %) wit h C M L -
C P/ -A P treate d wit h a c o m bi nati o n of asci mi ni b a n d i mati ni b e x peri e nce d at least o ne S A E 
assesse d b y t he i n vesti gat or as s us pecte d t o be relate d t o t he st u d y dr u g : pa ncreatitis, he patitis, 
decrease d n e utr o p hil c o u nt a n d m y o pat h y were re p or te d i n 1 patie nt eac h.  
Li ver relat e d A Es were s ee n i n 7 of 2 5 patie nts ( 2 8 %) treat e d wit h asci mi ni b i n c o m bi nati o n 
wit h i mati ni b. G 3 A S T i n creas e d, G 3 G G T i ncreas e d a n d G 4 a n d S A E he patitis were s ee n i n 1 
patie nt eac h ( 4 %).  
E C G data s h o ws n o re p orte d Q T pr ol o n gati o n (i ncreas e > 6 0 msec or ne w > 5 0 0 msec) i n a n y 
asci mi ni b a n d i mati ni b c o m bi nati o n gr o u ps.  
Asci mi ni b  has  bee n  st u die d i n 2 6  patie nts  wit h  C M L -C P/ -A P at  d ose  le vels of  2 0  m g BI D or 
4 0 m g BI D i n c o m bi nati o n wit h nil oti ni b 3 0 0 m g Q D. As of t he Fi nal A nal ysis data c ut -off ( 1 4 -
Mar -2 0 2 3), all 2 6 pati e nts reac he d e n d of st u d y treat me nt eit her t hr o u g h pre mat ure 
disc o nti n uati o n of st u d y treat me nt or t hr o u g h tra nsiti o n t o P T A o pti o ns or c o m mercial dr u g. 
T he m ost fre q ue nt pri mar y reas o n f or disc o nti n uati o n was p h ysicia n’s decisi o n ( 7 6. 9 %,  eit her 
patie nts tra nsiti o ne d t o P T A o pti o ns or disc o nti n ue d treat me nt  d ue t o lac k of efficac y).  
Asci mi ni b has bee n st u die d i n 3 2  patie nts wit h C M L -C P/ -A P at d ose le vels of 4 0 m g BI D, 8 0 
m g Q D a n d 1 6 0 m g Q D i n c o m bi nati o n wit h dasati ni b 1 0 0 m g Q D. As of t he Fi nal A nal ysis 
data c ut -off ( 1 4 -Mar -2 0 2 3), all 3 2 patie nts reac he d e n d of st u d y treat me nt eit her t hr o u g h 
pre mat ure disc o nti n uati o n of st u d y treat me nt or t hr o u g h tra nsiti o n t o P T A o pti o ns or 
c o m mercial dr u g. M ost of t he patie nts ( 2 1, 6 5. 5 %) c o nti n ue d treat me nt u n d er P T A o pti o ns.  
Efficac y  
As per [ Asci mi ni b I n vesti gat or’s Br oc h ure] preli mi nar y data fr o m t he P hase I FI H St u d y 
[ C A B L 0 0 1 X 2 1 0 1] i n dicate t hat asci mi ni b i n c o m bi nati o n wit h i mati ni b or nil oti ni b or dasati ni b 
e x hi bits a nti-le u ke mic acti vit y i n patie nts  wit h C M L w h o ha ve faile d at least t w o pri or T KIs or 
are i nt olera nt t o T KIs  as well as i n patie nts wit h C M L har b ori n g t he T 3 1 5I m utati o n w h o ha ve 
faile d at least o ne pri or T KI. 
Base d o n t otalit y of dat a, as ci mi ni b 4 0 m g a n d 6 0 m g Q D d ose h as b ee n rec o m me n de d i n 
c o m bi nati o n wit h i mati ni b 4 0 0 m g Q D i n C M L – C P or -A P patie nts wit h o ut T 3 1 5I m utati o n.  
O verall, bas e d o n t he e x p erie nce fr o m t h e o n g oi n g P hase 1 St u d y, [ C A B L 0 0 1 X 2 1 0 1], t he safet y 
pr ofile of as ci mi ni b is acce pta ble f or c o nti n ue d cli nical de vel o p me nt.  
Please refer t o t he latest [ Asci mi ni b I n vesti gat or's Br oc h ure] f or m or e details. 
P h ar m a c o ki n eti c s  
Asci mi ni b, a d mi nistere d as a t wi ce d ail y a n d o nce dail y d osi n g re gi me n, was ra pi dl y a bs or be d 
wit h a me dia n ti me t o reac h ma xi m u m plas ma c o nce ntrati o n ( T ma x ) of 2 t o 3 h o urs, i n de pe n de nt 
of d ose. S yste mic e x p os ure of asci mi ni b, after oral a d mi nistrati o n of a si n gl e d ose a n d m ulti ple 
d oses, as m eas ur e d b y C ma x  a n d A U C, i ncrease d i n a n a p pr o xi matel y d ose pr o p orti o nal ma n ner. 
Ge nerall y, t he v aria bilit y of e x p os ure was l o w t o m o derate wit h i nter -s u bject varia bilit y 

N o v arti s  
C o nfi d e nti al  
P a g e 4 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
( C oefficie nt of V ariati o n ( C V) p erce nta ge) ra n gi n g fr o m a p pr o xi matel y 2 5 % t o 7 0 % f or b ot h 
C ma x  a n d A U C last. Wit h t he t wice dail y d osi n g re gi me n, plas ma asci mi ni b acc u m ulate d sli g htl y 
wit h t he acc u m ulati o n rati os ra n gi n g fr o m 1. 3 t o 2. 5, w hile wit h t he o nce dail y d osi n g re gi me n 
t here was al m ost n o acc u m ulati o n of asci mi ni b ( 1. 1 t o 1. 4). 
T he data of t he h u ma n A D M E St u d y [ C A B L 0 0 1 A 2 1 0 2] s h o w t hat t he relati ve c o ntri b uti o n of 
t he gl uc ur o ni dati o n pat h wa y t o t he t otal cleara nce of asci mi ni b via meta b olis m is esti mate d t o 
ra n ge fr o m 3 0 % t o 6 1 %, w hereas t he relati ve c o ntri b uti o n of t he o xi dati ve pat h wa y is esti mate d 
t o ra n ge fr o m 3 5 % t o 6 3 %. C Y P 3 A 4 was t he mai n c o ntri b ut or f or t he cleara nce of as ci mi ni b 
via t he o xi dati ve pat h wa y w hile U G T 2 B 7 a n d U G T 2 B 1 7 were res p o nsi bl e f or t he cleara n ce of 
asci mi ni b via t he gl uc ur o ni dati o n pat h wa y. T h ere was n o m eta b olite detecte d wit h mea n 
c o ntri b uti o n t o plas ma ra di oacti vit y A U C 0 -2 4 h o urs ≥ 1 0 %. Asci mi ni b was t he pre d o mi na nt dr u g -
relate d c o m p o ne nt i n plas ma at all ti me p oi nts a nal yze d, ra n gi n g fr o m 9 1. 9 % t o 9 4. 2 % of t he 
t otal ra di oacti vit y A U C0 -2 4 h o urs A U C, wit h a n a vera ge val ue of 9 2. 7 % ( half -life is 1 4. 2 h o urs). 
T he effect of f o o d o n asci mi ni b P K was c haracteri ze d i n a P hase I St u d y [ C A B L 0 0 1 A 2 1 0 1] i n 
healt h y v ol u nteers usi n g t w o f or mer v aria nts of t he ta blet f or m ulati o n. F o o d was f o u n d t o 
i nfl ue nce t he p h ar mac o ki netics of as ci mi ni b a n d e x hi bite d a ne gati ve f o o d effect wit h t he t w o 
ta blet varia nts. T he o verall e x p os ure ( A U C) d ecrease d b y a p pr o xi matel y 3 0 % a n d 6 5 % w he n 
a d mi nistere d wit h a l o w -fat a n d hi g h-fat meal, r es pecti vel y f or b ot h ta blet varia nts. 
St u d y [ C A B L 0 0 1 A 2 1 0 4] assesse d t he rel ati ve bi o a vaila bilit y bet wee n a n e w asci mi ni b ta blet 
f or m ulati o n ( Fi nal Mar ket I ma g e ( F MI) 2. 2) i nte n de d t o be use d f or c o m mercial use a n d t he 
cli nical ser vice f or m ( C S F) f or m ulati o n (ca ps ul e). T he ge o metric mea n rati os a n d t w o -si de d 9 0 % 
co nfi de nce i nter vals of t he pri mar y P K para meters Area u n d er t he pl as ma dr u g c o nce ntrati o n -
ti me c ur ve fr o m ti me zer o t o i nfi nit y ( A U Ci nf ), A U Clast a n d C ma x  of asci mi ni b f or ta blet vers us  
ca ps ule c o m paris o n w ere 1. 0 0 ( 0. 9 0 9, 1. 1 0), 1. 0 1 ( 0. 9 1 1, 1. 1 1) a n d 0. 9 0 9 ( 0. 8 0 5, 1. 0 3), 
res pecti vel y. T h eref ore, t he t w o f or m ulati o ns ha ve s h o w n si milar bi oa vaila bilit y s u p p orti n g t he 
s witc h fr o m ca ps ule t o ta blet. T he f o o d effect o n t his ne w ta blet f or m ulati o n was assesse d i n 2 4 
patie nts  usi n g a n o pe n -la bel, ra n d o mize d a n d cr oss-o ver desi g n [ C A B L 0 0 1 E 2 1 0 1]. A ne g ati ve 
f o o d effect was o bser ve d f oll o wi n g l o w a n d hi g h fat meals. L o w-fat a n d hi g h-fat m eals 
decrease d t he bi o a vaila bilit y of asci mi ni b b y ~ 3 0 % a n d ~ 6 0 %, res pecti vel y,  
Please refer t o t he latest [ Asci mi ni b I n vesti gat or’s Br oc h ure] f or m or e details. 
E x p o s ur e -effi c a c y r el ati o n s hi p  
A p o p ulati o n P K P D is u n der de vel o p me nt. T he preli mi nar y p har mac o ki netic m o del f or 
asci mi ni b si n gle a ge nt is descri be d b y a t w o -c o m p art me nt m o del wit h a d ual a bs or pti o n pr ocess 
(zer o or der a bs or pti o n pr ocess f oll o we d b y a first or der a bs or pti o n pr ocess). 
Base d o n t his p o p ulati o n P K m o del, si m ulati o ns were c o n d u cte d a n d re v eal e d t hat a d ose of 4 0 
m g BI D mai ntai ns Ctr o u g hs a b o ve t he t hres h ol d tr o u g h c o nce ntrati o n re q uire d f or 9 0 % 
i n hi biti o n of p S T A T 5 deri ve d fr o m a precli nical P K-P D K C L - 2 2 m o use x e n o graft m o del (I C 9 0: 
3 0 t o 1 2 1 n g/ m L, after c orrecti o n f or pr otei n bi n di n g)  [Asci mi ni b I n vesti gat or's Br oc h ure] . 

N o v arti s  
C o nfi d e nti al  
P a g e 4 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
E x p o s ur e -s af et y r el ati o n s hi p  
T he relati o ns hi p bet wee n o bser ve d plas ma asci mi ni b a n d c ha n ge fr o m baseli ne Q T i nter val 
c orrecte d usi n g Fri derici a's c orrecti o n ( Δ Q Tc F) was assesse d i n St u d y [ C A B L 0 0 1 X 2 1 0 1] (c ut-
off 1 5 -J ul-2 0 1 8) i n 2 1 7 C M L a n d A L L p atie nts recei vi n g m o n ot hera p y i n ra n ge of d oses (fr o m 
1 0 m g t o 2 8 0 m g BI D a n d 8 0 m g t o 2 0 0 m g Q D) . Usi n g t he P K-Q Tc F m o del, t he esti mate d 
mea n ∆Q Tc F at t he ge o metric mea n C ma x of t he hi g hest e val uate d d ose of 2 8 0 m g BI D was 
5. 3 0 ms ( u p per b o u n d 9 0 % CI: 7. 1 0 ms), w hic h is bel o w t he re g ulat or y t hr e s h ol d of 1 0 msec. 
T he relati o ns hi p bet wee n o bser ve d plas ma as ci mi ni b c o nce ntrati o n a n d Q Tc F s h o w e d a 
s mall, c o nce ntrati o n de p e n de nt i ncreas e i n ∆Q Tc F,  w hic h is n ot cli nicall y rele va nt u p t o t he 
hi g hest e val uate d d ose of 2 8 0 m g BI D.  N o cli nicall y si g nifica nt effect o n Δ Q Tc F is e x pect e d 
at asci mi ni b d ose of 6 0 m g Q D bei n g use d i n t he c urre nt st u d y.   
1. 1. 1. 2  
O v er vi e w of i m ati ni b  
A m o n gst ot her a p pr o ve d i n dicati o ns, i mati ni b ( Gli vec ® / Glee vec® ) is i n dicate d f or t he tr eat me nt 
of a d ult a n d pe diatric p atie nts  wit h ne wl y dia g n ose d P hila del p hia c hr o m os o me p ositi ve c hr o ni c 
m yel oi d le u ke mia ( P h + C M L) f or w h o m b o ne marr o w tra ns pla nt ati o n is n ot c o nsi dere d as t he 
first li ne of treat me nt a n d f or t he treat me nt of a d ult a n d pe diatric patie nts  wit h P h + C M L i n 
c hr o nic p has e after fail ure of i nterfer o n -al p h a t hera p y, or i n accelerat e d p hase or blast 
crisis [ please refer t o t he latest Gli vec® / Glee vec®  l ocal a p pr o v e d pr o d uct i nf or mati o n]. 
1. 1. 1. 2. 1  N o n -cli ni c al o v er vi e w  
I mati ni b is n ot ge n ot o xic b ut it was f o u n d t o b e terat o ge nic ( Gli vec® / Glee v ec®  l ocal a p pr o ve d 
pr o d uct i nf or mati o n). T h e fertilit y of male a n d fe male rats was n ot affecte d, alt h o u g h t here was 
e vi de nce of effects o n s p er mat o ge nesis i n r ats a n d d o gs. I mati ni b was carci n o ge nic i n t he rat.  
I n vitr o, i mati ni b was f o u n d t o be a s u bstrate of C Y P 3 A 4/ 5 a n d t o a s maller e xte nt C Y P 2 C 8 
a n d a n i n hi bit or of C Y P 3 A 4/ 5 a n d C Y P 2 D 6 wit h p ote ntial cli nical rele va n ce. I n viv o, a si n gle 
d ose of t he p ote nt C Y P 3 A 4 i n hi bit or ket oc o naz ole i ncrease d m ea n m a xi m u m c o nce ntrati o n 
( Cma x ) a n d A U C of i mati ni b b y 2 6 % a n d 4 0 %, res pecti vel y. C o-a d mi nistrati o n wit h rifa m pi n, 
a n i n d ucer of C Y P 3 A 4, re d uce d plas ma i mati ni b A U C b y a p pr o xi matel y 7 0 %. I mati ni b 
i ncreas e d t he Cma x a n d A U C of si m vastati n b y 2 - a n d 3. 5-f ol d, res pecti vel y, i n dicati n g i n hi biti o n 
of C Y P 3 A 4. A U C of t he C Y P 2 D 6 s u bstrate met o pr ol ol was i ncreas e d bet wee n 1 7 % a n d 2 4 % 
b y i mati ni b c o -a d mi nistrati o n.  
1. 1. 1. 2. 2  Cli ni c al o v er vi e w  
I n 2 0 0 1, i mati ni b, a B C R:: A B L 1 t yr osi ne ki nase i n hi bit or, was a p pr o ve d f or t he tr eat me nt of 
C M L ( C o he n  et al 2 0 0 2 ), a n d si nce t he n m ore t ha n 1 0 0 0 0 0 patie nts recei ve d t he dr u g wit h 
s o me  
patie nts  
n o w  
o n  
treat me nt  
si nce  
m ore  
t ha n  
1 5  
years 
(Ga m bac orti -Passeri ni  a n d Piazza  2 0 1 5 ). Res ults fr o m t he P hase 3 I nter nati o nal Ra n d o mize d 
St u d y of I nterfer o n a n d S TI 5 7 1 (I RI S) s h o w e d t hat i mati ni b at a d ose of 4 0 0 m g o nce dail y was 
m ore acti ve a n d was ass ociate d wit h fe wer si de effects t ha n i nterfer o n -alf a pl us c ytara bi ne i n 
patie nts  wit h ne wl y dia g n ose d C M L i n c hr o nic p hase. At 1 8 m o nt hs, t he esti mate d rate of 
c o m plete c yt o ge netic res p o nse ( C C y R) was 7 6. 2 % i n t he i mati ni b gr o u p, as c o m pare d wit h 
1 4. 5 % i n t he gr o u p t hat recei ve d i nterfer o n -alf a pl us c ytara bi n e, a n d t h e esti mate d rate o f 

N o v arti s  
C o nfi d e nti al  
P a g e 4 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
free d o m fr o m pr o gressi o n t o t he accelerate d p h as e or blast crisis of C M L was 9 6. 7 % vers us  
9 1. 5 % ( O' Brie n  et al 2 0 0 3 ). I n 2 0 1 7, t he fi nal a n al ysis of I RI S St u d y was p u blis he d, wit h a 
me dia n f oll o w u p of 1 0. 9 years. I n t he i mati ni b gr o u p, t he c u m ulati ve rate of maj or c yt o ge netic 
res p o nse ( M C y R) at t he e n d of t he trial was 8 2. 8 % a n d a m o n g 1 3 4patie nts  wit h c yt o ge netic 
assess me nt at 1 0 years, 9 1. 8 % ha d C C y R. A m o n g 2 0 4 patie nts w h o ha d m olec ular assess me nt 
t hat c o ul d be e val uate d at 1 0 years, 9 3. 1 % ha d maj or m olec ular res p o nse ( M M R) a n d 6 3. 2 % 
ha d M R 4. 5. A m o n g t he patie nts  i n t he i mati ni b gr o u p, t he esti mate d o verall s ur vi val rate at 1 0 
years was 8 3 % ( H o c h ha us  et al 2 0 1 7 ). 
A d verse reacti o ns re p ort e d b y s yste m or ga n class ( > 1 0 %) are:  
•  Bl o o d a n d l y m p hatic s yste m dis or ders: ne utr o pe ni a, t hr o m b oc yt o pe nia, a n e mia;  
•  Ner v o us s yste m dis or ders: hea dac h e;  
•  Gastr oi ntesti nal dis or ders: na usea, diarr hea, v o miti n g, d ys pe psia a n d a b d o mi nal pai n;  
•  S ki n a n d s u bc uta ne o us tiss ue dis or ders: peri or bital oe de ma, der m atitis/ecze ma/ras h;  
•  M usc ul os keletal a n d c o n necti ve tiss ue dis or ders: m uscle s pas ms a n d cra m ps, m yal gia, 
art hral gia, b o n e pai n;  
•  Ge neral dis or ders a n d a d mi nistrati o n site c o n diti o ns: fl ui d rete nti o n a n d oe de ma, fati g ue;  
•  I n v esti gati o ns: wei g ht i ncreas e d. 
F or f urt her details please refer t o t he latest Gli vec ® / Glee vec®  l ocal a p pr o ve d pr o d uct 
i nf or mati o n. 
P h ar m a c o ki n eti c s  
I mati ni b is a bi o p har ma ce utical classificati o n s yste m ( B C S) class 1 c o m p o u n d wit h hi g h 
a bs ol ute bi oa vaila bilit y ( 9 8 %) t hat is u naffect e d b y f o o d ( Pe n g  et al 2 0 0 5 ). Base d o n a n a vera ge 
ter mi nal half-life of 1 8 h o urs (ra n ge 1 4 t o 2 5 h o urs), i mati ni b e x p os ure is e x pect e d t o reac h 
stea d y-state after f o ur c o nti n u o us dail y d oses i.e. b y da y 5 wit h a n acc u m ul ati o n rati o of 1. 5 - t o 
2. 5 -f ol d at stea d y state. T he rate of a bs or pti o n of i mati ni b, w he n gi ve n wit h a hi g h-fat meal, 
was mi ni mall y re d uce d ( 1 1 % decrease i n C ma x  a n d pr ol o n gati o n of T ma x  b y 1. 5 h), wit h a s mall 
re d ucti o n i n A U C ( 7. 4 %) c o m p are d t o fasti n g c o n diti o ns latest Gli v ec® / Glee vec®  l ocal 
a p pr o ve d 
pr o d uct i nf or mati o n. I n 
a d diti o n, 
bi oa vaila bilit y is 
u naffecte d 
b y f o o d 
(Pe n g  et al 2 0 0 5 ). T h e a v era ge ter mi nal eli mi nati o n half-life is a p pr o xi matel y 1 8 h o urs. I n vitr o 
meta b olis m st u dies i n dicate t hat C Y P 3 A 4 a n d t o a s maller e xte nt C Y P 2 C 8 are t he maj or h u ma n 
P 4 5 0 e nz y mes catal yzi n g t he bi otra nsf or mati o n of i mati ni b. T he N -des met h yl meta b olite 
C G P 7 4 5 8 8 was t he mai n meta b olite i de ntifie d i n h u ma ns, is bi ol o gicall y acti ve a n d c o ntri b utes 
t o s o me e xte nt t o t he t hera pe utic effect of i mati ni b. 
I n a cli nical D DI St u d y, c o-a d mi nistrati o n of rifa m pici n, a str o n g C Y P 3 A 4 i n d ucer i ncrease d 
i mati ni b oral-d ose cle ara nce b y 3. 8 -f ol d, w hic h si g nifica ntl y ( p < 0. 0 5) decreas e d mea n Cma x  
a n d A U C w hile c o -a d mi nistrati o n of ket oc o naz ol e, a str o n g C Y P 3 A 4 i n hi bit or i ncrease d t he 
a vera g e C ma x  a n d A U C b y 2 6 % a n d 4 0 %, res pecti vel y.  
I mati ni b was als o s h o w n t o be a c o m petiti ve i n hi bit or of mar ker s u bstrates f or C Y P 2 C 9, 
C Y P 2 D 6 a n d C Y P 3 A 4/ 5, wit h Ki val ues i n h u ma n li ver micr os o mes bei n g 2 7, 7. 5 a n d 7. 9 
μ m ol/ L, res pecti vel y. I n viv o, t he mea n e x p os ure t o met o pr ol ol, a C Y P 2 D 6 s u bstrate, was 

N o v arti s  
C o nfi d e nti al  
P a g e 4 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
i ncreas e d u p o n i mati ni b c o-a d mi nistrati o n b y 1 7 % i n i nter me diate C Y P 2 D 6 meta b olizers a n d 
b y 2 4 % i n e xte nsi ve C Y P 2 D 6 meta b olizers [ C S TI 5 7 1 A 2 1 0 6]. I m ati ni b i ncreas e d t he Cma x  of 
t he C Y P 3 A 4 s u bstrate si m vastati n 2-f ol d a n d t he A U C 3. 5-f ol d as s h o w n [ C S TI 5 7 1 A 2 1 0 8]. I n 
a P hase III trial i n p ul m o nar y arterial h y pert e nsi o n patie nts [ C Q TI 5 7 1 A 2 3 0 1], sil de nafil 
c o nce ntr ati o ns, b ot h a m o derate C Y P 2 C 1 9 a n d se nsiti ve C Y P 3 A 4 s u bstrate were raise d b y 6 4 % 
w he n c o -a d mi nistere d wit h i mati ni b. T heref ore, dr u gs w hic h are s u bst rates of C Y P 2 C 9, 
C Y P 2 D 6 a n d C Y P 3 A 4/ 5 c o ul d ha ve t heir e x p os ure affecte d b y i mati ni b.  
1. 1. 1. 3  
O v er vi e w of nil oti ni b  
Nil oti ni b ( Tasi g na ® ) is c urre ntl y a p pr o ve d f or t he treat me nt of a d ult patie nts  wit h P hila del p hia 
c hr o m os o me p ositi ve ( P h +) c hr o ni c m yel oi d le u ke mia ( C M L) i n c hr o nic p hase ( C P) a n d 
accelerat e d p hase ( A P) resista nt t o or i nt olera nt t o at least o ne pri or t hera p y i ncl u di n g i mati ni b 
a n d f or t he treat me nt of a d ult patie nts wit h ne wl y dia g n ose d P h + C M L i n C P. Disc o nti n uati o n 
of treat me nt ma y be c o nsi dere d i n eli gi ble P hila del p hia c hr o m os o me p ositi ve ( P h +) C M L 
patie nts i n c hr o nic p has e w h o ha ve bee n tr eate d wit h Ta si g na at 3 0 0 m g t wice dail y f or a 
mi ni m u m of 3 years if a dee p m olec ular res p o nse is s ustai ne d f or a mi ni m u m of o ne year 
i m me diatel y pri or t o disc o nti n uati o n of t hera p y. 
Nil oti ni b is a n a mi n o p yri mi di ne, a vaila ble as a n oral f or m ulati o n t hat is a n A de n osi ne 
tri p h os p hate ( A T P)-c o m petiti ve i n hi bit or of t he pr otei n t yr osi ne ki nas e acti vit y of B C R:: A B L 1, 
w hic h pre ve nts t he acti vati o n of B C R:: A B L 1 de pe n de nt mit o ge nic a n d a nti -a p o pt otic pat h wa ys 
(e. g. P h os p hati d yli n osit ol 3-ki nases ( PI -3 ki nase) a n d si g nal tra ns d ucer a n d acti vat or of 
tra nscri pti o n 5 ( S T A T 5)), lea di n g t o t he deat h of t he B C R:: A B L 1 p he n ot y pe. 
Please refer t o t he latest [ Nil oti ni b I n vesti gat or’s Br oc h ure] f or m or e details. 
1. 1. 1. 3. 1  N o n -cli ni c al e x p eri e n c e  
I n vitr o safet y p har ma c ol o g y st u dies re veale d a precli nical si g nal of p ote ntial Q T pr ol o n gati o n 
f or nil oti ni b. Des pite t hese fi n di n gs n o Q T i nter val effects were see n i n d o gs or m o n ke ys. 
T he mai n tar get or ga n of t o xicit y was t he li ver i n d o gs a n d m o n ke ys a n d t o a mi n or de gree i n 
rats a n d mice. A d diti o nal tar get or ga ns after l o n g ter m treat me nt were ut er us i n rats a n d s ki n, 
gr o wi n g teet h a n d t h y m us i n mice.  
Nil oti ni b was e m br y olet hal a n d pr o d uce d fet ot o xicit y i n e m br y o -fetal de vel o p me nt st u dies i n 
rats a n d ra b bits at d oses t hat als o pr o d uce d mater nal t o xicit y. T here were n o si g ns of 
terat o ge nicit y. Nil oti ni b is tra nsferre d i nt o t he mil k i n lactati n g rats. 
Nil oti ni b is n ot ge n ot o xic a n d was n ot carci n o ge nic i n a rat t w o year bi oassa y. I n a 2 6 -wee k 
T g.ras H 2 m o use m o del carci n o ge nicit y st u d y s ki n pa pill o mas/carci n o m a occ urre d at 3 0 0 
m g/ k g/ da y re prese nti n g a p pr o xi matel y 3 0 t o 4 0 ti mes ( base d o n A U C) t he h u ma n e x p os ure at 
t he ma xi m u m a p pr o ve d d ose 8 0 0 m g/ da y (a d mi nistere d as 4 0 0 m g t wi ce a da y) w hile n o 
i ncreas e occ urre d at 1 0 0 m g/ k g/ da y (a p pr o xi matel y 1 0 t o 2 0 ti mes h u ma n e x p os ure, b ase d o n 
A U C).  
I n vitr o h u ma n li ver micr os o mes e nz y me i n hi biti o n st u dies re veale d t hat nil oti ni b c o ul d act as 
a n i n hi bit or of C Y P 2 C 8, C Y P 2 C 9, C Y P 2 D 6, a n d C Y P 3 A 4/ 5 acti vit y a n d p ossi bl y, b ut less 

N o v arti s  
C o nfi d e nti al  
P a g e 4 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
li kel y, C Y P 2 C 1 9. E nz y me i n d ucti o n st u dies i n dicate t hat nil oti ni b ca n be c o nsi dere d t o be a n 
i n vitr o i n d ucer of C Y P 2 B 6, C Y P 2 C 8, a n d C Y P 2 C 9 acti vities. T heref ore, ca uti o n s h o ul d be 
e xercis e d w he n c o -a d mi nisteri n g nil oti ni b wit h dr u gs wit h narr o w t h era p e utic i n de x t hat are 
s u bstrates of t h ese e nz y mes. Nil oti ni b is n ot a n effecti ve i n hi bit or of t he h u ma n s o di u m -
de pe n de nt ta ur oc h ol ate c o -tra ns p ort pr otei n ( N T C P). Nil oti ni b was als o f o u n d t o be a s u bstrate 
f or t he P-g p tra ns p ort er as well as a p ossi ble i n hi bit o r of P-g p i n vitr o. 
1. 1. 1. 3. 2  Cli ni c al e x p eri e n c e  
T he P hase III E N E S T n d [ C A M N 1 0 7 A 2 3 0 3] - St u d y assesse d t he effi cac y a n d safet y of 
nil oti ni b vers us  i mati ni b i n ne wl y dia g n ose d P h + C M L-C P Res ults s h o we d statisticall y 
si g nifica nt differe n ces i n t he pri mar y e n d p oi nt defi ne d as rate of maj or m olec ular res p o nse 
( M M R) at 1 2 m o nt hs as well as ot her sec o n dar y e n d p oi nts s uc h as C C y R b y 1 2 m o nt hs a n d 
ti me-t o-p r o gressi o n t o A P/ B C o n treat me nt. T hese res ults were c o nfir m e d at 2 4, 3 6, 4 8, 6 0, 7 2 
a n d 8 4 m o nt hs F oll o w -u p, w hic h s u p p ort s u peri or efficac y of nil oti ni b o ver  i mati ni b [ Nil oti ni b 
I n v esti gat or’s Br oc h ure]. 
T he m ost c o m m o nl y re p orte d ( > 5 %) all -gra de n o n -he mat ol o gic a d verse reacti o ns i n patie nts  
wit h C M L were ras h, h ea dac he, na usea, pr urit us, al o pecia, m y al gia, dr y s ki n, fati g ue, art hral gia, 
m uscle s pas ms, v o miti n g, a b d o mi nal pai n u p per, diarr hea, c o nsti pati o n, peri p heral e de ma, 
a b d o mi nal pai n, er yt he ma, d ys pe psia a n d ast he nia. He mat ol o gic a d verse  dr u g reacti o ns 
i ncl u de d m yel os u p pressi o n: t hr o m b oc yt o pe nia, ne utr o pe nia a n d a ne mia. Cli nicall y rele va nt 
bi oc he mical a b n or malities i ncl u de h y per gl yce mia, h y per bilir u b i ne mia, h y p o p h os p hate mia, a n d 
i ncreas es i n li pase, A L T, a n d A S T. 
Ele vati o ns i n t otal c h olester ol a n d l o w de nsit y li p o pr otei n ( L D L) c h olest er ol ha ve bee n ver y 
c o m m o nl y o bser ve d.  
Ne wl y -dia g n ose d or w orse ne d isc he mic vasc ular or car di o vasc ular e ve nts ha ve occ urre d i n 
patie nts treate d wit h nil oti ni b. Car di o vasc ular ris k fact ors s h o ul d be m o nit ore d a n d ma na ge d 
d uri n g nil oti ni b t hera p y.  
U nc ha n ge d nil oti ni b re prese nts t he pre d o mi na nt circ ulati n g c o m p o ne nt i n ser u m. Meta b olites 
d o n ot si g nifica ntl y c o ntri b ute t o t he p h ar mac ol o gical acti vit y. Str o n g i n hi bit ors or i n d ucers of 
C Y P 3 A 4 ca n si g nifica ntl y alter t he p har mac o ki n etics a n d s yste mic e x p os ure of nil oti ni b i n 
h u ma ns, s o t hese dr u gs s h o ul d be a v oi de d or nil oti ni b d ose c ha n ges s h o ul d be c o nsi dere d. 
He patic i m pair me nt h as a m o dest effect o n nil oti ni b p har mac o ki n etics; h o we ver, i m pair e d re nal 
f u ncti o n is n ot e x pecte d t o i nfl ue nce nil oti ni b p har mac o ki netics.  
T he c urre ntl y a p pr o ve d d ose of nil oti ni b is 3 0 0 m g BI D f or ne wl y dia g n ose d P h + C M L patie nts . 
Please refer t o t he latest [ Nil oti ni b I n vesti gat or’s Br oc h ure] f or m or e details. 
1. 1. 1. 4  
P ot e nti al f or dr u g i nt er a cti o n  
T here is a p ote ntial f or dr u g -dr u g i nteracti o n bet w ee n i mati ni b a n d asci mi ni b.  

N o v arti s  
C o nfi d e nti al  
P a g e 5 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
Eff e ct of i m ati ni b o n a s ci mi ni b  
T he preli mi nar y cli nic al data fr o m t he first -i n h u ma n St u d y [ C A B L 0 0 1 X 2 1 0 1] s u g geste d a n 
i ncreas e i n asci mi ni b e x p os ure w he n c o-a d mi nistere d wit h i mati ni b. F oll o wi n g a d mi nistrati o n 
of asci mi ni b 4 0 m g BI D wit h i mati ni b 4 0 0 m g Q D, t he ge o mea n of t he area u n der t he pl as ma 
c o nce ntr ati o n -ti me c ur ve fr o m ti me zer o t o 1 2 h o urs ( A U C0 -1 2 h o urs) val ues (c oefficie nt of 
variati o n C V perce nta g e, n) of asci mi ni b after first d ose o n da ys 1, 8 a n d 2 2, res pecti vel y were 
esti mate d t o be 3 7 6 6 n g. h/ m L ( 1 6 %, n = 5), 8 7 2 1 n g. h/ m L ( 2 4 %, n = 4) a n d 8 8 9 0 ( 1 0 %, n = 2) 
c o m pare d t o 2 8 4 0 n g. h/ m L ( 5 7 %, n = 2 7), 5 4 0 2 n g. h/ m L ( 7 2 %, n = 1 5) a n d 5 1 7 1 n g. h/ m L 
( 8 0 %, n = 2 4), res p ecti vel y f or asci mi ni b al o ne ( ~ 1. 3 f ol d a n d ~ 1. 7 f ol d i ncrease o n da ys 1 a n d 
after re peate d 
d oses, res pecti vel y) 
[ Asci mi ni b I n vesti gat or's 
Br oc h ure]. I n 
St u d y 
[ C A B L 0 0 1 X 2 1 0 1], patie nts were i nstr uc te d t o ta ke asci mi ni b u n der li g ht meal c o n diti o ns (i.e. 
< 4 0 0 kcal a n d 2 0 % fat) w he n c o m bi ne d wit h i mati ni b, a n d u n der faste d c o n diti o ns w he n 
a d mi nistere d al o ne. Asci mi ni b e x hi bite d a ne gati ve f o o d effect, wit h l o w -fat a n d hi g h-fat meals 
decreasi n g t he bi o a v aila bilit y of asci mi ni b b y ~ 3 0 % a n d 6 5 %, res pecti vel y [ C A B L 0 0 1 A 2 1 0 1]. 
He nce, t he esti mate of t he D DI ma g nit u de mi g ht be re d uce d i n St u d y [ C A B L 0 0 1 X 2 1 0 1] as 
asci mi ni b was t o be ta ke n u n der differe nt f o o d c o n diti o ns w he n a d mi nistere d al o ne or i n 
c o m bi nati o n . As a res ult, ta ki n g i nt o acc o u nt a n i ncreas e i n A U C rati o of asci mi ni b bet wee n 
1. 3 t o 1. 7 u n der c o m bi nati o n t hera p y after si n gle a n d m ulti ple d oses, res pecti vel y a n d a n 
a d diti o nal fact or of a dj ust me nt o n t he basis of s a me f o o d c o n diti o ns (f urt her i ncreas e of ar o u n d 
3 0 %), t he D DI mi g ht var y bet wee n 1. 7 a n d 2. 3 -f ol d i ncrease. W he n i nte grati n g t he i n vitr o a n d 
i n viv o dat a i n a preli mi nar y P B P K m o del a n d f or a d osi n g re gi me n of asci mi ni b d oses bet wee n 
2 0 a n d 8 0 m g Q D, t he m o del pre dicti o ns s u g g este d a 1. 2 1 t o 1. 7 0 -f ol d i ncreas e i n asci mi ni b 
e x p os ure as me as ure d b y A U C u n der c o m bi nati o n wit h i mati ni b 4 0 0 m g Q D after si n gle a n d 
m ulti ple d oses, res pecti vel y. Base d o n t hese i nitial pre dicti o ns, a dr u g -dr u g i nteracti o n m a y b e 
e x pecte d, wit h a wea k t o m o derate i ncr ease i n asci mi ni b e x p os ure w he n c o -a d mi nistere d wit h 
i mati ni b. 
St u d y [ C A B L 0 0 1 E 2 1 0 1] c o nfir me d t he earlier fi n di n gs.  T he st u d y assesse d t he effect of 
m ulti ple d oses of i mati ni b o n t he p har mac o ki neti cs of a si n gle oral d ose (l o w -fat meal) of 4 0 
m g asci mi ni b i n healt h y patie nts . T he a nal ysis s h o we d t hat t he e x p os ure of asci mi ni b was 
hi g her w he n a d mi nistere d i n c o m bi nati o n wit h i mati ni b c o m pare d t o w he n asci mi ni b was 
a d mi nistere d al o ne. T he asci mi ni b e x p os ure, A U Ci nf a n d A U Clast was a p pr o xi matel y 1 0 8 % 
hi g her a n d C ma x was 5 9 % hi g h er w he n a d mi nistere d i n c o m bi nati o n wit h i ma ti ni b c o m pare d 
t o w he n a d mi nistere d al o ne. T he T ma x was n ot i m pacte d b y t he c o-a d mi nistrati o n of i mati ni b. 
T he effect of i mati ni b o n asci mi ni b ma y res ult fr o m t he i n hi biti o n of se veral meta b olis m a n d 
tra ns p ort pat h wa ys t hat are i n v ol ve d i n t he dis p ositi o n of asci mi ni b (i mati ni b is a n i n hi bit or of 
C Y P 3 A 4, U G T a n d P -g p).   
Eff e ct of a s ci mi ni b o n i m ati ni b  
Alt h o u g h t here is a p ote ntial ris k f or asci mi ni b t o alter i mati ni b p har mac o ki netics base d o n i n 
vitr o meta b olis m st u dies w here C Y P 3 A 4 a p pears t o be t he m ai n e n z y me res p o nsi ble f or 
meta b olis m of i mati ni b ( Fil p p ula  et al 2 0 1 2 ), t his has n ot bee n s h o w n t o be of cli nical 
si g nifica nce b ase d o n i nte grati o n of d ata fr o m cli nical a n d m o d eli n g st u dies. I n healt h y p atie nts , 
ket oc o naz ol e, a p ote nt C Y P 3 A 4 i n hi bit or, i ncrease d t he mea n of i mati ni b C ma x  a n d A U C b y 2 6 % 

N o v arti s  
C o nfi d e nti al  
P a g e 5 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
a n d 4 0 %, res pecti vel y, i n healt h y patie nts , c o nfir mi n g t hat i mati ni b is a C Y P 3 A 4 s u bstrate, yet 
n ot meeti n g t he criteria of a se nsiti ve s u bstrat e [ C S T 5 7 1 0 1 1 9]. Asci mi ni b i n hi bite d esta blis he d 
mar ker s u bstrates of C Y P 3 A 4/ 5 i n vitr o i n h u ma n li ver micr os o m es wit h I C 5 0 val u es of 1. 5 
μ M a n d u n b o u n d Ki of a p pr o xi matel y 0. 3 4 8 μ M b ut di d n ot e x hi bit a p pare nt ti me -de pe n d e nt 
i n hi biti o n of C Y P 3 A 4/ 5 at asci mi ni b c o nce ntr ati o ns of u p t o 5 0 μ M. T he cli nical rele va n ce of 
s uc h i nteracti o n is c o nsidere d li mite d. T he P B P K m o del pre dicti o ns di d n ot s u g gest a n y 
cli nicall y rele v a nt D DI f or i mati ni b 4 0 0 m g Q D w he n c o -a d mi nistere d wit h BI D d oses of 
asci mi ni b u p t o 4 0 
m g. T his is als o s u p p orte d b y preli mi nar y h u ma n data i n St u d y 
[ C A B L 0 0 1 X 2 1 0 1] w h ere t here w as n o a p pare nt c ha n ge i n i mati ni b stea d y -state c o n ce ntr ati o n 
u p o n c o -a d mi nistrati o n wit h re peat e d dail y d oses of asci mi ni b 4 0 m g BI D [ C A B L 0 0 1 X 2 1 0 1]. 
T heref ore, t h e p ote ntial f or asci mi ni b t o affect t h e p har mac o ki netics of i mati ni b is c o nsi dere d 
l o w. 
1. 2  
P ur p o s e  
T KIs ha ve re v ol uti o nize d t he treat me nt of p atie nts wit h C M L, res ulti n g i n a n o verall s ur vi val 
( O S) t hat is cl ose t o t hat of t he ge neral p o p ulati o n a n d t heref ore a near n or mal life e x pect a nc y. 
T his has c o nse q ue ntl y dra w n e m p hasis t o war ds t he nee d t o i m pr o ve  patie nt’s q ualit y of life, i n 
li ne wit h t hat of t h e ge neral p o p ulati o n. C urre nt treat me nt g ui deli nes are t heref ore m o vi n g 
t o war ds disc o nti n uati o n of treat me nt i n t he c o nte xt of “treat me nt free re missi o n” ( T F R). D M R 
is a prere q uisite f or T F R a n d is t heref ore e mer gi n g as a ne w tr eat me nt g oal f or C M L patie nts 
i n c hr o nic p h ase (N C C N  2 0 1 8 , Rea  a n d Ca y u ela  2 0 1 7 , Ma h o n  2 0 1 6 ). A s ustai ne d D M R f or at 
least 2 years is rec o g niz e d as o ne of t he esse ntial re q uire me nts t o atte m pt disc o nti n uati o n of 
T KI t hera p y i n P h + C M L -C P ( N C C N  2 0 1 8 , Baccara ni  et al 2 0 1 3 , H oc h ha us  et al 2 0 1 7 ). I n 
a d diti o n, D M R is ass ociate d wit h i m pr o ve d s ur vi v al rates a n d a v oi da nce of disease pr o gressi o n 
(C ortes  2 0 1 8 , 
D ul uc q  a n d Ma h o n  2 0 1 6 , 
Bra nf or d  2 0 1 6 , 
Ye u n g  et al 2 0 1 5 , 
He hl ma n n  et al 2 0 1 4 ; Etie n ne  et al 2 0 1 4 ; Falc hi  et  al 2 0 1 3 ). I n C M L St u d y I V wit h fr o ntli ne 
i mati ni b, patie nts wit h M R4. 5 at 4 years ha d a hi g her pr o ba bilit y of s ur vi val at 8 years vers us 
patie nts wit h B C R:: A B L 1 I S of 0. 1 – 1 % a n d n o patie nt w h o ac hie ve d M R 4. 5 i n t hat a nal ysis 
pr o gresse d t o accelerate d p hase/ blast crisis b y t he data c ut off ( He hl ma n n  et al 2 0 1 4 ). I n a 
retr os pecti ve a n al ysis of patie nts treate d wit h fr o ntli ne i mati ni b, (Etie n ne  et al 2 0 1 4 ) re p orte d 
t hat c o nfir me d C M R ( defi ne d i n t hat st u d y as M R4. 5) at a n y ti me ha d hi g her e ve nt-free s ur vi val 
( 9 5. 2 %) vers us t h ose wit h M M R, b ut n ot C M R ( 6 4. 7 %), a n d t h ose w h o ac hie ve d C C y R, b ut 
n ot M M R ( 2 7. 7 %). I n a n ot her retr os pecti ve st u d y b y ( Falc hi  et al 2 0 1 3 ), a l o wer ris k of l osi n g 
C C y R, pr o gressi o n t o A P or B P, or d eat h i n p atie nts wit h dee p er M R was re p orte d. F urt her m ore, 
t he ti mi n g of s witc h fr o m first li ne t o 2n d li ne treat me nt i n C M L i n t he c o nte xt of ac hie vi n g a 
faster a n d d ee per m olec ular res p o nse, is als o bei n g e x pl ore d acr oss vari o us st u dies. St u d y 
TI D E L -II st u die d t he effect of earl y s witc hi n g fr o m i mati ni b t o nil oti ni b. Of t he 2 1 0 patie nts 
e nr olle d i n t he s t u d y, s witc h t o nil oti ni b occ urre d i n 5 5 patie nts f or faili n g t o ac hie ve m olec ular 
res p o nse tar gets ( 1 9, 1 6 a n d 2 0 at 3, 6 a n d 1 2 m o nt hs, res pecti vel y). Of t he 1 5 3 patie nts i n 
M M R at 2 4 m o nt hs, 4 2 ( 2 7 %) were re p orte d t o h a ve ac hi e ve d M M R after s witc h t o nil oti ni b. 
Of t he 7 1 patie nts i n M R 4. 5 at 2 4 m o nt hs, 2 2 ( 3 1 %) ac hie ve d M R 4. 5 after s witc h t o nil oti ni b.  T he 
st u d y de m o nstrate d i m pr o ve d o utc o mes w he n pati e nts were s witc h e d fr o m i mati ni b t o nil oti ni b 
f or n o n-ac hie ve me nt of B C R:: A B L 1 le vel milest o nes as per t he E L N criteria, at m o nt h 3, 6 
a n d 1 2 (Ye u n g  et al 2 0 1 5 ). 

N o v arti s  
C o nfi d e nti al  
P a g e 5 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
T he maj orit y of ne wl y dia g n ose d C M L -C P patie nts is treate d wit h i mati ni b, b ut o nl y a 
pr o p orti o n of t hes e patie nts is a ble t o ac hie ve D M R wit h i mati ni b treat me nt. I n E N E S T n d 
[ C A M N 1 0 7 A 2 3 0 3], t h e c u m ulati ve rates of M R4. 5 were 2 3 % after 4 years a n d 3 3 % after 6 y ears 
of i mati ni b treat me nt ( Lars o n  et al 2 0 1 4 ). L a n d mar k a nal ysis (Bra nf or d  et al 2 0 1 5 ) perf or me d 
else w here ha v e s h o w n t h at patie nts  w h o ha v e n ot reac h e d B C R:: A B L 1 le vels of M R 4 f oll o wi n g 
2 4 m o nt hs of i mati ni b treat me nt ha v e l o w li keli h o o d of ac hie vi n g D M R wit h c o nti n ue d 
treat me nt; t h us t hese pati e nts w o ul d p ossi bl y be nefit fr o m a d diti o nal t hera p y (Fi g ure 1 -1 ). 
Fi g ur e 1 -1  
C u m ul ati v e i n ci d e n c e of M R 4. 5  a c c or di n g t o r e s p o n s e l e v el at 2 4 
m o nt h s of i m ati ni b tr e at m e nt  
 
C urre ntl y, a n o pti o n f or patie nts w h o d o n ot ac hie ve t he desire d le vel of m olec ular res p o nse 
wit h c o nti n ue d i mati ni b treat me nt is t o s witc h t o a m ore p ote nt sec o n d ge nerati o n T KI. Res ults 
fr o m E N E S Tc mr [ C A M N 1 0 7 A 2 4 0 5] s h o w t hat, after s witc hi n g fr o m i mati ni b t o nil oti ni b, 
nearl y h alf of t he patie nts wit h o ut M R 4. 5 at baseli ne will still n ot ac hie ve t his le vel of res p o nse 
e ve n after 4 years of s witc h. F urt her m ore, sec o n d ge nerati o n T KIs har b or a disti nct t o xicit y 
pr ofiles as c o m pare d t o i mati ni b, a n d t heref ore  ca n p ose t olera bilit y c o ncer ns, es peciall y f or 
patie nts  w h o ha ve ass oci ate d c o -m or bi dities. He n ce, t here is a n u n met nee d f or acti ve a n d safer 
re gi me ns f or t he af ore me nti o ne d patie nts (Bra nf or d  et al 2 0 1 5 ). 
Asci mi ni b is a n all osteric i n hi bit or of B C R:: A B L 1 w hic h tar gets t he a ut or e g ulat or y m yrist o yl 
bi n di n g p oc ket c o m pare d t o t he catal ytic T KIs. D ue t o its disti nct p har mac ol o gical pr ofile a n d 
as s h o w n b y precli nical p har mac ol o gical st u dies de m o nstrati n g a n a d d iti ve a nti-t u m or acti vit y, 
a c o m bi nati o n of asci mi ni b a n d a n A T P -bi n di n g site T KI has t he p ote ntial t o ac hie ve a D M R 
i n a hi g her pr o p orti o n of C M L patie nts as c o m pare d t o si n gle a ge nt T KI t h era p y. A d diti o nall y, 
tar geti n g t he A B L ki nase d o mai n at t w o disti nct l ocati o ns t hr o u g h t h e c o m bi nati o n ca n 
t he oreticall y pre v e nt t he e mer ge n ce of si n gle p oi nt m utati o n-ass ociate d tr eat me nt resista nce. 
T he val ue of n o n -o v erla p pi n g resista nce pr ofiles was e vi de nt i n m o use m o dels w here d ura bl e 
treat me nt-free re gressi o ns were o bser ve d wit h u pfr o nt a d mi nistrati o n of a nil oti ni b -asci mi ni b 
c o m bi nati o n ( W ylie  et al 2 0 1 7 ). F urt her m ore, a st u d y c o n d ucte d b y Sa u n ders et al. s h o we d t hat 
i n vitr o ki nase i n hi biti o n ac hie ve d wit h asci mi ni b i n c o m bi nati o n wit h i mati ni b, nil oti ni b or 
dasati ni b is greater t ha n t hat ac hie ve d wit h T KIs al o ne, e ve n at c o n ce ntr ati o ns 1 0 0 0 -f ol d l o wer 
t ha n t he a vera ge p ea k pl as ma c o nce ntrati o n o n asci mi ni b 4 0 m g BI D (c urre ntl y i n vesti gate d 

N o v arti s  
C o nfi d e nti al  
P a g e 5 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
m o n ot hera p y d ose), s u g g esti n g t hat si m ulta ne o us tar geti n g of t he m yristate a n d A T P bi n di n g 
p oc kets ma y be m or e effecti ve t ha n tar geti n g eit h er si de al o n e. Es peci all y, patie nts  wit h hi g h 
I C5 0, w h o w o ul d be pre di cte d t o res p o n d p o orl y t o i mati ni b, c o ul d ha ve dra maticall y i ncreas e d 
ki nase i n hi biti o n wit h t he a d diti o n of l o w d oses of asci mi ni b ( Sa u n ders  2 0 1 6 ). 
T he a d diti o n of asci mi ni b t o i mati ni b is e x pecte d t o res ult i n m ore p ote nt i n hi biti o n of t he A B L 
ki nase d o mai n e n ha nci n g cli nical efficac y. It is h y p ot hesize d t hat t he a d diti o n of asci mi ni b i n 
patie nts  w h o ha ve n ot ac hie ve d D M R wit h si n gle a ge nt i mati ni b will i ncrease t heir li keli h o o d 
of ac hie vi n g t his res p o nse o ver ti me a n d ma y all o w T KI disc o nti n uati o n i n t he c o nte xt of T F R. 
T he p ur p ose of t his tri al is t o e val uat e t he effi cac y a n d safet y of asci mi ni b a d de d o n t o i mati ni b 
treat me nt i n c o m paris o n t o c o nti nue d i mati ni b i n patie nts  w h o ha ve n ot ac hie ve d M R 4 after at 
least o ne year of i mati ni b first-li ne treat me nt. As a sec o n dar y e n d p oi nt, t he differe nce i n 
effic ac y bet w ee n t he c o m bi nati o n a n d nil oti ni b, a sec o n d ge n erati o n T KI, will be esti mate d.  
T h e a me n d m e nt 3 a d de d  a n asci mi ni b si n gle a ge nt c o h ort t o assess w het her as ci mi ni b si n gle 
a ge nt at t he rec o m me n de d d ose of 8 0  m g Q D lea ds t o si milar efficac y a n d safet y as o bser ve d 
i n t he a d d-o n ar ms of as ci mi ni b a n d i mati ni b. T his a d diti o nal c o h ort will hel p t o e val uate if t he 
c o m bi nati o n of asci mi ni b wit h i mati ni b is nee de d t o i ncrease t he li keli h o o d of ac hie vi n g D M R, 
or if t hi s ca n b e ac hie ve d b y asci mi ni b al o ne. T he pri mar y a nal ysis res ults s h o w acti vit y of 
asci mi ni b as a n a d d -o n t h era p y t o i mati ni b, assesse d b y M R 4. 5 rate at Wee k 4 8. T he M R 4. 5 rate 
at Wee k 4 8 was 1 9 %, 2 8. 6 %, 0 % a n d 4. 8 % i n t he asci mi ni b 4 0 m g + i mati ni b, asci mi ni b 6 0 m g 
+ i mati ni b, c o nti n ue d i mati ni b a n d s witc h t o nil oti ni b ar m ( Ma ur o et al, 2 0 2 1). Res ults fr o m 
ot her si n gle a ge nt st u dies i n patie nts wit h C M L -C P w h o ha v e bee n tr eate d wit h at least 2 pri or 
T KIs ha v e s h o w n acti vit y of si n gle a g e nt as ci mi ni b f or ac hie ve m e nt of D M R i n t his hea vil y 
pretreate d p o p ulati o n. I n St u d y A 2 3 0 1, M R 4 a n d M R 4. 5 rates of 1 0. 8 % a n d 7. 6 %, res pecti vel y 
were o bser ve d at Wee k 4 8.  I n t he s u b gr o u p of pati e nts wit h baseli ne B C R:: A B L 1 le vels ( > 0. 0 1 % 
a n d ≤1 %), t he M R 4. 5 rate ( 1 8. 8 %, 3 res p o n d ers a m o n g 1 6 patie nts) was si milar t o t hat o bser ve d 
i n E 2 2 0 1 wit h t he asci mi ni b as a d d o n t o i mati ni b at t he pri mar y a n al ysis ( data o n file).  
2  
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 2 -1 . 
T a bl e 2 -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( s)  
E n d p oi nt( s)  
Pri m ar y o bj e cti v e( s)  
E n d p oi nt( s) f or pri m ar y o bj e cti v e( s)  
•  
T o a s s e s s w h et h er a s ci mi ni b 4 0 m g Q D + i m ati ni b or 
a s ci mi ni b 6 0 m g Q D + i m ati ni b i s m or e eff e cti v e t h a n 
c o nti n u e d i m ati ni b  
•  
M ol e c ul ar R e s p o n s e ( M R)
4. 5  r at e at 4 8 
w e e k s  
S e c o n d ar y o bj e cti v e( s)  
E n d p oi nt( s) f or s e c o n d ar y o bj e cti v e( s)  
•  
- T o e sti m at e effi c a c y of s wit c h t o nil oti ni b  
-T o e sti m at e diff er e n c e i n effi c a c y b et w e e n a s ci mi ni b 6 0 
m g + i m ati ni b a n d s wit c h t o nil oti ni b  
- T o e sti m at e diff er e n c e i n effi c a c y b et w e e n a s ci mi ni b 4 0 
m g + i m ati ni b a n d s wit c h t o nil oti ni b  
•  
- M ol e c ul ar R e s p o n s e ( M R)
4. 5  r at e at 4 8 
w e e k s  
•  
- Diff er e n c e i n r at e of M R 4. 5  at 4 8 w e e k s  
•  
T o a s s e s s a d diti o n al p ar a m et er s of t h e effi c a c y of  
•  
- R at e of M R 4. 5  at 9 6 w e e k s  
- R at e of M R 4. 5  b y 4 8 a n d 9 6 w e e k s  

N o v arti s  
C o nfi d e nti al  
P a g e 5 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
O bj e cti v e( s)  
E n d p oi nt( s)  
•  
- a s ci mi ni b 6 0 m g a d d e d t o i m ati ni b v s c o nti n u e d i m ati ni b 
or s wit c h t o nil oti ni b  
•  
- a s ci mi ni b 4 0 m g a d d e d t o i m ati ni b v s c o nti n u e d i m ati ni b 
or s wit c h t o nil oti ni b  
•  
- S u st ai n e d M R 4. 5 at 9 6 w e e k s  
- Ti m e t o M R 4. 5  
•  
- D ur ati o n of M R 4. 5  
•  
T o c h ar a ct eri z e t h e s af et y a n d t ol er a bilit y pr ofil e of 
a s ci mi ni b 6 0 m g or 4 0 m g + i m ati ni b v s c o nti n u e d i m ati ni b 
or s wit c h t o nil oti ni b  
•  
I n ci d e n c e a n d s e v erit y of a d v er s e e v e nt s, 
c h a n g e s i n l a b or at or y v al u e s, cli ni c all y 
n ot a bl e E C G a b n or m aliti e s a n d vit al 
si g n s  
•  
T o a s s e s s t h e p h ar m a c o ki n eti c pr ofil e of a s ci mi ni b 6 0 m g 
or 4 0 m g a n d i m ati ni b w h e n a d mi ni st er e d i n c o m bi n ati o n  
 
• 
Pl a s m a c o n c e ntr ati o n s of a s ci mi ni b a n d 
i m ati ni b w h e n a d mi ni st er e d i n 
c o m bi n ati o n. P K p ar a m et er s i n cl u d e b ut 
ar e n ot li mit e d t o C m a x , Tm a x , Cmi n , A U Cl a st 
a n d A U C t a u 
•  
T o e sti m at e effi c a c y  of a s ci mi ni b 8 0 m g Q D  
 
•  
-M ol e c ul ar R e s p o n s e ( M R)
4. 5  r at e at 4 8 
w e e k s  
-Ti m e t o M R 4. 5  
•  
-D ur ati o n of M R 4. 5  
•  
T o c h ar a ct eri z e t h e s af et y  a n d t ol er a bilit y pr ofil e of 
a s ci mi ni b 8 0 m g Q D   
•  
I n ci d e n c e a n d s e v erit y of a d v er s e e v e nt s, 
c h a n g e s i n l a b or at or y v al u e s, cli ni c all y 
n ot a bl e E C G  a b n or m aliti e s a n d vit al 
si g n s  
•  
T o a s s e s s t h e p h ar m a c o ki n eti c  pr ofil e of a s ci mi ni b 8 0 m g 
Q D . 
•  
Pl a s m a c o n c e ntr ati o n s  of a s ci mi ni b. P K 
p ar a m et er s i n cl u d e b ut ar e n ot li mit e d t o 
C m a x , Tm a x , Cmi n , A U Cl a st a n d A U C t a u 
E x pl or at or y o bj e cti v e( s)  
E n d p oi nt( s) f or e x pl or at or y o bj e cti v e( s)  
•  
T o d e s cri b e t h e effi c a c y a n d s af et y of a s ci mi ni b 6 0 m g + 
i m ati ni b i n p ati e nt s r a n d o mi z e d t o c o nti n u e d i m ati ni b w h o 
cr o s s o v er t o r e c ei v e a s ci mi ni b 6 0 m g + i m ati ni b  
-Effi c a c y e n d p oi nt s s u c h a s ti m e t o M R 4. 5 
a n d d ur ati o n of M R 4. 5  
•  
- S af et y e n d p oi nt s s u c h a s i n ci d e n c e a n d 
s e v erit y of a d v er s e e v e nt s, c h a n g e s i n 
l a b or at or y v al u e s, cli ni c all y n ot a bl e E C G 
a b n or m aliti e s a n d vit al si g n s  
•  
T o a s s e s s t h e pr o p orti o n of p ati e nt s eli gi bl e f or T F R at e n d 
of t h e st u d y  
•  
P ati e nt s , wit h s u st ai n e d M R D* ( Mi ni m al 
R e si d u al Di s e a s e) at t h e e n d of t h e 
st u d y (i. e. 9 6 w e e k s aft er t h e fir st d o s e of 
st u d y dr u g of t h e l a st r a n d o mi z e d 
s u bj e ct)  
•  
 Pl e a s e r ef er t o gl o s s ar y f or t h e M R D 
d efi niti o n  
•  
T o e x pl or e r el e v a nt 
 
 
, a s w ell a s 
 
 
 
•  
A n al y si s of 
 
 
 
 
 
•  
T o e x pl or e 
 
 
 
•  
 
 
 
•  
T o e v al u at e 
 
 
•  
 
  
C CI
C CI
C CI
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
O bj e cti v e( s)  
E n d p oi nt( s)  
•  
T o e x pl or e t h e i m p a ct of tr e at m e nt o n p ati e nt r e p ort e d 
o ut c o m e s ( P R O s) i n cl u di n g C M L -s p e cifi c s y m pt o m 
a s s e s s m e nt ( di s e a s e a n d tr e at m e nt), tr e at m e nt 
s ati sf a cti o n a n d o v er all i m p a ct of si d e eff e ct s of tr e at m e nt 
fr o m b a s eli n e 
•  
O v er all S c or e s a n d i n di vi d u al d o m ai n s f or 
E O R T C Q L Q -C 3 0 pl u s C M L 2 4, F A CI T 
G P 5 a n d T S Q M q u e sti o n n air e  
3  
St u d y d e si g n  
T he st u d y is a P hase 2, m ulti -ce nter, o pe n -l a bel, ra n d o mize d st u d y of as ci mi ni b + i mati ni b 
vers us  c o nti n ue d i mati ni b vers us  s witc h t o nil oti ni b i n patie nts wit h C M L -C P w h o ha ve bee n 
pre vi o usl y treat e d wit h i mati ni b first li ne t hera p y f or at least o n e year ( 1 2 cale n dar m o nt hs) a n d 
ha ve n ot ac hi e ve d D M R.  
T he trial is desi g ne d t o assess t he acti vit y of 2 d oses of asci mi ni b + i mati ni b Q D vers us  i mati ni b 
c o nti n uati o n, a n d t o esti mate t he differe nce c o m pare d t o s witc h t o nil oti ni b, assesse d b y t he rat e 
of M R 4. 5 at 4 8 wee ks as well as a d diti o nal efficac y p ara met ers, P K, bi o mar kers, P R Os a n d 
safet y a n d t olera bilit y. A d diti o nall y, t he st u d y will esti mate safet y a n d effi cac y of si n gle a g e nt 
asci mi ni b.  
A p pr o xi matel y ei g ht y eli gi ble patie nts will be ra n d o mize d i n a 1: 1: 1: 1 rati o t o recei ve st u d y 
treat me nt i n t he bel o w ar ms: 
Treat me nt ar m 1: asci mi ni b 4 0 m g Q D as a d d -o n t hera p y t o i mati ni b 4 0 0 m g Q D, or  
Treat me nt ar m 2: asci mi ni b 6 0 m g Q D as a d d -o n t hera p y t o i mati ni b 4 0 0 m g Q D, or  
Treat me nt ar m 3: t o c o nti n ue i mati ni b 4 0 0 m g Q D, or  
Treat me nt ar m 4: t o s witc h t o nil oti ni b 3 0 0 m g BI D  
T he asci mi ni b si n gle a ge nt c o h ort will be c o n d ucte d as a n o pe n la bel c o h ort. A p pr o xi matel y 2 0 
eli gi ble patie nts will be e nr olle d t o recei ve asci mi ni b 8 0 m g Q D.  
I n Treat me nt ar ms 1-4, patie nts o n t he st u d y will c o nti n ue o n t he all ocate d treat me nt u ntil 
treat me nt fail ure, i nt olera bilit y, or f or u p t o 9 6 wee ks after t he last ra n d o mize d s u bject recei ve d 
t he first d ose of treat me nt. After t he last d ose recei ve d e v er y s u bject will be f oll o we d u p f or 
safet y f or 3 0 d a ys. 
F or patie nts i n t he asci mi ni b si n gle a ge nt c o h ort, patie nts will c o nti n ue o n asci mi ni b treat me nt 
u ntil treat me nt fail ure, i nt olera bilit y, or f or u p t o 4 8 wee ks after t he last e nr olle d s u bject i n t he 
c o h ort recei ve d t he first d ose of treat me nt. After t he last d ose recei ve d e v er y s u bject will be 
f oll o we d u p f or safety f or 3 0 da ys.  
I nt eri m a n al y si s  
A n i nteri m a nal ysis will be perf or m e d w he n at least 4 0 ( 5 0 %) patie nts ha ve bee n ra n d o mize d 
a n d ha v e bee n f oll o w e d f or t heir 2 4 wee ks visit assess me nt or h a ve disc o nti n ue d treat me nt. At 
t he ti me of t he i nteri m a nal ysis, if e xcessi ve t o xi cit y wit h o ut a d de d be nefit is o bser ve d i n o ne 
of t he i n vesti gati o nal ar ms, disc o nti n uati o n of t hat treat me nt ar m will be c o nsi dere d. T he 
decisi o n t o disc o nti n ue a n i n vesti gati o nal ar m i n t he st u d y will be ta ke n base d o n t he ris k be nefit 
bala nce of t he t w o i n vesti gati o nal ar ms , a n d i n c o nte xt of t he ot her t w o treat me nt o pti o ns 

N o v arti s  
C o nfi d e nti al  
P a g e 5 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
a vaila ble f or t he p atie nts i n t he st u d y, na mel y: c o nti n ue o n i mati ni b wit h n o p ote ntial 
i m pr o ve me nt of effi cac y; or s witc h t o nil oti ni b wit h a p ote ntial t o i m pr o ve efficac y h o we ver, 
wit h a relati vel y a d vers e safet y pr ofile as c o m pare d t o i mati ni b . If a decisi o n is ta ke n t o 
disc o nti n ue asci mi ni b 6 0 m g + i mati ni b treat me nt ar m a t i nteri m a n al ysis, patie nts  o n g oi n g o n 
t hat treat me nt ar m will be pr o vi de d a n o p p ort u nit y t o c o nti n ue o n t he st u d y at a l o wer d os e 
(asci mi ni b 4 0 m g + i mati ni b) if t he i n vesti gat or c onsi ders t hat is i n t he best i nterest of t he 
patie nt.  
Cr o s s o v er f or p ati e nt s i n t h e i m ati ni b ar m 
Patie nts w h o were ra n d o mize d t o c o nti n ue o n i mati ni b si n gle a ge nt treat me nt b ut w h o ha ve n ot 
ac hie ve d M R 4. 5 at 4 8 wee ks ma y cr oss -o v er t o recei ve t he a d d -o n wit hi n 4 wee ks after wee k 4 8 
visit ( Fi g ure 3 -1 ). It is pl a n ne d t hat t h ese p atie nts cr oss-o ver t o recei v e t he asci mi ni b 6 0 m g + 
i mati ni b, as t his d ose pr o vi des hi g her e x p os ure see ( Secti o n  4. 2 ). If a d ecisi o n is ta ke n t o 
disc o nti n ue asci mi ni b 6 0 m g + i mati ni b treat me nt ar m at i nteri m a nal ysis or u p o n e mer gi n g 
data, cr oss -o v er ma y b e c ha n ge d t o asci mi ni b 4 0 m g + i mati ni b treat me nt ar m.  T he cr oss -o ver 
is at discreti o n of t he i n v esti gat or a n d t h e patie nt. A part fr o m a P C R res ult of bel o w M R4. 5 at 
Wee k 4 8 visit, t here are n o ot her e ntr y criteria f or t he cr oss -o ver part. Patie nts o n nil oti ni b are 
n ot all o we d t o cr oss -o ver t o recei ve t h e a d d -o n tr eat me nt.  
Fi g ur e 3 -1  
St u d y d e si g n  
 
 
(*)Patie nts o n t he i mati ni b c o nti n uati o n ar m w h o ha ve n ot ac hie ve d M R 4. 5  at 4 8 wee ks ma y 
cr oss-o ver t o recei ve t he asci mi ni b 6 0 m g a d d -o n  treat me nt. Base d o n t h e res ults of t he i nteri m 
a nal ysis or e mer gi n g d ata, cr oss -o v er ma y b e c ha n ge d t o asci mi ni b 4 0 m g + i mati ni b ar m.   

N o v arti s  
C o nfi d e nti al  
P a g e 5 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
Pri m ar y a n al y si s  
F or patie nts i n tr eat me nt ar ms 1 –  4, t he pri mar y a nal ysis f or t he st u d y will be perf or me d w he n 
all patie nts  ha ve c o m plet e d t he Wee k 4 8 visit or ha ve disc o nti n ue d treat me nt earl y.  
E n d of St u d y Tr e at m e nt p eri o d  
T he e n d of st u d y treat me nt peri o d f or patie nts i n Treat me nt ar ms 1 -4 will be at 9 6 wee ks ( pl us 
3 0 da ys f or t he safet y f oll o w u p) after t he last ra n d o mize d s u bject recei v e d t he first d ose of 
st u d y treat me nt.  
T he e n d of st u d y treat m e nt peri o d f or p atie nts i n t he as ci mi ni b si n gle a ge nt c o h ort will be at 
4 8  wee ks ( pl us 3 0 da ys f or t he safet y f oll o w u p) after t h e last e nr olle d s u bject i n t hat c o h ort 
recei v e d t he first d ose of st u d y treat me nt.  
C o nti n u e d  a c c e s s  t o st u d y tr e at m e nt aft er t h e e n d of t h e st u d y 
Partici pa nts  w h o c o m plete partici pati o n i n t his trial a n d c o nti n ue t o deri ve cli nical  be nefit fr o m 
t he treat me nt base d o n t he I n v esti gat or’s e val uati o n will recei ve p ost-trial access base d o n t he 
criteria f or p ost -trial a ccess bei n g satisfie d. 
P T A mea ns t he pr o visi o n of treat me nt t o trial partici pa nts f oll o wi n g t heir  c o m pleti o n of trial 
partici pati o n. P T A will be pr o vi de d u ntil o ne of t he f oll o wi n g is met: p artici pa nt n o l o n ger 
deri ves cli nic al be n efit, I n vesti gat or disc o nti n ues treat me nt, la u nc h or  rei m b urse me nt ( w h ere 
a p plica ble), tr eat me nt fails t o ac hie ve re gistrati o n i n t he trial  partici pa nt’s c o u ntr y, or t h e 
cli nical pr o gra m is disc o nti n ue d f or a n y ot her reas o n.  
Mec ha nis ms f or pr o visi o n of P T A 
ma y i ncl u de a n e xte nsi o n p h ase t o t his st u d y, a 
se parat e e xte nsi o n 
pr ot oc ol, a r oll o ver 
pr ot oc ol, 
pr o visi o n 
of t he 
N o vartis/ S p o ns or 
i n vesti gati o nal pr o d uct i n a n o n -trial setti n g ( k n o w n as p ost-st u d y dr u g s u p pl y [ P S D S]) w he n 
n o f urt her safet y or effi cac y  d ata are re q uire d, or a n y ot her mec ha nis m a p pr o priate f or t he 
c o u ntr y. 
T he P T A me c ha nis m m ust c o m pl y wit h l ocal la ws a n d re g ul ati o ns i n t he partici p ati n g 
trial c o u ntries. If N o vartis/ S p o ns or disc o nti n ues t he P T A f or t his trial, N o vartis/ S p o ns or will 
w or k wit h I n v esti gat ors  t o tra nsiti o n partici pa nts  i nt o l ocall y a vaila ble alter nati ve treat me nt, or 
sta n dar d of care.  
4  
R ati o n al e  
4. 1  
R ati o n al e f or st u d y d e si g n  
T he de vel o p me nt of asci mi ni b prese nts a n o p p ort u nit y t o e val uate t he b e n eficial effects of a 
c o m bi ne d i n hi biti o n of B C R:: A B L 1 t o get her wit h A T P -bi n di n g site T KIs (e. g. i mati ni b) f or 
greater p har m ac ol o gical c o ntr ol of B C R:: A B L 1 i n t he treat me nt of patie nts  wit h C M L. T he 
pr o p ose d st u d y desi g n will all o w a n assess me nt of t he efficac y, s afet y, t olera bilit y a n d patie nts  
re p orte d o ut c o mes of asci mi ni b + i mati ni b i n a p o p ulati o n of patie nts  wit h c o nti n ui n g me dical 
nee d of ac hi e vi n g D M R. T o c haract erize t he p h ar mac o ki netics of asci mi ni b i n t he pr o p ose d 

N o v arti s  
C o nfi d e nti al  
P a g e 5 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
patie nt p o p ulati o n a n d assess t he p ote ntial f or dr u g -dr u g -i nteracti o n wit h i mati ni b (c o m pare d 
t o hist orical data), P K sa m ples of asci mi ni b will be c ollecte d. 
T he st u d y ra n d o mizes patie nts  1: 1: 1: 1 i n f o ur ar ms t o assess efficac y a n d safet y of t h e 
c o m bi nati o n of asci mi ni b a n d i mati ni b vers us  i mati ni b, a n d t o esti mate t he differe n ce i n 
effic ac y a n d safet y bet w ee n nil oti ni b a n d t he c o m bi nati o n ar ms. F or p atie nts ra n d o mize d t o 
c o nti n ue i mati ni b, a cr oss -o ver t o recei ve asci mi ni b + i mati ni b after 4 8 wee ks is i m ple me nte d 
s h o ul d t he y n ot ha ve ac hieve d M R 4. 5 at t he ti me of t he pri mar y e n d p oi nt. T his will all o w 
patie nts wit h o ut M R 4. 5 after c o nti n uati o n of i mati ni b t o p ote ntiall y be nefit fr o m t he c o m bi nati o n 
treat me nt. 
T his st u d y is c o n d ucte d as a n o pe n la bel st u d y; t he c o n diti o ns f or dr u g a d mi nistrati o n bei n g 
disti nct f or t he f o ur treat me nt ar ms ma kes bli n di n g ver y c o m ple x a n d w o ul d i ncreas e t he 
li keli h o o d of d osi n g err ors. A d diti o nall y, t he c haracteristic a d v erse e ve nt pr ofile of eac h of t he 
dr u gs f urt her precl u d e effecti ve bli n di n g.  
4. 1. 1  
R ati o n al e f or a d diti o n of a s ci mi ni b si n gl e a g e nt c o h ort  
T he pri mar y a nal ysis c ut -off f or t he st u d y was perf or me d o n 1 0 -Ja n-2 0 2 2. T he res ults of t he 
pri mar y a nal ysis s h o we d acti vit y of asci mi ni b as a n a d d -o n t hera p y t o i mati ni b, assesse d b y 
dee p m olec ular res p o nse ( M R 4. 5) rate at 4 8 wee ks. M R4. 5 was ac hie ve d i n hi g her n u m ber of 
patie nts  i n asci mi ni b 6 0 m g + i mati ni b ar m as c o m pare d t o c o nti n ue d i mati ni b a n d s witc h t o 
nil oti ni b ar m. At Wee k 4 8, 6 ( 2 8. 6 %) patie nts  i n asci mi ni b 6 0 m g + i mati ni b ar m a n d 4 ( 1 9 %) 
patie nts  i n asci mi ni b 4 0 m g + i mati ni b ar m ac hie ve d M R4 . 5 a n d 1 patie nt ( 4. 8 %) i n t h e nil oti ni b 
ar m ac hie v e d M R 4. 5. N o patie nts i n t he i mati ni b ar m ac hie ve d M R4. 5 b y Wee k 4 8.  
I n st u d y A 2 3 0 1 i n hea vil y pre-treat e d patie nts ( ≥3 L C M L-C P) treate d wit h asci mi ni b 4 0 m g 
BI D, t he M R 4. 5 rate at wee k 4 8 was 7. 6 % i n t he asci mi ni b ar m. Of t he patie nts wit h B C R:: A B L 1 
le vels > 0. 1 ≤1 % at bas eli ne, M R4. 5 res p o nse rate was 1 8. 8 % ( 3 res p o n ders a m o n g 1 6 p atie nts)  
at Wee k 4 8.  
A d d i n g a n asci mi ni b si n gle a ge nt c o h ort t o assess t he effi cac y a n d safet y at t he rec o m me n de d 
d ose of asci mi ni b i n > 3 L C M L -C P of 8 0 m g Q D will hel p t o e val uat e if t he c o m bi nati o n of 
asci mi ni b wit h i mati ni b is nee de d t o i ncrease t he li keli h o o d of ac hie vi n g D M R, or  if t his ca n 
be ac hie v e d b y asci mi ni b al o ne.  
At t he pri mar y a nal ysis i n E 2 2 0 1, asci mi ni b as a d d -o n t o i mati ni b was well t olerate d. A d verse 
e ve nts lea di n g t o disc o nti n uati o n were re p orte d f or 4. 8 % patie nts i n t he asci mi ni b 4 0 m g + 
i mati ni b ar m, 1 4. 3 % patie nts i n t he asci mi ni b 6 0 m g + i mati ni b, 2 3. 8 % patie nts i n nil oti ni b ar m 
a n d n o ne i n i mati ni b ar m. Safet y pr ofile of asci mi ni b a d d -o n t o i mati ni b was si milar t o t hat of 
asci mi ni b si n gle a ge nt o bser ve d i n t he st u dies i n hea vil y pretreate d patie nts ( H u g hes et al 2 0 1 9 , 
Ma ur o 2 0 2 1 ).  
T he e x p os ure ( A U Cta u) of asci mi ni b o btai ne d i n t his st u d y wit h asci mi ni b 6 0 m g Q D + i mati ni b 
(i n t he fe d state) was si milar t ha n t he e x p os ure i n st u d y X 2 1 0 1 o btai ne d wit h si n gle a ge nt 
asci mi ni b 8 0 m g Q D (i n t he faste d st ate). T h e C m a x was a p pr o xi matel y 6 0 %  hi g her i n X 2 1 0 1 
at 8 0 m g Q D c o m pare d t o asci mi ni b 6 0 m g Q D + i mati ni b i n t his st u d y.  

N o v arti s  
C o nfi d e nti al  
P a g e 5 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
Si n gle a ge nt treat me nt, if a ble t o deli ver t he sa m e be n efit t o t he p atie nt w o ul d be prefera ble 
o ver treat me nt wit h t w o a ge nts, wit h t he p ote ntial t o be safer a n d m ore t olera ble f or l o n g ter m 
treat me nt nee d e d b y patie nts wit h C M L-C P. T h us, t he a d diti o n of t he asci mi ni b si n gle a ge nt 
c o h ort ai ms t o i n v esti gate t he effi cac y a n d s afet y of si n gle a ge nt 8 0 m g Q D as ci mi ni b i n t he 
c urre nt st u d y.  
4. 2  
R ati o n al e f or d o s e/r e gi m e n a n d d ur ati o n of tr e at m e nt  
C urre ntl y t he maj orit y of ne wl y dia g n ose d C M L -C P patie nts  are treate d wit h i mati ni b at t he 
d ose of 4 0 0 m g Q D. I mati ni b is a d mi nistere d wit h a li g ht meal at t he d os e of 4 0 0 m g Q D i n t his 
st u d y. T heref ore, it is desira ble t o f oll o w t he s a me c o n diti o ns of a d mi nistrati o n f or as ci mi ni b. 
T he e x p os ure res ulti n g fr o m t h e Rec o m me n de d P hase 2 D ose ( R P 2 D) i n C M L -C P ( 4 0 m g BI D 
m o n ot hera p y) is e x p ecte d t o be altere d b y t he c o m bi ne d effect of dr u g i nteracti o n a n d f o o d 
effect a n d ma y re q uire a d ose a dj ust me nt t o ac hie ve c o m para ble e x p os ure t o t he esta blis he d 
R P 2 D (refer t o  Secti o n  1. 1. 1. 4  ). 
T he t w o d oses of 4 0 m g or 6 0 m g a d mi nistere d dail y i n c o m bi nati o n wit h i mati ni b 4 0 0 m g Q D 
pr o vi de p har mac ol o gicall y acti ve e x p os ure wit h differe nt P K pr ofiles; t he be nefit/ris k rati o of 
eac h d ose le v el nee ds t o be f urt her esta blis he d. I n dee d, 6 0 m g asci mi n i b Q D i n c o m bi nati o n 
wit h i mati ni b wit h l o w fat meals l ea ds t o c o m para ble e x p os ure t o t he m o n ot hera p y R 2 P D as 
meas ure d b y A U C, a n d hi g her C ma x  b y a p pr o xi matel y 1. 6 t o 1. 9 -f ol d, w hile A U C was l o wer 
wit h asci mi ni b 4 0 m g Q D (a p pr o xi matel y 4 0 %) b ut wit h C ma x  cl ose t o R P 2 D. Base d o n P K/ D DI 
data, safet y a n d t olera bilit y, b ot h c o m bi nati o n d oses will be i n vesti gate d i n t his st u d y.  
T he safet y pr ofile of asci mi ni b Q D d oses ( 4 0  m g, 6 0 m g a n d 8 0 m g) has bee n e val uate d i n 
c o m bi nati o n wit h i mati ni b 4 0 0 m g Q D. D ose Li miti n g T o xicities ( D L Ts) ha ve bee n o bser ve d 
at all d ose le v els, 1 i n 9 p atie nts  i n t h e as ci mi ni b 4 0 m g Q D c o h ort ( ne utr o p hil c o u nt decrease d 
G 4), 2 i n 6 patie nts i n t h e as ci mi ni b 6 0 m g Q D c o h ort (a b d o mi nal p ai n G 3, na usea G 3 ) a n d 2 
i n 4 patie nts  i n t he asci mi ni b 8 0 m g Q D c o h ort ( pa ncreatitis G 2, li pase i ncreas e d G 3). Fr o m 
cli nical p oi nt of vie w a n d s u p p orte d b y t he Ba yesia n L o gistic Re gressi o n M o del ( B L R M), b ot h 
asci m i ni b 4 0 m g Q D a n d 6 0 m g Q D see m t o be a p pr o priate i n c o m bi nati o n wit h i mati ni b 4 0 0 
m g Q D.  
T he d urati o n of treat me nt will all o w b ot h f or detecti o n of earl y acti vit y a n d t olera bilit y of t he 
c o m bi nati o n vers us  c o nti n ue d i mati ni b or s witc h t o nil oti ni b as well t o c o nfir m t he res ults at 
later ti me p oi nts u p t o 9 6 wee ks. 
T he asci mi ni b si n gle a g e nt c o h ort will e val uat e as ci mi ni b at a d ose of 8 0  m g o nce -dail y ( Q D) 
f or 4 8 wee ks.  
T he asci mi ni b d ose of 8 0 m g Q D is base d o n t he cli nical e x perie n ce i n p atie nts wit h C M L -C P 
i n st u dies X 2 1 0 1 a n d A 2 3 0 1 a n d P K/ P D m o delli n g base d e x p os ure-res p o nse a n d e x p os ure-
safet y a n al yses ( Please refer t o t he latest [ As ci mi ni b I n v esti gat or's Br oc h ure] f or m ore d etails). 
Asci mi ni b 8 0 m g Q D has bee n a p pr o ve d b y t he F D A f or t he treat me nt of a d ult patie nts wit h 
P h + C M L i n C P, pre vi o usl y treate d wit h 2 or m ore T KIs. T he o n g oi n g st u d y C A B L 0 0 1J 1 2 3 0 1 
i n vesti gati n g efficac y a n d safet y of si n gle a ge nt asci mi ni b i n patie nts wit h ne wl y dia g n ose d 
C M L is assessi n g as ci mi ni b at a d ose of 8 0 m g Q D. T he d urati o n of treat me nt of 4 8 wee ks will 

N o v arti s  
C o nfi d e nti al  
P a g e 6 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
all o w f or detecti o n of a nti -le u ke mic acti vit y a n d t olera bilit y of si n gle a ge nt asci mi ni b i n t he 
st u d y.  
4. 3  
R ati o n al e f or c h oi c e of c o m p ar at or a n d c o m bi n ati o n dr u g s  
Precli nical e vi d e nce s u p p orti n g t he rati o nal e f or t he c o m bi nati o n of a n A T P -bi n di n g site T KI 
a n d asci mi ni b is descri be d i n pre vi o us secti o ns ( Secti o n  1. 1. 1. 1 , Secti o n  1. 1. 1. 2  a n d 
Secti o n  1. 2 ). T he maj orit y of ne wl y dia g n ose d C M L-C P patie nts  are treate d wit h i mati ni b, 
w hic h has a w ell -defi ne d t olera bilit y pr ofile. F or p atie nts o n i mati ni b, w here t he tr eat me nt g oal 
is t o ac hie ve D M R, e. g. i n t he c o nte xt of atte m pti n g T F R, t he a d diti o n of as ci mi ni b c o ul d be a n 
effic aci o us a n d safe tr eat me nt o pti o n.  
B ot h E L N ( E ur o pea n Le u ke mia Net w or k) a n d N C C N ( Nati o nal C o m pre he nsi ve Ca ncer 
Net w or k) g ui deli nes rec o m me n d t he use of i mati ni b as a p pr o ve d first li ne treat me nt f or C M L -
C P, as well as ot her a p pr o ve d a g e nts, i ncl u di n g nil oti ni b. R o b ust cli nical e vi de nce has bee n 
ge nerat e d s o far wit h i mati ni b as first li ne treat me nt a n d it has bee n selecte d as c o m parat or ar m 
f or t he pri mar y st u d y e n d p oi nt. Bei n g t he i n vesti gati o nal ar ms asci mi ni b i n c o m bi nati o n wit h 
i mati ni b, kee pi n g i mati ni b as c o m parat or will s u p p ort t he assess me nt of t he asci mi ni b si n gle 
a ge nt c o ntri b uti o n i n t he i n vesti gati o nal ar m. I mati ni b will be a d mi nistere d at 4 0 0 m g Q D.  
T he c h oice of nil oti ni b as c o m parat or is s u p p orte d b y res ults fr o m 
E N E S Tc mr 
[ C A M N 1 0 7 A 2 4 0 5] St u d y w hic h s h o we d t hat patie nts wit h resi d ual disease after at least t w o 
years of i mati ni b treat me nt ca n ac hie ve hi g her rate of M R 4. 5 w he n treat me nt is s witc he d t o 
nil oti ni b as c o m pare d t o c o nti n uati o n wit h i mati ni b. T o get her wit h res ults fr o m t he o n g oi n g 
E N E S T o p [ C A M N 1 0 7 A 2 4 0 8] St u d y t his s u g gests t hat a hi g her pr o p orti o n of patie nts s witc hi n g 
t o nil oti ni b will be eli gi ble f or T F R (H u g hes  et al 2 0 1 6 ). T h us nil oti ni b c o nstit utes a c urre nt 
treat me nt o pti o n f or patie nts i n t he tar g et p o p ulati o n wit h t he g oal of a dee p m olec ular res p o nse. 
T he c o m paris o n t o nil oti ni b will all o w t o esti mate t he differe nce i n re g ar ds of efficac y a n d 
t olera bilit y vers us  t he c o m bi nati o n t hera p y. 
Base d o n data fr o m E N E S T n d [ C A M N 1 0 7 A 2 3 0 3], t he safet y pr ofile of t he nil oti ni b 3 0 0 m g 
BI D d ose is m or e fa v ora ble i n ter ms of t olera bilit y, A Es a n d la b orat or y e val uati o n t ha n t he 
nil oti ni b 4 0 0 m g BI D d ose, w hile s h o wi n g si milar efficac y. A d diti o nall y, t he fre q ue n c y of A Es 
lea di n g t o disc o nti n uati o n was l o wer i n t he 3 0 0 m g BI D ar m c o m pare d t o t he 4 0 0 m g BI D ar m. 
As C M L -C P patie nts  w h o are i n C C y R b ut less t ha n M R 4 are n ot c o nsi dere d t o be tr eat me nt 
fail ure acc or di n g t o c urre nt treat me nt g ui d eli nes, t he selectio n of 3 0 0 m g BI D d ose f or t h e 
nil oti ni b treat me nt ar m is c o nsi dere d a p pr o priat e.  
4. 4  
P ur p o s e a n d ti mi n g of i nt eri m a n al y s e s/ d e si g n a d a pt ati o n s  
A n i nteri m a nal ysis will be perf or me d i n or der t o gai n a n earl y i nsi g ht i nt o t he safet y a n d 
effic ac y of t he as ci mi ni b a d d -o n c o m bi nati o n w hic h will hel p i n pla n ni n g t he f ut ure 
de vel o p me nt of t he asci mi ni b c o m bi nati o n. T he i nteri m a nal ysis will be perf or me d w he n at 
least 4 0 ( 5 0 %) p atie nts h a ve bee n ra n d o mize d a n d ha ve bee n f oll o we d f or t heir 2 4 wee ks visit 
assess me nt or ha ve disc o nti n ue d treat me nt. T he e nr oll me nt will c o nti n ue d uri n g t his 2 4 wee ks 
f oll o w-u p. T he i nteri m a nal ysis will i ncl u de all ra n d o mize d p atie nts u ntil t he date of data c ut -
off, a n d i ncl u d e b ot h efficac y (e. g. B C R:: A B L 1 assess me nt o verti me, M R 4 a n d  M R
4. 5 rate at 

N o v arti s  
C o nfi d e nti al  
P a g e 6 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
differe nt ti me -p oi nts) a n d safet y (e. g. A d verse E ve nts a n d la b orat or y val ues) s u m maries, w hic h 
will be detaile d i n t he Statistical A nal ysis Pla n f or t he i nteri m a nal ysis.   
T he i nteri m a nal ysis is pla n ne d t o pr o vi de earl y i nsi g hts i nt o t he safet y a n d efficac y para meters 
t o i nf or m t he be nefit ris k assess me nt of asci mi ni b as a n a d d-o n t hera p y t o i mati ni b. If e x cessi ve 
t o xicit y wit h o ut a d de d be nefit is o bser ve d i n o ne of t he i n vesti gati o nal ar ms, disc o nti n uati o n of 
t hat treat me nt ar m will be c o nsi dere d. T he decisi o n of disc o nti n uati o n of a n i n vesti gati o nal ar m 
i n t he st u d y will be ta ke n base d o n t he ris k be nefit bala nce of t he t w o i n v esti gati o nal ar ms, a n d 
i n c o nte xt of t he ot her t w o treat me nt o pti o ns a vaila ble f or t he patie nts i n t he st u d y, na mel y: 
c o nti n ue o n i mati ni b wit h n o p ote ntial i m pr o ve me nt of efficac y; or s witc h t o nil oti ni b wit h a 
p ote ntial t o i m pr o ve efficac y h o we ver, wit h a rel ati vel y a d verse safet y pr ofile as c o m p are d t o 
i mati ni b. If a decisi o n is ta ke n t o disc o nti n ue asci mi ni b 6 0 m g + i mati ni b treat me nt ar m at 
i nteri m a nal ysis, patie nts  o n g oi n g o n t hat treat m e nt ar m will be pr o vi d e d a n o p p ort u nit y t o 
c o nti n ue o n t he st u d y at a l o wer d ose (asci mi ni b 4 0 m g + i mati ni b) if t he i n vesti gat or c o nsi ders 
t hat is i n t he best i nterest of t he patie nt. A d diti o nall y, cr oss-o ver ar m ma y be c ha n g e d t o 
asci mi ni b 4 0 m g + i mati ni b treat me nt ar m. It is n ot pla n ne d t o write a n i nteri m C S R base d o n 
t his i nteri m a nal ysis. 
4. 5  
Ri s k s a n d b e n efit s  
T he be nefit -ris k f or as ci mi ni b re mai ns p ositi ve f or t he treat me nt of P h + C M L a n d P h + A L L 
patie nts wit h or wit h o ut 
m utati o ns c o nferri n g resista nce t o A T P -c o m petiti ve i n hi bit ors, 
i ncl u di n g t he T 3 1 5I m utati o n. 
T he m ost fre q u e nt a d verse reacti o ns t o asci mi ni b a d mi nistere d i n m o n ot hera p y (i n > 2 0 % 
patie nts) i ncl u de h ea d ac he ( 2 3. 6 %), fati g ue ( 2 2. 8 %), t hr o m b o c yt o pe nia ( 2 2. 8 %), art hral gia 
( 2 1. 3 %) a n d na us ea ( 2 0. 2 %). T hr o m b oc yt o pe nia ( 1 5. 2 %), ne utr o pe ni a ( 1 1. 8 %) a n d li pase 
i ncreas e d ( 1 0. 7 %) were t he m ost fre q ue ntl y re p ort e d ( > 1 0. 0 %) Gra de ≥3 e ve nts. 
T he i m p orta nt i de ntifie d ris ks of asci mi ni b i ncl u de pa ncreatic t o xicit y (a m ylase a n d li pase 
ele vati o ns), 
m yel os u p pr essi o n a n d 
Q T pr ol o n gati o n. I m p orta nt p ote ntial ris ks i ncl u de, 
he pat ot o xicit y i ncl u di n g he patic tra nsa mi nas e a n d bilir u bi n ele vati o ns, re pr o d ucti ve t o xicit y 
a n d He patitis B viral reacti vati o n. I m p orta nt p ote ntial class ris ks i ncl u de car diac fail ure, e de ma 
a n d fl ui d rete nti o n, he m orr ha ge a n d isc he mic h eart a n d C N S c o n diti o ns. Of n ote t he ris ks w hic h 
ha ve bee n de m ote d are g astr oi ntesti nal t o xicit y, h y perse nsiti vit y a n d p h ot ot o xicit y.  
T he m ost c o m m o n a d verse reacti o ns t o asci mi ni b a d mi nistere d i n c o m bi nati o n wit h i mati ni b 
(i n > 1 0 % patie nts) i ncl u de na usea ( 2 5 %) a n d li pase i ncrease d ( 1 5 %). 
T he i m p orta nt i de ntifie d ris ks of nil oti ni b, a ut h orize d f or o ver 1 0 years, i ncl u de Q T 
pr ol o n gati o n, m yel os u p pressi o n, car di o vasc ul ar e ve nts, si g nifica nt blee di n g, se vere i nfecti o ns, 
he pat ot o xicit y, pa ncreatitis, li pase a n d a m ylase ele vati o ns, fl ui d rete nti o n, bl o o d gl uc os e 
i ncreas e d, bl o o d c h olester ol i ncreas e d, use i n patie nts wit h he patic i m pair me nt a n d i nteracti o ns 
wit h str o n g C Y P 3 A 4 i n hi bit ors, str o n g C Y P 3 A 4 i n d ucers, se nsiti ve C Y P 3 A 4 s u bstrates a n d 
f o o d. T he i m p orta nt i de ntifie d ris ks of nil oti ni b i nclu de s u d de n deat h, car diac fail ure, 
re pr o d ucti ve t o xicit y, s ki n mali g na nc y, a n d i nteracti o ns wit h P-g p i n hi bit ors, dr u gs eli mi nate d 
b y C Y P 2 C 8, C Y P 2 C 9, C Y P 2 D 6 or s u bstrates of U G T 1 A 1, a n d P -g p a n d O C T 1 tra ns p orters 
a n d dr u gs t hat ma y pr ol o n g t he Q T i nter val.  

N o v arti s  
C o nfi d e nti al  
P a g e 6 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
I n t his trial, t he af ore me nti o ne d ris ks are ma na ge d t hr o u g h detaile d i nf or mati o n pr o vi de d i n t he 
I B a n d re q uir e me nts deli neate d i n t he st u d y pr ot oc ol. T he l atter i n cl u de e xcl usi o n criteria, 
w hic h li mit e nr oll me nt of patie nts at u nacce pta bl e safet y ris ks, r e q uir e d assess me nts/ m o nit ori n g 
a n d rec o m me n dati o ns f or t he ma na g e me nt of a d verse e ve nts i ncl u di n g d ose re d u cti o n a n d 
i nterr u pti o n. T here m a y be u nf ores ee n ris ks wit h st u d y treat me nt w hic h c o ul d be seri o us.  
Refer t o t he latest [ Asci mi ni b I n vesti gat or’s Br oc h ure] a n d t he latest l ocal pr o d uct i nf or mati o n 
f or i mati ni b a n d nil oti ni b. 
W o me n of c hil d beari n g p ote ntial m ust be i nf or me d t hat ta ki n g t he st u d y treat me nt ma y i n v ol ve 
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 t he c o ntrace pti o n re q uire m e nts o utli ne d i n t he 
e xcl usi o n criteria. If t here is a n y q uesti o n t hat t he s u bject 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 or c o nti n u e i n t he st u d y.  
I mati ni b, o n t he ot her ha n d, alrea d y o n t he mar k et f or m ore t ha n 1 5 years, has a well-k n o w n 
effic ac y pr ofile, wit h hi g h m olec ular a n d c yt o g e netic res p o ns e rates offeri n g a n efficaci o us 
treat me nt t o C M L patie nts , a n d ver y l o w rates of se vere n o n-h e mat ol o gical a d verse e ve nts, as 
well as a n acce pta ble h e mat ol o gical t o xicit y. O nl y a mi n orit y of patie nts treate d wit h i mati ni b 
first-li ne will ha ve a hi g h li keli h o o d of ac hie vi n g D M R, all o wi n g patie nts t o bec o me eli gi ble 
f or T F R (Bra nf or d  et al 2 0 1 5 ). 
Precli nical st u dies de m o nstrate d t hat t he c o m bi nati o n of asci mi ni b a n d i mati ni b is p ote ntiati n g 
t he i n hi biti o n of t he B C R: A B L 1 ki nase (Sa u n ders  2 0 1 6 ), es peciall y f or patie nts  pre dicte d t o 
res p o n d p o orl y t o i mati ni b. F urt her m ore tar geti n g t he ki nase at t w o disti nct l ocati o ns a n d t he 
val ue of n o n -o verla p pi n g resista nce pr ofiles was e vi de nt i n a xe n o graft m o del, wit h d ura ble 
treat me nt free re missi o n o bser ve d wit h t he a d mi nistrati on of asci mi ni b a n d a n A T P -bi n di n g site 
T KI ( W ylie  et al 2 0 1 7 ). T his a d diti ve a nti-t u m or acti vit y s u g gests a hi g her pr o p orti o n of 
patie nts ac hie vi n g a D M R c o m pare d t o i mati ni b m o n o -t hera p y, a n d s u bs e q ue ntl y all o w f or 
c o nsi derati o n of T KI disc o nti n uati o n.  
I n s u m mar y, t h e c o m bi n ati o n of i mati ni b a n d asci mi ni b re pres e nts a n oral t hera p y o pti o n wit h 
a p ote ntiall y hi g h be nefit -ris k rati o f or t he treat me nt of patie nts  wit h C M L. T his is als o 
s u p p orte d b y d ata (al beit li mite d) fr o m t h e o n g oi n g c o m bi nati o n c o h ort of [ C A B L 0 0 1 X 2 1 0 1] 
St u d y s h o wi n g g o o d t olera bilit y a n d n o ne w safet y si g nals.  
A p ote ntial ris k f or patie nts e nr olli n g i n t he c o m bi nati o n ar m of t he st u d y is t hat t he a d diti o n of 
asci mi ni b ma y lea d t o n o i m pr o ve d efficac y i n ter ms of de pt h of res p o nse w hile e x p osi n g t he 
s u bject t o a d diti o nal t o xicit y. H o we ver, t he precli nical e vi de nce t o date (see  Secti o n  1. 1. 1. 1 ) 
s u p p orts t he h y p ot hesis of a p ote ntiati o n of acti vit y. F urt her m ore, t he a d v erse e ve nt pr ofile of 
asci mi ni b is si milar q ualitati vel y t o t hat o bser ve d wit h ot her T KIs tar g eti n g B C R:: A B L 1. T he 
ris k of asci mi ni b i n c o m bi nati o n wit h i mati ni b n ot bei n g effective is miti gate d b y o bser vi n g 
patie nts  cl osel y f or e vi de nce of efficac y, base d o n m olec ular res p o nse data, w hic h will per mit 
ra pi d decisi o n ma ki n g, a n d disc o nti n uati o n of t hera p y if necessar y (see  Secti o n  1 2   data 
a nal ysis). 

N o v arti s  
C o nfi d e nti al  
P a g e 6 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
4. 6  
R ati o n al e f or p u bli c h e alt h e m er g e n c y miti g ati o n pr o c e d ur e s  
D uri n g a p u blic healt h e mer ge nc y as declare d b y l ocal or re gi o nal a ut h orities e. g., pa n de mic, 
e pi de mic, or n at ural dis aster, miti gati o n pr oce d ures t o e ns ure partici pa nt safet y a n d trial 
i nte grit y ma y be i m ple me nte d. N otificati o n of t he p u blic healt h e mer genc y as declare d b y l ocal 
or re gi o nal a ut h orities s h o ul d be disc usse d a m o n g i n vesti gat ors a n d N o vartis. All pr oce d ures 
a da pte d t o t he sit uati o n m ust be s u b mitte d, if re q uire d as per l ocal re g ulati o ns, t hr o u g h a 
pr ot oc ol a me n d me nt f or a p pr o val b y l ocal or re gi o nal 
Healt h 
A ut h orities a n d Et hics 
C o m mittees pri or t o i m ple me ntati o n of miti gati o n pr oce d ures.  
5  
P o p ul ati o n  
A p pr o xi matel y ei g ht y p atie nts wit h C M L -C P w h o ha ve bee n pre vi o usl y treate d wit h i mati ni b 
a n d ha ve n ot ac hie ve d dee p m olec ular res p o nse will be ra n d o mize d i n a 1: 1: 1: 1 rati o t o recei ve 
asci mi ni b 6 0 m g as a d d -o n t hera p y t o i mati ni b, or asci mi ni b 4 0 m g as a d d -o n t hera p y t o 
i mati ni b, or t o c o nti n ue i mati ni b, or t o s witc h t o nil oti ni b.  
A p pr o xi matel y t we nt y p atie nts wit h C M L -C P w h o ha ve bee n pre vi o usl y tr eate d wit h i mati ni b 
f or at le ast 1 year a n d ha ve n ot ac hie ve d d ee p m olec ular res p o nse will be e nr olle d i n t h e 
asci mi ni b si n gle a ge nt c o h ort t o recei ve asci mi ni b 8 0 m g Q D. T he defi niti o n of C M L -C P will 
be acc or di n g t o E ur o pea n Le u ke mia Net w or k crit eria ( Baccara ni  et al 2 0 1 3 ). 
T he i n vesti gat or or d esi g nee m ust e ns ure t h at o nl y patie nts w h o m eet 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 treat me nt i n t he st u d y.  
5. 1  
I n cl u si o n crit eri a 
Patie nts  eli gi ble f or i ncl usi o n i n t his st u d y m ust meet all  of t he f oll o wi n g criteria:  
1. Si g ne d i nf or me d c o nse nt m ust be o btai ne d pri or t o partici pati o n i n t he st u d y.  
2. Male or fe mal e patie nts ≥ 1 8 years of a ge wit h a c o nfir me d dia g n osis of C M L -C P defi ne d as:  
•  < 1 5 % blasts i n peri p heral bl o o d a n d b o ne marr o w  
•  < 3 0 % blasts pl us pr o m yel oc ytes i n peri p heral bl o o d a n d b o ne marr o w  
•  < 2 0 % bas o p hils i n t he p eri p heral bl o o d  
•  ≥ 1 0 0 x 1 0 9/ L ( ≥ 1 0 0 0 0 0/ m m3) platelets 
•  N o e vi de nce of e xtr a me d ullar y le u ke mic i n v ol ve me nt, 
wit h t he e xce pti o n of 
he pat os ple n o me gal y  
3.  b. Mi ni m u m of o ne year ( 1 2 cale n dar m o nt hs) treat me nt wit h i mati ni b first li ne f or C M L -
C P ( patie nts ha ve t o be o n i mati ni b 3 0 0 m g Q D or hi g her)).  
4.  a. B C R:: A B L 1 le vels > 0. 0 1 % I S a n d ≤ 1 % I S at t he ti me of ra n d o mizati o n as c o nfir me d 
wit h a ce ntral assess me nt at scree ni n g; patie nts m ust n ot ha ve ac hie ve d dee p m olec ul ar 
res p o nse ( M R4 I S) c o nfir me d b y 2 c o nsec uti ve tests at a n y ti me d uri n g pri or i mati ni b 
treat me nt. A n is olate d, si n gle test res ult wit h B C R:: A B L 1 le vels < 0. 0 1 % ( M R4 I S) is 
all o we d, h o we v er it s h o ul d n ot ha ve bee n o bser ve d wit hi n t he 9 
m o nt hs pri or t o 
ra n d o mizati o n 
5.  a. Patie nt m ust meet t he f oll o wi n g la b orat or y val u es bef ore ra n d o mizati o n:  

N o v arti s  
C o nfi d e nti al  
P a g e 6 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
•  A bs ol ute Ne utr o p hil C o u nt ≥ 1. 5 x 1 0 9/ L 
•  Platelets ≥ 7 5 x 1 0 9/ L 
•  He m o gl o bi n ( H g b) ≥ 9 g/ d L  
•  Ser u m creati ni ne < 1. 5 m g/ d L  
•  T otal bilir u bi n ≤ 1. 5 x U L N e xce pt f or patie nts wit h Gil bert’s s y n dr o me w h o ma y o nl y 
be i ncl u de d wit h t otal bilir u bi n ≤ 3. 0 x U L N  
•  As partate tra nsa mi nase ( A S T) ≤ 3. 0 x U L N  
•  Ala ni ne tra nsa mi nas e ( A L T) ≤ 3. 0 x U L N  
•  Al kali ne p h os p hatase ≤ 2. 5 x U L N  
•  Ser u m li pase ≤ 1. 5 x U L N. F or ser u m li pase > U L N - ≤ 1. 5 x U L N, val ue m ust be 
c o nsi dere d n ot cli nicall y si g nifica nt a n d n ot ass ociate d wit h ris k fact ors f or ac ute 
pa ncreatitis  
6.  a. Patie nts m ust ha ve t he f oll o wi n g la b orat or y val ues ( ≥ L L N) or c orrect e d t o wit hi n n or mal 
li mits wit h s u p ple me nts pri or t o ra n d o mizati o n:  
•  P otassi u m ( p otassi u m i ncreas e of u p t o 6. 0 m m ol/ L is acce pt a ble if ass ociate d wit h 
creati ni ne cleara nce * wit hi n n or mal li mits)  
•  T otal calci u m (c orrecte d f or ser u m al b u mi n); (cal ci u m i ncrease of u p t o 1 2. 5 m g/ dl or 
3. 1 m m ol/ L is acce pta ble if ass ociate d wit h creati ni ne cleara nce * wit hi n n or mal li mits)  
•  Ma g nesi u m ( ma g nesi u m i ncreas e of u p t o 3. 0 m g/ d L or 1. 2 3 m m ol/ L if ass ociate d wit h 
creati ni ne cleara nce * wit hi n n or mal li mits)  
* Creati ni ne cleara n ce as calc ulate d usi n g C oc k cr oft -Ga ult f or m ula  
5. 2  
E x cl u si o n crit eri a  
Patie nts  meeti n g a n y of t he f oll o wi n g criteria are n ot eli gi ble f or i ncl usi o n i n t his st u d y.  
1. Treat me nt fail ure acc or di n g t o E ur o pea n L e u ke mia Net w or k criteria ( Baccara ni  et al 2 0 1 3 ) 
d uri n g i mati ni b treat me nt.  
•  after 3 m o nt hs of treat me nt n o C o m plete He mat ol o gic Res p o nse ( C H R) a n d/ or P h + > 
9 5 %  
•  after 6 m o nt hs of treat me nt B C R:: A B L 1 > 1 0 % a n d/ or P h + > 3 5 %  
•  after 1 2 m o nt hs of treat me nt B C R:: A B L 1 > 1 % a n d/ or P h + > 0  
•  at a n y ti me l oss of C H R, l oss of C C y R, c o nfir me d l oss of M M R *, m utati o ns, cl o nal 
c hr o m os o mal a b n or malities i n P h + cells ( C C A/ P h +)  
*I n 2 c o nsec uti ve t ests, of w hic h o ne wit h a B C R:: A B L le vel ≥1 %.  
2.  K n o w n sec o n d c hr o nic p hase of C M L aft er pre vi o us pr o gressi o n t o A P/ B C.  
3.  Pre vi o us treat me nt wit h a n y T KIs ot her t h a n i mati ni b.  
4.  Hist or y or c urre nt dia g n osis of E C G a b n or malities i n dicati n g si g nifica nt ris k or s afet y f or 
patie nts  partici pati n g i n t he st u d y s uc h as:  
•  Hist or y of m y ocar dial i nfarcti o n ( MI), a n gi na pect oris, c or o nar y art er y b y pass graft 
( C A B G) wit hi n 6 m o nt hs pri or t o ra n d o mizati o n 

N o v arti s  
C o nfi d e nti al  
P a g e 6 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
•  C o nc o mita nt cli nicall y si g nifica nt arr h yt h mias, e. g. s ustai ne d ve ntric ular t ac h ycar dia, 
a n d cli nicall y si g nifica nt sec o n d or t hir d de gree A V bl oc k wit h o ut a pace ma ker  
•  Resti n g Q Tc F ≥ 4 5 0 msec ( male) or ≥ 4 6 0 msec (fe male) pri or t o ra n d o mizati o n  
•  L o n g Q T s y n dr o me, fa mil y hist or y of i di o pat hic s u d de n deat h or c o n g e nital l o n g Q T 
s y n dr o me, or a n y of t h e f oll o wi n g:  
•  Ris k fact ors f or T orsa d es de P oi ntes i ncl u di n g u nc orrecte d h y p o kal e mia or 
h y p o ma g nese mia, 
hist or y 
of 
car di ac fail ure, 
or 
hist or y 
of 
cli nicall y 
si g nifica nt/s y m pt o matic bra d ycar dia 
•  C o nc o mita nt 
me dicati o ns wit h a " k n o w n" ris k of T orsa des de P oi nt es per 
cre di ble me ds. or g t hat ca n n ot be disc o nti n ue d or re place d b y safe alter nati ve 
me dicati o n   
•  i na bilit y t o deter mi ne t he Q Tc F i nter val 
5.  Se vere a n d/ or u nc o ntr olle d c o nc urre nt me dical disease t hat i n t he o pi ni o n of t he i n vesti gat or 
c o ul d ca use u nacce pta bl e safet y ris ks or c o m pr o mise c o m plia nce wit h t he pr ot oc ol (e. g. 
u nc o ntr olle d dia betes, acti ve or u nc o ntr olle d i nfecti o n, u nc o ntr olle d cli ni call y si g nifica nt 
h y perli pi de mia a n d hi g h ser u m a m ylase).  
6.  Hist or y of ac ute pa n creatitis wit hi n 1 year pri or t o ra n d o mizati o n or me dical hist or y of 
c hr o nic pa n creatitis.  
7.  a. Hist or y of c hr o ni c li ver disease or o n g oi n g ac ut e li ver disease.  
8.  Hist or y of ot her acti ve m ali g na nc y wit hi n 3 years pri or t o ra n d o mizati o n wit h t he e xce pti o n 
of basal c ell s ki n ca ncer, i n d ole nt pr ostate ca n cer a n d carci n o ma i n sit u treate d c urati vel y.  
9.  a. K n o w n hist or y of H u ma n I m m u n o deficie nc y Vir us ( HI V), c hr o nic He patitis B ( H B V), 
or c hr o nic H e patitis C ( H C V) i nfecti o n. Testi n g f or He p atitis B s urface a nti ge n ( H Bs A g), 
a n d He patitis B c ore a nti b o d y (a nti -H Bc) will be perf or me d at st u d y e ntr y. If H Bs A g or 
a nti-H Bc is p ositi ve, 
He patitis 
B s urface a nti b o d y (a nti -H Bs) a n d/ or  H B V -D N A 
meas ure me nt is rec o m me n de d t o c o nfir m ne g ati ve viral stat us.  
1 0.  I m pair me nt of gastr oi ntesti nal ( GI) f u ncti o n or GI dise ase t hat ma y si g nifica ntl y alter t he 
a bs or pti o n of st u d y dr u g (e. g. ul cerati ve diseas e, u nc o ntr olle d na us ea, v o miti n g, diarr hea, 
mala bs or pti o n s y n dr o me, s mall b o wel resecti o n, or gastric b y pass s ur g er y ).  
1 1.  a. Treat me nt wit h str o n g i n d ucers or i n hi bit ors of C Y P 3 A t hat ca n n ot be disc o nti n ue d or 
s witc he d t o a differe nt me dicati o n at least o n e wee k pri or t o t he start of tr eat me nt a n d f or 
t he d urati o n of t he st u d y. 
1 2.  Patie nts m ust a v oi d c o ns u m pti o n of gra pefr uit, S e ville ora n g es 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 wit h t he st u d y me dicati o ns . Ora n ge j uice 
is all o we d. 
1 3.  Hist or y of h y perse nsiti vit y t o a n y of t he st u d y treat me nts or its e xci pie nts or t o dr u gs of 
si milar c he mical classes. 
1 4.  Partici pati o n i n a pri or i n vesti gati o nal st u d y wit hi n 3 0 da ys pri or t o ra n d o mizati o n or wit hi n 
5 half -li ves of t he i n vesti gati o nal pr o d uct, w hic he ver is l o n ger. 
1 5.  c. (i) Pre g na nt or n ursi n g (lactati n g) w o me n.  

N o v arti s  
C o nfi d e nti al  
P a g e 6 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
(ii) 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 o gicall y ca pa bl e 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 
w hile ta ki n g st u d y treat me nt a n d f or 1 4 da ys  after st o p pi n g st u d y  me dicati o n i n 
treat me nt ar ms 1- 4, or f or 3 da ys after st o p pi n g asci mi ni b si n gle a ge nt tr eat me nt. If 
l ocal re g ulati o ns or l ocall y a p pr o ve d pres cri bi n g i nf or mati o n are m or e stri n ge nt t ha n 
t he pr ot oc ol re q uire d d urati o n of c o ntrace pti o n, t he l o n ger d urati o n m ust b e f oll o we d. 
Hi g hl y effecti ve c o ntrace pti o n met h o ds i ncl u de:  
•  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 us ual lifest yl e of t he 
s u bject. Peri o dic a bsti ne nce (e. g. cal e n dar, o v ulati o n, s y m pt ot her mal, p ost -
o v ulati o n met h o ds) a n d wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n.  
•  Fe male bilateral t u bal li gati 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 otal h ysterect o m y, 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 h e 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.  
•  Male sterilizati o n (at least 6 m o nt hs pri or t o scree ni n g). F or fe mal e patie nts  o n t he 
st u d y, t he vasect o mize d male part ner s h o ul d be t he s ole part ner f or t hat s u bject.  
•  Use of oral, (estr o ge n a n d pr o gester o n e), i njecte d or i m pla nte d h or m o nal met h o ds 
of c o ntrace pti o n or place me nt of a n i ntra uteri ne de vice (I U D) or i ntra uteri ne s yste m 
(I U S), or ot her f or ms of h or m o nal c o ntrace pti o n t hat ha ve c o m para ble efficac y 
(fail ure rate < 1 %), f or e xa m ple h or m o n e v a gi nal ri n g or tra ns d er mal h or m o ne 
c o ntrace pti o n.  
I n case of use of oral c o ntrace pti o n w o me n s h o ul d ha ve bee n sta ble o n t he sa me pill f or a 
mi ni m u m of 3 m o nt hs bef ore ta ki n g st u d y treat me nt.  
W o me n are c o nsi dere d p ost -me n o pa usal 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 wit h 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 y m pt o ms). 
W o me n are c o nsi dere d n ot of c hil d beari n g p ote ntial, if t he y are p ost -
me n o pa usal 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), 
t otal h ysterect o m y or bilateral t u bal li gati o n at least si x wee ks pri or t o e nr oll me nt o n st u d 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 dere d t o be n ot of c hil d 
beari n g p ote ntial.  
If l ocal re g ulati o ns are m ore stri n ge nt t ha n t he c o ntrace pti o n met h o ds liste d a b o ve t o 
pre ve nt pre g n a nc y, l ocal re g ulati o ns a p pl y a n d will be descri be d i n t he I nf or me d C o nse nt 
F or m (I C F).  
1 6.  Patie nts  w h o ha ve ac hie v e d dee p m olec ular res p o nse ( M R 4 I S), c o nfir m e d b y 2 c o nsec uti ve 
tests at a n y ti me d uri n g pri or i mati ni b treat me nt.  
N o a d diti o nal e xcl usi o ns ma y be a p plie d b y t he i n vesti gat or, i n or der t o e ns ure t hat t he st u d y 
p o p ulati o n will be re pres e ntati ve of all eli gi ble patie nts . 

N o v arti s  
C o nfi d e nti al  
P a g e 6 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
6  
Tr e at m e nt  
6. 1  
St u d y tr e at m e nt  
T he st u d y treat me nts are asci mi ni b ( 6 0 m g Q D), as ci mi ni b ( 4 0 m g Q D), asci mi ni b ( 8 0 m g Q D), 
i mati ni b ( 4 0 0 m g Q D) a n d nil oti ni b ( 3 0 0 m g BI D). N o vartis will s u p pl y all c o m p o u n ds t o t he 
i n vesti gati o nal sites: asci mi ni b as 4 0 m g a n d 2 0 m g ta blets, i mati ni b as 40 0 m g a n d 1 0 0 m g 
ta blets a n d nil oti ni b as 1 5 0 m g a n d 2 0 0 m g har d gelati n ca ps ules.  
6. 1. 1  
St u d y dr u g s  
T a bl e 6 -1  
St u d y dr u g  
Tr e at m e nt 
Titl e   
A s ci mi ni b 
( A B L 0 0 1)   2 0 
m g  
A s ci mi ni b 
( A B L 0 0 1)   
4 0 m g  
Gli v e c ®/ Gl e e v e c ® 
( S TI 5 7 1)             
1 0 0 m g a  
Gli v e c ®/ Gl e e v e c ® 
( S TI 5 7 1)         4 0 0 
m g  
T a si g n a ® 
( A M N 1 0 7) 
1 5 0 m g  
T a si g n a ® 
( A M N 1 0 7) 
2 0 0 m g b  
Tr e at m e nt 
D e s cri pti o n   
D o s e a n d tr e at m e nt s c h e d ul e ar e d e s cri b e d i n t h e T a bl e 6 -5  a n d all t h e i nf or m ati o n a b o ut t h e 
a d mi ni str ati o n of t h e st u d y dr u g ar e d e s cri b e d i n t h e  S e cti o n  6. 1. 3 . D o s e r e d u cti o n s c a n b e 
p erf or m e d a s d e s cri b e d i n T a bl e 6 -3   
T y p e    
Dr u g  
Dr u g  
Dr u g  
Dr u g  
Dr u g  
Dr u g  
D o s e 
F or m ul ati o n   
T a bl et  
T a bl et  
T a bl et  
T a bl et  
H ar d g el ati n 
c a p s ul e  
H ar d g el ati n 
c a p s ul e  
U nit D o s e 
Str e n gt h( s)   
2 0 m g  
4 0 m g  
1 0 0 m g  
4 0 0 m g  
1 5 0 m g  
2 0 0 m g  
D o s a g e 
L e v el( s)   
D o s e a m o u nt a n d fr e q u e n c y ar e m e nti o n e d i n S e cti o n 6. 7. 2  
R o ut e of 
A d mi ni str ati o n   
Or al  
Or al  
Or al   
Or al  
Or al  
Or al  
U s e   
E x p eri m e nt al  E x p eri m e nt al  E x p eri m e nt al  
E x p eri m e nt al  
E x p eri m e nt al  E x p eri m e nt al  
I M P  
Y e s   
Y e s   
Y e s   
Y e s  
Y e s  
Y e s  
S o ur ci n g   
Pr o vi d e d 
c e ntr all y b y 
t h e s p o n s or  
Pr o vi d e d 
c e ntr all y b y 
t h e s p o n s or 
Pr o vi d e d c e ntr all y 
b y t h e s p o n s or  
Pr o vi d e d c e ntr all y 
b y t h e s p o n s or  
Pr o vi d e d 
c e ntr all y b y 
t h e s p o n s or 
Pr o vi d e d 
c e ntr all y b y 
t h e s p o n s or 
P a c k a gi n g a n d 
L a b eli n g   
St u d y 
tr e at m e nt will 
b e pr o vi d e d i n 
a b ottl e. E a c h 
b ottl e will b e 
l a b el e d a s 
r e q uir e d p er 
c o u ntr y 
r e q uir e m e nt.  
St u d y 
tr e at m e nt will 
b e pr o vi d e d 
i n a b ottl e. 
E a c h b ottl e 
will b e 
l a b el e d a s 
r e q uir e d p er 
c o u ntr y 
r e q uir e m e nt.  
St u d y tr e at m e nt will 
b e pr o vi d e d i n a 
b ottl e. E a c h b ottl e 
will b e l a b el e d a s 
r e q uir e d p er c o u ntr y 
r e q uir e m e nt.  
St u d y tr e at m e nt will 
b e pr o vi d e d i n 
H D P E b ottl e. E a c h 
H D P E b ottl e will b e 
l a b el e d a s r e q uir e d 
p er c o u ntr y 
r e q uir e m e nt.  
St u d y 
tr e at m e nt will 
b e pr o vi d e d 
i n H D P E 
b ottl e. E a c h 
H D P E b ottl e 
will b e 
l a b el e d a s 
r e q uir e d p er 
c o u ntr y 
r e q uir e m e nt.  
St u d y 
tr e at m e nt will 
b e pr o vi d e d 
i n H D P E 
b ottl e. E a c h 
H D P E b ottl e 
will b e 
l a b el e d a s 
r e q uir e d p er 
c o u ntr y 
r e q uir e m e nt.  
6. 1. 2  
A d diti o n al st u d y tr e at m e nt s  
N o a d diti o nal treat me nt be y o n d i n vesti gati o nal dr u g a n d c o ntr ol dr u g are i ncl u de d i n t his trial.  

N o v arti s  
C o nfi d e nti al  
P a g e 6 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
6. 1. 3  
Tr e at m e nt ar m s/ gr o u p  
At Baseli ne, patie nts  will be ra n d o mize d t o o ne of t he f oll o wi n g 4 treat me nt ar ms: asci mi ni b 
6 0 m g + i mati ni b, asci mi ni b 4 0 m g + i mati ni b, i mati ni b, or nil oti ni b i n a rati o of 1: 1: 1: 1.  
Treat me nt ar m 1: Asci mi ni b 4 0 m g + i mati ni b ar m: asci mi ni b 4 0 m g a n d i mati ni b 4 0 0 m g will 
be a d mi nistere d orall y dail y o n a c o nti n u o us sc he d ule ( Q D).  
Treat me nt ar m 2: Asci mi ni b 6 0 m g + i mati ni b ar m: asci mi ni b 6 0 m g a n d i mati ni b 4 0 0 m g will 
be a d mi nistere d orall y dail y o n a c o nti n u o us sc he d ule ( Q D).  
Treat me nt ar m 3: I m ati ni b ar m: i mati ni b 4 0 0 m g will be a d mi nistere d orall y dail y o n a 
c o nti n u o us sc he d ule ( Q D).  
Treat me nt ar m 4: Nil oti ni b ar m: nil oti ni b will be a d mi nistere d orall y at 3 0 0 m g t wice dail y o n 
a c o nti n u o us sc he d ule ( BI D).  
Asci mi ni b si n gle a ge nt c o h ort: asci mi ni b 8 0 m g will be a d mi nistere d orall y o nce dail y o n a 
c o nti n u o us sc he d ule ( Q D).  
6. 1. 4  
G ui d eli n e s f or c o nti n u ati o n of tr e at m e nt  
Please refer t o Secti o n  6. 5. 1 . 
6. 1. 5  
Tr e at m e nt d ur ati o n  
Tr e at m e nt ar m s 1 -4  
All patie nts  will be gi ve n t he o p p ort u nit y t o recei ve st u d y tr eat me nt u ntil t he date t hat 
c orres p o n ds t o 9 6 wee ks after t he last ra n d o mize d s u bject recei ves t he first st u d y treat me nt d os e. 
Patie nts  ma y be disc o nti n ue d fr o m treat me nt at a n y ti me d ue t o u nacce pta ble t o xicit y, disease 
pr o gressi o n a n d/ or at t he discreti o n of t he i n vesti g at or or t he s u bject.  
A s ci mi ni b si n gl e a g e nt c o h ort  
All patie nts  will be gi ve n t he o p p ort u nit y t o recei ve st u d y tr eat me nt u ntil t he date t hat 
c orres p o n ds t o 4 8 w ee ks after t he last e nr olle d s u bject i n t he asci mi ni b si n gle a ge nt c o h ort 
recei v es t he first st u d y treat me nt d ose. Patie nts  ma y be disc o nti n ue d fr o m tr eat me nt at a n y ti me 
d ue t o u nacce pta ble t o xicit y, disease pr o gressi o n a n d/ or at t he discreti o n of t he i n vesti gat or or 
t he s u bject.  
6. 1. 5. 1  
Tr e at m e nt b e y o n d di s e a s e pr o gr e s si o n  
S h o ul d a disease pr o gressi o n occ ur d uri n g st u d y, t he s u bject m ust be disc o nti n ue d a n d ca n be 
treate d at i n vesti gat or’s discreti o n o utsi de of t he st u d y. 

N o v arti s  
C o nfi d e nti al  
P a g e 6 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
6. 2  
Ot h er tr e at m e nt( s)  
6. 2. 1  
C o n c o mit a nt t h er a p y  
I n g e neral, c o nc o mita nt me dicati o ns a n d t hera pies dee me d necessar y f or t he s u p p orti ve car e 
a n d safet y of t he s u bject are all o we d, pr o vi de d t h eir use is d oc u me nte d i n t he s u bject rec or ds 
a n d o n t he a p pr o priate electr o nic case re p ort f or m (e C R F), i ncl u di n g t he m e dicati o n’s d urati o n 
(start a n d e n d d ates or if c o nti n ui n g at fi nal e xa m). T hese i ncl u de bl o o d a n d platelet tra nsf usi o ns 
f or patie nts  wit h a ne mia a n d wit h t hr o m b oc yt o pe nia.  
All me dicati o ns, pr oce d ures a n d si g nifica nt n o n -dr u g t hera pies (i ncl u di n g p h ysical t hera p y a n d 
bl o o d tra nsf usi o ns) a d mi nistere d after t he s u bject was e nr olle d i nt o t he st u d y m ust be rec or de d 
i n t he c o nc o mita nt me dicati o ns/si g nifica nt n o n-dr u g t hera pies sec ti o n of t he e C R F. 
All pri or a nti ne o plastic s ur ger y, c h e m ot hera p y, bi ol o gic, i m m u n ol o gic a n d ra diati o n t hera p y 
m ust be rec or de d i n t he “ Pri or a nti ne o plastic t hera p y” secti o n of t he e C R F.  
Eac h c o nc o mita nt dr u g m ust be i n di vi d uall y assesse d a gai nst all e xcl usi o n criteria/ pr o hi bite d 
me dicati o n. If i n d o u bt t he i n vesti gat or s h o ul d c o ntact t he N o vartis me dical m o nit or bef ore 
ra n d o mizi n g a s u bject or all o wi n g a ne w me dicati o n t o be starte d. If th e s u bject is alrea d y 
e nr olle d, c o ntact N o v artis t o deter mi ne if t he s u bject s h o ul d c o nti n ue partici pati o n i n t he st u d y.  
H or m o nal c o ntr ace pti ves are all o we d as c o ntr ace pti o n met h o ds. Hi g hl y effecti ve c o ntrace pti o n 
s h o ul d be mai ntai ne d t hr o u g h o ut t he st u d y a n d f or 1 4 da ys after st u d y treat me nt disc o nti n uati o n.  
6. 2. 1. 1  
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 cti o n  
6. 2. 1. 1. 1  P er mitt e d c o n c o mit a nt m e di c ati o n r e q uiri n g c a uti o n f or a s ci mi ni b 
c o m bi n ati o n s a n d a s ci mi ni b si n gl e a g e nt c o h ort  
Base d u p o n t he cli nical h u ma n A D M E data a n d ali g n me nt wit h t he i n vitr o h u ma n he pat oc yte 
cleara nce a n d e nz y m e reacti o n p he n ot y pi n g st u dies, t he relati ve c o ntri b uti o n of C Y P - a n d 
U G T -me diate d asci mi ni b cleara nce was esti mate d t o be 3 6. 6 a n d 5 8. 3 %, res pecti vel y.  
Str o n g I n hi bit ors of C Y P 3 A 4 w he n gi ve n t o patie nts bei n g treate d wit h asci mi ni b i n 
c o m bi nati o n wit h i mati ni b ha ve t he p ot e ntial t o i ncrease asci mi ni b a n d i mati ni b c o nce ntr ati o ns. 
T heref ore, str o n g C Y P 3 A 4 i n hi bit ors s h o ul d be use d wit h ca uti o n i n patie nts b ei n g treate d wit h 
asci mi ni b i n c o m bi nati o n wit h i mati ni b.  
I n d u cers of C Y P 3 A 4 ha v e t he p ote ntial t o decreas e asci mi ni b c o nce ntr ati o ns. T heref ore, str o n g 
C Y P 3 A 4 i n d ucers s h o ul d be use d wit h ca uti o n i n patie nts bei n g treate d wit h asci mi ni b si n gle 
a ge nt. Base d o n cli nical data a vaila ble, C Y P 3 A 4/ 5 a n d C Y P 2 C 9 s u bstrate s wit h narr o w 
t hera pe utic i n de x s h o ul d be use d wit h ca uti o n. 
Use of a nti -e metics is all o we d. Pr o p h ylactic a nti -e metics s h o ul d be starte d o nl y o nce t he s u bject 
e x perie n ces na usea or v o miti n g, at t he discreti o n of t he i n vesti gat or. It is rec o m me n de d t hat 
patie nts  use dr u gs t hat d o n ot ca use Q T pr ol o n gati o n.  
All a ntic oa g ula nts or a nti -a g gre g ati o n a ge nts m a y be a d mi nistere d u n der t he discreti o n of t he 
i n vesti gat or. 

N o v arti s  
C o nfi d e nti al  
P a g e 7 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
T hera p e utic d oses of 
warfari n s o di u m ( C o u ma di n ® ) or a n y ot her c o u mari n-deri vati v e 
a ntic oa g ula nts s h o ul d b e use d wit h ca uti o n a n d f ull y a v oi de d w he ne v er p ossi ble beca us e of its 
k n o w n i nteracti o n wit h ma n y c o m m o nl y use d me dicati o ns a n d certai n f o o ds. As warfari n has 
a narr o w t hera pe utic ra n ge, a n d asci mi ni b is p ossi bl y a n i n hi bit or of C Y P 2 C 9, t he maj or 
meta b olizi n g e nz y me of S -warfari n ( R -warfari n is meta b olize d b y m ulti ple C Y P e nz y mes), 
warfari n s h o ul d be caref ull y m o nit ore d w he ne ver use d.  
Ca uti o n is als o a d vise d w he n asci mi ni b is c o -a d mi nistere d wit h a nti -platelet pr o -dr u gs s uc h as 
cl o pi d o grel, ticl o pi di ne a n d pras u grel, w hic h re q uire meta b olic acti vati o n b y C Y P 3 A 4 a n d 
C Y P 2 C 9. 
W hile t he i n viv o p ote ntial of asci mi ni b t o i nteract wit h se nsiti ve C Y P 3 A 4 a n d 
C Y P 2 C 9 s u bstrates has bee n e val u ate d b y P B P K m o deli n g a n d i n dicates a mi ni mal or 
ne gli gi ble ris k, patie nts  usi n g a nti -platelet pr o -dr u gs s h o ul d still be caref ull y m o nit ore d.  
S u bstrates of O A T P 1 B, B C R P or b ot h tra ns p orters, i ncl u di n g, b ut n ot li mite d t o s ulfasalazi n e, 
met h otre xate, pra v astati n, at or vastati n, pita vastati n, r os u vastati n a n d si m vastati n s h o ul d be use d 
wit h ca uti o n. Refer t o O A T P 1 B a n d B C R P s u bstrates’ d ose re d ucti o ns, as rec o m me n de d i n 
t heir prescri bi n g i nf or m ati o n. As far as p ossi ble a v oi d c o -a d mi nisteri n g r os u vastati n a n d 
c o nsi der alter nati ve stati ns. If d uri n g t he st u d y c o -a d mi nistrati o n of r os u vastati n is re q uire d, 
t he n t he d ose of r os u vastati n s h o ul d be re d uced, as rec o m me n de d i n its prescri bi n g i nf or mati o n.   
Ca uti o n s h o ul d be e x ercise d d uri n g c o nc o mita nt a d mi nistrati o n of asci mi ni b at all 
rec o m me n de d d os es wit h P-g p s u bstrates k n o w n t o ha ve a narr o w t hera pe utic i n de x, i ncl u di n g 
b ut n ot li mite d t o di g o xi n, da bi gatra n, a n d c olc hici ne.  Refer t o Secti o n 1 6. 3  f or m ore det ails. 
Direct t hr o m bi n i n hi bit ors ( D TIs) a n d Fact or Xa i n hi bit ors are all o we d as a ntic o a g ula nts. 
I n di vi d ual me dicati o ns fr o m eac h of t h e classes s h o ul d be c hec k e d if t he y are n ot pr o hi bite d 
d ue t o ot her dr u g -dr u g i nteracti o ns wit h asci mi ni b. Alter nati vel y, t hera p e utic a ntic oa g ulati o n 
ma y be acc o m plis he d usi n g l o w -m olec ular wei g ht he pari n.  
Q T pr ol o n gi n g a g e nt s  
As far as p ossi ble a v oi d c o -a d mi nistrati o n of dr u gs wit h a " k n o w n" ris k of T orsa des de P oi ntes 
( T d P) d uri n g t he c o urs e of t he st u d y. 
If c o n c 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 bas e d o n t h e 
i n vesti gat or assess me nt a n d cli nical nee d, st u d y tr eat me nt ma y b e c o nti n ue d u n der cl ose E C G 
m o nit ori n g t o e ns ure s u bject’s safet y.  
A list 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 at 
//cre di ble me ds. or g/. 
Please refer t o Secti o n 1 6. 3  f or m ore  det ails.  
6. 2. 1. 1. 2  P er mitt e d c o n c o mit a nt m e di c ati o n r e q uiri n g c a uti o n f or i m ati ni b c o nti n u ati o n 
ar m a n d nil oti ni b ar m  
Nil oti ni b a n d i mati ni b s h o ul d be a d mi nistere d acc or di n g t o t he l ocall y a p pr o ve d pr o d uct 
i nf or mati o n. 

N o v arti s  
C o nfi d e nti al  
P a g e 7 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
6. 2. 2  
Pr o hi bit e d m e di c ati o n  
T he c o nc o mita nt a d mi nistrati o n of ot her i n vesti gati o nal dr u gs is n ot all o we d. 
T he 
a d mi nistrati o n of a n y ot her a ntica ncer a ge nts i ncl u di n g c he m ot hera p y a n d bi ol o gic a ge nts is 
n ot per mitte d e xce pt f or a nti -ca ncer tr eat me nts of ne wl y dia g n ose d s oli d ca ncers ( e. g. pr ostat e 
ca ncer) t hat w o ul d n ot i m pact t he le vel of mi ni mal resi d ual dis ease of p atie nts . T hese patie nts  
ma y re mai n i n st u d y after c o ns ultati o n wit h N o vartis. T he a d mi nistrati o n of ot her t yr osi ne 
ki nase i n hi bit ors i n dicate d f or treat me nt of P h + C M L is  n ot all o we d.  
Use of t he tr eat me nts dis pla ye d i n t he b el o w s ecti o ns are n ot all o we d after start of st u d y 
treat me nt. 
Please refer t o Secti o n 1 6. 3  f or m ore det ails. 
6. 2. 2. 1  
Pr o hi bit e d m e di c ati o n f or a s ci mi ni b c o m bi n ati o n ar m s  
Str o n g C Y P 3 A 4/ 5 i n d ucers  
E ver y eff ort s h o ul d be ma de N O T t o c o nc o mita ntl y a d mi nister str o n g C Y P 3 A 4/ 5 i n d ucers 
(Secti o n 1 6. 3 ). C Y P 3 A 4/ 5 i n d ucers ha v e t he p ote ntial t o re d uce asci mi ni b a n d i mati ni b 
c o nce ntr ati o ns. If a d mi nistrati o n of a str o n g C Y P 3 A 4/ 5 i n d ucer ca n n ot be a v oi de d i n t he 
c o m bi nati o n ar ms d uri n g t he st u d y a n d ca n n ot b e s witc he d t o a n alter nati ve t hera p y, te m p orar y 
d isc o nti n uati o n of st u d y treat me nt is N O T nee de d.  
H er b al m e di c ati o n s  
Her bal pre parati o ns/ me dicati o ns are n ot all o we d t hr o u g h o ut t he st u d y. T hese h er bal 
me dicati o ns 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 her bal m e dicati o ns 7 da ys pri or t o first d ose of st u d y dr u g.  
Gra pefr uit a n d gra pefr uit pr o d ucts are pr o hi bite d.  
6. 2. 2. 2  
Pr o hi bit e d c o n c o mit a nt m e di c ati o n f or i m ati ni b c o nti n u ati o n ar m  
I mati ni b s h o ul d be a d mi nistere d acc or di n g t o t he l ocall y a p pr o ve d pr o d uct i nf or mati o n. 
I n a d diti o n, t he f oll o wi n g a p plies: 
•  E ver y eff ort s h o ul d be 
ma de 
N O T t o a d mi nister str o n g 
C Y P 3 A 4 i n hi bit ors. If 
a d mi nistrati o n of a str o n g C Y P 3 A 4 i n hi bit or ca n n ot be a v oi de d d uri n g t he st u d y a n d ca n n ot 
be s witc he d t o a n alter nati ve t hera p y, st u d y treat me nt m ust be S T O P P E D.  
•  E ver y eff ort s h o ul d b e ma de N O T t o a d mi nister str o n g C Y P 3 A 4 i n d ucers h o we v er, if 
a d mi nistrati o n of a C Y P 3 A 4 i n d ucer ca n n ot be a v oi de d d uri n g t he st u d y, te m p orar y 
disc o nti n uati o n of st u d y treat me nt is N O T re q uire d.  
6. 2. 2. 3  
Pr o hi bit e d c o n c o mit a nt m e di c ati o n f or nil oti ni b tr e at m e nt ar m  
Nil oti ni b s h o ul d be a d mi nistere d acc or di n g t o t he l ocall y a p pr o ve d pr o d uct i nf or m ati o n. 
F urt her m ore, t he f oll o wi n g a p plies:  

N o v arti s  
C o nfi d e nti al  
P a g e 7 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
E ver y eff ort s h o ul d be ma de N O T t o a d mi nister str o n g C Y P 3 A 4 i n hi bit ors. If a d mi nistrati o n of 
a str o n g C Y P 3 A 4 i n hi bit or ca n n ot b e a v oi d e d d uri n g t he st u d y a n d ca n n ot be s witc he d t o a n 
alter nati ve t hera p y, st u d y treat me nt m ust be S T O P P E D.  
E ver y eff ort s h o ul d be ma de N O T t o a d mi nister str o n g C Y P 3 A 4 i n d ucers h o we v er, if 
a d mi nistrati o n of a C Y P 3 A 4 i n d ucer ca n n ot be a v oi de d d uri n g t he st u d y, te m p orar y 
disc o nti n uati o n of st u d y treat me nt is N O T re q uire d.  
W he ne v er a v oi d c o -a d mi nisteri n g dr u gs wit h a “ K n o w n”, “ P ossi ble” or “ C o n diti o nal” ris k of 
T orsa des de P oi nte ( per cre di ble me ds. or g) d uri n g t he c o urse of t he st u d y:  
•  If c o n c 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 ors a d es de P oi nte” is 
re q uire d a n d ca n n ot be a v oi de d, st u d y dr u g m ust be i nterr u pte d. If, base d o n t he i n vesti gat or 
assess me nt a n d cli nical n ee d, st u d y tr eat me nt is res u me d, cl ose E C G m o nit ori n g is a d vise 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 ris k of T orsa des de P oi nte” 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 c o nti n ue d u n der cl os e E C G m o nit ori n g t o e ns ure 
s u bject safet y. 
A list of dr u gs ass ociate d wit h Q T pr ol o n gati o n a n d/ or T orsa d es de P oi nte is a vaila ble o nli n e 
at qt dr u gs. or g.  
If a me dicati o n liste d i n Secti o n  1 6  a p pears o n b ot h t he list of pr o hi bite d a n d t he list of 
me dicati o ns t o be use d wit h ca uti o n, t he me dicati o n is pr o hi bite d.  
6. 3  
S u bj e ct n u m b eri n g, tr e at m e nt a s si g n m e nt, r a n d o mi z ati o n  
6. 3. 1  
S u bj e ct n u m b eri n g  
Eac h s u bject is i de ntifie d i n t he st u d y b y a S u bject N u m ber ( S u bject N o.), t hat is assi g ne d w he n 
t he s u bject 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 s u bject 
t hr o u g h o ut his/ her e ntire partici p ati o n i n t he tri al. 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 s u bject 
n u m ber s uffi xe d t o it, s o t hat eac h s u bject is n u m bere d u ni q uel y acr oss t he e ntire data base. 
U p o n si g ni n g t he i nf or me d c o n se nt f or m, t he s u bject is assi g ne d t o t he ne xt se q ue ntial S u bject 
N o. a vaila ble.  
O nce t he s u bject n u m ber is assi g ne d, it ca n n ot be re use d f or a n y ot her s u bject.  
6. 3. 2  
Tr e at m e nt a s si g n m e nt, r a n d o mi z ati o n  
Patie nts  will be assi g ne d t o o ne of t he 4 ra n d o mize d treat me nt ar ms ( Secti o n  3 ) i n a rati o of 
1: 1: 1: 1.  
At visit “ baseli ne”, all eli gi ble patie nts  will be ra n d o mize d via I nteracti ve Res p o nse Tec h n ol o g y 
(I R T) t o o ne of t he treat me nt ar ms. T he i n vesti gat or or his/ her dele gate will c o ntact t he I R T 
after c o nfir mi n g t h at t he s u bject f ulfills all t he i ncl usi o n/e xcl usi o n criteria. T he I R T will assi g n 
a ra nd o mizati o n n u m ber t o t he s u bject, w hic h will be use d t o li n k t he s u bject t o a treat me nt ar m 
a n d will s pecif y a u ni q ue me dicati o n n u m ber f or t he first pac ka ge of st u d y treat me nt t o be 
dis pe nse d t o t he s u bject.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
T he ra n d o mizati o n n u m bers will be ge nerate d usi n g t he f oll o wi n g ce ntralize d pr oce d ure t o 
e ns ure t hat treat me nt assi g n me nt is u n biase d a n d c o nceale d fr o m p atie nts  a n d i n vesti gat or staff. 
A s u bject ra n d o mizati o n list will be pr o d uce d b y t he I R T pr o vi der usi n g a v ali date d s yste m t hat 
a ut o mates t he ra n d o m assi g n me nt of s u bject n u m bers t o ra n d o mizati o n n u m bers. T hese 
ra n d o mizati o n n u m bers are li n ke d t o t he differe nt treat me nt ar ms, w hic h i n t ur n are li n ke d t o 
me dicati o n n u m bers. A s e parat e me dicati o n list will b e pr o d uce d b y or u n d er t he res p o nsi bilit y 
of N o vartis Dr u g S u p pl y Ma na ge me nt usi n g a vali date d s yste m t hat a ut o mates t he ra n d o m 
assi g n me nt of me dicati o n n u m bers t o pac ks c o ntai ni n g t he st u d y treat me nt.  
T he ra n d o mizati o n sc he me f or patie nts  will be re vie we d a n d a p pr o ve d b y a me m ber of t he 
Ra n d o mizati o n Office.  
6. 3. 3  
Tr e at m e nt a s si g n m e nt f or a s ci mi ni b si n gl e a g e nt c o h ort  
Patie nts  will be e nr olle d i n asci mi ni b si n gle a ge nt c o h ort wit h o ut ra n d o mizati o n. T he I R T will 
assi g n a n u m ber t o t he s u bject, w hic h will be use d t o li n k t he s u bject t o t he treat me nt ar m a n d 
will s pecif y a u ni q ue me dicati o n n u m ber f or t he first pac ka ge of st u d y tr eat me nt t o be dis pe nse d 
t o t he s u bject. 
6. 4  
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  
D o s e e s c al ati o n a n d d o s e m o difi c ati o n  
D ose escalati o n is n ot a p plica ble. F or d ose re -es calati o n f oll o wi n g d ose re d u cti o n or 
i nterr u pti o n, please refer t o Secti o n  6. 5. 1 . 
6. 5. 1  
D o s e m o difi c ati o n s  
6. 5. 1. 1  
Crit eri a f or d o s e r e d u cti o n/i nt err u pti o n a n d r e -i niti ati o n of st u d y 
tr e at m e nt f or a d v er s e dr u g r e a cti o n s i n a s ci mi ni b + i m ati ni b ar m 
F or patie nts  w h o d o n ot t olerate t he pr ot oc ol -s p ecifie d d osi n g sc he d ule, d ose i nterr u pti o ns 
a n d/ or re d u cti o ns are eit her rec o m me n de d or m a n date d i n or der t o all o w patie nts  t o c o nti n ue 
t he st u d y treat me nt. 
If a s u bject re q uir es a d ose i nterr u pti o n of > 2 8 d a ys f or a n o n-he m at ol o gic t o xicit y, t he n t he 
s u bject m ust be disc o nti n ue d fr o m t he st u d y treat me nt, u nl ess ot her wise s pecifi e d. If a 
he mat ol o gic t o xicit y (c yt o pe nia Gra de 3 or 4) lasts f or m ore t ha n 4 2 da y s wit h o ut rec o ver y t o 
at least a Gra de 2, des pite T KI i nterr u pti o n a n d a de q uate ma na g e me nt (i n cl u di n g he mat o p oietic 
gr o wt h fact ors), t he n t he patie nt m ust be disc o nti n ue d fr o m t he st u d y treat me nt.  A s u bject m ust 
disc o nti n ue treat me nt if, after treat me nt is  res u me d at a l o wer d ose, t he t o xicit y rec urs wit h t he 
sa me or w ors e se verit y, e xce pt f or rec urre n ce of c yt o pe nias ( See Ta bl e 6 -2 ).  
T hese d ose m o dificati o ns are s u m marize d i n Ta ble 6 -2 . De viati o ns t o ma n dat or y d ose 
i nterr u pti o ns a n d/ or re d ucti o ns are n ot all o we d. Per ma ne nt treat me nt disc o nti n uati o n is 
ma n dat or y f or s p ecific e ve nts i n dicate d as s uc h i n Ta ble 6 -2  . 
T hese d ose c h a n ges m ust be rec or de d o n t he a p pr o priate C R F.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
T he f oll o wi n g criteri a a p pl y t o patie nts  u n der asci mi ni b + i mati ni b treat me nt.  
T a bl e 6 -2  
Crit eri a f or d o s e r e d u cti o n/i nt err u pti o n a n d r e -i niti ati o n of a s ci mi ni b + 
i m ati ni b, or a s ci mi ni b si n gl e a g e nt tr e at m e nt f or a d v er s e dr u g 
r e a cti o n s 
D o s e m o difi c ati o n s f or a s ci mi ni b + i m ati ni b a n d a s ci mi ni b si n gl e a g e nt  
W or st t o xi cit y a s p er  
C T C A E v er si o n  5. 0 a  
d uri n g tr e at m e nt  
  
I n v e sti g ati o n s ( H e m at ol o gi c) 
H e m at ol o gi c t o xi citi e s  
If a h e m at ol o gi c t o xi cit y ( c yt o p e ni a Gr a d e 3 or 4) l a st s f or m or e t h a n 4 2 d a y s wit h o ut r e c o v er y t o at l e a st a 
Gr a d e 2, d e s pit e T KI i nt err u pti o n a n d a d e q u at e m a n a g e m e nt (i n cl u di n g h e m at o p oi eti c gr o wt h f a ct or s), t h e n t h e 
p ati e nt m u st b e di s c o nti n u e d fr o m t h e st u d y tr e at m e nt.  
Gr a d e 1  
R e c o m m e n d ati o n : m ai nt ai n d o s e l e v el 
Gr a d e 2  
R e c o m m e n d ati o n : m ai nt ai n d o s e l e v el  
Gr a d e 3  
M a n d at or y : H ol d d o s e u ntil r e s ol v e d t o ≤ Gr a d e 2 (r e c h e c k C B C ( C o m pl et e Bl o o d 
C o u nt) 2 x/ w e e k), t h e n:  
If r e s ol v e d i n ≤ 1 4 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 > 1 4 d a y s, t h e n r e d u c e d o s e ↓ 1 d o s e l e v el 
Gr a d e 4  
M a n d at or y : H ol d d o s e u ntil r e s ol v e d t o ≤ Gr a d e 2 (r e c h e c k C B C 2 x/ w e e k), t h e n:  
If r e s ol v e d i n ≤ 1 4 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 > 1 4 d a y s, t h e n r e d u c e d o s e ↓ 1 d o s e l e v el 
R e c urr e n c e of all 
c yt o p e ni a s  
R e c o m m e n d ati o n:  H ol d d o s e u ntil r e s ol v e d t o ≤ Gr a d e 2, t h e n m ai nt ai n c urr e nt 
d o s e l e v el.  
F or r e c urr e nt Gr a d e 3 -4 c yt o p e ni a s:  
If r e s ol v e d t o ≤ Gr a d e 2 i n ≤ 1 4 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 > 1 4 d a y s, t h e n r e d u c e d o s e ↓ 1 d o s e l e v el 
N o n -h e m at ol o gi c a d v er s e r e a cti o n s e x c e pt w h er e f urt h er s p e cifi e d i n i n di vi d u al s e cti o n s  
If a s u bj e ct r e q uir e s a d o s e i nt err u pti o n of > 2 8 d a y s f or a n o n-h e m at ol o gi c t o xi cit y, t h e n t h e s u bj e ct m u st b e 
di s c o nti n u e d fr o m t h e st u d y tr e at m e nt, u nl e s s ot h er wi s e s p e cifi e d.  
Gr a d e 1  
R e c o m m e n d ati o n : M ai nt ai n d o s e l e v el 
Gr a d e 2  
R e c o m m e n d ati o n : H ol d d o s e u ntil r e s ol v e d t o ≤ Gr a d e 1, t h e n m ai nt ai n d o s e l e v el  
Gr a d e 3  
M a n d at or y:  H ol d d o s e ( m a x 2 8 d a y s) u ntil r e s ol v e d t o ≤ Gr a d e 1 t h e n r e s u m e at ↓ 1 
d o s e l e v el  
Gr a d e 4  
M a n d at or y : P er m a n e ntl y di s c o nti n u e s u bj e ct fr o m st u d y dr u g tr e at m e nt 
I n v e sti g ati o n s ( H e p ati c)  
C o m bi n e d c  el e v ati o n s of A S T or A L T a n d t ot al bilir u bi n  
F or p ati e nt s  wit h 
n or m al b a s eli n e A L T 
a n d A S T a n d t ot al 
bilir u bi n v al u e:  
A S T or A L T > 3. 0 x 
U L N c o m bi n e d wit h 
t ot al bilir u bi n > 2. 0 x 
U L N wit h o ut e vi d e n c e 
of c h ol e st a si s d  
F or p ati e nt s  wit h 
el e v at e d b a s eli n e A S T 
M a n d at or y : P er m a n e ntl y di s c o nti n u e s u bj e ct fr o m tr e at m e nt. 
R e p e at a s s o o n a s p o s si bl e, pr ef er a bl y wit hi n 4 8 h o ur s fr o m a w ar e n e s s of t h e 
a b n or m al r e s ult s, t h e n wit h w e e kl y m o nit ori n g of li v er t e st sb , or m or e fr e q u e ntl y if 
cli ni c all y i n di c at e d, u ntil A S T, A L T, or bilir u bi n h a v e r e s ol v e d t o b a s eli n e or 
st a bili z ati o n o v er 4 w e e k s. R ef er t o t h e S e cti o n  6. 5. 2  f or a d diti o n al f oll o w-u p 
e v al u ati o n s a s a p pli c a bl e.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
or A L T or t ot al bilir u bi n 
v al u e  
[ A S T or A L T > 2 x 
b a s eli n e A N D > 3. 0 
x U L N]  
I s ol at e d A S T or A L T el e v ati o n 
> U L N - 3. 0 x U L N  
R e c o m m e n d ati o n:  M ai nt ai n d o s e l e v el  
R e p e at li v er t e st s wit hi n 4 8 - 7 2 h o ur s, t h e n m o nit or w e e kl y u ntil r e c o v er y t o ≤Gr a d e 
1 or t o b a s eli n e  
> 3. 0 - 5. 0 x U L N  
R e c o m m e n d ati o n:  M ai nt ai n d o s e l e v el. R e p e at li v er t e st sb  a s s o o n a s p o s si bl e, 
pr ef er a bl y wit hi n 4 8 -7 2 h o ur s fr o m a w ar e n e s s of t h e a b n or m al r e s ult s;  
if a b n or m al l a b v al u e s ar e c o nfir m e d u p o n t h e r e p e at t e st, t h e n m o nit or li v er t e st sb  
w e e kl y, or m or e fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤ 3. 0 x U L N  
> 5. 0 - 1 0. 0 x U L N  
M a n d at or y:  H ol d d o s e. R e p e at li v er t e st s b a s s o o n a s p o s si bl e, pr ef er a bl y wit hi n 4 8 -
7 2 h o ur s fr o m a w ar e n e s s of t h e a b n or m al r e s ult s; m o nit or li v er t e st sb  w e e kl y, or 
m or e fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤ 3. 0 x U L N: T h e n  
If r e s ol v e d i n ≤ 1 4 d a y s, r e s u m e at pri or d o s e l e v el  
If r e s ol v e d i n > 1 4 d a y s, r e s u m e wit h r e d u c ed  d o s e ↓ 1 d o s e l e v el  
> 1 0. 0 - 2 0. 0 x U L N  
M a n d at or y:  H ol d d o s e. R e p e at li v er t e st s b a s s o o n a s p o s si bl e, pr ef er a bl y wit hi n 4 8 -
7 2 h o ur s fr o m a w ar e n e s s of t h e a b n or m al r e s ult s; m o nit or li v er t e st sb  w e e kl y, or 
m or e fr e q u e ntl y if cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤ 3. 0 x U L N . T h e n r e s u m e 
wit h r e d u c ed  d o s e ↓ 1 d o s e l e v el.  
> 2 0. 0 x U L N  
M a n d at or y: P er m a n e ntl y di s c o nti n u e  
I s ol at e d t ot al Bilir u bi n el e v ati o n 
> U L N –  1. 5 x U L N  
irr e s p e cti v e of b a s eli n e 
l e v el s 
R e c o m m e n d ati o n:  M ai nt ai n d o s e l e v el  
> 1. 5 - 3. 0 x U L N  
irr e s p e cti v e of b a s eli n e 
l e v el s 
R e c o m m e n d ati o n:  H ol d d o s e.  
M o nit or li v er t e st sb  wit hi n 4 8 -7 2  h o ur s, t h e n  w e e kl y, or m or e fr e q u e ntl y if cli ni c all y 
i n di c at e d, u ntil r e s ol v e d t o ≤ 1. 5 x U L N:  
If r e s ol v e d i n ≤ 1 4 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 > 1 4 d a y s, t h e n r e d u c e d o s e ↓ 1 d o s e l e v el 
> 3. 0 - 1 0. 0 x U L N*  
irr e s p e cti v e of b a s eli n e 
l e v el s 
M a n d at or y:  H ol d d o s e.  
M o nit or  li v er t e st sb  wit hi n 4 8 -7 2 h o ur s, t h e n m o nit or  w e e kl y, or m or e fr e q u e ntl y if 
cli ni c all y i n di c at e d, u ntil r e s ol v e d t o ≤ 1. 5 x U L N  or b a s eli n e :  
If r e s ol v e d i n ≤ 1 4 d a y s, t h e n r e d u c e d o s e ↓1 d o s e l e v el  
If r e s ol v e d i n > 1 4 d a y s, t h e n di s c o nti n u e p ati e nt fr o m st u d y dr u g tr e at m e nt.  
T h e p ati e nt s h o ul d b e m o nit or e d w e e kl y (i n cl u di n g  li v er t e st sb ), or m or e fr e q u e ntl y if 
cli ni c all y i n di c at e d, u ntil t ot al bilir u bi n h a v e r e s ol v e d t o b a s eli n e or st a bili z ati o n o v er 
4 w e e k s  
> 1 0. 0 x U L N*  
irr e s p e cti v e of b a s eli n e 
l e v el s 
M a n d at or y:  P er m a n e ntl y di s c o nti n u e p ati e nt fr o m st u d y dr u g tr e at m e nt.  
T h e p ati e nt s h o ul d b e m o nit or e d w e e kl y (i n cl u di n g li v er t e st sb ), or m or e fr e q u e ntl y if 
cli ni c all y i n di c at e d, u ntil t ot al bilir u bi n h a v e r e s ol v e d t o b a s eli n e or st a bili z ati o n o v er 
4 w e e k s.  
I n v e sti g ati o n s ( R e n al) 
S er u m cr e ati ni n e  
Gr a d e 1 ( > U L N - 1. 5 x 
U L N)  
R e c o m m e n d ati o n:  M ai nt ai n d o s e l e v el  
Gr a d e 2 ( > 1. 5 - 3. 0 x 
U L N)  
R e c o m m e n d ati o n:  H ol d d o s e u ntil r e s ol v e d t o ≤ Gr a d e 1 or b a s eli n e, t h e n m ai nt ai n 
d o s e l e v el  

N o v arti s  
C o nfi d e nti al  
P a g e 7 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
Gr a d e 3 ( > 3. 0 - 6. 0 x 
U L N)  
M a n d at or y:  P er m a n e ntl y di s c o nti n u e p ati e nt fr o m st u d y dr u g tr e at m e nt.  
Gr a d e 4 ( > 6. 0 x U L N)  
M a n d at or y:  P er m a n e ntl y di s c o nti n u e p ati e nt fr o m st u d y dr u g tr e at m e nt.  
I n v e sti g ati o n ( m et a b oli c) 
A s y m pt o m ati c a m yl a s e a n d/ or li p a s e el e v ati o n  
> U L N - 1. 5 x U L N  
R e c o m m e n d ati o n:  M ai nt ai n d o s e l e v el, m e a s ur e 2 x w e e k  
> 1. 5 - 2. 0 x U L N  
R e c o m m e n d ati o n:  M ai nt ai n d o s e l e v el, m e a s ur e 2 x w e e k  
> 2. 0 - 5. 0 x U L N  
M a n d at or y:  H ol d d o s e u ntil r e s ol v e d t o < 1. 5 x U L N : 
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 d o s e ↓ 1 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 di s c o nti n u e tr e at m e nt a n d o bt ai n a p pr o pri at e i m a gi n g 
(i. e., M RI, C T s c a n or ultr a s o u n d). 
> 5. 0 x U L N  
M a n d at or y:  H ol d d o s e u ntil r e s ol v e d t o ≤ 1. 5 x U L N or b a s eli n e: 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 d o s e ↓ 1 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 di s c o nti n u e 
tr e at m e nt a n d o bt ai n a p pr o pri at e i m a gi n g (i. e., M a g n eti c r e s o n a n c e i m a gi n g ( M RI ), 
C T s c a n or ultr a s o u n d).  
> 5. 0 x U L N  a n d wit h 
si g n s a n d s y m pt o m s   
M a n d at or y: P er m a n e ntl y di s c o nti n u e p arti ci p a nt fr o m st u d y tr e at m e nt. O bt ai n 
a p pr o pri at e i m a gi n g (i. e., M RI, C T s c a n or ultr a s o u n d). 
G a str o i nt e sti n al  
P a n cr e atiti s**  
Gr a d e 2 ( e n z y m e 
el e v ati o n s wit h 
r a di ol o gi c fi n di n g s f or 
p a n cr e atiti s a s p er 
C T C A E v 5 . 0. F or 
i s ol at e d i n cr e a s e d 
e n z y m e s pl e a s e s e e 
t a bl e f or a s y m pt o m ati c 
a m yl a s e a n d/ or li p a s e 
el e v ati o n)  
M a n d at or y:  If r a di ol o gi c fi n di n g s, h ol d tr e at m e nt u ntil r e s ol v e d t o  b a s eli n e.  
If tr e at m e nt d el a y i s ≤ 1 4 d a y s, t h e n r e d u c e d o s e ↓ 1 d o s e l e v el. 
If tr e at m e nt d el a y > 1 4 d a y s, di s c o nti n u e tr e at m e nt a n d a p pr o pri at e i m a gi n g (i. e. 
M RI, C T s c a n or ultr a s o u n d) s h o ul d b e o bt ai n e d.  
Gr a d e ≥ 3  
M a n d at or y:  P er m a n e ntl y di s c o nti n u e s u bj e ct fr o m st u d y dr u g tr e at m e nt. 
A p pr o pri at e i m a gi n g (i. e. M RI, C T s c a n or ultr a s o u n d) s h o ul d b e o bt ai n e d.  
Di arr h e a***  
Gr a d e 1  
R e c o m m e n d ati o n:  M ai nt ai n d o s e l e v el b ut, i niti at e a nti -di arr h e a tr e at m e nt  
Gr a d e 2  
R e c o m m e n d ati o n:  H ol d d o s e u ntil r e s ol v e d t o ≤ gr a d e 1, t h e n m ai nt ai n d o s e l e v el.  
If di arr h e a r et ur n s a s ≥ gr a d e 2, t h e n h ol d d o s e u ntil r e s ol v e d t o ≤ gr a d e 1, t h e n 
r e d u c e d o s e ↓ 1 d o s e l e v el 
Gr a d e 3  
R e c o m m e n d ati o n:  Di s c o nti n u e p ati e nt fr o m st u d y dr u g tr e at m e nt  
Gr a d e 4  
M a n d at or y:  P er m a n e ntl y di s c o nti n u e p ati e nt fr o m st u d y dr u g tr e at m e nt  
S ki n a n d s u b c ut a n e o u s ti s s u e di s or d er s  
R a s h/ p h ot o s e n siti vit y  
Gr a d e 1  
R e c o m m e n d ati o n:  M ai nt ai n d o s e l e v el.  
C o n si d er t o i niti at e a p pr o pri at e s ki n t o xi cit y t h er a p y ( s u c h a s a nti hi st a mi n e s, t o pi c al 
c orti c o st er oi d s a n d l o w -d o s e s y st e mi c c orti c o st er oi d s)  
Gr a d e 2  
R e c o m m e n d ati o n : M ai nt ai n d o s e l e v el, b ut i niti at e/i nt e n sif y a p pr o pri at e s ki n t o xi cit y 
t h er a p y ( s u c h a s a nti hi st a mi n e s, t o pi c al c orti c o st er oi d s a n d l o w-d o s e s y st e mi c 
c orti c o st er oi d s)  
Gr a d e 3, d e s pit e s ki n 
t o xi cit y t h er a p y 
R e c o m m e n d ati o n:  H ol d d o s e u ntil r e s ol v e d t o Gr a d e ≤ 1, t h e n:  
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 d o s e ↓ 1 d o s e l e v el  
If r e s ol v e d i n > 7 d a y s ( d e s pit e a p pr o pri at e s ki n t o xi cit y t h er a p y), t h e n di s c o nti n u e 
p ati e nt fr o m st u d y dr u g tr e at m e nt  

N o v arti s  
C o nfi d e nti al  
P a g e 7 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
Gr a d e 4, d e s pit e s ki n 
t o xi cit y t h er a p y 
M a n d at or y:  P er m a n e ntl y di s c o nti n u e p ati e nt fr o m st u d y dr u g tr e at m e nt.  
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  
F ati g u e/ A st h e ni a  
Gr a d e 1 or 2  
R e c o m m e n d ati o n:  M ai nt ai n d o s e l e v el  
Gr a d e 3  
R e c o m m e n d ati o n:  H ol d d o s e u ntil r e s ol v e d t o ≤ gr a d e 1, t h e n :  
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 d o s e ↓ 1 d o s e l e v el 
All d o s e m o difi c ati o n s s h o ul d b e b a s e d o n t h e w or st pr e c e di n g t o xi cit y.  
a  C o m m o n T o xi cit y Crit eri a f or A d v er s e E v e nt s ( C T C A E V er si o n 5 . 0) 
b  C or e Li v er te st s c o n si st of A L T, A S T, G G T, t ot al bilir u bi n (fr a cti o n at e d [ dir e ct a n d i n dir e ct], if t ot al bilir u bi n > 
2. 0 x U L N), a n d al k ali n e p h o s p h at a s e (fr a cti o n at e d [ q u a ntifi c ati o n of i s of or m s], if al k ali n e p h o s p h at a s e > 2. 0 x 
U L N.)  
c “ C o m bi n e d” d efi n e d a s t ot al bilir u bi n i n cr e a s e t o t h e d efi n e d t hr e s h ol d c o n c urr e ntl y wit h A L T/ A S T i n cr e a s e t o 
t h e d efi n e d t hr e s h ol d. If c o m bi n e d el e v ati o n s of A S T or A L T a n d t ot al bilir u bi n d o n ot m e et t h e d efi n e d 
t hr e s h ol d s, pl e a s e f oll o w t h e i n str u cti o ns f or g e n er al n o n -h e m at ol o gi c t o xi cit y a n d t a k e a c o n s er v ati v e a cti o n 
b a s e d o n t h e d e gr e e of t h e el e v ati o n s ( e. g. di s c o nti n u e tr e at m e nt at t h e sit u ati o n w h e n o mit d o s e i s n e e d e d f or 
o n e p ar a m et er a n d di s c o nti n u e tr e at m e nt i s r e q uir e d f or a n ot h er p ar a m et er ). Aft er all el e v ati o n s r e s ol v e t o t h e 
d efi n e d t hr e s h ol d s t h at all o w tr e at m e nt r e -i niti ati o n, r e-st art t h e tr e at m e nt eit h er at t h e s a m e d o s e or at o n e 
d o s e l o w er if m e eti n g a crit eri o n f or d o s e r e d u cti o n  
d “ C h ol e st a si s” d efi n e d a s A L P el e v ati o n ( > 2. 0 x U L N a n d R v al u e < 2) N ot e: T h e R v al u e i s c al c ul at e d b y 
di vi di n g t h e A L T b y t h e A L P, u si n g m ulti pl e s of t h e U L N f or b ot h v al u e s. It d e n ot e s w h et h er t h e r el ati v e p att er n 
of A L T a n d/ or A L P el e v ati o n i s d u e t o c h ol e st ati c ( R ≤ 2), h e p at o c ell ul ar ( R ≥ 5), or mi x e d ( R > 2 a n d < 5) li v er 
i nj ur y 
* N ot e: If t ot al bilir u bi n > 3. 0 x U L N i s d u e t o t h e i n dir e ct ( n o n-c o nj u g at e d) c o m p o n e nt o nl y, a n d h e m ol y si s a s t h e 
eti ol o g y h a s b e e n r ul e d o ut a s p er i n stit uti o n al g ui d eli n e s ( e. g., r e vi e w of p eri p h er al bl o o d s m e ar a n d h a pt o gl o bi n 
d et er mi n ati o n), t h e n ↓ 1  d o s e l e v el a n d c o nti n u e tr e at m e nt at t h e di s cr eti o n of t h e i n v e sti g at or.  
** N ot e: A C T s c a n or ot h er i m a gi n g st u d y t o a s s e s s t h e p a n cr e a s, li v er, a n d g all bl a d d er m u st b e p erf or m e d wit hi n 
1 w e e k of t h e fir st o c c urr e n c e of a n y ≥ g r a d e 3 of a m yl a s e a n d/ or li p a s e. If a s y m pt o m ati c Gr a d e 2 el e v ati o n s of 
li p a s e a n d/ or a m yl a s e o c c ur a g ai n at t h e r e d u c e d d o s e, p ati e nt s will b e di s c o nti n u e d p er m a n e ntl y fr o m st u d y 
tr e at m e nt. 
*** N ot e: a nti di arr h e al m e di c ati o n i s r e c o m m e n d e d at t h e fir st si g n of a b d o mi n al cr a m pi n g, l o o s e st o ol s or o v ert 
di arr h e a  
D o s e r e -e s c al ati o n f or a s ci mi ni b a n d i m ati ni b  
Re -escal ati o n t o asci mi ni b 6 0 m g Q D or 4 0 m g Q D, res pecti vel y, a n d i mati ni b 4 0 0 m g Q D at 
t he discreti o n of t he i n vesti gat or. Re-escal ati o n will be all o we d o nl y o nce f or a n y gi ve n s u bject 
o n t he asci mi ni b + i mati ni b ar ms per pr ot oc ol.  
D o s e r e -e s c al ati o n f or a s ci mi ni b 8 0 m g Q D si n gl e a g e nt  
Re -escal ati o n t o asci mi ni b 8 0 m g Q D is per mitte d o nl y o nce f or a n y s u bject per pr ot oc ol a n d 
o nl y if t here is a c h a n ge i n t he s u bject's i n di vi d ual be nefit/ris k assess me nt at t he l o w er d os e 
le vel.  
A n y d ose c ha n g es m ust be rec or de d o n t he a p pr o priate e C R F ( D osa ge A d mi nistrati o n Rec or d 
e C R F).  

N o v arti s  
C o nfi d e nti al  
P a g e 7 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
T a bl e 6 -3  
D o s e r e d u cti o n f or a s ci mi ni b a n d i m ati ni b  
D o s e r e d u cti o n * 
  
St arti n g d o s e l e v el –  0  
D o s e l e v el –  1  
A s ci mi ni b ( A B L 0 0 1)  
6 0 m g ( Q D)  
4 0 m g ( Q D)  
A s ci mi ni b ( A B L 0 0 1)  
4 0 m g ( Q D)  
2 0 m g ( Q D)**  
* D o s e r e d u cti o n s h o ul d b e b a s e d o n t h e w or st t o xi cit y d e m o n str at e d at t h e l a st d o s e.  
** D o s e r e d u cti o n b el o w 2 0 m g i s n ot all o w e d. 
D o s e r e d u cti o n * 
  
St arti n g d o s e l e v el –  0  
D o s e l e v el –  1  
I m ati ni b ( S TI 5 7 1) 
4 0 0 m g ( Q D)  
3 0 0 m g ( Q D) ** 
* D o s e r e d u cti o n s h o ul d b e b a s e d o n t h e w or st t o xi cit y d e m o n str at e d at t h e l a st d o s e. 
** D o s e r e d u cti o n b el o w 3 0 0 m g i s n ot all o w e d. 
T a bl e 6 -4  
D o s e r e d u cti o n f or a s ci mi ni b si n gl e a g e nt c o h ort  
D o s e r e d u cti o n*  
 
 
A s ci mi ni b ( A B L 0 0 1)  
St arti n g d o s e l e v el –  0  
8 0 m g ( Q D)  
D o s e l e v el –  1  
4 0 m g ( Q D)**  
* D o s e r e d u cti o n s h o ul d b e b a s e d o n t h e w or st t o xi cit y d e m o n str at e d at t h e l a st d o s e.  
** D o s e r e d u cti o n b el o w 4 0 m g ( Q D) i s n ot all o w e d.  
6. 5. 1. 2  
Crit eri a f or d o s e r e d u cti o n/i nt err u pti o n a n d r e -i niti ati o n of i m ati ni b f or 
a d v er s e dr u g r e a cti o n s i n i m ati ni b c o nti n u ati o n ar m  
D ose re d u cti o ns f or i m ati ni b s h o ul d be d o ne i n acc or da nce t o l ocall y a p pr o ve d pr o d uct 
i nf or mati o n f or i mati ni b. 
6. 5. 1. 3  
Crit eri a f or d o s e r e d u cti o n/i nt err u pti o n a n d r e -i niti ati o n of nil oti ni b f or 
a d v er s e dr u g r e a cti o n s  
D ose re d ucti o ns f or nil oti ni b s h o ul d be d o ne i n acc or da nce t o l ocall y a p pr o ve d pr o d uct 
i nf or mati o n f or nil oti ni b. 
6. 5. 1. 4  
D o s e a dj u st m e nt s f or Q T c F pr ol o n g ati o n  
If Q Tc F > 5 0 0 msec or Q Tc F pr ol o n gati o n > 6 0 msec fr o m bas eli ne is o bser ve d at a n y p oi nt 
d uri n g st u d y treat me nt, a n d c o nfir me d, t he b el o w g ui da nce m ust be f oll o w e d:  
1.  Assess t he q ualit y of t he E C G rec or di n g a n d t he Q T val ue a n d re peat if nee de d  
2.  I nterr u pt st u d y treat me nt u ntil c o nfir me d res ol uti o n of Q Tc F pr ol o n gati o n. 
3.  Deter mi ne t he ser u m ele ctr ol yte le vels (i n partic ular h y p o kale mia, h y p o ma g nese mia). If 
a b n or mal, c orrect a b n or malities bef ore res u mi n g st u d y dr u g treat me nt.  
4.  Re vie w c o nc o mita nt me dicati o n use f or ot her ca uses f or Q T pr ol o n gati o n (refer t o 
qt dr u gs. or g f or k n o w n Q T pr ol o n gi n g dr u gs), a n d f or dr u gs wit h t he p ote ntial t o i ncrease 
t he ris k of dr u g e x p os ure rel ate d Q T pr ol o n gati o n (e. g., c o nc o mita nt use of C Y P 3 A 4 
i n hi bit ors, if t he st u d y dr u g is a C Y P 3 A 4 s u bstrate) 
5.  C hec k st u d y dr u g d osi n g sc he d ule a n d tr eat me nt c o m plia nce  
6.  I n crease d E C G safet y m o nit ori n g is rec o m me n de d d uri n g or i n-bet wee n s u bse q ue nt visits.  

N o v arti s  
C o nfi d e nti al  
P a g e 7 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
After c o nfir mi n g E C G rea di n g at site, if Q Tc F > 5 0 0 msec  
1.  I nterr u pt st u d y treat me nt 
2.  Re peat E C G a n d c o nfir m E C G dia g n osis b y a car di ol o gist or ce ntral E C G la b  
3.  If Q Tc F c o nfir me d > 5 0 0 msec  
•  C orrect ele ctr ol ytes, eli mi nate c ul prit c o nc o mita nt me dicati o n, a n d i de ntif y cli nical 
c o n diti o ns t hat c o ul d p ote ntiall y pr ol o n g t he Q T i nter val  
•  C o ns ult wit h a car di ol o gist ( or q ualifie d s p ecialist) a n d i ncrease car di ac m o nit ori n g as 
i n dicate d, u ntil Q Tc F ret ur ns ≤ 4 8 0 msec 
After res ol uti o n t o ≤ 4 8 0 msec, c o nsi der rei ntr o d uci n g treat me nt at re d u ce d d ose, a n d i ncrease 
E C G m o nit ori n g f or t he ne xt treat me nt  
1.  If Q Tc F re mai ns ≤ 5 0 0 msec aft er d ose re d ucti o n, c o nti n ue pla n ne d E C G m o nit ori n g d uri n g 
s u bse q ue nt treat me nt 
2.  If Q Tc F rec urs > 5 0 0 msec aft er d ose re d ucti o n, disc o nti n ue s u bject fr o m trial 
Patie nts  s h o ul d be wit h dra w n fr o m t he st u d y f or a n y o ne of t he f oll o wi n g treat me nt -rel ate d, 
cli nicall y si g nifica nt safet y fi n di n gs, i ncl u di n g, b ut n ot li mite d t o:  
•  D oc u me nte d e pis o de of ve ntric ular 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 o c k) or Sec o n d de gree A V bl o c k M o bitz t y pe II  
6. 5. 2  
F oll o w -u p f or t o xi citi e s  
Patie nts  w h ose treat me nt is per ma ne ntl y disc o nti n ue d d ue t o a st u d y dr u g relate d a d verse e v e nt 
or cli nicall y si g nifica nt la b orat or y val ue s h o ul d be f oll o we d u p at least o nce a wee k f or 4 wee ks, 
u ntil res ol uti o n or sta bilizati o n of t he e v e nt, w hic h e ver c o mes first.  A p pr o priate cli nical e x p erts 
s uc h as o p ht hal m ol o gist, e n d ocri n ol o gist, der mat ol o gist, ps yc hiatrists etc. s h o ul d be c o ns ulte d 
as dee m e d necessar y. All patie nts  m ust be f oll o we d u p f or a d verse e ve nts a n d seri o us a d v erse 
e ve nts f or 3 0 d a ys f oll o wi n g t he last d ose of st u d y treat me nt. 
6. 5. 2. 1  
F oll o w u p o n p ot e nti al dr u g -i n d u c e d li v er i nj ur y ( DI LI) c a s e s 
Patie nts  wit h tra nsa mi nase i ncrease c o m bi ne d wit h t otal bilir u bi n i ncrease ma y be i n dicati ve of 
p ote ntial DI LI, a n d s h o ul d be c o nsi dere d as cli nicall y i m p orta nt e ve nts.  
T he t hres h ol d f or p ote ntial DI LI m a y de pe n d o n t he s u bject’s baseli ne A S T/ A L T a n d t otal 
bilir u bi n 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 otal bilir u bi n 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 otal bilir u bi n > 2. 0 x U L N  
•  F or patie nts  wit h ele v ate d A S T or A L T or t otal bilir u bi n 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] , c o m bi ne d wit h [t otal bilir u bi n > 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.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
N ote: T he R val ue is cal c ulate d b y di vi di n g t he A L T b y t he A L P, usi n g m ulti ples of t he U L N 
f or b ot h val ues. It de n ot es w het her t he relati ve patter n of A L T a n d/ or A L P ele vati o n is d ue t o 
c h olestatic ( R ≤ 2), he p at ocell ular ( R ≥ 5), or mi xe d ( R > 2 a n d < 5) li ver i nj ur y. 
I n t h e a bse n ce 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 
treat me nt, a n d re p eat li v er tests  as s o o n as p ossi ble, prefera bl y wit hi n 4 8 h o urs fr o m t h e 
a ware ness of t h e a b n or mal res ults. T he e v al uati o n s h o ul d i ncl u de 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.  
1.  La b orat or y tests s h o ul d i ncl u de A L T, A S T, al b u mi n, creati ne ki nase, t otal bilir u bi n, direct 
a n d 
i n direct 
bilir u bi n, 
ga m ma -gl uta m yl -tra nsferas e 
( G G T), 
pr ot hr o m bi n 
ti me 
( P T)/I nt er nati o nal N or malize d Rati o (I N R) a n d al kali ne p h os p hatase. 
2.  A detaile d hist or y, i ncl u di n g rele va nt i nf or mati o n, s uc h as re vi e w of et ha n ol, c o nc o mita nt 
me dicati o ns, her bal re me dies, s u p ple me nt c o ns u m pti o n, hist or y of a n y pre -e xisti n g li ver 
c o n diti o ns or ris k fact ors, s h o ul d be c ollecte d.  
3.  F urt her testi n g f or ac ute he patitis A, B, C or E i nfecti o n a n d li ver i ma gi n g (e. g. biliar y tract) 
ma y be warra nte d.  
4.  O btai n P K sa m ple (f or patie nts  treate d wit h asci mi ni b + i mati ni b), as cl ose as p ossi ble t o 
last d ose of st u d y dr u g. 
5.  A d diti o nal testi n g f or ot her he pat otr o pic viral i nfecti o n ( C M V ( C yt o me gal o vir us), E B V 
( E pstei n– Barr vir us) or H S V ( Her pes si m ple x vir us)), a ut oi m m u ne he patitis or li ver bi o ps y 
ma y be c o nsi dere d as cli nicall y i n dicate d or after c o ns ultati o n wit h s pecialist/ he pat ol o gist.  
All cases c o nfir me d o n re peat testi n g meeti n g t he la b orat or y criteria defi ne d a b o ve, wit h n o 
ot her alter nati ve ca use f or li ver tests a b n or malities i de ntifie d s h o ul d be c o nsi d ere d as 
“ me dicall y si g nifica nt”, t h us, met t he defi niti o n of S A E a n d re p orte d as S A E usi n g t he ter m 
“ p ote ntial dr u g-i n d uc e d li ver i nj ur y”. All e ve nts s h o ul d be f oll o we d u p wit h t he o utc o me clearl y 
d oc u me nte d.  
6. 6  
A d diti o n al tr e at m e nt g ui d a n c e  
6. 6. 1  
Tr e at m e nt c o m pli a n c e  
T he i n vesti gat or m ust pr o m ote c o m plia nce b y i nstr ucti n g t he s u bject t o ta ke t he st u d y treat me nt 
e xactl y as prescri b e d a n d b y stati n g t hat c o m plia nce is necessar y f or t he s u bject’s safet y a n d 
t he vali dit y of t he st u d y. T he s u bject m ust als o be i nstr ucte d t o c o ntact t he i n vesti gat or if he/s he 
is u na ble f or a n y reas o n t o ta ke t he st u d y treat me nt as prescri be d. C o m plia nce will be assesse d 
b y t he i n vesti gat or a n d/ or st u d y pers o n nel at eac h visit usi n g pill c o u nts (if a p plica ble at t he 
visit) a n d i nf or mati o n pr o v i de d b y t he s u bject. T his i nf or mati o n s h o ul d be ca pt ur e d i n t h e 
s o urce d o c u me nt at eac h visit. All st u d y treat me nt dis pe nse d a n d ret ur ne d m ust be rec or de d i n 
t he Dr u g Acc o u nta bilit y L o g. T otal dail y d ose of st u d y treat me nt a d mi nistere d wit h start a n d 
e n d date will be c ollecte d o n t he de dicate d e C R F p a ge.  
P har mac o ki netic para meters ( meas ures of treat me nt e x p os ure) will be deter mi ne d i n t he 2 0 
patie nts  ra n d o mize d t o asci mi ni b 6 0 m g Q D as a d d-o n t hera p y t o i mati ni b 4 0 0 m g Q D i n t h e 
2 0 patie nts  ra n d o mize d t o asci mi ni b 4 0 m g Q D as a d d-o n t hera p y t o i mati ni b 4 0 0 m g Q D a n d 

N o v arti s  
C o nfi d e nti al  
P a g e 8 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
i n t he 2 0 patie nts  e nr olle d i n t he asci mi ni b 8 0 m g Q D si n gle a ge nt c o h ort, as detaile d i n 
p har mac o ki netics s ecti o n ( Secti o n  8. 5. 2 ). 
6. 6. 2  
E m er g e n c y br e a ki n g of a s si g n e d tr e at m e nt c o d e  
N ot a p plica ble.  
6. 7  
Pr e p ar ati o n a n d di s p e n s ati o n  
Eac h st u d y site will be s u p plie d wit h st u d y dr u g i n pac ka gi n g as des cri be d u n der i n vesti gati o nal 
a n d c o ntr ol dr u gs secti o n.  
A u ni q ue me dicati o n n u m ber is pri nte d o n t he st u d y me dicati o n la bel.  
I n v esti gat or staff will i de ntif y t he st u d y me dicati o n kits t o dis pe nse t o t h e s u bject b y c o nt acti n g 
t he I R T a n d o btai ni n g t he me dicati o n n u m ber(s). Res p o nsi ble site pers o n nel will i de ntif y t he 
st u d y treat me nt pac ka ge(s) t o dis pe nse b y t he me dicati o n n u m ber(s) assi g ne d b y I R T t o t he 
s u bject. Site pers o n nel will a d d t he s u bject n u m ber o n t he la bel. If t he la bel has 2 parts ( base 
pl us tear -off la bel), i m m e diatel y bef ore dis pe nsi n g t he pac k a ge t o t he s u bject, site pers o n nel 
will detac h t h e o uter part of t he la b el fr o m t he p ac ka g e a n d affi x it t o t h e s u bject’s s o urce 
d oc u me nt.  
6. 7. 1  
H a n dli n g of st u d y tr e at m e nt a n d a d diti o n al tr e at m e nt  
6. 7. 1. 1  
H a n dli n g of st u d y tr e at m e nt  
St u d y treat me nt m ust be recei v e d b y a desi g nate d pers o n at t he 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 k e 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 nat e d 
site pers o n nel ha ve access. U p o n recei pt, all st u d y treat me nt m us t 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 i mati ni b a n d nil oti ni b la bels a n d i n t he [ Asci mi ni b I n vesti gat or’s 
Br oc h ure] . Cli nical s u p plies are t o be dis p e nse d o nl y i n acc or da nce wit h t he pr ot oc ol. Tec h ni cal 
c o m plai nts are t o be re p orte d t o t he res pecti ve N o vartis C o u ntr y Q ualit y Ass ura nce. 
Me dicati o n la bels will be i n t he l ocal la n g ua ge a n d c o m pl y wit h t he le gal re q uire me nts of eac h 
c o u ntr y. T he y will i ncl u d e st ora ge c o n diti o ns f or t he st u d y treat me nt b ut n o i nf or mati o n a b o ut 
t he s u bject e xce pt f or t he me dicati o n n u m ber. 
T he i n vesti gat or m ust m ai ntai n a n acc urate rec or d of t he s hi p me nt a n d dis pe nsi n g of st u d y 
treat me nt i n a dr u g acc o u nta bilit y l o g. M o nit ori n g of dr u g acc o u nta bilit y will be perf or me d b y 
m o nit ors d uri n g site visits a n d at t he c o m pleti o n of t he trial. Patie nts  will be as ke d t o ret ur n all 
u n use d st u d y treat me nt a n d pac ka gi n g o n a re g ular basis, a n d at t he e n d of t he st u d y or at t he 
ti me of disc o nti n uati o n of st u d y treat me nt. 
At t he c o ncl usi o n of t he st u d y, a n d as a p pr o priate d uri n g t he c o urse of t he st u d y, t he i n vesti gat or 
will ret ur n all u n use d st u d y treat me nt, pac k a gi n g, dr u g la bels, a n d a c o p y of t he c o m plet e d dr u g 
acc o u nta bilit y l o g t o t he N o vartis m o nit or or t o t he N o vart is a d dress pr o vi de d i n t he i n vesti gat or 
f ol der at e ac h site.  
As per Secti o n 4. 6 , d uri n g a p u blic healt h e mer ge nc y as declare d b y l ocal or re gi o nal a ut h orities 
i.e. pa n de mic, e pi de mic, ge o p olitical sit uati o n  or nat ural disaster, t h at li mits or pre v e nts o n -site 

N o v arti s  
C o nfi d e nti al  
P a g e 8 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
st u d y visits, deli ver y of I M P directl y t o a s u bject's h o me ma y be per mitte d (if all o we d b y l ocal 
or re gi o nal healt h a ut h orities a n d et hics c o m mittees, as a p pr o priate) i n t he e ve nt t he I n vesti gat or 
has deci d e d t hat a n o n -site visit b y t he s u bject is n o l o n ger a p pr o priat e or p ossi ble, a n d t hat it 
is i n t he i nterest of t he s u bject's healt h t o a d mi nister t he st u d y treat me nt e ve n wit h o ut 
perf or mi n g a n o n -site visit. T he dis patc h of I M P fr o m t he site t o t h e s u bj ect’s h o me re mai ns 
u n der t he acc o u nta bilit y of t he I n v esti gat or. E ac h s hi p me nt/ pr o visi o ni n g will be f or a ma xi m u m 
of 3 m o nt hs s u p pl y. I n t his case, re g ul ar p h o ne calls or virt ual c o ntacts (as nee de d) will occ ur 
bet wee n t he site a n d t he s u bject f or i nstr ucti o nal p ur p oses, safet y m o nit ori n g, i n vesti gati o n of 
a n y a d vers e e ve nts, e ns uri n g patie nts  c o nti n ue t o be nefit fr o m treat me nt, a n d disc ussi o n of t he 
s u bject's healt h stat us u ntil t he patie nts  ca n res u me visits at t he st u d y site.  
6. 7. 1. 2  
H a n dli n g of a d diti o n al tr e at m e nt  
N ot a p plica ble.  
6. 7. 2  
I n str u cti o n f or pr e s cri bi n g a n d t a ki n g st u d y tr e at m e nt 
St u d y treat me nt (asci mi ni b, i mati ni b a n d nil oti ni b) will be pr o vi de d as gl o bal cli nical o pe n -
la bel s u p pl y a n d will be pac ke d a n d la bele d u n d er t he res p o nsi bilit y of N o vartis, Dr u g S u p pl y 
Ma na ge me nt.  
St u d y treat me nt la bels will c o m pl y wit h t he le gal re q uire me nts of eac h c o u ntr y a n d will i ncl u de 
st ora ge c o n diti o ns a n d a u ni q ue me dicati o n n u m ber (c orres p o n di n g t o st u d y treat me nt a n d 
stre n gt h). 
D ose a n d treat me nt sc he d ule are descri b e d i n t he Ta ble 6 -4  a n d all t he i nf or mati o n a b o ut t he 
a d mi nistrati o n of t he st u d y dr u g are des cri be d i n t he  Secti o n  6. 1. 3 . D ose re d ucti o ns ca n b e 
perf or me d as descri be d i n Ta ble 6 -3 . 
T a bl e 6 -5  
D o s e a n d tr e at m e nt s c h e d ul e  
St u d y Dr u g  
D o s e  
Fr e q u e n c y  
A s ci mi ni b ( A B L 0 0 1)  
6 0 m g  
o n c e d ail y  
A s ci mi ni b ( A B L 0 0 1)  
4 0 m g  
o n c e d ail y  
I m ati ni b ( S TI 5 7 1) 
4 0 0 m g  
o n c e d ail y  
Nil oti ni b ( A M N 1 0 7)  
3 0 0 m g  
t wi c e d ail y 
At baseli ne visit t he patie nts  will be ra n d o mize d i nt o o ne of t he 4 ar ms, a n d t he res p o nsi ble site 
pers o n nel will i de ntif y t h e st u d y treat me nt pac ka g e(s) t o dis pe ns e b y t h e m e dicati o n n u m ber(s) 
assi g ne d b y I R T t o t he s u bject.  
Asci mi ni b + I mati ni b ar ms: asci mi ni b 6 0 m g or 4 0 m g a n d i mati ni b 4 0 0 m g will be a d mi nistere d 
orall y dail y o n a c o nti n u o us sc he d ule ( Q D). Asci mi ni b a n d i mati ni b ta blets s h o ul d be i n geste d 
as f oll o ws:  
•  Patie nts  s h o ul d ta ke asci mi ni b dail y at a p pr o xi matel y t he sa me ti me eac h da y i n t he m or ni n g, 
i m me diatel y f oll o we d b y i mati ni b 4 0 0 m g a d mi nistrati o n. 
•  O n da ys t hat P K s a m ples are o btai ne d, t h e s u bject s h o ul d ta ke asci mi ni b a n d i mati ni b d uri n g 
t he cli nic visit after t he pre-d ose P K sa m ples, w he n i nstr ucte d b y t he st u d y staff.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
•  Patie nts  s h o ul d ta ke as ci mi ni b a n d i mati ni b wit h a l o w-fat meal a n d a lar ge glass of wat er, 
a p pr o xi matel y 2 4 0 m L ( 8 o u nces) of water. A l o w -fat meal is d efi ne d as a n y meal wit h less 
t ha n 2 0 % fat a n d n ot m or e t ha n 4 0 0 cal ori es. 
•  Patie nts  s h o ul d be i nstr ucte d t o s wall o w w h ole ta blets a n d n ot t o c he w or t o brea k t he m.  
•  If v o miti n g occ urs d uri n g t he first h o ur after ta ki n g t he dr u g, re-d osi n g is all o we d b ef ore 
t he ne xt sc he d ule d d os e. 
•  If t he s u bject d oes n ot t a ke asci mi ni b a n d i mati ni b wit hi n 6 h o urs after t he us ual d osi n g 
ti me, t hat d ose s h o ul d be s ki p pe d a n d treat me nt s h o ul d c o nti n ue wit h t h e ne xt dail y d ose at 
t he prescri b e d le vel. 
•  Patie nts  s h o ul d a v oi d c o ns u m pti o n of gra pefr 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 wit h t he st u d y me dicati o ns. Ora n ge j uice 
is all o we d. C o ns u m pti o n of t he af ore me nti o ne d fr uits or j uices c o ntai ni n g t he fr uits ma y 
e n ha nce a n d pr ol o n g t he e x p os ure of p atie nts  t o t he st u d y treat me nt. 
•  Patie nts  s h o ul d use s u n bl oc k w he n g oi n g o ut i n t he s u n a n d a v oi d ta n ni n g be ds. 
I mati ni b ar m: i mati ni b 4 0 0 m g ta blets will be a d mi nistere d orall y dail y o n a c o nti n u o us 
sc he d ule ( Q D). I mati ni b ta blets s h o ul d be i n geste d as f oll o ws: 
•  Patie nts  s h o ul d ta ke i mati ni b dail y at a p pr o xi matel y t he sa me ti me eac h da y i n t he m or ni n g.  
•  Patie nts  s h o ul d ta ke i mati ni b wit h a l o w-fat meal a n d a lar g e glass of water, a p pr o xi matel y 
2 4 0 m L ( 8 o u nces) of water. A l o w -fat meal is defi ne d as a n y meal wit h less t ha n 2 0 % fat 
a n d n ot m ore t ha n 4 0 0 cal ories.  
•  Patie nts  s h o ul d be i nstr ucte d t o s wall o w w h ole ta blets a n d n ot t o c he w or o pe n t he m. 
•  If v o miti n g occ urs d uri n g t he first h o ur after ta ki n g t he dr u g, re-d osi n g is all o we d b ef ore 
t he ne xt sc he d ule d d os e. 
•  If t he s u bject d oes n ot ta ke i mati ni b wit hi n 6 h o urs after t he us ual d osi n g ti me, t hat d ose 
s h o ul d be s ki p pe d a n d tr eat me nt s h o ul d c o nti n ue wit h t he ne xt dail y d ose at t he prescri be d 
le vel. 
•  Patie nts  s h o ul d a v oi d c o ns u m pti o n of gra pefr 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 wit h t he st u d y me dicati o ns. Ora n ge j uice 
is all o we d. C o ns u m pti o n of t he af ore me nti o ne d fr uits or j uices c o ntai ni n g t he fr uits ma y 
e n ha nce a n d pr ol o n g t he e x p os ure of p atie nts  t o t he st u d y treat me nt. 
•  Patie nts  m ust a v oi d c o nc o mita nt i nta ke of str o n g a n d m o derat e C Y P 3 A 4/ 5 i n hi bit ors a n d 
i n d ucers. 
•  Patie nts  s h o ul d use s u n bl oc k w he n g oi n g o ut i n t he s u n a n d a v oi d ta n ni n g be ds. 
Nil oti ni b ar m: nil oti ni b will be a d mi nistere d orall y at 3 0 0 m g t wice dail y ( BI D). Nil oti ni b har d 
gelati n ca ps ules f or oral use s h o ul d be i n geste d as f oll o ws:  
•  Patie nts  s h o ul d ta ke nil oti ni b dail y at a p pr o xi matel y t he sa me ti me eac h da y i n t he m or ni n g 
a n d i n e ve ni n g at a p pr o xi matel y 1 2 h o ur i nter vals  

N o v arti s  
C o nfi d e nti al  
P a g e 8 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
•  Patie nts  s h o ul d ta ke nil oti ni b o n a n e m pt y st o mac h. N o f o o d s h o ul d be c o ns u me d f or t w o 
h o urs bef ore a n d at l east o ne h o ur after t he d ose is ta ke n. Eac h d ose ma y be ta ke n wit h a 
glass of water, a p pr o xi m atel y 2 4 0 m L ( 8 o u nces) of water.  
•  Patie nts  s h o ul d be i nstr ucte d t o s wall o w w h ole ca ps ules a n d n ot t o c he w or o pe n t he m.  
•  If v o miti n g occ urs d uri n g t he c o urse of tr eat me nt, n o re-d osi n g of t h e s u bject is all o we d 
bef ore t h e ne xt sc he d ul e d d ose.  
•  If t he s u bject d o es n ot ta ke t he dr u g wit hi n 6 h o urs after t he us ual d osi n g ti me, t hat d ose 
s h o ul d be s ki p pe d a n d tr eat me nt s h o ul d c o nti n ue wit h t he ne xt dail y d ose at t he prescri be d 
le vel. 
•  Patie nts  s h o ul d a v oi d c o ns u m pti o n of gra pefr 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 wit h t he st u d y me dicati o ns. Ora n ge j uice 
is all o we d. C o ns u m pti o n of t he af ore me nti o ne d fr uits or j uices c o ntai ni n g t he fr uits ma y 
e n ha nce a n d pr ol o n g t he e x p os ure of p atie nts  t o t he st u d y treat me nt. 
All d osa ges f or all c o m p o u n ds prescri be d a n d dis pe nse d t o t he patie nts  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 os a ge A d mi nistrati o n Rec or d e C R F.  
T he patie nts  ra n d o mize d i n t he i mati ni b ar m w h o ha ve n ot ac hie ve d M R4. 5 at 4 8 wee ks ma y 
cr oss-o ver t o recei ve t h e a d d -o n tr eat me nt (asci mi ni b 6 0 m g + i mati ni b) wit hi n 4 wee ks aft er 
wee k 4 8 visit ( Fi g ur e 3 -1 ). 
Patie nts  w h o c h o ose t o cr oss -o ver will ha ve t o perf or m t he " C O baseli ne" visit; i n t he ti mefra me 
fr o m wee k 4 8 t o C O baseli ne visit, t hese patie nts  will c o nti n ue t o ta ke i mati ni b. At t he C O 
baseli ne visit, t he y will be re gistere d i n t he cr oss -o ver ar m i n t he I R T s yste m a n d will be 
dis pe nse d t he ne w me di cati o n n u m ber(s) of asci mi ni b a n d i mati ni b.  
T he patie nts  w h o prefer t o c o nti n ue t he i mati ni b treat me nt will c o nti n ue t o ta ke i mati ni b u ntil 
t he e n d of treat me nt. 
All kits of st u d y treat me nt assi g ne d b y t he I R T will be rec or de d i n t he I R T s yste m.  
6. 7. 3  
A s ci mi ni b si n gl e a g e nt c o h ort - I n str u cti o n f or pr e s cri bi n g a n d t a ki n g 
st u d y tr e at m e nt  
Asci mi ni b will be pr o vi de d as gl o bal cli nical o pe n -la bel s u p pl y a n d will be pac ke d a n d la bele d 
u n der t he res p o nsi bilit y of N o vartis, Dr u g S u p pl y Ma na ge me nt.  
St u d y treat me nt la bels will c o m pl y wit h t he le gal re q uire me nts of eac h c o u ntr y a n d will i ncl u de 
st ora ge c o n diti o ns a n d a u ni q ue me dicati o n n u m ber (c orres p o n di n g t o st u d y treat me nt a n d 
stre n gt h). 
Asci mi ni b si n gle a ge nt c o h ort: asci mi ni b 8 0 m g will be a d mi nistere d orall y d ail y o n a 
c o nti n u o us sc he d ule ( Q D). Asci mi ni b ta blets s h o ul d be i n geste d as f oll o ws:  
•  Patie nts  s h o ul d ta ke asci mi ni b dail y at a p pr o xi matel y t he sa me ti me eac h da y i n t he m or ni n g. 
•  O n da ys t hat P K sa m ples are o btai ne d, t h e s u bject s h o ul d ta ke asci mi ni b d uri n g t he cli nic 
visit after t he pre -d ose P K sa m ples, w he n i nstr uct e d b y t he st u d y staff.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
•  Asci mi ni b s h o ul d be a d mi nistere d i n t he faste d state: a v oi d f o o d f or at least 2 h o urs bef ore 
t he d ose is ta ke n a n d f or at least 1 h o ur aft er t he d ose is ta ke n. Wat er is per mitte d d uri n g 
t his peri o d. 
•  Asci mi ni b s h o ul d be ta ke n wit h a p pr o xi matel y 8 o u nces ( 2 4 0 m L) of water.  
•  S u bject s h o ul d be i nstr ucte d t o s wall o w w h ole ta blets a n d n ot t o c he w or t o brea k t he m.  
•  If v o miti n g occ urs d uri n g t he first h o ur after ta ki n g t he dr u g, re-d osi n g is all o we d b ef ore 
t he ne xt sc he d ule d d os e. 
•  If t he s u bject d o es n ot ta ke asci mi ni b wit hi n 1 2 h o urs after t h e us ual d osi n g ti me, t hat d ose 
s h o ul d be s ki p pe d a n d tr eat me nt s h o ul d c o nti n ue wit h t he ne xt dail y d ose at t he prescri be d 
le vel.  
All d osa ges f or all c o m p o u n ds prescri be d a n d dis pe nse d t o t he patie nts  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 h e D osa ge A d mi nistrati o n Rec or d e C R F. All kits of st u d y 
treat me nt assi g ne d b y t he I R T will be rec or de d i n t he I R T s yste m. 
7  
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 ( wit nesse d, w here re q uir e d 
b y la w or re g ulati o n), I nstit uti o nal Re vie w B oar d (I R B)/I n d e pe n de nt Et hics C o m mittee (I E C) -
a p pr o ve d i nf or me d c o nse nt.  
If a p plica ble, i n cases w h ere t he s u bject's re prese ntati ve(s) gi ves c o nse nt (if all o we d acc or di n g 
t o l ocal re q uire m e nts), t h e s u bject m ust be i nf or me d a b o ut t he st u d y t o t he e xte nt p ossi ble gi ve n 
his/ her u n dersta n di n g. If t he s u bject is ca pa bl e of d oi n g s o , he/s he m ust i n dicate a gree me nt b y 
pers o nall y si g ni n g a n d dati n g t he writte n i nf or me d c o nse nt d oc u me nt.  
I nf or me d c o nse nt m ust b e o btai ne d bef ore c o n d ucti n g a n y st u d y-s pecific pr oce d ures (e. g. 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 btai ni n g i nf or me d c o nse nt m ust be 
d oc u me nte d i n t he s u bject s o urce d oc u me nts.  
N o vartis will pr o vi de t o i n vesti gat ors i n a se parate d oc u me nt a pr o p ose d i nf or me d c o nse nt f or m 
t hat c o m plies wit h t he I nter nati o nal C o u nsel f or Har m o nizati o n G o o d Cli nical Practice (I C H 
G C P) g ui deli nes a n d re g ulat or y re q uire me nts a n d is c o nsi dere d a p pr o pri ate f or t his st u d y. A n y 
c ha n ges t o t he pr o p os e d c o nse nt f or m s u g geste d b y t he i n vesti gat or m ust be a gree d b y N o vartis 
bef ore s u b missi o n t o t he I R B/I E C.  
I nf or mati o n a b o ut c o m m o n si de effects alrea d y k n o w n a b o ut t he i n vesti gati o nal dr u g ca n be 
f o u n d i n t he [ As ci mi ni b I n vesti gat or's Br oc h ure] a n d/ or t he l atest  l ocal a p pr o ve d pr o d uct 
i nf or mati o n f or i mati ni b a n d nil oti ni b. T his i nf or mati o n will be i ncl u de d i n t he s u bject i nf or me d 
c o nse nt a n d s h o ul d be disc usse d wit h t he s u bj ect d uri n g t h e st u d y as nee d e d. A n y n e w 
i nf or mati o n re g ar di n g t he safet y pr ofile of t he i nvesti gati o nal dr u g t hat is i d e ntifie d bet w ee n I B 
u p dates will be c o m m u nicate d as a p pr o priate, f or e xa m ple, vi a a n i n vesti gat or n otificati o n or 
a n a g gre gate safet y fi n di n g. Ne w i nf or m ati o n mi g ht re q uire a n u p date t o t h e i nf or me d c o ns e nt 
a n d t he n m ust be disc usse d wit h t he s u bject.  

N o v arti s  
C o nfi d e nti al  
P a g e 8 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
W o me n of c hil d beari n g p ote ntial m ust be i nf or me d t hat ta ki n g t he st u d y treat me nt 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 h at 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 t he c o ntrace pti o n re q uire me nts w hile ta ki n g st u d y 
treat me nt a n d f or 1 4 da ys after st o p pi n g st u d y  me dicati o n i n treat me nt ar ms 1 –  4, a n d f or 3 
da ys after st o p pi n g asci mi ni b si n gle a ge nt. If l ocal re g ulati o ns or l ocall y a p pr o ve d prescri bi n g 
i nf or mati o n are m or e stri n ge nt t ha n t he pr ot oc ol re q uire d d urati o n of c o ntr ace pti o n, t he l o n ger 
d urati o n m ust be f oll o we d . 
patie nts As per Secti o n 4. 6 , d uri n g a p u blic healt h e mer ge n c y as declare d b y l ocal or re gi o nal 
a ut h orities i.e. pa n de mic, e pi de mic, ge o p olitical sit uati o n  or nat ur al disaster, t hat ma y c halle n g e 
t he a bilit y t o o btai n a sta n dar d writte n i nf or me d c o nse nt d ue t o li mits t hat pre ve nt a n o n-site 
visit, I n vesti gat or ma y c o n d uct t he i nf or me d c o nse nt disc ussi o n re m ot el y (e. g. tele p h o ne, 
vi de oc o nfere nce) if all o wa ble  b y a l ocal healt h a ut h orit y.  
G ui da nce iss ue d b y l o cal re g ulat or y b o di es o n t his as pect pre vail a n d m ust b e i m ple me nte d a n d 
a p pr o priatel y d oc u me nt e d (e. g. t he prese nce of a n i m partial wit ness, si g n/ dati n g se parate I C Fs 
b y trial s u bject a n d pers o n o btai ni n g i nf or me d c o nse nt, etc.).  
A c o p y of t he a p pr o ve d v ersi o n of all c o nse nt f or ms m ust be pr o vi de d t o N o vartis after I R B/I E C 
a p pr o val.  
8  
Vi sit s c h e d ul e a n d a s s e s s m e nt s  
Assess me nt sc he d ul e lists all of t h e ass ess me nts w he n t he y are p erf or m e d. All data o btai ne d 
fr o m t hese ass ess me nts m ust be s u p p orte d i n t he s u bject’s s o urce d oc u me ntati o n. 
Patie nts  s h o ul d be see n f or all visits/assess me nts as o utli ne d i n t he assess me nt sc he d ule or as 
cl ose t o t he d esi g nate d d a y/ti me as p ossi ble. Misse d or resc h e d ule d visits s h o ul d n ot lea d t o 
a ut o matic disc o nti n uati o n.  
N ote: wee k 2, 4, 6, 8, a n d 1 0 visits are n ot ma n dat or y f or patie nts ra n d o mize d t o i mati ni b or 
nil oti ni b ar ms.  
F or all visits, a ± 3 da y visit wi n d o w is all o we d.  
Patie nts  w h o pre mat urel y disc o nti n ue t he st u d y f or a n y reas o n s h o ul d be sc he d ule d f or a visit 
as s o o n as p ossi ble, at w hic h ti me all of t he assess me nts liste d f or t he fi nal visit will be 
perf or me d. At t his fi nal visit, all dis pe nse d st u d y dr u gs s h o ul d be rec o ncil e d, a n d t h e a d v erse 
e ve nt a n d c o n c o mita nt me dicati o ns rec or de d o n t h e C R F.  
As per Secti o n 4. 6 , d uri n g a p u blic healt h e mer ge nc y as declare d b y l ocal or re gi o nal a ut h orities 
i.e. pa n de mic, e pi de mic, ge o p olitical sit uati o n  or nat ural disaster t hat li mits or pre v e nts o n -site 
st u d y visits, alter nati ve met h o ds of pr o vi di n g c o nti n ui n g care ma y b e i m ple me nte d b y t he 
I n v esti gat or as t he sit uati o n dictates. If all o wa ble b y a l ocal healt h a ut h orit y, nati o nal a n d l ocal 
re g ulati o ns an d de p e n di n g o n o perati o nal ca pa bilities, p h o ne calls, virt ual c o ntacts (e. g. t ele 
c o ns ultati o n) or visits b y site staff/ off -site healt hcare pr ofessi o n al(s) staff t o t he s u bject´s h o me, 
ca n re place certai n pr ot o c ol assess me nts, f or t h e d urati o n of t he disr u pti o n u ntil it is safe f or t he 
s u bject t o visit t he site a gai n. If t he I n vesti gat or dele gates tas ks t o a n off -site healt hcare 
pr ofessi o nal, t he I n vesti gat or m ust e ns ure t he i n di vi d ual(s) is/are q u alifie d a n d a p pr o priatel y 
trai ne d t o perf or m assi g ne d d uties. T he I n vesti g at or m ust o versee t h eir c o n d uct a n d re mai n 
res p o nsi ble f or t he e val u ati o n of t he data c ollecte d. 

N o v arti s  
 
C o nfi d e nti al  
 
P a g e 8 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
T a bl e 8 -1  
A s s e s s m e nt S c h e d ul e, r a n d o mi z e d tr e at m e nt  ar m s 1 –  4 a n d a s ci mi ni b si n gl e a g e nt c o h ort  
P eri o d  
S cr e e ni n g  
R a n d o mi z e d Tr e at m e nt  
E n d of  
Tr e at m e nt  
P o st -Tr e at m e nt F oll o w -U p  
Vi sit N a m e  
S cr e e ni n g  B a s eli n e  W e e k 
2 1  
W e e k 
4 1  
W e e k 
6 1  
W e e k 
8 1  
W e e k 
1 0 1  
W e e k 
1 2  
W e e k 
2 4  
W e e k 
3 6  
W e e k 
4 8 2  
E v er y 1 2 w e e k s u p 
t o 9 6 / 4 8 w e e k s 
aft er t h e fir st d o s e 
of t h e l a st 
r a n d o mi z e d / 
e nr oll e d s u bj e ct 3  
E n d of  
Tr e at m e nt 4, 5  
S af et y F oll o w -
U p  
E n d of 
St u d y 
Vi sit 4, 5  
D a y s  
-2 1 t o -1  
1  
1 4  
2 8  
4 2  
5 6  
7 0  
8 4  
1 6 8  
2 5 2  
3 3 6  
- 
Wit hi n l a st  
d o s e + 1 4  
L a st d o s e  
+ 3 0 d a y s  
- 
I nf or m e d c o n s e nt X  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
I W R S/I R T 
R e gi str ati o n  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
  
R a n d o mi z ati o n  
 
X  
 
 
 
 
 
 
 
 
 
 
 
  
  
D e m o gr a p h y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
I n cl u si o n / 
E x cl u si o n crit eri a  X  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
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 s e a s e Hi st or y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
Pri or 
A nti n e o pl a sti c 
T h er a p y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
Pri or c o n c o mit a nt 
m e di c ati o n s  
X  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
C o n c o mit a nt 
m e di c ati o n s  
 
O n g oi n g b a si s  
  
P h y si c al 
E x a mi n ati o n  
S  
S  
S  
S  
S  
S  
S  
S  
S  
S  
S  
S  
S  
  
  

N o v arti s  
 
C o nfi d e nti al  
 
P a g e 8 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
P eri o d  
S cr e e ni n g  
R a n d o mi z e d Tr e at m e nt  
E n d of  
Tr e at m e nt  
P o st -Tr e at m e nt F oll o w -U p  
Vi sit N a m e  
S cr e e ni n g  B a s eli n e  W e e k 
2 1  
W e e k 
4 1  
W e e k 
6 1  
W e e k 
8 1  
W e e k 
1 0 1  
W e e k 
1 2  
W e e k 
2 4  
W e e k 
3 6  
W e e k 
4 8 2  
E v er y 1 2 w e e k s u p 
t o 9 6 / 4 8 w e e k s 
aft er t h e fir st d o s e 
of t h e l a st 
r a n d o mi z e d / 
e nr oll e d s u bj e ct 3  
E n d of  
Tr e at m e nt 4, 5  
S af et y F oll o w -
U p  
E n d of 
St u d y 
Vi sit 4, 5  
D a y s  
-2 1 t o -1  
1  
1 4  
2 8  
4 2  
5 6  
7 0  
8 4  
1 6 8  
2 5 2  
3 3 6  
- 
Wit hi n l a st  
d o s e + 1 4  
L a st d o s e  
+ 3 0 d a y s  
- 
E xtr a m e d ull ar y 
i n v ol v e m e nt 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
  
Vit al Si g n s  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
  
B o d y H ei g ht  
X  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
B o d y W ei g ht  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
  
P eri p h er al Bl o o d 
B C R -A B L 1 R T -
q P C R  
X  
 
 
X  
 
X  
 
X  
X  
X  
X  
X  
X  
  
  
B o n e m arr o w 
a s s e s s m e nt f or 
c yt o g e n eti c 
a s s e s s m e nt  
 
 
U p o n Tr e at m e nt F ail ur e  
  
  
H e m at ol o g y  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
  
Cli ni c al C h e mi str y  X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
  
H b A 1 c  
X  
 
 
 
 
 
 
X  
X  
 
X  
W e e k 7 2  
X  
  
  
H e p atiti s s cr e e n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
Pr e g n a n c y T e st 
( s er u m) 
X  
X  
 
X  
 
X  
 
X  
X  
X  
X  
X  
X  
  
  
Pr e g n a n c y T e st 
( uri n e) 
 
 
S - E v er y 4 w e e k s if s er u m pr e g n a n c y t e st i s n ot p erf or m e d  
  
  
El e ctr o c ar di o gr a m 
( E C G) 
X  
X  
X  
X  
 
 
 
X  
X  
 
X  
E v er y 4 8 w e e k s u p 
t o 9 6 w e e k s aft er 
t h e fir st d o s e of t h e 
X  
  
  

N o v arti s  
 
C o nfi d e nti al  
 
P a g e 8 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
P eri o d  
S cr e e ni n g  
R a n d o mi z e d Tr e at m e nt  
E n d of  
Tr e at m e nt  
P o st -Tr e at m e nt F oll o w -U p  
Vi sit N a m e  
S cr e e ni n g  B a s eli n e  W e e k 
2 1  
W e e k 
4 1  
W e e k 
6 1  
W e e k 
8 1  
W e e k 
1 0 1  
W e e k 
1 2  
W e e k 
2 4  
W e e k 
3 6  
W e e k 
4 8 2  
E v er y 1 2 w e e k s u p 
t o 9 6 / 4 8 w e e k s 
aft er t h e fir st d o s e 
of t h e l a st 
r a n d o mi z e d / 
e nr oll e d s u bj e ct 3  
E n d of  
Tr e at m e nt 4, 5  
S af et y F oll o w -
U p  
E n d of 
St u d y 
Vi sit 4, 5  
D a y s  
-2 1 t o -1  
1  
1 4  
2 8  
4 2  
5 6  
7 0  
8 4  
1 6 8  
2 5 2  
3 3 6  
- 
Wit hi n l a st  
d o s e + 1 4  
L a st d o s e  
+ 3 0 d a y s  
- 
l a st r a n d o mi z e d / 
e nr oll e d s u bj e ct  
A d v er s e E v e nt s  
O n g oi n g b a si s  
  
St u d y dr u g 
di s p e n s ati o n  
  
X  
 
 
 
 
 
X  
X  
X  
X  
X  
 
  
  
St u d y dr u g 
a d mi ni str ati o n  
  
O n g oi n g b a si s  
 
  
  
P K s a m pli n g 
( A s ci mi ni b + 
I m ati ni b ar m s a n d 
a s ci mi ni b si n gl e 
a g e nt c o h ort o nl y)  
  
 
X  
X  
 
 
 
X  
X  
X  
 
W e e k 6 0 a n d 9 6  
 
  
  
W h ol e bl o o d f or 
 
 
 b y 
 
C CI
C CI
C CI
C CI

N o v arti s  
 
C o nfi d e nti al  
 
P a g e 9 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
P eri o d  
S cr e e ni n g  
R a n d o mi z e d Tr e at m e nt  
E n d of  
Tr e at m e nt  
P o st -Tr e at m e nt F oll o w -U p  
Vi sit N a m e  
S cr e e ni n g  B a s eli n e  W e e k 
2 1  
W e e k 
4 1  
W e e k 
6 1  
W e e k 
8 1  
W e e k 
1 0 1  
W e e k 
1 2  
W e e k 
2 4  
W e e k 
3 6  
W e e k 
4 8 2  
E v er y 1 2 w e e k s u p 
t o 9 6 / 4 8 w e e k s 
aft er t h e fir st d o s e 
of t h e l a st 
r a n d o mi z e d / 
e nr oll e d s u bj e ct 3  
E n d of  
Tr e at m e nt 4, 5  
S af et y F oll o w -
U p  
E n d of 
St u d y 
Vi sit 4, 5  
D a y s  
-2 1 t o -1  
1  
1 4  
2 8  
4 2  
5 6  
7 0  
8 4  
1 6 8  
2 5 2  
3 3 6  
- 
Wit hi n l a st  
d o s e + 1 4  
L a st d o s e  
+ 3 0 d a y s  
- 
E O R T C Q L Q -C 3 0 
pl u s C M L 2 4  
  
X  
 
X  
 
 
 
X  
X  
 
X  
W e e k 9 6  
 
  
  
T S Q M  
  
X  
 
X  
 
 
 
X  
X  
 
X  
W e e k 9 6  
 
  
  
F A CI T G P 5  
  
X  
 
X  
 
 
 
X  
X  
 
X  
W e e k 9 6  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
A nti n e o pl a sti c 
t h er a pi e s si n c e 
di s c o nti n u ati o n of 
st u d y tr e at m e nt  
  
  
  
  
  
  
  
  
  
  
  
  
 
X  
 
Di s p o siti o n  
  
  
  
  
  
  
  
  
  
  
  
  
X  
 
X  
X  A s s e s s m e nt t o b e r e c or d e d i n t h e cli ni c al d at a b a s e or r e c ei v e d el e ctr o ni c all y fr o m a v e n d or  
S  A s s e s s m e nt t o b e r e c or d e d i n t h e s o ur c e d o c u m e nt ati o n o nl y  
1  N ot m a n d at or y vi sit s f or p ati e nt s  i n i m ati ni b a n d nil oti ni b ar m 
2  P ati e nt s  i n i m ati ni b c o nti n u ati o n ar m m a y cr o s s-o v er t o r e c ei v e a s ci mi ni b +i m ati ni b aft er W e e k 4 8 vi sit  
3  A s ci mi ni b si n gl e a g e nt c o h ort, e v er y 1 2 w e e k s u p t o 4 8 w e e k s aft er t h e fir st d o s e of t h e l a st e nr oll e d s u bj e ct  
4 Tr e at m e nt ar m s 1 –  4: t h e st u d y tr e at m e nt will e n d at 9 6 w e e k s ( pl u s 3 0 d a y s f or t h e s af et y f oll o w u p) aft er t h e l a st r a n d o mi z e d s u bj e ct r e c ei v e d t h e fir st do s e of st u d y 
tr e at m e nt. 
5  A s ci mi ni b si n gl e a g e nt c o h ort: t h e st u d y tr e at m e nt will e n d at 4 8 w e e k s ( pl u s 3 0 d a y s f or t h e s af et y f oll o w u p) aft er t h e l a s t e nr oll e d s u bj e ct r e c ei v e d t h e fir st d o s e of 
st u d y tr e at m e nt  
6 W h ol e bl o o d f or 
 b y  
 will N O T b e c oll e ct e d i n a s ci mi ni b si n gl e a g e nt c o h ort. 
C CI
C CI

N o v arti s  
 
C o nfi d e nti al  
 
P a g e 9 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
T a bl e 8 -2  
A s s e s s m e nt S c h e d ul e, p ati e nt s  r a n d o mi z e d t o t h e c o nti n u e d i m ati ni b ar m w h o cr o s s-o v er t o r e c ei v e a s ci mi ni b 
6 0 m g + i m ati ni b  
P eri o d  
Cr o s s -O v er 
B a s eli n e  
Cr o s s -O v er Tr e at m e nt  
E n d of 
Tr e at m e nt  
P o st -Tr e at m e nt 
F oll o w -U p  
Vi sit N a m e  
C O B a s eli n e 1  
C O 
W e e k 2  
C O 
W e e k 4  
C O 
W e e k 6  
C O 
W e e k 8  
C O 
W e e k 
1 0  
St art fr o m 1 2 w e e k s aft er 
cr o s s -o v er, e v er y 1 2 w e e k s u p t o 
9 6 w e e k s aft er t h e fir st d o s e of 
t h e l a st r a n d o mi z e d s u bj e ct 
E n d of 
Tr e at m e nt  
S af et y 
F oll o w -U p  
E n d of 
St u d y  
D a y s  
1  
1 4  
2 8  
4 2  
5 6  
7 0  
- 
Wit hi n l a st 
d o s e + 1 4  
L a st d o s e 
+ 3 0  
- 
I W R S/I R T 
R e gi str ati o n  
X  
X  
X  
X  
X  
X  
X  
X  
 
  
C o n c o mit a nt 
m e di c ati o n s  
O n g oi n g b a si s  
  
P h y si c al E x a mi n ati o n  S  
S  
S  
S  
S  
S  
S  
S  
 
  
E xtr a m e d ull ar y 
i n v ol v e m e nt 
X  
X  
X  
X  
X  
X  
X  
X  
 
  
Vit al Si g n s  
X  
X  
X  
X  
X  
X  
X  
X  
 
  
B o d y W ei g ht  
X  
X  
X  
X  
X  
X  
X  
X  
 
  
P eri p h er al Bl o o d 
B C R -A B L 1 R T -q P C R  
 
 
X  
 
X  
 
X  
X  
 
  
B o n e m arr o w 
a s s e s s m e nt f or 
c yt o g e n eti c 
a s s e s s m e nt  
U p o n Tr e at m e nt f ail ur e  
 
  
H e m at ol o g y  
X  
X  
X  
X  
X  
X  
X  
X  
 
  
Cli ni c al C h e mi str y  
X  
X  
X  
X  
X  
X  
X  
X  
 
  
H b A 1 c  
 
 
 
 
 
 
1 2, 2 4, 4 8 a n d 7 2 w e e k s aft er 
cr o s s -o v er  
X  
 
  
Pr e g n a n c y T e st 
( s er u m) 
X  
 
X  
 
X  
 
X  
X  
 
  
Pr e g n a n c y T e st 
( uri n e) 
S - E v er y 4 w e e k s if s er u m pr e g n a n c y t e st i s n ot p erf or m e d  
 
  

N o v arti s  
 
C o nfi d e nti al  
 
P a g e 9 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
P eri o d  
Cr o s s -O v er 
B a s eli n e  
Cr o s s -O v er Tr e at m e nt  
E n d of 
Tr e at m e nt  
P o st -Tr e at m e nt 
F oll o w -U p  
Vi sit N a m e  
C O B a s eli n e 1  
C O 
W e e k 2  
C O 
W e e k 4  
C O 
W e e k 6  
C O 
W e e k 8  
C O 
W e e k 
1 0  
St art fr o m 1 2 w e e k s aft er 
cr o s s -o v er, e v er y 1 2 w e e k s u p t o 
9 6 w e e k s aft er t h e fir st d o s e of 
t h e l a st r a n d o mi z e d s u bj e ct 
E n d of 
Tr e at m e nt  
S af et y 
F oll o w -U p  
E n d of 
St u d y  
D a y s  
1  
1 4  
2 8  
4 2  
5 6  
7 0  
- 
Wit hi n l a st 
d o s e + 1 4  
L a st d o s e 
+ 3 0  
- 
El e ctr o c ar di o gr a m 
( E C G) 
X  
X  
X  
 
 
 
1 2, 2 4, 4 8 w e e k s aft er cr o s s -o v er 
a n d e v er y 4 8 w e e k s u p t o 9 6 w e e k s 
aft er t h e fir st d o s e of t h e l a st 
r a n d o mi z e d s u bj e ct 
X  
 
 
A d v er s e E v e nt s  
O n g oi n g b a si s  
 
St u d y dr u g 
di s p e n s ati o n  
X  
 
 
 
 
 
X  
 
 
 
St u d y dr u g 
a d mi ni str ati o n  
O n g oi n g b a si s  
 
 
 
E O R T C Q L Q -C 3 0 
pl u s C M L 2 4  
 
 
 
 
 
 
C O w e e k 4 8, C O W e e k 9 6  
 
 
 
T S Q M  
 
 
 
 
 
 
C O W e e k 4 8, C O W e e k 9 6  
 
 
 
F A CI T G P 5  
 
 
 
 
 
 
C O W e e k 4 8, C O W e e k 9 6  
 
 
 
A nti n e o pl a sti c 
t h er a pi e s si n c e 
di s c o nti n u ati o n of 
st u d y tr e at m e nt  
 
 
 
 
 
 
 
 
X  
 
Di s p o siti o n  
 
 
 
 
 
 
 
X  
 
X  
X  A s s e s s m e nt t o b e r e c or d e d i n t h e cli ni c al d at a b a s e or r e c ei v e d el e ctr o ni c all y fr o m a v e n d or  
S  A s s e s s m e nt t o b e r e c or d e d i n t h e s o ur c e d o c u m e nt ati o n o nl y  
1  If t h e cr o s s-o v er tr e at m e nt st art s wit hi n 7 d a y s fr o m W e e k 4 8 vi sit, it i s n ot r e q uir e d t o p erf or m a g ai n h e m at ol o g y, c h e mi str y a n d s er u m p r e g n a n c y t e st a s w ell a s t h e 
E C G a s s e s s m e nt s at t h e C O B a s eli n e vi sit.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
8. 1  
S cr e e ni n g  
Writte n i nf or me d c o nse nt m ust be o btai ne d bef ore a n y st u d y s pecific me dical pr oce d ures are 
perf or me d.  
All scree ni n g/ baseli ne assess me nts s h o ul d occ ur wit hi n 2 1 da ys bef ore ra n d o mizati o n.  
Scree ni n g assess me nts i ncl u de: p h ysical e xa mi nati o n, e xtra me d ullar y i n v ol ve me nt, vital si g ns, 
b o d y hei g ht a n d wei g ht, E C G, la b orat or y ( he mat ol o g y, bi oc he mistr y, he m o gl o bi n A 1c 
( H b A 1c), He p atitis scree n, ser u m pre g n a nc y test, peri p heral bl o o d c ollecti o n f or B C R -A B L 1 
R T -q P C R), e val uati o n of all rel e va nt me dical hist or y i ncl u di n g car di o v asc ular ris k fact ors, 
C M L disease hist or y, i ncl u di n g pri or T KI t hera p y, a nti ne o plastic me dicati o n, pri or a n d 
c o nc o mita nt 
me dicati o n a n d 
m ust be perf or m e d pri or t o ra n d o mizati o n . F or det ails of 
assess me nts re q uir e d d uri n g scree ni n g please refer t o Ta ble 8 -1 . 
D uri n g t he scree ni n g visit, i ncl usi o n a n d e xcl usi o n criteria will be assesse d. Scree ni n g 
assess me nts t o c o nfir m eli gi bilit y m ust be perf or me d pri or t o ra n d o mizati o n.  
Patie nts  wit h p otassi u m, a n d/ or m a g nesi u m a n d/ or t otal calci u m le vels t hat are < L L N at 
scree ni n g, m ust ha ve t heir p otassi u m, a n d/ or m a g nesi u m, a n d/ or calci u m re ple nis he d t hr o u g h 
s u p ple me ntati o n a n d t he le vels m ust be wit hi n n or mal li mits pri or t o ra n d o mizati o n.  
T he ce ntral rea di n g of t he scree ni n g E C Gs as well as t he res ults of t he B C R -A B L 1 R T -q P C R, 
he mat ol o g y, c he mistr y a n d he patitis scree n m ust b e a v aila ble pri or t o ra n d o mizati o n t o e val uat e 
eli gi bilit y. 
A s u bject w h o has a la b orat or y test ( peri p heral bl o o d test) or E C G res ults t hat d o n ot satisf y t he 
e ntra nce criteria ma y ha ve t he tests re peate d. T hese tests ma y be re peate d as s o o n as t he 
i n vesti gat or belie ves t he re-test res ults are li kel y t o be wit hi n the acce pta bl e ra n g e t o satisf y t h e 
e ntra nce criteria, b ut s h o ul d be c o m plete d wit hi n t he 2 1 da y scree ni n g peri o d. I n t his case, t he 
s u bject will n ot be re q uire d t o si g n a n ot her I C F, a n d t he ori gi nal s u bject i de ntificati o n (I D) 
n u m ber assi g ne d b y t he i n vest i gat or will be use d. 
I n t h e e ve nt t hat t he l a b orat or y tests ca n n ot be p erf or me d wit hi n t he scree ni n g visit wi n d o w, or 
t he re-tests d o n ot meet t he e ntra n ce criteria, or ot her eli gi bilit y criteria ha ve c ha n ge d a n d are 
n ot met a n y m ore, t he s u bject is c o nsi dere d a scree n fail ure,  a n d m ust b e dis c o nti n ue d fr o m t h e 
st u d y. A ne w I C F will nee d t o be si g ne d if t he i n vesti gat or c h o oses t o re-scree n t he s u bject after 
a s u bject has scree n faile d a n d t he s u bject will be assi g ne d a ne w s u bject I D n u m ber. All 
re q uire d s cree ni n g acti vities m ust be perf or me d w he n t he s u bject is re-s cree n e d f or p artici pati o n 
i n t he st u d y. A n i n di vi d ual s u bject ma y o nl y be re-s cree n e d o nce f or t he st u d y. O nce t he n u m ber 
of patie nts  scree ne d a n d e nr olle d is li kel y t o e ns ure tar g et e nr oll me nt, t he S p o ns or ma y cl ose 
t he st u d y t o f urt her scree ni n g. I n t his case, t he patie nts  w h o scree n faile d will n ot be per mitte d 
t o re-scree n. 
8. 1. 1  
Eli gi bilit y s cr e e ni n g  
F oll o wi n g re gisteri n g i n t he I R T f or scree ni n g, s u bject eli gi bilit y c hec k will be e m be d de d i n 
t he I R T s yste m b y a n eli gi bilit y tra nsacti o n. T he eli gi bilit y will be c o nfir me d i n t he I R T after 
scree ni n g pr oce d ures a n d pri or t o ra n d o mizati o n visit. Please ref er a n d c o m pl y wit h detaile d 
g ui deli nes i n t he I R T ma n ual.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
8. 1. 2  
I nf or m ati o n t o b e c oll 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 n a n i nf or me d c o nse nt a n d s u bse q ue ntl y are f o u n d t o be i neli gi ble pri or t o 
ra n d o mizati o n f or tr eat m e nt ar ms 1- 4, a n d pri or t o e nr oll me nt f or as ci mi ni b si n gle a ge nt c o h ort 
will be c o nsi dere d a s cree n fail ure. T he de m o gra p hic i nf or mati o n, i nf or me d c o ns e nt, a n d 
I n cl usi o n/ E xcl usi o n pa ges m ust als o be c o m plete d f or scree n fail ure patie nts . N o ot her data will 
be e ntere d i nt o t he cli nical data b ase f or p atie nts  w h o are s cree n fail ures, u nless t he s u bject 
e x perie n ce d a seri o us a d verse e ve nt d uri n g t he scree ni n g p h ase (see S A E s ecti o n f or re p orti n g 
details). If t he s u bject fails t o be ra n d o mize d or e nr olle d, t he I R T m ust be n otifie d wit hi n 2 da ys 
of t he scree n fail t hat t he s u bject was n ot ra n d o mize d or e nr olle d.  
8. 2  
S u bj e ct 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  
S u bject de m o gra p hic a n d baseli ne c h aracteristic data t o be c ollect e d o n all patie nts  i ncl u de: a ge, 
ge n der, race, et h nicit y, hei g ht, 
wei g ht, s o urce of s u bj ect referral, rele va nt 
me dical 
hist or y/c urre nt me dical c o n diti o n prese nt bef ore si g ni n g i nf or me d c o nse nt w here p ossi ble, 
C M L disease hist or y, a n d pri or a n d c o n c o mita nt me dicati o n i ncl u di n g pri or T KI t hera p y a n d 
a nti ne o plastic me dicati o n. Dia g n oses a n d n ot s y m pt o ms will be rec or de d.  
Baseli ne assess me nts i ncl u de: p h ysical e xa mi nati o n, e xtra m e d ullar y i n v ol ve me nt, vital si g ns, 
b o d y wei g ht, E C G, la b orat or y ( he m at ol o g y, bi oc he mistr y, ser u m pre g na nc y test, bl o o d 
c ollecti o n f or B C R -A B L 1 m utati o nal a nal ysis), bi o mar ker assess me nts a n d P R Os.  
If t he baseli ne ass ess me nts will be perf or me d wit hi n 7 da ys fr o m scree ni n g, it is n ot re q uire d t o 
perf or m a gai n t he he mat ol o g y, c he mistr y a n d s er u m pre g n a nc y t est as well as t he E C G 
assess me nts.  
I n v esti gat ors will ha ve t he discreti o n t o rec or d a b n or mal test fi n di n gs o n t he me dical hist or y 
C R F w he ne v er i n t heir j u d g me nt, t he test a b n or malit y occ urre d pri or t o t he i nf or me d c o ns e nt 
si g nat ure. Si g nifica nt ne w fi n di n gs t hat be gi n or w orse n after i nf or m e d c o nse nt m ust be 
rec or de d o n t he A E p a ge of t he s u bject’s e C R F. 
8. 3  
Effi c a c y  
8. 3. 1  
M ol e c ul ar r e s p o n s e a n d B C R:: A B L 1 R T -q P C R  
M olec ular res p o nse ( M R) will be assesse d i n all p atie nts  ra n d o mize d t o eac h treat me nt ar m. 
Le vels of B C R:: A B L 1 tra nscri pts will be d eter mi ne d b y real -ti me q ua ntitati v e P C R ( R T-q P C R) 
testi n g of peri p heral bl o o d a n d a nal yze d at a ce ntral testi n g la b orat or y. L o g re d ucti o n i n 
B C R:: A B L 1 tra nscri pts le vels fr o m t he sta n dar dize d bas eli ne val ue, or t he perce nt rati o of 
B C R:: A B L 1 tra nscri pts vers us  c o ntr ol g e ne ( A B L) tra nscri pts c o n verte d t o a refere nce sta n dar d, 
i nter nati o nal scale (I S), will be calc ulate d f or eac h sa m ple. 
Maj or m olec ular res p o ns e a n d rel ate d varia bles are defi ne d as t he f oll o wi n g:  
•  M M R: B C R:: A B L ≤ 0. 1 % (I S)  
•  M R
4. 0: B C R:: A B L ≤ 0. 0 1 % (I S) 
•  M R
4. 5: B C R:: A B L ≤0. 0 0 3 2 % (I S) 

N o v arti s  
C o nfi d e nti al  
P a g e 9 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
U nc o nfir me d l oss of M M R is defi ne d as i ncrease of B C R:: A B L t o > 0. 1 % b y I nter n ati o nal 
Scale (I S) i n ass ociati o n wit h 5 -f ol d rise i n t he B C R:: A B L fr o m t he l o west val ue ac hie ve d o n 
st u d y treat me nt a n d c o nfir me d b y a d u plicate a nal ysis of t he sa me sa m ple. L os s of M M R is 
c o nfir me d b y a s u bse q ue nt a nal ysis of a s a m ple c ollecte d wit hi n 4 -6 wee ks u nless t he l oss of 
M M R is ass ociate d wit h c o nfir me d l oss of C H R, l oss of C C y R, pr o gressi o n t o A P/ B C, or C M L -
relate d deat h. 
U p o n c o nfir me d l oss of 
M M R b y R T -q P C R, m utati o n a nal ysis will be perf or me d at a 
desi g nate d la b orat or y b y Sa n ger se q ue n ci n g usi n g re m na nt R N A fr o m sa m ple alrea d y c ollecte d 
a n d teste d f or R T -q P C R.  
B C R:: A B L 1 R T -q P C R a nal ysis will be p erf or me d at a desi g nat e d la b orat or y at s cree ni n g, 
Wee k 4 (if a p plica ble), Wee k 8 (if a p plica ble), Wee k 1 2, 2 4, 3 6, 4 8, e ver y 1 2 wee ks u p t o 9 6 
wee ks after t he first d ose of t he last ra n d o mize d s u bject a n d at e n d of treat me nt; f or t he 
cr oss-o ver ar m at C O Wee k 4, 8, start fr o m 1 2 wee ks after cr oss -o v er, e v er y 1 2 wee ks u p t o 9 6 
wee ks after t he first d ose of t he last ra n d o mize d s u bject a n d at e n d of treat me nt.  
T he bl o o d sa m ples will be ta ke n as d escri be d i n T a ble 8 -3  a n d T a ble 8 -4 . 
T a bl e 8 -3  
Bl o o d s a m pl e s f or P C R ( pri m ar y a n d s e c o n d ar y effi c a c y e n d p oi nt s) i n 
all r a n d o mi z e d tr e at m e nt ar m s 1 - 4, a n d a s ci mi ni b si n gl e a g e nt c o h ort  
S a m pl e T y p e  
V ol u m e  
Vi sit  
Ti m e p oi nt  
Bl o o d f or B C R:: A B L 
q u a ntifi c ati o n b y R T -
q P C R  
2 0 m L  
S cr e e ni n g  
Pr e -d o s e  
2 0 m L  
W e e k 4*  
Pr e -d o s e  
2 0 m L  
W e e k 8*  
Pr e -d o s e  
2 0 m L  
W e e k 1 2  
Pr e -d o s e  
2 0 m L  
W e e k 2 4  
Pr e -d o s e  
2 0 m L  
W e e k 3 6  
Pr e -d o s e  
2 0 m L  
W e e k 4 8  
Pr e -d o s e  
2 0 m L  
E v er y 1 2 w e e k s u p t o 9 6 
/ 4 8 w e e k s aft er t h e fir st 
d o s e of t h e l a st 
r a n d o mi z e d / e nr oll e d 
s u bj e ct**  
Pr e -d o s e  
2 0 m L  
E n d of Tr e at m e nt  
A n yti m e  
* N ot m a n d at or y vi sit s f or p ati e nt s i n I m ati ni b a n d Nil oti ni b ar m  
** A s ci mi ni b si n gl e a g e nt c o h ort, e v er y 1 2 w e e k s u p t o 4 8 w e e k s aft er t h e fir st d o s e of t h e l a st e nr oll e d s u bj e ct  
T a bl e 8 -4  
Bl o o d s a m pl e s f or P C R i n cr o s s -o v er  
S a m pl e T y p e  
V ol u m e  
Vi sit  
Ti m e p oi nt  
Bl o o d f or B C R:: A B L 
q u a ntifi c ati o n b y R T -
q P C R  
2 0 m L  
C O W e e k 4  
Pr e -d o s e  
2 0 m L  
C O W e e k 8  
Pr e -d o s e  
2 0 m L  
St art fr o m 1 2 w e e k s aft er 
cr o s s -o v er, e v er y 1 2 
w e e k s u p t o 9 6 w e e k s 
aft er t h e fir st d o s e of t h e 
l a st r a n d o mi z e d s u bj e ct 
Pr e -d o s e  
2 0 m L  
E n d of Tr e at m e nt  
A n yti m e  

N o v arti s  
C o nfi d e nti al  
P a g e 9 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
8. 3. 2  
B o n e m arr o w a n al y si s a n d c yt o g e n eti c s  
B o ne marr o w as pir ate f or c yt o ge n etic a n al yses will be perf or me d o nl y u p o n treat me nt fail ure 
(f or defi niti o n of treat me nt fail ure, see Secti o n  9. 1. 1 ). 
Q ua ntificati o n of t he n u m ber of m eta p hases assesse d, n u m ber of meta p h ases p ositi ve f or P h 
c hr o m os o me, a d diti o nal c hr o m os o mal a b n or m alities as well as d ata fr o m micr osc o pic a nal ysis 
of perce nta ge of blasts a n d pr o m yel oc ytes will be rec or de d o n t he B o ne 
Marr o w a n d 
c yt o ge netics e C R F. T h es e e xa ms will be perf or m e d a n d a n al yze d l ocall y. Fl u oresce nt I n -sit u 
h y bri dizati o n ( FI S H) a nal ysis will n ot be acce pte d.  
8. 3. 3  
A p pr o pri at e n e s s of effi c a c y a s s e s s m e nt s  
Assessi n g m olec ular res p o nse wit h R T -q P C R is c o nsi dere d as sta n dar d i n C M L t hera p y a n d 
rec o m me n de d i n tr eat me nt g ui deli nes (Baccara ni  et al 2 0 1 3 , N C C N  2 0 1 8 ). It is ac k n o wle d ge d 
t hat res p o nse ca n be ass esse d usi n g o nl y sta n dar dize d res ults via I nter nati o nal Scale (I S) as 
B C R:: A B L %. 
M utati o nal a nal ysis is re q uire d i n case of tr eat me nt fail ure. C yt o ge netic 
assess me nt is re q uire d i n case of treat me nt fail ure ( Baccara ni  et al 2 0 1 3 , Baccara ni  et al 2 0 1 5 ). 
8. 4  
S af et y a n d  t ol er a bilit y 
Safet y assess me nts are s pecifie d b el o w wit h t he assess me nt sc h e d ule d etaili n g w he n eac h 
assess me nt is t o be perf or me d.  
F or details o n A E c ollecti o n a n d re p orti n g, refer t o A E secti o n.  
As per Secti o n 4. 6 , d uri n g a p u blic healt h e mer ge nc y as declare d b y l ocal or re gi o nal a ut h orities 
i.e. pa n de mic, e pi de mic, ge o p olitical sit uati o n  or nat ural disaster, t h at li mits or pre v e nts o n -site 
st u d y visits, re g ular p h o ne or virt ual calls ca n o cc ur (as nee d e d) f or safet y m o nit ori n g a n d 
disc ussi o n of t he s u bject´s healt h stat us u ntil it is safe f or t he s u bject t o visit t he site a gai n.  
T a bl e 8 -5  
S af et y a n d t ol er a bilit y a s s e s s m e nt s  
A s s e s s m e nt  
S p e cifi c ati o n  
P h y si c al e x a mi n ati o n  
A c o m pl et e p h y si c al e x a mi n ati o n will i n cl u d e t h e e x a mi n ati o n of g e n er al a p p e ar a n c e, 
s ki n, n e c k (i n cl u di n g t h yr oi d), e y e s, e ar s, n o s e, t hr o at, l u n g s, h e art, a b d o m e n, b a c k, 
l y m p h n o d e s, e xtr e miti e s, v a s c ul ar, a n d n e ur ol o gi c al. 
I nf or m ati o n f or all p h y si c al e x a mi n ati o n s m u st b e i n cl u d e d i n t h e s o ur c e 
d o c u m e nt ati o n at t h e st u d y sit e a s u ni q u e s o ur c e d at a, t hi s i nf or m ati o n will n ot b e 
c a pt ur e d i n t h e C R F. Cli ni c all y r el e v a nt fi n di n g s t h at ar e pr e s e nt pri or t o si g ni n g 
i nf or m e d c o n s e nt m u st b e i n cl u d e d i n t h e M e di c al Hi st or y p art of t h e C R F. Si g nifi c a nt 
fi n di n g s m a d e aft er fir st a d mi ni str ati o n of st u d y dr u g w hi c h m e et t h e d efi niti o n of a n 
A d v er s e E v e nt m u st b e r e c or d e d o n t h e A d v er s e E v e nt s e cti o n of t h e C R F.  
P h y si c al e x a mi n ati o n will b e e v al u at e d d uri n g e a c h p erf or m e d vi sit.  
E xtr a m e d ull ar y 
i n v ol v e m e nt 
Pr e s e n c e of e xtr a m e d ull ar y l e u k e mi c i n v ol v e m e nt will b e c h e c k e d wit h e a c h p h y si c al 
e x a mi n ati o n a s o utli n e d a b o v e. Fi n di n g s o n p h y si c al e x a mi n ati o n c o n si st e nt wit h 
e xtr a -m e d ull ar y l e u k e mi c i n v ol v e m e nt will b e r e c or d e d ( e. g. a n y or g a n i n v ol v e m e nt). 
Wit h r e g a r d s t o l y m p h n o d e s, o nl y t h o s e p al p a bl e l y m p h n o d e s s h o ul d b e c o n si d er e d 
t o b e C M L r el at e d if l e u k e mi c bl a st i nfiltr ati o n h a s b e e n c o nfir m e d vi a bi o p s y/ hi st ol o g y 
or b y t e c h ni c all y a d e q u at e a s pir ati o n c yt ol o g y. W h e n e xtr a m e d ull ar y i n v ol v e m e nt 
ot h er t h a n of t h e s pl e e n or li v er i s t h e o nl y e vi d e n c e of bl a st cri si s, t hi s fi n di n g m u st b e 
c o nfir m e d b y t e c h ni c all y a d e q u at e ( n ot c o nt a mi n at e d wit h p eri p h er al bl o o d) a s pir ati o n 
c yt ol o g y a n d/ or bi o p s y ( e s p e ci all y f or i s ol at e d l y m p h n o d e s) a n d d at a e nt er e d i nt o t h e 
e xtr a m e d ull ar y i n v ol v e m e nt e C R F.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
A s s e s s m e nt  
S p e cifi c ati o n  
E xtr a m e d ull ar y i n v ol v e m e nt will b e e v al u at e d d uri n g e a c h p erf or m e d vi sit.  
Vit al si g n s  
Vit al si g n s i n cl u d e s y st oli c a n d di a st oli c bl o o d pr e s s ur e ( s u pi n e p o siti o n pr ef err e d 
w h e n E C G i s c oll e ct e d), p ul s e r at e m e a s ur e m e nt, a n d b o d y t e m p er at ur e.  
Vit al si g n s will b e e v al u at e d d uri n g e a c h p erf or m e d vi sit.  
H ei g ht a n d w ei g ht  
H ei g ht i n i n c h e s or c e nti m et er s ( c m) a n d b o d y w ei g ht (i n p o u n d s or t o t h e n e ar e st 0. 1 
kil o gr a m ( k g) i n i n d o or cl ot hi n g, b ut wit h o ut s h o e s) will b e m e a s ur e d.  
B o d y h ei g ht will b e e v al u at e d o nl y d uri n g s cr e e ni n g vi sit.  
B o d y w ei g ht will b e e v al u at e d d uri n g e a c h p erf or m e d vi sit.  
8. 4. 1  
L a b or at or y e v al u ati o n s  
Ce ntral la b orat or y will b e use d f or a n al ysis of he mat ol o g y, bi oc he mistr y, ser u m pre g na n c y a n d 
he patitis mar ker s peci me ns c ollecte d (safet y m o nit ori n g). Details o n t he c ollecti o ns, s hi p me nt 
of t he s a m ples a n d re p orti n g of res ults b y t he ce ntr al la b orat or y a re pr o vi de d t o i n vesti gat ors i n 
t he [ C A B L 0 0 1 E 2 2 0 1 la b orat or y ma n ual]. T h e ti me wi n d o ws gra nte d f or la b orat or y e val uati o ns 
are i de ntic al wit h t he c orres p o n di n g visit ti me wi n d o ws f or eac h visit (see  Secti o n  8 ). 
A b n or mal la b orat or y val ues or test res ults c o nstit ute a d verse e ve nts o nl y if t he y f ulfill at least 
o ne of t he f oll o wi n g criteria: 1) t he y i n d uce cli nical si g ns or s y m pt o ms, 2) t he y are c o nsi dere d 
cli nicall y si g nifica nt, or 3) t he y re q uire c o nc o mita nt t hera p y or pr oce d ures. Cli nicall y 
si g nifica nt a b n or mal la b orat or y val u es or test res ults s h o ul d be i de ntifie d t hr o u g h a re vie w of 
val ues o utsi de of n or mal ra n ges/cli nicall y n ota ble ra n ges, si g nifica nt c ha n ges fr o m scree ni n g 
or t he pre vi o us visit.  
U nsc he d ule d l ocal la b orat or y assess me nts ma y be perf or me d if me dicall y i n dicate d t o assess a 
( p ote ntial) a d verse e v e nt or w he n t he treati n g p h ysicia n ca n n ot w ait f or ce ntral la b orat or y 
res ults f or decisi o n ma ki n g (e. g. t hera pe utic i nter ve nti o n, i nterr u pti on of st u d y treat me nt). I n 
t his partic ular sit uati o n, if p ossi ble, t he bl o o d sa m ple o btai ne d at t he sa me ti me p oi nt s h o ul d 
be s u b mitte d t o t he ce ntr al la b orat or y f or a n al ysis i n parallel wit h l ocal a nal ysis. T he res ults of 
t he l ocal la b orat or y will be rec orde d i n t he e C R F if a n y of t he f oll o wi n g criteria are met:  
•  A treat me nt de cisi o n was ma de base d o n t he l o cal res ults, or  
•  L ocal la b res ults d oc u me nt a n a d verse e ve nt n ot re p orte d b y t he ce ntral la b, or  
•  L ocal la b res ults d oc u me nt a n a d verse e ve nt se v erit y is w orse t ha n t he o ne re p orte d b y t he 
ce ntral la b, or  
•  T here are n o c o nc o mita nt ce ntral r es ults a vaila ble  
F or a s s e s s m e nt of p ati e nt s’ eli gi bilit y t o t h e st u d y, o nl y l a b or at or y r e s ult s fr o m 
t h e c e ntr al l a b or at or y will b e u s e d. 
As per Secti o n 4. 6 , d uri n g a p u blic healt h e mer ge nc y as declare d b y l ocal or re gi o nal a ut h orities’ 
i.e. pa n de mic, e pi de mic, ge o p olitical sit uati o n  or nat ural disaster, t h at li mits or pre v e nts o n -site 
st u d y visits, if patie nts  ca n n ot visit t he site f or pr ot oc ol s pecifie d safet y la b assess me nts d uri n g 
t he trial, a n alter nati ve la b (l ocal) c ollecti o n site ma y be use d. 
At a n y ti me d uri n g t he st u d y, a b n or mal la b orat or y para meters w hic h are cli nicall y rele va nt a n d 
re q uire a n acti o n t o be ta ke n wit h st u d y treat me nt (e. g., re q uire d ose m o dificati o n a n d/ or 
i nterr u pti o n of st u d y treat me nt, lea d t o cli nical s y m pt o ms or si g ns, or re q uire t hera p e utic 

N o v arti s  
C o nfi d e nti al  
P a g e 9 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
i nter ve nti o n), w het h er s p ecificall y re q ueste d i n t he pr ot oc ol or n ot, will be rec or de d o n t he A E 
e C R F pa ge. La b orat or y data will be s u m marize d usi n g 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 5. A d diti o nal a nal yses are left t o t he d iscreti o n of t he 
i n vesti gat or. 
N o vartis m ust be pr o vi de d wit h a c o p y of t he l ocal la b orat or y’s certificati o n (if a p plica ble), a n d 
a ta b ulati o n of t he n or mal ra n ges a n d u nits of eac h para meter c ollecte d i n t he C R F. A n y c ha n ges 
re gar di n g n or mal ra n g es a n d u nits f or la b orat or y val ues assesse d d uri n g t he st u d y m ust be 
re p orte d via a n u p date d ta b ulati o n i n dicati n g t he date of re vali dati o n. A d diti o nall y, if at a n y 
ti me a patie nt has la b orat or y para met ers o btai ne d fr o m a differe nt la b orat or y, N o vartis m ust be 
pr o vi de d wit h a c o p y of t he certifi cati o n a n d a ta b ulati o n of t he n or mal ra n ges a n d u nits f or t his 
la b orat or y as w ell. T he i n vesti gat or is res p o nsi ble f or re vi e wi n g all la b orat or y re p orts f or 
patie nts i n t he st u d y a n d e val uati n g a n y a b n or malities f or cli nical si g nifica n ce.  
T a bl e 8 -6  
L a b or at or y a s s e s s m e nt s  
T e st C at e g or y  
T e st N a m e  
H e m at ol o g y  
H e m at o crit, H e m o gl o bi n, M e a n C or p u s c ul ar H e m o gl o bi n ( M C H), M e a n C or p u s c ul ar 
H e m o gl o bi n  C o n c e ntr ati o n ( M C H C), M e a n C or p u s c ul ar V ol u m e  ( M C V), Pl at el et s, R e d bl o o d 
c ell s, W hit e bl o o d c ell s, Diff er e nti al ( B a s o p hil s, E o si n o p hil s, L y m p h o c yt e s, M o n o c yt e s, 
N e utr o p hil s, Bl a st s, Pr o m y el o c yt e s, M y el o c yt e s, M et a m y el o c yt e s, B a n d s)  
C h e mi str y  
Al b u mi n, Al k ali n e p h o s p h at a s e, A L T, A S T, G a m m a -gl ut a m yl -tr a n sf er a s e ( G G T), L a ct at e 
d e h y dr o g e n a s e ( L D H), T ot al C al ci u m, M a g n e si u m, P h o s p h or u s, S o di u m, P ot a s si u m, 
Cr e ati ni n e, Cr e ati n e ki n a s e, Dir e ct Bilir u bi n, I n dir e ct Bilir u bi n, T ot al Bilir u bi n, T ot al 
C h ol e st er ol, L o w D e n sit y Li p o pr ot ei n ( L D L), Hi g h D e n sit y Li p o pr ot ei n ( H D L), T ot al Pr ot ei n, 
Tri gl y c eri d e s, Bl o o d Ur e a Nitr o g e n ( B U N) or Ur e a, Uri c A ci d, A m yl a s e, Li p a s e, Gl u c o s e 
(f a sti n g), H e m o gl o bi n A 1 c 
H e p atiti s 
m ar k er s  
H B s A g, a nti -H B c  
Pr e g n a n c y 
T e st*  
S er u m b et a fr a cti o n of h u m a n c h ori o ni c g o n a d otr o pi n ( ß -H C G) t e sti n g  
* F or d et ail s o n pr e g n a n c y t e sti n g, pl e a s e r ef er t o S e cti o n  8. 4. 3 . 
8. 4. 1. 1  
H e m at ol o g y  
He mat ol o g y assess me nts ha ve t o be a nal yze d at eac h sc he d ule d visit b y a ce ntral la b orat or y, 
acc or di n g t o  T a ble 8 -1  a n d Ta ble 8 -2 . F or details of t he He mat ol o g y pa nel refer t o Ta ble 8 -6 . 
8. 4. 1. 2  
Cli ni c al c h e mi str y  
Cli nical c he mistr y assess me nts ha ve t o be a nal yze d b y a ce ntr al la b orat or y, acc or di n g t o  
Ta ble 8 -1  a n d T a ble 8 -2 . F or details of t he cli nical c he mistr y pa nel r efer t o Ta ble 8 -6  . 
Cli nical c he mistr y assess me nts ha ve t o be a n al yze d at eac h s c he d ule d visit.  
H b A 1c assess me nt h as t o be a nal yz e d as re p orte d bel o w:  
•  Ra n d o mize d treat me nt: Scree ni n g, Wee k 1 2, 2 4, 4 8, 7 2 a n d E n d of Treat me nt.  
•  Cr oss o ver treat me nt: C O Wee k 1 2, 2 4, 4 8, 7 2 a n d E n d of Treat me nt.  
T he he patitis mar kers are a nal yze d o nl y at scree ni n g visit.  

N o v arti s  
C o nfi d e nti al  
P a g e 9 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
8. 4. 2  
El e ctr o c ar di o gr a m ( E C G)  
E C Gs s h o ul d be rec or de d after 1 0 mi n utes rest i n t he s u pi ne p ositi o n t o e ns ure a sta bl e baseli ne . 
T he preferre d se q u e nce of car di o vasc ul ar data c oll ecti o n d uri n g st u d y visits is E C G c ollecti o n 
first, f oll o we d b y vital si g ns, a n d bl o o d sa m pli n g. T he Fri dericia Q T c orrecti o n f or m ula ( Q Tc F) 
s h o ul d be use d f or cli nic al decisi o ns. 
T hree s erial E C Gs (tri pli cate) s h o ul d b e perf or me d half a n h o ur pri or t o d osi n g f or pre -d ose 
assess me nt a n d pri or t o a n y P K bl o o d dra ws sc he d ule d f or t he visit. T he serial E C Gs s h o ul d be 
ta ke n a p pr o xi matel y 5 mi n utes a part. Aft er t he s u bject has rest e d a p pr o xi matel y 1 0 mi n utes i n 
a s u pi ne p ositi o n, t hree se q ue ntial sta n dar d 1 2 -lea d E C Gs (tri plicate) m ust be o btai ne d wit h a 
rec o m me n de d mi ni mal i nter val of 5 mi n utes bet wee n eac h E C G at t he ti me p oi nts s pecifie d i n 
Ta ble 8 -1 , Ta bl e 8 -2 , f or details please refer t o Ta ble 8 -7  a n d Ta bl e 8 -8 . 
T hese t hree se q u e ntial 1 2 -lea d E C Gs are t o be c ollecte d wit h E C G mac hi nes s u p plie d b y t he 
ce ntral l a b orat or y (e R T) a n d all t hree E C Gs f or eac h ti me p oi nt s h o ul d be se nt t o e R T.  All 
E C Gs perf or m e d 
will be i n de pe n d e ntl y re vie we d. I nstr ucti o ns f or t he c ollecti o n a n d 
tra ns missi o n of t hese E C Gs t o t he i n de pe n de nt ce ntral rea der (e R T) will be pr o vi de d i n t he 
[ C A B L 0 0 1 E 2 2 0 1 E C G Ma n ual]. 
F or a n y E C G wit h s u bject safet y c o ncer ns, t w o a d diti o nal E C Gs m ust be perf or me d as s o o n as 
p ossi ble t o c o nfir m t he safet y fi n di n g. A m o nit ori n g or re vie w pr ocess s h o ul d be i n place f or 
cli nicall y si g nifica nt E C G fi n di n gs t hr o u g h o ut t he st u d y a n d es p eciall y  at baseli ne b ef ore 
a d mi nistrati o n of st u d y treat me nt.  
Rea di n gs f or Q Tc pr ol o n gati o n will be base d o n t he a vera g e see n i n t he sca ns f or eac h ti me 
p oi nt. T he e nr oll me nt of patie nts  has t o b e bas e d o n ce ntr all y assesse d Q Tc F ti me. If o ne of t h e 
3 serial E C Gs pri or t o d osi n g o n da y 1 s h o ws a Q Tc F ≥ 4 5 0 msec ( male) or ≥ 4 6 0 msec (fe male) 
b y a ut o mate d rea di n g, a n i m me diate ma n ual ce ntral rea di n g m ust be re q ueste d b y calli n g e R T. 
T he s u b ject ma y n ot be d ose d if t he a v era g e of t he ma n uall y rea d E C Gs c o nfir ms a Q Tc F ≥ 4 5 0 
msec ( male) or ≥ 4 6 0 msec (fe male).  
I n t he e v e nt t hat a cli nicall y si g nifica nt E C G a b n or malit y is i de ntifie d at t he site (e. g. se vere 
arr h yt h mia, c o n d ucti o n a b n or malit y of Q Tc F > 5 0 0 msec), a c o p y of t h e assess me nt is se nt t o 
t he c ore la b orat or y f or e x pe dite d re vie w if a p plica ble, a n d t he E CG is re peate d t o c o nfir m t h e 
dia g n osis. If t he s u bject is he m o d y na micall y c o m pr o mise d, t he i n vesti gat or or a m e dicall y 
q ualifie d pers o n m ust i nitiate a p pr o priate safet y pr oce d ures wit h o ut dela y (f or e x a m pl e 
car di o versi o n).  
Cli nicall y si g nifica nt a b n or malities 
m ust be rec or de d o n t he C R F as eit her 
me dical 
hist or y/c urre nt me dic al c o n diti o ns or a d verse e v e nts as a p pr o priate.  
A sta n dar d 1 2 le a d E C G will be perf or me d at t he f oll o wi n g ti me p oi nts.  
Ra n d o mize d treat me nt ar ms 1 –  4, asci mi ni b si n gle a ge nt c o h ort:  
•  at scree ni n g a n d baseli ne  
•  at Wee k 2, 4, 1 2, 2 4, 4 8, e ver y 4 8 wee ks u ntil t he e n d of treat me nt  
•  at t he e n d of tr eat me nt  
Cr oss -o ver treat me nt:  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
•  at C O baseli ne, C O Wee k 2, 4, 1 2, 2 4, 4 8, e ver y 4 8 wee ks u ntil t he e n d of treat me nt  
•  at t he e n d of tr eat me nt  
T a bl e 8 -7  
C e ntr al E C G c oll e cti o n pl a n i n all r a n d o mi z e d tr e at m e nt ar m s 1 - 4, a n d 
a s ci mi ni b si n gl e a g e nt c o h ort  
W e e k  
D a y  
Ti m e  
E C G T y p e  
S cr e e ni n g  
-2 1 t o -1  
A n yti m e  
1 2 L e a d, tri pli c at e  
B a s eli n e  
1  
Pr e -d o s e, * P o st -d o s e 2 
h o ur s  
1 2 L e a d, tri pli c at e  
W e e k 2**  
1 4  
Pr e -d o s e, * P o st -d o s e 2 
h o ur s, 3 h o ur s, 4 h o ur s  
1 2 L e a d, tri pli c at e  
W e e k 4**  
2 8  
Pr e -d o s e, * P o st -d o s e 2 
h o ur s, 3 h o ur s, 4 h o ur s  
1 2 L e a d, tri pli c at e  
W e e k 1 2  
8 4  
Pr e -d o s e  
1 2 L e a d, tri pli c at e  
W e e k 2 4  
1 6 8  
Pr e -d o s e  
1 2 L e a d, tri pli c at e  
W e e k 4 8  
3 3 6  
Pr e -d o s e  
1 2 L e a d, tri pli c at e  
E v er y 4 8 w e e k s u p t o 9 6 
w e e k s aft er t h e fir st d o s e 
of t h e l a st r a n d o mi z e d / 
e nr oll e d s u bj e ct  
- 
Pr e -d o s e  
1 2 L e a d, tri pli c at e  
E O T  
- 
Pr e -d o s e  
1 2 L e a d, tri pli c at e  
U n s c h e d ul e d E C G  
- 
A n yti m e  
1 2 L e a d, tri pli c at e  
* P o st-d o s e E C G s f or a s ci mi ni b + i m ati ni b ar m s, a n d a s ci mi ni b si n gl e a g e nt c o h ort o nl y  
** N ot m a n d at or y vi sit s f or p ati e nt s  i n i m ati ni b a n d nil oti ni b ar m 
T a bl e 8 -8  
C e ntr al E C G c oll e cti o n pl a n i n cr o s s -o v er  
W e e k  
D a y  
Ti m e  
E C G T y p e  
B a s eli n e cr o s s -o v er  
1  
Pr e -d o s e, P o st -d o s e 2 
h o ur s  
1 2 L e a d, tri pli c at e  
2 w e e k s aft er cr o s s -o v er  
1 4  
Pr e -d o s e, P o st -d o s e 2 
h o ur s, 3 h o ur s, 4 h o ur s  
1 2 L e a d, tri pli c at e  
4 w e e k s aft er cr o s s -o v er  
2 8  
Pr e -d o s e, P o st -d o s e 2 
h o ur s, 3 h o ur s, 4 h o ur s  
1 2 L e a d, tri pli c at e  
1 2 w e e k s aft er 
cr o s s -o v er  
8 4  
Pr e -d o s e  
1 2 L e a d, tri pli c at e  
2 4 w e e k s aft er 
cr o s s -o v er  
1 6 8  
Pr e -d o s e  
1 2 L e a d, tri pli c at e  
4 8 w e e k s aft er 
cr o s s -o v er  
3 3 6  
Pr e -d o s e  
1 2 L e a d, tri pli c at e  
E v er y 4 8 w e e k s u p t o 9 6 
w e e k s aft er t h e fir st d o s e 
of t h e l a st r a n d o mi z e d 
s u bj e ct  
- 
Pr e -d o s e  
1 2 L e a d, tri pli c at e  
E O T  
- 
Pr e -d o s e  
1 2 L e a d, tri pli c at e  
U n s c h e d ul e d E C G  
- 
A n yti m e  
1 2 L e a d, tri pli c at e  
I n or der t o e na ble E C G e val uati o n b y t he ce ntral la b orat or y f or eli gi bilit y assess me nt, E C Gs 
s h o ul d be s u b mitte d t o t he E C G c ore la b orat or y i n a de q uate ti me pri or t o t he pla n ne d 
ra n d o mizati o n date. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
I n t he e v e nt t hat a Q Tc F v al ue of > 5 0 0 msec is o bser ve d or if a n u nsc he d ule d E C G is perf or me d 
f or safet y reas o ns, it is rec o m me n de d t o c ollect a ti me-matc he d P K sa m ple a n d rec or d t he ti m e 
a n d date of t he last st u d y dr u g i nta ke t o deter mi ne t he dr u g e x p os u re. D ose a dj ust me nts i n case 
of Q T pr ol o n gati o n s h o ul d be perf or me d per  Secti o n  6. 5. 1. 4 . 
A d diti o nal, u nsc he d ule d, safet y E C Gs 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 as cli nicall y i n dicate d. U nsc he d ule d E C Gs wit h cli nicall y si g nifica nt 
fi n di n gs s h o ul d be c ollecte d i n tri plicate. L ocal car di ol o gist E C G assess me nt ma y als o be 
perf or me d at a n y ti me d uri n g t he st u d y at t he discreti o n of t he i n vesti gat or.  
All E C Gs, i ncl u di n g u nsc he d ule d tri plicate safet y E C Gs wit h cli nicall y rele va nt fi n di n gs, 
c ollecte d d uri n g t he st u d y s h o ul d be tra ns mitte d t o t he ce ntral c ore E C G la b orat or y f or re vie w.  
T he res ults of t he ce ntr all y assesse d E C Gs are a ut o maticall y tra nsferre d i nt o t he cli nical 
data base.  
8. 4. 3  
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  
All w o me n of c hil d beari n g p ote ntial ha v e t o c o m plete a ser u m pre g na n c y test ( Ser u m ß -H C G) 
as i n dicate d i n Ta ble 8 -1  a n d Ta ble 8 -2 . Pre g na n c y testi n g is n ot re q uire d f or patie nts  w h o are 
deter mi ne d t o be p ost -me n o pa usal. T h e ti me wi n d o ws gra nte d f or pre g na nc y testi n g ar e 
i de ntical wit h t he c orres p o n di n g visit ti me wi n d o ws f or eac h visit.  
Ser u m pre g na nc y assess me nts ha ve t o be a nal yze d b y a ce ntral la b orat or y, acc or di n g t o  
Ta ble 8 -1  a n d T a ble 8 -2 , d uri n g t he f oll o wi n g ti me p oi nts: 
•  Ra n d o mize d treat me nt: scree ni n g, bas eli ne, Wee k 4 (if a p plica ble), Wee k 8 (if a p plica ble), 
a n d at eac h visit fr o m W ee k 1 2 o n war ds u ntil t he e n d of treat me nt.  
•  Cr oss o ver treat me nt: C O baseli ne (if t he cr oss o ver treat me nt starts wit hi n 7 da ys fr o m Wee k 
4 8 visit, it is n ot re q uire d t o perf or m  s er u m pre g na nc y test a gai n), C O Wee k 4, C O Wee k 8 
a n d at eac h visit fr o m C O Wee k 1 2 o n war ds u ntil t he e n d of treat me nt.  
Uri ne pre g na n c y tests ha ve t o be perf or me d at h o me e ver y 4 wee ks if ser u m pre g na nc y test is 
n ot perf or me d. Test res ults perf or me d at h o me s h o ul d be rec or de d o nt o a s u bject diar y a n d 
br o u g ht t o eac h sc he d ule d visit f or t he site t o re vie w. I nf or mati o n f or ur i ne pre g na nc y test m ust 
be i ncl u de d i n t he s o ur ce d oc u me ntati o n at t he st u d y site as u ni q ue s o urce data, t his i nf or mati o n 
will n ot be ca pt ur e d i n t h e C R F. If a test res ult i n dicates a pre g n a nc y, t h e s u bject m ust c o ntact 
t he i n vesti gat or i m me diatel y. 
As per Secti o n 4. 6 , d uri n g a p u blic healt h e mer ge nc y as declare d b y l ocal or re gi o nal a ut h orities’ 
i.e. pa n de mic, e pi de mic, ge o p olitical sit uati o n  or nat ural disaster, t h at li mits or pre v e nts o n -site 
st u d y visits, if partici pa nts ca n n ot visit t he site t o h a ve ser u m pre g n a nc y tests, uri ne pre g n a nc y 
test kits ma y be use d. Rel e va nt patie nts  ca n perf or m t he uri ne pre g na nc y test at h o me a n d re p ort 
t he res ult t o t h e site. It is i m p orta nt t hat patie nts  are i nstr ucte d t o perf or m t he uri ne pre g n a nc y 
test first a n d o nl y if t he test res ult is ne g ati ve pr ocee d wit h t he a d mi nistrati o n of t he st u d y 
treat me nt. A c o m m u nicati o n pr ocess s h o ul d be esta blis he d wit h t he s u bject s o t hat t he site is 
i nf or me d a n d ca n verif y t he pre g na n c y test res ults (e. g., f oll o wi n g c o u ntr y s pecific meas ures). 
All pre g na ncies 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 Dr u g Safet y a n d E pi de mi ol o g y De p art me nt ( D S & E). 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
D uri n g t he w h ole st u d y, w o me n of c hil d beari n g p ote ntial s h o ul d e m pl o y t he use of hi g hl y 
effecti ve c o ntr ace pti o n. Hi g hl y effecti ve c o ntrace pti o n met h o ds are defi ne d i n Secti o n  5. 2 . 
A w o ma n is c o nsi dere d of c hil d beari n g p ote ntial fr o m 
me narc he a n d u ntil bec o mi n g 
p ost me n o pa usal u nless per ma ne ntl y sterile. 
Per ma ne nt sterilizati o n 
met h o ds i ncl u de 
h ysterect o m y, bilateral s al pi n gect o m y a n d bilateral o o p h orect o m y. Me dical d oc u me ntati o n of 
o o p h orect o m y, h ysterect o m y, or bilateral t u b al li gati o n m ust be retai n e d as s o urce d o c u me nts. 
A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical 
ca use a n d a n a p pr o priate cli nical pr ofile.  
I n a bse n ce of t he me dical d oc u me ntati o n, c o nfir mi n g per ma ne nt sterilizati o n, or if t he p ost -
me n o pa usal stat us is n ot clear, t he i n v esti gat or s h o ul d use his me dical j u d g me nt t o a p pr o priatel y 
e val uate t he fertilit y state of t he w o ma n a n d d o c u me nt it i n t he s o urce d oc u me nt.  
8. 4. 4  
A p pr o pri at e n e s s of s af et y m e a s ur e m e nt s  
T he safet y assess me nts s electe d are sta n d ar d f or t his i n dicati o n/s u bject p o p ulati o n.  
8. 5  
A d diti o n al a s s e s s m e nt s  
T he f oll o wi n g a d diti o nal assess me nts will be perf or me d o n patie nts  e ntere d i nt o t his st u d y:  
•  Patie nt Re p orte d O utc o m es  
•  P har mac o ki netics  
•  Bi o mar ker  
8. 5. 1  
Cli ni c al O ut c o m e A s s e s s m e nt s ( C O A s)  
P atie nt Re p orte d O utc o mes ( P R O)  
T he f oll o wi n g P R Os will be use d:  
•  E ur o pea n or ga nizati o n f or researc h a n d treat me nt of ca ncer - q u alit y of life q uesti o n naire 
( E O R T C Q L Q-C 3 0 a n d E O R T C Q L Q -C M L 2 4)  
•  F u ncti o nal assess me nt of c hr o nic ill ness t hera p y - ge neral p o p ulati o n 5 ( F A CI T G P 5)  
•  Treat me nt satisfacti o n q uesti o n naire f or m e dicati o n  ( T S Q M) 
T hese q uesti o n naires will ca pt ure data o n t he patie nt -re p orte d o utc o me m eas ures of healt h-
relate d q ualit y-of life, treat me nt satisfacti o ns a n d treat me nt -relate d si de effects per Secti o n 8 . 
T he T S Q M will be use d t o assess h o w satisfie d t he s u bject is wit h treat me nt o verall a n d F A CI T 
G P 5 t o assess treat me nt -relate d si de effects. All t o ols re q uire s u bject’s direct c o m pleti o n a n d 
will be a d mi nistere d utilizi n g a ta blet pr o vi de d b y a t hir d part y ve n d or. Data tra nsfers of clea ne d 
data will be perf or me d b y t he P R O ve n d or.  
All q uesti o n naires s h o ul d be a d mi nistere d i n t he la n g ua ge m ost fa miliar t o t he s u bject at t he 
be gi n ni n g of sc he d ule d visit pri or t o a n y i nteracti o n wit h t he st u d y i n vesti gat or i ncl u di n g a n y 
tests, treat me nts or recei pt of res ults fr o m a n y tests t o a v oi d biasi n g t he s u bject’s pers pecti ve. 
At baseli ne, t he q uesti o n naire(s) will be a p plie d pri or t o ra n d o mizati o n. T his is t o a v oi d 
p ote ntiall y biasi n g patie nts  or t heir res p o nses t o st u d y q uesti o n naires.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
T he s u bject s s h o ul d be gi ve n s ufficie nt s pace a n d ti me t o c o m plete t he q u esti o n naires o n t he 
electr o nic de vi ce a n d t he a d mi nistere d q uesti o n naire s s h o ul d be re vie we d f or c o m plete ness. If 
missi n g res p o nses are n ot e d, patie nts  s h o ul d b e e nc o ura ge d t o c o m plete a n y missi n g res p o nses. 
Atte m pts s h o ul d be ma de t o c ollect res p o nses t o all q uesti o n naires f or all patie nts , h o we ver, if 
patie nts  ref use t o c o m plete all or a n y part of a q u esti o n naire, t his s h o ul d be d oc u me nte d i n t he 
st u d y data ca pt ur e s yste m a n d s h o ul d n ot be ca pt ure d as a pr ot oc ol de viati o n.  I n cas e of ta blet 
malf u ncti o ni n g or ot her iss ues, n o pa per P R O c ollecti o n will be all o we d, a n d t he iss ue s h o ul d 
be d oc u me nte d i n t he s o urce.   
C o m plete d q uesti o n naire(s) s h o ul d b e 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 bef ore a n y cli nical st u d y e xa mi nati o ns. T his 
assess me nt s h o ul d be d oc u me nte d i n st u d y s o urce rec or ds. If A Es or S A Es are c o nfir me d, st u d y 
i n vesti gat ors s h o ul d n ot e nc o ura g e t he s u bject t o c ha n ge res p o nses re p orte d i n t he c o m plete d 
q uesti o n naires. 
St u d y 
i n vesti gat ors 
m ust 
f oll o w 
re p orti n g 
i nstr ucti o ns 
o utli ne d 
i n  Secti o n  1 0   (e. g. refere nce “ A d verse E ve nts” s ecti o n) of t he st u d y pr ot o c ol. 
P R O assess me nts ha ve t o be perf or me d fr o m all patie nts  d uri n g t he treat me nt peri o d, b ut n ot 
fr o m patie nts  w h o disc o nti n ue fr o m st u d y treat me nt.  
F or P R O c ollecti o n ti me p oi nts, please refer t o Ta ble 8 -1  a n d Ta bl e 8 -2 . 
T he P R O meas ure(s) s h o ul d be c o m plete d i n t he f oll o wi n g or der: E O R T C Q L Q -C 3 0, E O R T C 
Q L Q -C M L 2 4, T S Q M a n d F A CI T G P 5.  
As per Secti o n 4. 6 , d uri n g a p u blic healt h e mer ge nc y as declare d b y l ocal or re gi o nal a ut h orities 
i.e. pa n de mic, e pi de mic, ge o p olitical sit uati o n  or nat ural disaster, t h at li mits or pre v e nts o n -site 
st u d y visits, C O A data ma y be c ollecte d re m otel y, de pe n di n g o n t he l ocal re g ulati o ns, tec h nical 
ca pa bilities, a n d f oll o wi n g a n y a p plica ble trai ni n g.  
8. 5. 1. 1  
E O R T C Q L Q -C 3 0 a n d E O R T C Q L Q -C M L 2 4  
T he E O R T C Q L Q -C 3 0 Versi o n 3. 0 is a q uesti o n naire de vel o p e d t o assess t he q ualit y of life of 
ca ncer p atie nts w hic h has bee n tr a nslate d a n d vali d ate d i nt o 8 1 la n g ua g es a n d has bee n use d i n 
m ore t ha n 3 0 0 0 st u dies w orl d wi de. T he E O R T C c o ntai ns 3 0 ite ms a n d is c o m p ose d of b ot h 
m ulti -ite m scales a n d si n gle-ite m meas ures. T hese i ncl u de fi ve f u ncti o nal scales ( p h ysical, r ole, 
e m oti o nal, c o g niti ve a n d s ocial f u ncti o ni n g), t hree s y m pt o m scales (fati g ue, na usea a n d 
v o miti n g, a n d pai n), si x si n gle ite ms ( d ys p nea, i ns o m nia, a p petite l oss, c o nsti pati o n, diarr hea 
a n d fi na ncial i m pact) a n d a gl o bal healt h stat us a n d Q o L scale ( Aar o ns o n  et al 1 9 9 3 ). T he 
E O R T C Q L Q -C M L 2 4 ( Efficace  et al 2 0 1 4 ) is use d i n c o nj u ncti o n wit h t he E O R T C Q L Q-C 3 0 
a n d pr o vi des i nf or mati o n o n a n a d diti o nal 2 4 ite ms s pecificall y relate d t o c hr o nic m yel oi d 
le u ke mia. T h e Q L Q-C M L 2 4 i nc or p orates f o ur m ulti -ite m scales assessi n g s y m pt o m b ur de n ( 1 3 
ite ms), i m pact o n w orr y/ m o o d ( 4 ite ms), i m pact o n dail y life ( 3 ite ms), a n d satisfacti o n wit h 
care a n d i nf or mati o n ( 2 it e ms), as well as t w o si n gle ite ms assessi n g b o d y i ma ge pr o ble ms a n d 
satisfacti o n wit h s oci al life. F or c o u ntries w here t he E O R T C Q L Q -C M L 2 4 will n ot be a v aila ble, 
be ca use of missi n g la n g ua ge vali dati o n, it will n ot be c o m plete d b y t he patie nts. T h ose 
q uesti o n naires will be l oc ke d wit hi n t he a p plicati o n a n d will n ot be a vaila ble f or c o m pleti o n.  
All of t he scales a n d si n gle -ite m meas ures ra n ge i n sc ore fr o m 0 t o 1 0 0. A hi g h scale sc ore 
re pres e nts a hi g her res p o nse le vel. T h us a hi g h sc ore f or a f u ncti o nal scale re pres e nts a 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
hi g h/ healt h y le vel of f u ncti o ni n g; a hi g h sc ore f or t he gl o bal h ealt h stat us/ Q o L re prese nts a hi g h 
Q o L, 
b ut a 
hi g h sc ore f or a s y m pt o m scale/ite m re prese nts 
a 
hi g h le vel 
of 
s y m pt o mat ol o g y/ pr o ble ms. All sc ori n g will f oll o w t he sc ori n g pr oce d ures defi n e d b y t he 
E O R T C Sc ori n g Ma n ual ( Fa y ers  2 0 0 1 ). 
8. 5. 1. 2  
T S Q M  
T he 1 4 -ite m Treat me nt Satisfacti o n Q uesti o n naire f or Me dicati o n ( T S Q M, Versi o n 1. 4) is a 
ge neric, m ulti di me nsi o nal, self -a d mi nistere d meas ure of patie nt s atisfacti o n wit h a m e dicati o n. 
T he i nstr u me nt has 1 4 ite ms meas uri n g f o ur d o mai ns: effecti ve n ess, si de  effects, c o n v e nie nce, 
a n d gl o bal satisfacti o n. D o mai n sc ores ra n ge fr o m 0 t o 1 0 0, wit h a hi g her sc ore i n dicati n g 
hi g her satisfacti o n ( At ki ns o n  et al 2 0 0 4 ). 
Res p o nses t o ite ms are s u m me d a n d tra nsf or me d s o t hat hi g h er s c ores i n dicat e greater 
satisfacti o n. S pecificall y, T S Q M scale sc ores are c o m p ute d b y a d di n g t he it e ms l oa di n g o n eac h 
d o mai n. T he l o west p ossi ble sc ore is s u btracte d fr o m t he c o m p osite sc ore a n d  di vi de d b y t he 
greatest p ossi ble sc ore ra n ge. T his pr o vi des a tra nsf or me d sc ore b et wee n 0 a n d 1 t hat is t he n 
m ulti plie d b y 1 0 0. If m or e t ha n o n e ite m is missi n g fr o m a s u bscale of t he T S Q M f or a p artic ular 
patie nt, t his s u bscale s h o ul d be c o nsi dere d i n v al i d f or t hat res p o n d e nt. 
8. 5. 1. 3  
F A CI T G P 5  
T he F A CI T G P 5 Versi o n 4 . 0, w hic h is a si n gle q uesti o n, will be use d t o assess t he o verall 
b ot hers o me ness wit h tr eat me nt si de effects. T he G P 5 has a s e ve n -d a y recall peri o d a n d uses a 
5 -p oi nt rati n g scale ( 0 = N ot at all; 1 = A little bit; 2 = S o me w hat; 3 = Q uite a bit; a n d 4 = Ver y 
m uc h) t o ass ess h o w b ot here d t h e s u bject is b y si de effects of treat me nt rate d o n a 5 -p oi nt Li kert 
scale. 
8. 5. 2  
 P h ar m a c o ki n eti c s  
Plas ma sa m ples will be o btai ne d t o c haracterize t he dis p ositi o n of t he st u d y dr u gs (as ci mi ni b, 
i mati ni b) after oral a d mi nistrati o n. I n a d diti o n t o pare nt dr u g a nal yses, e x pl orat or y meta b olite 
a nal yses o n re mai ni n g plas ma material ma y b e perf or me d usi n g a n o n -vali date d, se mi -
q ua ntitati ve or q ualitati ve li q ui d c hr o mat o gra p h y/ta n de m mass s pectr o metr y ( L C -M S/ M S) 
met h o d, if dee m e d a p pr o priate. Plas ma sa m ples re mai ni n g fr o m t he a nal ysis ma y be retai ne d 
b y N o vartis f or a d diti o nal i n vesti gati o ns (i.e. l o n g ter m sta bilit y, re pr o d uci bilit y).  
8. 5. 2. 1  
P h ar m a c o ki n eti c bl o o d c oll e cti o n a n d h a n dli n g  
P K sa m ples will be c ollecte d f or b ot h t he c o m bi nati o n ar ms asci mi ni b 6 0 m g + i mati ni b a n d 
asci mi ni b 4 0 m g + i mati ni b, as well as f or t he asci mi ni b si n gle a ge nt c o h ort. Bl o o d sa m ples 
will be ta ke n fr o m t he ar m b y eit her direct ve ni p u nct ure or a n i n d welli n g cat heter i nserte d i n a 
f orear m vei n. At s pecifi e d ti me p oi nts, 4 m L bl o o d (see Ta bl e 8 -9 ) will be c ollecte d. 
T he re mai ni n g ali q u ots, m ust be ke pt at t he cli nical site as bac k u p sa m ples, a n d s h o ul d o nl y be 
dis p ose d of after a p pr o val b y N o vartis.  
T he sa m ple re q uisiti o n f or m s h o ul d be c o m plete d a n d t he t u bes la bel e d a p pr o priatel y. O n t he 
re q uisiti o n f or m, it is i m p orta nt t o rec or d t he E X A C T ti me t he sa m ple was dra w n rat her t ha n 
bei n g cl ose t o t he s c he d ule d sa m pli n g ti me. A n y sa m pli n g pr o ble ms (e. g. s u bject t o o k st u d y 

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
dr u g bef ore a dra w t o o k place) m ust be n ote d i n t he patie nt rec or ds. P K sa m pli n g sc he me ma y 
be m o difie d t o o pti mize t he sa m pli n g ti me f or t he st u d y treat me nt dis p ositi o n as nee de d. T he 
la bel i n t he P K kits (i.e. P K plas ma sa m ple) s h o ul d be use d a n d t he actual c ollecti o n date a n d 
ti me s h o ul d be n ote d o n t he la bel a n d rec or de d i n t he e C R F. La b els will be pr o vi de d b y t h e site 
wit h all la bel i nf or mati o n pre pri nte d. L a bels will h a ve a barc o de, al o n g wit h t he s u bject n u m ber 
a n d t he se q ue ntial P K sa m ple n u m ber as re p orte d i n t he P K Sa m ple Sc he d uli n g Ta ble  
(Ta ble 8 -9 ). 
T a bl e 8 -9  
P h ar m a c o ki n eti c bl o o d c oll e cti o n l o g  
W e e k  
D a y  
S c h e d ul e d 
Ti m e  
P oi nt  
A s ci mi ni b 
D o s e 
R ef er e n c e 
I D 
I m ati ni b 
D o s e 
R ef er e n c e 
I D 
A s ci mi ni b 
P K S a m pl e 
N o  
I m ati ni b 
P K 
S a m pl e 
N o  
S a m pl e  
V ol u m e  
2  
1 4  
Pr e -d o s e 
( 0 h) 
1  
2 0 1  
1  
1 0 1  
4  
2  
1 4  
1 h ( ± 1 0 
mi n)  
1  
2 0 1  
2  
1 0 2  
4  
2  
1 4  
2 h ( ± 1 0 
mi n)  
1  
2 0 1  
3  
1 0 3  
4  
2  
1 4  
3 h ( ± 1 5 
mi n)  
1  
2 0 1  
4  
1 0 4  
4  
2  
1 4  
4 h ( ± 1 5 
mi n)  
1  
2 0 1  
5  
1 0 5  
4  
2  
1 4  
8 h ( ± 6 0 
mi n)  
1  
2 0 1  
6  
1 0 6  
4  
2  
1 4  
2 4 h ( ± 6 0 
mi n)/ Pr e -
d o s e  
1  
2 0 1  
7  
1 0 7  
4  
4  
2 8  
Pr e -d o s e 
( 0 h) 
5  
2 0 5  
8  
1 0 8  
4  
4  
2 8  
2 h ( ± 1 0 
mi n)  
5  
2 0 5  
9  
1 0 9  
4  
4  
2 8  
3 h ( ± 1 5 
mi n)  
5  
2 0 5  
1 0  
1 1 0  
4  
4  
2 8  
4 h ( ± 1 5 
mi n)  
5  
2 0 5  
1 1  
1 1 1  
4  
1 2  
8 4  
Pr e -d o s e 
( 0 h) 
6  
2 0 6  
1 2  
1 1 2  
4  
2 4  
1 6 8  
Pr e -d o s e 
( 0 h) 
7  
2 0 7  
1 3  
1 1 3  
4  
3 6  
2 5 2  
Pr e -d o s e 
( 0 h) 
8  
2 0 8  
1 4  
1 1 4  
4  
6 0  
4 2 0  
Pr e -d o s e 
( 0 h) 
9  
2 0 9  
1 5  
1 1 5  
4  
9 6  
6 7 2  
Pr e -d o s e 
( 0 h) 
1 0  
2 1 0  
1 6  
1 1 6  
4  
U n s c h e d ul e d  
- 
  
  
  
1 0 0 1 +  
2 0 0 1 +  
4  
T ot al  
  
  
  
  
  
  
6 4  

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
8. 5. 2. 2  
A n al yti c al m et h o d  
Plas ma c o nce ntrati o ns of asci mi ni b will be meas ure d at t he desi g nate d la b orat or y usi n g a 
vali date d hi g h -perf or m a nce li q ui d c hr o mat o gra p h y/ta n de m mass s pectr o metr y ( L C -M S/ M S) 
met h o d wit h a l o wer li mit of q ua ntificati o n ( L L O Q) of 1. 0 0 n g/ m L.  
Plas ma c o nce ntrati o ns of i mati ni b a n d its meta b olite N -des met h yl i mati ni b ( C G P 7 4 5 8 8) will 
be deter mi ne d usi n g a vali date d li q ui d c hr o mat o gra p h y -ta n de m mass s pectr o metr y ( L C-
M S/ M S) assa y wit h a l o wer li mit of q ua ntificati o n ( L L O Q) of 2 0. 0 n g/ m L.  
8. 5. 3  
Bi o m ar k er s  
Bi o mar ker a nal yses will be use d t o 
 
 as well as t o deter mi ne 
 
 I n a d diti o n, p ote ntial pre dicti ve mar kers of 
 
 will als o be e x pl ore d. 
All assess me nts will be perf or me d b y a N o vartis -desi g nate d la b orat or y. I nstr ucti o ns f or 
c ollecti o n, st ora ge a n d s hi p me nt of all bi o mar ker s a m ples 
will b e pr o vi de d i n t he 
[ C A B L 0 0 1 E 2 2 0 1 la b orat or y ma n ual]. Re q uire d sa m ple c ollecti o n i nf or m ati o n m ust be e nt ere d 
o n t he a p pr o priat e C R F p a ges a n d re q uisiti o n f or ms.  
Bi o m ar k er a s s e s s m e nt s i n bl o o d s a m pl e s  
C h ar a ct eri z ati o n of 
 
A p pr o xi matel y 1 0 m L of bl o o d sa m ple will be c ollecte d t o assess 
 
 via  
 f or patie nts i n treat me nt ar ms 1-4. T he a nal ysis ai ms t o  
 
 
 
 
 will be perf or me d at a N o vartis desi g nate d la b orat or y at 
, at  
 a n d at 
 i n  treat me nt ar ms 1-4 o nl y, a 
sa m ple is n ot c ollecte d or a nal yze d f or patie nts i n t he asci mi ni b si n gle a ge nt c o h ort.  
 
A p pr o xi matel y 1 2 m L of bl o o d will be c ollecte d f or 
 at t he visits as 
i n dicate d i n   T a ble 8 -1 0  . T he a n al ysis ai ms t o 
 
  
  
  
  
  
 
  
  
  
  
  
 
 
 
  
A p pr o xi matel y 2. 5 m L of bl o o d will be c ollect e d f or 
 
 at t he visits i n dicate d i n   Ta ble 8 -1 0  .  
 s a m ples ma y be use d t o 
 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
 
 
 T a bl e 8 -1 0  
Bi o m ar k er s a m pl e c oll e cti o n pl a n  
  
V ol u m e  
Vi sit  
Ti m e p oi nt  
W h ol e bl o o d f or 
 
 a n al y si s b y  
 (tr e at m e nt 
ar m s 1 -4 o nl y)  
1 0 m L  
Pr e -d o s e  
1 0 m L  
A n yti m e  
1 0 m L  
A n yti m e  
 
 
1 2 m L  
Pr e -d o s e  
1 2 m L  
A n yti m e  
1 2 m L  
A n yti m e  
1 2 m L  
A n yti m e  
  
2. 5 m L  
Pr e -d o s e  
2. 5 m L  
A n yti m e  
2. 5 m L  
A n yti m e  
9  
St u d y di s c o nti n u ati o n a n d c o m pl eti o n  
9. 1  
Di s c o nti n u ati o n  
9. 1. 1  
Di s c o nti n u ati o n of st u d y tr e at m e nt  
Disc o nti n uati o n of st u d y treat me nt f or a s u bject occ urs w he n st u d y treat me nt is st o p pe d earlier 
t ha n t he pr ot oc ol pla n ne d d urati o n, a n d ca n be i nitiate d b y eit her t he s u bject or t he i n vesti gat or.  
T he i n vesti gat or m ust disc o nti n ue st u d y treat me nt f or a gi ve n s u bj ect if h e/s he belie v es t hat 
c o nti n uati o n w o ul d ne gati vel y i m pact t he s u bject's well -bei n g.  
St u d y treat me nt m ust be disc o nti n ue d u n der t he f oll o wi n g circ u msta nces:  
•  S u bject/ g uar dia n decisi o n  
•  Pre g na nc y  
•  Use of pr o hi bite d treat me nt as per e pr o hi bite d treat me nt secti o n  
•  A n y sit uati o n i n w hic h st u d y partici pati o n mi g ht res ult i n a safet y ris k t o t he s u bject  
•  Treat me nt f ail ure a n d dis ease pr o gressi o n  
•  I n t he case of certai n a d v erse e v e nts a n d re-occ urre nce of a d verse e ve nts (see Secti o n  6. 5. 1 )  
Pr o gressi o n is defi ne d b y o ne of t he f oll o wi n g crit eria:  
1.  C M L -relate d deat h as det er mi ne d b y i n vesti gat or. 
2.  Pr o gressi o n t o Accel erat e d p hase ( A P) as defi ne d b y a n y of t he f oll o wi n g:  
•  ≥ 1 5 % blasts i n t he peri p heral bl o o d or b o ne m arr o w as pirate, b ut < 3 0 % blasts i n b ot h 
t he peri p heral bl o o d a n d b o ne marr o w as pirate 
•  ≥ 3 0 % blasts pl us pr o m yel oc ytes i n peri p h eral bl o o d or b o ne marr o w as pirate, b ut < 
3 0 % blast i n peri p heral bl o o d or b o ne marr o w as pirate  
•  ≥ 2 0 % bas o p hils i n t he peri p heral bl o o d  
•  T hr o m b oc yt o pe nia ( < 1 0 0 x 1 0 9/ L) u nrelate d t o t hera p y 
C CI
C CI
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
3.  Pr o gressi o n t o blast crisis ( B C) defi ne d b y a n y of t he f oll o wi n g:  
•  ≥ 3 0 % blasts i n peri p heral bl o o d or b o ne marr o w as pirate  
•  A p peara nce of e xtr a me d ullar y i n v ol ve me nt ot her t ha n he p at o -/s ple n o me gal y pr o ve n b y 
bi o ps y (i.e. c hl or o ma)  
A n y val ue of A P or B C wit hi n t he first 4 wee ks of st u d y treat me nt is n ot defi ne d as pr o gressi o n 
t o A P/ B C wit hi n t he st u d y u nless t he s u bject disc o nti n ues st u d y treat me nt d ue t o pr o gressi o n 
or t he treati n g p h ysicia n deter mi nes t here is u nsatisfact or y t hera p e utic effect wit hi n t he first 8 
wee ks.  
Treat me nt fail ure is defi ne d acc or di n g t o E L N g ui deli nes ( Baccara ni  et al 2 0 1 3 ) as n o C H R 
a n d/ or P h + > 9 5 % after 3 m o nt hs, B C R:: A B L 1 > 1 0 % a n d/ or P h + > 3 5 % after 6 m o nt hs, 
B C R ::A B L 1 > 1 % a n d/ or P h + > 0 after 1 2 m o nt hs of treat me nt i nitiati o n, or as l oss of C H R, 
l oss of C C y R, c o nfir me d l oss of 
M M R *, B C R:: A B L m utati o ns, a n d maj or r o ute cl o nal 
c hr o m os o me a b n or maliti es i n P h + cells at a n y ti me.  
* I n 2 c o nsec uti ve t ests, of w hic h o ne wit h a B C R:: A B L le vel ≥1 %.  
If disc o nti n uati o n of st u d y treat me nt occ urs, t he i n vesti gat or s h o ul d ma ke a reas o na ble eff ort 
t o u n dersta n d t he pri mar y reas o n f or t he s u bject’s pre mat ure disc o nti n uati o n of st u d y treat me nt 
a n d rec or d t his i nf or mati o n.  
Patie nts  w h o disc o nti n ue st u d y treat me nt or w h o deci de t he y d o n ot wis h t o partici pate i n t he 
st u d y f urt her s h o ul d N O T be c o nsi dere d wit h dra w n fr o m t he st u d y U N L E S S t he y wit h dra w 
t heir c o nse nt (see wit h dra wal of i nf or me d c o ns e nt, Secti o n  9. 1. 2 ). W here p ossi ble, t he y 
s h o ul d ret ur n as s o o n as p ossi ble f or t he assess me nts i n dic ate d f or t he e n d of tre at me nt 
visit i n t he assess me nt sc he d ule. If t he y fail t o ret ur n 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 s u bject/ pre -d esi g nate d 
c o ntact as s pecifi e d i n t he l ost t o f oll o w -u p s ecti o n. T his c o n tact s h o ul d prefera bl y b e d o n e 
acc or di n g t o t he st u d y visit sc he d ule.  
T he f oll o wi n g assess me nts, acc or di n g t o Ta ble 8 -1  a n d Ta ble 8 -2 , will be perf or me d d uri n g t he 
e n d of treat me nt visit: p h ysical e xa mi nati o n, e xtra me d ullar y i n v ol ve me nt, vital si g ns, b o d y 
wei g ht, bl o o d c ollecti o n (f or he mat ol o g y, c h e mistr y, B C R:: A B L 1 R T -q P C R, 
 
 a nal ysis, bi o mar kers, ser u m pre g na n c y test), E C G, assess me nts of a d verse e v e nts 
a n d c o nc o mita nt me dicati o ns.  
If t he s u bject c a n n ot or is u n willi n g t o atte n d a n y visit(s), t he site staff s h o ul d mai ntai n re g ular 
tele p h o ne c o ntact wit h t he s u bject, or wit h a pers o n pre-desi g n ate d b y t he s u bject. T his 
tele p h o ne c o nta ct s h o ul d prefera bl y be d o ne acc or di n g t o t he st u d y visit sc he d ule.  
After st u d y treat me nt disc o nti n uati o n, at a mi ni m u m, i n a b bre viate d visits, t he f oll o wi n g data 
s h o ul d be c ollecte d at cli nic visits or via tele p h o ne/e mail c o ntact:  
•  ne w/c o nc o mita nt treat me nts  
•  a d verse e ve nts/ Seri o us A d verse E ve nts  
T he i n vesti gat or m ust als o c o ntact t he I R T t o re gister t he s u bject’s disc o nti n uati o n fr o m st u d y 
treat me nt. 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
9. 1. 2  
Wit h dr a w al of i nf or m e d c o n s e nt  
Patie nts  ma y v ol u ntaril y wit h dra w c o nse nt t o p artici pate i n t he st u d y f or a n y reas o n at a n y ti me. 
Wit h dra wal of c o nse nt o cc urs o nl y w he n a s u bject:  
•  D oes n ot wa nt t o partici p ate i n t he st u d y a n y m ore, a n d  
•  D oes n ot all o w f urt her c ollecti o n of pers o nal dat a  
I n t his sit uati o n, t he i n v esti gat or s h o ul d ma ke a reas o na ble eff ort (e. g. tele p h o ne, e-mail, letter) 
t o u n dersta n d t he pri mar y reas o n f or t he s u bject’s decisi o n t o wit h dra w his/ her c o nse nt a n d 
rec or d t his i nf or mati o n.  
St u d y treat me nt m ust be disc o nti n ue d a n d n o f urt her ass ess me nts c o n d uct e d, a n d t h e data t hat 
w o ul d ha ve bee n c ollect e d at s u bse q ue nt visits will be c o nsi dere d missi n g.  
F urt her atte m pts t o c o ntact t he s u bj ect are n ot all o we d u nless safet y fi n di n gs re q uire 
c o m m u nicati n g or f oll o w -u p.  
All eff orts s h o ul d b e m a de t o c o m plet e t he assess me nts pri or t o st u d y wit h dra wal. A fi nal 
e val uati o n at t he ti me of t he s u bject’s st u d y wit h dra wal s h o ul d be m a de as d etaile d i n t h e 
assess me nt ta ble.  
N o vartis will c o nti n ue t o kee p a n d us e c ollecte d st u d y i nf or mati o n (i ncl u di n g a n y data res ulti n g 
fr o m t he a nal ysis of a s u bject’s sa m ples u ntil t heir ti me of wit h dra wal) acc or di n g t o a p plica ble 
la w.  
F or U S a n d Ja p a n: All bi ol o gical sa m ples n ot yet a nal yze d at t he ti me of wit h dra wal ma y still 
be use d f or f urt her testi n g/a nal ysis i n acc or da nce wit h t he ter ms of t his pr ot oc ol a n d of t h e 
i nf or me d c o nse nt f or m.  
F or E U a n d R o W: All bi ol o gical sa m ples n ot yet a nal yze d at t he ti me of wit h dra wal will n o 
l o n ger be use d, u nless per mitte d b y a p plica ble la w. T he y will be st ore d acc or di n g t o a p plica ble 
le gal re q uir e me nts. 
9. 1. 3  
L o st t o f oll o w -u p  
F or patie nts  w h ose stat us is u nclear b eca use t he y fail t o a p pear f or st u d y visits wit h o ut stati n g 
a n i nte nti o n t o disc o nti n ue or wit h dra w, t he i n vesti gat or m ust 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 s u bject, e. g. dates of tele p h o ne 
calls, re gistere d letters, etc. A s u bject s h o ul d n ot be c o nsi dere d as l ost t o f oll o w -u p u ntil d ue 
dili ge nce has bee n c o m pl ete d . 
9. 1. 4  
E arl y st u d y t er mi n ati o n b y t h e s p o n s or  
T he st u d y ca n be ter mi nate d b y N o vartis at a n y ti me f or a n y reas o n. T his ma y i ncl u de reas o ns 
relate d t o t h e be n efit/ris k assess me nt of partici pati n g i n t he st u d y, practical reas o ns (i ncl u di n g 
sl o w e nr oll me nt), or f or re g ulat or y or me dical reas o ns. I n ta ki n g t he decisi o n t o ter mi nate, 
N o vartis will al wa ys c o nsi der t he s u bject's welf are a n d safet y. S h o ul d earl y ter mi nati o n b e 
necessar y, patie nts  m ust be see n as s o o n as p ossi ble ( pr o vi de i nstr ucti o n f or c o ntacti n g t he 
s u bject, w he n t h e s u bject s h o ul d st o p ta kin g dr u g, w he n t he s u bject s h o ul d c o me f or a fi nal visit) 
a n d treate d as a pre mat urel y wit h dra w n s u bject. 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 w e d i n or der t o e ns ure t hat a de q uat e c o nsi derati o n is gi ve n t o t he 

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
pr otecti o n of t he s u bject’s i nterests. T h e i n vesti gat or or s p o ns or de p e n di n g o n t he l ocal 
re g ulati o n will be res p o nsi ble f or i nf or mi n g I R Bs/I E Cs of t h e earl y ter mi nati o n of t he trial. 
9. 2  
St u d y c o m pl eti o n a n d p o st -st u d y tr e at m e nt  
E n d of St u d y will be declare d 9 6 wee ks after t he last ra n d o mize d s u bject recei ve d t he first d ose 
of treat me nt ( pl us 3 0 da ys f or t he safet y f oll o w u p) i n ar ms 1 t o 4, or 4 8 wee ks after t he last 
e nr olle d s u bject i n t he as ci mi ni b si n gle a ge nt c o h ort recei ve d t he first d os e of st u d y treat me nt 
( pl us 3 0 da ys f or t he safet y f oll o w u p), w hic he ver occ urs later, or w he n all patie nts  c o m plete 
t heir e n d of st u d y visit, a n d a n y re peat assess me nts ass ociate d wit h t his visit ha ve bee n 
d oc u me nte d a n d f oll o we d -u p a p pr o priat el y b y t he I n vesti gat or. I n t he e ve nt of a n earl y st u d y 
ter mi nati o n decisi o n, s o o n after t he date of t hat decisi o n eac h s u bject will be re q uire d t o 
c o m plete t he e n d of st u d y visit i n its e ntiret y a n d t hereafter n o f urt her st u d y treat me nt will be 
ma de a vail a ble t o t he m. All ra n d o mize d a n d/ or treate d patie nts  s h o ul d ha ve a safet y f oll o w-u p 
call c o n d ucte d 3 0 da ys after last a d mi nistrati o n of st u d y treat me nt. T he i nf or mati o n c ollecte d 
is ke pt as s o ur ce d o c u me ntati o n. All S A Es re p orte d d uri n g t his ti me peri o d m ust be re p ort e d as 
descri be d i n Secti o n  1 0. 1. 3 . D oc u me ntati o n of atte m pts t o c o ntact t he s u bject s h o ul d b e 
rec or de d i n t he s o urce d o c u me ntati o n. 
•  T he pri mar y a n al ysis f or t he st u d y will be perf or m e d w he n all patie nts  i n r a n d o mize d 
treat me nt ar ms 1 - 4 h a ve c o m plete d t he Wee k 4 8 visit or ha ve disc o nti n ue d earl y.  
•  T he Wee k 9 6 a nal ysis will occ ur w he n all patie nts  i n ra n d o mize d treat me nt ar ms 1 - 4 
ha ve c o m plete d t h e e n d of t he st u d y visit. T he res ults will be s u m marize d i n a wee k 9 6 
Cli nical St u d y Re p ort ( C S R).  
•  All a vaila ble data fr o m asci mi ni b si n gle a ge nt c o h ort u p t o t he E n d of St u d y will be 
a nal yze d a n d s u m mariz e d i n a fi nal Cli nical St u d y Re p ort ( C S R).  
At t he ti me of t he e n d of st u d y visit, patie nts  w h o c o nti n ue t o deri ve cli nical  be nefit fr o m t he 
st u d y dr u g base d o n t he I n vesti gat or’s e val u ati o n will recei ve p ost -trial access as descri b e d i n 
Secti o n 3 . 
1 0  
S af et y m o nit ori n g a n d r e p orti n g  
1 0. 1  
D efi niti o n of a d v er s e e v e nt s a n d r e p orti n g r e q uir e m e nt s  
1 0. 1. 1  
A d v er s e e v e nt s  
A n a d verse e ve nt ( A E) is a n y u nt o w ar d m e dical occ urre nce (e. g. a n y u nfa v ora ble a n d 
u ni nte n de d si g n [i ncl u di n g a b n or mal la b orat or y fi n di n gs], s y m pt o m or disease) i n a s u bject or 
cli nical i n vesti gati o n s u bject after pr o vi di n g writte n i nf or me d c o ns e nt f or partici pati o n i n t he 
st u d y. T heref ore, a n A E ma y or ma y n ot be t e m p orall y or ca usall y ass ociate d wit h t he use of a 
me dici nal (i n vesti gati o nal) pr o d uct.  
T he i n vesti gat or h as t h e res p o nsi bilit y f or ma na gi n g t he safet y of i n di vi d ual s u bject a n d 
i de ntif yi n g a d verse e ve nts. 
N o vartis q ualifie d me dical pers o n nel will be rea dil y a vaila ble t o a d vise o n trial relate d me dical 
q uesti o ns or pr o ble ms.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
T he occ urre nce of a d vers e e ve nts m ust be s o u g ht b y n o n -directi ve q uesti o ni n g of t he s u bject at 
eac h visit d uri n g t he st u d y. A d verse e v e nts als o ma y be detect e d w he n t he y are v ol u nteere d b y 
t he s u bject d uri n g or bet wee n visits or t hr o u g h p h ysical e x a mi nati on fi n di n gs, la b orat or y test 
fi n di n gs, or ot her assess me nts. 
A d verse e v e nts m ust be rec or de d i n t he A d verse E ve nts C R F u n der t he si g ns, s y m pt o ms or 
dia g n osis ass ociate d wit h t he m, acc o m pa nie d b y t he f oll o wi n g i nf or mati o n (as far as p ossi ble) 
(if t he e ve nt is seri o us r efer t o  Secti o n  1 0. 1. 2 ): 
1.  T he C o m m o n T o xicit y Criteria ( C T C) A E gra de ( versi o n 5).  
Gra de 1 t o 5 will be use d t o c haracterize t he se v erit y of t he A d verse E ve nt.  
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 v ere, 
a n d life-t hreat e ni n g, deat h relate d t o t he A E c orres p o n di n g res pecti vel y t o Gra des 1 - 5, will be 
use d.  
2.  its relati o ns hi p t o t he st u d y treat me nt. If t he e v e nt is d ue t o lac k of efficac y or pr o gressi o n 
of u n derl yi n g ill ness (i.e. pr o gressi o n of t he st u d y i n dicati o n) t he assess me nt of ca usalit y 
will us uall y be ‘ N ot s us pecte d’. T h e rati o nale f or t his g ui da nce is  t hat t he s y m pt o ms of a 
lac k of efficac y or pr o gressi o n of u n d erl yi n g ill ness are n ot ca use d b y t h e trial dr u g, t he y 
ha p pe n i n s pite of its a d mi nistrati o n a n d/ or b ot h lac k of efficac y a n d pr o gressi o n of 
u n derl yi n g disease ca n o nl y be e val u ate d mea ni n gf ull y  b y a n a n al ysis of c o h orts, n ot o n a 
si n gle s u bject 
3.  its d urati o n (start a n d e n d dates) or if t h e e v e nt is o n g oi n g, a n o utc o me of n ot rec o v ere d/ n ot 
res ol ve d m ust be re p orte d. 
4.  w het her it c o nstit utes a S A E (see Secti o n  1 0. 1. 2  f or defi niti o n of S A E) a n d w hic h 
seri o us ness criteria ha ve bee n met 
5.  acti o n ta ke n re gar di n g wit h st u d y treat me nt.  
All a d verse e v e nts m ust be treate d a p pr o priat el y. Treat me nt ma y i ncl u de o ne or m ore of t h e 
f oll o wi n g: 
•  D ose n ot c ha n g e d  
•  D ose Re d uce d/i ncreas e d  
•  Dr u g i nterr u pte d/ wit h dr a w n  
6.  its o utc o me  
a. n ot rec o vere d/ n ot res ol ve d;  
b.  rec o vere d/r es ol ve d; 
c. rec o vere d/r es ol ve d wit h se q uelae; 
d.  fatal; or u n k n o w n. 
If t he e ve nt w orse ns t he e ve nt s h o ul d be re p orte d a sec o n d ti me i n t he C R F n oti n g t he start date 
w he n t he e v e nt w orse ns i n t o xicit y. F or gra d e 3 a n d 4 a d verse e ve nts o nl y, if i m pr o ve me nt t o a 
l o wer gra de is d eter mi ne d a ne w e ntr y f or t his e v e nt s h o ul d be re p orte d i n t he C R F n oti n g t he 
start date w he n t h e e ve nt i m pr o ve d fr o m ha vi n g bee n Gra d e 3 or Gra de 4.  
C o n diti o ns t hat were alrea d y pres e nt at t he ti me of i nf or me d c o nse nt s h o ul d be rec or de d i n 
me dical hist or y of t he s u bject.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
A d verse e v e 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 h a 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.  
A d verse e v e 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 f oll o wi n g t he last d ose of 
st u d y treat me nt. 
O nce a n a d verse e ve nt is detecte d, it m ust 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 (e. g. C o nti n ui n g at t he e n d of t he st u d y), a n d assess me nt m ust 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 v e rit y, t he s us p ecte d relati o ns hi p t o 
t he i nter ve nti o ns re q uir e d t o treat it, a n d t he o utc o me. 
Pr o gressi o n of mali g na n c y (i ncl u di n g fatal o utc o mes), if d o c u me nte d b y use of a p pr o priat e 
met h o d (f or e xa m ple, l oss of res p o ns e, pr o gressi o n t o accelerate d p has e or blast crisis), 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 v e nts se parate fr o m t he pr o gressi o n of mali g na nc y 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 rel ate d ness t o t he dr u g.  
I nf or mati o n a b o ut a d verse dr u g reacti o ns f or t h e i n vesti gati o nal dr u g ca n be f o u n d i n t he 
[ Asci mi ni b I n v esti gat or Br oc h ure]. 
A b n or mal la b orat or y val ues or test res ults c o nstit ute a d verse e ve nts o nl y if t he y f ulfill at least 
o ne of t he f oll o wi n g criteria:  
•  t he y i n d uce cli nical si g ns or s y m pt o ms 
•  t he y are c o nsi dere d cli nicall y si g nifica nt 
•  t he y re q uire t h era p y 
Cli nicall y si g nifica nt a b n or mal la b orat or y v al ues or test res ults m ust be i de ntifie d t hr o u g h a 
re vie w of val u es o utsi de of n or mal ra n ges/cli nicall y n ota ble ra n ges, si g nifica nt c ha n g es fr o m 
baseli ne or t he pre vi o us visit, or val ues w hic h are c o nsi dere d t o b e n o n-t y pical i n patie nts  wit h 
t he u n derl yi n g disease. 
1 0. 1. 2  
S eri o u s a d v er s e e v e nt s  
A n S A E is defi ne d as a n y a d verse e v e nt [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 ns(s) w hic h meets a n y o ne of t he f oll o wi n g 
criteria:  
•  fatal 
•  life-t hreat e ni n g 
Life -t hreate ni n g i n t he c o nte xt of a S A E refers t o a reacti o n i n w hic h t he s u bject was at ris k of 
deat h at t he ti me of t he reacti o n; it d oes n ot refer t o a reacti o n t hat h y p ot h eticall y mi g ht ha ve 
ca use d deat h if it were m ore se vere ( pl ease refer t o t he I C H -E 2 D G ui deli n es).  
•  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  
•  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, u nless 
h os pitalizati o n is f or:  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
•  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 (e. g. l oss of res p o nse, treat me nt fail ure, pr o gressi o n t o 
A P/ B C)  
•  electi ve or pre -pla n ne d treat me nt f or a pre -e xisti n g c o n diti o n t hat is u nrelate d t o t he 
i n dicati o n u n der st u d y a n d has n ot w orse ne d si nce si g ni n g t he i nf or me d c o nse nt 
•  s ocial reas o ns a n d res pite care i n t he a bs e nce of a n y d eteri or ati o n i n t h e s u bject’s 
ge neral c o n diti o n  
•  treat me nt o n a n e mer g e nc y o ut patie nt basis f or a n e v e nt n ot f ulfilli n g a n y of t he 
defi niti o ns of a S A E gi ve n a b o ve a n d n ot r es ulti n g i n h os pital a d missi o n  
•  is me dicall y si g nifica nt, e. g. defi n e d as a n e v e nt t hat je o par di zes t he s u bject or ma y re q uir e 
me dical or s ur gic al 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 v e  
Me dical a n d s cie ntific j u d g me nt s h o ul d be e xercis e d i n deci di n g w het her ot her sit uati o ns s h o ul d 
be c o nsi dere d seri o us reacti o ns, s uc h as i m p orta nt me dical e ve nts t hat mi g ht n ot be i m me diatel y 
life t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut mi g ht je o par dize t he s u bject or mi g ht 
re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d a b o ve. S uc h e ve nts s h o ul d be 
c o nsi dere d me di call y si g nifica nt. E xa m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n 
e mer ge n c y r o o m or at h o me f or aller gic br o n c h os p as m, bl o o d d yscrasias or c o n v ulsi o ns t hat d o 
n ot res ult i n h os pitalizati o n or de vel o p me nt of d e pe n de nc y or a b use.  
All mali g na nt ne o plas ms will be assesse d as seri o us me dicall y si g nifica nt if ot her seri o us ness 
criteria are n ot met a n d t he mali g na nt n e o plas m is n ot a dise ase pr o gressi o n of t h e st u d y 
i n dicati o n. 
A n y s us pecte d tra ns missi o n via a me dici nal pr o d uct of a n i nfecti o us a ge nt is als o c o nsi dere d a 
seri o us a d vers e reacti o n. 
All re p orts of i nte nti o nal mis use a n d a b use of t he pr o d uct are als o c o nsi dere d seri o us a d verse 
e ve nt irres p ecti ve if a cli nical e ve nt has o cc urre d.  
1 0. 1. 3  
S A E r e p orti n g  
T o e ns ure s u bject safet y, e ver y S A E, re gar dless of ca usalit y, occ urri n g after t he s u bject has 
pr o vi de d i nf or me d c o ns e nt a n d u ntil 3 0 da ys after s u bject st o p pe d t he st u d y treat me nt m ust be 
re p orte d t o N o v artis safet y i m me diatel y wit h o ut u n d ue dela y, b ut u n der n o circ u msta nces later 
t ha n wit hi n 2 4 h o urs of o btai ni n g k n o wle d ge of t he e ve nts ( N ote: if m ore stri n ge nt, l ocal 
re g ulati o ns re gar di n g re p orti n g ti meli nes pre vail). T he I n v esti gat or m ust c o m plete a n d s u b mit 
t he S A E re p ort f or m directl y i n t he C R F. Detaile d i nstr ucti o ns re gar di n g t he s u b missi o n pr ocess 
a n d re q uir e me nts are t o be f o u n d i n t he i n vesti gat or f ol der pr o vi d e d t o eac h site.  
A n y a d diti o nal i nf or mati o n f or t he S A E i ncl u di n g c o m plicati o ns, pr o gressi o n of t he i nitial S A E, 
a n d rec urre nt e pis o des m ust be re p orte d as f oll o w -u p t o t he ori gi nal e pis o de wit hi n 2 4 h o urs of 
t he i n vesti gat or recei vi n g t he f oll o w-u p i nf or mati o n. A n S A E occ urri n g at a differe nt ti me 
i nter val or ot her wise c o nsi dere d c o m plet el y u nrel ate d t o a pre vi o usl y re p orte d o ne s h o ul d b e 
re p orte d se p aratel y as a n e w e ve nt. 
T he f oll o wi n g S A E re p orti n g ti mefra mes a p pl y:  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
1.  Scree n Fail ures (e. g. a s u bject w h o is s cree ne d b ut is n ot treate d or ra n d o mize d): S A Es 
occ urri n g after t he s u bj ect has pr o vi d e d i nf or m e d c o nse nt u ntil t he ti me t he s u bject is 
dee me d a Scree n Fail ure m ust be re p orte d t o N o vartis.  
2.  Ra n d o mize d O R Treate d Patie nts : S A Es c ollecte d bet wee n ti me s u bject si g ns I C F u ntil 3 0 
da ys after t h e s u bject has disc o nti n ue d or st o p pe d st u d y treat me nt  
All f oll o w -u p i nf or mati o n f or t he S A E i n cl u di n g i nf or mati o n o n c o m plicati o ns, pr o gressi o n of 
t he i nitial S A E a n d rec urre nt e pis o des m ust be re p orte d as f oll o w-u p t o t he ori gi nal e pis o de 
i m me diatel y, wit h o ut u n d ue dela y, b ut u n der n o circ u msta nces l ater t h an wit hi n 2 4 h o urs of t h e 
I n v esti gat or recei vi n g t he f oll o w-u p i nf or mati o n ( N ote: If m ore stri n ge nt, l ocal re g ulati o ns 
re gar di n g re p orti n g ti meli nes pre vail). A n S A E occ urri n g at a differe nt ti me i nter val or 
ot her wise c o nsi dere d c o m pletel y u nrelate d t o a pr e vi o usl y re p orte d o ne m ust be re p orte d 
se parat el 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 ns ert ( ne w 
occ urre nce) a n d is t h o u g ht t o be relate d t o t he st u d y treat me nt, a C M O & P S De part me nt 
ass ociate ma y ur ge ntl y re q uire f urt her i nf or mati o n fr o m t he i n vesti gat or f o r 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 st u d y treat me nt t hat t his S A E has b ee n 
re p orte d. 
Treat me nt -e mer ge nt ele v ati o ns i n A S T or A L T ( > 3 x U L N) i n c o m bi nati o n wit h t otal bilir u bi n 
> 2 x U L N or  ja u n dice i n t he a bse n ce of c h olestasis ( defi n e d as A L P < 2 U L N) or ot her ca uses 
of h y per bilir u bi ne mia ca n  be a n i n dicat or of se vere dr u g i n d uce d li ver i nj ur y ( H y’s La w). F or 
t his reas o n, a p ote ntial H y’s La w cas e re q uires e x pe dite d re p orti n g, a n d will be ha n dle d as a 
seri o us u ne x pecte d a d verse e v e nt (ass essi n g it as  me dicall y si g nifica nt i n t he a bse n ce of a n y 
ot her seri o us n ess criteria). It m ust be re p orte d as a n S A E t o t he  s p o ns or pr o m ptl y (i.e., e v e n 
bef ore all ot her p ossi ble ca uses of li ver i nj ur y ha ve bee n e xcl u de d). Re p orti n g  s h o ul d i ncl u de 
all a vaila ble i nf or mati o n, es peciall y t hat nee d e d f or e val uati n g t he dia g n osis, se verit y, a n d  
li keli h o o d t hat t he st u d y treat me nt ca use d t he reacti o n. F or patie nt m o nit ori n g a n d t o better 
u n dersta n d  p ote ntial eti ol o gies, t he i n vesti gat or m ust i nitiate a cl ose f oll o w -u p u ntil c o m plete 
res ol uti o n of t he pr o ble m a n d c o m pleti o n of all atte m pts t o o btai n s u p ple me ntar y dat a.  Pleas e 
refer t o S ecti o n 6. 5. 2. 1  F oll o w u p o n p ote ntial DI LI cases.  
S us pecte d U n e x pect e d S eri o us A d verse Reacti o ns ( S U S A Rs) will be c ollecte d a n d re p ort e 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 E U G ui da nce 
2 0 1 1/ C 1 7 2/ 0 1, E U Cli nical Tri al Re g ulati o n 5 3 6/ 2 0 1 4 ( o nce tr a nsfer is c o m plete d), or as per 
nati o nal re g ulat or y re q uir e me nts i n partici pati n g c o u ntries. A n y S A Es e x p erie nce d after t he 3 0 
da y safet y e v al uati o n peri o d s h o ul d o nl y be re p orte d t o N o vartis Safet y if t he i n vesti gat or 
s us pects a ca us al relati o ns hi p t o st u d y treat me nt. 
S A E R e p orti n g vi a a n El e ctr o ni c D at a C oll e cti o n T o ol  
T he pri mar y mec h a nis m f or re p orti n g a n S A E t o N o vartis will be t he el ectr o nic data c ollecti o n 
t o ol. 
If t he electr o nic s yste m is u na vaila ble, t he n t he sit e will use t he pa per S A E data c ollecti o n t o ol 
(see ne xt se cti o n) t o re p ort t he e ve nt wit hi n 2 4 h o urs. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
T he site will e nter t he S A E data i nt o t he electr o nic s yste m as s o o n as it bec o mes a vaila ble.  
After t h e st u d y is c o m pl ete d at a gi ve n site, t he electr o nic data c ollecti o n t o ol will be ta ke n 
offli ne t o pre ve nt t he e ntr y of ne w data or c h a n ges t o e xisti n g data.  
If a site recei v es a re p ort of a ne w S A E fr o m a st u d y partici pa nt or recei v es u p date d data o n a 
pre vi o usl y re p orte d S A E after t he electr o nic data c ollecti o n t o ol has bee n ta ke n offli ne, t he n t h e 
site ca n re p ort t his i nf or mati o n o n a pa per S A E f or m (see ne xt s ecti o n) or b y tele p h o ne. 
S A E R e p orti n g vi a P a p er D at a C oll e cti o n T o ol  
Facsi mile tr a ns missi o n of t he S A E pa per dat a c ollecti o n t o ol is t he preferre d met h o d t o tra ns mit 
t his i nf or mati o n t o N o vartis. 
I n rare circ u msta nces a n d i n t he a bse n ce of facsi mile e q ui p me nt, n otificati o n b y tele p h o ne is 
acce pta ble wit h a c o p y of t he S A E data c ollecti o n t o ol se nt b y o ver ni g ht mail or c o urier ser vi ce.  
I nitial n otificati o n via tel e p h o ne d oes n ot re place t he nee d f or t he i n vesti gat or t o c o m plete a n d 
si g n t he S A E data c ollecti o n t o ol wit hi n t he desi g nate d re p orti n g ti mefra mes.  
1 0. 1. 4  
Pr e g n a n c y r e p orti n g  
Pr e g n a n ci e s  
T o e ns ure s u bject safet y, eac h pre g na nc y o cc urri n g after si g ni n g t he i nf or me d c o nse nt m ust be 
re p orte d t o N o vartis wit hi n 2 4 h o urs of lear ni n g of its occ urre n ce. T he pre g na nc y s h o ul d b e 
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 g e 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 a n d re p ort e d b y t he i n vesti gat or t o t he N o vartis C hief Me dical 
Office a n d P atie nt Safet y ( C M O & P S). Pre g na nc y f oll o w -u p s h o ul d b e rec or de d o n t he s a me 
f or m a n d s h o ul d i ncl u d e a n assess me nt of t he p ossi ble relati o ns hi p t o t he st ud y treat me nt of a n y 
pre g na nc y o ut c o me. A n y S A E e x perie n ce d d uri n g pre g na nc y m ust be re p orte d.  
F or all pre g na n cies wit h li ve birt h a n d/ or u n k n o w n o utc o me t he ne w b or n has t o be f oll o we d u p 
t o o btai n i nfa nt healt h stat us a n d de vel o p me nt u p t o t wel ve m o nt hs after d eli ver y. 
1 0. 1. 5  
R e p orti n g of st u d y tr e at m e nt err or s i n cl u di n g mi s u s e/ a b u s e  
St u d y treat me nt  err ors are u ni nte nti o nal err ors i n t he prescri bi n g, dis pe nsi n g, a d mi nistrati o n or 
m o nit ori n g of a me dici ne w hile u n der t he c o ntr ol of a healt hcare pr ofessi o nal, s u bject or 
c o ns u mer ( defi niti o n fr o m E ur o pea n Me dici n es A ge nc y).  
St u d y treat me nt m is use refers t o sit uati o ns w here t he me di ci nal pr o d uct is i nte nti o nall y a n d 
i na p pr o priatel y use d n ot i n acc or da nce wit h t he pr ot oc ol. 
St u d y treat me nt a b use c orres p o n ds t o t he persiste nt or s p ora dic, i nte nti o nal e xcessi ve use of a 
me dici nal pr o d uct, w hic h is acc o m pa nie d b y h ar mf ul p h ysical or ps yc h ol o gical effects.  
St u d y treat me nt err ors a n d uses o utsi de of w hat is f oresee n i n t he pr ot oc ol will be c ollecte d i n 
t he D A R ( d os e a d mi nistrati o n rec or d) e C R F irres pecti ve of w het h er or n ot ass ociate d wit h a n 

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
A E/ S A E a n d ( u ntil tr a nsiti o n t o E U C T R) re p orte d t o Safet y o nl y if ass ociate d wit h a n S A E. 
Mis use or a b use (a n d u p o n tra nsiti o n t o E U C T R, als o st u d y treat me nt err ors a n d uses o utsi de 
of w hat is f oresee n i n t he pr ot oc ol) will be c ollecte d a n d re p orte d i n t he safet y data base 
irres pecti ve of it b ei n g ass ociate d wit h a n A E/ S A E wit hi n 2 4 h o urs of I n vesti gat or’s a ware ness. 
F or m ore i nf or mati o n o n A E a n d S A E defi niti o n a n d re p orti n g re q uire me nts, please see t he, 
res pecti ve s ecti o ns. 
1 0. 2  
A d diti o n al S af et y M o nit ori n g  
1 0. 2. 1  
Li v er s af et y m o nit ori n g  
T o e ns ure s u bject safet y a n d e n ha n ce relia bilit y i n deter mi ni n g t he he pat ot o xic p ote ntial of a 
st u d y dr u g, a sta n dar dize d pr ocess f or i de ntificati o n, m o nit ori n g a n d e val uati o n of li ver e ve nts 
has t o be f oll o we d.  
T he f oll o wi n g t w o cate g ories of a b n or malities/a d verse e ve nts ha v e t o b e c o nsi dere d d uri n g t h e 
c o urse of t he st u d y (irres pecti ve of w h et her classifie d/re p orte d as A E/ S A E):  
•  Li ver la b orat or y tri g gers, w hic h will re q uire re peate d assess me nts of t he a b n or mal 
la b orat or y para meter 
•  Li ver e ve nts, w hic h will re q uire cl ose o bser vati o n, f oll o w -u p m o nit ori n g  
Please refer t o Ta ble 1 6 -1  i n Secti o n  1 6. 1  f or c o m plete defi niti o ns of li ver la b orat or y tri g gers 
a n d li ver e ve nts.  
E ver y li ver e v e nt defi n e d i n Ta ble 1 6 -1  s h o ul d b e f oll o we d u p b y t h e i n vesti gat or or desi g nate d 
pers o n nel at t he trial site, as s u m marize d bel o w. A d diti o nal details o n acti o ns re q uire d i n cas e 
of li ver e ve nts are o utli ne d i n Ta ble 1 6 -2 . Re p eat li ver c he mistr y tests ( A L T, A S T, T B L, 
P T/I N R, A L P a n d G G T) t o c o nfir m ele vati o n.  
•  T hese li ver c he mistr y re p eats will be perf or me d usi n g t he ce ntr al la b orat or y. If res ults will 
n ot be a vaila ble fr o m t he ce ntral la b orat or y, t he n t he re peats ca n als o be perf or me d at a l ocal 
la b orat or y t o m o nit or t he safet y of t he s u bject. If a li ver e ve nt is s u bse q ue ntl y re p orte d, a n y 
l ocal li ver c he mistr y tests pre vi o usl y c o n d u cte d t hat are ass o ciate d wit h t his e ve nt s h o ul d 
ha ve res ults r e p orte d o n t he u n pla n ne d l ocal la b orat or y C R F.  
•  If t he i nitial ele vati o n is c o nfir me d, cl ose o bser vati o n of t he s u bject will be i nitiate d, 
i ncl u di n g c o nsi derati o n of treat me nt i nterr u pti o n if dee me d a p pr o priate. 
•  Disc o nti n uati o n of t he st u d y dr u g (refer t o t he Disc o nti n uati o n of st u d y treat me nt secti o n), 
if a p pr o priate 
•  H os pitalizati o n of t he s u bject if a p pr o pri ate  
•  Ca usalit y assess me nt of t he li ver e ve nt  
•  T h or o u g h f oll o w -u p of t he li ver e ve nt s h o ul d i ncl u de  
•  T hese i n vesti gati o ns ca n i ncl u de bas e d o n i n v esti gat or’s discreti o n: ser ol o g y tests, 
i ma gi n g a n d pat h ol o g y assess me nts, he p at ol o gist’s c o ns ulta nc y; o btai ni n g 
m ore 
detaile d hist or y of s y m pt o ms a n d pri or or c o nc urre nt diseases, hist or y of c o nc o mita nt 
dr u g us e, e xcl usi o n of u n derl yi n g li ver disease  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
All f oll o w -u p i nf or m ati o n, a n d t he pr oce d ures perf or me d m ust b e rec or de d as a p pr o priate i n 
t he C R F. 
1 0. 2. 2  
R e n al s af et y m o nit ori n g  
E ver y re n al la b orat or y tri g ger or re n al e ve nt as defi ne d i n Ta ble 1 6 -3  s h o ul d be f oll o we d u p b y 
t he i n vesti gat or or desi g n ate d pers o n nel at t he trial site as s u m marize d i n Secti o n  1 6. 2 . 
1 0. 2. 3  
St e eri n g C o m mitt e e  
A steeri n g c o m mittee ( S C) will be esta blis he d c o m prisi n g of i n vesti gat ors partici pati n g i n t h e 
trial, i.e. n ot bei n g me m bers of t he N o vartis/s p o ns or re prese ntati ves fr o m t he Cli nical Trial 
Tea m. A d diti o nall y, a patie nt a d v ocate will be a n acti ve me m ber of t his c o m mittee. 
T he S C will e ns ur e tr a ns pare nt ma na ge me nt of t he st u d y acc or di n g t o t h e 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 uir e. T he S C will re vie w 
pr ot oc ol a me n d me nts as a p pr o pri ate. T o g et her wit h t he cli nical tri al tea m, t he S C  will als o 
de vel o p rec o m me n d ati o ns f or p u blicati o ns of st u d y res ults i ncl u di n g a ut h ors hi p r ules. T he 
details of t he r ole of t h e steeri n g c o m mittee will be defi ne d i n t he ste eri n g c o m mittee c harter.  
1 1  
D at a C oll e cti o n a n d D at a b a s e m a n a g e m e nt  
1 1. 1  
D at a c oll e cti o n  
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 v e b ee n b uilt usi n g f ull y vali date d sec ure we b -
e na ble d s oft w are t hat c o nf or ms t o 2 1 C F R Part 1 1 re q uire me nts, I n v esti gat or site staff will n ot 
be gi ve n access t o t he electr o nic dat a ca pt ure ( E D C) s yste m u ntil t he y ha ve b ee n tr ai ne d. 
A ut o matic vali dati o n pr o gra ms c hec k f or data discre pa n cies i n t he e C R Fs, all o w m o dificati o n 
a n d/ or verific ati o n of t he e ntere d d ata b y t he i n vesti gat or staff.  
T he i n vesti gat or/ desi g ne e is res p o nsi ble f or ass uri n g t hat t he data (rec or de d o n C R Fs) (e ntere d 
i nt o e C R F) is c o m plete, acc urat e, 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. 
T he I n vesti gat or m ust certif y t hat t he data e ntere d are c o m plet e a n d acc urat e 
After fi nal d ata base l o c k, t he i n vesti gat or will recei ve c o pies of t he s u bject data f or arc hi vi n g 
at t he i n vesti gati o nal site.  
Data c ollecte d b y t hir d parties ( he m at ol o g y, bi oc he mistr y, P C R assess me nts, bi o mar kers, E C G, 
P K a n d P R Os) will be se nt electr o nicall y t o N o vartis.  
All data s h o ul d b e rec or de d, ha n dle d a n d st or e d i n a wa y t hat all o ws its acc urate re p orti n g, 
i nter pretati o n a n d v erific ati o n. 
1 1. 2  
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 o ntract Researc h Or ga nizati o n ( C R O)) will re vie w t he data 
e ntere 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 clarifi cati o n will be create d f or discre pa n cies 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 

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
site staff are re q uire d t o res p o n d pr o m ptl y t o q u eri es a n d t o ma ke a n y necessar y c h a n ges t o t he 
data.  
C o nc o mita nt treat me nts a n d pri or me dicati o ns e ntere d i nt o t he data bas e will be c o de d usi n g t he 
W H O Dr u g Refere nce List, w hic h e m pl o ys t he A nat o mical T hera pe utic C he mical classificati o n 
s yste m. Me dical hist or y/c urre nt me dical c o n diti o ns a n d a d verse e ve nts w ill be c o de d usi n g t he 
Me dical dicti o nar y f or re g ulat or y acti vities ( Me d D R A) ter mi n ol o g y.  
Ra n d o mizati o n c o des a n d data a b o ut all st u d y tr eat me nt (s) dis pe ns e d t o t he s u bject a n d all 
d osa ge c ha n ges will be trac ke d usi n g a n I nteracti ve Res p o nse Tec h n ol o g y (I R T). T he s yste m 
will be s u p plie d b y a v e n d or, w h o will als o m a na ge t h e data base. T he data will be se nt 
electr o nicall y t o N o vartis ( or a desi g nat e d C R O) at s pecific ti meli nes.  
O nce all t he necessar y acti o ns ha ve bee n c o m plete d a n d t h e d ata base has bee n d eclare d t o be 
c o m plete a n d acc urate, it will be l oc ke d a n d ma de a vaila ble f or d ata a n al 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 aft er writte n a gree me nt b y N o vartis de vel o p me nt 
ma na ge me nt.  
After d ata bas e l oc k, t h e i n vesti gat or will recei ve c o pies of t he s u bj ect dat a f or arc hi vi n g at t h e 
i n vesti gati o nal site. 
1 1. 3  
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 n vesti gat or’s 
meeti n g, a 
N o vartis/ dele gate d C R O re pres e ntati ve will r e vie w t he pr ot oc ol a n d d ata ca pt ure re q uire me nts 
(i.e. e C R Fs) wit h t he i n vesti gat ors a n d t h eir staff. D uri n g t he st u d y, N o vartis e m pl o ys se veral 
met h o ds of e ns uri n g pr ot oc ol a n d G C P c o m plia nce a n d t he q u alit y/i nte grit y of t he sites’ d ata. 
T he fiel d 
m o nit or/ Cli nical Researc h Ass ociate ( C R A) will visit t he site t o c hec k t h e 
c o m plete ness of s u bject rec or ds, t he acc urac y of data ca pt ur e/ data e ntr y, t he a d here nce t o t he 
pr ot oc ol a n d t o G o o d Cli nical Practice, t h e pr o gress of e nr oll me nt, a n d t o e ns ure t hat st u d y 
treat me nt is bei n g st ore d, dis pe nse d, a n d acc o u nte d f or acc or di n g t o s pecificati o ns. Ke y st u d y 
pers o n nel m ust be a vaila ble t o assist t he fiel d m o nit or d uri n g t hese visits. C o nti n u o us re m ote 
m o nit ori n g of eac h site’s data ma y be perf or m e d b y a ce ntralize d N o vartis/ dele gate d C R O/ C R A 
or ga nizati o n. A d diti o nall y, a  ce ntral a nal ytics or ga nizati o n ma y a nal yze d ata & i de ntif y ris ks 
& tre n ds f or site o perati o nal para met ers, a n d pr o vi de re p orts t o N o vartis cli nical tea ms t o assist 
wit h trial o versi g ht.  
T he i n vesti gat or m ust mai ntai n s o urce d o c u me nts f or eac h s u bject i n t he st u d y, c o nsisti n g of 
case a n d visit n otes ( h os pital or cli nic me dical rec or ds) c o ntai ni n g de m o gra p hic a n d me dical 
i nf or mati o n, la b orat or y data, ele ctr ocar di o gra ms, a n d t he res ults of an y ot her tests or 
assess me nts. All i nf or m ati o n o n C R Fs m ust be tracea ble t o t hese s o urce d oc u me nts i n t he 
s u bject’s file. T he i n vesti gat or m ust als o kee p t he ori gi nal i nf or me d c o nse nt f or m si g ne d b y t he 
s u bject (a si g ne d c o p y is gi ve n t o t he s u bject). Rec o r ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, 
pertai ni n g t o t he c o n d uct of t his st u d y m ust be retai ne d b y t he I n vesti gat or f or 1 5 years after 
st u d y c o m pleti o n u nless l ocal re g ulati o ns or i nstit uti o nal p olicies re q uire a l o n ger rete nti o n 
peri o d. N o rec or ds ma y be destr o ye d d uri n g t he rete nti o n peri o d wit h o ut t he writte n a p pr o val 
of N o vartis. N o rec or ds ma y be tra nsferre d t o a n ot her l ocati o n or part y wit h o ut writte n 
n otificati o n t o N o vartis.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 1 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
T he i n vesti gat or m ust gi ve t he m o nit or access t o all rele va nt s o urce d o c u me nts t o c o nfir m t heir 
c o nsiste nc y wit h t he data ca pt ur e a n d/ or data e ntr y. N o vartis m o nit ori n g st a n dar ds re q uir e f ull 
verificati o n f or t he pres e nce of i nf or m e d c o nse nt, a d here n ce t o t he i ncl usi o n/e xcl usi o n criteria, 
d oc u me ntati o n of S A Es, a n d of data t hat will be use d f or all pri mar y varia bles. A d diti o nal 
c hec ks of t he c o nsiste n c y of t he s o urce d ata wit h t he C R Fs are perf or m e d acc or di n g t o t he 
st u d y-s pecific m o nit ori n g pla n. N o i nf or mati o n i n s o urce d oc u m e nts a b o ut t he i de ntit y of t he 
patie nts  will be discl ose d.  
1 2  
D at a a n al y si s a n d st ati sti c al m et h o d s  
T he p ri mar y safet y a n d efficac y a nal ysis will be c o n d ucte d o n all ra n d o mize d s u bject data at 
t he ti me all patie nts  i n t he 1-4 ra n d o mize d treat me nt ar ms will ha ve c o m plete d at least 4 8 wee ks 
of st u d y treat me nt or disc o nti n ue d earlier.   
A n y a d diti o nal data f or ra n d o mize d patie nts  c o nti n ui n g t o recei v e st u d y treat me nt past t his ti me, 
as all o we d b y t he pr ot oc ol, will be f urt her s u m marize d i n a Wee k 9 6 st u d y re p ort o nce t hese 
patie nts  c o m plete t he st u d y.  
All a vaila ble data fr o m t h e as ci mi ni b si n gle a ge nt c o h ort u p t o t he E n d of St u d y will be a nal yze d 
a n d s u m marize d i n a fi nal Cli nical St u d y Re p ort ( C S R).  
T he data will be a nal y ze d b y N o vartis. It is pla n ne d t hat all data fr o m partici pati n g ce nters 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.  
St u d y data will be s u m marize d wit h res p ect t o de m o gra p hic a n d b aseli ne c haracteristics, 
effic ac y o bser vati o ns a n d meas ure me nts, safet y o bser vati o ns a n d meas ure me nts, a n d all 
rele va nt P K, bi o mar k er meas ure me nts. 
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.  
1 2. 1  
A n al y si s s et s  
T he F ull A n al 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 
b y ra n d o mizati o n. A cc or di n g t o t he i nte nt t o treat (I T T) pri nci ple, patie nts  will be a nal y ze d 
acc or di n g t o t he tr eat me nt, t he y ha ve bee n assi g ne d t o d uri n g t he ra n d o mizati o n pr oce d ure.  
T he F ull A n al ysis Set -Asci mi ni b Si n gle A ge nt C o h ort ( F A S -A S A C)  c o m prises all s u bjects 
assi g ne d t o t he asci mi ni b si n gle a ge nt c o h ort.  
T he S afet y Set  i ncl u des all patie nts  w h o recei ve d a n y st u d y treat me nt (i.e. at least o ne d ose of 
t he i n vesti gati o nal dr u g or c o ntr ol dr u g i n case of m o n ot hera p y, or at least o ne d ose of a n y 
c o m p o ne nt of t h e st u d y treat me nt i n case of a c o m bi nati o n t hera p y). Patie nts  will be a n al yze d 
acc or di n g t o t he st u d y treat me nt recei ve d, w here treat me nt recei ve d is defi ne d as t h e 
ra n d o mize d tr eat me nt if t he s u bject t o o k at least o n e d ose of t hat tr eat me nt or t he first treat me nt 
recei v e d if t he ra n d o mize d treat me nt was ne ver recei ve d.  
T he S afet y Set -A S A C  i n cl u des all s u bjects assi g n e d t o t he asci mi ni b si n gle a ge nt c o h ort w h o 
recei v e d at least o ne d ose of asci mi ni b 8 0 m g Q D. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
T he P h ar m ac o ki netic a n al ysis set ( P A S)  i ncl u des all patie nts  ra n d o mi ze d t o asci mi ni b + 
i mati ni b ar m or asci mi ni b si n gle a ge nt c o h ort w h o recei v e d at least o ne d ose of asci mi ni b or 
i mati ni b a n d pr o vi de at least o ne e v al ua ble P K c o nce ntrati o n. 
F or a c o nce ntrati o n t o be e val ua ble, p atie nts  are re q uire d t o:  
•  Ta ke a d os e of as ci mi ni b or i mati ni b pri or t o sa m pli n g,  
•  F or p ost -d ose s a m ples, d o n ot v o mit wit hi n 4 h o urs after t h e d osi n g of asci mi ni b or 
i mati ni b. 
•  F or pre -d ose s a m ples, ha ve t he sa m ple c ollecte d bef ore t h e ne xt d ose a d mi nistrati o n.  
T he P h ar m ac o ki netic a n al ysis set –  A S A C ( P A S - A S A C)  i ncl u des all s u bjects assi g ne d t o 
t he asci mi ni b si n gle a ge nt c o h ort w h o recei ve d at least o ne d ose of as ci mi ni b 8 0 m g Q D a n d 
pr o vi de at l east o n e e v al ua ble P K c o nce ntr ati o n. F or a c o nce ntr ati o n t o be e val ua bl e, s u bjects 
are re q uire d t o:  
•  Ta ke a d os e of as ci mi ni b pri or t o sa m pli n g.  
•  F or p ost -d ose s a m ples, d o n ot v o mit wit hi n 4 h o urs after t h e d osi n g of asci mi ni b . F or pre -
d ose sa m ples, ha ve t he s a m ple c ollecte d bef ore t he ne xt d ose a d mi nistrati o n.  
T he M R
4. 5 Res p o n der set  a n d t he M R
4. 5 Res p o n der set - A S A C  c o nsist of t he patie nts  i n t he 
F A S a n d i n t he F A S -A S A C res pecti vel y w h o ac hie ve d M R 4. 5 b y t he c orres p o n di n g c ut -off date. 
It will be use d f or t he ti m e t o M R4. 5 a n d d urati o n of M R 4. 5 a nal ys es. 
T he Cr oss -o ver set  c o nsists of t he patie nts  ra n d o mize d t o t he c o nti n ue d i mati ni b ar m w h o 
cr osse d o v er t o recei ve as ci mi ni b a d d -o n tr eat me nt after 4 8 wee ks of st u d y treat me nt. T his will 
be use d i n t he a nal ys es of t he data after cr oss -o ver.  
1 2. 2  
S u bj e ct 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  
De m o gra p hic a n d ot her baseli ne data i ncl u di n g disease c haracteristics will be liste d a n d 
s u m marize d descri pti vel y b y treat me nt ar m a n d f or t he asci mi ni b si n gle a ge nt c o h ort f or t he 
F A S s a n d Safet y s et s. 
Cate g orical d ata will be prese nte d as fre q u e ncies a n d perce nta ges. F or c o nti n u o us data, mea n, 
sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m will be prese nte d. F or s electe d para meters, 
2 5 t h a n d 7 5 t h perce ntiles will als o be prese nte d.  
Rele va nt me dical hist ori es a n d c urre nt m e dical c o n diti o ns at baseli ne will be s u m marize d 
se parat el y b y s yste m or ga n class a n d preferre d ter m, b y treat me nt ar m a n d f or t he asci mi ni b 
si n gle a ge nt c o h ort. 
1 2. 3  
Tr e at m e nt s  
T he Safet y set s will be use d f or t he a n al yses bel o w. Cate g orical dat a will be s u m marize d as 
fre q ue n cies a n d p erce nta ges. F or c o nti n u o us data, mea n, sta n dar d de viati o n, me dia n, 2 5 t h a n d 
7 5 t h perce ntiles, mi ni m u m, a n d ma xi m u m will be prese nte d.  
T he d urati o n of e x p os ure i n da ys t o asci mi ni b, i mati ni b a n d nil oti ni b as well as t he d ose 
i nte nsit y (c o m p ute d as t he rati o of act u al c u m ul ati ve d ose recei ve d a n d act ual d urati o n of 
e x p os ure) a n d t he relati v e d ose i nte nsit y (c o m p ut e d as t he rati o of d ose i n te nsit y a n d pla n ne d 

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
d ose i nte nsit y) will be s u m marize d b y treat me nt ar m a n d f or as ci mi ni b si n gle a ge nt c o h ort b y 
mea ns of d escri pti ve statistics usi n g t he safet y s et. T he d urati o n of e x p os ure will als o b e 
prese nte d f or asci mi ni b + i mati ni b.  
C o nc o mita nt me dicati o ns a n d si g nifica nt n o n -dr u g t hera pies pri or t o a n d after t he start of t h e 
st u d y treat me nt will be liste d a n d s u m marize d acc or di n g t o t he A nat o mical T hera pe utic 
C he mical ( A T C) classifi cati o n s yste m, b y treat m e nt ar m a n d f or  t he as ci mi ni b si n gle a ge nt 
c o h ort. 
T he n u m ber of p atie nts  wit h d ose a dj ust me nts (re d u cti o ns, i nterr u pti o n, or per ma ne nt 
disc o nti n uati o n) a n d t he reas o ns will be s u m marize d b y treat me nt ar m a n d f or t he asci mi ni b 
si n gle a ge nt c o h ort a n d all d osi n g data will be liste d. 
1 2. 4  
A n al y si s of t h e pri m ar y e n d p oi nt( s)  
T he pri mar y o bje cti ve of t he st u d y is:  
•  T o assess w het her asci mi ni b 4 0 m g + i mati ni b or asci mi ni b 6 0 m g + i mati ni b is m ore 
effecti ve t ha n c o nti n ue d i mati ni b i n patie nts  wit h C M L -C P w h o ha ve recei ve d i mati ni b 
f or at least o ne y ear ( 1 2-cale n dar m o nt hs) a n d ha ve n ot ac hie ve d D M R  
1 2. 4. 1  
D efi niti o n of pri m ar y e n d p oi nt( s)   
T he pri mar y effic ac y e n d p oi nt of t he st u d y is t he rate of M R 4. 5 at 4 8 wee ks, defi ne d as t he 
pr o p orti o n of patie nts  still treate d wit h t he ra n d o mize d treat me nt at 4 8 wee ks a n d are i n M R 4. 5 
( B C R:: A B L 1 rati o of ≤ 0. 0 0 3 2 %) at 4 8 wee ks ( ± assess me nt wi n d o w), a m o n g all patie nts  
ra n d o mize d t o t he res pecti ve treat me nt ar m. Patie nts  w h o disc o nti n ue t he ra n d o mize d treat me nt 
f or a n y reas o n pri or t o 4 8 wee ks are i ncl u de d i n t he de n o mi nat or a n d c o nsi dere d as n o n-
res p o n ders. 
1 2. 4. 2  
St ati sti c al m o d el, h y p ot h e si s, a n d m et h o d of a n al y si s  
T he rate of M R 4. 5 at 4 8 wee ks will be cal c ulate d b ase d o n t he F A S.  
T he rate of M R 4. 5 at 4 8 wee ks a n d its 2 -si de d 9 0 % c o nfi de nce i nter val base d o n t he Cl o p per-
Pears o n met h o d will be prese nte d b y treat me nt ar m (asci mi ni b 6 0 m g + i mati ni b, asci mi ni b 4 0 
m g + i mati ni b a n d c o nti n ue d i mati ni b).  T he differe nce i n rate of M R 4. 5 bet wee n 1) as ci mi ni b 
6 0 
m g 
+ 
i mati ni b  vers us  c o nti n ue d 
i mati ni b 
a n d 
2) 
asci mi ni b 
4 0 
m g 
+ 
i mati ni b vers us  c o nti n ue d i mati ni b wit h its  2 -si de d 9 0 % c o nfi de nce i nter val will be pr o vi de d 
usi n g t he Wal d met h o d.  
1 2. 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  
O nl y patie nts  still treate d wit h t he ra n d o mize d treat me nt at 4 8 wee ks wit h M R 4. 5 at 4 8 wee ks 
are c o nsi dere d res p o n d ers. I n ot her w or ds, a n y s u bject w h o ac hie ves M R 4. 5 bef ore 4 8 wee ks, 
b ut is n o l o n ger i n M R 4. 5 at 4 8 w ee ks, will be c o nsi dere d as a n o n -res p o n d er f or t his e n d p oi nt. 
Patie nts  disc o nti n ui n g t he ra n d o mize d tr eat me nt pri or t o 4 8 wee ks d u e t o a n y reas o n will be 
c o nsi dere d as n o n -res p o n ders. O ne e x ce pti o n t o t he r ule a b o ve is if t he 4 8-wee k P C R e val uati o n 
is missi n g, b ut b ot h a P C R e val uati o n at 3 6 wee ks a n d a P C R e val uati o n at 6 0 wee ks ar e 
a vaila ble a n d i n dicate M R 4. 5, t he n t he 4 8-wee k assess me nt is i m p ute d as a ‘ Res p o nse’.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
1 2. 4. 4  
S u p p orti v e a n al y s e s  
T he f oll o wi n g s u p p orti ve a nal yses f or t h e pri mar y e n d p oi nt will be perf or m e d o n t he F A S.  
1) T he rate of M R 4. 5 at 4 8 wee ks a n d its 2 si des 9 0 % c o nfi de nce i nter val b ase d o n t he Cl o p per -
Pears o n met h o d will be prese nte d b y treat me nt ar m (asci mi ni b 6 0 m g + i mati ni b, asci mi ni b 4 0 
m g + i mati ni b a n d c o nti n ue d i mati ni b) f or t he f oll o wi n g s u b gr o u ps if, wit hi n eac h treat me n t 
ar m, eac h s u b gr o u p i ncl u des at least 5 patie nts : 
•  pri or i mati ni b d urati o n < 5 years vers us  ≥ 5 years  
•  m olec ular res p o nse at scree ni n g ( 0. 1 % < B C R:: A B L 1 ≤ 1. 0 % vers us  0. 0 1 % < 
B C R:: A B L 1 ≤ 0. 1 %)  
2) A l o gistic re gressi o n of M R4. 5 stat us at 4 8 wee ks o n tr eat me nt ar m (asci mi ni b 6 0 m g + 
i mati ni b, asci mi ni b 4 0 m g + i mati ni b a n d c o nti n ue d i mati ni b), pri or i mati ni b d urati o n cate g or y 
a n d m olec ular res p o nse stat us at scree ni n g will be perf or me d.  
1 2. 5  
A n al y si s of s e c o n d ar y e n d p oi nt s  
T he sec o n d ar y o bjecti ves are:  
•  T o esti mate effic ac y ( Rate of M R 4. 5 at 4 8 wee ks) of s witc h t o nil oti ni b  
•  T o esti mate t he differe nce i n efficac y ( Rate of M R 4. 5 at 4 8 wee ks) bet wee n asci mi ni b 6 0 m g 
Q D + i mati ni b a n d s witc h t o nil oti ni b  
•  T o esti mate t he differe n ce i n efficac y bet wee n asci mi ni b 4 0 m g Q D + i mati ni b a n d s witc h 
t o nil oti ni b 
•  T o assess a d diti o nal para meters of t he efficac y of asci mi ni b 6 0 m g Q D or 4 0 m g Q D a d de d 
t o i mati ni b vers us  c o nti n ue d i mati ni b or s witc h t o nil oti ni b  
•  T o c haracteriz e t he safet y a n d t olera bilit y pr ofile of asci mi ni b 6 0 m g or 4 0 m g + i mati ni b 
vs c o nti n ue d i mati ni b or s witc h t o nil oti ni b  
•  T o assess t he p h ar mac o ki netic pr ofile of asci mi ni b 6 0 m g or 4 0 m g a n d i mati ni b w he n 
a d mi nistere d i n c o m bi nati o n  
•  T o esti mate effic ac y ( Rate of M R 4. 5 at 4 8 wee ks , ti me t o M R
4. 5 a n d d urati o n of M R
4. 5) of 
asci mi ni b 8 0 m g Q D  
•  T o c haracteri ze  t he safet y a n d t olera bilit y pr ofile of asci mi ni b 8 0 m g Q D   
•  T o assess t he p har m ac o ki netic pr ofile of as ci mi ni b 8 0 m g Q D . 
1 2. 5. 1  
Effi c a c y a n d/ or P h ar m a c o d y n a mi c e n d p oi nt( s)  
T he sec o n d ar y efficac y e n d p oi nts of t his st u d y are:  
•  Rate of M R 4. 5 at 4 8 wee ks f or s witc h t o nil oti ni b, f or asci mi ni b si n gle a ge nt a n d differe nce 
bet wee n asci mi ni b + i mati ni b a n d nil oti ni b  
•  S ustai ne d rate of M R 4. 5 at 9 6 wee ks (f or all 4 ra n d o mize d treat me nt ar ms)  
•  Rate of M R 4. 5 at 9 6 wee ks (f or all 4 ra n d o mize d tr eat me nt ar ms)  
•  Rate of M R 4. 5 b y 4 8 a n d 9 6 wee ks (f or all 4 ra n d o mize d treat me nt ar ms)  
•  Rate of M R 4. 5 b y 4 8 wee ks (f or as ci mi ni b si n gle a ge nt c o h ort)  
•  Ti me t o M R 4. 5 (f or all 4 ra n d o mize d treat me nt ar ms a n d asci mi ni b si n gle a ge nt c o h ort) 

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
•  D urati o n of M R 4. 5 (f or all 4 ra n d o mize d treat me nt ar ms a n d asci mi ni b si n gle a ge nt c o h ort) 
1 2. 5. 1. 1  R at e of M R 4. 5  at 4 8 w e e k s  
T o esti mate t he efficac y of s witc h t o nil oti ni b, t he rate of M R 4. 5 at 4 8 wee ks a n d its 2 si de d 9 0 % 
c o nfi de nce i nter val bas e d o n t he Cl o p per -Pears o n met h o d will be prese nt e d f or t he s witc h t o 
nil oti ni b ar m usi n g t he F A S.  
I n a d diti o n, t he differe nce i n efficac y will be esti mate d bet wee n: 
•  asci mi ni b 6 0 m g + i mati ni b a n d s witc h t o nil oti ni b  
a n d bet wee n  
•  asci mi ni b 4 0 m g + i mati ni b a n d s witc h t o nil oti ni b  
T o esti mate t he differe nce i n efficac y bet wee n asci mi ni b 6 0 m g + i mati ni b ( or asci mi ni b 4 0 m g 
+ i mati ni b) a n d s witc h t o nil oti ni b, t he differe nce i n t he rate of M R 4. 5 bet wee n asci mi ni b 6 0 m g 
+ i mati ni b ( or asci mi ni b 4 0 m g + i mati ni b) a n d s witc h t o nil oti ni b at 4 8 wee ks a n d its 2 si d e d 
9 0 % c o nfi de n ce i nter val will be pr o vi de d usi n g t he Wal d met h o d.  
T o esti mate t he efficac y of asci mi ni b si n gle a ge nt, t he rate of M R 4. 5 at 4 8 wee ks a n d its 2 si de d 
9 0 % c o nfi de nce i nter val base d o n t he Cl o p per -Pears o n met h o d will be prese nte d usi n g t he 
F A S – A S A C . N o f or mal c o m paris o n or esti mate of t he differe n ce wit h t he ot her treat me nt ar ms 
will be perf or me d f or t his a d diti o nal c o h ort.  
1 2. 5. 1. 2  R at e of s u st ai n e d M R 4. 5  at 9 6 w e e k s  
T he rate of s ustai n e d  M R
4. 5 at 9 6 wee ks is defi ne d as t he pr o p orti o n of patie nts  w h o are i n M R 4. 5 
at b ot h 4 8 a n d 9 6 w ee ks u n der ra n d o mize d tr eat me nt a n d w h o h a ve n o l oss of M R 4. 5 i n bet wee n 
t h ose t w o ti me p oi nts a m o n g all patie nts  ra n d o mize d t o t he res pecti ve treat me nt ar m. Rate of 
s ustai ne d M R
4. 5 a n d its 2 si de d 9 0 % c o nfi de n ce i nter val base d o n t he Cl o p p er -Pears o n met h o d 
will be prese nte d b y treat me nt ar m usi n g t he F A S.  
As t he treat me nt d urati o n f or t he as ci mi ni b si n gle a ge nt c o h ort is s h orter, t he rate of s ustai n e d 
M R
4. 5 at 9 6 wee ks will n ot be prese nte d f or t he asci mi ni b si n gle a ge nt c o h ort.  
1 2. 5. 1. 3  R at e of M R 4. 5  at 9 6 w e e k s  
T he rate of M R 4. 5 at 9 6 wee ks will be cal c ulate d b ase d o n t he F A S.  
I n t his a nal ysis “at” 9 6 wee ks, o nl y patie nts  wit h M R 4. 5 u n der ra n d o mize d treat me nt at 9 6 wee ks 
are c o nsi dere d as res p o n ders. A s u bject w h o has ac hie ve d M R 4. 5 bef ore 9 6 wee ks, b ut w h o is 
n o l o n ger i n M R 4. 5 at 9 6 wee ks, will be c o nsi dere d as a n o n -res p o n d er at 9 6 wee ks. Patie nts  
w h o disc o nti n ue d t he ra n d o mize d treat me nt f or a n y reas o n pri or t o 9 6 wee ks will be c o nsi dere d 
as n o n-res p o n d ers. 
Rate of M R 4. 5 a n d its 2 si de d 9 0 % c o nfi de nce i nter val base d o n t he Cl o p per -Pears o n met h o d 
will be prese nte d b y treat me nt ar m.  
T he rate of M R 4. 5 at 9 6 wee ks will n ot be prese nt e d f or t he asci mi ni b si n gle a ge nt c o h ort.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
1 2. 5. 1. 4  R at e of M R 4. 5  b y 4 8 a n d 9 6 w e e k s  
T he rat e of M R 4. 5 b y 4 8 a n d 9 6 wee ks f or all 4 ra n d o mize d treat me nt ar ms will be cal c ulate d 
base d o n t he F A S.  
T he rate of M R 4. 5 b y 4 8 wee ks f or  t he asci mi ni b si n gle a ge nt c o h ort will be calc ulate d base d o n 
t he F A S - A S A C . 
I n t h e a n al yses “ b y ” a s p ecific ti me p oi nt, patie nts  w h o ha d ac hie ve d M R 4. 5 u n der ra n d o mize d  
or assi g ne d  tr eat me nt at or bef ore t he ti me p oi nt will be dis pla ye d as res p o n ders, w het her t he y 
l ost t he res p o nse/ disc o nti n ue d treat me nt or n ot. T h eref ore, t his res p o nse rate re pres e nts t he best 
o bser ve d rate of M R 4. 5 u n der ra n d o mize d/ assi g ne d treat me nt u p t o t hat s pecific ti me p oi nt.  
Rate of M R 4. 5 a n d its 2 si de d 9 0 % c o nfi de nce i nter val base d o n t he Cl o p per -Pears o n met h o d 
will be prese nte d b y treat me nt ar m a n d f or t h e asci mi ni b si n gle a ge nt c o h ort.  
T he c u m ulati ve i nci de nce of M R 4. 5 will als o be gra p hicall y dis pla y e d b y a n i ncreasi n g ste p -
f u ncti o n. T his c ur ve will i ncreas e eac h ti me (after ra n d o mizati o n or first d ose of tr eat me nt f or 
patie nts i n t he asci mi ni b si n gle a ge nt c o h ort ) at w hic h a ne w res p o n der is o bser ve d a n d t h us 
will i ncrease u p t o t he best o bser ve d res p o nse rate (e. g. u p t o 5 0 % if half of t he patie nts  i n t he 
a nal ysis p o p ulati o n are a ble t o ac hie ve res p o nse).  
1 2. 5. 1. 4. 1  
Ti m e t o M R 4. 5  
Ti m e t o M R 4. 5 is defi ne d f or patie nts  i n t he M R4. 5 Res p o n der set at t he c orres p o n di n g c ut -off 
as: date of first M R 4. 5 –  date of ra n d o mizati o n + 1. It is defi ne d f or patie nts i n t he M R4. 5 
Res p o n der set –  A S A C as: date of first M R 4. 5 –  date of first d ose of asci mi ni b + 1. Descri pti v e 
statistics (ra n ge, me dia n, q uartiles, mea n, S D) of ti me t o M R 4. 5 will be pr o vi de d f or t he 4 
ra n d o mize d tr eat me nt ar ms a n d f or t he as ci mi ni b si n gle a ge nt c o h ort se p aratel y.  
1 2. 5. 1. 4. 2  
D ur ati o n of M R 4. 5  
D ur ati o n of M R 4. 5 is defi ne d f or patie nts  i n t he M R4. 5 Res p o n der set s as t he ti me fr o m first 
d oc u me nte d M R 4. 5 a n d t he e n d dat e of M R 4. 5 i.e. t he earliest date of l oss of M R4. 5 or C M L -
relate d d eat h. L oss of M R4. 5 is defi ne d as a n i ncrease of t h e B C R:: A B L rati o t o > 0. 0 0 3 2 % i n a 
si n gle bl o o d sa m ple, b y I nter nati o nal Scale. 
F or patie nts f or w h o m n o ne of t he e v e nts a b o ve are re p ort e d, t he d urati o n will be ce ns ore d. T h e 
d urati o n of M R 4. 5 (i n wee ks) is cal c ulate d as: (e n d date or ce ns ori n g date of M R4. 5 - date of first 
M R
4. 5 + 1)/ 7.  
T he s ur vi val distri b uti o n of d urati o n of M R 4. 5 will be esti mate d usi n g t he Ka pla n -Meier m et h o d, 
a n d Ka pla n-M eier c ur ves, me dia ns a n d 9 5 % c o nfi de nce i nter vals [Br o o k me yer a n d Cr o wle y 
1 9 8 2 ] of t he me dia ns, al o n g wit h t he pr o p orti o n of patie nts w h o are still i n M R 4. 5 at 2 4, 4 8, 7 2 
a n d 9 6 wee ks a n d t he ass ociate d 9 5 % c o nfi d e nce i nter vals, will be prese nte d f or eac h 
ra n d o mize d tr eat me nt ar m. 
A n a d diti o nal a nal ysis of t he d urati o n of M R
4. 5 will be perf or me d w here t he e n d date of M R 4. 5 
is defi ne d as t he earliest date of c o nfir me d  l oss of M R4. 5 or C M L -relate d deat h. C o nfir me d  
l oss of M R4. 5 is defi ne d as a n i ncreas e of t he B C R:: A B L rati o t o > 0. 0 0 3 2 % i n t w o c o nsec uti ve 

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
bl o o d sa m ples, b y I nter nati o nal Scale. T h e dat e of c o nfir me d  l oss of M R4. 5 is t he date of t he 
first o ne of t he t w o bl o o d sa m ple assess me nts. 
Descri pti ve statistics (ra n ge, me dia n, q uartiles, mea n, S D) of d urati o n of M R 4. 5 will be pr o vi de d 
f or t he asci mi ni b si n gle a ge nt c o h ort 
1 2. 5. 2  
S af et y e n d p oi nt s  
F or all safet y a nal yses, t he safet y set s will be us e d. All listi n gs a n d ta bles will be pres e nte d b y 
treat me nt ar m. 
Safet y s u m maries (ta bles, fi g ures) i ncl u de o nl y data fr o m t he o n -tr eat m e nt peri o d wit h t he 
e xce pti o n of baseli ne dat a w hic h will als o be s u m marize d w here a p pr o priate (e. g. c ha n ge fr o m 
baseli ne s u m maries). I n a d diti o n, a se parate s u m m ar y f or d eat h i ncl u di n g  o n treat me nt a n d p ost 
treat me nt deat hs will be pr o vi de d. I n partic ular, s u m mar y ta bles f or a d verse e ve nts ( A Es) will 
s u m marize o nl y o n-treat me nt e ve nts, wit h a start date d uri n g t he o n-treat me nt peri o d 
(treat me nt-e mer ge nt A Es). Data fr o m t he cr oss -o ver pe ri o d will be s u m marize d s e paratel y. 
Data fr o m t he asci mi ni b si n gle a ge nt c o h ort ( Safet y S et - A S A C)  will be s u m marize d s e paratel y.  
T he o n -treat me nt peri o d lasts fr o m t he date of first a d mi nistrati o n of st u d y treat me nt t o 3 0 da ys 
after t he d ate of t he l ast a ct ual a d mi nistrati o n of a n y st u d y treat me nt.  
T he o verall o bser vati o n peri o d will be di vi de d i nt o f o ur 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 s u bject’s i nf or me d c o nse nt t o t he da y b ef 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 (f or p atie nts  w h o will cr oss o ver t o recei ve as ci mi ni b 6 0 m g + i mati ni b, 
t he o n-treat me nt p eri o d will be fr o m da y of first a d mi nistrati o n of st u d y me dicati o n t o t he 
da y bef ore t he first a d mi nistrati o n of asci mi ni b),  
3.  p ost -treat me nt peri o d: starti n g at da y 3 1 after last d ose of st u d y treat me nt (f or patie nts  w h o 
will cr oss o ver, t he p ost -treat me nt peri o d will start at da y 3 1 after last d ose of cr oss o ver 
st u d y treat me nt), 
4.  cr oss-o ver peri o d (f or patie nts  w h o will cr oss o v er t o recei ve asci mi ni b a d d -o n treat me nt), 
fr o m da y of first d ose of asci mi ni b a d d-o n treat me nt t o 3 0 da ys after last d ose of cr oss o ver 
st u d y treat me nt. 
A d v er s e E v e nt s  
All i nf or mati o n o btai ne d o n a d verse e ve nts will be dis pla ye d b y treat me nt ar m a n d s u bject.  
S u m mar y ta bles f or a d verse e ve nts ( A Es) will 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 p eri o d, t he treat me nt-e mer g e nt A Es.  
T he i nci de nce of tr eat me nt -e mer ge nt a d verse e v e nts ( ne w or w orse ni n g fr o m baseli ne) will be 
s u m marize d b y s yste m or ga n cl ass a n d or preferre d ter m, s e verit y ( base d o n C T C A E gra d es), 
t y pe of a d verse e v e nt, rel ati o n t o st u d y treat me nt. 
Seri o us a d vers e e v e nts, n o n -seri o us a d v erse e ve nts a n d a d v erse e ve nts of s p ecial i nterest ( A E SI) 
d uri n g t he o n -treat me nt p eri o d will be ta b ulate d. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
All deat hs ( o n -treat me nt a n d p ost-treat me nt) will be s u m marize d. 
All A Es, deat hs a n d seri o us a d vers e e v e nts (i ncl u di n g t h ose fr o m t he pre - a n d p ost -tr eat 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 -tr eat me nt a n d p ost-treat me nt peri o d 
will be fla g ge d.  
Vit al si g n s  
All vital si g ns data will be liste d b y treat me nt ar m, s u bject, a n d visit/ti me a n d if ra n g es are 
a vaila ble, a b n or malities will be fla g ge d. S u m mar y statistics will be pr o vi de d b y treat me nt a n d 
visit/ti me.  
1 2 -l e a d E C G 
All E C G data will be liste d b y treat me nt ar m, s u bject a n d visit/ti me, a b n or malities will be 
fla g ge d. S u m mar y statistics will be pr o vi de d b y treat me nt a n d visit/ti me. 
P R, Q R S, Q T, Q Tc F, a n d R R i nter vals will be o btai ne d f or eac h s u bject d uri n g t he st u d y. E C G 
data will be rea d a n d i nter prete d ce ntrall y.  
Cate g orical a nal ysis of Q T/ Q Tc i nter val d ata b ase d o n t he n u m b er of patie nts  meeti n g or 
e xcee di n g pre d efi ne d li mits i n ter ms of a bs ol ute Q T/ Q Tc i nter vals or c h a n ges fr o m b aseli ne 
will be prese nte d. I n a d diti o n, a listi n g of t hese patie nts  will be pr o d uce d b y treat me nt ar m.  
Cli ni c al l a b or at or y e v al u ati o n s  
Gra di n g of la b orat or y val ues will be assi g ne d pr o gra m maticall y as per Nati o nal Ca ncer I nstit ute 
( N CI) C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) v ersi o n 5. T he calc ulati o n 
of C T C A E gra d es will be base d o n t he o bser ve d la b orat or y v al ues o nl y, cli nical assess me nts 
will n ot be ta ke n i nt o acc o u nt.  
C T C A E Gra de 0 will be assi g ne d f or all n o n -missi n g val ues n ot gra d e d as 1 or hi g her. Gra d e 5 
will n ot be use d.  
F or la b orat or y tests w h ere gra d es are n ot defi ne d b y C T C A E versi o n 5, res ults will be 
cate g orize d as l o w/ n or m al/ hi g h base d o n la b orat or y n or mal ra n g es.  
T he f oll o wi n g s u m maries will be ge nerat e d se paratel y f or he m at ol o g y, a n d bi oc he mistr y tests:  
•  Listi n g of all la b orat or y d ata wit h v al ues fla g ge d t o s h o w t he c orres p o n di n g C T C A E versi o n 
5 gra des if a p plica ble a n d t he classificati o ns rel ati ve t o t he la b orat or y n or mal ra n ges  
F or la b orat or y tests w here gra des are d efi ne d b y C T C A E versi o n 5,  
•  W orst p ost -baseli ne C T C A E gra de (re g ar dless of t he baseli ne stat us). Eac h s u bject will be 
c o u nte d o nl y o nce f or t he w orst gra de o bs er ve d p ost -baseli ne.  
•  S hift ta bles usi n g C T C A E versi o n 5 gra des t o c o m pare baseli ne t o t he w orst o n -treat me nt 
val ue  
F or la b orat or y tests w here gra des are n ot d efi ne d b y C T C A E versi o n 5,  
•  S hift ta bles usi n g t he l o w/ n or mal/ hi g h (l o w a n d hi g h) classificati o n t o c o m pare bas eli ne t o 
t he w orst o n-treat me nt val ue. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
F or t otal c h olest er ol, cal c ulate d L D L a n d H b A 1 c, a d diti o nal a nal yses will be c o n d ucte d t o 
descri be t he n u m ber a n d perce nt a ge of patie nts  d e vel o pi n g val ues o utsi de of defi n e d t hres h ol ds.  
I n a d diti o n t o t he a b o ve me nti o ne d ta bles a n d listi n gs, ot her e x pl orat or y a nal yses mi g ht be 
s pecifie d i n t he a n al ysis pla n. 
1 2. 5. 3  
P h ar m a c o ki n eti c s  
P A S will be use d i n all p har mac o ki netic d ata a nal ysis a n d P K s u m mar y statistics. Descri pti ve 
s u m mar y statistics will be pr o vi de d b y treat m e nt a n d visit/sa m pli n g ti me p oi nt. Plas ma 
c o nce ntr ati o n data will b e liste d b y treat me nt, s u bj ect, a n d visit/sa m pli n g ti me p oi nt f or patie nts 
treate d wit h as ci mi ni b + i mati ni b i n t he Safet y set. Data fr o m t he asci mi ni b si n gle a ge nt c o h ort 
( P A S - A S A C) will be s u m marize d se p aratel y.  
S u m mar y statistics will i ncl u de mea n (arit h metic a n d ge o metric), st a n dar d de viati o n ( S D), C V 
(arit h metic a n d ge o metri c), me dia n, mi ni m u m a n d ma xi m u m. C o nce ntrati o ns bel o w L L O Q will 
be treate d as zer o i n s u m mar y statistics a n d f or P K para meter calc ulati o ns b ut will n ot be 
i ncl u de d i n t he ge o metric mea n a n d C V calc ulati o n. T he mea n a n d i n di vi d ual plas ma 
c o nce ntr ati o n b y treat me nt a n d visit/sa m pli n g ti me p oi nt will be dis pla ye d gra p hicall y.  
P har mac o ki netic para meters will be deter mi ne d b y n o n -c o m part me ntal met h o d(s) usi n g t he 
p har mac o ki netic pr ofile of asci mi ni b a n d i mati ni b. P har mac o ki netic p ara meters liste d i n  
Ta ble 1 2 -1  will be d eri ve d a n d re p orte d, w he n feasi ble. F or i mati ni b meta b olite ( N -des met h yl 
i mati ni b [ C G P 7 4 5 8 8]), o nl y Cma x , Tma x , A U Clast a n d t he meta b olite -t o-pare nt A U C rati o will be 
calc ulate d.  
P har mac o ki netic p ara meters will be liste d b y tr eat me nt a n d s u bject. Descri pti ve s u m mar y 
statistics will i ncl u de mea n (arit h metic a n d g e o metric), S D, a n d C V (arit h metic a n d g e o metric), 
me dia n, mi ni m u m a n d ma xi m u m. A n e xce pti o n t o t his is T ma x  w here me dia n, mi ni m u m a n d 
ma xi m u m will be prese nte d.  
T a bl e 1 2 -1  
N o n -c o m p art m e nt al p h ar m a c o ki n eti c p ar a m et er s  
A U C l a st 
T h e A U C fr o m ti m e z er o t o t h e l a st m e a s ur a bl e c o n c e ntr ati o n s a m pli n g ti m e ( Tl a st) ( m a s s x ti m e 
x v ol u m e -1)  
A U C t a u 
T h e A U C c al c ul at e d t o t h e e n d of a d o si n g i nt er v al (t a u) at st e a d y -st at e ( a m o u nt x ti m e x v ol u m e -
1)  
C m a x  
T h e m a xi m u m ( p e a k) o b s er v e d pl a s m a, bl o o d, s er u m, or ot h er b o d y fl ui d dr u g c o n c e ntr ati o n aft er 
si n gl e d o s e a d mi ni str ati o n ( m a s s x v ol u m e -1)  
T m a x  
T h e ti m e t o r e a c h m a xi m u m ( p e a k) pl a s m a, bl o o d, s er u m, or ot h er b o d y fl ui d dr u g c o n c e ntr ati o n 
aft er si n gl e d o s e a d mi ni str ati o n (ti m e)  
T l a st 
Ti m e of l a st m e a s ur e m e nt (ti m e)  
If a p pr o pri ate, t he p ote ntial relati o ns hi p bet wee n asci mi ni b e x p os ure a n d pri mar y efficac y 
e n d p oi nt or m ost critical safet y e n d p oi nts ma y be assesse d b y gra p hic e x pl orati o n a n d/ or 
statistical m o deli n g as a p pr o priate. Det ails of t he a nal ysis a n d res ults ma y be re p orte d se p aratel y.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
1 2. 6  
A n al y si s of e x pl or at or y e n d p oi nt s  
1 2. 6. 1  
Effi c a c y e x pl or at or y e n d p oi nt s  
O ne e x pl or at or y o bjecti v e f or t his trial is t o assess t he pr o p orti o n of patie nts  eli gi ble f or T F R at 
e n d of t he st u d y. F or t he p ur p ose of e n d p oi nt d efi niti o n t o meet t he T F R criteria, patie nts  h a ve 
t o be treate d wit h ra n d o mize d treat me nt u p t o t h e e n d of st u d y ( 9 6 wee ks after t he first d ose of 
st u d y dr u g of t he last ra n d o mize d s u bject) a n d bas e d o n t he last fi ve q u arterl y perf or me d P C R 
assess me nts: ( 1) b ot h first a n d last assess me nts are M R 4. 5, ( 2) n o assess me nt is w orse t ha n M R4, 
a n d ( 3) n o m or e t ha n t w o a ssess me nts are bet wee n 
M R 4 a n d 
M R 4. 5, a m o n g all patie nts  
ra n d o mize d t o t he res pecti ve treat me nt ar m. 
1 2. 6. 2  
Ot h er e x pl or at or y e n d p oi nt s  
F or cr oss -o ver p atie nts  (s ee Secti o n  1 2. 1 ), t he effi cac y (e. g. t he ti me fr o m cr oss-o ver t o M R 4. 5) 
a n d safet y of cr oss -o ver treat me nt (asci mi ni b a d d -o n treat me nt) will be s u m marize d. A d diti o nal 
a nal yses ma y b e perf or m e d. T he d etails will be f urt her s pecifie d i n t he statistical a nal ysis pla n 
( S A P). 
1 2. 6. 3  
Bi o m ar k er s  
As a pr oject sta n d ar d, o nl y bi o mar kers c ollecte d i n t he cli nical data bas e will be a nal yze d. Si nce 
t his st u d y is n ot a de q uatel y p o were d t o ass ess s pecific bi o mar ker relat e d h y p ot heses, t h e 
statistical a nal yses of t hese data s h o ul d be c o nsi dere d e x pl orat or y a n d h y p ot heses ge n erati n g i n 
nat ure. A nal ytical res ults fr o m s uc h a nal yses ma y be use d t o ge nerate a d diti o nal h y p ot heses 
t hat m ust t he n be verifie d wit h data deri ve d fr o m s u bse q ue nt cli nical trials. F urt her m ore, 
a d diti o nal p ost h oc  e x pl orat or y assess me nts ma y be perf or me d.  
W hile t he g oal of t he bi o mar ker a n al yses is t o pr o vi de s u p p orti ve data f or t he cli nical st u d y, 
t here ma y be cir c u msta nces w he n a decisi o n is ma de t o st o p a sa m ple c ollecti o n, or n ot perf or m 
or disc o nti n ue t he a n al ysis of bl o o d d ue t o eit her practical or st rate gic reas o ns (e. g. iss ues 
relate d t o t he q ualit y a n d or q ua ntit y of sa m ples, or iss ues relate d t o t he ass a y t hat precl u de t he 
a nal ysis of sa m ples). U n der s uc h cir c u msta nces, t he n u m ber of sa m ples m a y be i na de q u ate t o 
perf or m a ri g or o us data a nal ysis a n d  t he a vaila ble data will o nl y be liste d. 
T he bi o mar ker a nal yses ma y be re p orte d i n a se p arate bi o mar ker re p ort.  
T he pr o p ose d dat a a nal ysis ali g ne d wit h t he e x pl orat or y bi o mar ker o bjecti ves as well as t he 
rele va nt as p ects of d ata h a n dli n g will be a d dresse d i n a de dicate d S A P. 
U nless ot her wise s pecifi e d, all patie nts  wit h e val ua ble bi o mar ker meas ure m e nts i n t he F A S will 
be i ncl u de d i n t he bi o mar ker data a nal ysis.  
A d diti o nal e x pl orat or y bi o mar ker a nal yses ma y be perf or me d d e pe n di n g o n t he data.  
F or all patie nts , t he bi o m ar ker o bj ecti ves are: 
•  T o e x pl ore me c ha nis ms of resista nce ass oci ate d wit h asci mi ni b a n d ot her T KI treat me nts 
via assess me nt of 
 
. T his a nal ysis will be d o ne f or o nl y treat me nt ar ms 1-4, a sa m ple is n ot 
c ollecte d or a nal yz e d f or patie nts i n t he asci mi ni b si n gle a ge nt c o h ort.  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 2 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
•  T o e x pl ore rele v a nt 
 
 
 
 
•  T o e val uate 
. 
1 2. 6. 4  
P ati e nt R e p ort e d O ut c o m e s  
T he E O R T C Q L Q -C 3 0 q uesti o n naire al o n g wit h t he disease -s p ecific c hr o nic m yel oi d le u ke mia 
m o d ule ( E O R T C Q L Q -C M L 2 4), T S Q M a n d F A CI T G P 5 will be use d t o c ollect d ata o n t he 
patie nt -re p ort e d o utc o me meas ures of healt h-relat e d q ualit y-of life, treat me nt satisfa cti o ns a n d 
treat me nt-relate d si de effects fr o m baseli ne t o E O T b y treat me nt ar ms. Sc ori n g of ra w Q o L data 
a n d met h o ds f or ha n dli n g of missi n g ite ms or missi n g assess me nts will be ha n dle d acc or di n g 
t o sc ori n g ma n u als f or eac h res pecti ve patie nt q u esti o n naire ( Fa y ers  2 0 0 1 ). N o i m p utati o n will 
be a p plie d if t he t otal or s u bscale sc ores are missi n g at a visit. T he n u m ber of patie nts 
c o m pleti n g eac h p atie nt q uesti o n naire a n d t he n u m ber of missi n g or i nc o m plete assess me nts 
will be s u m marize d b y eac h treat me nt ar m f or eac h sc he d ule d ass ess me nt ti me p oi nts.  
T he F A S will be use d f or a nal yzi n g P R O data. N o f or mal statistical tests will be perf or me d of 
P R O data.  
Descri pti ve statistics will be use d t o s u m marize t he sc ore d scal es f or t he E O R T C, G P 5 a n d 
T S Q M q uesti o n naires at eac h sc he d ule d ass ess me nt ti me p oi nt b y treat me nt ar 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 w ill be s u m marize d. 
Patie nts wit h a n e val ua bl e baseli ne s c ore a n d at least o ne e v al 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 h a n ge fr o m baseli ne a n al yses.  
A d diti o nal a nal ysis ma y be perf or me d a n d d etails will be descri be d i n t he a nal ysis pla n.  
1 2. 7  
I nt eri m a n al y s e s 
A n i nteri m a nal ysis will be perf or me d i n or der t o gai n a n earl y i nsi g ht i nt o t he safet y a n d 
effic ac y of t he as ci mi ni b a d d -o n c o m bi nati o n w hic h will hel p i n pla n ni n g t he f ut ure 
de vel o p me nt of t he asci mi ni b c o m bi nati o n. T he i nteri m a nal ysis will be perf or me d w he n at 
least 4 0 ( 5 0 %) p atie nts h a ve bee n ra n d o mize d a n d ha ve bee n f oll o we d f or t heir 2 4 wee ks visit 
assess me nt or ha ve disc o nti n ue d treat me nt. T he e nr oll me nt will c o nti n ue d uri n g t his 2 4 wee ks 
f oll o w-u p. T he i nteri m a nal ysis will i ncl u de all ra n d o mize d p atie nts u ntil t he date of data c ut -
off, a n d i ncl u de b ot h effi cac y (e. g. B C R:: A B L 1 assess me nt o verti me, M R 4 a n d M R 4. 5 rate at 
differe nt ti me -p oi nts) a n d safet y (e. g. A d verse E ve nts a n d la b orat or y val ues) s u m maries, w hic h 
will be detaile d i n t he Statistical A nal ysis Pla n f or t he i nteri m a nal ysis. It is n ot pla n ne d t o write 
a n i nteri m C S R base d o n t his i nteri m a nal ysis.  Base d o n t he res ults of t he i nteri m a nal ysis a 
be nefit ris k bala n ce will be assesse d f or t he t w o a d d -o n treat me nt ar ms.  
T he pri mar y a nal ysis will be perf or me d after all patie nts  i n t he 4 ra n d o mi ze d treat me nt ar ms 
ha ve c o m plete d 
Wee k 4 8 or disc o nti n ue d pri or t o 
Wee k 4 8. A 
Wee k 9 6 a nal ysis will be 
perf or me d after all patie nts  i n t he 4 ra n d o mize d treat me nt ar ms h a ve c o m plete d Wee k 9 6 a n d/ or 
disc o nti n ue d st u d y pri or t o Wee k 9 6. A fi nal a nal ysis will be perf or m e d wit h all a vaila ble data 
fr o m asci mi ni b si n gle a g e nt c o h ort at t he E n d of St u d y.  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
1 2. 8  
S a m pl e si z e c al c ul ati o n  
1 2. 8. 1  
Pri m ar y e n d p oi nt( s)  
Base d o n t he s u bset data i n E N E S Tc mr [C A M N 1 0 7 A 2 4 0 5 ] a n d E N E S T n d [ C A M N 1 0 7 A 2 3 0 3], 
it is ass u me d t hat t he rate of M R4. 5 at 4 8 wee ks is ra n gi n g bet wee n 3 % a n d 1 0 % i n t he c o nti n ue d 
i mati ni b ar m.  
Wit h 2 0 patie nts  per ar m e nr olle d i n t he t w o asci mi ni b + i mati ni b ar ms a n d t he c o nti n ue d 
i mati ni b ar m, t he precisi o n of t he esti mates of t he differe n ce bet w ee n 1) asci mi ni b 6 0 m g + 
i mati ni b vers us  c o nti n ue d i mati ni b a n d 2) asci mi ni b 4 0 
m g + i mati ni b  vers us  c o nti n ue d 
i mati ni b f or differe nt s ce nari os is s h o w n i n Ta ble 1 2 -2 . 
T a bl e 1 2 -2  
9 0 % C o nfi d e n c e i nt er v al s f or 3 0 % diff er e n c e r at e b et w e e n t h e ar m s  
C o nti n u e d i m ati ni b  
M R 4. 5  r at e 
A s ci mi ni b + i m ati ni b  
M R 4. 5  r at e 
Diff er e n c e  
9 0 % CI  
3 %  
3 3 %  
3 0 %  
[ 1 2 % - 4 8 %]  
5 %  
3 5 %  
3 0 %  
[ 1 1 % - 4 9 %]  
7 %  
3 7 %  
3 0 %  
[ 1 0 % - 5 0 %]  
1 0 %  
4 0 %  
3 0 %  
[ 9 % - 5 1 %]  
Wit h 2 0 patie nts  per ar m, t he wi dt h of t he t w o -si de d 9 0 % c o nfi de nce i nter val f or t he differe nce 
i n M R4. 5  rate at 4 8 wee ks bet wee n eac h asci mi ni b + i mati ni b a n d s witc h t o nil oti ni b will n ot be 
lar ger t ha n 0. 5 2 0 (c orres p o n di n g t o t he sit uati o n w he n t he esti mate d M R4. 5  rate is 0. 5 i n b ot h 
ar ms (i.e. n o differe nce)). Its  l o wer b o u n d will e xcl u de 0 ass u mi n g a tr ue 3 0 % differe n ce i n t he 
M R
4. 5 rate at 4 8 wee ks. 
I n a d diti o n, t he t w o-si de d 9 0 % Cl o p per-Pears o n c o nfi de nce i nter val f or t he M R 4. 5  rate at 4 8 
wee ks will ha ve a wi dt h n ot lar g er t h a n 0. 3 9 6  (t he w orst cas e c orres p o n di n g t o t he sit uati o n 
w he n t he M R 4. 5  rate at 4 8 wee ks is 0. 5).  
A n i nteri m a nal ysis will be perf or m e d w he n at least 4 0 ( 5 0 %) patie nts ha ve bee n ra n d o mize d 
a n d ha v e bee n f oll o w e d f or t heir 2 4 wee ks visit ass ess me nt or h a ve dis c o nti n ue d treat me nt. T h e 
i nteri m a nal ysis will i ncl u de all ra n d o mize d p atie nts u ntil t he date of data c ut-off, a n d i ncl u d e 
b ot h efficac y (e. g. B C R:: A B L 1 assess me nt o verti me, M R 4 a n d M R 4. 5 rate at differe nt ti me-
p oi nts) a n d safet y (e. g. A d verse E ve nts a n d la b orat or y val ues) s u m maries. T here will h o we v er 
be n o a dj ust me nt f or m ulti plicit y d ue t o t he i n teri m a nal ysis as t here is n o f or mal c o m paris o n 
t o be perf or me d b et wee n t he treat me nt ar ms, a n d o nl y t he esti mati o n of effect size is pla n ne d 
i n t he pri mar y a nal yses. 
T hese calc ulati o ns were ma de usi n g t he s oft ware pac ka g e P A S S 1 1.  
1 2. 8. 2  
S e c o n d ar y e n d p oi nt( s)  
F or t he pri mar y o bjecti ve, 2 0 patie nts  per ar m will be e nr olle d i n t he t w o as ci mi ni b + i mati ni b 
ar ms a n d t h e c o nti n ue d i mati ni b ar m. Wit h t he s a me n u m ber of patie nts , i. e. 2 0 patie nts , i n t he 
s witc hi n g t o nil oti ni b ar m, t he t w o-si de d 9 0 % Cl o p per-Pears o n c o nfi de nce i nter val f or t h e 
M R
4. 5 rate at 4 8 wee ks will ha ve a wi dt h n ot lar ger t ha n 0. 3 9 6 (t he w orst case c orres p o n di n g t o 
t he sit uati o n w he n t he M R4. 5 rate at 4 8 wee ks is 0. 5). 

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
I n a d diti o n, t he wi dt h of t he t w o-si de d 9 0 % Wal d c o nfi de nce i nter val f or t he differe n ce i n M R 4. 5 
pr o p orti o ns rate at 4 8 wee ks bet w ee n eac h as ci mi ni b + i mati ni b a n d s witc h t o nil oti ni b will n ot 
be lar g er t ha n 0. 5 2 0 (c orres p o n di n g t o t he sit uati o n w he n t he esti mate d M R 4. 5 rate is 0. 5 i n b ot h 
ar ms (i.e. n o differe n ce)).  
F or t he 2 0 patie nts  e nr olle d i n t he asci mi ni b si n gle a ge nt c o h ort, t he t w o -si de d 9 0 % Cl o p per-
Pears o n c o nfi de nce i nter val f or t he M R 4. 5 rate at 4 8 wee ks will ha v e a wi dt h n ot lar ger t ha n 
0. 3 9 6 (t he ma xi m u m wi dt h c orres p o n di n g t o t he sit uati o n w he n t he M R 4. 5 rate at 4 8 wee ks is 
0. 5).  
T hese calc ulati o ns were ma de usi n g t he s oft ware pac ka g e P A S S 1 1.  
1 3  
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 3. 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 d esi g ne d a n d s hall be i m ple me nte d, e xec ute 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, E U Cli nical Trial Re g ulati o n 
5 3 6/ 2 0 1 4  o nce tra nsf er is c o m plete d , U S C F R 2 1), a n d wit h t he et hical pri n ci ples lai d d o w n i n 
t he Declarati o n of H elsi n ki. 
1 3. 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  
Bef ore i nitiati n g a trial, t h e i n vesti gat or/i nstit uti o n m ust o btai n a p pr o val/fa v ora ble o pi ni o n fr o m 
t he I nstit uti o nal Re vie w B oar d/I n de pe n d e nt Et hics C o m mittee (I R B/I E C) f or t he trial pr ot oc ol, 
writte n i nf or me d c o nse nt f or m, c o nse nt f or m u p dates, s u bject r ecr uit me nt pr oce d ures (e. g. 
a d vertise me nts) a n d a n y ot her writte n i nf or mati o n t o be pr o vi de d t o  partici pa nt patie nts . 
A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a n d Healt h A ut h orit y a p pr o val b ef ore 
i m ple me ntati o n of c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n g es necessar y t o eli mi nate 
a n 
i m me diate 
hazar d 
t o 
st u d y 
partici pa nts.  
Pr ot oc ols 
a n d 
a n y 
s u bsta ntial 
a me n d me nts/ m o dificati o ns t o t he pr ot oc ol will re q uire healt h a ut h orit y a p pr o val pri or t o 
i nitiati o n e xce pt f or c ha n ges necess ar y t o eli mi nat e a n i m me diate hazar d t o st u d y partici pa nts.  
T he i n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:  
•  Si g ni n g 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 o c 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 Q ualit y Ass ura n ce re prese nt ati ves, desi g nate d a ge nts of N o vartis, I R Bs/ I E Cs, 
a n d re g ulat or y a ut h orities as re q uire d.  
•  Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C a n n uall y or m ore 
fre q ue ntl y i n a cc or da nce wit h t he re q uire me nts, p olicies, a n d pr oce d ures esta blis he d b y 
t he I R B/I E C. 
•  N otif yi n g t he I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ures. 
•  Ta ki n g a n y i m me diate acti o n re q uire d f or t h e safet y of a n y partici p a nt i ncl u de d i n t his 
st u d y, e ve n if t his acti o n re pres e nts a de viati o n fr o m t he pr ot oc ol. I n s uc h cases, N o vartis 

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
m ust 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 m ust be i nf or me d 
acc or di n g t o l ocal re g ulati o ns.  
•  Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at t he site a n d a d here nce t o re q uire me nts 
of 2 1 C F R, I C H g ui deli nes, t he I R B/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical 
st u dies (if a p plica ble), E ur o pea n Me di cal De vi ce Re g ulati o n 2 0 1 7/ 7 4 5 f or cli nical de vice 
researc h (if a p plica ble), a n d all ot her a p plica ble l o cal re g ulati o ns. 
•  I nf or mi n g N o vartis i m me diatel y if a n i ns pecti o n of t he cli nical site is re q u este d b y a 
re g ulat or y a ut h orit y.  
1 3. 3  
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  
T he pr ot oc ol will be re gistere d i n a p u blicl y accessi ble data base s uc h as cli nicaltrials. g o v a n d 
as re q uir e d i n t he E ur o pea n U ni o n Dr u g Re g ulati n g A ut h orities Cli nical Trials ( E u dra C T) or 
t he Cli nical Trials I nf or mati o n S yste m ( C TI S) p u blic we bsite. I n a d diti o n, after st u d y 
c o m pleti o n ( defi ne d as last patie nt last visit) a n d fi nalizati o n of t he st u d y re p ort t he res ults of 
t his trial will be s u b mitte d f or p u blicati o n a n d p ost e d i n a p u blicl y accessi ble data bas e of cli nical 
trial res ults, s uc h as t he N o vartis cli nical trial res ults we bsite a n d all re q uire d Healt h A ut h orit y 
we bsites (e. g. Cli nicaltrials. g o v, E u dra C T or C TI S p u blic we bsite  o nce tra nsfer t o E U Cli nical 
Trial Re g ulati o n 5 3 6/ 2 0 1 4 is c o m plete d , etc). 
S u m mar y res ults of pri mar y a n d sec o n d ar y e n d p oi nts will be discl ose d base d u p o n t he gl o bal 
Last Partici pa nt Last Visit ( L P L V) date, si nc e m ulti nati o nal st u dies are l oc ke d a n d re p ort e d 
base d u p o n t he gl o bal L P L V.  
F or details o n t he N o vartis p u blicati o n p olic y i ncl u di n g a ut h ors hi p criteria, please refer t o t he 
N o vartis p u blicati o n p olic y trai ni n g materials t hat were pr o vi de d t o y o u at t he trial i n vesti gat or 
meeti n gs.  
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 v esti gat or 
m ust be s u b mitte d 
t o N o vartis  bef ore p u blicati o n or prese ntati o n.  
1 3. 4  
Q u alit y C o ntr ol a n d Q u alit y A s s ur a n c e  
N o vartis mai ntai ns a r o b ust Q ualit y Ma na ge me nt S yste m ( Q M S) t hat i ncl u des all acti vities 
i n v ol ve d i n q ualit y ass ura nce a n d q ualit y c o ntr ol, t o e ns ure c o m plia nce wit h writte n Sta n dar d 
O perati n g Pr oce d ures ( S O Ps) as well as a p plica ble gl o bal/l ocal G C P re g ula ti o ns a n d I C H 
G ui deli nes.  
A u dits of i n vesti gat or sites, ve n d ors, a n d N o vartis s yste ms are perf or me d b y a u dit ors, 
i n de pe n de nt fr o m t h ose i n v ol ve d i n c o n d ucti n g, m o nit ori n g or perf or mi n g q ualit y c o ntr ol of t he 
cli nical trial. T he cli nical a u dit pr ocess uses a k n o wle d ge/ris k base d a p p r oac h. 
A u dits are c o n d ucte d t o assess G C P c o m plia nce wit h gl o bal a n d l ocal re g ulat or y re q uire me nts, 
pr ot oc ols a n d i nter nal S O Ps, a n d are p erf or me d acc or di n g t o writte n N o v artis pr ocesses.  
1 3. 5  
P arti ci p a nt e n g a g e m e nt  
T he f oll o wi n g s u bject e n ga ge me nt i nitiati ves are i ncl u de d i n t his st u d y a n d will be pr o vi de d, as 
a vaila ble, f or distri b uti o n t o st u d y partici pa nts at t he ti me p oi nts i n dicate d. If c o m plia nce is 

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
i m pacte d b y c ult ural n or ms or l ocal la ws a n d re g ulati o ns, sites ma y disc uss m o dificati o ns t o 
t hese re q uir e me nts wit h N o vartis. 
•  T ha n k Y o u letter  
•  Plai n la n g ua ge trial s u m mar y - aft er C S R p u blicati o n  
•  I n di vi d ual st u d y res ults –  after C S R p u blicati o n  
1 4  
Pr ot o c ol a d h er e n c e  
T his pr ot oc ol defi nes t he st u d y o bjecti ves, t he st u d y pr oce d ures a n d t he data t o be c ollecte d o n 
st u d y partici pa nts. A d diti o nal assess me nts re q uire d t o e ns ure safet y of patie nts  s h o ul d be 
a d mi nistere d as dee me d necessar y o n a case b y case basis. U n der n o cir c u msta nces i ncl u di n g 
i nci de ntal c ollecti o n is a n i n vesti gat or all o we d t o c ollect a d diti o nal data or c o n d uct a n y 
a d diti o nal pr oce d ures f or a n y p ur p ose i n v ol vi n g a n y i n vesti gati o nal dr u gs u n der t he pr ot oc ol, 
ot her t ha n t h e p ur p os e of t he st u d y. If d es pite t his i nter dicti o n pr o hi biti o n, data, i nf or mati o n, 
o bser vati o n w o ul d b e i n ci de ntall y c ollect e d, t he i n vesti gat or s hall i m me diatel y discl ose it t o 
N o vartis a n d n ot use it f or a n y p ur p os e ot her t ha n t he st u d y, e xce pt f or t he a p pr o priate 
m o nit ori n g o n st u d y partici pa nts.  
I n v esti 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. If a n 
i n vesti gat or feels a pr ot o c ol de viati o n w o ul d i m pr o ve t he c o n d u ct of t he st u d y t his m ust be 
c o nsi dere d a pr ot oc ol a m e n d me nt, a n d u nless s u c 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 a n d healt h a ut h orities, w here re q uir e d, it ca n n ot be i m ple me nte d.  
1 4. 1  
Pr ot o c ol A m e n d m e nt s  
A n y c ha n g e or a d diti o n t o t he pr ot oc ol ca n o nl y b e ma de i n a writte n pr ot o c 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 q uire d, a n d t h e I R B/I E C pri or t o 
i m ple me ntati o n. 
O nl y a me n d me nts t hat are re q uire d f or s u bject safet y ma y be i m ple me nte d i m me diatel y 
pr o vi de d t he healt h a ut h orities are s u bs e q ue ntl y n otifie d b y pr ot oc ol a me n d me nt a n d t he 
re vie wi n g I R B/I E C is n otifie d. 
N ot wit hsta n di n g t he nee d f or a p pr o val of f or mal pr ot oc ol a me n d m e 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 uir e d f or t he safet y of a n y s u bject 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 suc h cases, N o vartis s h o ul d 
be n otifie d of t his acti o n a n d t he I R B/I E C at t he st u d y site s h o ul d be i nf or me d acc or di n g t o 
l ocal re g ulati o ns. 

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 4  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
1 5  
R ef er e n c e s  
Refere n ces are a vaila ble u p o n re q uest  
( 2 0 1 1)  
F D A  
G ui da nce  
f or  
I n d ustr y.  
(I nter n et)  
A vaila ble  
fr o m: 
f da. g o v/ A ni mal Veteri nar y/ G ui da nce C o m plia nce E nf orce m e nt/ G ui da ncef orI n d ustr y/ defa ult. ht
m  
Aar o ns o n N K, A h me d zai S, Ber g ma n B, et al ( 1 9 9 3) T he E ur o pea n Or ga nizati o n f or Researc h 
a n d Treat me nt of Ca ncer Q L Q -C 3 0: a q ualit y -of -life i nstr u me nt f or us e i n i nter nati o nal cli nical 
trials i n o nc ol o g y. J. Natl. Ca ncer I nst. p. 3 6 5-7 6.  
At ki ns o n MJ, Si n ha A, Hass S L, et al ( 2 0 0 4) Vali dati o n of a ge neral m eas ure of treat me nt 
satisfacti o n, t he Treat me nt Satisfacti o n Q uesti o n n aire f or Me di cati o n ( T S Q M), usi n g a n ati o nal 
pa nel st u d y of c hr o nic disease. H ealt h Q ual Life O utc o mes p. 1 2.  
Baccara ni M, Casta g netti F, G u gli otta G, et al ( 2 0 1 5) A re vie w of t he E ur o pea n Le u k e mia Net 
rec o m me n dati o ns f or t he ma na ge me nt of C M L. A n n. He mat ol. p. S 1 4 1-7.  
Baccara ni M, Dei ni n ger M W, R osti G, et al ( 2 0 1 3) E ur o pea n Le u k e mia Net rec o m me n dati o ns 
f or t he ma na g e me nt of c hr o nic m yel oi d le u ke mia: 2 0 1 3. Bl o o d p. 8 7 2-8 4.  
Bas na ya ke C, Rat na m D ( 2 0 1 5) Bl o o d tests f or ac ute pa ncreatitis. A ust Prescr p. 1 2 8 -3 0.  
Bra nf or d S ( 2 0 1 6) M ole c ular m o nit ori n g i n c hr o nic m yel oi d le u ke mia -h o w l o w ca n y o u g o? 
He mat ol o g y A m S oc He mat ol E d uc Pr o gra m p. 1 5 6 -1 6 3.  
Bra nf or d S, Ye u n g D, Alta m ura H ( 2 0 1 5) B C R -A B L le vels at la n d mar k ti me p oi nts bet wee n 1 -
3 years of i mati ni b are pre dicti ve of ti me t o a dee p m olec ular res p o nse a n d ca n g ui de t hera p y 
s witc h decisi o ns w here T KI disc o nti n uati o n is t he g oal p. A bstract: S 4 9 0 (release date: Ma y 2 1, 
2 0 1 5)  
Br o o k me yer R a n d Cr o wle y J ( 1 9 8 2). A C o nfi de nce I nter v al f or t he Me dia n S ur vi val Ti me. 
Bi o metrics, 3 8: 2 9 -4 1.  
C o he n M H, Willia ms G, J o h ns o n J R, et al ( 2 0 0 2) A p pr o val s u m mar y f or i mati ni b mes ylate 
ca ps ules i n t he treat me nt of c hr o nic m yel o g e n o us le u ke mia. Cli n. Ca ncer R es. p. 9 3 5 -4 2.  
C ortes J E ( 2 0 1 8) A sec o n d -ge nerati o n T KI s h o ul d al wa ys be use d as i nitial t hera p y f or C M L. 
Bl o o d A d v p. 3 6 5 3 -3 6 5 5.  
Dei ni n ger M W, Vieira S, Me n di ola R, et al ( 2 0 0 0) B C R -A B L t yr osi ne ki nase acti vit y re g ul ates 
t he e x pressi o n of m ulti ple ge nes i m plicate d i n t he pat h o ge nesis of c hr o nic m yel oi d le u ke mia. 
Ca ncer Res. p. 2 0 4 9 -5 5.  
D ul uc q S, Ma h o n F X ( 2 0 1 6) Dee p m olec ular res p o nses f or treat me nt -free re missi o n i n c hr o nic 
m yel oi d le u ke mia. Ca ncer Me d p. 2 3 9 8 -4 1 1.  
E M A 
( 2 0 1 2) 
E M A 
G ui deli ne 
o n 
t he 
i n vesti gati o n 
of 
dr u g 
i nteracti o ns. 
C P M P/ E W P/ 5 6 0/ 9 5/ Re v. 1 C orr. 2. J u ne 2 0 1 2.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 5  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
Efficace F, Baccara ni M, Breccia M, et al ( 2 0 1 4) I nter n ati o nal de vel o p m e nt of a n E O R T C 
q uesti o n naire f or assessi n g healt h -relate d q ualit y of life i n c hr o nic m yel oi d le u ke mia patie nts: 
t he E O R T C Q L Q-C M L 2 4. Q ual Life Res p. 8 2 5 -3 6.  
E nri g ht H a n d Mc Gla ve P H ( 2 0 0 0) C hr o nic M yel o ge n o us Le u ke mia. I n: He mat ol o g y Basic 
Pri nci ples a n d Practice. p. C ha pter 6 2, p. 1 1 5 5 –  1 1 7 1.  
Etie n ne G, D ul u c q S, Nic oli ni F E, et al ( 2 0 1 4) Ac hie vi n g d ee p er m olec ular res p o nse is 
ass ociate d wit h a b etter cli nical o utc o me i n c hr o nic m yel oi d le u ke mia p atie nts o n i mati ni b 
fr o nt-li ne t hera p y. Hae mat ol o gica p. 4 5 8-6 4.  
F D A ( 2 0 1 7) Dr u g I nt eracti o n St u dies - St u d y Desi g n, Data A nal ysis, I m plicati o ns f or D osi n g, 
a n d La beli n g Rec o m me n dati o ns, draft Oct o ber 2 0 1 7 .  
Fa derl S, Tal paz M, Estr o v Z, et al ( 1 9 9 9) T he bi ol o g y of c hr o nic m yel oi d le u ke mia. N. E n gl. 
J. Me d. 
Falc hi L, K a ntarjia n H M, Wa n g X, et al ( 2 0 1 3) Si g nifica nce of dee p er m ol ec ular res p o nses i n 
patie nts wit h c hr o nic m yel oi d le u ke mia i n earl y c hr o nic p has e treate d wit h t yr osi ne ki nase 
i n hi bit ors. A m. J. He mat ol. p. 1 0 2 4-9.  
Fa yers P M ( 2 0 0 1) I nter preti n g q ualit y of life d ata: p o p ulati o n -base d refere n ce d ata f or t h e 
E O R T C Q L Q -C 3 0. E ur. J. Ca ncer  
Fil p p ula A M, Laitila J, Ne u v o ne n PJ, et al ( 2 0 1 2) P ote nt mec ha nis m -base d i n hi biti o n of 
C Y P 3 A 4 b y i mati ni b e x plai ns its lia bilit y t o i nteract wit h C Y P 3 A 4 s u bstrates. Br. J. P har mac ol. 
p. 2 7 8 7 -9 8.  
Ga m bac orti -Pass eri ni C, Piazza R ( 2 0 1 5) H o w I tr eat ne wl y dia g n os e d c hr o nic m yel oi d 
le u ke mia i n 2 0 1 5. A m. J. He mat ol. p. 1 5 6-6 1.  
He hl ma n n R, M üller M C, La use ker M, et al ( 2 0 1 4) Dee p m olec ular res p o nse is reac he d b y t h e 
maj orit y of patie nts tr eat e d wit h i mati ni b, pre di cts s ur vi val, a n d is ac hi e v e d m ore q uic kl y b y 
o pti mize d hi g h -d ose i mati ni b: res ults fr o m t he ra n d o mize d C M L -st u d y I V. J. Cli n. O nc ol. p. 
4 1 5 -2 3.  
H oc h ha us A, L a R osée P ( 2 0 1 3) [ Tail ore d ma na g e me nt of c hr o nic m yel oi d le u ke mia]. I nter nist 
( Berl) p. 1 5 5-6, 1 5 8 -6 0, 1 6 2 -3.  
H oc h ha us A, Lars o n R A, G uil h ot F, et al ( 2 0 1 7) L o n g -Ter m O utc o mes of I mati ni b Treat me nt 
f or C hr o nic M yel oi d Le u ke mia. N. E n gl. J. Me d. p. 9 1 7-9 2 7.  
H oc h ha us A, Sa ussele S, R osti G, et al ( 2 0 1 7) C hr o nic m yel oi d le u kae mi a: E S M O Cli nical 
Practice G ui deli nes f or dia g n osis, treat me nt a n d f oll o w -u p p. A n n O nc ol ( 2 0 1 7) 2 8 (s u p pl 4): 
i v 4 1– i v 5 1. 
H u g hes T, B o q ui m pa ni C, Ki m D W, et al ( 2 0 1 6) Treat me nt -free re missi o n ( T F R) i n patie nts 
( pts) wit h c hr o nic m y el oi d le u ke mia i n c hr o nic p hase ( C M L-C P) tr eate d wit h sec o n d -li n e 
nil oti ni b ( NI L): First res ults fr o m t he E N E S T o p st u d y. p. J Cli n O nc ol 2 4, 2 0 1 6 ( s u p pl; a bstr 
7 0 5 4).  

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 6  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
H u g hes T P, Ma ur o MJ, C ortes J E, et al ( 2 0 1 9) Asci mi ni b i n C hr o nic M yel oi d Le u ke mia after 
A B L Ki nase I n hi bit or Fail ure. N E n gl J Me d; 3 8 1( 2 4): 2 3 1 5 -2 6.  
Ki m HJ, C h u n g C H, M o o n C O, et al ( 1 9 9 0) Deter mi na nts of ma g nit u de of pse u d o h y per kal e mia 
i n t hr o m b oc yt osis. K orea n J. I nter n. Me d. p. 9 7-1 0 0.  
Kle m mt L, Scialli A R ( 2 0 0 5) T he tra ns p ort of c he micals i n se me n. Birt h Defects Res. B De v. 
Re pr o d. T o xic ol. p. 1 1 9 -3 1.  
Lars o n R A, Ki m D W, Iss ara grisil S, et al ( 2 0 1 4) Efficac y a n d safet y of nil oti ni b vs i mati ni b i n 
patie nts wit h ne wl y dia g n ose d c hr o nic m yel oi d le u ke mia i n c hr o nic p has e: l o n g -ter m f oll o w-
u p of E N E S T n d. p. Bl o o d. 2 0 1 4; 1 2 4( 2 1). A bstract 4 5 4 1.  
Ma h o n F X ( 2 0 1 6) Disc o nti n uati o n of T KI t hera p y a n d 'f u n cti o nal' c ure f or C M L. Best Pract 
Res Cli n Hae mat ol p. 3 0 8 -3 1 3.  
Ma h o n F X ( 2 0 1 6) Disc o nti n uati o n of T KI t hera p y a n d 'f u n cti o nal' c ure f or C M L. Best Pract 
Res Cli n Hae mat ol p. 3 0 8 -3 1 3.  
Ma ur o MJ, Mi na mi Y, Rea D, et al ( 2 0 2 1)  Efficac y a n d Safet y Res ults fr o m A S C E M B L, a 
M ultice nter, O pe n -l a bel, P hase 3 St u d y of Asci mi ni b, a First-i n-Class S T A M P I n hi bit or, vs 
B os uti ni b i n Patie nts wit h C hr o nic M yel oi d Le u ke mia i n C hr o nic P hase After ≥2 Pri or T yr osi ne 
Ki nase I n hi bit ors: U p dat e Aft er 4 8 Wee ks A S H [a bstract] Bl o o d; 1 3 8: 3 1 0 -3 A.  
N C C N  
( 2 0 1 8) 
Nati o nal  
C o m pre he nsi ve  
Ca ncer  
Net w or k 
( ncc n. or g/ pr ofessi o nals/ p h ysicia n _ gls/ p df/c ml _ bl oc ks. p df). 
O' Brie n S G, G uil h ot F, Lars o n R A, et al ( 2 0 0 3) I mati ni b c o m pare d wit h i nterfer o n a n d l o w -
d ose c ytara bi ne f or n e wl y dia g n ose d c hr o nic -p h as e c hr o ni c m yel oi d le u ke mia. N. E n gl. J. Me d. 
p. 9 9 4 -1 0 0 4.  
Pe n g B, Ll o y d P, Sc hra n H ( 2 0 0 5) Cli nical p har mac o ki netics of i mati ni b. Cli n P har mac o ki net 
p. 8 7 9 -9 4.  
Rea D, Ca y uela J M ( 2 0 1 7) Treat me nt -free re missi o n i n patie nts wit h c hr o nic m yel oi d le u ke mia. 
I nt. J. H e mat ol.. 
Sa u n ders V A ( 2 0 1 6) A L o w C o nce ntr ati o n  of  A B L 0 0 1 P ote ntiates  i n vitr o T KI -i n d uce d Bcr -
A bl Ki nase  I n hi biti o n i n C M L Cells p. A bstract # 1 1 2 1.  
Sa w yers C L ( 1 9 9 9) C hr o nic m yel oi d le u ke mia. N. E n gl. J. Me d. p. 1 3 3 0 -4 0.  
Va n Ette n R A ( 2 0 0 4) 
Mec ha nis ms of tra nsf or mati o n b y t he B C R -A B L o nc o ge ne: ne w 
pers pecti ves i n t he p ost -i mati ni b era. p. 2 8 S u p pl 1: S 2 1-8.  
W ylie A A, Sc h oe pfer J, Ja h n ke W, et al ( 2 0 1 7) T he all osteric i n hi bit or A B L 0 0 1 e na bles d ual 
tar geti n g of B C R-A B L 1. Nat ure p. 7 3 3 -7 3 7.  
Ye u n g D T, Os b or n M P, W hite D L, et al ( 2 0 1 5) TI D E L -II: first-li ne use of i mati ni b i n C M L 
wit h earl y s witc h t o nil oti ni b f or fail ure t o ac hie ve ti me -de pe n de nt m olec ul ar tar gets. Bl o o d p. 
9 1 5 -2 3.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 7  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
1 6  
A p p e n di c e s  
1 6. 1  
A p p e n di x 1: Li v er e v e nt a n d L a b or at or y tri g g er D efi niti o n s a n d 
F oll o w -u p R e q uir e m e nt s  
T a bl e 1 6 -1  
Li v er E v e nt a n d L a b or at or y Tri g g er D efi niti o n s  
  
D efi niti o n/t hr e s h ol d  
LI V E R L A B O R A T O R Y 
T RI G G E R S  
•  
3 x U L N < A L T/ A S T ≤ 5 x U L N  
•  
1. 5 x U L N < T B L ≤ 2 x U L N  
LI V E R E V E N T S  
•  
A L T or A S T > 5 × U L N  
  
•  
A L P > 2 × U L N (i n t h e a b s e n c e of k n o w n b o n e p at h ol o g y)  
  
•  
T B L > 2 × U L N (i n t h e a b s e n c e of k n o w n Gil b ert s y n dr o m e)  
  
•  
A L T or A S T > 3 × U L N a n d I N R > 1. 5  
  
•  
P ot e nti al H y’ s L a w c a s e s ( d efi n e d a s A L T or A S T > 3 × U L N a n d T B L > 2 
× U L N [ m ai nl y c o nj u g at e d fr a cti o n] wit h o ut n ot a bl e i n cr e a s e i n A L P t o > 2 
× U L N)  
  
•  
A n y cli ni c al e v e nt of j a u n di c e ( or e q ui v al e nt t er m)  
  
•  
A L T or A S T > 3 × U L N a c c o m p a ni e d b y ( g e n er al) 
m al ai s e, f ati g u e, 
a b d o mi n al p ai n, n a u s e a, or v o miti n g, or r a s h wit h e o si n o p hili a  
  
•  
A n y a d v er s e e v e nt p ot e nti all y i n di c ati v e of a li v er t o xi cit y*  
* T h e s e e v e nt s c o v er t h e f oll o wi n g: h e p ati c f ail ur e, fi br o si s a n d cirr h o si s, a n d ot h er li v er d a m a g e -r el at e d 
c o n diti o n s; t h e n o n -i nf e cti o u s h e p atiti s; t h e b e ni g n, m ali g n a nt a n d u n s p e cifi e d li v er n e o pl a s m s T B L: t ot al 
bilir u bi n; U L N: u p p er li mit of n or m al  
T a bl e 1 6 -2  
F oll o w U p R e q uir e m e nt s f or Li v er E v e nt s a n d L a b or at or y Tri g g er s  
Crit eri a  
A cti o n s r e q uir e d  
F oll o w -u p m o nit ori n g  
P ot e nti al H y’ s L a w c a s e a  
•  
Di s c o nti n u e  t h e  
st u d y 
tr e at m e nt i m m e di at el y 
•  
H o s pit ali z e, if 
cli ni c all y 
a p pr o pri at e  
•  
E st a bli s h c a u s alit y  
A L T, A S T, T B L, Al b, P T/I N R, A L P 
a n d γ G T u ntil r e s ol uti o n c 
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)  
A L T or A S T  
> 8 × U L N  
•  
Di s c o nti n u e  
t h e  
st u d y 
tr e at m e nt i m m e di at el y 
•  
H o s pit ali z e  if  
cli ni c all y 
a p pr o pri at e  
•  
E st a bli s h c a u s alit y  
A L T, A S T, T B L, Al b, P T/I N R, A L P 
a n d γ G T u ntil r e s ol uti o n c 
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)  
> 3 × U L N a n d I N R > 1. 5  
•  
Di s c o nti n u e  t h e  
st u d y 
tr e at m e nt i m m e di at el y 
•  
H o s pit ali z e, if 
cli ni c all y 
a p pr o pri at e  
•  
E st a bli s h c a u s alit y  
A L T, A S T, T B L, Al b, P T/I N R, A L P 
a n d γ G T u ntil r e s ol uti o n c 
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)  
> 5 t o ≤ 8 × U L N  
•  
R e p e at li v er t e st s wit hi n 
4 8 h o ur s  
•  
If  
el e v ati o n  
p er si st s, 
c o nti n u e  
f oll o w -u p 
m o nit ori n g  
A L T, A S T, T B L, Al b, P T/I N R, A L P 
a n d γ G T u ntil r e s ol uti o n c 
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)  

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 8  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
Crit eri a  
A cti o n s r e q uir e d  
F oll o w -u p m o nit ori n g  
•  
If el e v ati o n p er si st s f or 
m or e  t h a n  
2  
w e e k s, 
di s c o nti n u e t h e st u d y dr u g  
•  
E st a bli s h c a u s alit y  
> 3 × U L N a c c o m p a ni e d b y 
s y m pt o m s b  
•  
Di s c o nti n u e  t h e  
st u d y 
tr e at m e nt i m m e di at el y 
•  
H o s pit ali z e  if  
cli ni c all y 
a p pr o pri at e  
•  
E st a bli s h c a u s alit y  
A L T, A S T, T B L, Al b, P T/I N R, A L P 
a n d γ G T u ntil r e s ol uti o n c 
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)  
> 3 t o ≤ 5 × U L N ( p ati e nt i s 
a s y m pt o m ati c)  
•  
R e p e at li v er t e st s wit hi n 
t h e n e xt w e e k 
•  
If el e v ati o n i s c o nfir m e d, 
i niti at e cl o s e o b s er v ati o n 
of t h e p ati e nt  
I n v e sti g at or di s cr eti o n 
M o nit or li v er t e st s wit hi n 1 t o 4 
w e e k s  
A L P (i s ol at e d)  
  
  
> 2 × U L N (i n t h e a b s e n c e of 
k n o w n b o n e p at h ol o g y)  
•  
R e p e at li v er t e st s wit hi n 
4 8 h o ur s  
•  
If  
el e v ati o n  
p er si st s, 
e st a bli s h c a u s alit y  
I n v e sti g at or di s cr eti o n 
M o nit or li v er t e st s wit hi n 1 t o 4 
w e e k s or at n e xt vi sit  
T B L (i s ol at e d)  
  
  
> 2 × U L N (i n t h e a b s e n c e of 
k n o w n Gil b ert s y n dr o m e)  
•  
R e p e at li v er t e st s wit hi n 
4 8 h o ur s  
•  
If  
el e v ati o n  
p er si st s, 
di s c o nti n u e t h e st u d y dr u g 
i m m e di at el y 
•  
H o s pit ali z e  if  
cli ni c all y 
a p pr o pri at e  
•  
E st a bli s h c a u s alit y  
A L T, A S T, T B L, Al b, P T/I N R, A L P 
a n d γ G T u ntil r e s ol uti o n c 
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)  
T e st f or h e m ol y si s ( e. g. 
r eti c ul o c yt e s, h a pt o gl o bi n, 
u n c o nj u g at e d [i n dir e ct] bilir u bi n)  
> 1. 5 t o ≤ 2 × U L N ( p ati e nt i s 
a s y m pt o m ati c)  
•  
R e p e at li v er t e st s wit hi n 
t h e n e xt w e e k 
•  
If el e v ati o n i s c o nfir m e d, 
i niti at e cl o s e o b s er v ati o n 
of t h e p ati e nt  
I n v e sti g at or di s cr eti o n 
M o nit or li v er t e st s wit hi n 1 t o 4 
w e e k s or at n e xt vi sit  
J a u n di c e  
•  
Di s c o nti n u e  t h e  
st u d y 
tr e at m e nt i m m e di at el y 
•  
H o s pit ali z e t h e p ati e nt  
•  
E st a bli s h c a u s alit y  
A L T, A S T, T B L, Al b, P T/I N R, A L P 
a n d γ G T u ntil r e s ol uti o n c 
(fr e q u e n c y at i n v e sti g at or 
di s cr eti o n)  
A n y A E p ot e nti all y i n di c ati v e of a 
li v er t o xi cit y* 
•  
C o n si d er st u d y tr e at m e nt 
i nt err u pti o n 
or 
di s c o nti n u ati o n  
•  
H o s pit ali z ati o n if cli ni c all y 
a p pr o pri at e  
•  
E st a bli s h c a u s alit y  
I n v e sti g at or di s cr eti o n 
a El e v at e d A L T/ A S T > 3 × U L N a n d T B L > 2 × U L N b ut wit h o ut n ot a bl e i n cr e a s e i n A L P t o > 2 × U L N  
b  ( G e n er al) m al ai s e, f ati g u e, a b d o mi n al p ai n, n a u s e a, or v o miti n g, or r a s h wit h e o si n o p hili a  
c  R e s ol uti o n i s d efi n e d a s a n o ut c o m e of o n e of t h e f oll o wi n g: ( 1) r et ur n t o b a s eli n e v al u e s, ( 2) st a bl e v al u e s at 
t hr e e s u b s e q u e nt m o nit ori n g vi sit s at l e a st 2 w e e k s a p art, ( 3) r e m ai n at el e v at e d l e v el aft er a m a xi m u m of 6 
m o nt h s, ( 4) li v er tr a n s pl a nt ati o n, a n d ( 5) d e at h.  

N o v arti s  
C o nfi d e nti al  
P a g e 1 3 9  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
Crit eri a  
A cti o n s r e q uir e d  
F oll o w -u p m o nit ori n g  
* T h e s e e v e nt s c o v er t h e f oll o wi n g: h e p ati c f ail ur e, fi br o si s a n d cirr h o si s, a n d ot h er li v er d a m a g e -r el at e d 
c o n diti o n s; t h e n o n -i nf e cti o u s h e p atiti s; t h e b e ni g n, m ali g n a nt a n d u n s p e cifi e d li v er n e o pl a s m s T B L: t ot al 
bilir u bi n; U L N: u p p er li mit of n or m al  

N o v arti s  
C o nfi d e nti al  
P a g e 1 4 0  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
1 6. 2  
A p p e n di x 2: S p e cifi c R e n al Al ert Crit eri a a n d A cti o n s a n d E v e nt 
F oll o w -u p  
T a bl e 1 6 -3  
S p e cifi c R e n al Al ert Crit eri a a n d A cti o n s  
S er u m E v e nt  
S er u m cr e ati ni n e i n cr e a s e 2 5 –  4 9 % c o m p ar e d t o 
b a s eli n e  
C o nfir m 2 5 % i n cr e a s e aft er 2 4 -4 8 h  
F oll o w u p wit hi n 2 -5 d a y s  
A c ut e Ki d n e y I nj ur y: S er u m cr e ati ni n e i n cr e a s e ≥ 
5 0 % +  c o m p ar e d t o b a s eli n e  
F oll o w u p wit hi n 2 4 -4 8 h if p o s si bl e  
C o n si d er st u d y tr e at m e nt i nt err u pti o n  
C o n si d er p ati e nt h o s pit ali z ati o n / s p e ci ali z e d tr e at m e nt  
Uri n e E v e nt  
N e w di p sti c k pr ot ei n uri a ≥ 1 +  
Al b u mi n - or Pr ot ei n -cr e ati ni n e r ati o i n cr e a s e ≥ 2 -f ol d 
Al b u mi n -cr e ati ni n e r ati o ( A C R) ≥ 3 0 m g/ g or ≥ 3 
m g/ m m ol;  
Pr ot ei n -cr e ati ni n e r ati o ( P C R) ≥ 1 5 0 m g/ g or > 1 5 
m g/ m m ol  
C o nfir m v al u e aft er 2 4 -4 8 h  
P erf or m uri n e mi cr o s c o p y  
C o n si d er st u d y tr e at m e nt i nt err u pti o n or 
di s c o nti n u ati o n  
N e w di p sti c k gl y c o s uri a ≥ 1 + n ot d u e t o di a b et e s  
Bl o o d gl u c o s e (f a sti n g)  
P erf or m s er u m cr e ati ni n e, A C R  
N e w di p sti c k h e m at uri a ≥ 1 + n ot d u e t o tr a u m a  
Uri n e s e di m e nt mi cr o s c o p y  
P erf or m s er u m cr e ati ni n e, A C R  
F or all r e n al e v e nt s:  
D o c u m e nt c o ntri b uti n g f a ct or s i n t h e C R F: c o -m e di c ati o n, ot h er c o -m or bi d c o n diti o n s, a n d a d diti o n al di a g n o sti c 
pr o c e d ur e s p erf or m e d  
M o nit or p ati e nt r e g ul arl y (fr e q u e n c y at i n v e sti g at or’ s di s cr eti o n) u ntil eit h er:  
E v e nt r e s ol uti o n: s Cr wit hi n 1 0 % of b a s eli n e or pr ot ei n -cr e ati ni n e r ati o wit hi n 5 0 % of b a s eli n e, or  
E v e nt st a bili z ati o n: s Cr l e v el wit h ± 1 0 % v ari a bilit y o v er l a st 6 m o nt h s or pr ot ei n -cr e ati ni n e r ati o st a bili z ati o n at a 
n e w l e v el wit h ± 5 0 % v ari a bilit y o v er l a st 6 m o nt h s.  
+ C orr e s p o n d s t o K DI G O crit eri a f or A c ut e Ki d n e y I nj ur y  

N o v arti s  
C o nfi d e nti al  
P a g e 1 4 1  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
1 6. 3  
A p p e n di x 3: Li st of c o n c o mit a nt m e di c ati o n s w hi c h ar e 
pr o hi bit e d or t o b e u s e d wit h c a uti o n  
I n ge neral, t he us e of a n y c o nc o mita nt me dicati o n dee me d necess ar y f or t he care of t h e patie nt 
is per mitte d i n t his st u d y, e xce pt as s p ecificall y pr o hi bite d i n Secti o n  6. 2 . 
T he f oll o wi n g lists are b ase d o n t he [ O n c ol o g y Cli nical P har mac ol o g y Dr u g-Dr u g I nteracti o n 
Data base]  (release d ate: A pril 2 0 2 1), 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 “ Cli nicall y Rele va nt” T a ble a n d s u p ple me nte d wit h t h e F o o d a n d Dr u g 
A d mi nistrati o n ( F D A) Draft G ui da n ce f or I n d ustr y, Dr u g I nteracti o n St u dies –  St u d y Desi 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 ( 2 0 1 7), a n d t he U ni versit y of 
Was hi n gt o n’s Dr u g I nteracti o n Dat a base ( 2 0 1 7). T hese lists are n ot c o m pre h e nsi ve a n d are o nl y 
mea nt t o be use d as a g ui de. Please c o nt act t h e me dical m o nit or wit h a n y q ue sti o ns. If a 
me dicati o n a p pears o n b ot h t he list of pr o hi bite d a n d t he list of me dicati o ns t o be use d wit h 
ca uti o n, t he me dicati o n is pr o hi bite d.  
1 6. 3. 1  
C o n c o mit a nt m e di c ati o n s t o b e u s e d wit h c a uti o n f or a s ci mi ni b + 
i m ati ni b ar m s  
T a bl e 1 6 -4  
C o n c o mit a nt m e di c ati o n s t o b e u s e d wit h c a uti o n f or a s ci mi ni b + 
i m ati ni b ar m s  
C at e g or y  
Dr u g N a m e s  
Str o n g C Y P 3 A 4 i n hi bit or s  
o m bit a s vir/ p arit a pr e vir/ d a s a b u vir/rit o n a vir ( Vi e kir a P a k) 3 , i n di n a vir/rit o n a vir3 , 
ti pr a n a vir/rit o n a vir3 , rit o n a vir, c o bi ci st at, i n di n a vir, k et o c o n a z ol e, 
tr ol e a n d o m y ci n, t el a pr e vir, d a n o pr e vir/rit o n a vir3 , el vit e gr a vir/rit o n a vir3 , 
s a q ui n a vir/rit o n a vir 3 , l o pi n a vir/rit o n a vir3 , itr a c o n a z ol e, v ori c o n a z ol e, 
mi b efr a dil, cl arit hr o m y ci n, p o s a c o n a z ol e, t elit hr o m y ci n, gr a p efr uit j ui c e
2 , 
c o ni v a pt a n, n ef a z o d o n e, n elfi n a vir, i d el ali si b, b o c e pr e vir, 
at a z a n a vir/rit o n a vir 3 , d ar u n a vir/rit o n a vir3  
N arr o w T h er a p e uti c i n d e x 
s u b str at e s of C Y P 2 C 9  
p h e n yt oi n, w arf ari n  
C Y P 3 A 4/ 5 s u b str at e s wit h 
n arr o w t h er a p e uti c i n d e x  
alf e nt a nil, c y cl o s p ori 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, sir oli m u s, 
t a cr oli m u s, t erf e n a di n e 
T or s a d e d e p oi nt e ( T d P) 
T d P/ Q T ri s k: K n o w n*  
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 ( off U S m ar k et), 
a zit hr o m y ci n, b e pri dil ( off U S m ar k et), c hl or o q ui n e, c hl or pr o m a zi n e, 
cil o st a z ol, ci s a pri d e ( off U S m ar k et), cit al o pr a m, cl arit hr o m y ci n, c o c ai n e, 
di s o p yr a mi d e, d of etili d e, d o m p eri d o n e ( n o t o n U S m ar k et), 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, 
gr e p afl o x a ci n ( off m ar k et w orl d wi d e), 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 et h a d yl ( off m ar k et w orl d wi d e), m e s ori d a zi n e ( off m ar k et 
w orl d wi d 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 y dr o c hl ori d e, p e nt a mi di n e, pi m o zi d e, pr o b u c ol ( off m ar k et w orl d wi d e), 
pr o c ai n a mi d e ( or al off U S m ar k et), pr o p of ol, q ui ni di n e, s e v ofl ur a n e, s ot al ol, 
s p arfl o x a ci n ( off U S m ar k et), s ul piri d e ( n ot o n U S m ar k et), t erf e n a di n e ( off 
U S m ar k et), t hi ori d a zi n e, v a n d et a ni b  

N o v arti s  
C o nfi d e nti al  
P a g e 1 4 2  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
N TI s u b str at e s of P -g p  
b ari citi ni b, c y cl o s p ori n e, d a bi g atr a n, di g o xi n, d o c et a x el, d o x e pi n, d o x or u bi ci n , 
eri b uli n, e v er oli m u s f e nt a n yl, i d el ali si b, i v o si d e ni b, p a clit a x el, p a z o p a ni b, 
p h e n yt oi n, q ui ni di n e, sir oli m u s, s or af e ni b, t a cr oli m u s, t al a z o p ari b, t ol v a pt a n, 
t o p ot e c a n, vi n cri sti n e 
1  H er b al pr o d u ct  
2 T h e eff e ct of gr a p efr uit j ui c e v ari e s wi d el y a m o n g br a n d s a n d i s c o n c e ntr ati o n -, d o s e-, a n d pr e p ar ati o n-
d e p e n d e nt. St u di e s h a v e s h o w n t h at it c a n b e cl a s sifi e d a s a “ str o n g C Y P 3 A i n hi bit or” w h e n a c ert ai n pr e p ar ati o n 
w a s u s e d ( e. g. hi g h d o s e, d o u bl e str e n gt h) or a s a “ m o d er at e C Y P 3 A i n hi bit or” w h e n a n ot h er pr e p ar ati o n w a s 
u s e d ( e. g. l o w d o s e, si n gl e str e n gt h)  
3 C o m bi n ati o n rit o n a vir -b o o st e d r e gi m e n s ar e li st e d h er e a s str o n g C Y P 3 A i n hi bit or s (t o a v oi d p ot e nti al 
c o nf u si o n), e v e n t h o u g h s o m e ar e c o n si d er e d m o d er at e C Y P 3 A i n hi bit or s i n t h e U ni v er sit y of W a s hi n gt o n' s D DI 
D at a b a s e  
1 6. 3. 2  
Pr o hi bit e d c o m e di c ati o n s f or a s ci mi ni b + i m ati ni b ar m s  
T a bl e 1 6 -5  
Pr o hi bit e d c o m e di c ati o n f or a s ci mi ni b + i m ati ni b ar m s  
C at e g or y  
Dr u g N a m e s  
Str o n g C Y P 3 A 4 i n d u c er s  
c ar b a m a z e pi n e, e n z al ut a mi d e, l u m a c aft or, p h e n o b ar bit al, p h e n yt oi n, rif a b uti n, 
rif a m pi ci n, mit ot a n e, St. J o h n’ s w ort (H y p eri c u m p erf or at u m ) 
1 6. 3. 3  
C o n c o mit a nt m e di c ati o n s t o b e u s e d wit h c a uti o n f or a s ci mi ni b si n gl e 
a g e nt c o h ort  
T a bl e 1 6 -6  
C o n c o mit a nt m e di c ati o n s t o b e u s e d wit h c a uti o n f or a s ci mi ni b si n gl e 
a g e nt c o h ort  
C at e g or y  
Dr u g N a m e s  
Str o n g C Y P 3 A 4 
i n d u c er s 
c ar b a m a z e pi n e, e n z al ut a mi d e, l u m a c aft or, p h e n o b ar bit al, p h e n yt oi n, rif a b uti n, 
rif a m pi ci n, mit ot a n e, St. J o h n’ s w ort (H y p eri c u m p erf or at u m ) 
C Y P 3 A 4/ 5 s u b str at e s 
wit h n arr o w t h er a p e uti c 
i n d e x 
alf e nt a nil, c y cl o s p ori 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, sir oli m u s, 
t erf e n a di n e 
N arr o w T h er a p e uti c 
i n d e x s u b str at e s of 
C Y P 2 C 9  
p h e n yt oi n, w arf ari n  
O A T P 1 B s u b str at e s  
ali s kir e n, a m bri s e nt a n, a n a c etr a pi b, at e n ol ol, a s u n a pr e vir, at o g e p a nt, at or v a st ati n, 
b o s e nt a n, br o m o cri pti n e, c a s p of u n gi n, c eli pr ol ol, d a n o pr e vir, di g o xi n, d o c et a x el, 
eli gl u st at, e m p a n glifl o zi n, e z eti mi b e, fi m a s art a n, f e x of e n a di n e, fl u v a st ati n, gl y b uri d e, 
i br e x af u n g er p, m ar a vir o c, m et h otr e x at e, m o nt el u k a st, n at e gli ni d e, ol m e s art a n, 
p a clit a x el, pir at a pr e vir, pit a v a st ati n, pr a v a st ati n, r e p a gli ni d e, r e v ef e n a ci n, rif a m pi ci n, 
r o s u v a st ati n, s a q ui n a vir, si m v a st ati n, t el mi s art a n, t e z a c aft or, ti cl o pi di n e, v al s art a n 
B C R P s u b str at e s  
al p eli si b, at or v a st ati n, b ari citi ni b, 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, o z a ni m o d, p arit a pr e vir, 
pit a v a st ati n, ri m e g e p a nt, 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, si m v a st ati n, 
s of o s b u vir, s ulf a s al a zi n e, t e n of o vir, t e z a c aft or, t o p ot e c a n, u br o g e p a nt, v e n et o cl a x  
N TI s u b str at e s of P -g p  
b ari citi ni b, c y cl o s p ori n e, d a bi g atr a n, di g o xi n, d o c et a x el, d o x e pi n, d o x or u bi ci n, 
eri b uli n, e v er oli m u s f e nt a n yl, i d el ali si b, i v o si d e ni b, p a clit a x el, p a z o p a ni b, p h e n yt oi n, 
q ui ni di n e, sir oli m u s, s or af e ni b, t a cr oli m u s, t al a z o p ari b, t ol v a pt a n, t o p ot e c a n, 
vi n cri sti n e  
T or s a d e d e p oi nt e 
( T d P) T d P/ Q T ri s k: 
K n o w n*  
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 ( off U S m ar k et), a zit hr o m y ci n, 
b e pri dil ( off U S m ar k et), c hl or o q ui n e, c hl or pr o m a zi n e, cil o st a z ol, ci s a pri d e ( off U S 
m ar k et), cit al o pr a m, cl arit hr o m y ci n, c o c ai n e, di s o p yr a mi d e, d of etili d e, d o m p eri d o n e 
( n ot o n U S m ar k et), 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, 

N o v arti s  
C o nfi d e nti al  
P a g e 1 4 3  of 1 4 3  
A m e n d e d Pr ot o c ol V er si o n 0 5  (Cl e a n ) 
 
Pr ot o c ol N o. C A B L 0 0 1 E 2 2 0 1  
 
 
C at e g or y  
Dr u g N a m e s  
fl e c ai ni d e, fl u c o n a z ol e, gr e p afl o x a ci n ( off m ar k et w orl d wi d e), 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 et h a d yl ( off m ar k et w orl d wi d e), 
m e s ori d a zi n e ( off m ar k et w orl d wi d 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 y dr o c hl ori d e, p e nt a mi di n e, pi m o zi d e, pr o b u c ol ( off m ar k et 
w orl d wi d e), pr o c ai n a mi d e ( or al off U S m ar k et), pr o p of ol, q ui ni di n e, s e v ofl ur a n e, 
s ot al ol, s p arfl o x a ci n ( off U S m ar k et), s ul piri d e ( n ot o n U S m ar k et), t erf e n a di n e ( off 
U S m ar k et), t hi ori d a zi n e, v a n d et a ni b  
* C h e c k cr e di bl e m e d s. or g/ h e alt h c ar e -pr o 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. 
**I m ati ni b m u st n ot b e c o m bi n e d wit h A B L 0 0 1 i n a s ci mi ni b si n gl e a g e nt c o h ort .