A Prospective International Multicenter Phase II Study to Evaluate the Efficacy, Safety and Quality of Life of Pazopanib in Patients With Advanced and/or Metastatic Renal Cell Carcinoma After Previous Therapy With Checkpoint Inhibitor Treatment
Phase: PHASE2
Conditions: Advanced Renal Cell Carcinoma, Metastatic Renal Cell Carcinoma
Sponsor: Novartis Pharmaceuticals



N o v arti s
C o nfi d e nti al
P a g e 2
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
T a bl e of c o nt e nt s
Ta ble of c o nte nts .................................................................................................................2
List of fi g ures ......................................................................................................................5
List of ta bles ........................................................................................................................5
List of a b bre viati o ns ............................................................................................................7
Gl ossar y  of ter ms.................................................................................................................9
A m e n d me nt 2 ( 1 4 - Se p-2 0 2 0) ............................................................................................1 0
A me n d me nt 1 ( 9 -Fe b -2 0 1 8) ..............................................................................................1 1
Pr ot oc ol s u m mar y ..............................................................................................................1 4
1 
Bac k gr o u n d ........................................................................................................................1 7
1. 1 
O ver vie w of disease pat h o ge nesis, e pi de mi ol o g y a n d c urre nt treat me nt ..............1 7
1. 2  
I ntr o d ucti o n t o i n ve sti gati o nal treat me nt(s) a n d ot her st u d y treat me nt(s).............1 8
1. 2. 1 
O ver vie w of paz o pa ni b ( V otrie nt ® )......................................................1 8
2 
Rati o nale ............................................................................................................................2 2
2. 1 
St u d y  rati o nale a n d p ur p ose...................................................................................2 2
2. 2 
Rati o nale f or t he st u d y desi g n ...............................................................................2 2
2. 3 
Rati o nale f or d ose a n d re gi me n selecti o n ..............................................................2 3
2. 4  
Rati o nale f or c h oice of c o m bi nati o n dr u gs............................................................ 2 3
2. 5  
Rati o nale f or c h oice of c o m parat or s dr u gs ............................................................2 3
2. 6 
Ris ks a n d be nefits ..................................................................................................2 3
3 
O bjecti ves a n d e n d p oi nts ...................................................................................................2 4
4 
St u d y  desi g n ......................................................................................................................2 6
4. 1 
Descri pti o n of st u d y desi g n ...................................................................................2 6
4. 1. 1 
Scree ni n g p hase ( Da y  -2 8 t o Da y  -1 or Da y  -7 t o Da y  -1 f or certai n 
pr oce d ures) ............................................................................................2 6
4. 1. 2 
Treat me nt p hase ( C ycle 1 Da y 1 t o E O T) .............................................2 6
4. 1. 3 
Safet y  f oll o w-u p ( E O T + 3 0 da y s)........................................................2 6
4. 1. 4 
Efficac y  f oll o w-u p ( E O T u ntil pr o gressi o n or 1 y ear fr o m L P F V) ......2 7
4. 2 
Ti mi n g of i nteri m a nal ys es a n d desi g n a da ptati o ns ...............................................2 7
4. 3 
Defi niti o n of e n d of st u d y ......................................................................................2 7
4. 4 
Earl y st u d y ter mi nati o n ..........................................................................................2 8
5 
P o p ulati o n ..........................................................................................................................2 8
5. 1 
Patie nt p o p ulati o n ..................................................................................................2 8
5. 2 
I ncl usi o n criteria ....................................................................................................2 8
5. 3 
E xcl usi o n criteria ...................................................................................................2 9
6 
Treat me nt ...........................................................................................................................3 2
6. 1 
St u d y  treat me nt......................................................................................................3 2

N o v arti s
C o nfi d e nti al
P a g e 3
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
6. 1. 1 
D osi n g re gi me n .....................................................................................3 2
6. 1. 2 
Treat me nt d urati o n ................................................................................3 3
6. 1. 3 
Starti n g d ose rati o nale ...........................................................................3 3
6. 1. 4 
Pr o visi o nal d ose le vels ..........................................................................3 3
6. 2 
D ose m o dificati o ns ................................................................................................3 3
6. 2. 1 
D ose m o dificati o n a n d d ose dela y ........................................................3 3
6. 3  
C o nc o mita nt me dicati o ns...................................................................................... 4 3
6. 3. 1 
Per mitte d c o nc o mita nt t hera p y .............................................................4 3
6. 3. 2 
Per mitte d c o nc o mita nt t hera p y re q uiri n g ca uti o n a n d/ or acti o n ...........4 3
6. 3. 3 
Pr o hi bite d c o nc o mita nt t hera p y............................................................ 4 4
6. 3. 4 
Use of bis p h os p h o nates ( or ot her c o nc o mita nt a ge nts) .........................4 5
6. 4 
Patie nt n u m beri n g, treat me nt assi g n me nt or ra n d o mizati o n .................................4 5
6. 4. 1  
Patie nt n u m beri n g................................................................................. 4 5
6. 4. 2 
Treat me nt assi g n me nt or ra n d o mizati o n............................................... 4 5
6. 4. 3 
Treat me nt bli n di n g ................................................................................4 5
6. 5 
St u d y  dr u g pre parati o n a n d dis pe nsati o n...............................................................4 6
6. 5. 1 
St u d y  treat me nt pac ka gi n g a n d la beli n g...............................................4 6
6. 5. 2 
Dr u g s u p pl y  a n d st ora ge........................................................................4 6
6. 5. 3 
St u d y  dr u g c o m plia nce a n d acc o u nta bility........................................... 4 6
6. 5. 4 
Dis p osal a n d destr ucti o n .......................................................................4 7
7   
Visit sc he d ule a n d assess me nts .........................................................................................4 7
7. 1 
St u d y  fl o w a n d visit sc he d ule................................................................................4 7
7. 1. 1 
Scree ni n g ...............................................................................................5 3
7. 1. 2 
Treat me nt peri o d ...................................................................................5 5
7. 1. 3 
Disc o nti n uati o n of st u d y  treat me nt.......................................................5 5
7. 1. 4 
Wit h dra wal of c o nse nt
..........................................................................5 6
7. 1. 5 
F oll o w -u p p hases ..................................................................................5 6
7. 1. 6 
L ost t o f oll o w - u p...................................................................................5 8
7. 2 
Assess me nt t y pes ...................................................................................................5 8
7. 2. 1 
Efficac y  assess me nts.............................................................................5 8
7. 2. 2 
Safet y  a n d t olera bilit y assess me nts.......................................................6 0
6 5
7. 2. 4 
Res o urce utilizati o n ...............................................................................6 7
7. 2. 5 
Patie nt re p orte d o utc o mes .....................................................................6 7
8 
Safet y  m o nit ori n g a n d re p orti n g........................................................................................6 9
8. 1 
A d verse e ve nts .......................................................................................................6 9

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

N o v arti s
C o nfi d e nti al
P a g e 5
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
8 2
1 0. 7 
I nteri m a nalys is......................................................................................................8 3
1 0. 8 
Sa m ple size calc ulati o n.......................................................................................... 8 3
1 0. 9 
P o wer f or a nal ys is of ke y sec o n dar y varia bles......................................................8 4
1 1
Et hical c o nsi derati o ns a n d a d mi nistrati ve p r oce d ures ......................................................8 4
1 1. 1 
Re g ulat or y a n d et hical c o m plia nce ........................................................................8 4
1 1. 2 
Res p o nsi bilit ies of t he i n vesti gat or a n d I R B/I E C/ R E B.........................................8 4
1 1. 3 
I nf or me d c o nse nt pr oce d ures.................................................................................8 4
1 1. 4 
Disc o nti n uati o n of t he st u d y ..................................................................................8 5
1 1. 5 
P u blicati o n of st u d y  pr ot oc ol a n d res ults...............................................................8 5
1 1. 6 
St u d y  d oc u me ntati o n, rec or d kee pi n g a n d rete nti o n of d oc u me nts.......................8 6
1 1. 7 
C o nfi de ntia lit y of st u d y d oc u me nts a n d patie nt rec or ds .......................................8 6
1 1. 8 
A u dits a n d i ns pecti o ns........................................................................................... 8 7
1 1. 9 
Fi na ncial discl os ures ..............................................................................................8 7
1 2
Pr ot oc ol a d here nce ............................................................................................................8 7
1 2. 1 
A me n d me nts t o t he pr ot oc ol ..................................................................................8 7
1 3
Refere nces (a vaila ble u p o n re q uest) ..................................................................................8 8
1 4
A p pe n dices ........................................................................................................................9 0
1 4. 1 
A p pe n di x 1: Str o n g C Y P 3 A 4 i n hi bit ors a n d i n d ucers ..........................................9 0
1 4. 2 
A p pe n di x 2: G ui deli nes f or res p o nse, d urati o n of o verall res p o nse, T T F, T T P, 
pr o gressi o n -free s ur vi val a n d o verall s ur vi val ( base d o n R E CIS T 1. 1) ................9 1
Li st of fi g ur e s
Fi g ure 4 - 1 
St u d y  desi g n..........................................................................................2 7
Li st of t a bl e s
Ta ble 3 - 1
O bjecti ves a n d relate d e n d p oi nts ..........................................................2 5
Ta b le 6-1
D ose a n d treat me nt sc he d ule................................ .................................3 2
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 
paz o pa ni b treat me nt f or a d verse dr u g reacti o ns ....................................3 4
Ta ble 6 - 3
D ose re d ucti o n ste ps f or paz o pa ni b ......................................................4 2
Ta ble 7 - 1
Visit e val uati o n sc he d ule ......................................................................4 8
Ta ble 7 - 2
M S K C C pr o g n ostic criteria................................ ...................................5 5
Ta ble 7 - 3
I ma gi n g assess me nt c ollecti o n pla n......................................................6 0
Ta ble 7 - 4
Kar n ofs k y perf or ma nce stat us ...............................................................6 1
Ta ble 7 - 5
Cli nical la b orat or y  para meters c ollecti o n pla n .....................................6 2

N o v arti s
C o nfi d e nti al
P a g e 6
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Ta ble 7 - 6
L ocal E C G c ollecti o n pla n................................ ....................................6 4
Ta ble 7 - 7
L ocal car diac i ma gi n g c ollecti o n pla n ..................................................6 5
6 6
Ta ble 1 0 - 1 
Sa m ple size a n d esti mate d 9 5 % CI  f or me dia n P F S.............................8 3

N o v arti s
C o nfi d e nti al
P a g e 7
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Li st of a b br e vi ati o n s
A E
A d v er s e E v e nt
A L P
Al k ali n e p h o s p h at a s e
A L T
Al a ni n e a mi n otr a n sf er a s e/ gl ut a mi c p yr u vi c tr a n s a mi n a s e/ G P T
A S T
A s p art at e a mi n otr a n sf er a s e/ gl ut a mi c o x al o a c eti c tr a n s a mi n a s e/ G O T
A T C
A n at o mi c al T h er a p e uti c C h e mi c al
B P
Bl o o d pr e s s ur e
C B R
Cli ni c al b e n efit r at e
C F R
C o d e of F e d er al R e g ul ati o n s
C H M P
C o m mitt e e f or M e di ci n al Pr o d u ct s f or H u m a n U s e
CI
C o nfi d e n c e i nt er v al
C M O & P S 
C hi ef M e di c al Offi c e a n d P ati e nt S af et y
C M V
C yt o m e g al o vir u s
C R
C o m pl et e r e s p o n s e
C R F
C a s e R e p ort/ R e c or d F or m
C S R
Cli ni c al st u d y r e p ort
C T
C o m p ut eri z e d t o m o gr a p h y
C Y P 3 A 4
C yt o c hr o m e P 4 5 0 3 A 4
D B P
Di a st oli c bl o o d pr e s s ur e
D DI
Dr u g Dr u g I nt er a cti o n
DI LI
Dr u g -i n d u c e d li v er i nj ur y
D O R
D ur ati o n of r e s p o n s e
D V T
D e e p V e n o u s T hr o m b o si s
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 C H O
E c h o c ar di o gr a m
e C R F
El e ctr o ni c C a s e R e p ort/ R e c or d F or m
E D C
El e ctr o ni c D at a C a pt ur e
e G F R
E sti m at e d gl o m er ul ar filtr ati o n r at e
E S M O
E ur o p e a n S o ci et y of M e di c al O n c ol o g y
E U
E ur o p e a n U ni o n
E ur o Q ol
E ur o Q ol Gr o u p
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
F K SI -D R S 
F u n cti o n al A s s e s s m e nt of C a n c er T h er a p y -Ki d n e y S y m pt o m I n d e x -Di s e a s e R el at e d 
S y m pt o m s
G C P
G o o d Cli ni c al Pr a cti c e
G S K
Gl a x o S mit h Kli n e
H B V
H e p atiti s B vir u s
H C V
H e p atiti s C vir u s
H F S
H a n d -f o ot s y n dr o m e
H R
H a z ar d r ati o
H S V
H er p e s si m pl e x vir u s
I C H
I nt er n ati o n al C o nf er e n c e o n H ar m o ni z ati o n
I C M J E
I nt er n ati o n al C o m mitt e e of M e di c al J o ur n al E dit or s

N o v arti s
C o nfi d e nti al
P a g e 8
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
I E C
I n d e p e n d e nt Et hi c s C o m mitt e e
I M D C
I nt er n ati o n al M et a st ati c R e n al C ell C ar ci n o m a D at a b a s e C o n s orti u m
I N R
I nt er n ati o n al n or m ali z e d r ati o
I O
I m m u n o-o n c ol o g y
I R B
I n stit uti o n al R e vi e w B o ar d
I R C
I n d e p e n d e nt R e vi e w C o m mitt e e
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 t h at i n cl u d e s I nt er a cti v e V oi c e R e s p o n s e S y st e m a n d 
I nt er a cti v e We b R e s p o n s e S y st e m
L F T
Li v er f u n cti o n t e st s
L P F V
L a st p ati e nt fir st vi sit
M A A
M ar k eti n g a ut h ori z ati o n a p pli c ati o n
m R C C
M et a st ati c r e n al c ell c ar ci n o m a
M RI
M a g n eti c R e s o n a n c e I m a gi n g
M S K C C
M e m ori al Sl o a n K ett eri n g C a n c er C e nt er
m T O R
M e c h a ni sti c T ar g et Of R a p a m y ci n
M U G A
M ulti g at e d a c q ui siti o n s c a n
N CI -C T C A E 
N ati o n al C a n c er I n stit ut e C o m m o n T o xi cit y Crit eri a f or A d v er s e E v e nt s
O A T P 1 B 1 
Or g a ni c A ni o n Tr a n s p ort er Pr ot ei n B 1
O R R
O v er all r e s p o n s e r at e
O S
O v er all s ur vi v al
P D
Pr o gr e s si v e di s e a s e
P D -L 1
Pr o gr a m m e d d e at h -li g a n d 1
P F S
Pr o gr e s si o n -Fr e e S ur vi v al
P P S
P er -Pr ot o c ol S et
P R
P arti al r e s p o n s e
P R O
P ati e nt r e p ort e d o ut c o m e s
Q T c F
Q T c c orr e ct e d b y Fri d eri ci a’ s f or m ul a
R C C
R e n al c ell c ar ci n o m a
R V al u e
A L T/ 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
S A E
S eri o u s A d v er s e E v e nt
S A P
T h e St ati sti c al A n al y si s Pl a n ( R A P) i s a r e g ul at or y d o c u m e nt w hi c h pr o vi d e s e vi d e n c e of 
pr e pl a n n e d a n al y s e s
S B P
S y st oli c bl o o d pr e s s ur e
S C
St e eri n g C o m mitt e e
S D
St a bl e di s e a s e
S T S
S oft Ti s s u e S ar c o m a
T BI L
T ot al bilir u bi n
T KI
T yr o si n e ki n a s e i n hi bit or
U L N
U p p er li mit of n or m al
U P C
Uri n e Pr ot ei n t o Cr e ati ni n e R ati o
U S
U nit e d St at e s
V E G F R
V a s c ul ar e n d ot h eli al gr o wt h f a ct or r e c e pt or

N o v arti s
C o nfi d e nti al
P a g e 9
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Gl o s s ar y  of t er m s
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), s ali v a, 
ti s s u e, uri n e, st o ol, et c. t a k e n fr o m a st u d y s u bj e ct or st u d y p ati e nt
C y cl e s
N u m b er a n d ti mi n g or r e c o m m e n d e d r e p etiti o n s of t h er a p y ar e u s u all y 
e x pr e s s e d a s n u m b er of d a y s ( e. g. , q 2 8 d a y s)
D o s e l e v el
T h e d o s e of dr u g gi v e n t o t h e p ati e nt (t ot al d ail y or w e e kl y et c.)
I n v e sti g ati o n al dr u g
T h e st u d y tr e at m e nt w h o s e pr o p erti e s ar e b ei n g t e st e d i n t h e st u d y; t hi s 
d efi niti o n i s c o n si st e nt wit h U S C F R 2 1 S e cti o n 3 1 2. 3 a n d i s s y n o n y m o u s wit h 
“i n v e sti g ati o n al n e w dr u g.”
I n v e sti g ati o n al tr e at m e nt 
Dr u g w h o s e pr o p erti e s ar e b ei n g t e st e d i n t h e st u d y a s w ell a s t h eir a s s o ci at e d 
pl a c e b o a n d a cti v e tr e at m e nt c o ntr ol s ( w h e n a p pli c a bl e). T hi s al s o i n cl u d e s 
a p pr o v e d dr u g s u s e d o ut si d e of t h eir i n di c ati o n/ a p pr o v e d d o s a g e, or t h at ar e 
t e st e d i n a fi x e d c o m bi n ati o n. I n v e sti g ati o n al tr e at m e nt g e n er all y d o e s n ot 
i n cl u d e ot h er st u d y tr e at m e nt s a d mi ni st er e d a s c o n c o mit a nt b a c k gr o u n d t h er a p y 
r e q uir e d or all o w e d b y t h e pr ot o c ol w h e n u s e d i n wit hi n a p pr o v e d 
i n di c ati o n/ d o s a g e
M e di c ati o n n u m b er
A u ni q u e i d e ntifi er o n t h e l a b el of e a c h st u d y tr e at m e nt p a c k a g e w hi c h i s li n k e d 
t o o n e of t h e tr e at m e nt gr o u p s of a st u d y
Ot h er st u d y tr e at m e nt
A n y dr u g a d mi ni st er e d t o t h e p ati e nt a s p art of t h e r e q uir e d st u d y pr o c e d ur e s 
t h at w a s n ot i n cl u d e d i n t h e i n v e sti g ati o n al tr e at m e nt
S u bj e ct N u m b er
( S u bj e ct N o.)
A u ni q u e i d e ntif yi n g n u m b er a s si g n e d t o e a c h p ati e nt/ s u bj e ct/ h e alt h y v ol u nt e er 
w h o e nr oll s i n t h e st u d y
St u d y tr e at m e nt
I n cl u d e s a n y dr u g or c o m bi n ati o n of dr u g s i n a n y st u d y ar m a d mi ni st er e d t o t h e 
p ati e nt ( s u bj e ct) a s p art of t h e r e q uir e d st u d y pr o c e d ur e s, i n cl u di n g pl a c e b o a n d 
a cti v e dr u g r u n -i n s.
I n s p e cifi c e x a m pl e s, it i s i m p ort a nt t o j u d g e i n v e sti g ati o n al tr e at m e nt c o m p o n e nt 
r el ati o n s hi p r el ati v e t o a st u d y tr e at m e nt c o m bi n ati o n; st u d y tr e at m e nt i n t hi s 
c a s e r ef er s t o t h e i n v e sti g ati o n al a n d n o n- i n v e sti g atio n al tr e at m e nt s i n 
c o m bi n ati o n.
St u d y tr e at m e nt 
di s c o nti n u ati o n
P oi nt/ti m e w h e n p ati e nt p er m a n e ntl y st o p s t a ki n g st u d y tr e at m e nt f or a n y r e a s o n
V ari a bl e
I d e ntifi er u s e d i n t h e d at a a n al y si s; d eri v e d dir e ctl y or i n dir e ctl y fr o m d at a 
c oll e ct e d u si n g s p e cifi e d a s s e s s m e nt s at s p e cifi e d ti m e p oi nt s
Wi t h dr a w al of c o n s e nt 
Wi t h dr a w al of c o n s e nt o c c ur s o nl y w h e n a p ati e nt d o e s n ot w a nt t o p arti ci p at e i n 
t h e st u d y an y l o n g er, a n d d o e s n ot w a nt a n y f urt h er vi sit s or a s s e s s m e nt s, a n d 
d o e s n ot w a nt a n y f urt h er st u d y r el at e d c o nt a ct

N o v arti s
C o nfi d e nti al
P a g e 1 0
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
A m e n d m e nt 2 ( 1 4 -S e p -2 0 2 0 )
A m e n d m e nt r ati o n al e 
As of a me n d me nt date, 8 patie nts re mai n o n st u d y treat me nt i n t w o c o u ntries ( C hile -2 sites a n d 
Fra nce -1 site). 
N o vartis pr oce d ures f or c ollecti n g f oll o w u p i nf or mati o n o n pre g na ncies ha ve bee n re vise d t o 
har m o nize f oll o w- u p ti meli nes acr oss pr o d uct platf or ms. T he f oll o w u p peri o d f or c ollecti n g 
i nf or mati o n after a li ve birt h has bee n e xte n de d fro m 3 m o nt hs t o 1 2 m o nt hs.  The I CFs f or 
pre g na nt partici pa nt a n d pre g na nt part ner are u p date d acc or di n gl y.   
A t y p o gra p hical err or is als o c orrecte d.
T he c ha n ges reflecte d i n t his a me n d me nt are liste d bel o w. 
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 deleti o ns a n d re d u n derli ne f or i nserti o ns.

Secti o n 8. 4 Pre g na ncies : E xte n de d t he d urati o n of t he pre g na nc y  f oll o w u p peri o d fr o m 3 
m o nt hs t o u p t o 1 2 m o nt hs p ost -birt h . 

Secti o n 7. 2. 1, Ta ble 7 -3 I ma gi n g Assess me nt C ollecti o n Pla n: T y p o gra p hical err or 
c orrecte d.  D uri n g efficac y f oll o w u p, sca ns are ma n date d e ver y 8 wee ks ( ± 7 d ays ), n ot 
e ver y 8 wee ks ( ± 7 wee ks). 

N o v arti s
C o nfi d e nti al
P a g e 1 1
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
A m e n d m e nt 1 ( 9 -F e b -2 0 1 8)
A m e n d m e nt r ati o n al e 
As of 3 0 -Ja n- 2 0 1 8:

2 patie nts i n 2 c o u ntries ha ve bee n e nr olle d;

1 patie nt has disc o nti n ue d treat me nt
Si nce t he ori gi nal pr ot oc ol was fi nalize d i n A pril 2 0 1 7, t he R C C treat me nt la n dsca pe has 
e v ol ve d. T here are se veral o n g oi n g trials e val uati n g i m m u ne c hec k p oi nt i n hi bit or c o m bi nati o ns 
(I O-I O) or I O-T y r osi ne Ki nase I n hi bit or ( T KI) c o m bi nati o ns as first li ne t hera py,  an d I O is 
e x pecte d t o bec o me t he sta n dar d of care i n first li ne t hera py.  Data c ollecte d fr o m t he use of 
paz o pa ni b i n t he 2 n d li ne setti n g p ost -i m m u ne c hec k p oi nt i n hi bit or t hera p y are n o w m ore 
rele va nt. F urt her m ore, t he a vaila bilit y of ot her a ge nts i ncl u di n g ca b oza nti ni b ma y  prese nt 
p ot e ntial c halle n ges t o recr uit me nt. T heref ore, t he sa m ple size is bei n g re d uce d fr o m 1 4 0 t o 
a p pr o xi matel y 10 0 patie nts t o o btai n rele va nt data i n a ti mel y ma n ner. T he re d uce d sa m ple size 
will pr o vi de 2. 7 8 m o nt hs precisi o n wit h a 9 5 % CI of ( 4. 7 7, 7. 5 5) f or a n esti mate me dia n P F S 
of 6 m o nt hs. 
T hera pe utic li nes of paz o pa ni b – w het her i n t he 2 n d or 3 r d li ne setti n g - will be trac ke d at 
scree ni n g usi n g I nte grati ve Res p o nse Tec h n ol o g y (IR T) wit h a n e nr oll me nt ca p t o e ns ure t hat 
a p pr o xi matel y 
40 % 
patie nts 
e nr oll 
w it h 
paz o pa ni b 
a d mi nistere d 
as 
2 n d
li ne 
treat me nt. Descri pti ve s u m mar y statistics f or t he pri mar y  efficac y an d safety data will be 
pr o vi de d b y paz o pa ni b li ne of treat me nt i n a d diti o n t o ot her rele va nt s u b gr o u ps. 
As t here is li mite d e vi de nce t o s u p p ort re-c halle n ge wit h paz o pa ni b after pri or 1 st li ne paz o pa ni b 
f oll o we d b y  IO, patie nts wit h pre vi o us e x p os ure t o paz o pa ni b will be e xcl u de d fr o m st u d y 
partici pati o n. 
T o all o w f or earl y m o nit ori n g of bl o o d press ure s o o n after starti n g treat me nt wit h paz o pa ni b, 
v ital si g ns meas ure me nt has bee n a d de d o n C y cle 1 Da y 8.  T he fre q ue nc y of car diac i ma gi n g 
has bee n re d uce d t o e ver y 5- 6 c ycles u nless ot her wise i n dicate d. T hese c ha n ges are c o nsiste nt 
wit h t he I n vesti gat or’s Br oc h ure. 
T he maj or c ha n ges reflecte d i n t his a me n d me nt are liste d bel o w. 
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 secti o ns of t he pr ot oc ol are s h o w n i n t he trac k c ha n ges versi o n of t he 
pr ot oc ol usi n g stri ke t hr o u g h re d f o nt f or deleti o ns a n d re d u n derli ne f or i nserti o ns.

Secti o n 1. 2. 1. 2: U p date d n u m ber of patie nts e x p ose d t o paz o pa ni b per I n vesti gat or’s 
Br oc h ure v 1 6.

Secti o n 2. 2: A d de d te xt s u p p orti n g re d ucti o n i n sa m ple size a n d a d diti o n of e nr oll me nt 
ca p f or patie nts recei vi n g paz o pa ni b as 3 r d li ne t hera py. A d de d precisi o n f or esti mate d 
me dia n P F S f or 2 n d a n d 3 r d li ne s u b gr o u ps. 

Secti o n 4. 1: A d de d t hat t hera pe utic li nes of paz o pa ni b will be trac ke d at scree ni n g wit h a n 
e nr oll me nt ca p t o e ns ure t hat a p pr o xi matel y  4 0 patie nts recei ve paz o pa ni b a d mi nistere d as 
2 n d li ne treat me nt.

N o v arti s
C o nfi d e nti al
P a g e 1 2
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0

Secti o n 5. 1: C ha n ge d sa m ple size fr o m 1 4 0 t o a p pr o xi matel y  1 0 0 patie nts, wit h 
a p pr o xi matel y 4 0 patie nts recei vi n g 2n d li ne paz o pa ni b t hera py.

Secti o n 5. 2: Clarifie d i ncl usi o n criteri o n # 5 t o all o w e nr oll me nt of patie nts wit h pri or 
m T O R i n hi bit or treat me nt.  A d de d re q uire me nt f or ser u m calci u m t o be wit hi n n or mal 
li mits at scree ni n g. 

Secti o n 5. 3: A d de d e xcl usi o n criteri o n t o disall o w e nr oll me nt of patie nts pre vi o usl y  
treate d wit h paz o pa ni b.

Secti o n 5. 3: U p date d e xcl usi o n criteri o n # 2 t o all o w e nr oll me nt of patie nts w h o ha ve 
p re vi o usl y-treate d C N S metastases t hat meet t hree a d diti o nal criteria.

Ta ble 6 -2: C ha n ge d u nits f or fe brile ne utr o pe nia ( A N C < 1 0 0 0/ m m 3) f or c o nsiste nc y. 

Ta ble 6 - 2, 7-2:  If Q Tc F i nter val is ≥ 5 0 0 msec, a d de d t hat m o nit ori n g i n a h os pital is 
re q uire d u ntil a car di ol o gist’s e val uati o n has bee n o btai ne d. 

Secti o n 6. 4. 2: A d de d details of e nr oll me nt ca p i m ple me ntati o n via I R T. 

Ta ble 7 -1: A d de d C ycl e 1 Da y 8 assess me nt of vital si g ns. Re d uce d fre q ue nc y of car diac 
i ma gi n g t o scree ni n g, C ycles 5, 1 1, 1 6 a n d e ver y 6 t h c ycle t hereafter u ntil e n d of 
treat me nt)

Ta ble 7 - 1, Secti o n 7. 1. 1. 3: Clarifie d t hat scree ni n g q uality of life q uesti o n naires ca n be 
o btai ne d fr o m Da y  -7 u ntil C y cle 1 Da y 1 pre d ose.

Secti o n 7. 2. 2. 5. 8: Clarifie d t hat at -h o me uri ne pre g na nc y  test kits will be s u p plie d t o 
patie nts b y  eac h site, n ot b y ce ntral la b ( C o va nce)

Secti o n 7. 2. 5: Clarifie d t hat b ot h scree ni n g q ualit y  of life q uesti o n naires m ust be 
c o m plete d d uri n g t he scree ni n g p hase wit hi n 7 da ys bef ore t he first d ose of st u d y  
me dicati o n ( paz o pa ni b) o nl y  after patie nt eli gi bilit y is c o nfir me d, or o n Cyc le 1 Da y 1 
pre d ose.

Secti o n 7. 2. 2. 6. 2: T o s u p p ort re d uce d fre q ue nc y  of car diac i ma gi n g, a d de d t hat patie nts 
s h o ul d be cl osel y m o nit ore d f or si g ns a n d sy m pt o ms of c o n gesti ve heart fail ure.  I n 
parti c ular, patie nts at ris k of car diac d ys f u ncti o n or wit h pri or a nt hrac ycli ne e x p os ure ma y 
warra nt m ore fre q ue nt m o nit ori n g.

Ta ble 7. 5: A d de d f o ot n ote t hat i nterfere nce wit h T otal T 3 a n d Free T 4 assa y s ma y be 
o bser ve d i n patie nt ta ki n g hi g h d oses of bi oti n. I t is rec o m me n de d t hat bi oti n s u p ple me nts 
be st o p pe d f or 3 da y s pri or t o sa m pli n g.  

Ta ble 7. 5: U p date d f o ot n ote re gar di n g l ocal la b tests f or he pat o xicit y  f oll o w-u p. A d de d 
“ w here l ocall y a vaila ble”. 

Ta ble 7 -7: U p date d car diac i ma gi n g ti me p oi nts (as reflec te d i n Ta ble 7-1 sc he d ule of 
assess me nts)

Secti o ns 1 0, 1 0. 4. 4: Defi ne d s u b gr o u ps f or pri mar y efficac y  a n d selecte d safet y a nalys es

Secti o n 1 0. 5. 3. 2, 1 0. 5. 3. 3: A d de d t hat a d verse e ve nts a n d la b orat or y  a b n or malities will 
als o be ta b ulate d b y li ne of t hera p y s u b gr o u p ( 2 n d/ 3r d), a ge cate g or y a n d M S K C C a n d 
I M D C ris k gr o u ps.

Secti o n 1 0. 8: U p date d sa m ple size a n d esti mate d 9 5 % CI  f or me dia n P F S.

N o v arti s
C o nfi d e nti al
P a g e 1 3
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
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 
(IR Bs)/I n de pe n de nt Et hics C o m mi ttee (IE Cs) a n d Healt h A ut h orities.
T he c ha n ges descri be d i n t his a me n de d pr ot oc ol re q uire I RB/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 1 4
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Pr ot o c ol s u m m ar y
Titl e
A pr o s p e cti v e i nt er n ati o n al m ulti c e nt er p h a s e II st u d y t o e v al u at e t h e effi c a c y, 
s af et y a n d q u alit y of lif e of p a z o p a ni b i n p ati e nt s wit h a d v a n c e d a n d/ or m et a st ati c 
r e n al c ell c ar ci n o m a aft er pr e vi o u s t h er a p y wit h c h e c k p oi nt i n hi bit or tr e at m e nt
Bri ef titl e
St u d y of effi c a c y a n d s af et y of p a z o p a ni b i n p ati e nt s wit h a d v a n c e d a n d/ or 
m et a st ati c r e n al c ell c ar ci n o m a aft er pri or c h e c k p oi nt i n hi bit or tr e at m e nt
S p o n s or a n d Cli ni c al 
P h a s e
N o v arti s P h ar m a A G
II
I n v e sti g ati o n t yp e
Dr u g
St u d y  t yp e
I nt er v e nti o n al
P ur p o s e a n d r ati o n al e
I m m u n ot h er a p y h a s pl a y e d a n i m p ort a nt r ol e i n t h e tr e at m e nt of r e n al c ell 
c ar ci n o m a ( R C C). F or o v er 2 d e c a d e s, c yt o ki n e t h er a p y wit h i nt erl e u ki n -2 (I L -2) or 
i nt erf er o n al p h a w a s t h e m ai n st a y 1 st t h er a p y f or p ati e nt s wit h m et a st ati c R C C b ut 
e v e nt u all y w a s r e pl a c e d b y V E G F t ar g et e d a g e nt s. A d v a n c e s i n o ur u n d er st a n di n g 
of t h e i m m u n e c h e c k p oi nt s h a v e l e d t o t h e d e v el o p m e nt of n o v el a p pr o a c h e s f or 
c a n c er t h er a p y, i n cl u di n g a nti -C T L A -4, a nti -P D -1 a n d a nti -P D -1 L a nti b o di e s. T h e 
R C C l a n d s c a p e i s e v ol vi n g r a pi dl y w it h m ulti pl e tr e at m e nt o pti o n s i n s e c o n d li n e. 
C urr e ntl y, t h er e ar e s e v er al o n g oi n g cli ni c al tri al s wit h i m m u n e c h e c k p oi nt 
i n hi bit or s i n diff er e nt m ali g n a n ci e s i n cl u di n g R C C; h o w e v er c o m bi n ati o n s of d u al 
i m m u n e c h e c k p oi nt i n hi bit or s, a n d c o m bi n ati o n s of va s c ul ar e n d ot h eli al gr o wt h 
f a ct or r e c e pt or ( V E G F)-dir e ct e d a g e nt s wit h i m m u n e c h e c k p oi nt i n hi bit or s, m a y n ot 
pr o d u c e d ur a bl e r e s p o n s e s i n all p ati e nt s a n d m a n y p ati e nt s wil l e v e nt u all y r el a p s e 
(L ar ki n 2 0 1 6 , At ki n s 2 0 1 6 , H a m m er s 2 0 1 6 ). V E G F- dir e ct e d t h er a pi e s will, 
t h er ef or e, c o nti n u e t o pl a y a m aj or r ol e i n t h e m a n a g e m e nt of pati e nt s wit h m R C C 
( m et a stati c R C C), e v e n a s n o v el i m m u n e t h er a pi e s g ai n F D A a p pr o v al f or m R C C. 
N o pr o s p e cti v e d at a ar e a v ail a bl e o n t h e effi c a c y of p a z o p a ni b aft er pr e vi o u s 
tr e at m e nt wit h a n i m m u n e c h e c k p oi nt i n hi bit or. A d diti o n all y, t h e m aj orit y of cli ni c al 
tri al s c o n d u ct e d i n fir st li n e R C C wit h c h e c k p oi nt i n hi bit or s u s e a c o ntr ol ar m 
tr e at m e nt wit h s u niti ni b. I nt eri m a n al y s e s of s o m e fir st li n e tri al s w er e r e p ort e d i n 
2 0 1 7 a n d ar e o n g oi n g i n 2 0 1 8 wit h p ot e nti al t o c h a n g e fir st li n e st a n d ar d of c ar e 
(N C T 0 2 8 5 3 3 3 1, N C T 0 2 2 3 1 7 4 9, N C T 0 2 6 8 4 0 0 6, a n d N C T 0 2 4 2 0 8 2 1).
T h e g o al of t hi s p h a s e II tri al i s t o e v al u at e t h e effi c a c y, t ol er a bilit y, s af et y a n d 
q u alit y of lif e of p ati e nt s wit h m R C C tr e at e d wit h p a z o p a ni b f oll o wi n g tr e at m e nt 
wit h i m m u n e c h e c k p oi nt i n hi bit or s.
Pri m ar y  O bj e cti v e( s)  
Pri m ar y : T o a s s e s s t h e pr o gr e s si o n -fr e e s ur vi v al ( P F S) b a s e d o n l o c al i n v e sti g at or 
a s s e s s m e nt u si n g R E CI S T 1. 1.
S e c o n d ar y  O bj e cti v e s
● T o a s s e s s o v er all r e s p o n s e r at e ( O R R) a n d cli ni c al b e n efit r at e ( C B R) b a s e d o n 
l o c al i n v e sti g at or a s s e s s m e nt
● T o a s s e s s o v er all s ur vi v al ( O S)
● T o a s s e s s d ur ati o n of r e s p o n s e ( D O R) i n p ati e nt s wit h c o nfir m e d c o m pl et e 
r e s p o n s e ( C R) or p arti al r e s p o n s e ( P R)
● T o e v al u at e s af et y a n d t ol er a bilit y
● T o a s s e s s q u alit y of lif e

N o v arti s
C o nfi d e nti al
P a g e 1 5
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
St u d y  d e si g n
A n i nt er n ati o n al, m ulti c e nt er, si n gl e ar m P h a s e II tri al t o d et er mi n e t h e effi c a c y, 
s af et y a n d q u alit y of lif e of p a z o p a ni b tr e at m e nt aft er pr e vi o u s t h er a p y wit h i m m u n e 
c h e c k p oi nt tr e at m e nt
A p pr o xi m at el y 1 0 0 p ati e nt s will b e e nr oll e d. Si n c e d at a c oll e ct e d fr o m t h e u s e of 
p a z o p a ni b i n t h e 2 n d li n e s etti n g p o st-I O t h er a p y will b e t h e m o st r el e v a nt, 
t h er a p e uti c li n e s of p a z o p a ni b – w h et h er i n t h e 2 n d or 3 r d li n e s etti n g - will b e 
tr a c k e d at s cr e e ni n g u si n g I nt e gr ati v e R e s p o n s e T e c h n ol o g y (I R T) wit h a n 
e nr ol l m e nt c a p t o e n s ur e t h at a p pr o xi m at el y 4 0 p ati e nt s r e c ei v e p a z o p a ni b a s 2 n d
li n e tr e at m e nt.
P ati e nt s will r e c ei v e tr e at m e nt wit h st a n d ar d d o s e p a z o p a ni b u ntil di s e a s e 
pr o gr e s si o n, u n a c c e pt a bl e t o xi cit y, pr e g n a n c y, d e at h, di s c o nti n u ati o n fr o m t h e 
st u d y tr e at m e nt f or a n y ot h er r e a s o n or u ntil 2 y e a r s aft er L P F V, w hi c h e v er e v e nt 
c o m e s fir st . All p ati e nt s w h o di s c o nti n u e tr e at m e nt will b e f oll o w e d f or s ur vi v al f or 2 
y e ar s aft er L P F V . P ati e nt s w h o di s c o nti n u e tr e at m e nt wit h o ut d o c u m e nt e d di s e a s e 
pr o gr e s si o n will b e f oll o w e d f or effi c a c y f or 1 y e ar aft er L P F V .
P o p ul ati o n
T h e st u d y will i n cl u d e a p pr o xi m at el y 1 0 0 a d ult s wit h a d v a n c e d a n d/ or m et a st ati c 
r e n al c ell c ar ci n o m a 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 m u n e c h e c k p oi nt 
t h er a p y.
K e y i n cl u si o n crit eri a
● P ati e nt i s ≥ 1 8 y e ar s ol d at t h e ti m e o f i nf or m e d c o n s e nt.
● P ati e nt h a s hi st ol o gi c all y c o nfir m e d l o c all y r e c urr e nt or m et a st ati c pr e d o mi n a ntl y 
cl e ar c ell r e n al c ell c ar ci n o m a.
● P ati e nt m u st h a v e m e a s ur a bl e di s e a s e b a s e d o n R E CI S T 1. 1 crit eri a
● P ati e nt m u st h a v e r e c ei v e d pri or s y st e mi c t h er a p y wit h a n i m m u n e c h e c k p oi nt 
i n hi bit or ( m o n ot h er a p y or c o m bi n ati o n) a s 1st or 2 n d li n e R C C tr e at m e nt. N ot e: 
p ati e nt s wit h pri or T KI tr e at m e nt or m T O R i n hi bit or a s m o n ot h er a p y or i n 
c o m bi n ati o n wit h i m m u n e c h e c k p oi nt i n hi bit or ar e all o w e d; h o w e v er, tr e at m e nt wit h 
i m m u n e c h e c k p oi nt i n hi bit or ( m o n ot h er a p y or i n c o m bi n ati o n) m u st h a v e b e e n t h e 
l a st tr e at m e nt pri or t o st u d y e ntr y.
● L a st d o s e of i m m u n e c h e c k p oi nt i n hi bit or t h er a p y m u st h a v e b e e n r e c ei v e d 4 or 
m or e w e e k s b ef or e st art of st u d y tr e at m e nt
● P ati e nt m u st h a v e a K ar n of s k y p erf or m a n c e st at u s ≥7 0 %.
K e y e x cl u si o n crit eri a
● R e n al c ell c ar ci n o m a wit h o ut a n y cl e ar ( c o n v e nti o n al) c ell c o m p o n e nt
● Pr e s e n c e of C e ntr al N er v o u s S y st e m m et a st a s e s (p ati e nt s wit h pr etr e at e d 
m et a st a s e s ar e eli gi bl e u n d er c ert ai n c o n diti o n s)
● Pri or tr e at m e nt wit h b e v a ci z u m a b t h at w a s n ot gi v e n i n c o m bi n ati o n wit h i m m u n e 
c h e c k p oi nt i n hi bit or t h er a p y.
● Pri or tr e at m e nt wit h m or e t h a n 2 li n e s of t h er a p y ( c o m bi n ati o n tr e at m e nt s ar e 
c o n si d er e d 1 li n e of t h er a p y)
● Pri or tr e at m e nt wit h p a z o p a ni b
● P ati e nt h a s n ot r e c o v er e d fr o m t o xi cit y fr o m pri or i m m u n e c h e c k p oi nt i n hi bit or 
t h er a p y. R e c o v er y i s d efi n e d a s ≤ N CI -C T C A E Gr a d e 1, e x c e pt f or li v er f u n cti o n 
t e st ( L F T) l e v el s w hi c h m u st b e < Gr a d e 1.
● Di s e a s e r e c urr e n c e l e s s t h a n 6 m o nt h s fr o m t h e l a st d o s e of pri or n e o a dj u v a nt or 
a dj u v a nt t h er a p y (i n cl u di n g V E G F -R T KI)
● P ati e nt s r e c ei vi n g pr o hi bit e d c o n c o mit a nt m e di c ati o n s 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 at l e a st 5 h alf -li v e s of t h e 
c o n c o mit a nt m e di c ati o n or 7 d a y s, w hi c h e v er i s l o n g er, pri or t o t h e st art of 
p a z o p a ni b tr e at m e nt.
● A d mi ni str ati o n of a n y i n v e sti g ati o n al dr u g wit hi n 4 w e e k s pri or t o t h e fir st d o s e of 
st u d y tr e at m e nt
I n v e sti g ati o n al a n d 
r ef er e n c e t h er a p y
P a z o p a ni b 8 0 0 m g Q D

N o v arti s
C o nfi d e nti al
P a g e 1 7
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
1 
B a c k gr o u n d
1. 1 
O v er vi e w of di s e a s e p at h o g e n e si s, e pi d e mi ol o g y  a n d c urr e nt 
tr e at m e nt
R C C arises i n t he cells of t he re nal t u b ules a n d is t he m ost c o m m o n ( 9 0-9 5 %) of se veral 
cli nicall y an d e pi de mi ol o gicall y disti nct t ypes of re nal carci n o ma (G u pta 2 0 0 8 ). T he mai n 
hist ol o gic t u m or t ypes of R C C i ncl u de clear cell ( n o n-pa pillar y ), pa pillar y  (c hr o m o p hilic), 
c hr o m o p h o be, o nc oc ytic, c ollecti n g d uct a n d u nclassifie d (C o he n 2 0 0 5 ).
Ki d ne y  ca ncer acc o u nts f or 5 % a n d 3 % of all a d ult mali g na ncies i n me n a n d w o me n 
res pecti vely, t h us re prese nti n g t he 6t h m ost c o m m o n ca ncer i n me n a n d t he 1 0
t h m ost c o m m o n 
ca ncer i n w o me n 
(Sie gel 2 0 1 7 ). H o we ver,
a vaila ble statistics i ncl u de n ot o nl y  re nal 
pare nc h y m al t u m ors (a de n ocarci n o ma cell t ype [ R C C]), b ut als o re nal pel vic t u m ors (re nal 
tra nsiti o nal cell t ype ). Re nal cell carci n o ma ( R C C) acc o u nts f or ~ 9 0 % of all ki d ne y  ca ncers 
(C h o w 2 0 1 0 ).
After o ver t w o deca des of i ncreasi n g rates, R C C i nci de nce tre n ds w orl d wi de ha ve s h o w n si g ns 
of platea ui n g or decreasi n g i n rece nt ye ars. F urt her m ore, ki d ne y  ca ncer m ortalit y rates o verall 
ha ve le vele d. T hese patter ns are c o nsiste nt wit h re p orts of i nci de ntal dia g n osis a n d a d o w n war d 
s hift of t u m or sta ge a n d size d ue t o earl y detecti o n. Asi de fr o m well -k n o w n ris k fact ors f or 
R C C, s uc h as ci garette s m o ki n g, o besit y a n d h y perte nsi o n, e vi de nce is acc u m ulati n g t o s u g gest 
a n ass ociati o n bet wee n t he de vel o p me nt of R C C a n d ot her fact ors, s uc h as p h y sical acti vit y,  
alc o h ol c o ns u m pti o n a n d occ u pati o nal e x p os ure t o tric hl or oet h yle ne a n d parit y  in w o me n 
(C h o w 2 0 1 0 ). R C C als o a p pears t o be m ore c o m m o n i n patie nts wit h e n d sta ge re nal fail ure or 
ac q uire d re nal c ystic disease, a n d i n patie nts o n dial y sis, t h ose w h o ha ve ha d ki d ne y 
tra ns pla ntati o n, or t h ose wit h t u ber o us scler osis s yn dr o me. A p pr o xi matel y  2 %– 3 % of all R C Cs 
are here ditar y  an d se veral a ut os o mal d o mi na nt s yn dr o mes are descri be d, eac h wit h a disti nct 
ge netic basis a n d p he n ot y pe, t he m ost c o m m o n o ne bei n g V o n Hi p pel Li n da u ( V H L) disease 
(Esc u dier 2 0 1 6 ).
T hree treat me nts ha ve de m o nstrate d efficac y in pi v otal p hase III trials first-li ne treat me nt of 
patie nts wit h m R C C a n d g o o d or i nter me diate pr o g n osis: be vaciz u ma b (c o m bi ne d wit h 
i nterfer o n) (Esc u dier 2 0 0 7 ), s u niti ni b (M otzer 2 0 0 7 ), a n d paz o pa ni b (Ster n ber g 2 0 1 0 ). All t hree 
dr u gs ha ve bee n re gistere d base d o n i m pr o ve me nt of pr o gressi o n -free s ur vi val ( P F S) o ver eit her 
i nterfer o n or place b o. M ore rece ntl y, paz o pa ni b has bee n s h o w n t o be n o n-i nferi or t o s u niti ni b 
i n a lar ge p hase III trial ( C O M P A R Z- M otzer 2 0 1 3 ). T he pri mar y  en d p oi nt was P F S; sec o n dar y 
e n d p oi nts i ncl u de o verall s ur vi val, d urati o n of res p o nse, q ualit y  of life, me dical res o urce 
utilizati o n a n d safety assess me nts. T he st u d y de m o nstrate d n o n- i nferi orit y of paz o pa ni b f or P F S 
i n t he i nte nti o n t o treat p o p ulati o n a n d paz o pa ni b statisticall y fa v o ure d q ualit y  of life i n 1 1 of 
t he 1 4 d o mai ns meas ure d (M otzer 2 0 1 3 ). Efficac y  of b ot h s u niti ni b a n d paz o pa ni b has bee n 
c o nfir me d b y  real-w orl d e vi de nce st u dies. T hese t w o t yr osi ne ki nase i n hi bit ors ( T KIs) are 
c urre ntl y t he m ost c o m m o nl y use d treat me nts (Esc u dier 2 0 1 6 ). Te msir oli m us is c urre ntl y t he 
o nl y  dr u g teste d i n a p hase III st u d y, de m o nstrati n g e vi de nce of act i vit y as a first li ne treat me nt 
i n patie nt wit h p o or pr o g n osis. T he pi v otal trial de m o nstrate d i m pr o ve me nt of O S c o m pare d 
wit h i nterfer o n or t he c o m bi nati o n of te msir oli m us a n d i nterfer o n ( H u des 2 0 0 7 ).

N o v arti s
C o nfi d e nti al
P a g e 1 9
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
after ( ne o) a dj u va nt t hera p y (t he P hase III trial p o p ulati o n e xcl u de d patie nts wit h 
gastr oi ntesti nal str o mal t u m or ( GI S T) or a di p oc y tic S T S i n t he E U).
1. 2. 1. 1 
N o n -cli ni c al e x p eri e n c e
A ra n ge of n o ncli nical p har mac ol o g y , p har mac o ki n etic a n d t o xic ol o g y st u dies ha ve bee n 
perf or me d wit h paz o pa ni b. I t is descri be d i n t he latest In vesti gat or’s Br oc h ure.
1. 2. 1. 2 
Cli ni c al e x p eri e n c e
C u m ulati vel y , as of 0 9 Se pte m ber 2 0 1 7, a p pr o xi matel y 8 7 2 4 patie nts a n d healt h y  vol u nteers 
were e nr olle d a n d treate d i n paz o pa ni b cli nical st u dies, of w h o m 5 8 9 7 recei ve d paz o pa ni b as 
m o n ot hera p y or i n c o m bi nati o n wit h ot her c he m ot hera pe utic a ge nts. Data c ollecte d t o date 
s h o w t hat paz o pa ni b a d mi nistrati o n at 8 0 0 m g dail y  is ass ociate d wit h a reas o na ble safety 
pr ofile a n d e nc o ura gi n g efficac y  i n vari o us o nc ol o g y setti n gs.
1. 2. 1. 2. 1 Effi c a c y of p a z o p a ni b i n a d v a n c e d/ m et a st ati c R C C
I n st u d y VE G 1 0 5 1 9 2 (a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d P hase III st u d y of 
paz o pa ni b m o n ot hera p y i n s u bjects wit h a d va nce d R C C), t he pri mar y  anal y sis of t he pri mar y 
e n d p oi nt, pr o gressi o n -free s ur vi val ( P F S), re veale d a hi g hl y statisticall y si gnifica nt 
i m pr o ve me nt i n P F S i n t he paz o pa ni b- treate d s u bjects c o m pare d t o place b o -treate d s u bjects 
( hazar d rati o [ H R] 0. 4 6, 9 5 % CI  0. 3 4 t o 0. 6 2, p < 0. 0 0 0 0 0 0 1). T he me dia n P F S i n t he paz o pa ni b 
ar m was m ore t ha n d o u ble t hat i n t he place b o ar m: 9. 2 m o nt hs ( 9 5 % CI , 7. 4, 1 2. 9) vers us 4. 2 
m o nt hs ( 9 5 % CI , 2. 8, 4. 2), res pecti vely. T he res p o nse rate was si g nificantl y  hi gher f or t he 
paz o pa ni b ar m c o m pare d wit h t he place b o ar m b y I RC a ssess me nt ( 3 0 % vs. 3 %, p < 0. 0 0 1). I n 
t he paz o pa ni b ar m, t he me dia n d urati o n of res p o nse was 5 8. 7 wee ks ( 9 5 % CI , 5 2. 1 t o 6 8. 1 
wee ks) a n d t he me dia n ti me t o res p o nse was 1 1. 9 wee ks ( 9 5 % C I, 9. 4 t o 1 2. 3 wee ks) b y 
i n de pe n de nt ra di ol o gic re vie w assess me nt (Ster n ber g 2 0 1 0 ). T he me dia n O S at fi nal a nal ysis 
was 2 2. 9 m o nt hs i n t he paz o pa ni b ar m a n d 2 0. 5 m o nt hs i n t he place b o ar m. T he fi nal O S w as 
n ot statisticall y differe nt bet wee n t he paz o pa ni b ar m a n d t he place b o ar m i n ( H R = 0. 9 1, 
stratifie d l o g-ra n k p-val ue, 0. 2 2 4) ( Ster n ber g 2 0 1 3 ).
I n st u d y VE G 1 0 8 8 4 4, paz o pa ni b de m o nstrate d t o be n o n- i nferi or t o s u niti ni b wit h res pect t o 
I R C-assesse d P F S ( H R 1. 0 4 7; 9 5 % CI 0. 8 9 8 2, 1. 2 1 9 5). T he me dia n P F S was 8. 4 m o nt hs ( 9 5 % 
CI , 8. 3, 1 0. 9) f or paz o pa ni b a n d 9. 5 m o nt hs ( 9 5 % CI , 8. 3, 1 1. 1) f or s u niti ni b. O S was si milar 
bet wee n t he treat me nt ar ms ( H R 0. 9 0 8; 9 5 % CI  0. 7 6 2, 1. 0 8 2, p = 0. 2 7 5). T he me dia n O S was 
2 8. 4 m o nt hs ( 9 5 % CI : 2 6. 2, 3 5. 6) i n paz o pa ni b a n d 2 9. 3 m o nt hs ( 9 5 % CI: 2 5. 3, 3 2. 5) i n t he 
s u niti ni b ar m. IR C -assesse d o verall res p o nse rate was greater i n t he paz o pa ni b ar m ( 3 1 %; 9 5 % 
CI  26. 9, 3 4. 5) t ha n t he s uniti ni b ar m ( 2 5 %; 9 5 % CI  21. 1, 2 8. 4) a n d t he differe nce ( 6 %) was 
statisticall y si g nifica nt ( p = 0. 0 3 2). O verall, t he res ults f or P F S, O S, a n d O R R s u p p ort si milar 
efficac y for paz o pa ni b a n d s u niti ni b (M otzer 2 0 1 3 ). At t he ti me of t he fi nal O S a nal ys is ( data 
c ut-off 3 0 Se pte m ber 2 0 1 3), a gai n O S was si milar bet wee n t he treat me nt ar ms wit h a hazar d 
rati o of 0. 9 1 5 ( 9 5 % CI : 0. 7 8 6, 1. 0 6 5, p = 0. 2 4 5). Me dia n O S was 2 8. 3 m o nt hs ( 9 5 % CI : 2 6. 0, 
3 5. 5) i n t he paz o pa ni b ar m a n d 2 9. 1 m o nt hs ( 9 5 % CI : 2 5. 4, 3 3. 1) i n t he s u niti ni b ar m (M otzer 
2 0 1 3 ). I n st u d y VE G 1 0 7 7 6 9 t he res p o nse rate was 3 7. 5 %, t he me dia n P F S was 9. 2 m o nt hs, a n d 
t he me dia n O S was 2 3. 5 m o nt hs. T he data c ut-o ff f or t his a nal ysis was 1 5 Marc h 2 0 1 0 b y t hat 
ti me 6 4 % of s u bjects ha d die d, c o m pare d wit h 3 0 % at t he ti me of t he pri mar y a nalys is.

N o v arti s
C o nfi d e nti al
P a g e 2 0
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
1. 2. 1. 2. 2 S af et y of p a z o p a ni b i n a d v a n c e d/ m et a st ati c R C C
I n V E G 1 0 5 1 9 2, t he me dia n ti me o n treat me nt was a p pr o xi matel y twice t hat o n p lace b o ( 7. 4 
m o nt hs vers us 3. 8 m o nt hs) (Ster n ber g 2 0 1 0 ). T he o verall fre q ue nc y of a d verse e ve nts ( A Es) 
re p orte d d uri n g t he st u d y was hi g her i n t he paz o pa ni b ar m ( 9 3 %) c o m pare d wit h place b o ( 7 4 %). 
M ost c o mm o n A Es re p orte d i n > 2 0 % s u bjects i n t he paz o pa ni b ar m, re gar dless of gra de a n d 
ca usalit y (as of 2 9 Dec 2 0 1 4 – e n d of st u d y), were diarr hea ( 5 2 %), h y perte nsi o n ( 4 0 %), hair 
c ol or c ha n ges ( 3 8 %), na usea ( 2 6 %), decrease d a p petite ( 2 4 %), a n d v o miti n g ( 2 1 %). T he se A Es 
were all re p orte d at a hi g her i nci de nce i n t he paz o pa ni b ar m t ha n i n t he place b o ar m. M ost of 
t hese e ve nts were Gra de 1 or 2 usi n g t he N CI C o m m o n T o xicit y  Criteria f or A d verse E ve nts 
( N CI C T C A E) Versi o n 3. 0. M ore Gra de 3 A Es were re p orte d i n t he paz o pa ni b ar m ( 3 3 %) 
c o m pare d wit h t he place b o ar m ( 1 4 %). T he fre q ue nc y of Gra de 4 A E a n d Gra de 5 e ve nts was 
si milar bet wee n t he paz o pa ni b a n d place b o ar ms: Gra de 4 i n 7 % a n d 6 %, res pecti vel y;  Gra de 5 
i n 4 % a n d 3 %, res pecti vel y. T he m ost c o m m o n Gra de 3/ 4 e ve nts i n t he paz o pa ni b ar m were 
A L T i ncrease d, h y perte nsi o n, A S T i ncrease d, diarr hea a n d ast he nia/fati g ue.
Base d o n t he a nal ys is of t he safety data i nte grate d acr oss t he 3 R C C st u dies V E G 1 0 2 6 1 6 (a 
P hase II st u d y of paz o pa ni b m o n ot hera p y  in s u bjects wit h a d va nce d R C C), V E G 1 0 5 1 9 2, a n d 
V E G 1 0 7 7 6 9 (a si n gle ar m P hase III e xte nsi o n st u d y of paz o pa ni b m o n ot hera p y  in s u bjects wit h 
a d va nce d R C C) as of 0 9 Ja n uar y 20 0 9 ( N = 5 9 3), t he m ost c o m m o n A Es a n d seri o us a d verse 
e ve nts ( S A Es) were si milar t o t h ose o bser ve d i n t he paz o pa ni b ar m of V E G 1 0 5 1 9 2.
St u d y  VE G 1 0 2 6 1 6 (c o m plete d 1 0 Se pte m ber 2 0 1 3) c o nfir ms t he safet y pr ofile of paz o pa ni b 
a n d n o ne w safet y s i gnals were o bser ve d. T he m ost c o m m o n A Es were diarr hea ( 6 6 %), fati g ue 
( 4 8 %), hair c ol or c ha n ges ( 4 4 %), h y perte nsi o n ( 4 4 %) a nd na usea ( 4 4 %), w hic h is c o nsiste nt 
wit h t he pri mar y  a nalys is (safety data c ut -off date, 2 4 Marc h 2 0 0 8).
St u d y  VE G 1 0 7 7 6 9 was c o m plete d ( 2 0 Dece m ber 2 0 1 2), a n d a gai n n o ne w safety si g nals f or 
paz o pa ni b were o bser ve d. T he me dia n d urati o n of e x p os ure t o paz o p a ni b was 9. 7 m o nt hs (ra n ge: 
0 m o nt hs t o 5 6 m o nt hs). T he m ost c o m m o n A Es ( > 2 0 % s u bjects) were h y perte nsi o n ( 4 5 %), 
diarr hea ( 4 5 %), hair c ol or c ha n ges ( 4 4 %), decrease d a p petite ( 3 0 %), a n d na usea ( 2 5 %). T hirt y -
se ve n perce nt of s u bjects e x perie nce d a n A E of ma xi m u m gra de 3 se verit y or hi g her.
St u d y  VE G 1 0 8 8 4 4 is a ra n d o mize d, o pe n -la bel, parallel gr o u p P hase III n o n -i nferi ority st u d y 
t o e val uate t he efficac y a n d safety of paz o pa ni b c o m pare d wit h s u niti ni b i n s u bjects wit h 
a d va nce d R C C w h o ha d n ot recei ve d pri or sys te mic t herap y f or a d va nce d or metastatic R C C. 
A p pr o xi matel y  87 6 eli gi ble s u bjects (a p pr o xi matel y 4 3 8 per treat me nt ar m) were pla n ne d t o be 
e nr olle d o ver t he c o urse of t he st u d y. H o we ver, d ue t o hi g her t ha n e x pecte d wit h dra wal rates 
a n d disc or da nce rates bet wee n
I n de pe n de nt Re vie w C o m mittee (IR C) a n d i n vesti gat or 
assess me nts of pr o gressi o n, t he pr ot oc ol was a me n de d t o i ncrease t he n u m ber of s u bjects t o 
a p pr o xi matel y 1 1 0 0 t otal b y i ncl u di n g all s u bjects e nr olle d i n V E G 1 0 8 8 4 4 a n d V E G 1 1 3 0 7 8 (a 
s u bst u d y of V E G 1 0 8 8 4 4). V E G 1 1 3 0 7 8 was c o n d ucte d i n C hi na, K orea, a n d Tai wa n; e nr olle d 
t he sa me s u bject p o p ulati o n as V E G 1 0 8 8 4 4; a n d is al m ost i de ntical i n st u d y desi g n a n d c o n d uct 
t o all o w i nte grati o n of efficac y a n d safet y data.
A t otal of 1 1 0 2 s u bjects were i ncl u de d i n t he safety p o p ulati o n ( paz o pa ni b 5 5 4 s u bjects; 
s u niti ni b 5 4 8 s u bjects). At t he ti me of t he O S a nal ysis ( data c ut-off 3 0 Se pte m ber 2 0 1 3) t he 
me dia n ti me o n treat me nt was 8. 1 m o nt hs f or paz o pa ni b a n d 7. 6 m o nt hs f or s u niti ni b. T he 
o verall fre q ue nc y of A Es rep orte d d uri n g t he st u d y was si milar f or eac h treat me nt gr o u p; 5 5 2 

N o v arti s
C o nfi d e nti al
P a g e 2 1
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
s u bjects ( > 9 9 %) ha d A Es i n t he paz o pa ni b ar m a n d 5 4 4 s u bjects ( > 9 9 %) ha d A Es i n t he 
s u niti ni b ar m. H o we ver, differe ntial safety p r ofiles were o bser ve d bet wee n t he treat me nt ar ms, 
wit h a statistically s i gnifica nt differe nce i n fre q ue ncies ( u na dj uste d f or m ulti plicit y ) f or se veral 
A Es. T he m ost c o m m o n A Es ( > 3 5 % i n eit her treat me nt ar m) were diarr hea ( 6 3 % i n paz o pa ni b 
ar m, 5 7 % i n s u niti ni b ar m), fati g ue ( 5 5 % i n paz o pa ni b ar m, 6 3 % i n s u niti ni b arm), h y perte nsi o n 
( 4 7 % i n paz o pa ni b ar m, 4 1 % i n s u niti ni b ar m), na usea ( 4 5 % i n paz o pa ni b ar m, 4 6 % i n s u niti ni b 
ar m), decrease d a p petite ( 3 8 % i n paz o pa ni b ar m, 3 7 % i n s u niti ni b ar m), d y s ge usia ( 2 6 % i n 
paz o pa ni b ar m, 3 6 % i n s u niti ni b ar m), a n d pal mar -pla ntar er yt hr o dys est hesia ( P P E) s yn dr o me 
( or ha n d-f o ot s yn dr o me [ H F S]) ( 3 0 % i n paz o pa ni b ar m, 5 0 % i n s u niti ni b ar m).
Of t hese A Es, fati g ue, H F S, a n d d ys ge usia occ urre d m ore fre q ue ntly i n t he s u niti ni b ar m 
c o m pare d wit h t he paz o pa ni b ar m base d o n 9 5 % c o nfi de nce i nter val ( CI; u na dj uste d f or 
m ulti plicit y ) f or relati ve ris k e xcl u di n g 1. T he pr o p orti o n of s u bjects wit h diarr hea a n d 
h y perte nsi o n was hi g her i n paz o pa ni b c o m pare d wit h s u niti ni b. T hree a d diti o nal s u bjects i n t he 
paz o pa ni b ar m ha d a n A E of diarr hea si nce t he c ut-off date f or t he pri mar y  a nalys is. As a res ult, 
t he 9 5 % CI  for relati ve ris k f or t his e ve nt n o w e xcl u des 1, w hereas pre vi o usl y  it di d n ot. T he 
pr o p orti o n of s u bjects wit h ma xi m u m Gra de 3 a n d 4 A Es was si milar bet wee n t he treat me nt 
ar ms, wit h n o differe nce i n t he relati ve ris k. Gra de 3 A Es of i ncrease d A L T, i ncrease d as partate 
a mi n otra nsferase ( A S T), a n d hea dac he occ urre d m ore fre q ue ntly i n t he paz o pa ni b ar m 
c o m pare d wit h t he s u niti ni b ar m. Gra de 3 A Es of fati g ue, decrease d a p petite, H F S, ne utr o pe nia, 
m uc osal i nfla m mati o n, t hr o m b oc yt o pe nia, le u k o pe nia, decrease d platelet c o u nt, a ne mia, a n d 
decrease d ne utr o p hil c o u nt occ urre d m ore fre q ue ntl y in t he s u niti ni b ar m c o m pare d wit h t he 
paz o pa ni b ar m. Gra de 5 A Es were re p orte d i n 1 3 ( 2 %) s u bjects i n t he paz o pa n i b ar m a n d 1 9 
( 3 %) s u bjects i n t he s u niti ni b ar m. Si nce t he data c ut-off f or t he pri mar y a nal ys is C S R, o ne 
a d diti o nal s u bject i n t he paz o pa ni b ar m ha d a fatal S A E of l u n g i nfecti o n
1. 2. 1. 2. 3 S u m m ar y of p h ar m a c o ki n eti c a n d p h ar m a c o d y n a mi c d at a
Res ults of p har mac o ki ne tic a n d p har mac o d y n a mic a nal yses de m o nstrate t hat paz o pa ni b is 
a bs or be d after oral a d mi nistrati o n; a platea u is reac he d i n stea d y-state s yste mic e x p os ure at a 
d ose of 8 0 0 m g  dail y;  theref ore, i ncreases i n d oses a b o ve 8 0 0 m g , u p t o t he hi g hest d ose 
e val uated ( 2 0 0 0 m g ), i n t he faste d state d o n ot res ult i n a c o nsiste nt i ncrease i n s yste mic 
e x p os ure. Oral a bs or pti o n is si g nifica ntly e n ha nce d w he n paz o pa ni b is d ose d wit h f o o d; 
t heref ore, it is rec o m me n de d t o a d mi nister paz o pa ni b o n a n e m pt y st o mac h.
C o nsiste nt wit h V E G F rece pt or i n hi biti o n, a m o n ot hera p y  d ose of 8 0 0 m g o nce daily, res ulte d 
i n i ncrease d bl o o d press ure, i ncreases i n V E G F, a n d decreases i n s ol u ble V E G F R -2. 
C o nce ntrati o n -effect relati o ns hi ps were 
o bser ve d 
bet wee n 
paz o pa ni b 
tr o u g h plas ma 
c o nce ntrati ons a n d a n i ncrease i n bl o o d press ure ( St u d y VE G 1 0 0 0 3), as well as i n t he perce nt 
c ha n ge fr o m baseli ne i n s ol u ble V E G F R -2 ( St u d y  V E G 1 0 2 6 1 6).
1. 2. 1. 2. 4 Dr u g - dr u g i nt er a cti o n s
Paz o pa ni b is meta b olize d pri maril y b y C Y P 3 A 4 a n d s yste mic e x p os ure t o paz o pa ni b is altere d 
b y i n hi bit ors a n d i n d ucers of t his e nz yme. C o -a d mi nistrati o n of paz o pa ni b wit h str o n g C Y P 3 A 4 
i n hi bit ors or i n d ucers is pre dicte d t o i ncrease or decrease, res pecti vely, t he s yste mic e x p os ure 
t o paz o pa ni b. T he c o nc o mita nt use of str o n g C Y P 3 A 4 i n hi bit ors or i n ducers s h o ul d be a v oi de d. 

N o v arti s
C o nfi d e nti al
P a g e 2 2
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
If c o-a d mi nistrati o n wit h 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, paz o pa ni b d ose s h o ul d 
be re d uce d (see A p pe n di x 1 ).
T here were n o cli nicall y mea ni n gf ul c ha n ges i n Q Tc i nterval f oll o wi n g paz o pa ni b i n a 
de dicate d Q T H olter st u d y .
2 
R ati o n al e
2. 1 
St u d y r ati o n al e a n d p ur p o s e
I m m u n ot hera py has pla ye d a n i m p orta nt r ole i n t he treat me nt of R C C. F or o ver 2 deca des, 
c yt o ki ne t hera p y wit h i nterle u ki n- 2 (I L-2) or i nterfer o n al p ha was t he mai nsta y  first-li ne 
t hera py f or patie nts wit h metastatic R C C b ut e ve nt uall y was re place d b y  VE G F tar gete d a ge nts. 
A d va nces i n o ur u n dersta n di n g of t he i m m u ne c hec k p oi nts ha ve le d t o t he de vel o p me nt of n o vel 
a p pr oac hes f or ca ncer t hera p y, i ncl u di n g a nti-C T L A - 4, a nti-P D -1 a n d a nti -P D -1 L  anti b o dies. 
T he R C C la n dsca pe is e v ol vi n g ra pi dly wit h m ulti ple treat me nt o pti o ns i n sec o n d li ne. 
Ni v ol u ma b was rece ntly a p pr o ve d i n sec o n d li ne f oll o wi n g t he res ults of t he C hec k mate-0 2 5 
st u d y (M otzer 2 0 1 5 ).
C urre ntl y , t here are se veral o n g oi n g cli nical trials wit h i m m u ne c hec k p oi nt i n hi bit ors i n 
differe nt mali g na ncies i ncl u di n g R C C; h o we ver c o m bi nati o ns of d ual i m m u ne c hec k p oi nt 
i n hi bit ors, a nd c o m bi nati o ns of i m m u ne c hec k p oi nt i n hi bit ors wit h V E G F -directe d a ge nts, ma y 
n ot pr o d uce d ura ble res p o nses i n all patie nts a n d ma n y patie nts  will e ve nt uall y rela pse (Lar ki n 
2 0 1 6 , At ki ns 2 0 1 6 , Ha m mers 2 0 1 6 ). V E G F-directe d t hera pies will, t heref ore, c o nti n ue t o pla y 
a maj or r ole i n t he ma na ge me nt of patie nts wit h m R C C, e ve n as n o vel i m m u ne t hera pies gar ner 
F D A a p pr o val f or m R C C. N o pr os pecti ve data are a vaila ble o n t he efficac y of paz o pa ni b after 
pre vi o us treat me nt wit h a n i m m u ne c hec k p oi nt i n hi bit or. A d diti o nall y , t he maj orit y of cli nical 
trials c o n d ucte d i n first li ne R C C wit h c hec k p oi nt i n hi bit ors us e a c o ntr ol ar m treat me nt wit h 
s u niti ni b. I nteri m a nal yses of s o me first li ne trials were re p orte d i n 2 0 1 7 a n d ot hers will be 
a vaila ble i n 2 0 1 8 wit h p ote ntial t o c ha n ge first li ne sta n dar d of care ( N C T 0 2 8 53 3 3 1, 
N C T 0 2 2 3 1 7 4 9, N C T 0 2 6 8 4 0 0 6, a n d N C T 0 2 4 2 0 8 2 1).
T he g oal of t his p hase II trial is t o e val uate t he efficac y, t olera bilit y, safety a n d q ualit y  of life 
of patie nts wit h m R C C treate d wit h paz o pa ni b f oll o wi n g pri or treat me nt wit h i m m u ne 
c hec k p oi nt i n hi bit ors.
2. 2 
R ati o n al e f or t h e st u d y  d e si g n
I n a retr os pective st u d y , Na dal et al ( 2 0 1 6) re p orte d a n O R R of 2 7 % i n m R C C patie nts treate d 
wit h V E G F R -T KI  thera p y  after a n y P D -1 c o m bi nati o n, wit h me dia n P F S ( m P F S) of 6. 9 m o nt hs 
( 9 5 % Cl: 3. 7 t o 1 0. 1). Al bi ges et al ( 2 0 1 5) re p orte d a me dia n ti me t o treat me nt fail ure of 6. 9 
m o nt hs a n d 5. 7 m o nt hs i n patie nts w h o recei ve d V E G F R -T KI a n d m T O R i n hi bit ors after 
c hec k p oi nt i n hi bit or, res pecti vel y.
T he efficac y an d safet y of a nti-V E G F T KI after i m m u ne c hec k p oi nt i n hi bit or t hera py nee d t o 
be st u die d i n a pr os pecti ve trial. Si nce t he ai m of t he st u d y  is t o e val uate efficac y a n d safet y of 
paz o pa ni b i n patie nt s pre vi o usl y  treate d wit h c hec k p oi nt i n hi bit ors, a n d c urre ntl y t here is n o 
a p pr o ve d sta n dar d of care treat me nt f or t his s pecific patie nt p o p ulati o n, n o c o ntr ol ar m has bee n 
i ncl u de d i n t he trial desi g n. T h is trial is neit her desi g ne d n or i nte n de d t o c o m pare efficac y  a n d 

N o v arti s
C o nfi d e nti al
P a g e 2 3
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
safety t o a sta n dar d of care, b ut t o a d dress t he use of T KI  thera p y p ost i m m u ne c hec k p oi nt 
i n hi bit or. Res ults will be e val uate d i n li g ht of pre vi o usl y  re p orte d data i n si milar p o p ulati o ns i n 
t he c o nte xt of t he e v ol vi n g R C C treat me nt la n dsca pe. 
T here are se veral o n g oi n g trials e val uati n g i m m u ne c hec k p oi nt i n hi b it or c o m bi nati o ns (IO- I O) 
or I O-T y r osi ne Ki nase I n hi bit or ( T KI) c o m bi nati o ns as 1 st li ne t hera p y, a n d I O is e x pecte d t o 
bec o me t he sta n dar d of care i n 1 st li ne t hera p y. Data c ollecte d fr o m t he use of paz o pa ni b i n t he 
2 n d li ne setti n g p ost -I O thera p y will be m ore rele va nt, b ut t hese patie nt s ma y  als o be m ore 
diffic ult t o recr uit f or t his st u d y base d o n l ocal treat me nt practices .  Gi ve n t he ver y  specific 
patie nt p o p ulati o n, a sa m ple size of 1 0 0 patie nts is base d o n t he esti mate d feasi bilit y of e nr olli n g 
a s ufficie nt n u m ber of rele va nt patie nt s i n a ti mel y ma n ner, a n d n ot base d o n a n y statistical 
p o wer c o nsi derati o ns.   T h is sa m ple size will pr o vi de 2. 7 8 m o nt hs precisi o n wit h a 9 5 % CI  of 
( 4. 7 7, 7. 5 5) f or a n esti mate me dia n P F S of 6 m o nt hs ( o verall). F or 2 n d li ne a n d 3 r d li ne patie nts, 
t he precisi o n wit h a 9 5 % CI f or esti mate d P F S is pr o vi de d i n Secti o n 1 0. 8 .
T hera pe utic li nes of paz o pa ni b – w het her i n t he 2 n d- or 3 r d-li ne setti n g - will be trac ke d at 
screeni n g usi n g I nte grati ve Res p o nse Tec h n ol o g y (IR T) wit h a n e nr ollme nt ca p t o e ns ure t hat 
a p pr o xi matel y 4 0 patie nts e nr oll wit h paz o pa ni b a d mi nistere d as 2 n d-li ne treat me nt.
2. 3 
R ati o n al e f or d o s e a n d r e gi m e n s el e cti o n
V otrie nt ( paz o pa ni b) is a p pr o ve d f or t he treat me nt of patie nts wit h a d va nce d re nal cell 
carci n o ma ( R C C). T he rec o m me n de d a n d a p pr o ve d starti n g d ose is 8 0 0 m g  orall y once dail y 
w hic h is t he starti n g d ose t hat will be use d i n t his st u d y .
2. 4 
R ati o n al e f or c h oi c e of c o m bi n ati o n dr u g s
N ot a p plica ble
2. 5 
R ati o n al e f or c h oi c e of c o m p ar at or s dr u g s
N ot a p plica ble
2. 6 
Ri s k s a n d b e n efit s
Paz o pa ni b 8 0 0 m g dail y  is c o nsi dere d t o ha ve a p ositi ve be nefit -ris k pr ofile f or patie nts wit h 
a d va nce d re nal cell carci n o ma; t he be nefits of t hera p y wit h paz o pa ni b o ut wei g h a n y p o te ntial 
ris ks. Per t he I nvesti gat or’s Br oc h ure, t he last re vie w of all a vaila ble paz o pa ni b data d oes n ot 
c ha n ge t he Be nefit/ Ris k pr ofile w hic h re mai ns p ositi ve a n d s u p p orts t he use of paz o pa ni b i n 
t his patie nt p o p ulati o n.
A p pr o priate eli gi bilit y criteria as well as s pecific d ose m o dificati o n a n d st o p pi n g r ules, are 
i ncl u de d i n t his pr ot oc ol. Rec o m me n de d g ui deli nes f or pr o p h y lactic or s u p p orti ve ma na ge me nt 
of st u d y-dr u g i n d uce d a d verse e ve nts are pr o vi de d i n Se cti o n 6. 2 . T he ris k t o patie nts i n t his 
trial ma y be mi ni mize d b y c o m plia nce wit h t he eli gi bilit y criteria a n d st u dy pr oce d ures, as well 
as, cl ose cli nical m o nit ori n g. T here ma y be u nf oresee n ris ks wit h paz o pa ni b . Refer t o t he latest 
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 2 4
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
3 
O bj e cti v e s a n d e n d p oi nt s
O bjecti ves a n d relate d e n d p oi nts are descri be d i n Ta ble 3 - 1 bel o w.

N o v arti s
C o nfi d e nti al
P a g e 2 5
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
T a bl e 3- 1 
O bj e cti v e s a n d r el at e d e n d p oi nt s
O bj e cti v e
E n d p oi nt
A n al y s i s
Pri m ar y
R ef er t o S e cti o n 1 0. 4 .
T o a s s e s s t h e pr o gr e s si o n -fr e e s ur vi v al ( P F S) b a s e d 
o n l o c al i n v e sti g at or a s s e s s m e nt
P F S b a s e d o n l o c al i n v e sti g at or a s s e s s m e nt u si n g R E CI S T v 1. 1 d efi n e d a s 
t h e ti m e fr o m t h e fir st a d mi ni str ati o n of st u d y tr e at m e nt u ntil t h e fir st 
d o c u m e nt e d pr o gr e s si v e di s e a s e ( P D) or d e at h d u e t o a n y c a u s e.
S e c o n d ar y
R ef er t o S e cti o n 1 0. 5. 2 .
T o a s s e s s o v er all r e s p o n s e r at e ( O R R) a n d cli ni c al 
b e n efit r at e ( C B R) b a s e d o n l o c al i n v e sti g at or 
a s s e s s m e nt
O R R d efi n e d a s t h e pr o p orti o n of p ati e nt s wit h b e st o v er all r e s p o n s e of 
c o nfir m e d c o m pl et e r e s p o n s e ( C R) or p arti al r e s p o n s e ( P R) b a s e d o n l o c al 
i n v e sti g at or’ s a s s e s s m e nt a c c or di n g t o R E CI S T v 1. 1
C B R d efi n e d a s t h e pr o p orti o n of p ati e nt s wit h a b e st o v er all r e s p o n s e of C R 
or P R or a n o v er all l e si o n r e s p o n s e of st a bl e di s e a s e ( S D), or N o n - C R/ N o n-
P D l a sti n g ≥ 2 4 w e e k s b a s e d o n l o c al i n v e sti g at or’ s a s s e s s m e nt a c c or di n g t o 
R E CI S T v 1. 1.
T o a s s e s s o v er all s ur vi v al ( O S)
O v er all s ur vi v al ( O S) d efi n e d a s t h e ti m e fr o m t h e fir st a d mi ni str ati o n of st u d y 
tr e at m e nt u ntil d e at h d u e t o a n y c a u s e
T o a s s e s s d ur ati o n of r e s p o n s e ( D O R) i n p ati e nt s wit h 
C R or P R
D O R d efi n e d a s t h e ti m e fr o m t h e d at e of fir st d o c u m e nt e d r e s p o n s e 
( c o nfir m e d C R or P R) t o t h e d at e of t u m or pr o gr e s si o n
T o e v al u at e t h e s af et y a n d t ol er a bilit y
T y p e, fr e q u e n c y a n d s e v erit y of A E s p er N CI -C T C A E v 4. 0 3. T y p e, fr e q u e n c y 
a n d s e v erit y of l a b or at or y t o xi citi e s p er N CI- C T C A E v 4. 0 3
R ef er t o S e cti o n 1 0. 5. 3 .
T o a s s e s s q u alit y of lif e
Q u alit y of lif e a s a s s e s s e d b y t h e E ur o Q o L E Q -5 D -5 L a n d F K SI -D R S h e alt h 
q u e sti o n n air e
R ef er t o S e cti o n 1 0. 5. 5 .

N o v arti s
C o nfi d e nti al
P a g e 2 6
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
4 
St u d y  d e si g n
4. 1 
D e s cri pti o n of st u d y  d e si g n
T his is a m ulti -ce nter, o pe n -la bel, si n gle-ar m p hase II st u d y to deter mi ne t he efficac y, 
t olera bilit y, safety a n d q ualit y  of life of treat me nt wit h paz o pa ni b i n patie nts wit h a d va nce d 
a n d/ or metastatic re nal cell carci n o ma f oll o wi n g pri or treat me nt wit h i m m u ne c hec k p oi nt 
i n hi bit ors.
T hera pe utic li nes of paz o pa ni b – w het her i n t he 2 n d- or 3 r d-li ne setti n g - will be trac ke d at 
scree ni n g usi n g Inte grati ve Res p o nse Tec h n ol o g y  (IR T) . E nr oll me nt of 3 r d li ne patie nt s ma y be 
restricte d t o e ns ure a p pr o xi matel y 4 0 patie nts recei ve paz o pa ni b as 2n d li ne t hera py. 
Patie nts will recei ve sta n dar d d ose of paz o pa ni b dail y  until disease pr o gressi o n, u nacce pta ble 
t o xicit y, deat h, pre g na nc y , start of a ne w a nti -ne o plastic t hera py, disc o nti n uati o n at t he 
discreti o n of t he i n vesti gat or or patie nt, l ost t o f oll o w- u p, e n d of st u d y or st u d y is ter mi nate d 
b y  t he s p o ns or, w hic he ver c o mes first. D ose m o dificati o ns will be all o we d f or patie nts w h o d o 
n ot t olerate t he sta n dar d starti n g d ose of 8 0 0 m g  dail y. Patie nts will be f oll o we d f or s ur vi val 
(e xce pt if c o nse nt is wit h dra w n or patie nt is l ost t o f oll o w-u p).
T he c ut -off da te f or t he pri mar y a nalys is will occ ur after all patie nts ha ve recei ve d a mi ni m u m 
of 6 c yc les of st u dy t reat me nt or ha ve disc o nti n ue d st u d y treat me nt earl y. T he pri mar y a nal ysis 
data will be s u m marize d i n t he pri mar y  cli nical st u d y re p ort ( C S R).
4. 1. 1 
S cr e e ni n g p h a s e ( D a y -2 8 t o D a y  -1 or D a y -7 t o D a y  -1 f or c ert ai n 
pr o c e d ur e s)
Patie nts m ust pr o vi de a si g ne d I nf or me d C o nse nt F or m (IC F) pri or t o a n y st u d y specific 
e val uati o ns 
i ncl u di n g scree ni n g. Eli gi bilit y  
will be 
deter mi ne d 
acc or di n g 
t o t he 
i ncl usi o n/e xcl usi o n criteria as descri be d i n Secti o n 5 . A list of pr oce d ures t o be perf or me d at 
t he ti me of scree ni n g is s u m marize d i n Ta ble 7- 1 . Patie nts m ust meet all eli gi bilit y criteria t o 
e nter t he st u d y.
4. 1. 2 
Tr e at m e nt p h a s e ( C y cl e 1 D a y  1 t o E O T)
Patie nt eli gi bilit y  will be c hec ke d o nce all scree ni n g pr oce d ures are c o m plete d. T he eli gi bilit y 
c hec k will be perf or me d t hr o u g h t he I RT s yste m. Please refer a n d c o m pl y wit h detaile d 
g ui del i nes i n t he I R T ma n ual.
Efficac y  assess me nts will be c o n d ucte d e ver y 8 wee ks d uri n g t he first 1 2 m o nt hs a n d e ver y 1 2 
wee ks t hereafter. Safet y assess me nts a n d P R O q uesti o n naires will be perf or me d acc or di n g t o 
Ta ble 7- 1 . Please refer t o Ta ble 7- 1 a n d Secti o n 7 f or t he c o m plete assess me nt sc he d ule a n d 
details.
4. 1. 3 
S af et y  f oll o w-u p ( E O T + 3 0 d a y s)
After disc o n ti n uati o n of st u d y treat me nt, all patie nts will be f oll o we d f or safety f or 3 0 da ys 
e xce pt i n case of deat h, l oss t o f oll o w u p or wit h dra wal of c o nse nt. F or details, please refer t o 
Secti o n 7. 1. 5. 1 .

N o v arti s
C o nfi d e nti al
P a g e 2 7
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
4. 1. 4 
Effi c a c y  f oll o w-u p ( E O T u ntil p r o gr e s si o n or 1 y e ar fr o m L P F V)
Patie nts w h o disc o nti n ue st u d y treat me nt wit h o ut disease pr o gressi o n b y  RE CI S T 1. 1 bef ore 
L P F V + 1 ye ar will c o nti n ue t o be f oll o we d f or efficac y ever y  8 wee ks u ntil disease pr o gressi o n, 
deat h, pre g na nc y , wit h dra wal of c o nse nt, l oss t o f oll o w- u p, patie nt / g uar dia n decisi o n, st u d y 
ter mi nate d b y  sp o ns or or u ntil L P F V + 1 year, w hic he ver c o mes first. F or f urt her details, please 
refer t o Ta ble 7 - 1 a n d Secti o n 7. 1. 5. 2 .
4. 1. 4. 1 
S ur vi v al f oll o w -u p ( E O T + 2 y e ar s fr o m L P F V)
Patie nts will be f oll o we d f or s ur vi val e ver y 12 wee ks u ntil L P F V + 2 years. Patie nts, w h o 
disc o nti n ue st u d y treat me nt wit h o ut disease pr o gres si o n a n d e nter t he efficac y foll o w -u p, will 
n ot be gi n s ur vi val f oll o w- u p u ntil after t he efficac y foll o w - u p peri o d. F or patie nts w h o 
disc o nti n ue st u d y treat me nt d ue t o disease pr o gressi o n b y  RE CI S T 1. 1 at a n y ti me or f or a n y 
reas o n after L P F V + 1 year, s urvi val f oll o w -u p will be gi n f oll o wi n g e n d of treat me nt. S ur vi val 
i nf or mati o n ca n be o btai ne d by cli nical visits or tele p h o ne calls ( Secti o n 7. 1. 6 ) u ntil deat h, l ost 
t o f oll o w u p or t he patie nt wit h dra ws c o nse nt f or s ur vi val f oll o w-u p. F or f urt her details, please 
refer t o Ta ble 7 - 1 a n d Secti o n 7. 1. 5. 3 .
Fi g ur e 4 - 1 
St u d y  de si g n
4. 2 
Ti mi n g of i nt eri m a n al y s e s a n d d e si g n a d a pt ati o n s
N o f or mal i nteri m a nal ys is is pla n ne d.
4. 3 
D efi niti o n of e n d of st u d y
T he e n d of st u d y will occ ur 2 ye ars after t he last patie nt is e nr olle d, or w he n all patie nt s ha ve 
die d or disc o nti n ue d fr o m t he st u d y an d are n o l o n ger bei n g f oll o we d f or s ur vi val, w hic he ver 
occ urs first. All a vaila ble data fr o m all patie nts will be a nal yz e d a n d s u m marize d i n a fi nal C S R.

N o v arti s
C o nfi d e nti al
P a g e 2 8
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Patie nts w h o are still deri vi n g be nefit fr o m t he treat me n t at t he e n d of t he st u d y, i n t he o pi ni o n 
of t he i n vesti gat or, s h o ul d be s witc he d t o a l ocal prescri pti o n i n case V otrie nt is c o m merciall y 
a vaila ble a n d rei m b urse d i n t hat c o u ntr y. F or c o u ntries i n w hic h V otrie nt is n ot rei m b urse d, n or 
c o m merciall y a vaila ble or f or patie nts w h o ca n n ot aff or d treat me nt, N o vartis will ma ke e ver y 
eff ort t o c o nti n ue t o pr o vi de treat me nt wit h paz o pa ni b t hr o u g h a n ot her pr o gra m per l ocal 
re g ulati o ns.
4. 4 
E arl y st u d y  t er mi n ati o n
T he st u d y ca n be ter mi nate d at a n y ti me f or a n y reas o n b y N o vartis. S h o ul d t his be necessar y, 
t he patie nt s h o ul d be see n as s o o n as p ossi ble a n d t he sa me assess me nts s h o ul d be perf or me d 
as descri be d i n Secti o n 7 f or a patie nt w h o has disc o nti n ue d or bee n wit h dr a w n fr o m treat me nt. 
T he i n vesti gat or m a y  be i nf or me d of a d diti o nal pr oce d ures t o be f oll o we d i n or der t o e ns ure 
t hat a de q uate c o nsi derati o n is gi ve n t o t he pr otecti o n of t he patie nt’s i nterests. T he i n vesti gat or 
will be res p o nsi ble f or i nf or mi n g I R Bs a n d/ o r E Cs of t he early ter mi nati o n of t he trial.
5 
P o p ul ati o n
5. 1 
P ati e nt p o p ul ati o n
T he st u d y will i ncl u de a d ult patie nts wit h a d va nce d a n d/ or metastatic R C C i m me diatel y after 
pre vi o us t hera p y wit h i m m u ne c hec k p oi nt i n hi bit or, eit her as si n gle a ge nt or i n c o m bi natio n 
wit h ot her t hera pies ( T KIs or ot her i m m u ne c hec k p oi nt i n hi bit ors) i n t he first or sec o n d li ne. 
Eli gi ble patie nts ma y  ha ve als o ha d pri or si n gle a ge nt T KI  treat me nt i n 1 st li ne setti n g; h o we ver, 
t he last t hera p y bef ore e nr oll me nt i n t he st u d y, m ust be a c hec k p oi nt i n hi bit or (si n gle a ge nt or 
i n c o m bi nati o n) eit her i n 1st or 2 n d li ne setti n g.
A t otal of a p pr o xi matel y 1 0 0 patie nts are pla n ne d t o e nr oll i n t his st u d y, wit h a p pr o xi matel y 4 0 
of t h ose patie nts recei vi n g paz o pa ni b as 2 n d-li ne t hera py. Patie nts e n r olle d i n t his st u d y are n ot 
per mitte d t o partici pate i n a n y  ot her i n vesti gati o nal dr u g or de vice st u dies.
T he i n vesti gat or or desi g nee m ust e ns ure t hat o nl y patie nts w h o meet all t he f oll o wi n g i ncl usi o n 
a n d n o ne of t he e xcl usi o n criteria are offere d treat me nt i n t he st u d y .
5. 2 
I n cl u si o n crit eri a
Patie nts eli gi ble f or i ncl usi o n i n t his st u d y  ha ve t o meet all of t he f oll o wi n g criteria:
1.
Writte n i nf or me d c o nse nt m ust be o btai ne d pri or t o a n y  scree ni n g pr oce d ures.
2.
Patie nt is ≥ 1 8 y ears ol d at t he ti me of i nf or me d c o nse nt.
3.
Patie nt has hist ol o gicall y c o nfir me d l ocall y  rec urre nt or metastatic pre d o mi na ntl y clear 
cell re nal cell carci n o ma.
4.
Patie nt m ust ha ve meas ura ble disease base d o n R E CI S T 1. 1 criteria
5.
Patie nt m ust ha ve recei ve d pri or s ys te mic t hera p y wit h a n i m m u ne c hec k p oi nt i n hi bit or 
( m o n ot hera py or c o m bi nati o n) as 1 st or 2 n d li ne R C C treat me nt. N ote: patie nts wit h pri or 
m T O R i n hi bit or or T KI  treat me nt as m o n ot hera p y or i n c o m bi nati o n wit h i m m u ne 
c heck p oi nt i n hi bit or are all o we d; h o we ver, treat me nt wit h i m m u ne c hec k p oi nt i n hi bit or 
( m o n ot hera py or i n c o m bi nati o n) m ust ha ve bee n t he last treat me nt pri or t o st u d y e ntr y.

N o v arti s
C o nfi d e nti al
P a g e 2 9
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
6.
Last d ose of i m m u ne c hec k p oi nt i n hi bit or t hera p y m ust ha ve bee n recei ve d 4 or m ore 
wee ks bef ore start of st u d y  treat me nt
7.
F or patie nts recei vi n g treat me nt wit h bis p h os p h o nates, patie nt m ust be o n a sta ble, well-
t olerate d d ose f or at least 4 wee ks pri or t o start of st u d y treat me nt
8.
Patie nt m ust meet t he f oll o wi n g la b orat or y  val ues at t he screeni n g visit:

A bs ol ute Ne utr o p hil C o u nt ≥ 1. 5 x 1 0 9/ L

Platelets ≥ 1 0 0 x 1 0 9/ L

He m o gl o bi n ≥ 9 g/ d L

P otassi u m, s o di u m, calci u m a n d ma g nesi u m wit hi n n or mal li mits of t he ce ntral 
la b orat or y

Ser u m creati ni ne < 1. 5 m g/ d L

O R if > 1. 5 m g/ d L ; calc ulate d creati ni ne cleara nce ≥4 0 m L / mi n or e G F R > 3 0 
m L / mi n/ 1. 7 2 m2

Uri ne Pr otei n t o Creati ni ne Rati o ( U P C) < 1

O R if U P C ≥ 1, t he n 2 4- h o ur uri ne pr otei n < 1 g
N ote: Use of uri ne di pstic k f or re n al f u ncti o n assess me nt is n ot acce pt a ble.

T otal bilir u bi n ≤1 . 5 x U L N

As partate tra nsa mi nase ( A S T) < 2. 5 x U L N

Ala ni ne tra nsa mi nase ( A L T) < 2. 5 x U L N
9.
Patie nt m ust ha ve a Kar n ofs k y  perf or ma nce stat us ≥7 0 %.
1 0. Patie nt is a ble t o s wall o w a n d retai n oral me dicati o n i n t he f or m of ta blets or ca ps ules.
1 1. N or mal E C G defi ne d as t he f oll o wi n g:

Resti n g heart rate 5 0 -9 0 b p m

Q Tc F at scree ni n g < 4 5 0 ms ( male patie nts), < 4 6 0 ms (fe male patie nts)
5. 3 
E x cl u si o n crit eri a
Patie nts eli gi ble f or t his st u d y  m ust n ot meet a n y of t he f oll o wi n g criteria:
1.
Re nal cell carci n o ma wit h o ut a n y  clear (c o n ve nti o nal) cell c o m p o ne nt
2.
Hist or y  or cli nical e vi de nce of ce ntral ner v o us sys te m ( C N S) metastases. 

N ote: Patie n ts w h o ha ve pre vi o usl y-treate d C N S metastases (s ur ger y ± ra di ot hera py, 
ra di os ur ger y, or ga m ma k nife) a n d meet all 3 of t he f oll o wi n g criteria are eli gi ble:
a.
A s ym pt o matic a n d,
b.
Ha ve ha d n o e vi de nce of acti ve C N S metastases f or ≥6 m o nt hs pri or t o 
e nr oll me nt a n d,
c.
Ha ve n o re q uire me nt f or ster oi ds or e nz y me -i n d uci n g a ntic o n v ulsa nts ( EI A C)
3.
Pri or treat me nt wit h paz o pa ni b 
4.
Pri or treat me nt wit h be vaciz u ma b t hat was n ot gi ve n i n c o m bi nati o n wit h i m m u ne 
c hec k p oi nt i n hi bit or t hera p y.
5.
Pri or treat me nt wit h m ore t ha n 2 li nes of t hera p y  (c o m bi nati o n treat me nts are c o nsi dere d 1 
li ne of t hera py)

N o v arti s
C o nfi d e nti al
P a g e 3 0
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
6.
Patie nt has n ot rec o vere d fr o m t o xicit y  fr o m pri or i m m u ne c heck p oi nt i n hi bit or t hera p y . 
Rec o ver y  is defi ne d as ≤ N CI -C T C A E Gra de 1, e xce pt f or L F T le vels w hic h m ust be 
< Gra de 1.
7.
Disease rec urre nce less t ha n 6 m o nt hs fr o m t he last d ose of pri or ne oa dj u va nt or a dj u va nt 
t hera py (i ncl u di n g V E G F -R T KI)
8.
Ra diati o n t hera p y w it hi n 2 wee ks of starti n g st u dy treat me nt; h o we ver, pri or palliati ve 
ra di ot hera py t o metastatic lesi o n(s) is per mitte d pr o vi de d t here is at least o ne meas ura ble 
lesi o n t hat has n ot bee n irra diate d.
9.
C o nc urre nt t hera p y gi ve n t o treat ca ncer i ncl u di n g treat me nt wit h a n i n vesti gati o nal a ge nt 
or c o nc urre nt partici pati o n i n a n ot her cli nical trial i n v ol vi n g a nti -ca ncer i n vesti gati o nal 
dr u g.
1 0. Patie nts recei vi n g pr o hi bite d c o nc o mita nt me dicati o ns t hat ca n n ot be disc o nti n ue d or 
re place d by safe alter nati ve me dicati o n at least 5 half-li ves of t he c o nc o mita nt me dicati o n 
or 7 da y s, w hic he ver is l o n ger, pri or t o t he start of paz o pa ni b treat me nt (refer t o Secti o n 
6. 3. 3 f or pr o hi bite d c o nc o mita nt me dicati o ns w hic h are i n d ucers a n d/ or str o n g i n hi bit ors 
of C Y P 3 A 4 is oe nz y me).
1 1. A d mi nistrati o n of a n y  i n vesti gati o nal dr u g wit hi n 4 wee ks pri or t o t he first d ose of st u d y 
treat me nt
1 2. Gra de 3 he m orr ha ge wit hi n 4 wee ks of starti n g st u d y treat me nt.
1 3. U nc o ntr olle d h y perte nsi o n ( defi ne d as s ys t olic bl o o d press ure ( S B P) of ≥1 4 0 m m H g or 
diast olic bl o o d press ure ( D B P) of ≥9 0 m m H g)
1 4. Car diac or car diac re p olarizati o n a b n or malit y , i ncl u di n g a ny of t he f oll o wi n g:

Hist or y  of my o car dial i nfarcti o n ( MI), a n gi na pect oris, c or o nar y  arter y b ypass graft 
( C AB G) wit hi n 6 m o nt hs pri or t o starti n g st u d y  treat me nt

Cli nicall y  si g nifica nt car diac arr h yt h mias (e. g., ve ntric ular tac h yc ar dia), c o m plete left 
b u n dle bra nc h bl oc k, hi g h -gra de A V bl oc k (e. g ,. bifascic ular bl oc k, M o bitz t ype II 
a n d t hir d de gree A V bl oc k)

L o n g Q T s y n dr o me, fa mil y  hist or y of i di o pat hic s u d de n deat h or c o n ge nital l o n g Q T 
s yn dr o me, or a n y of t he f oll o wi n g:

Ris k fact ors f or T orsa des de P oi nte ( T d P) i ncl u di n g u nc orrecte d h y p o kale mia or 
h y p o ma g nese mia, hist or y  of car diac fail ure, or hist or y of cli nicall y 
si g nifica nt/sy m pt o matic bra d y car dia

I na bilit y t o deter mi ne t he Q Tc F i nter val

Hist or y  of Class III or I V c o n gesti ve heart fail ure, as defi ne d by t he Ne w Y or k 
Heart Ass ociati o n Classificati o n of C o n gesti ve Heart Fail ure

C o nc o mita nt me dicati o n wit h a “ K n o w n ris k of T orsa des de P oi ntes” per 
w w w. qt dr u gs. or g t hat ca n n ot be disc o nti n ue d or re place d b y s afe alter nati ve 
me dicati o n wit hi n 7 da y s pri or t o starti n g st u d y dr u g
1 5. Cli nicall y  si g nifica nt gastr oi ntesti nal a b n or malities t hat ma y i ncrease t he ris k f or 
gastr oi ntesti nal blee di n g i ncl u di n g, b ut n ot li mite d t o:

Acti ve pe ptic ulcer disease

K n o w n i ntral u mi nal metastatic lesi o n/s wit h ris k of blee di n g

N o v arti s
C o nfi d e nti al
P a g e 3 1
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0

I nfla m mat or y b o wel disease (e. g., ulcerati ve c olitis, Cr o h n’s disease), or ot her 
gastr oi ntesti nal c o n diti o ns wit h i ncrease d ris k of perf orati o n

Hist or y  of a b d o mi nal fist ula, gastr oi ntesti nal perf orati o n, or i ntra-a b d o mi nal a bscess 
wit hi n 2 8 da ys pri or t o be gi n ni n g st u d y  treat me nt
1 6. Cli nicall y  si g nifica nt gastr oi ntesti nal a b n or malities t hat ma y affect a bs or pti o n of
i n vesti gati o nal pr o d uct i ncl u di n g, b ut n ot li mite d t o:

Mala bs or pti o n s y n dr o me

Maj or resecti o n of t he st o mac h or s mall b o wel

Acti ve diarr hea of a n y gra de
1 7. Hist or y  of cere br o vasc ular acci de nt i ncl u de tra nsie nt isc he mic attac k, p ul m o nar y 
e m b olis m or u ntreate d dee p ve n o us t hr o m b osis ( D V T) wit hi n t he past 6 m o nt hs. N ote: 
S u bjects wit h rece nt D V T w h o ha ve bee n treate d wit h t hera pe utic a nti -c oa g ulati n g a ge nts 
f or at least 6 wee ks are eli gi ble.
1 8. Hist or y  of h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n
1 9. Hist or y  of c hr onic acti ve he patitis i ncl u di n g s u bjects w h o are carriers of he patitis B vir us 
( H B V) or he patitis C vir us ( H C V)
2 0. Maj or s ur ger y  wit hi n 4 wee ks of starti n g st u d y treat me nt
2 1. Ot her se vere ac ute or c hr o nic me dical or ps yc hi atric c o n diti o n or la b orat or y a b n or malit y
t hat ma y i ncrease t he ris k ass ociate d wit h st u d y partici pati o n or st u d y dr u g a d mi nistrati o n, 
or ma y  i nterfere wit h t he i nter pretati o n of st u d y res ults, a n d i n t he j u d g me nt of t he 
i n vesti gat or w o ul d ma ke t he s u bject i na p pr o priate f or e ntr y i nt o t he st u d y.
2 2. Pre g na nt or n ursi n g (lactati n g) w o me n
2 3. 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 ble of 
bec o mi n g pre g na nt, are e xcl u de d u nless t he y are usi n g hi g hl y effecti ve met h o ds of 
c o ntrace pti o n d uri n g d osi n g a n d f or 2 wee ks after st o p pi n g me dicati o n. 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., cale n dar, o v ulati o n, s ym 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 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 y sterect o my), t otal h ys terect o my, or t u bal li gati o n at least si x wee ks bef ore ta ki n g 
st u d y treat me nt. I n case of o o p h orect o my 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

Male sterilizati o n (at least 6 m o nt hs pri or t o scree ni n g). 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, 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 ys te 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 ne 
va gi nal ri n g or tra ns der 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 dy treat me nt.

N o v arti s
C o nfi d e nti al
P a g e 3 2
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
W o me n are c o nsi dere d p ost -me n o pa usal a n d n ot of c hil d beari n g p ote ntia l 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 (i.e. , a ge a p pr o priate, hist or y of vas o m ot or s ym pt o ms) or ha ve ha d s ur gical 
bilateral o o p h orect o m y  ( wit h or wit h o ut h ysterect o m y), t otal hys terect o my, or t u bal 
li gati o n at least si x wee ks a g o. I n t he case of o o p h orect o my 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 n ot of c hil d beari n g p ote ntial.
2 4. Se x uall y  acti ve males u nless t he y 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 
d uri n g treat me nt a n d f or 2 wee ks 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. A c o n d o m is re q uire d t o be use d als o b y vasect o mize d me n as well as d uri n g 
i nterc o urse wit h a male part ner i n or der t o pre ve nt deli ver y of t he dr u g via se me n.
2 5. Patie nts wit h k n o w n i m me diate or dela y e d h yperse nsiti vit y  reacti o n or i di os yncras y t o 
dr u gs c he micall y relate d t o paz o pa ni b.
6 
Tr e at m e nt
6. 1 
St u d y tr e at m e nt
Paz o pa ni b m o n o h y dr oc hl ori de salt is s up plie d as a q ue o us fil m-c oate d ta blets c o ntai ni n g 2 0 0 
m g or 4 0 0 m g of t he free base. Refer t o t he paz o pa ni b I n vesti gat or ’s Br oc h ure f or i nf or mati o n 
re gar di n g t he p hys ical a n d c he mical pr o perties of paz o pa ni b a n d a list of e xci pie nts.
All d osa ges prescri be d a n d dis pe nse d t o t he patie nt a n d all d ose c ha n ges d uri n g t he st u d y m ust 
be rec or de d.
6. 1. 1 
D o si n g r e gi m e n
T a bl e 6- 1 
D o s e a n d tr e at m e nt s c h e d ul e
St u d y  tr e at m e nt s
P h ar m a c e uti c al f or m a n d 
r o ut e of a d mi ni str ati o n 
D o s e
Fr e q u e n c y  a n d/ or 
R e gi m e n
P a z o p a ni b
T a bl et s f or or al u s e
8 0 0 m g Q D
D ail y
Paz o pa ni b will be a d mi nistere d as a flat-fi xe d d ose a n d n ot b y  bo d y  wei g ht or b o d y  surface 
area. O ne c ycle is e q ui vale nt t o 2 8 da ys or 4 wee ks.
Patie nts m ust be i nstr ucte d t o ret ur n u n use d st u d y dr u gs t o t he site at disc o nti n uati o n or 
c o m pleti o n of treat me nt. T he site pers o n nel m ust e ns ure t hat t he a p pr o priate d ose of eac h st u d y 
dr u g is a d mi nistere d a n d t hat t he dr u g acc o u nta bilit y  is perf or me d.
P az o pa ni b m ust be ta ke n as f oll o ws:

Patie nts s h o ul d ta ke paz o pa 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.

Paz o pa ni b m ust be ta ke n wit h o ut f o o d at least 1 h o ur bef ore or 2 h o urs after meals.

Patie nts s h o ul d be i nstr ucte d t o s wall o w t he paz o pa ni b ta blets w h ole a n d n ot t o c he w or
cr us h t he m.

If v o miti n g occ urs d uri n g t he c o urse of treat me nt, patie nts s h o ul d n ot ta ke paz o pa ni b 
a gai n bef ore t he ne xt sc he d ule d d ose.

N o v arti s
C o nfi d e nti al
P a g e 3 3
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0

If a d ose is misse d, t he s u bject s h o ul d ta ke t he d ose as s o o n as p ossi ble, but o nl y  if t here 
are 1 2 or m ore h o urs re mai ni n g bef ore t he ne xt d ose is d ue. If t he ne xt d ose is d ue i n less 
t ha n 1 2 h o urs, t he s u bject s h o ul d s ki p t he misse d d ose a n d ta ke t he ne xt d ose as 
sc he d ule d.
6. 1. 2 
Tr e at m e nt d ur ati o n
Patie nts ma y  c o nti n ue o n st u d y treatme nt u ntil 2 years after t he last patie nt is e nr olle d. Patie nts 
ma y  be disc o nti n ue d fr o m treat me nt wit h st u d y dr u g earlier d ue t o u nacce pta ble t o xicit y, 
disease pr o gressi o n a n d/ or treat me nt disc o nti n uati o n at t he discreti o n of t he i n vesti gat or or t he 
patie nt. F or patie nts, w h o i n t he o pi ni o n of t he i n vesti gat or are still deri vi n g cli nical be nefit 
fr o m paz o pa ni b, e ver y eff ort will be ma de t o c o nti n ue pr o visi o n of st u d y treat me nt t hr o u g h 
a n ot her pr o gra m.
6. 1. 2. 1 
D o s e e s c al ati o n g ui d eli n e s
N ot a p plica ble
6. 1. 3 
St arti n g d o s e r ati o n al e
V otrie nt ( paz o pa ni b) is a p pr o ve d f or t he treat me nt of patie nts wit h a d va nce d re nal cell 
carci n o ma ( R C C). T he rec o m me n de d a n d a p pr o ve d starti n g d ose is 8 0 0 m g  orall y once dail y 
w hic h is t he starti n g d ose t hat will be use d i n t his st u d y .
6. 1. 4 
Pr o vi si o n al d o s e l e v el s
N ot a p plica ble
6. 2 
D o s e m o difi c ati o n s
6. 2. 1 
D o s e m o difi c ati o n a n d d o s e d el a y
F or patie nts w h o d o n ot t olerate t he pr ot oc ol -s pecifie d d osi n g sc he d ule, d ose i nterr u pti o ns 
a n d/ or re d ucti o ns are eit her rec o m me n de d or ma n date d i n or der t o all o w pa tie nts t o c o nti n ue 
t he st u d y treat me nt.
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  dose 
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 uat i o n is 
ma n dat or y  f or s pecific e ve nts i n dicate d as s uc h i n Ta ble 6 - 2 or liste d i n Secti o n 6. 2. 1. 1 .
T hese d ose c ha n ges m ust be rec or de d o n t he D osa ge A d mi nistrati o n Rec or d C R F.
Eac h patie nt is o nl y  all o we d 2 d ose re d ucti o ns. I n a d diti o n, a patie nt m ust disc o nti n ue treat me nt 
wit h paz o pa ni b if, after treat me nt is res u me d at a l o wer d ose, t he t o xicit y  rec urs wit h t he sa me 
or w orse se verit y.
If a patie nt re q uires a d ose i nterr u pti o n of > 2 1 d a y s fr o m t he i nte n de d da y  of t he ne xt sc he d ule d 
d ose, 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. Patie nts w h o disc o nti n ue 
st u d y treat me nt f or a st u d y relate d a d verse e ve nt or a n a b n or mal la b orat or y val ue m ust be 
f oll o we d as descri be d i n Secti o n 8. 1 .

N o v arti s
C o nfi d e nti al
P a g e 3 4
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
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 p a z o p a ni b 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 v e sti g ati o n s ( H e m at ol o gi c)
N e utr o p e ni a ( A N C)
Gr a d e 1 ( A N C < L L N - 1 5 0 0/ m m 3)
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 o nit or a s cli ni c all y i n di c at e d
Gr a d e 2 ( A N C < 1 5 0 0 - 1 0 0 0/ m m 3)
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 o nit or a s cli ni c all y i n di c at e d
Gr a d e 3 ( A N C < 1 0 0 0 - 5 0 0/ m m 3)
R e c o m m e n d ati o n:
St e p 1: O mit d o s e u ntil r e s ol v e d t o ≤ Gr a d e 2
St e p 2: R e st art p a z o p a ni b at a d o s e -r e d u c e d b y 2 0 0 m g a n d m o nit or a s cli ni c all y i n di c at e d.
If n o r e c o v er y t o ≤ Gr a d e 2 or r e c urr e nt Gr a d e 3 n e utr o p e ni a, di s c o nti n u e p a z o p a ni b a n d f oll o w -u p p er 
pr ot o c ol
Gr a d e 4 ( A N C < 5 0 0/ m m 3)
M a n d at or y:
St e p 1: O mit d o s e u ntil r e s ol v e d t o ≤ Gr a d e 2
St e p 2: R e st art p a z o p a ni b at a d o s e-r e d u c e d b y 2 0 0 m g a n d m o nit or a s cli ni c all y i n di c at e d.
If n o r e c o v er y t o ≤ Gr a d e 2 or r e c urr e nt Gr a d e 4 n e utr o p e ni a, di s c o nti n u e p a z o p a ni b a n d f oll o w -u p p er 
pr ot o c ol
F e bril e n e utr o p e ni a ( A N C < 1 0 0 0/ m m 3 , f e v er ≥ 3 8. 5° C) 
M a n d at or y: O mit d o s e u ntil r e s ol v e d, t h e n r e st art p a z o p a ni b at a d o s e
r e d u c e d b y 2 0 0 m g
T hr o m b o c y t o p e ni a
Gr a d e 1 ( P L T < L L N - 7 5, 0 0 0/ m m 3)
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 o nit or a s cli ni c all y i n di c at e d
Gr a d e 2 ( P L T < 7 5, 0 0 0 - 5 0, 0 0 0/ m m 3)
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 o nit or a s cli ni c all y i n di c at e d
Gr a d e 3 ( P L T < 5 0, 0 0 0 - 2 5, 0 0 0/ m m 3)
R e c o m m e n d ati o n:
St e p 1: O mit d o s e u ntil r e s ol v e d t o ≤ Gr a d e 2
St e p 2: R e st art st u d y dr u g at a d o s e-r e d u c e d b y 2 0 0 m g a n d m o nit or a s cli ni c all y i n di c at e d.
If n o r e c o v er y t o ≤ Gr a d e 2 or r e c urr e nt Gr a d e 3 t hr o m b o c yt o p e ni a, di s c o nti n u e p a z o p a ni b a n d f oll o w -u p p er 
pr ot o c ol
Gr a d e 4 ( P L T < 2 5, 0 0 0/ m m 3)
M a n d at or y:
St e p 1: O mit d o s e u ntil r e s ol v e d t o ≤ Gr a d e 2
St e p 2: R e st art p a z o p a ni b at a d o s e-r e d u c e d b y 2 0 0 m g a n d m o nit or a s cli ni c all y i n di c at e d.
If n o r e c o v er y t o ≤ Gr a d e 2 or r e c urr e nt Gr a d e 3 t hr o m b o c yt o p e ni a, di s c o nti n u e p a z o p a ni b a n d f oll o w -u p p er 
pr ot o c ol
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

N o v arti s
C o nfi d e nti al
P a g e 3 5
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
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: O mit 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
Gr a d e 3 ( > 3. 0 - 6. 0 x U L N)
R e c o m m e n d ati o n: O mit d o s e a n d p er m a n e ntl y di s c o nti n u e p ati e nt fr o m p a z o p a ni b
Gr a d e 4 ( > 6. 0 x U L N)
M a n d at or y: O mit d o s e a n d p er m a n e ntl y di s c o nti n u e p ati e nt fr o m p a z o p a ni b
Pr ot ei n uri a
U P C < 3
R e c o m m e n d ati o n: C o nti n u e st u d y dr u g at t h e c urr e nt d o s e; m o nit or a s cli ni c all y i n di c at e d
U P C ≥3 or 2 4 -h uri n e pr ot ei n 3 g
M a n d at or y:
St e p 1. I nt err u pt p a z o p a ni b.
St e p 2. W e e kl y m o nit ori n g wit h U P C or 2 4- hr uri n e t ot al pr ot ei n u ntil U P C i s < 3 or 2 4 - hr uri n e t ot al pr ot ei n i s 
< 3 g, t h e n r e st art p a z o p a ni b wit h d o s e -r e d u c e d b y 2 0 0 m g.
If U P C ≥3 or 2 4- hr uri n e pr ot ei n ≥ 3 g r e c ur s, r e p e at t h e a b o v e st e p s. P a z o p a ni b s h o ul d b e p er m a n e ntl y 
di s c o nti n u e d if U P C ≥3 or 2 4 hr uri n e pr ot ei n ≥ 3 g p er si st s w h e n tr e ati n g at 4 0 0 m g d o s e l e v el.
I n v e sti g ati o n s ( H e p ati c)
( A) A L T of ≤ 3. 0 x U L N
R e c o m m e n d ati o n: C o nti n u e p a z o p a ni b at c urr e nt d o s e.
( B) A L T > 3. 0 x U L N t o ≤5. 0 x U L N wit h o ut bilir u bi n el e v ati o n 
( d efi n e d a s t ot al bilir u bi nb ≤2. 0 x U L N, or dir e ct bilir u bi n 
≤3 5 %) a n d wit h o ut h y p er s e n siti vit y s y m pt o m s ( e. g., f e v er, 
r a s h)
M a n d at or y:
1. 
I nt err u pt p a z o p a ni b.
2. 
M o nit or s u bj e ct cl o s el y f or cli ni c al si g n s a n d s y m pt o m s f or li v er f ail ur e. P erf or m f ull li v er p a n el a at l e a st 
w e e kl y u ntil A L T i s r e d u c e d t o ≤ Gr a d e 1 ( 3. 0 x U L N).
 
S u bj e ct s h o ul d p er m a n e ntl y di s c o nti n u e p a z o p a ni b if A L T d o e s n ot r e c o v er t o ≤3. 0 x U L N wit hi n 6 
w e e k s
1. 
If A L T r e c o v er s t o ≤3. 0 x U L N wit hi n 6 w e e k s, s u bj e ct i s eli gi bl e t o b e r e -c h all e n g e d at 4 0 0 m g d ail y.
 
It i s d e sir a bl e f or t h e A L T l e v el t o h a v e r e c o v er e d t o ≤U L N or pl at e a u e d b ef or e r e -c h all e n g e t o 
a v oi d di s c o nti n u ati o n d u e t o r e c urr e n c e of A L T > 3. 0 x U L N. Di s c u s s wit h st u d y p h y si ci a n a s n e e d e d.
2. 
F oll o wi n g r e -c h all e n g e, m o nit or s u bj e ct cl o s el y f or cli ni c al si g n s a n d s y m pt o m s. P erf or m f ull li v er p a n el 
w e e kl y f or 4 w e e k s a n d, if st a bl e, e v er y ot h er w e e k f or 4 w e e k s.
R e c urr e n c e St o p pi n g Crit eri a:
If A L T el e v ati o n r e c ur s t o > 3. 0 x U L N, p er m a n e ntl y di s c o nti n u e p a z o p a ni b a n d m o nit or s u bj e ct cl o s el y f or 
cli ni c al si g n s a n d s y m pt o m s; p erf or m f ull li v er p a n el L F T s 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 A L T i s r e d u c e d t o ≤U L N or st a bili z e d.
If r e c urr e nt A L T el e v ati o n m e et s t h e crit eri a f or S c e n ari o D or S c e n ari o E, r e p ort t h e e v e nt t o N o v arti s a s a n 
S A E wit hi n 2 4 h o ur s of l e ar ni n g of it s o c c urr e n c e a n d f oll o w t h e i n str u cti o n u n d er S c e n ari o ( D) or S c e n ari o 
( E) of t hi s t a bl e a s i n di c at e d b el o w a c c or di n gl y

N o v arti s
C o nfi d e nti al
P a g e 3 6
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
( C) A L T > 5. 0 x U L N t o ≤8. 0 x U L N wit h o ut bilir u bi n 
el e v ati o n ( d efi n e d a s t ot al bilir u bi n b ≤2. 0 x U L N, or dir e ct 
bilir u bi n ≤3 5 % a n d wit h o ut h y p er s e n siti vit y s y m pt o m s 
( e. g., f e v er, r a s h)
M a n d at or y:
1. 
I nt err u pt p a z o p a ni b.
2. 
M o nit or s u bj e ct cl o s el y f or cli ni c al si g n s a n d s y m pt o m s of li v er f ail ur e. P erf or m f ull li v er p a n el 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 A L T i s r e d u c e d t o ≤3. 0 x U L N. Li v er i m a gi n g i s o pti o n al a n d 
d e p e n d e nt u p o n cli ni c al s c e n ari o.
 
S u bj e ct s h o ul d p er m a n e ntl y di s c o nti n u e p a z o p a ni b if A L T d o e s n ot r e c o v er t o ≤3. 0 x U L N wit hi n 2 
w e e k s
3. 
If A L T r e c o v er s t o ≤3. 0 x U L N wit hi n 2 w e e k s, s u bj e ct i s eli gi bl e t o b e r e- c h all e n g e d at 4 0 0 m g d ail y
 
It i s d e sir a bl e f or t h e A L T l e v el t o h a v e r e c o v er e d t o ≤U L N or pl a t e a u e d b ef or e r e-c h all e n g e t o 
a v oi d di s c o nti n u ati o n d u e t o r e c urr e n c e of A L T > 3. 0 x U L N. Di s c u s s wit h st u d y p h y si ci a n a s n e e d e d.
4. 
F oll o wi n g r e -c h all e n g e, m o nit or s u bj e ct cl o s el y f or cli ni c al si g n s a n d s y m pt o m s; p erf or m f ull li v er p a n el 
w e e kl y f or 4 w e e k s a n d, if st a bl e, e v er y ot h er w e e k f or 4 w e e k s.
R e c urr e n c e St o p pi n g Crit eri a:
If A L T el e v ati o n r e c ur s t o > 3. 0 x U L N, p er m a n e ntl y di s c o nti n u e p a z o p a ni b a n d m o nit or s u bj e ct cl o s el y f or 
cli ni c al si g n s a n d s y m pt o m s; p erf or m f ull li v er p a n el w e e kl y or m or e fr e q u e ntl y i f cli ni c all y i n di c at e d u ntil A L T 
i s r e d u c e d t o ≤U L N or st a bili z e d.
If r e c urr e nt A L T el e v ati o n m e et s t h e crit eri a f or S c e n ari o D or S c e n ari o E, r e p ort t h e e v e nt t o N o v arti s a s a n 
S A E wit hi n 2 4 h o ur s of l e ar ni n g of it s o c c urr e n c e a n d f oll o w t h e i n str u cti o n u n d er S c e n ari o ( D) or S c e n ari o 
( E) of t hi s t a bl e a s i n di c at e d b el o w a c c or di n gl y.
( D) A L T > 8. 0 x U L N wit h o ut bilir u bi n el e v ati o n ( d efi n e d a s 
t ot al bilir u bi nb ≤2. 0 x U L N, or dir e ct bilir u bi n ≤3 5 %) a n d 
wit h o ut h y p er s e n siti vit y s y m pt o m s ( e. g., f e v er, r a s h)
M a n d at or y:
1. 
P er m a n e ntl y di s c o nti n u e p a z o p a ni b.
2. 
R e p ort t h e e v e nt t o N o v arti s a s a n S A E wit hi n 2 4 h o ur s of l e ar ni n g of it s o c c urr e n c e a n d c o m pl et e t h e 
e C R F li v er e v e nt f or m s.
3. 
M a k e e v er y r e a s o n a bl e att e m pt t o h a v e s u bj e ct s r et ur n t o t h e cli ni c wit hi n 2 4 t o 7 2 h o ur s f or r e p e at li v er 
c h e mi stri e s. M o nit or s u bj e ct cl o s el y f or cli ni c al si g n s a n d s y m pt o m s; p erf or m f ull li v er p a n el 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 A L T i s r e c o v er e d t o ≤U L N or st a bili z e d.
4. 
Li v er i m a gi n g i s o pti o n al a n d d e p e n d e nt u p o n cli ni c al s c e n ari o. P erf or m li v er i m a gi n g if t h e s u bj e ct 
e x hi bit s a p o s si bl e bili ar y e v e nt ( e. g. , a b d o mi n al p ai n l a sti n g f or h o ur s, f e v er, j a u n di c e, p al p a bl e ri g ht 
u p p er q u a dr a nt m a s s).

N o v arti s
C o nfi d e nti al
P a g e 3 7
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
( E) A L T > 3. 0 x U L N wit h c o n c o mit a nt el e v ati o n i n bilir u bi n b
( d efi n e d a s t ot al bilir u bi n 2. 0 x U L N; wit h dir e ct 
bilir u bi n > 3 5 %) or wit h h y p er s e n siti vit y s y m pt o m s ( e. g., 
f e v er, r a s h).
N ot e: if A L T > 3. 0 x U L N wit h c o n c o mit a nt t ot al 
bilir u bi n > 2. 0 x U L N, b ut bilir u bi n fr a cti o n ati o n i s n ot 
a v ail a bl e, t h e li v er e v e nt s h o ul d al s o b e c o n si d er e d a s 
c at e g or y E.
M a n d at or y:
1. 
P er m a n e ntl y di s c o nti n u e p a z o p a ni b.
2. 
R e p ort t h e e v e nt t o N o v arti s a s a n S A E wit hi n 2 4 h o ur s of l e ar ni n g of it s o c c urr e n c e a n d c o m pl et e t h e 
e C R F li v er e v e nt f or m s.
3. 
M a k e e v er y r e a s o n a bl e att e m pt t o h a v e s u bj e ct s r et ur n t o t h e cli ni c wit hi n 2 4 t o 7 2 h o ur s f or r e p e at li v er 
c h e mi stri e s a n d p erf or m t h e f oll o wi n g a d diti o n al e v al u ati o n s a n d pr o c e d ur e s:
 
C o n s ult a g a str o e nt er ol o gi st / h e p at ol o gi st.
 
C oll e ct bl o o d s a m pl e s f or t h e f oll o wi n g l a b or at or y a s s e s s m e nt s f or e x cl u si o n of h y p er s e n siti vit y a n d 
ot h er c o ntri b uti n g f a ct or s. T h e bl o o d s a m pl e s s h o ul d b e s u b mitt e d t o t h e l o c al l a b or at or y f or 
a n al y s i sc:
 
E o si n o p hil c o u nt
 
Vir al s er ol o g y f or h e p atiti s A, B, C a n d E, c yt o m e g al o vir u s, E p st ei n -B arr vir u s, h er p e s si m pl e x 
vir u s (I g M a nti b o d y, h et er o p hil e a nti b o d y, or m o n o s p ot t e sti n g)
 
A nti -n u cl e ar a nti b o d y, a nti - s m o ot h m u s cl e a nti b o d y, T y p e 1 a nti-li v er- ki d n e y mi cr o s o m al 
a nti b o di e s.
 
S er u m cr e ati ni n e p h o s p h o ki n a s e
 
Li v er i m a gi n g i s o pti o n al a n d d e p e n d e nt u p o n cli ni c al s c e n ari o
 
M e di c al r e vi e w n e e d s t o e n s ur e t h at li v er t e st el e v ati o n s ar e n ot c a u s e d b y 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 wit h R v al u e < 2 i n p ati e nt s wit h o ut b o n e m et a st a si s, or el e v ati o n of A L P 
li v er fr a cti o n i n p ati e nt s wit h b o n e m et a st a si s.
4. 
M o nit or s u bj e ct cl o s el y f or cli ni c al si g n s a n d s y m pt o m s; r e c or d t h e a p p e ar a n c e or w or s e ni n g of cli ni c al 
s y m pt o m s of h e p atiti s, or h y p er s e n siti vit y, s u c h a s f ati g u e, n a u s e a, v o miti n g, ri g ht u p p er q u a dr a nt p ai n 
or t e n d er n e s s, f e v er r a s h or e o si n o p hili a a s r el e v a nt o n t h e S A E r e p ort f or m.
P erf or m f ull p a n el L F T s a 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 A L T i s r e c o v er e d t o ≤U L N or 
st a bili z e d.
( F) F or i s ol at e d t ot al bilir u bi n el e v ati o n c wit h o ut c o n c urr e nt 
A L T i n cr e a s e s ( d efi n e d a s A L T < 3 X U L N) a n d wit h n o 
ot h er si g n s or s y m pt o m s of li v er i nj ur y)
R e c o m m e n d ati o n:
1. 
If t ot al bilir u bi n el e v ati o n i s ≤2. 0 x U L N, c o nti n u e c urr e nt d o s e, n o a d diti o n al t e sti n g i s r e q uir e d.
2. 
If t ot al bilir u bi n i s > 2. 0 xU L N, bilir u bi n fr a cti o n ati o n m u st b e p erf or m e d.
 
If bilir u bi n i s pr e d o mi n a ntl y i n dir e ct (i. e. c o nj u g at e d or dir e ct bilir u bi n i s ≤3 5 %), c o nti n u e p a z o p a ni b 
at c urr e nt d o s e c.
If dir e ct ( or c o nj u g at e d) bilir u bi n i s > 3 5 %, d o s e-i nt err u pt a n d p erf or m f urt h er e v al uati o n f or u n d erl yi n g c a u s e 
of c h ol e st a si s. B a s e d o n t h e fi n di n g, i n v e sti g at or c a n t h e n d et er mi n e w h et h er t o c o nti n u e o n p a z o p a ni b

N o v arti s
C o nfi d e nti al
P a g e 3 8
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
a. 
F ull li v er p a n el i n cl u d e s: A L T, A S T, al b u mi n, cr e ati n e ki n a s e, t ot al bilir u bi n, dir e ct bilir u bi n, G G T a n d al k ali n e p h o s p h at a s e. C o a g ul ati o n t e st s s h o ul d b e p erf or m e d a s 
cli ni c all y i n di c at e d.
b. 
S er u m bilir u bi n fr a cti o n ati o n m u st b e p erf or m e d if t ot al bilir u bi n > 2. 0 x U L N. S er u m bilir u bi n fr a cti o n ati o n ( dir e ct bili r u bi n) s h o ul d n’t b e of c o n c er n if t ot al bilir u bi n i s 
≤2. 0 x U L N.
c. 
P a z o p a ni b i s k n o w n t o i n hi bit U G T 1 A 1 a n d O A T P 1 B 1, w hi c h c a n c a u s e el e v ati o n of i n dir e ct ( u n c o nj u g at e d) bilir u bi n i n t h e a b s e n c e of li v er i nj ur y.
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 y l a s e a n d/ or li p a s e el e v ati o n
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, m o nit or a s cli ni c all y i n di c at e d
Gr a d e 2 ( > 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 o nit or a s cli ni c all y i n di c at e d
Gr a d e 3 ( > 2. 0 - 5. 0 x U L N)
R e c o m m e n d ati o n: O mit d o s e of 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:
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 st art st u d y dr u g at a d o s e r e d u c e d b y 2 0 0 m g
Gr a d e 4 ( > 5. 0 x U L N)
M a n d at or y: O mit d o s e a n d 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.
V a s c ul ar di s or d er s
H y p ert e n si o n
( A) A s y m pt o m ati c a n d p er si st e ntd 1 4 0 ≤ S B P < 1 6 0 
m m H g, or 9 0 ≤ D B P < 1 0 0 m m H g, or a cli ni c all y si g nifi c a nt 
i n cr e a s e i n D B P of 2 0 m m H g ( b ut still b el o w 1 0 0 m m H g).
Hi g hl y r e c o m m e n d e d:
St e p 1. C o nti n u e p a z o p a ni b at t h e c urr e nt d o s e.
St e p 2. A dj u st c urr e nt or i niti at e n e w a nti h y p ert e n si v e m e di c ati o n( s) e t o a c hi e v e a n d m ai nt ai n a B P l e v el of < 
1 4 0/ 9 0 m m H g.
If B P c a n n ot b e c o ntr oll e d t o < 1 4 0/ 9 0 m m H g wit hi n 3 w e e k s aft er 2 or m ore diff er e nt a nti h y p ert e n si v e 
m e di c ati o n a dj u st m e nt s, d o s e r e d u cti o n of p a z o p a ni b b y 2 0 0 m g s h o ul d b e c o n si d er e d.
( B) A s y m pt o m ati c S B P ≥1 6 0 m m H g, or D B P ≥1 0 0 m m H g
Hi g hl y r e c o m m e n d e d:
St e p 1. D o s e r e d u c e b y 2 0 0 m g or i nt err u pt p a z o p a ni b a s p er cli ni c al j u d g m e nt
St e p 2. A dj u st c urr e nt or i niti at e n e w a nti h y p ert e n si v e m e di c ati o n( s) e t o a c hi e v e a n d m ai nt ai n a B P l e v el of < 
1 4 0/ 9 0 m m H g.
If B P c a n b e c o ntr oll e d t o < 1 4 0/ 9 0 m m H g wit hi n 3 w e e k s a n d p a z o p a ni b h a s b e e n i nt err u pt e d, it c a n b e 
r e s u m e d wit h d o s e r e d u c e d b y 2 0 0 m g fr o m t h e pr e - e v e nt d o s e.
If B P c a n n ot b e a d e q u at el y c o ntr oll e d wit h t h e s e m e a s ur e s, c o n si d er r ef erri n g t h e s u bj e ct t o a s p e ci ali st f or 
f urt h er e v al u ati o n a n d m a n a g e m e nt.
( C) S y m pt o m ati c h y p ert e n si o n or r e c urri n g S B P≥1 6 0 
m m H g, or D B P ≥1 0 0 m m H g, d e s pit e m o difi c ati o n of 
a nti h y p ert e n si v e m e di c ati o n( s)
Hi g hl y r e c o m m e n d e d:
St e p 1. I nt err u pt p a z o p a ni b
St e p 2. Str o n gl y r e c o m m e n d r ef erri n g t h e s u bj e ct t o a s p e ci ali st f or f urt h er e v al u ati o n a n d m a n a g e m e nt
O n c e B P i s c o ntr oll e d t o < 1 4 0/ 9 0 m m H g vi a a dj u st m e n t of c urr e nt or i niti ati n g n e w a nti h y p ert e n si v e 
m e di c ati o n( s)
e , p a z o p a ni b c a n b e r e s u m e d wit h d o s e r e d u c e d b y 2 0 0 m g. B P s h o ul d b e m o nit or e d a s 
cli ni c all y i n di c at e d

N o v arti s
C o nfi d e nti al
P a g e 3 9
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
( D) R efr a ct or y h y p ert e n si o n u nr e s p o n si v e t o a b o v e 
i nt er v e nti o n s i n cl u di n g m ali g n a nt h y p erte n si o n, 
h y p ert e n si v e cri si s, tr a n si e nt or p er m a n e nt n e ur ol o gi c al 
d efi cit r el at e d t o u n c o ntr oll e d h y p ert e n si o 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 a z o p a ni b a n d c o nti n u e f oll o w -u p p er pr ot o c ol.
d. 
P er si st e nt S B P a n d / or D B P i s d efi n e d a s S B P of ≥1 4 0 or D B P ≥9 0 f or at l e a st 2 4 h o ur s p er N CI-C T C A E v 4. 0 3
R e c o m m e n d ati o n of a nti h y p ert e n si v e a g e nt s f or tr e at m e nt -e m er g e nt B P el e v ati o n s: A C E i n hi bit or s, a n gi ot e n si n r e c e pt or bl o c ki n g a g e nt s, b et a bl o c k er s, c al ci u m 
c h a n n el bl o c k er s a n d di ur eti c s h a v e all s h o w n t o r e d u c e bl o o d pr e s s ur e i n s u bj e ct s tr e at e d wit h p a z o p a ni b
G a str oi nt e sti n al
P a n cr e atiti 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
Gr a d e ≥ 3
M a n d at or y: O mit d o s e a n d di s c o nti n u e p ati e nt fr o m p a z o p a ni b
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: O mit d o s e u ntil r e s ol v e d t o ≤ gr a d e 1, t h e n 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 o mit d o s e u ntil r e s ol v e d t o ≤ gr a d e 1, t h e n r e d u c e d o s e b y 2 0 0 m g.
O mit d o s e u ntil r e s ol v e d t o ≤ gr a d e 1, t h e n r e d u c e d o s e b y 2 0 0 m g
Gr a d e 3
R e c o m m e n d ati o n: O mit d o s e a n d di s c o nti n u e p ati e nt fr o m p a z o p a ni b
Gr a d e 4
M a n d at or y: O mit d o s e
M a n d at or y: Di s c o nti n u e p ati e nt fr o m p a z o p a ni b
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 i n stit ut 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: O mit d o s e u ntil r e s ol v e d t o Gr a d e ≤ 1, t h e n:
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 b y 2 0 0 m g.
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
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: O mit d o s e
M a n d at or 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 a m e nt
F ati g u e/ A st h e ni a ( 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)
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

N o v arti s
C o nfi d e nti al
P a g e 4 0
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Gr a d e 3
R e c o m m e n d ati o n: O mit d o s e u ntil r e s ol v e d t o ≤ gr a d e 1, t h e n :
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 b y 2 0 0 m g
H e m orr h a g e/ Bl e e di n g: I n v e sti g at e a n d d o c u m e nt u n d erl yi n g eti ol o g y of t h e bl e e di n g
Gr a d e 1
R e c o m m e n d ati o n:
F or h e m o pt y si s, i nt err u pt p a z o p a ni b a n d c o nt a ct t h e M e di c al M o nit or t o di s c u s s w h et h er f ur t h er tr e at m e nt 
wit h p a z o p a ni b i s a p pr o pri at e.
F or ot h er Gr a d e I h e m orr h a g e/ bl e e di n g e v e nt s, c o nti n u e p a z o p a ni b at t h e c urr e nt d o s e; m o nit or a s cli ni c all y 
i n di c at e d.
Gr a d e 2
R e c o m m e n d ati o n:
F or p ul m o n ar y or GI bl e e d ( ot h er t h a n h e m orr h oi d al bl e e di n g), di s c o nti n u e p a z o p a ni b a n d c o nti n u e f oll o w -u p 
p er pr ot o c ol.
F or ot h er G 2 h e m orr h a g e / bl e e di n g e v e nt s, i nt err u pt p a z o p a ni b u ntil t h e A E r e s ol v e d t o ≤Gr a d e 1. R e st art 
p a z o p a ni b d o s e r e d u c e d b y 2 0 0 m g, m o nit or a s cli ni c all y i n di c at e d
Gr a d e 3 or 4, or
R e c urr e nt Gr a d e 2 e v e nt aft er d o s e 
i nt err u pti o n/r e d u cti o 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 a z o p a ni b a n d c o nti n u e wit h f oll o w -u p p er pr ot o c ol.
V e n o u s T hr o m b o si s ( D V T, P E)
Gr a d e 1
R e c o m m e n d ati o n: C o nti n u e p a z o p a ni b at t h e c urr e nt d o s e; m o nit or a s cli ni c all y i n di c at e d
Gr a d e 2 or 3
R e c o m m e n d ati o n:
St e p 1: I nt err u pt p a z o p a ni b
St e p 2: I niti at e a n d m o nit or a nti c o a g ul ati o n a s cli ni c all y i n di c at e d.
St e p 3: R e s u m e p a z o p a ni b (r e d u c e d b y 2 0 0 m g) o nl y if all of t h e f oll o wi n g crit eri a ar e m et:
 
T h e s u bj e ct m u st h a v e b e e n tr e at e d wit h a nti c o a g ul a nt at t h e d e sir e d l e v el of a nti c o a g ul ati o n f or at l e a st 
o n e w e e k.
 
N o Gr a d e 3 or 4 or cli ni c all y si g nifi c a nt Gr a d e 2, h e m orr h a gi c e v e nt s h a v e o c c urr e d w hil e o n 
a nti c o a g ul ati o n tr e at m e nt.
S u bj e ct s h o ul d b e m o nit or e d a s cli ni c all y i n di c at e d d uri n g a nti c o a g ul ati o n tr e at m e nt a n d aft er r e s u mi n g 
p a z o p a ni b. W h e n tr e ati n g wit h w arf ari n, i nt er n ati o n al n or m ali z e d r ati o (I N R) s h o ul d b e m o nit or e d wit hi n t hr e e 
t o fi v e d a y s aft er a n y c h a n g e i n p a z o p a ni b d o si n g ( e. g., r e-i niti ati n g, es c al ati n g/ d e -e s c al ati n g, or 
di s c o nti n ui n g p a z o p a ni b), a n d t h e n at l e a st w e e kl y u ntil t h e I N R i s st a bl e. T h e d o s e of w arf ari n ( or it s 
d eri v ati v e s) m a y n e e d t o b e a dj u st e d t o m ai nt ai n t h e d e sir e d l e v el of a nti c o a g ul ati o n
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 a z o p a ni b a n d f oll o w -u p p er pr ot o c ol.

N o v arti s
C o nfi d e nti al
P a g e 4 1
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Art eri al T hr o m b o si s/I s c h e mi a
A n y Gr a d e
M a n d at or y: P er m a n e ntl y di s c o nti n u e p a z o p a ni b a n d f oll o w -u p p er pr ot o c ol.
C ar di a c
Pr ol o n g ati o n of Q T c F I nt er v al: If a Q T c F r e a di n g i s ≥ 5 0 0 m s e c, t h e E C G s h o ul d b e m a n u all y r e a d t o e n s ur e a c c ur a c y of t h e r e a di n g
4 8 0 < Q T c F < 5 0 0 m s e c
R e c o m m e n d ati o n: C o nti n u e p a z o p a ni b; m o nit or a s cli ni c all y i n di c at e d
Q T c F ≥ 5 0 0 m s e c
M a n d at or y: P er m a n e ntl y di s c o nti n u e p a z o p a ni b a n d f oll o w u p p er pr ot o c ol.
P ati e n t m u st b e m o nit or e d
cl o s el y i n a h o s pit al s etti n g u ntil a c ar di ol o gi st’ s e v al u ati o n h a s b e e n o bt ai n e d. 
Ot h er cli ni c all y  si g nifi c a nt n o n-li v er r el at e d a d v er s e e v e nt s
Gr a d e 1
R e c o m m e n d ati o n:
1: C o nti n u e p a z o p a ni b at c urr e nt d o s e
2: M a n a g e t h e si d e eff e ct s wit h a p pr o pri at e m e di c al tr e at m e nt s/ s u p p orti v e c ar e. A d o s e r e d u cti o n of 2 0 0 m g 
m a y b e c o n si d er e d if a s u bj e ct e x p eri e n c e s m ulti pl e Gr a d e 1 A E s a n d c a n n ot t ol er at e t h e c urr e nt 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
1: M a n a g e si d e eff e ct s wit h a p pr o pri at e m e di c al tr e at m e nt s/ s u p p orti v e c ar e
2: A d o s e r e d u cti o n of 2 0 0 m g or i nt err u pti o n of p a z o p a ni b m a y b e c o n si d er e d if a s u bj e ct e x p eri e n c e s a 
cli ni c all y si g nifi c a nt Gr a d e 2 A E or m ulti pl e Gr a d e 2 a n d 1 A E s a n d c a n n ot t ol er at e t h e c urr e nt d o s e l e v el
If A E s ar e f ull y r e s ol v e d or r e c o v er t o Gr a d e 1, t h e d o s e c a n b e e s c al at e d t o t h e pr e- e v e nt l e v el or 
m ai nt ai n e d at t h e c urr e nt l e v el. F or s u bj e ct s wit h d o s e i nt err u pti o n, d o s e c a n b e r e s u m e d at t h e pr e -e v e nt 
l e v el or d o s e-r e d u c e d b y 2 0 0 m g b a s e d o n cli ni c al j u d g e m e nt
Gr a d e 3
R e c o m m e n d ati o n:
1: I nt err u pt p a z o p a ni b
2: M a n a g e t h e si d e eff e ct s wit h a p pr o pri at e m e di c al tr e at m e nt s/ s u p p orti v e c ar e
If A E s f ull y r e c o v er or r e c o v er t o Gr a d e 1, r e st art p a z o p a ni b wit h d o s e-r e d u c e d b y 2 0 0 m g. M o nit or a s 
cli ni c all y i n di c at e d f or A E r e c urr e n c e.
D o s e c a n b e i nt err u pt e d or f urt h er r e d u c e d f or r e c urr e nt G 3 A E s
Gr a d e 4
R e c o m m e n d ati o n:
P er m a n e ntl y di s c o nti n u e p a z o p a ni b a n d f oll o w u p p er pr ot o c ol
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 ci t y.
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 v 4. 0 3)
** 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

N o v arti s
C o nfi d e nti al
P a g e 4 2
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
T a bl e 6- 3 
D o s e r e d u cti o n st e p s f or p a z o p a ni b
P a z o p a ni b d o s e 
N u m b er of t a bl et s & str e n gt h
St arti n g d o s e
8 0 0 m g Q D
2 x 4 0 0 m g t a bl et s
Fir st d o s e r e d u cti o n
6 0 0 m g Q D
1 x 4 0 0 m g t a bl et a n d 1 x 2 0 0 m g t a bl et
S e c o n d d o s e r e d u cti o n
4 0 0 m g Q D
1 x 4 0 0 m g t a bl et
6. 2. 1. 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 BI L 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 patie nt’s baseli ne A S T/ A L T a n d T BI L 
val ue; pati e nts meeti n g a n y of the f oll o wi n g criteria will re q uire f urt her f oll o w- u p as o utli ne d 
bel o w:

F or patie nts wit h n or mal A L T a n d A S T a n d T BI L val ue at baseli ne: A S T or A L T > 3. 0 x 
U L N c o m bi ne d wit h T BI L > 2. 0 x U L N

F or patie nts wit h ele vate d A S T or A L T or T BI L val ue at baseli ne: [ A S T or A L T > 2 x 
baseli ne A N D > 3. 0 x U L N] O R [ A S T or A L T > 8. 0 x U L N], c o m bi ne d wit h [ T BI L > 2 x 
baseli ne A N D > 2. 0 x U L N]
T hese patie nts s h o ul d be i m me diatel y  disc o nti n ue d fr o m st u d y dr u g treat me nt, a n d re peat L F T 
testi n g as s o o n as p ossi ble, prefera bl y w it hi n 2 4 t o 7 2 h o urs fr o m t he a ware ness of t he a b n or mal 
res ults. T he e val uati o n s h o ul d i ncl u de la b orat or y tests, detaile d hist or y , p h y sical 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 
bilir u bi n, G G T, al kali ne p h os p hatase a n d pr ot hr o m bi n ti me ( P T)/I N R.
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 vie w of et ha n ol, c o nc omita 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 m ust be perf or me d. L i ver i ma gi n g 
(e. g., biliar y  tract) ma y be warra nte d.
4.
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, E B V or H S V), 
a ut oi m m u ne he patitis m ust be perf or me d. L i 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.
5.
Me dical re vi e w nee ds t o e ns ure t hat li ver test ele vati o ns are n ot ca use d b y c h olestasis, 
defi ne d as A L P ele vati o n > 2. 0 x U L N wit h R val ue < 2 i n patie nts wit h o ut b o ne 
metastasis, or ele vati o n of A L P li ver fracti o n i n patie nts wit h b o ne metastasis.
N ote: ( T he R val ue is calc ulate d b y di vi di n g t he A L T b y t he A LP, usi n g m ulti ples of t he 
U L N f or b ot h val ues. It de n otes 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 pat ocell ular ( R ≥ 5), or mi xe d ( R > 2 a n d < 5) li ver i nj ur y ).
All cases 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 L F T 
a b n or malities i de ntifie d s h o ul d be c o nsi dere d as “ me dicall y si g nifica nt”, t h us, met 
t he 
defi niti o n of S A E ( Secti o n 8. 2. 1 ) a n d m ust be re p orte d as S A E usi n g t he ter m “ p ote ntial dr u g-
i n d uce 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.

N o v arti s
C o nfi d e nti al
P a g e 4 3
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
6. 3 
C o n c o mit a nt m e di c ati o n s
D uri n g scree ni n g, all patie nts will be as ke d t o pr o vi de a c o m plete list of pre scri pti o n a n d o ver-
t he-c o u nter me dicati o ns t hat t he patie nt is ta ki n g. If a patie nt is ta ki n g a n y me dicati o ns 
pr o hi bite d per pr ot oc ol, t he i n vesti gat or s h o ul d deter mi ne w het her t h ose me dicati o ns ca n be 
re place d wit h ot her me dicati o ns f or t he sa me i n dicati o n.
A s u bject will be i neli gi ble if he/s he is u na ble or u n willi n g t o disc o nti n ue use of pr o hi bite d 
me dicati o ns ( pri maril y str o n g C Y P 3 A 4 i n hi bit ors a n d str o n g C Y P 3 A 4 i n d ucers) f or at least 
fi ve half -li ves of t he pr o hi bite d me dicati o n, or 7 da y s, w hic he ver is l o n ger, pri or t o t he first 
d ose of st u d y  treat me nt a n d f or t he d urati o n of t he st u d y.
F or s u bjects wit h o n- g oi n g A Es or ne w A Es wit hi n t he 3 0 da y s p ost -treat me nt peri o d, 
c o nc o mita nt me dicati o ns will be c ollecte d f or t he sa me peri o d. C o nc o mita nt me dicati o n s will 
n ot be c ollecte d be y o n d t his p oi nt.
6. 3. 1 
P er mitt e d c o n c o mit a nt t h er a p y
T he patie nt m ust be t ol d t o n otif y  the i n vesti gati o nal site a b o ut a n y ne w me dicati o ns he/s he 
ta kes after t he start of t he st u d y dr u g. All me dicati o ns ( ot her t ha n st u d y dr u g) a n d si g nifica nt 
n o n- dr u g t hera pies (i ncl u di n g p h y sical t hera p y, her bal/ nat ural me dicati o ns 
a n d bl o o d 
tra nsf usi o ns) a d mi nistere d d uri n g t he st u d y  must be liste d o n t he C o nc o mita nt Me dicati o ns or 
t he Pr oce d ures a n d Si g nifica nt N o n-Dr u g T hera pies C R F.
6. 3. 2 
P er mitt e d c o n c o m it 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
Paz o pa ni b is a p ote ntial i n hi bit or f or C Y P 3 A 4, C Y P 2 C 8, a n d C Y P 2 D 6. T he c o nc o mita nt use 
of paz o pa ni b wit h certai n me dicati o ns (s u bstrates of C Y P 3 A 4, C Y P 2 C 8, a n d C Y P 2 D 6) wit h a 
narr o w t hera pe utic wi n d o w s h o ul d be u n derta ke n wit h C A U TI O N
[ See A p pe n di x 1 ]. I n 
a d diti o n, t he p ote ntial f or dr u g i nteracti o n wit h s uc h me dicati o ns, alt h o u g h di mi nis he d, m a y  
persist after t he last d ose of paz o pa ni b d ue t o its l o n g half -life (i.e., mea n 3 0. 9 h o urs); t heref ore, 
c o nti n ue t o e xercise C A U TI O N f or at least 7 da ys  an d u p t o 1 5 da y s after t he last d ose of 
paz o pa ni b w he n a d mi nisteri n g t hese me dicati o ns.
6. 3. 2. 1 
S p e cifi c r e c o m m e n d ati o n s r e g ar di n g t h e u s e of si m v a st ati n a n d ot h er 
st ati n s
C o nc o mita nt use of paz o pa ni b a n d si m vastati n i ncreases t he ris k of A L T ele vati o ns. If a patie nt 
recei vi n g c o nc o mita nt si m vastati n de vel o ps A L T ele vati o ns, f oll o w g ui deli nes f or paz o pa ni b 
d ose m o dificati o n a n d disc o nti n ue si m vastati n. I ns ufficie nt data are a vaila ble t o assess t he ris k 
of c o nc o mita nt a d mi nistrati o n of alter nati ve stati ns a n d paz o pa ni b.
6. 3. 2. 2 
S p e cifi c r e c o m m e n d ati o n s r e g ar di n g a nti c o a g ul a nt s
Res ults fr o m dr u g -dr u g i nteracti o n st u dies c o n d ucte d i n s u bjects wit h ca ncer s u g gest t hat 
paz o pa ni b has n o effect o n t he meta b olis m of S -warfari n. He m orr ha gic e ve nts, h o we ver, ha ve 
bee n re p orte d i n cli nical st u dies wit h paz o pa ni b; t heref ore, paz o pa ni b s h o ul d be use d wit h 
ca uti o n i n s u bjects wit h i ncrease d ris k of se vere blee di n g or w h o are recei vi n g c o nc o mita nt 
a ntic oa g ula nt t hera py (e. g., warfari n 
or its deri vati ves, l o w m olec ular 
wei g ht he pari n, 
u nfracti o nat e d he pari n). S u bjects ta ki n g c o nc o mita nt a ntic oa g ula nt t hera p y sh o ul d be 

N o v arti s
C o nfi d e nti al
P a g e 4 4
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
m o nit ore d re g ularly f or c ha n ges i n rele va nt c oa g ulati o n para meters as cli nicall y in dicate d, as 
well as f or a n y cli nical blee di n g e pis o des.
6. 3. 2. 3 
S p e cifi c r e c o m m e n d ati o n s r e g ar di n g h y p o gl y c e mi c t h er a p y  i n cl u di n g 
i n s uli n
Res ults fr o m dr u g -dr u g i nteracti o n st u dies c o n d ucte d i n s u bjects wit h ca ncer s u g gest t hat 
cli nicall y rele va nt p har mac o ki netic i nteracti o n bet wee n paz o pa ni b a n d hy p o gl yc e mic a ge nts is 
n ot e x pecte d. Tra nsie nt decreases i n ser u m gl uc ose ( mai nl y Gra de 1 a n d 2, rarely G ra de 3) ha ve 
bee n o bser ve d i n cli nical st u dies wit h paz o pa ni b. I n ad diti o n, decreases i n bl o o d s u gar ha ve 
bee n rece ntly r e p orte d i n s u bjects treate d wit h a n ot her s mall m olec ule t yr osi ne ki nase i n hi bit or, 
s u niti ni b (Bille m o nt 2 0 0 8 ). S uc h c ha n ges ma y  re q uire a n a dj ust me nt i n t he d ose of 
h y p o gl yc e mic a n d/ or i ns uli n t hera p y. S u bjects s h o ul d be a d vise d t o re p ort s ym pt o ms of 
h y p o gl yc e mia (e. g., c o nf usi o n, vis ual dist ur ba nc es, pal pitati o ns, s weati n g). Ser u m gl uc ose 
s h o ul d be teste d d uri n g treat me nt wit h paz o pa ni b as o utli ne d i n t he pr ot oc ol a n d as cli nicall y 
i n dicate d.
6. 3. 3 
Pr o hi bit e d c o n c o mit a nt t h er a p y
Paz o pa ni b meta b olis m is me diate d pri maril y  by C Y P 3 A 4, wit h mi n or c o ntri b uti ons fr o m 
C Y P 1 A 2 a n d C Y P 2 C 8.
Me dicati o ns t hat i n hi bit C Y P 3 A 4 ma y  res ult i n i ncrease d plas ma paz o pa ni b c o nce ntrati o ns. 
C o -a d mi nistrati o n of str o n g C Y P 3 A 4 i n hi bit ors is pr o hi bite d; t heref ore selecti o n of a n alter nate 
c o nc o mita nt me dicati o n wit h n o or mi ni mal p ote ntial t o i n hi bit C Y P 3 A 4 is rec o m me n de d.
C Y P 3 A 4 i n d ucers ma y  decrease plas ma paz o pa ni b c o nce ntrati o ns. Selecti o n of a n alter nate 
c o nc o mita nt me dicati o n wit h n o or mi ni mal e nz y me i n d ucti o n p ote ntial is rec o m me n de d.
A s u bject will be i neli gi ble if he/s he is u na ble or u n willi n g t o disc o nti n ue use of pr o hi bite d 
me dicati o ns f or at least fi ve half -li ves or 7 da y s, w hic he ver is l o n ger, pri or t o t he first d ose of 
st u d y treat me nt a n d f or t he d urati o n of t he st u d y. A list of pr o hi bite d me dicati o ns is i ncl u de d i n 
A p pe n di x 1 .
S u bjects s h o ul d n ot recei ve ot her a nti-ca ncer t hera py [ c yt ot o xic, bi ol o gic, ra diati o n, or 
h or m o nal ] pri or t o esta blis he d disease rec urre nce i n t he st u d y .
6. 3. 3. 1 
Dr u g s wit h Q T pr ol o n g ati o n
I n t he cli nical R C C st u dies of paz o pa ni b ( V E G 1 0 2 6 1 6, V E G 1 0 5 1 9 2, V E G 1 0 7 7 6 9), Q T 
pr ol o n gati o n (≥5 0 0 msec) was i de ntifie d o n r o uti ne E C G m o nit ori n g i n less t ha n 2 % ( 1 1/ 5 5 8) 
of patie nts. Re vie w of t he car diac safety i n 1 1 paz o pa ni b m o n ot hera p y  st u dies, a m o u ntin g t o 
data o n 9 7 7 patie nts, i n dicate d t hat T orsa de de p oi ntes occ urre d i n less t ha n 1 % ( 2/ 9 7 7) of t he 
patie nts. H o we ver, c o -a d mi nistrati o n of Q T pr ol o n gi n g dr u gs or a n y ot her dr u gs wit h t he 
p ote ntial t o i ncrease t he ris k of dr u g -relate d Q T pr ol o n gati o n (e. g., via a p ote ntial d r u g- dr ug 
interacti o n (D DI ) t hat i ncreases t he e x p os ure of paz o pa ni b or t he e x p os ure of t he Q T pr ol o n gi n g 
dr u g) s h o ul d be a v oi de 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 dr u gs wit h a “ K n o w n ris k of 
T orsa des de P oi ntes” 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, 

N o v arti s
C o nfi d e nti al
P a g e 4 5
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
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 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 ntes” 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 ose E C G m o nit ori n g t o e ns ure patie nt 
safety.
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 
w w w. qt dr u gs. or g.
6. 3. 4 
U s e of bi s p h o s p h o n at e s ( or ot h er c o n c o mit a nt a g e nt s)
T he use of bis p h os p h o nates is all o we d if patie nts ha ve bee n o n sta ble a n d well t olerate d d oses 
of bis p h os p h o nate treat me nt f o r at least 4 wee ks pri or t o t he start of st u d y treat me nt.
6. 4 
P ati e nt n u m b eri n g, tr e at m e nt a s si g n m e nt or r a n d o mi z ati o n
6. 4. 1 
P ati e nt n u m b eri n g
Eac h patie nt is i de ntifie d i n t he st u d y by a  Su bject N u m ber ( S u bject N o.), t hat is assi g ne d w he n 
t he patie nt is first e nr olle d f or scree ni n g a n d is retai ne d as t he pri mar y i de ntifier f or t he patie nt 
t hr o u g h o ut his/ her e ntire partici pati o n i n t he trial. T he S u bject N o. c o nsists of t he Ce nter 
N u m ber ( Ce nter N o.) (as assi g ne d b y  No vartis t o t he i n vesti gati ve site) wit h a se q ue ntial patie nt 
n u m ber s uffi xe d t o it, s o t hat eac h s u bject is n u m bere d u ni q uel y acr oss t he e ntire data base. 
U p o n si g ni n g t he i nf or me d c o nse nt f or m, t he patie nt is assi g ne d t o t he ne xt se q ue ntial S u bject 
N o. a vaila ble t o t he i n vesti gat or t hr o u g h t he Oracle Cli n ical R D C i nterface.
T he i n vesti gat or or desi g nate d staff will c o ntact t he I RT a n d pr o vi de t he re q ueste d i de ntif yi n g 
i nf or mati o n f or t he patie nt t o re gister t he m i nt o t he I RT. O nce assi g ne d, t he S u bject N o. m ust 
n ot be re use d f or a n y ot her s u bject a n d t he S u bject N o. f or t hat i n di vi d ual m ust n ot be c ha n ge d, 
e ve n if t he patie nt is re -scree ne d. If t he patie nt fails t o start treat me nt f or a ny reas o n, t he reas o n 
will be e ntere d i nt o t he Scree ni n g Dis p ositi o n pa ge.
I R T m ust be n otifie d wit hi n 2 da ys t hat t he patie nt was n ot starte d o n treat me nt.
6. 4. 2 
Tr e at m e nt a s si g n m e nt or r a n d o mi z ati o n
T he i n vesti gati o nal treat me nt, paz o pa ni b, will be pr o vi de d t o all partici pa nts of t his si n gle ar m 
st u d y an d n o ra n d o mizati o n pr ocesses will a p pl y. Pri or t o d osi n g, all patie nts w h o f ulfill all 
i ncl usi o n/e xcl usi o n criteria will be e nr olle d via I R T t o t he treat me nt ar m. T he i n vesti gat or or 
his/ her dele gate will call or l o g o n t o t he I R T a n d c o nfir m t hat t he patie nt f ulfills all t he 
i ncl usi o n/e xcl usi o n criteria. T he I RT will be use d t o trac k e nr oll me nt of patie nts i n 2n d a n d 3 r d
li ne t o e ns ure t hat a p pr o xi matel y 4 0 patie nts recei ve paz o pa ni b as 2n d li ne treat me nt. 
6. 4. 3 
Tr e at m e nt bli n di n g
All st u d y  partici pa nts will be treate d wit h paz o pa ni b; t heref ore, bli n di n g is n ot a p plica ble.

N o v arti s
C o nfi d e nti al
P a g e 4 6
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
6. 5 
St u d y dr u g pr e p ar ati o n a n d di s p e n s ati o n
T he i n vesti gat or or res p o nsi ble site pers o n nel m ust i nstr uct t he patie nt or care gi ver t o ta ke t he 
st u d y dr u gs as per pr ot oc ol. St u d y  dr u g(s) will be dis pe nse d t o t he patie nt b y  aut h orize d site 
pers o n nel o nl y. All d osa ges prescr i be d t o t he patie nt a n d all d ose c ha n ges d uri n g t he st u d y must 
be rec or de d o n t he D osa ge A d mi nistrati o n Rec or d C R F.
6. 5. 1 
St u d y tr e at m e nt p a c k a gi n g a n d l a b eli n g
T he st u d y treat me nt, paz o pa ni b, will be s o urce d as l ocal c o m mercial s u p pl y (i n t he l ocally 
a p pr o ve d for m ulati o n a n d pac ka gi n g c o nfi g urati o n) a n d la bele d i n t he c o u ntr y  w he n p ossi ble.
St u d y  treat me nt la bels f or l ocal c o m mercial s u p pl y 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 an d will i ncl u de st ora ge c o n diti o ns, a u ni q ue me dicati o n n u m ber (c o rres p o n di n g 
t o st u d y treat me nt a n d stre n gt h) or ra n d o mizati o n n u m ber if a p pr o priate.
If t he la bel has 2-parts ( base pl us tear -off la bel), i m me diatel y  bef ore dis pe nsi n g t he pac ka ge t o 
t he patie nt, site pers o n nel will detac h t he o uter part of t he la bel fr o m t he pac ka ge a n d affi x it t o 
t he patie nt’s s o urce d oc u me nt.
Paz o pa ni b i n differe nt f or m ulati o ns a n d stre n gt hs ca n be use d o nce t he y  are a p pr o ve d.
6. 5. 2 
Dr u g s u p pl y  a n d st or a g e
St u d y  treat me nts m ust be recei ve d b y  desi g nate d pers o n nel at t he st u d y site, ha n dle d a nd st ore d 
safely a n d pr o perl y, a n d ke pt i n a sec ure d l ocati o n t o w hic h o nl y t he i n vesti gat or a n d desi g nate d 
site pers o n nel ha ve access. U p o n recei pt, t he st u d y treat me nt s h o ul d be st ore d acc or di n g t o t he 
i nstr ucti o ns s pecifie d o n t he dr u g la bels a n d i n t he I nvesti gat or’s Br oc h ure.
6. 5. 3 
St u d y dr u g c o m pli a n c e a n d a c c o u nt a bilit y
6. 5. 3. 1 
St u d y dr u g c o m pli a n c e
C o m plia nce will be assesse d b y  the i n vesti gat or a n d/ or st u d y pers o n nel at eac h patie nt visit a n d 
i nf or mati o n pr o vi de d b y t he patie nt a n d/ or care gi ver will 
be ca pt ure d i n t he Dr u g 
Acc o u nta bilit y  F or m. T his i nf or mati o n m ust be ca pt ure d i n t he s o urce d oc u me nt at eac h patie nt 
visit.
6. 5. 3. 2 
St u d y dr u g a c c o u nt a bilit y
T he i n vesti gat or or desi g nee m ust mai ntai n a n acc urate rec or d of t he s hi p me nt a n d dis pe nsi n g 
of st u d y treat me nt i n a dr u g acc o u nta bilit y lo g. Dr u g acc o u nta bilit y will be n ote d b y  the fiel d 
m o nit or d uri n g site visits a n d at t he c o m pleti o n of t he st u d y. Patie nts will be as ke d t o ret ur n all 
u n use d st u d y treat me nt a n d pac ka gi n g o n a re g ular basis, at t he e n d of t he st u d y or at t he ti me 
of st u d y  treat me nt disc o nti n uati o n.
At st u d y cl ose-o ut, a n d, as a p pr o priate d uri n g t he c o urse of t he st u d y, t he i n vesti gat or will ret ur n 
all use d an d u n use d st u d y  treat me nt, pac ka gi n g, dr u g la bels, a n d a c o p y of t he c o m plete d dr u g 
acc o u nta bilit y lo g t o t he N o vartis m o nit or or t o t he N o vartis a d dress pr o vi de d i n t he i n vesti gat or 
f ol der at eac h site.

N o v arti s
C o nfi d e nti al
P a g e 4 7
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
6. 5. 3. 3 
H a n dli n g of ot h er st u d y  tr e at m e nt
N ot a p plica ble
6. 5. 4 
Di s p o s al a n d d e str u cti o n
T he st u d y dr u g s u p ply ca n be destr o ye d at t he l ocal N o vartis facilit y, Dr u g S u p pl y  gr o u p or 
t hir d part y, as a p pr o priate.
7 
Vi sit s c h e d ul e a n d a s s e s s m e nt s
7. 1 
St u d y fl o w a n d vi sit s c h e d ul e
Ta ble 7- 1 lists all of t he assess me nts a n d i n dicates wit h a n “ X” t he visits w he n t he y are t o be 
perf or me d. All data o btai ne d fr o m t hese assess me nts m ust be s u p p orte d i n t he patie nt’s s o urce 
d oc u me ntati o n. T he ta ble i n dicates w hic h data assess me nts pr o d uce data t o be e ntere d i nt o t he 
cli nical data base ( D) or re mai n i n s o urce d oc u me nts o nl y  (S) (see Ta ble 7- 1 “ Cate g or y” c ol u m n).
N o e C R F will be use d as a s o urce d oc u me nt.

Scree ni n g assess me nts, a part fr o m t h ose liste d bel o w, m ust occ ur wit hi n 2 8 da y s pri or t o 
C y cle 1 Da y 1 as per Ta ble 7 -1 .

P h y sical e xa m, Kar n ofs k y perf or ma nce stat us, hei g ht, wei g ht, vital si g ns, 
he mat ol o g y , c he mistr y ( L F T a n d ot her), t h yr oi d pa nel, c oa g ulati o n, uri nal ysis, 
pre g na nc y  test, E C G, car diac i ma gi n g a n d P R O q uesti o n naires s h o ul d be perf or me d 
wit hi n 7 da y s pri or t o Cycle 1 Da y 1. All ot her scree ni n g assess me nts m ust be 
c o m plete d wit hi n 2 8 da ys pri or t o C y cle 1 Da y 1. E ver y eff ort s h o ul d be ma de t o 
f oll o w t he sc he d ule.

F or all visits t here is a ± 3 da y  wi n d o w o n assess me nts t o ta ke i nt o acc o u nt sc he d uli n g 
o ver wee ke n ds a n d p u blic h oli da y s.

Ra di ol o gical assess me nts m ust be perf or me d as o utli ne d i n Ta ble 7 - 1. A visit wi n d o w of ±
7 da y s is all o we d.

Efficac y  f oll o w u p will o nl y be perf or me d i n patie nts w h o disc o nti n ue st u d y treat me nt 
wit h o ut dis ease pr o gressi o n b y R E CIS T 1. 1 bef ore L P F V + 1 y ear.

S ur vi val f oll o w u p will be perf or me d i n all patie nts. F or patie nts w h o e nter t he efficac y  
f oll o w u p, s ur vi val f oll o w u p will n ot be gi n u ntil after t he efficac y f oll o w u p is c o m plete d. 
F or patie nts w h o di sc o nti n ue st u d y treat me nt d ue t o disease pr o gressi o n at a n y ti me or f or 
a n y reas o n after LP F V + 1 y ear, s ur vi val f oll o w -u p will be gi n after e n d of treat me nt.

N o v arti s
C o nfi d e nti al
P a g e 4 8
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
T a bl e 7- 1 
Vi sit e v al u ati o n s c h e d ul e
S C R E E NI N G 
P H A S E
T R E A T M E N T P H A S E
F O L L O W U P P H A S E
Vi sit N a m e
C at e g or y
Pr ot o c ol 
S e cti o n
S cr e e ni n g 
C 1   
C 2   
C 3   
C 4   
C 5   
C 6
C y cl e s 
7, 9, 
1 1, 1 3
C y cl e 1 6 a n d 
e v er y 3 r d c y cl e 
t h er e aft er u ntil 
E O T
E n d of st u d y 
tr e atm e nt ( E o T)
S af et y f oll o w u p
Effi c a c y f oll o w u p 
u ntil P D or u ntil 1 
y e ar fr o m L P F V
S ur vi v al f o ll o w u p 
u ntil 2 y e ar s fr o m 
L P F V
D a y of c y cl e
-2 8 t o 
- 1
-7 t o 
- 1
1
8
1 5 
1 
1 5 
1  
1  
1  
1  
1  
1
3 0 d a y s 
f oll o wi n g 
E O T
E v er y 
8 
w e e k s
E v er y 
1 2 
w e e k s
I nf or m e d C o n s e nt
M ai n I nf or m e d C o n s e nt 
D 
7. 1. 1 .  
X
P ati e nt hi st or y
D e m o gr a p h y
D 
7. 1. 1. 3 .  
X
I n cl u si o n/ e x cl u si o n crit eri a 
D 
5. 2 & 5. 3 .
X
M e di c al hi st or y
D 
7. 1. 1. 3 .  
X
Di a g n o si s a n d e xt e nt of 
c a n c er
D
7. 1. 1. 3 .
X
M S K C C crit eri a
D 
7. 1. 1. 3. 1 .
X
Pri or a nti n e o pl a sti c 
t h er a p y ( s ur g er y, 
r a di ot h er a p y, m e di c ati o n)
D
7. 1. 1. 3 .
X
Pri or/ c o n c o mit a nt 
m e di c ati o n s
D
7. 1. 1. 3 .
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X

N o v arti s
C o nfi d e nti al
P a g e 4 9
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
S C R E E NI N G 
P H A S E
T R E A T M E N T P H A S E
F O L L O W U P P H A S E
Vi sit N a m e
C at e g or y
Pr ot o c ol 
S e cti o n
S cr e e ni n g 
C 1   
C 2   
C 3   
C 4   
C 5   
C 6 
C y cl e s 
7, 9, 
1 1, 1 3
C y cl e 1 6 a n d 
e v er y 3 r d c y cl e 
t h er e aft er u ntil 
E O T
E n d of st u d y 
tr e atm e nt ( E o T)
S af et y f oll o w u p
Effi c a c y f oll o w u p 
u ntil P D or u ntil 1 
y e ar fr o m L P F V
S ur vi v al f o ll o w u p 
u ntil 2 y e ar s fr o m 
L P F V
D a y of c y cl e
-2 8 t o 
- 1
-7 t o 
- 1
1
8
1 5 
1 
1 5 
1  
1  
1  
1  
1  
1
3 0 d a y s 
f oll o wi n g 
E O T
E v er y 
8 
w e e k s
E v er y 
1 2 
w e e k s
I R T
I R T-s cr e e ni n g/
di s c o nti n u ati o n
S
7. 1. 1. 1 & 
7. 1. 3 .
X
X
I R T- eli gi bilit y c h e c kli st 
S 
7. 1. 1. 1 .
X
D at e of tr e at m e nt 
a s si g n m e nt
S
/
D
6. 4. 2 .
X
P h y s i c al e x a mi n ati o n
P h y si c al e x a mi n ati o n 
S 
7. 2. 2. 1 .
X
X  
X  
X  
X  
X  
X  
X  
X
K ar n of s k y P erf or m a n c e 
st at u s
D
7. 2. 2. 4 .
X
X  
X  
X  
X  
X  
X  
X  
X
H ei g ht
D 
7. 2. 2. 3 .
X
W e i g ht
D 
7. 2. 2. 3 .
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
Vit al si g n s
D 
7. 2. 2. 3 .
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
L a b or at or y  a s s e s s m e nt s
H e m at ol o g y
D
7. 2. 2. 5. 1 .
X
X
X  
X
A s cli ni c all y 
i n di c at e d
X
C h e mi str y - L F T
D
7. 2. 2. 5. 2 .
X
X  
X  
X  
X  
X  
X  
X
A s cli ni c all y 
i n di c at e d
X
C h e mi str y - ot h er
D
7. 2. 2. 5. 2 .
X
X
X  
X
A s cli ni c all y 
i n di c at e d
X

N o v arti s
C o nfi d e nti al
P a g e 5 0
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
S C R E E NI N G 
P H A S E
T R E A T M E N T P H A S E
F O L L O W U P P H A S E
Vi sit N a m e
C at e g or y
Pr ot o c ol 
S e cti o n
S cr e e ni n g 
C 1   
C 2   
C 3   
C 4   
C 5   
C 6 
C y cl e s 
7, 9, 
1 1, 1 3
C y cl e 1 6 a n d 
e v er y 3 r d c y cl e 
t h er e aft er u ntil 
E O T
E n d of st u d y 
tr e atm e nt ( E o T)
S af et y f oll o w u p
Effi c a c y f oll o w u p 
u ntil P D or u ntil 1 
y e ar fr o m L P F V
S ur vi v al f o ll o w u p 
u ntil 2 y e ar s fr o m 
L P F V
D a y of c y cl e
-2 8 t o 
- 1
-7 t o 
- 1
1
8
1 5 
1 
1 5 
1  
1  
1  
1  
1  
1
3 0 d a y s 
f oll o wi n g 
E O T
E v er y 
8 
w e e k s
E v er y 
1 2 
w e e k s
T h yr oi d P a n el
D
7. 2. 2. 5. 5 .
X
X
X  
X
A s cli ni c all y 
i n di c at e d
X
C o a g ul ati o n
D 
7. 2. 2. 5. 4 .
X
A s cli ni c all y i n di c at e d
X
Uri n al y si s
D 
7. 2. 2. 5. 3 .
X
X  
X  
X  
X  
X  
X  
X  
X
Uri n e Pr ot ei n/ Cr e ati ni n e 
r ati o
D
7. 2. 2. 5. 6 .
X
A s cli ni c all y i n di c at e d
X
2 4 - hr uri n e c oll e cti o n   
D 
7. 2. 2. 5. 7 .
A s cli ni c all y i n di c at e d
S er u m Pr e g n a n c y t e st
(if a p pli c a bl e)
D
7. 2. 2. 5. 8 .
X
X
Uri n e Pr e g n a n c y t e st
(if a p pli c a bl e)
D
7. 2. 2. 5. 8 .
X  
X  
X  
X  
X 
M o nt hl y at h o m e
P ati e nt di ar y f or 
pr e g n a n c y t e st
S
7. 2. 2. 5. 8 .
M o nt hl y at h o m e
T u m or a s s e s s m e nt s
T u m or e v al u ati o n
D 
7. 2. 1 .  
X
E v er y 8 w e e k s d uri n g t h e fir st y e ar a n d e v er y 1 2 w e e k s t h er e aft er 
X
X
B o n e s c a n
S 
7. 2. 1 .  
X
A s cli ni c all y i n di c at e d
C ar di a c a s s e s s m e nt s
E C G
D 
7. 2. 2. 6. 1 .
X
X  
X
X  
X  
X

N o v arti s
C o nfi d e nti al
P a g e 5 1
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
S C R E E NI N G 
P H A S E
T R E A T M E N T P H A S E
F O L L O W U P P H A S E
Vi sit N a m e
C at e g or y
Pr ot o c ol 
S e cti o n
S cr e e ni n g 
C 1   
C 2   
C 3   
C 4   
C 5   
C 6 
C y cl e s 
7, 9, 
1 1, 1 3
C y cl e 1 6 a n d 
e v er y 3 r d c y cl e 
t h er e aft er u ntil 
E O T
E n d of st u d y 
tr e atm e nt ( E o T)
S af et y f oll o w u p
Effi c a c y f oll o w u p 
u ntil P D or u ntil 1 
y e ar fr o m L P F V
S ur vi v al f o ll o w u p 
u ntil 2 y e ar s fr o m 
L P F V
D a y of c y cl e
-2 8 t o 
- 1
-7 t o 
- 1
1
8
1 5 
1 
1 5 
1  
1  
1  
1  
1  
1
3 0 d a y s 
f oll o wi n g 
E O T
E v er y 
8 
w e e k s
E v er y 
1 2 
w e e k s
C ar di a c i m a gi n g
D
7. 2. 2. 6. 2 .
X
X
C 1 1
o nl y
C 1 6
t h e n 
e v er y 6 t h
c y cl e
X
S af et y
A d v er s e e v e nt s
D 
8. 1 .
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
S ur gi c al/ m e di c al 
pr o c e d ur e s
D
7. 1. 1. 3 .
X  
X  
X 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
H e p at ot o xi cit y f oll o w -u p 
D 
6. 2. 1. 1 .
A s cli ni c all y i n di c at e d

N o v arti s
C o nfi d e nti al
P a g e 5 2
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
S C R E E NI N G 
P H A S E
T R E A T M E N T P H A S E
F O L L O W U P P H A S E
Vi sit N a m e
C at e g or y
Pr ot o c ol 
S e cti o n
S cr e e ni n g 
C 1   
C 2   
C 3   
C 4   
C 5   
C 6 
C y cl e s 
7, 9, 
1 1, 1 3
C y cl e 1 6 a n d 
e v er y 3 r d c y cl e 
t h er e aft er u ntil 
E O T
E n d of st u d y 
tr e atm e nt ( E o T)
S af et y f oll o w u p
Effi c a c y f oll o w u p 
u ntil P D or u ntil 1 
y e ar fr o m L P F V
S ur vi v al f o ll o w u p 
u ntil 2 y e ar s fr o m 
L P F V
D a y of c y cl e
-2 8 t o 
- 1
-7 t o 
- 1
1
8
1 5 
1 
1 5 
1  
1  
1  
1  
1  
1
3 0 d a y s 
f oll o wi n g 
E O T
E v er y 
8 
w e e k s
E v er y 
1 2 
w e e k s
P ati e nt R e p ort e d O ut c o m e s
E ur o Q o L E Q -5 D -5 L 
D
7. 2. 5 .
X 
( pr e d o s e)
X  
X  
X  
X  
X  
X  
X  
X
F K SI -D R S
D
7. 2. 5 .
X 
( pr e d o s e)
X  
X  
X  
X  
X  
X  
X  
X
Tr e at m e nt
St u d y Dr u g a d mi ni str ati o n 
D 
6. 1 .
D ail y d o si n g
Di s c o nti n u ati o n
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
D
7. 1. 5 .
X  
X  
X
S ur vi v al F oll o w -u p 
D 
7. 1. 5. 3 .
X
Di s p o siti o n
St u d y p h a s e di s p o siti o n 
D
7. 1. 1 , 
7. 1. 3 & 
7. 1. 5. 2 .
X
X
X

N o v arti s
C o nfi d e nti al
P a g e 5 3
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
7. 1. 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 pr oce d ure is perf or me d.
U p o n o btai ni n g c o nse nt , t he i n vesti gat or or his/ her dele gate will re gister t he patie n t i n t he IR T 
a n d pr o vi de t he i nf or mati o n re q ueste d b y t he s ys te m. 
Scree ni n g assess me nts t o c o nfir m eli gi bilit y will be d o ne wit hi n 1 t o 2 8 da ys pri or t o treat me nt 
start date or wit hi n 1 t o 7 da ys pri or t o treat me nt start date f or selecte d assess me nts (see Ta ble 
7- 1 f or list of assess me nt t o be perf or me d).
A n y  scree ni n g assess me nt t hat is d o ne o utsi de t he scree ni n g wi n d o w ( Da y -2 8 t o Da y  -1 or Da y 
-7 t o Da y  -1) m ust be re peate d pri or t o t he s u bject’s first d ose.
Re -scree ni n g of patie nts is per missi ble at t he discreti o n of t he i n vesti gat or. Re -scree ni n g s h o ul d 
o nl y  occ ur after a patie nt has faile d scree ni n g. T he sa me patie nt I D n u m ber s h o ul d be use d t o 
re-scree n. Re -scree ni n g s h o ul d n ot occ ur m ore ofte n t ha n e ver y 7 da ys. A re-scree ne d patie nt 
ma y  e nter t he st u d y o nly if all i ncl usi o n a n d n o e xcl usi o n criteria are met.
I ma gi n g assess me nts pre vi o usl y  perf or me d as part of t he patie nt’s r o uti ne disease care, 
i ncl u di n g t h ose d o ne bef ore si g ni n g t he mai n I C F, ca n be c o nsi dere d as t he baseli ne i ma ges f or 
t he st u d y if t he assess me nts were d o ne wit hi n 2 8 da ys pri or t o t he start of treat me nt.
T he Scree ni n g P hase Dis p ositi o n e C R F pa ge will be c o m plete d f or all patie nts at t he e n d of t he 
scree ni n g p hase.
7. 1. 1. 1 
Eli gi bilit y  s cr e e ni n g
Patie nts m ust meet all i ncl usi o n criteria (Secti o n 5. 2 ) a n d n o ne of t he e xcl usi o n criteria (Secti o n 
5. 3 ) criteria d uri n g t he scree ni n g p hase i n or der t o be eli gi ble for t he st u d y.
I n or der t o c o nfir m t he eli gi bilit y of the patie nt, a n eli gi bilit y chec klist m ust be c o m plete d via 
I R T b y  the i n vesti gat or or desi g nee o nce all scree ni n g pr oce d ures are c o m plete d a n d pri or t o 
t he patie nt’s first d ose. Please refer t o 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.
7. 1. 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
A patie nt w h o si g ns a n i nf or me d c o nse nt b ut fails t o satisf y all eli gi bilit y criteria f or a n y re as o n 
will be c o nsi dere d a scree n fail ure. T he f oll o wi n g i nf or mati o n will be c ollecte d i n t he cli nical 
data base f or all scree ni n g fail ures:

Visit date

I nf or me d co nse nt

De m o gra p h y

I ncl usi o n/ E xcl usi o n Criteria

Scree ni n g P hase Dis p ositi o n Pa ge

A d verse e ve nts ( o nl y if a n S A E occ urs - see Secti o n 8 f or S A E re p orti n g details)

Deat h (if a p plica ble)

Wit h dra wal of C o nse nt (if a p plica ble)

N o v arti s
C o nfi d e nti al
P a g e 5 4
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
N o ot her data will be e ntere d i nt o t he cli nical data base f or patie nts w h o are scree n fail ures. 
I n vesti gati ve staff m ust n otif y t he I R T sys te m of all scree n fail ures, prefera bl y wit hi n 2 da ys of 
t he scree n fail ure.
7. 1. 1. 3 
P ati e nt d e m o gr a p hi c s a n d ot h er b a s eli n e c h ar a ct eri sti c s
T he f oll o wi n g data will be c ollecte d o n patie nt c haracteristics at scree ni n g, u nless ot her wise 
s pecifie d i n t he res pecti ve secti o n:

De m o gra p h y (i ncl u di n g: year of birt h, ge n der, c hil d beari n g p ote ntial, race a n d et h nicit y , 
or as all o we d b y l ocal re g ulati o ns)

Dia g n osis a n d e xte nt of ca ncer (i ncl u di n g sta gi n g at st u d y  e ntr y a n d hist ol o g y/ c yt ol o g y)

M S K C C ris k sc ore (refer t o Secti o n 7. 1. 1. 3. 1 )

Me dical hist or y  (e. g., i m p orta nt medical, s ur gical, a n d aller gic c o n diti o ns fr o m t he 
patie nt’s me dical hist or y  w hic h c o ul d ha ve a n i m pact o n t he patie nt’s e val uati o n) / c urre nt 
me dical c o n diti o ns (e. g., all rele va nt c urre nt me dical c o n diti o ns w hic h are prese nt at t he 
ti me of si g ni n g i nf or med c o nse nt). O n g oi n g me dical c o n diti o ns, s y m pt o ms a n d disease 
w hic h are rec or de d o n t he Me dical Hist or y  e C R F s h o ul d i ncl u de t he t o xicit y gra de.

All pri or a nti ne o plastic t hera pies i ncl u di n g s ur gical i nter ve nti o ns a n d c he m o -, bi ol o gic-, 
i m m u n ol o gic- a n d ra diati o n-t hera pies pr o vi de d as treat me nt f or ca ncer pri or t o t he 
a d mi nistrati o n of st u d y dr u g.

All me dicati o ns a n d si g nifica nt n o n -dr u g t hera pies ta ke n wit hi n 3 0 da y s bef ore t he first 
d ose is a d mi nistere d m ust be rec or de d o n t he Pri or a n d C o nc o mita nt me dicati o n or 
S ur gical a n d me dical pr oce d ures e C R F pa ge a n d u p date d o n a c o nti n ual basis if t here are 
a n y ne w c ha n ges t o t he me dicati o ns.

Patie nt -re p orte d o utc o me q uesti o n naires ( E Q- 5 D-5 L  a n d F K SI-D R S ( See Secti o n 7. 2. 5 )).
Baseli ne (i.e ., scree ni n g peri o d) q uesti o n naires s h o ul d n ot be a d mi nistere d u ntil t he patie nt
is c o nfir me d t o be eli gi ble f or t he st u d y;  q uesti o n naires ma y be c o m plete d o n C ycle 1 Da y 
1 pri or t o start of treat me nt. 
F urt her m ore t he f oll o wi n g ass ess me nts will be perf or me d:

Vital si g ns

Hei g ht, wei g ht

P h y sical e xa mi nati o n

Perf or ma nce stat us ( Kar n ofs k y )

La b orat or y  e val uati o ns ( he mat ol o g y, c he mistr y, uri nal ysis, c oa g ulati o n, t h yr oi d, U P C, a n d 
2 4- hr uri ne c ollecti o n, if necessar y, ser u m pre g na nc y  test as a p plica ble)

E C G

E C H O/ M U G A

Ra di ol o gical assess me nts (e. g. , C T Sca n)

C ollecti o n of arc hi val t u m or sa m ple

C ollecti o n of ne wl y  o btai ne d t u m or sa m ple ( o pti o nal)

N o v arti s
C o nfi d e nti al
P a g e 5 5
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
7. 1. 1. 3. 1 Ri s k f a ct or s f or M S K C C pr o g n o si s
T he f oll o wi n g pr o g n ostic criteria were i de ntifie d i n pre vi o usl y  treate d patie nts wit h a d va nce d 
R C C ( M otzer et al 2 0 0 4 ):

Kar n ofs k y perf or ma nce stat us ( < 8 0 %)

L o w ser u m he m o gl o bi n ( ≤ 1 3 g/ d L f or males a n d < 1 1. 5 g/ d L f or fe males)

Hi g h c orrecte d ser u m calci u m ( ≥ 1 0 m g/ d L )
T a bl e 7- 2 
M S K C C pr o g n o sti c crit eri a
Pr o g n o si s
N u m b er of Ri s k F a ct or s
F a v or a bl e
0
I nt er m e di at e
1
P o or
2 or 3
M ot z er et al ( 2 0 0 4) .
7. 1. 2 
Tr e at m e nt p eri o d
Patie nts will be treate d wit h paz o pa ni b u ntil disease pr o gressi o n, u nacce pta ble t o xicit y , deat h,
disc o nti n uati o n fr o m t he st u d y treat me nt d ue t o a n y ot her reas o n or u ntil t w o years after t he last 
patie nt is e nr olle d. F or details of assess me nts, refer t o Ta ble 7 - 1.
7. 1. 3 
Di s c o nti n u ati o n of st u d y tr e at m e nt
Patie nts ma y  v ol u ntarily disc o nti n ue fr o m t he st u d y treat me nt f or a n y reas o n at a n y ti me.
If a patie nt deci des t o disc o nti n ue fr o m t he st u d y treat me nt, t he i n vesti gat or s h o ul d ma ke a 
reas o na ble eff ort (e. g., tele p h o ne, e-mail, letter) t o u n dersta n d t he pr i mary reas o n f or t his 
decisi o n a n d rec or d t his i nf or mati o n i n t he patie nt’s c hart a n d o n t he a p pr o priate e C R F pa ges. 
T he y  ma y be c o nsi dere d wit h dra w n if t he y state a n i nte nti o n t o wit h dra w, fail t o ret ur n f or visits, 
or bec o me l ost t o f oll o w -u p f or a n y ot h er reas o n.
T he i n vesti gat or m a y  disc o nti n ue st u d y treat me nt f or a gi ve n patie nt if he/s he belie ves t hat 
c o nti n uati o n w o ul d be detri me ntal t o t he patie nt’s well- bei n g.
I n a d diti o n t o ma n dat or y d ose i nterr u pti o ns a n d/ or re d ucti o ns of st u dy t reat me nt liste d i n Ta ble 
6- 3 , st u d y treat me nt m ust als o be disc o nti n ue d u n der t he f oll o wi n g circ u msta nces:

A d verse e ve nt or la b a b n or malit y  as i n dicate d i n Secti o n 6. 2 , or a d ose i nterr u pti o n of 
m ore t ha n 2 1 da y s

Pr o gressi ve disease

Pre g na nc y

Deat h

S u bject/ g uar dia n decisi o n

L ost t o f oll o w - u p
St u d y  treat me nt ma y als o be disc o nti n ue d if a n y of t he f oll o wi n g occ ur:

Pr ot oc ol de viati o n

St u d y  ter mi nate d b y s p o ns or

N o v arti s
C o nfi d e nti al
P a g e 5 6
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0

Tec h nical pr o ble ms

P h y sicia n decisi o n
Patie nts w h o disc o nti n ue st u d y treat me nt s h o ul d N O T be c o nsi dere d wit h dra w n fr o m t he st u d y. 
T he y  sh o ul d ret ur n f or t he assess me nts i n dicate d i n Ta ble 7- 1 . 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 m as s pecifie d i n Secti o n 7. 1. 6 .
Patie nts w h o disc o nti n ue st u d y treat me nt s h o ul d u n der g o a n E n d of St u d y  treat me nt visit 
f oll o we d b y a 3 0 da y safet y foll o w -u p. T he “ E n d of Treat me nt P hase Dis p ositi o n” e C R F pa ge 
m ust be c o m plete d, gi vi n g t he date a n d pri mar y  reas o n f or disc o nti n uati o n.
T he i n vesti gat or m ust als o c o ntact t he I RT t o re gister t he patie nt’s disc o nti n uati o n fr o m st u d y 
treat me nt.
F or patie nts w h o disc o nti n ue treat me nt f or reas o ns ot her t ha n d oc u me nte d disease pr o gressi o n, 
deat h, l ost t o f oll o w-u p, or wit h dra wal of c o nse nt bef ore L P F V + 1 ye ar, t u m or assess me nts 
m ust c o nti n ue t o be perf or me d e ver y 8 wee ks u ntil d oc u me nte d disease pr o gressi o n, deat h, l ost 
t o f oll o w-u p, wit h dra wal of c o nse nt or u ntil o ne ye ar fr o m L P F V.
7. 1. 3. 1 
R e pl a c e m e nt p oli c y
N ot a p plica ble
7. 1. 4 
Wit h dr a w al of c o n s e nt
Patie nts ma y  vol u ntaril y w it h dra w c o nse nt t o partici pate i n t he st u d y for a n y reas o n at a n y t i me. 
Wit h dra wal of c o nse nt occ urs o nl y w h e n a patie nt d oes n ot wa nt t o partici pate i n t he st u d y a n y 
l o n ger, a n d d oes n ot wa nt a n y f urt her visits or assess me nts, a n d d oes n ot wa nt a n y furt her st u d y 
relate d c o ntact.
N o vartis wi ll c o nti n ue t o retai n a n d use all researc h res ults t hat ha ve alrea d y bee n c ollecte d f or 
t he st u d y eval uati o n. All bi ol o gical sa m ples t hat ha ve alrea d y bee n c ollecte d m a y  be retai ne d 
a n d a nal yz e d at a later date ( or as re q uire d b y l ocal re g ulati o ns).
If a p atie nt wit h dra ws c o nse nt, t he i n vesti gat or s h o ul d ma ke a reas o na ble eff ort (e. g. tele p h o ne, 
e-mail, letter) t o u n dersta n d t he pri mar y  reas o n f or t his decisi o n a n d rec or d t his i nf or mati o n.
St u d y  treat me nt m ust be disc o nti n ue d a n d n o f urt her assess me nts c o n d ucte d.
F urt her atte m pts t o c o ntact t he patie nt
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 o n or f oll o w u p.
7. 1. 5 
F oll o w - u p p h a s e s
7. 1. 5. 1 
S af et y  foll o w -u p
All patie nts m ust ha ve safet y  e val uati o ns f or 3 0 da ys after t he last d ose of st u d y treat me nt.
Data collecte d s h o ul d be a d de d t o t he A d verse E ve nts e C R F, t he S ur gical a n d Me dical 
Pr oce d ures e C R F, t he C o nc o mita nt Me dicati o ns e C R F a n d t he “ A nti ne o plastic T hera p y  Si nce 
Disc o nti n uati o n 
of St u d y  Treat me nt” e C R F f or t he first a nti ne o plastic t hera py t o be 
a d mi nistere d t o t he patie nt si nce st u d y dr u g disc o nti n uati o n.

N o v arti s
C o nfi d e nti al
P a g e 5 7
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Patie nt s w h ose treat me nt is i nterr u pte d or per ma ne ntl y  disc o nti n ue d d ue t o a n a d verse e ve nt, 
i ncl u di n g a b n or mal la b orat or y val ue, m ust be f oll o we d u ntil res ol uti o n or sta bilizati o n of t he 
e ve nt, w hic h e ver c o mes first. If patie nt s ref use t o ret ur n f or safety e val uati o n visits or are u na ble 
t o d o s o, e ver y eff ort s h o ul d be ma de t o c o ntact t he m b y  tele p h o ne t o deter mi ne t heir stat us. 
Atte m pts t o c o ntact t he patie nt s h o ul d be d oc u me nte d i n t he s o urce d oc u m e nts (e. g., dates of 
tele p h o ne calls, re gistere d letters, etc.).
7. 1. 5. 2 
Effi c a c y  foll o w -u p
Patie nts w h o disc o nti n ue st u d y treat me nt wit h o ut disease pr o gressi o n b y  RE CI S T 1. 1 bef ore 
L P F V + 1 year will c o nti n ue t o be f oll o we d f or efficac y ever y  8 wee ks. I n ad diti o n t o t he 
efficac y f oll o w-u p, t he first a nti ne o plastic t hera p y t o be a d mi nistere d t o t he patie nt si nce st u d y 
dr u g disc o nti n uati o n will be d oc u me nte d o n t he “ A nti ne o plastic T hera p y Si nce Disc o nti n uati o n 
of St u d y  Treat me nt” e C R F pa ges. F or f urt her details, please refer t o Ta ble 7 - 1.
E n d of p ost -treat me nt f oll o w- u p (i.e., efficac y foll o w u p) m a y  occ ur d ue t o o ne of t he f oll o wi n g 
reas o ns:

L P F V + 1 ye ar

A d verse e ve nt

Deat h

Pr o gressi ve disease

Pre g na nc y

Pr ot oc ol de viati o n

St u d y  ter mi nate d b y s p o ns or

Tec h nical pr o ble ms

L ost t o f oll o w - u p

P h y sicia n decisi o n

S u bject/ g uar dia n decisi o n
At t hat ti me, t he patie nt will e nter i nt o t he s ur vi val f oll o w-u p p hase, if a p plica ble, a n d t he reas o n 
f or c o m pleti o n of t he efficac y f oll o w- u p p hase will be rec or de d o n t he “ E n d of P ost Treat me nt 
P hase Dis p ositi o n” e C R F pa ge.
7. 1. 5. 3 
S ur vi v al foll o w -u p
I n or der t o assess o verall s ur vi val, patie nts will be f oll o we d f or s ur vi val e ver y 12 wee ks u ntil 
t he st u d y en ds (i.e., L P F V + 2 years). Patie nts, w h o disc o nti n ue st u d y treat me nt wit h o ut disease 
pr o gressi o n b y  RE CI S T 1. 1 a n d e nter t he efficac y foll o w - u p, will n ot be gi n t he s ur vi val f oll o w-
u p u ntil after t he efficac y f oll o w -u p peri o d e n ds. Patie nts, w h o disc o nti n ue st u d y treat me nt d ue 
t o pr o gressi o n b y R E CI S T 1. 1 at a n y ti me or f or a n y reas o n after L P F V + 1 ye ar, will be gi n 
s ur vi val f oll o w- u p f oll o wi n g e n d of treat me nt. S ur vi val i nf or mati o n ca n be o btai ne d b y  cli nical 
visits or tele p h o ne calls u ntil deat h, l ost t o f oll o w u p, t he patie nts wit h dra ws c o nsent f or s ur vi val 
f oll o w- u p or t he st u d y en ds. I n a d diti o n t o t his s ur vi val f oll o w- u p, t he first a nti ne o plastic 
t hera py t o be a d mi nistere d t o t he patie nt si nce st u d y dr u g disc o nti n uati o n will be d oc u me nte d 
o n t he “ A nti ne o plastic T hera p y Si nce Disc o nti n uati o n of St u d y  Treat me nt” e C R F pa ges.

N o v arti s
C o nfi d e nti al
P a g e 5 8
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
7. 1. 6 
L o st t o f oll o w -u p
F or patie nts w h ose stat us is u nclear beca 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 wit h dra w c o nse nt, t he i n vesti gat or s h o ul d s h o w " d ue dili ge nce" b y  co ntacti n g 
t he patie nt, fa mil y or fa mil y ph y sicia n as a gree d i n t he i nf or me d c o nse nt a n d b y  doc u me nti n g 
i n t he s o urce d oc u me nts ste ps ta ke n t o c o ntact t he patie nt, e. g., dates of tele p h o ne calls, 
re gistere d letters, etc. A patie nt s h o ul d n ot be c o nsi dere d l ost t o f oll o w- u p u ntil d ue dili ge nce 
has bee n c o m plete d. Patie nts l ost t o f oll o w u p s h o ul d be rec or de d as s uc h o n t he a p pr o priate 
Dis p ositi o n C R F.
7. 2 
A s s e s s m e nt t y p e s
7. 2. 1 
Effi c a c y  a s s e s s m e nt s
T u m or res p o nse will be assesse d l ocall y acc or di n g t o t he N o vartis g ui deli ne versi o n 3. 1 
(A p pe n di x 2 ) base d o n R E CIS T 1. 1 ( Eise n ha uer 2 0 0 9 ).
S cr e e ni n g i m a gi n g a s s e s s m e nt s
I ma gi n g assess me nts will be perf or me d at scree ni n g wit hi n 2 8 da y s pri or t o t he start date of 
treat me nt.
A n y  i ma gi n g assess me nts alrea d y co m plete d d uri n g t he re g ular w or k -u p f or t he patie nt wit hi n 
2 8 da y s pri or t o start of treat me nt, i ncl u di n g bef ore si g ni n g t he mai n st u d y IC F, ca n be 
c o nsi dere d as t he scree ni n g i ma ges f or t his st u d y .
T he f oll o wi n g i ma gi n g assess me nts are re q uire d at scree ni n g:

C hest, a b d o me n a n d pel vis C T or M RI

W h ole b o d y  b o ne sca n

Brai n C T or M RI, o nl y if s us pecte d brai n metastases

L ocalize d b o ne C T, M RI or x -ra y, f or a n y lesi o ns i de ntifie d o n t he w h ole b o d y b o ne sca n 
t hat are n ot visi ble o n t he c hest, a b d o me n a n d pel vis C T or M RI

C T or M RI  of ot her metastatic sites (e. g., nec k), if cli nicall y i n dicate d
If a patie nt is k n o w n t o ha ve a c o ntrai n dicati o n t o C T i ntra ve n o us c o ntrast me dia or de vel o ps a 
c o ntrai n dicati o n d uri n g t he trial, a n o n-c o ntrast C T of t he c hest pl us a c o ntrast -e n ha nce d M RI 
(if p ossi ble) of t he a b d o me n a n d pel vis s h o ul d be perf or me d. M RI 
of t he c hest is n ot 
rec o m me n de d d ue t o res pirat or y artifacts; h o we ver, if C T is n ot feasi ble per l ocal re g ulati o ns, 
M RI  ca n be perf or me d i nstea d.
If brai n metastases are s us pecte d d uri n g scree ni n g or at a n y ti me o n st u d y, brai n M RI  or C T 
s h o ul d be c o m plete d. C o ntrast e n ha nce d brai n M RI  is preferre d; h o we ver, if M RI c o ntrast is 
c o ntrai n dicate d, t he n M RI wit h o ut c o ntrast or C T wit h/ wit h o ut c o ntrast is acce pta ble.
A w h ole b o d y  sca n s h o ul d be perf or me d per i nstit uti o nal sta n dar d of care [e. g., T c - 9 9 b o ne 
sca n, w h ole b o d y  bo ne M RI , Fl u or o de o x y gl uc ose p ositr o n e missi o n t o m o gra p hy ( F D G-P E T) 
or s o di u m fl u ori de ( Na F) P E T] . L o calize d C T, M RI or X -ra ys s h o ul d be ac q uire d f or all s keletal 
lesi o ns i de ntifie d o n t he scree ni n g w h ole b o d y  bo ne sca n, w hic h are n ot visi ble o n t he c hest, 
a b d o me n a n d pel vis C T/ M RI.

N o v arti s
C o nfi d e nti al
P a g e 5 9
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
If cli nicall y i n dicate d, C T or M RI of ot her areas (e. g., nec k) of dis ease as a p pr o priate s h o ul d be 
perf or me d.
A n y  p ote ntiall y meas ura ble lesi o n t hat has bee n pre vi o usl y  treate d wit h ra di ot hera py s h o ul d be 
c o nsi dere d as a n o n- meas ura ble 
lesi o n. H o we ver, 
if a lesi o n pre vi o usl y  treate d wit h 
ra di ot hera py h as clearl y pr o gresse d si nce t he ra di ot hera p y, it ca n be c o nsi dere d as a meas ura ble 
lesi o n.
C hest x -ra ys a n d ultras o u n d s h o ul d n ot be use d t o meas ure t u m or lesi o ns.
P o st -b a s eli n e i m a gi n g a s s e s s m e nt s
I ma gi n g assess me nts as descri be d i n Ta ble 7- 3 s h o ul d be perf or me d at t he ti me p oi nts s pecifie d 
usi n g t he sa me i ma gi n g m o dalit y  use d at scree ni n g. I ma gi n g assess me nts f or res p o nse 
e val uati o n will be perf or me d e ver y 8 wee ks ( ± 7 da y s) d uri n g t he first year, a n d e ver y 12 wee ks 
(± 7 d a y s) t hereafter u ntil st u d y treat me nt disc o nti n uati o n f or disease pr o gressi o n, deat h, l ost t o 
f oll o w- u p, wit h dra wal of c o nse nt or t he e n d of t he st u d y. I ma gi n g assess me nts s h o ul d be 
sc he d ule d usi n g t he treat me nt start date ( Cycl e 1 Da y 1) as t he refere nce date ( n ot t he pre vi o us 
t u m or assess me nt date), a n d s h o ul d be res pecte d re gar dless of w het her t he st u d y treat me nt is 
te m p orarily wit h hel d or u nsc he d ule d assess me nts perf or me d.
A d diti o nal i ma gi n g assess me nts ma y  be perf or me d at a n y ti me d uri n g t he st u d y at t he
i n vesti gat or’s discreti o n t o s u p p ort t he efficac y e val uati o ns f or a s u bject, as necessar y. Cli nical 
s us pici o n of disease pr o gressi o n at a n y ti me re q uires a p h y sicia n e xa mi nati o n a n d i ma gi n g 
assess me nts t o be perf or me d pr o m ptl y  rat her t ha n waiti n g f or t he ne xt sc he d ule d i ma gi n g 
assess me nt.
Eac h lesi o n t hat is meas ure d at scree ni n g m ust be meas ure d b y  the sa me met h o d a n d w he n 
p ossi ble, t he sa me l ocal ra di ol o gist/ p hys icia n t hr o u g h o ut t he st u d y so t hat t he c o m paris o n is 
c o nsiste nt. If a n off -sc he d ule i ma gi n g assess me nt is perf or me d beca use pr o gressi o n is 
s us pecte d, s u bse q ue nt i ma gi n g assess me nts s h o ul d be perf or me d i n acc or da nce wit h t he 
ori gi nal i ma gi n g sc he d ule.
Partial Res p o nse ( P R) a n d C o m plete Res p o nse ( C R) m ust be c o nfir me d b y  re peat assess me nts 
perf or me d n ot less t ha n 4 wee ks a n d after t he criteria f or res p o nse are first met. P ositr o n 
E missi o n T o m o gra p h y ( P E T)/ C T ma y  be use d o nl y if t he C T c o m p o ne nt is of si milar dia g n ostic 
q ualit y  as a C T perf or me d wit h o ut P E T, i ncl u di n g t he utilizati o n of oral a n d i. v. c o ntrast me dia. 
At t he discreti o n of t he I n vesti gat ors, F D G -P E T sca ns m a y  be perf or me d t o d oc u me nt 
pr o gressi ve disease per R E CI S T 1. 1 ( A p pe n di x 2 ). If p ossi ble, a si n gle ra di ol o gist s h o ul d 
perf or m all t u m or res p o nse e val uati o ns f or a n i n di vi d ual patie nt. A n y  lesi o ns i n pre vi o usl y 
irra diate d areas s h o ul d n ot be c o nsi dere d meas ura ble u nless t he y ha ve e x perie nce d pr o gressi o n 
si nce t he ra di ot hera py. A n y pre -e xisti n g ra di o gra p hic fi n di n gs w hic h ma y  mi mic metastatic 
disease a n d a n y pri or ra di ot hera p y s h o ul d be rec or de d i n t he e C R F.
Res ults fr o m tiss ue or b o d y fl ui d c ollecti o n s h o ul d be rec or de d i n t he e C R F t o c o m ple me nt 
ra di o gra p hic fi n di n gs.
If a patie nt disc o nti n ues treat me nt f or reas o ns ot her t ha n ra di ol o gical d oc u me ntati o n of 
pr o gressi o n of disease, a n efficac y assess me nt s h o ul d be perf or me d at t he ti me of E n d of 

N o v arti s
C o nfi d e nti al
P a g e 6 0
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Treat me nt u nless a C T/ M RI  for t u m or meas ure me nt was perf or me d wit hi n 2 1 da y s. Efficac y  
assess me nts s h o ul d t he n c o nti n ue as per t he sc he d ule d visits i n Ta ble 7 - 1 a n d Ta ble 7 - 3.
F or patie nts w h o disc o nti n ue treat me nt f or reas o ns ot her t ha n d o c u me nte d disease pr o gressi o n 
b y  RE CI S T 1. 1, deat h, l ost t o f oll o w- u p, or wit h dra wal of c o nse nt bef ore L P F V + 1 year, t u m or 
assess me nts m ust 
c o nti n ue t o be perf or me d e ver y 8 
wee ks u ntil d oc u me nte d disease 
pr o gressi o n, deat h, l ost t o f oll o w - u p, wit h dra wal of c o nse nt or u ntil LP F V + 1 y ear.
T he first s u bse q ue nt a nti-ne o plastic t hera py, i ncl u di n g start/e n d date, will be ca pt ure d i n t he 
a nti ne o plastic t hera p y si nce disc o nti n uati o n of treat me nt e C R F f or all patie nts.
T a bl e 7- 3 
I m a gi n g a s s e s s m e nt c oll e cti o n pl a n
Pr o c e d ur e
S cr e e ni n g/ B a s eli n e
D uri n g Tr e at m e nt/ F oll o w- u p
C h e st, a b d o m e n a n d 
p el vi s C T or M RI 
( wit h i ntr a v en o u s 
c o ntr a st 
e n h a n c e m e nt)
M a n d at e d wit hi n 2 8 d a y s pri or t o 
C y cl e 1 D a y 1
D uri n g tr e at m e nt: M a n d at e d, e v er y 8 w e e k s ( ± 7 
d a y s) d uri n g fir st y e ar a n d e v er y 1 2 w e e k s ( ± 7 
d a y s) t h er e aft er t h e n at E n d of Tr e at m e nt.
D uri n g effi c a c y f oll o w -u p: M a n d at e d, e v er y 8 
w e e k s ( ± 7 d a y s ) u ntil P D or u ntil 1 y e ar fr o m 
L P F V ( w hi c h e v er c o m e s fir st)
W h ol e b o d y b o n e 
s c a n
M a n d at e d wit hi n
2 8 d a y s pri or t o 
C y cl e 1 D a y 1
A s cli ni c all y i n di c at e d
Br ai n C T or M RI 
O nl y if s u s p e ct e d br ai n m et a st a s e s 
A s cli ni c all y i n di c at e d
L o c ali z e d b o n e C T, 
M RI or x -r a y
F or a n y l e si o n s i d e ntifi e d o n t h e 
w h ol e b o d y b o n e s c a n t h at ar e n ot 
vi si bl e o n t h e c h e st, a b d o m e n a n d 
p el vi s C T or M RI
If l e si o n s w er e d o c u m e nt e d at b a s eli n e, f oll o w 
s a m e s c h e d ul e a s C T/ M RI of c h e st, a b d o m e n, 
a n d p el vi s.
F or a n y n e w l e si o n s i d e ntifi e d o n t h e w h ol e b o d y 
b o n e s c a n t h at ar e n ot vi s i bl e o n t h e c h e st, 
a b d o m e n a n d p el vi s C T or M RI.
C T or M RI of ot h er 
m et a st ati c sit e s ( e. g., 
n e c k)
If cli ni c all y i n di c at e d
If l e si o n s w er e d o c u m e nt e d at b a s eli n e, f oll o w 
s a m e s c h e d ul e a s C T/ M RI of c h e st, a b d o m e n, 
a n d p el vi s
7. 2. 2 
S af et y  a n d t ol er a bilit y a s s e s s m e nt s
Safet y  will be m o nit ore d b y  assessi n g p h y sical e xa mi nati o ns, Kar n ofs k y perf or ma nce stat us, 
hei g ht a n d wei g ht, vital si g ns, E C G, car diac i ma gi n g, patie nt re p orte d o utc o mes, la b orat or y 
assess me nts i ncl u di n g he mat ol o g y , c he mistr y, c oa g ulati o n, t h yr oi d pa nel, pre g na nc y  testi n g 
a n d uri nal y sis.  
All a d verse e ve nts, s ur gical a n d me dical 
pr oce d ures a n d c o nc o mita nt 
me dicati o ns will be c ollecte d at e ver y visit. F or details o n A E c ollecti o n a n d re p orti n g, refer t o 
Secti o n 8 .
7. 2. 2. 1 
P h y si c al e x a mi n ati o n
T he p h y sical e xa mi nati o n c o m prises a t otal b o d y e xa mi nati o n t hat s h o ul d i ncl u de: ge neral 
a p peara nce, s ki n, nec k (i ncl u di n g t h yr oi d), e yes, ears, n ose, t hr oat, l u n gs, heart, a b d o me n, bac k, 
l ym p h -n o des, e xtre mities, vasc ular a n d ne ur ol o gical re vie w. If i n dicate d, rectal, e xter nal 
ge nitalia, breast a n d pel vis e xa ms will be perf or me d. I nf or mati o n a b o ut t he p h y sical 
e xa mi nati o n m ust be prese nt i n t he s o urce d oc u me ntati o n at t he st u d y site. P h y sical e xa mi nati o n 
is t o be perf or me d acc or di n g t o t he visit sc he d ule as o utli ne d i n Ta ble 7 -1 .
Si g nifica nt fi n di n gs t hat were prese nt pri or t o t he si g ni n g of i nf or me d c o nse nt m ust be i ncl u de d 
i n t he Me dical Hist or y  pa ge o n t he pat ie nt’s e C R F. Si g nifica nt ne w fi n di n gs t hat be gi n or 

N o v arti s
C o nfi d e nti al
P a g e 6 1
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
w orse n after i nf or me d c o nse nt m ust be rec or de d o n t he A d verse E ve nt pa ge of t he patie nt’s 
e C R F.
7. 2. 2. 2 
Vit al si g n s
Vital si g ns i ncl u de bl o o d press ure (s u pi ne p ositi o n preferre d w he n E C G is c ollecte d), p ulse 
meas ure me nt, a n d b o d y  te m perat ure. Vital si g ns will be m o nit ore d as per t he visit sc he d ule (see 
Ta ble 7 - 1).
7. 2. 2. 3 
H ei g ht a n d w ei g ht
Hei g ht will be meas ure d at scree ni n g.
B o d y wei g ht (i n i n d o or cl ot hi n g, b ut wit h o u t s h oes) will be meas ure d at scree ni n g a n d at 
s u bse q ue nt ti me p oi nts as s pecifie d i n Ta ble 7 - 1.
7. 2. 2. 4 
P erf or m a n c e st at u s
Perf or ma nce stat us will be assesse d acc or di n g t o t he Kar n ofs k y p erf or ma nce stat us scale (Ta ble 
7- 4 ) f oll o wi n g t he sc he d ule gi ve n i n Ta ble 7 - 1.
T a bl e 7 - 4 
K ar n of s k y  p erf or m a n c e st at u s
S c or e ( %)
P erf or m a n c e St at u s
1 0 0
N or m al: n o c o m pl ai nt s
9 0
A bl e t o c arr y o n n or m al a cti vit y; mi n or si g n s or s y m pt o m s of di s e a s e
8 0
N or m al a cti vit y wit h eff ort; s o m e si g n s or s y m pt o m s of di s e a s e
7 0
C ar e s f or s elf; u n a bl e t o c arr y o n n or m al a cti vit y or d o a cti v e w or k
6 0
R e q uir e s o c c a si o n al a s si st a n c e b ut i s a bl e t o c ar e f or m o st of hi s n e e d s
5 0
R e q uir e s c o n si d er a bl e a s si st a n c e a n d fr e q u e nt m e di c al c ar e
4 0
Di s a bl e d: r e q uir e s s p e ci al c ar e a n d a s si st a n c e
3 0
S e v er el y di s a bl e d: h o s pit ali z ati o n i s i n di c at e d t h o u g h d e at h n ot i m mi n e nt
2 0
V er y si c k; h o s pit ali z ati o n i s n e c e s s ar y; a cti v e s u p p ort tr e at m e nt i s n e c e s s ar y
1 0
M ori b u n d; f at al pr o c e s s e s pr o gr e s si n g r a pi dl y
0
D e a d
7. 2. 2. 5 
L a b or at or y  e val u ati o n s
Cli nical la b orat or y anal yses ( he mat ol o g y, c he mistr y, c oa g ulati o n, t h yr oi d pa nel, U P C, 2 4- hr 
uri ne c ollecti o n a n d pre g na nc y  testi n g) will be perf or me d b y  the ce ntral la b orat or y. Di pstic k 
uri nal y sis a n d uri ne pre g na nc y testi n g will be perf or me d l ocall y wit h materials s u p plie d b y  t he 
ce ntral la b orat or y. Details o n t he c ollecti o n, s hi p me nt of sa m ples a n d re p orti n g of res ults b y  the 
ce ntral la b orat or y are pr o vi de d t o i n vesti gat ors i n t he la b orat or y ma n ual. Visit wi n d o ws of ± 3 
da y s are all o we d.
I n or der t o m o nit or patie nts’ safet y d uri n g t he st u d y, t he la b orat or y assess me nts o utli ne d i n t he 
pr ot oc ol are t he mi ni m u m re q uire me nt. S o me patie nts ma y  nee d m ore fre q ue nt la b orat ory 
assess me nts or ot her s pecific la b orat or y testi n g. A d diti o nal la b orat or y testi n g ma y  be per f or me d 
ce ntrall y or at a l ocal la b orat or y, i n e mer ge nc y sit uati o ns. He pat ot o xicit y f oll o w- u p testi n g 
( descri be d i n Ta ble 6 -2 , Ta ble 7 - 5 a n d Secti o n 6. 2. 1. 1 ) m ust be d o ne l ocall y.

N o v arti s
C o nfi d e nti al
P a g e 6 2
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
W he ne ver 
l ocal la b orat or y assess me nts (i.e., f or a n y u nsc he d ule d la b orat or y assess me nts), 
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 e C R F. A n y 
c ha n ges re gar di n g n or mal ra n ges 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 must 
be re p orte d via a n u p date d ta b ulati o n i n dicati n g the ne w effecti ve date. A d diti o nall y , if at a n y 
ti me a patie nt has la b orat or y  para meters o btai ne d fr o m a differe nt ( o utsi de) la b orat or y, N o vartis 
m ust be pr o vi de d wit h a c o p y of t he certificati o n a n d a ta b ulati o n of t he n or mal ra n ges a n d u nits 
f or t his la b orat or y as well. T he i n vesti gat or is res p o nsi ble f or re vie 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 nce.
At a n y t i 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 rel e 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 ym pt o ms or si g ns, or re q uire t hera pe utic 
i nter ve nti o n), w het her s pecifically re q ueste d i n t he pr ot oc ol o r 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 ( N CI-C T C A E) versi o n 4. 0 3. A d diti o nal a nal yses are left t o t he discreti o n of t he 
i n vesti gat or.
U nless s pecifie d i n Ta ble 7- 5, all la b orat or y an al y ses will be perf or me d ce ntrall y an d t he ce ntral 
res ults will be electr o nicall y tra nsferre d t o t he data base.
T a bl e 7- 5 
Cli ni c al l a b or at or y  p ar a m et er s c oll e cti o n pl a n
T e st C at e g or y
T e st N a m e
H e m at ol o g y
W h it e bl o o d c ell s, H e m o gl o bi n, Pl at el et s, Diff er e nti al ( N e utr o p hil s, L y m p h o c yt e s, 
E o si n o p hil s, B a s o p hil s, M o n o c yt e s, B a n d s, Ot h er)
C h e mi str y - L F T
Li v er f u n cti o n t e st s: Al k ali n e p h o s p h at a s e ( A L P), Al a ni n e a mi n otr a n sf er a s e ( A L T), 
A s p art at e a mi n otr a n sf er a s e ( A S T), Di r e ct Bilir u bi n, T ot al Bilir u bi n
C h e mi str y - ot h er 
Al b u mi n, C al ci u m, M a g n e si u m, P h o s p h at e, S o di u m, P ot a s si u m, T ot al C h ol e st er ol,
Cr e ati ni n e, Bl o o d Ur e a Nitr o g e n ( B U N) or Ur e a, A m yl a s e, Li p a s e, Gl u c o s e (f a sti n g or 
n o n -f a sti n g), L D H, Uri c a ci d, Cr e ati ni n e ki n a s e
Uri n al y si s 1
M a cr o s c o pi c P a n el ( Di p sti c k) ( Bilir u bi n, Bl o o d, Gl u c o s e, K et o n e s, L e u k o c yt e s 
e st er a s e, p H, Pr ot ei n)
C o a g ul ati o n
I nt er n ati o n al n or m ali z e d r ati o [I N R], A cti v at e d p arti al t hr o m b o pl a sti n ti m e ( A P T T) i n 
s e c s, A cti v at e d p arti al t hr o m b o pl a sti n ti m e ( A P T T P) i n %
T h yr oi d 2
T 3 [fr e e], T 4 [fr e e], T S H
Uri n e Pr ot ei n/ 
Cr e ati ni n e r ati o ( U P C)
At s cr e e ni n g, e n d of tr e at m e nt a n d a s cli ni c all y i n di c at e d.
2 4 - hr uri n e c oll e cti o n 
T ot al uri n e v ol u m e c oll e ct e d, uri n e cr e ati ni n e e x cr eti o n, uri n e pr ot ei n e x cr eti o n, t ot al 
uri n e cr e ati ni n e cl e ar a n c e t o b e d o n e a s cli ni c al l y i n di c at e d.
Pr e g n a n c y T e st 1, 3
S er u m pr e g n a n c y t e st i s r e q uir e d at s cr e e ni n g a n d e n d of tr e at m e nt.
M o nt hl y uri n e pr e g n a n c y t e s ti n g i s r e q uir e d d uri n g tr e at m e nt. Uri n e pr e g n a n c y t e st s 
will b e c o n d u ct e d l o c all y d uri n g sit e vi sit s o n D a y 1 of C y cl e s 2 t hr o u g h 6. Aft er C y cl e 
6, p ati e nt s will b e r e q uir e d t o p erf or m m o nt hl y at -h o m e uri n e pr e g n a n c y t e st s w hi c h 
will b e r e c or d e d o n a p ati e nt di ar y.

N o v arti s
C o nfi d e nti al
P a g e 6 3
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
T e st C at e g or y
T e st N a m e
Vir al h e p atiti s s er ol o gi c 
t e st s a n d ot h er t e st s f or 
h e p at ot o xi cit y f oll o w -u p 4
Li v er E v e nt – A ut oi m m u n e:: A nti - s m o ot h m u s cl e a nti b o di e s, A N A tit er, L K M-1 
a nti b o di e s, A nti - S L A a nti b o di e s, A nti n u cl e ar a nti b o di e s – p att er n
Li v er E v e nt - I m m u n o gl o b uli n: I m m u n o gl o b uli n G, M, E, A
Li v er E v e nt - Vir al S er ol o g y: A nti -H A V I g M ( c o d e d 5 ), H A V T ot al S er ol o g y, H B s A g, 
A nti - H B c I g M ( c o d e d), H B V D N A ( c o d e d), H C V a nti b o d y, H C V-R N A ( c o d e d), H D V 
R N A ( c o d e d), A nti - H E V I g M ( c o d e d), H E V I g G ( c o d e d), H E V-R N A ( c o d e d), A n ti-E B V 
I g M ( c o d e d), A nti-H S V I g M ( c o d e d), A nti -C M V I g M ( c o d e d)
Li v er E v e nt - Li v er F u n cti o n T e st s: A S T ( S G O T), A L T ( S G P T), Al k ali n e p h o s p h at a s e, 
G G T, 5 Pri m e n u cl e oti d a s e, Bilir u bi n (t ot al), Dir e ct bilir u bi n, Al b u mi n, Pr ot hr o m bi n 
ti m e, Pr ot hr o m bi n ti m e % (Q ui c k s t e st), I N R, L D H, E o si n o p hil s ( %), E o si n o p hil s 
( a b s ol ut e), Cr e ati n e ki n a s e ( Cr e ati n e p h o s p h o ki n a s e)
1 U ri n al y si s a s w ell a s t h e o n -sit e uri n e pr e g n a n c y t e sti n g will b e d o n e l o c all y wit h m at eri al s pr o vi d e d b y t h e 
c e ntr al l a b or at or y. Uri n al y si s r e s ult s m u st b e e nt er e d o n t h e e C R F.
2 I nt erf er e n c e wit h T ot al T 3 a n d Fr e e T 4 a s s a y s m a y b e o b s er v e d i n p ati e n ts t a ki n g hi g h d o s e s of bi oti n. It i s 
r e c o m m e n d e d a n y bi oti n s u p pl e m e nt s b e st o p p e d f or 3 d a y s pri or t o s a m pli n g.  
3 At h o m e pr e g n a n c y t e st kit s will b e pr o vi d e d b y t h e i n v e sti g at or.
4 H e p at ot o xi cit y f oll o w -u p t e sti n g/ pr o c e d ur e s will b e p erf or m e d l o c all y , w h er e l o c all y a v ail a bl e.
5 W h er e v er i n di c at e d, “( c o d e d)” m e a n s a q u alit ati v e r e s ult ( n e g ati v e or p o siti v e) i s r e q uir e d.
7. 2. 2. 5. 1 H e m at ol o g y
He mat ol o g y  tests are t o be perf or me d ce ntrall y acc or di n g t o t he Visit E val uati o n Sc he d ule 
o utli ne d i n Ta ble 7 - 1. F or details of t he he mat ol o g y panel refer t o Ta ble 7 - 5.
7. 2. 2. 5. 2 Cli ni c al c h e mi str y
Cli nical c he mistr y tests are t o be perf or me d ce ntrall y acc or di n g t o t he Visit E val uati o n Sc he d ule 
o utli ne d i n Ta ble 7 - 1. F or details of t he c he mistr y pa nels, refer t o Ta ble 7 - 5.
7. 2. 2. 5. 3 Uri n al y si s
Uri nal y sis usi n g a di pstic k is t o be perf or me d l ocall y wit h materials s u p plie d b y  the ce ntral la b. 
F or details of t he test, refer t o Ta ble 7 - 5.
7. 2. 2. 5. 4 C o a g ul ati o n
C oa g ulati o n is t o be perf or me d ce ntrall y acc or di n g t o t he Visit E val uati o n Sc he d ule o utli ne d i n 
Ta ble 7 - 1. F or details of t he c oa g ulati o n pa nel, refer t o Ta ble 7 - 5.
7. 2. 2. 5. 5 T h yr oi d
T h y r oi d pa nel is t o be perf or me d ce ntrally acc or di n g t o t he Visit E val uati o n Sc he d ule o utli ne d 
i n Ta ble 7 - 1. F or details of t he t h yr oi d pa nel, refer t o Ta ble 7 - 5.
7. 2. 2. 5. 6 Uri n e pr ot ei n/ cr e at i ni n e rati o
U P C is t o be perf or me d ce ntrall y acc or di n g t o t he Visit E val uati o n Sc he d ule o utli ne d i n Ta ble 
7- 1 .

N o v arti s
C o nfi d e nti al
P a g e 6 4
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
7. 2. 2. 5. 7 2 4 -h o ur uri n e c o ll e cti o n
2 4 -h o ur uri ne c ollecti o n is t o be perf or me d acc or di n g t o t he Visit E val uati o n Sc he d ule o utli ne d 
i n Ta ble 7- 1 . Uri ne will be c ollecte d o ver a 2 4- h o ur peri o d usi n g materials s u p plie d b y  the 
ce ntral la b. T he a nal ys is of t he 2 4-h o ur uri ne c ollecti o n will be perf or me d ce ntra ll y.
7. 2. 2. 5. 8 Pr e g n a n c y t e sti n g
Ser u m pre g na nc y  tests are re q uire d at scree ni n g a n d e n d of treat me nt f or w o me n of c hil d-
beari n g p ote ntial.
M o nt hl y  uri ne pre g na nc y  testi n g is re q uire d d uri n g treat me nt f or w o me n of c hil d-beari n g 
p ote ntial. Uri ne pre g na nc y  tests f or use d uri n g o n-site visits will be s u p plie d b y  t he ce ntral la b 
a n d will be perf or me d l ocall y  d uri n g site visits o n Da y 1 of C ycles 2 t hr o u g h 6. After C ycle 6, 
w o me n of c hil d-beari n g p ote ntial will be re q uire d t o perf or m m o nt hl y  at-h o me uri ne pre g na nc y 
tests. At -h o me pre g na nc y test kits will be s u p plie d b y  the i n vesti gat or.  Patie nts w h o a d mi nister 
t he uri ne pre g na nc y  test at h o me will c o m plete a si m ple diar y  wit h t he dates a n d o utc o me of 
t he uri ne pre g na nc y  test w hile o n st u d y treat me nt. Patie nts s h o ul d be i nstr ucte d t o bri n g t he 
diar y wit h t he m t o e ver y  visit.
Please refer t o t he Secti o n 5. 3 f or t he defi niti o n of w o me n of c hil d-beari n g p ote ntial.
7. 2. 2. 6 
C ar di a c a s s e s s m e nt s
7. 2. 2. 6. 1 El e ctr o c ar di o gr a m ( E C G)
A sta n dar d 1 2- lea d E C G will be perf or me d l ocall y at t he ti me p oi nts i n dicate d i n Ta ble 7- 6
bel o w. E C Gs s h o ul d be d o ne after t he patie nt has bee n resti n g f or 5- 1 0 mi n pri or t o eac h ti me 
p oi nt.
U nsc he d ule d E C Gs m a y  be perf or me d at t he discreti o n of t he i n vesti gat or at a n y ti me d uri n g 
t he st u d y a n d as cli nicall y i n dicate d.
T a bl e 7- 6 
L o c al E C G c oll e cti o n pl a n
C y cl e/ Vi sit
D a y
Ti m e p oi nt 
E C G T y p e
S cr e e ni n g
-7 t o - 1 
A n yti m e
1 2 L e a d
3
1
A n yti m e
1 2 L e a d
5
1
A n yti m e
1 2 L e a d
7
1
A n yti m e
1 2 L e a d
9
1
A n yti m e
1 2 L e a d
1 1
1
A n yti m e
1 2 L e a d
1 3
1
A n yti m e
1 2 L e a d
C y cl e 1 6 a n d e v er y 3 r d c y cl e (i. e. c y cl e 1 9, 2 2, 2 5, et c.) 
a n d E n d of Tr e at m e nt
1
A n yti m e
1 2 L e a d
U n s c h e d ul e d
A n yti m e
1 2 L e a d
I nter pretati o n of t he traci n g m ust be ma de b y  a qualifie d p h y sicia n a n d d oc u me nte d o n t he E C G 
C R F pa ge. Eac h E C G traci n g s h o ul d be la bele d wit h t he st u d y nu m ber, patie nt i nitials ( w here 
re g ulati o ns per mit), patie nt n u m ber, date, a n d ke pt i n t he s o urce d oc u me nts at t he st u d y site. 
Cli nicall y  si gnifica nt a b n or malities prese nt at scree ni n g s h o ul d be re p orte d o n t he Me dical 

N o v arti s
C o nfi d e nti al
P a g e 6 5
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Hist or y  CR F pa ge. Cli nicall y  sig nifica nt fi n di n gs m ust be disc usse d wit h N o vartis pri or t o 
e nr olli n g t he patie nt i n t he st u d y. Ne w or w orse ne d cli nicall y si g nifica nt fi n di n gs occ urri n g 
after i nf or me d c o nse nt m ust be rec or de d o n t he A d verse E ve nts C R F pa ge .  Refer t o Ta ble 6. 2 
f or a d ditio nal m o nit ori n g re q uire me nts if t he Q Tc F i nter val is ≥ 5 0 0 msec.
7. 2. 2. 6. 2 C ar di a c i m a gi n g - m ulti pl e g at e d a c q ui siti o n ( M U G A) s c a n or 
e c h o c ar di o gr a m ( E C H O)
Car diac i ma gi n g will be perf or me d l ocall y b y M U G A sca n or E C H O i n or der t o assess t he left 
ve ntric ular ejecti on fracti o n. T his assess me nt will be perf or me d acc or di n g t o t he sc he d ule 
i n dicate d i n Ta ble 7 - 7 bel o w .
U nsc he d ule d car diac i ma gi n g m a y  be perf or me d at t he discreti o n of t he i n vesti gat or at a n y t i me 
d uri n g t he st u d y a n d as cli nicall y i n dicate d. Patie nts s h o ul d be cl osel y m o nit ore d f or si g ns a n d 
s ym pt o ms of c o n gesti ve heart fail ure.  In partic ular, patie nts at ris k of car diac d y sf u ncti o n or 
wit h pri or a nt hrac y cli ne e x p os ure ma y warra nt m ore fre q ue nt m o nit orin g.
T a bl e 7- 7 
L o c al c ar di a c im a gi n g c oll e cti o n pl a n
C y cl e/ Vi sit
D a y
Ti m e p oi nt
S cr e e ni n g
-7 t o - 1
A n yti m e
5
1
A n yti m e
1 1
1
A n yti m e
C y cl e 1 6 a n d e v er y 6 t h c y cl e t h er e aft er (i. e., c y cl e s 2 2, 2 8 et c.) a n d E n d of 
Tr e at m e nt
1
A n yti m e
U n s c h e d ul e d
A n yti m e  
A n yti m e

N o v arti s
C o nfi d e nti al
P a g e 6 6
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0

N o v arti s
C o nfi d e nti al
P a g e 6 7
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
7. 2. 4   
R e s o ur c e utili z ati o n
N ot a p plica ble.
7. 2. 5 
P ati e nt r e p ort e d o ut c o m e s
Patie nt re p orte d o utc o mes ( P R Os) pr o vi de patie nts, p h y sicia ns, a n d pa y ers wit h val ua ble 
i nf or mati o n a b o ut t he i m pact of a gi ve n treat me nt o n all facets of t he patie nt’s life. P R O 
meas ures f or use i n cli nical trial assess s ym pt o ms, f u ncti o ni n g, healt h relate d q ualit y  of life a n d 
q ualit y  of life or a c o m bi nati o n of t hese o utc o mes. 
B ot h q uesti o n naires ( E Q- 5 D-5 L  an d F K SI -D R S) will be pr o vi de d electr o nicall y (e P R O) a n d 
are t o be c o m plete d b y t he patie nt.
B ot h q uesti o n naires m ust be c o m plete d d uri n g t he scree ni n g p hase wit hi n 7 da y s bef ore t he first 
d ose of st u d y me dicati o n ( paz o pa ni b) o nl y  after patie nt eli gi bilit y is c o nfir me d, or o n C y cle 1 
Da y  1 pre d ose . D uri n g t he treat me nt p hase , b ot h q uesti o n naires s h o ul d be c o m plete d o n Da y 1 

N o v arti s
C o nfi d e nti al
P a g e 6 8
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
of e ver y cyc le u ntil C y cle 7 a n d t he n e ver y 2n d c ycle u ntil C y cle 1 6 a n d t he n e ver y 3r d c ycle 
t hereafter u ntil t he e n d of st u d y me dicati o n treat me nt.
T he q uesti o n naires s h o ul d be c o m plete d i n t he la n g ua ge m ost fa miliar t o t he patie nt.
T he i n vesti gat or or desi g nee will a d mi nister b ot h q uesti o n naires u n der t he f oll o wi n g c o n diti o ns:

u p o n arri val t o t he cli nic, bef ore t he patie nt has t heir e val uati o n visit wit h t he treati n g 
o nc ol o gist

u p o n arri val t o t he cli nic, bef ore t he patie nt has t heir ra di ol o gical t u m or e val uati o ns ( C T 
sca n or M RI).
T he patie nt 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 uesti o n naires. T he site 
staff s h o ul d c hec k t he q uesti o n naire f or c o mplete ness a n d e nc o ura ge t he patie nt t o c o m plete 
a n y missi n g res p o nses.
C o m plete d q uesti o n naire(s) a n d a n y uns olicite d c o m me nts writte n b y  the patie nt s h o ul d be 
re vie we d a n d assesse d b y t he i n vesti gat or f or res p o nses w hic h ma y  in dicate p ote ntial A Es or 
S A Es bef ore a n y cli nical st u d y exa mi nati o ns. T his assess me nt s h o ul d be d oc u me nte d i n t he 
st u d y s o urce rec or ds.
7. 2. 5. 1 
E ur o Q O L -E Q -5 D -5 L ( E Q -5 D -5 L)
T he E Q - 5 D-5 L  is a ge neral healt h stat us a n d healt h utilit y  meas ure (Ra bi n 2 0 0 1 ). It meas ures 
5 di me nsi o ns of healt h state: m o bilit y , self-care, us ual acti vities, pai n/ disc o mf ort, a n d 
a n xiet y/ de pressi o n eac h assesse d b y  a si n gle q uesti o n o n a t hree p oi nt or di nal scale. It als o 
i ncl u des a V A S scale t o meas ure healt h state. The E Q - 5 D-5 L  will be i ncl u de d i n t his st u d y f or 
t he p ur p ose of t he c o m p utati o n of utilities t hat ca n be use d i n healt h ec o n o mic st u dies. T his 
i nstr u me nt has bee n use d e xte nsi vel y i n ca ncer st u dies a n d p u blis he d res ults fr o m t hese st u dies 
s u p p ort its vali dity a n d relia bilit y (Pic kar d 2 0 0 7 ).
7. 2. 5. 2 
F K SI- D R S
T he F u ncti o nal Assess me nt of Ca ncer T hera p y - Ki d ne y  Sy m pt o m I n de x, Disease Relate d 
S y m pt o ms ( F K SI-D R S) is a set of ite ms selecte d w hic h was de vel o pe d a n d vali d ate d t o 
s pecifically assess s ym pt o ms e x perie nce d b y  patie nts wit h a d va nce d ki d ne y  ca ncer (Cella 2 0 0 7 ). 
Ite m de vel o p me nt was c o n d ucte d usi n g b ot h cli nicia n a n d patie nt i n p ut t o deter mi ne t he 9 m ost 
i m p orta nt s y m pt o ms a n d c o ncer ns of pe o ple bei n g treate d f or a d va nce d ki d ne y ca ncer. T hese 9 
ite ms were t he n vali date d b y  ad mi nisteri n g t he s ym pt o m i n de x t o patie nts dia g n ose d wit h 
a d va nce d ki d ne y  ca ncer. T he s ym pt o ms c o vere d b y  the 9- ite m F K SI -D R S i ncl u de fati g ue, pai n, 
wei g ht l oss, d ys p nea, c o u g h, fe ver a n d he mat uria. T he F K SI-D R S will be sc ore d acc or di n g t o 
t he de vel o pers’ i nstr ucti o ns. A differe nce of 2- 3. 0 p oi nts is s u g geste d b y  the de vel o pers t o 
c orres p o n d t o a mea ni n gf ul differe nce i n treat me nt effects usi n g t he 9 q uesti o n t o ol.

N o v arti s
C o nfi d e nti al
P a g e 6 9
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
8 
S af et y  m o nit ori n g a n d r e p orti n g
8. 1 
A d v er s e e v e nt s
8. 1. 1 
D efi niti o n s a n d r e p orti n g
A n a d verse e ve nt is defi ne d as t he a p peara nce of ( or w orse ni n g of a n y p re-e xisti n g) u n desira ble 
si g n(s), sy m pt o m(s), or me dical c o n diti o n(s) t hat occ ur after pa tie nt’s si g ne d i nf or me d c o nse nt 
has bee n o btai ne d.
A b n or mal la b orat or y val ues or test res ults occ urri n g after i nf or me d c o nse nt c o nstit ute a d verse 
e ve nts o nl y  if t he y in d uce cli nical si g ns or s ym pt o ms, are c o nsi dere d cli nicall y si gnifica nt, 
re q uire t hera p y (e. g., he mat ol o gic a b n or malit y t hat re q uires tra nsf usi o n or he mat ol o gical ste m 
cell s u p p ort), or re q uire c ha n ges i n st u d y  me dicati o n(s).
A d verse e ve nts t hat be gi n or w orse n after i nf or me d c o nse nt s h o ul d be rec or de d i n t he A d verse 
E ve nts C R F. C o n diti o ns t hat were alrea d y prese nt at t he ti me of i nf or me d c o nse nt s h o ul d be 
rec or de d i n t he Me dical Hist or y  pa ge of t he patie nt’s C R F. A d verse e ve nt m o nit ori n g s h o ul d 
be c o nti n ue d f or at least 3 0 d a y s f oll o wi n g t he last d ose of st u d y treat me nt. A d verse e ve nts 
(i ncl u di n g la b a b n or malities t hat c o nstit ute A Es) s h o ul d be descri be d usi n g a dia g n osis 
w he ne ver p ossi ble, rat her t ha n i n di vi d ual u n derl y i n g si g ns a n d s ym pt o ms. W he n 
a clear 
dia g n osis ca n n ot be i de ntifie d, eac h si g n or s y m pt o m s h o ul d be re p orte d as a se parate A d verse 
E ve nt.
A d verse e ve nts will be assesse d a n d gra de d acc or di n g t o t he C o m m o n Ter mi n ol o g y  Criteria f or 
A d verse E ve nts ( C T C A E) versi o n 4. 0 3.
Gra de 1 t o 5 will be use d t o c haracterize t he se verit y  of t he A d verse E vent.
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 verity of mil d, m o derate, se vere, 
a n d life-t hreate ni n g, deat h relate d t o t he A E c orres p o n di n g res pecti vel y t o Gra des 1 - 5, will be 
use d. I nf or mati o n a b o ut a n y d eat hs (relate d t o a n A d verse E v e nt or n ot) will als o be c ollecte d 
t h o u g h a Deat h f or m.
T he occ urre nce of a d verse e ve nts s h o ul d be s o u g ht b y  n o n-directi ve q uesti o ni n g of t he patie nt 
(s u bject) d uri n g t he scree ni n g pr ocess after si g ni n g i nf or me d c o nse nt a n d at eac h visit d uri n g 
t he st u d y. A d verse e ve nts als o m a y  be detecte d w he n t he y are v ol u nteere d b y  the patie nt 
(s u bject) d uri n g t he scree ni n g pr ocess or bet wee n visits, or t hr o u g h p h ysical e xa mi nati o n, 
la b orat or y test, or ot her assess me nts. As far as p ossi ble, eac h a d verse e ve nt s h o ul d be e val uate d 
t o deter mi ne:
1.
T he se verit y gra de ( C T C A E Gra de 1 - 5)
2.
Its d urati o n ( Start a n d e n d dates)
3.
Its relati o ns hi p t o t he st u d y treat me nt ( Reas o na ble p ossi bilit y t hat A E is relate d: N o, Yes)
4.
Acti o n ta ke n wit h res pect t o st u d y  treat me nt ( n o ne, d ose a dj uste d, te m p oraril y i nterr u pte d, 
per ma ne ntl y disc o nti n ue d, u n k n o w n, n ot a p plica ble)
5.
W het her me dicati o n or t hera p y was gi ve n ( n o c o nc o mita nt me dicati o n/ n o n -dr u g t hera p y,  
c o nc o mita nt me dicati o n/ n o n -dr u g t hera p y)
6. 
W het her it is seri o us, w here a seri o us a d verse e ve nt ( S A E) is defi ne d as i n Secti o n 8. 2. 1
a n d w hic h seri o us ness criteria ha ve bee n met

N o v arti s
C o nfi d e nti al
P a g e 7 0
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
7.
O utc o me ( n ot rec o vere d/ n ot res ol ve d, rec o vere d/res ol ve d, rec o veri n g/res ol vi n g, 
rec o vere d/res ol ve d wit h se q uelae, fatal, u n k n o w n)
If the e ve nt w orse ns t he e ve nt s h o ul d be re p orte d a sec o n d ti me i n t he C R F n oti n g t he start date 
w he n t he e ve nt w orse ns i n t o xicit y . F or gra de 3 a n d 4 a d verse e ve nts o nly, if i m pr o ve me nt t o a 
l o wer gra de is deter mi ne d a ne w e ntr y for t his e ve nt s h o ul d be re p or te d i n t he C R F n oti n g t he 
start date w he n t he e ve nt i m pr o ve d fr o m ha vi n g bee n Gra de 3 or Gra de 4.
All a d verse e ve nts s h o ul d be treate d a p pr o priatel y. If a c o nc o mita nt me dicati o n or n o n- dr u g 
t hera py is gi ve n, t his acti o n s h o ul d be rec or de d o n t he A d verse E v e nt C R F.
O nce a n a d verse e ve nt is detecte d, it s h o ul d be f oll o we d u ntil its res ol uti o n or u ntil it is j u d ge d 
t o be per ma ne nt, a n d assess me nt s h o ul d be ma de at eac h visit ( or m ore fre q ue ntl y, if necessar y ) 
of a n y c ha n ges i n se verit y, t h e s us pecte d relati o ns hi p t o t he st u d y treat me nt, t he i nter ve nti o ns 
re q uire d t o treat it, a n d t he o utc o me.
Pr o gressi o n of mali g na nc y  (i ncl u di n g fatal o utc o mes), if d oc u me nte d b y  use of a p pr o priate 
met h o d (i.e. as per R E CI S T criteria), s h o ul d n ot be re p orte d as a seri o us a d verse e ve nt.
A d verse e ve nts se parate fr o m t he pr o gressi o n of mali g na nc y  (e xa m ple, dee p vei n t hr o m b osis 
at t he ti me of pr o gressi o n or he m o pt y sis c o nc urre nt wit h fi n di n g of disease pr o gressi o n) will 
be re p orte d as per us ual g ui deli nes use d f or s uc h e ve nts wit h pr o per attri b uti o n re gar di n g 
relate d ness t o t he dr u g.
8. 1. 2 
L a b or at or y  t e st a b n or m aliti e s
8. 1. 2. 1 
D efi niti o n s a n d r e p orti n g
La b orat or y  ab n or malities t hat c o nstit ute a n A d verse e ve nt i n t heir o w n ri g ht (are c o nsi dere d 
cli nicall y si gnifica nt, i n d uce cli nical si g ns or s ym pt o ms, re q uire c o nc o mita nt t hera py o r re q uire 
c ha n ges i n st u d y treat me nt), s h o ul d be rec or de d o n t he A d verse E ve nts C R F. W he ne ver 
p ossi ble, a dia g n osis, rat her t ha n a s ym pt o m s h o ul d be pr o vi de d (e. g., a ne mia i nstea d of l o w 
he m o gl o bi n). La b orat or y a b n or malities t hat meet t he criteria f or A d verse E ve nts s h o ul d be 
f oll o we d u ntil t he y ha ve ret ur ne d t o n or mal or a n a de q uate e x pla nati o n of t he a b n or malit y is 
f o u n d. W he n a n a b n or mal la b orat or y or test res ult c orres p o n ds t o a si g n/sy m pt o m of a n alrea d y 
re p orte d a d vers e e ve nt, it is n ot necessar y  to se paratel y rec or d t he la b/test res ult as a n a d diti o nal 
e ve nt.
La b orat or y  ab n or malities, t hat d o n ot meet t he defi niti o n of a n a d verse e ve nt, s h o ul d n ot be 
re p orte d as a d verse e ve nts. A Gra de 3 or 4 e ve nt (se vere) as per C T C A E d oes n ot a ut o maticall y 
i n dicate a S A E u nless it meets t he defi niti o n of seri o us as defi ne d bel o w a n d/ or as per 
i n vesti gat or’s discreti o n. A d ose h ol d or me dicati o n f or t he la b a b n or malit y ma y be re q uire d by 
t he pr ot oc ol i n w hic h case t he la b a b n or malit y w o ul d still, b y  defi niti o n, be a n a d verse e ve nt 
a n d m ust be re p orte d as s uc h.
8. 1. 3 
A d v er s e e v e nt s of s p e ci al i nt er e st
A d verse e ve nts of s pecial i nterest ( A E SI) are defi ne d as e ve nts (seri o us or n o n- seri o us) w hic h 
are o nes of scie ntific a n d me dical c o ncer n s pecific t o t he s p o ns or’s pr o d uct or pr o gra m, f or 
w hic h o n g oi n g m o nit ori n g a n d ra pi d c o m m u nicati o n b y  t he i n vesti gat or t o t he s p o ns or ma y be 

N o v arti s
C o nfi d e nti al
P a g e 7 1
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
a p pr o priate. S uc h e ve nts ma y  re q uire f urt her i n vesti gati o n i n or der t o c haracterize a n d 
u n dersta n d t he m.
A d verse e ve nts of s pecial i nterest are defi ne d o n t he basis of a n o n g oi n g re vie w of t he safety 
data. A E SIs are disc usse d i n detail i n t he I n vesti gat or ’s Br oc h ure.
A E SI s f or t his trial i ncl u de he patic t o xicit y, hy perte nsi o n, t h yr oi d -relate d dis or ders a n d car diac 
dis or ders .
8. 2 
S eri o u s a d v er s e e v e nt s
8. 2. 1 
D efi niti o n s
Seri o us a d verse e ve nt ( S A E) is defi ne d as o ne of t he f oll o wi n g:

Is fatal or life-t hreate ni n g

Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y

C o nstit utes a c o n ge nital a n o mal y / birt h defect

Is me dically si g nifica nt, i.e., defi ne d as a n e ve nt t hat je o par dizes t he patie nt or ma y 
re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve

Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n,

N ote t hat h os pitalizati o ns f or t he f oll o wi n g reas o ns s h o ul d n ot be re p orte d as seri o us 
a d verse e ve nts:

R o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass ociate d wit h a n y  
deteri orati o n i n c o n diti o n

Electi ve or pre -pla n ne d treat me nt f or a pre -e xisti n g c o n dit i o n t hat is u nrelate d t o t he 
i n dicati o n u n der st u d y a n d has n ot w orse ne d si nce si g ni n g t he i nf or me d c o nse nt

S ocial reas o ns a n d res pite care i n t he a bse nce of a n y  deteri orati o n i n t he patie nt’s 
ge neral c o n diti o n

N ote t hat treat me nt o n a n e mer ge nc y  o ut patie nt basis t hat d oes n ot res ult i n h os pital 
a d missi o n a n d i n v ol ves a n e ve nt n ot f ulfilli n g a n y of t he defi niti o ns of a S A E gi ve n a b o ve 
is n ot a seri o us a d verse e ve nt

Pr o gressi o n of mali g na nc y (i ncl u di n g fatal o utc o mes), if d oc u me nte d b y use of 
a p pr o priate meth o d (i.e. as per R E CI S T criteria), s h o ul d n ot be re p orte d as a seri o us 
a d verse e ve nt.
8. 2. 2 
R e p orti n g
T o e ns ure patie nt safety, e ver y SA E, re gar dless of s us pecte d ca usalit y, occ urri n g after t he 
patie nt has pr o vi de d i nf or me d c o nse nt a n d u ntil at least 3 0 da y s after t he patie nt has st o p pe d 
st u d y treat me nt m ust be re p orte d t o N o vartis wit hi n 2 4 h o urs of lear ni n g of its occ urre nce.
A n y  ad diti o nal i nf or mati o n f or t he S A E i ncl u di n g c o m plicati o ns, pr o gressi o n of t he i nitial S A E, 
a n d rec urre nt e pis o des m ust be re p orte d a s f oll o w-u p t o t he ori gi nal e pis o de wit hi n 2 4 h o urs of 
t he i n vesti gat or recei vi n g t he f oll o w-u p i nf or mati o n. A n S A E occ urri n g at a differe nt ti me 
i nter val or ot her wise c o nsi dere d c o m pletel y unrelate d t o a pre vi o usl y re p orte d o ne s h o ul d be 
re p orte d se paratel y as a ne w e ve nt.

N o v arti s
C o nfi d e nti al
P a g e 7 2
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
A n y  SA Es e x perie nce d after t he 3 0 da y  safet y e val uati o n f oll o w- u p peri o d s h o ul d o nl y  be 
re p orte d t o N o vartis if t he i n vesti gat or s us pects a ca usal relati o ns hi p t o t he st u d y treat me nt.
I nf or mati o n a b o ut all S A Es is c ollecte d a n d rec or de d o n t he Seri o us A d verse E ve nt Re p ort 
F or m; all a p plica ble secti o ns of t he f or m m ust be c o m plete d i n or der t o pr o vi de a cli nicall y 
t h or o u g h re p ort. T he i n vesti gat or m ust assess a n d rec or d t he relati o ns hi p of eac h S A E t o eac h 
s pecific st u d y treat me nt (if t here is m ore t ha n o ne st u d y treat me nt), c o m plete t he S A E Re p ort 
F or m i n E n glis h, a n d s u b mit t he c o m plete d f or m wit hi n 2 4 h o urs t o N o vartis. Detaile d 
i nstr ucti o ns re gar di n g t he S A E s u b missi o n pr ocess a n d re q uire me nts f or si g nat ures are t o be 
f o u n d i n t he i n vesti gat or f ol der pr o vi de d t o eac h site.
F oll o w - u p i nf or mati o n is s u b mitte d i n t he sa me wa y  as t he ori gi nal S A E Re p ort. Eac h re-
occ urre nce, c o m plicati o n, or pr o gressi o n of t he ori gi nal e ve nt s h o ul d be re p orte d as a f oll o w-
u p t o t hat e ve nt re gar dless of w he n it occ urs. T he f oll o w- u p i nf or mati o n s h o ul d descri be 
w het her t he e ve nt has res ol ve d or c o nti n ues, if a n d h o w it was treate d, w het her t he bli n d was 
br o ke n or n ot, a n d w het her t he patie nt c o nti n ue d or wit h dre w fr o m st u d y  partici pati o n.
If t he S A E is n ot pre vi o usl y  d oc u me nte d i n t he I n vesti gat or’s Br oc h ure or Pac ka ge I nsert ( ne w 
occ urre nce) a n d is t h o u g ht t o be relate d t o t he N o vartis st u d y treat me nt, a n o nc ol o g y No vartis 
C hief Me dical Office a n d Patie nt Safet y  (C M O & P S) de part me nt ass ociate ma y  ur ge ntl y req uire 
f urt her i nf or mati o n fr o m t he i n vesti gat or f or Healt h A ut h orit y re p orti n g. N o vartis ma y nee d t o 
iss ue a n I n vesti gat or N otificati o n (I N), t o i nf or m all i n vesti gat ors i n v ol ve d i n a n y st u d y wit h 
t he sa me dr u g t hat t his S A E has bee n re p orte d. S us pecte d U n e x pecte d Seri o us A d verse 
Reacti o ns ( S U S A Rs) will be c ollecte d a n d re p orte d t o t he c o m pete nt a ut h orities a n d rele va nt 
et hics c o m mittees i n acc or da nce wit h Directi ve 2 0 0 1/ 2 0/ E C or as per nati o nal re g ulat or y 
re q uire me nts i n partici pati n g c o u ntries.
8. 3 
E m er g e n c y  u n bli n di n g of tr e at m e nt a s si g n m e nt
N ot a p plica ble.
8. 4 
Pr e g n a n ci e s
T o e ns ure patie nt safet y, eac h pre g na nc y occ urri n g w hile t he patie nt is o n st u d y treat me 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 nce. T he pre g na nc y s h o ul d be 
f oll o we d u p t o deter mi ne o utc o me, i ncl u di n g s p o nta ne o us or v ol u ntar y  t er 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 b irt h defects, c o n ge nital a b n or malities, or mater nal 
a n d/ or ne w b or n c o m plicati o ns.
Pre g na nc y  sh o ul d be rec or de d o n a Cl i nical Trial Pre g na nc y  For m a n d re p orte d b y  the 
i n vesti gat or t o t he o nc ol o g y  No vartis C hief Me dical Office a n d Patie nt Safet y  (C M O & P S). 
Pre g na nc y  foll o w - u p s h o ul d be rec or de d o n t he sa me f or m a n d s h o ul d i ncl u de a n assess me nt 
of t he p ossi ble relati o ns hi p of paz o pa ni b t o a n y pre g na nc y  outc o me. A n y  SA E e x perie nce d 
d uri n g pre g na nc y  m ust be re p orte d o n t he S A E Re p ort F or m.
Pre g na nc y  outc o mes s h o ul d be c ollecte d f or t he fe male part ners of a n y males w h o t o o k st u d y 
treat me nt i n t his st u d y. C o nse nt t o re p ort i nf or mati o n re gar di n g t hese pre g na nc y  outc o mes 
s h o ul d be o btai ne d fr o m t he m ot her.

N o v arti s
C o nfi d e nti al
P a g e 7 3
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
T he c ollecti o n of t his i nf or mati o n c o ul d last u p u ntil t o birt h a n d p ote ntiall y  up t o 1 2 m o nt hs 
f oll o wi n g t he birt h of t he c hil d i n s o me cases.
8. 5 
W ar ni n g s a n d pr e c a uti o n s
N o e vi de nce a vaila ble at t he ti me of t he a p pr o val of t his st u d y pr ot oc ol i n dicate d t hat s pecial 
war ni n gs or preca uti o ns were a p pr o priate, ot her t ha n t h ose n ote d i n t he pr o vi de d I n vesti gat or ’s
Br oc h ure. A d diti o nal safet y inf or mati o n c ollecte d bet wee n I B u p dates will b e c o m m u nicate d 
i n t he f or m of I nvesti gat or N otificati o ns. T his i nf or mati o n will be i ncl u de d i n t he patie nt 
i nf or me d c o nse nt a n d s h o ul d be disc usse d wit h t he patie nt d uri n g t he st u dy as nee de d.
8. 6 
D at a M o nit ori n g C o m mitt e e
N ot a p plica ble.
8. 7 
St e eri n g C o m mitt e e
T h e steeri n g c o m mittee ( S C) will be esta blis he d c o m prisi n g i n vesti gat ors partici pati n g i n t he 
trial a n d N o vartis re prese ntati ves fr o m t he Cli nical Trial Tea m.
T he S C will e ns ure tra ns pare nt ma na ge me nt of t he st u d y acc or di n g t o t he pr ot oc ol t hr o u g h 
rec o m me n din g a n d a p pr o vi n g m o dificati o ns as circ u msta nces re q uire. T he S C will re vie w 
pr ot oc ol a me n d me nts as a p pr o priate. T o get her wit h t he cli nical trial tea m, t he S C will als o 
de vel o p rec o m me n dati o ns f or p u blicati o ns of st u d y res ults i ncl u di n g a ut h ors hi p r ules. T h e 
details of t he r ole of t he Steeri n g C o m mittee will be defi ne d i n a Steeri n g C o m mittee c harter.
9 
D at a c oll e cti o n a n d m a n a g e m e nt
9. 1 
D at a c o nfi d e nti alit y
I nf or mati o n a b o ut st u d y su bjects will be ke pt c o nfi de ntial a n d ma na ge d u n der t he a p plica ble 
la ws a n d re g ulati o ns. T h ose re g ulati o ns re q uire a si g ne d s u bject a ut h orizati o n i nf or mi n g t he 
s u bject of t he f oll o wi n g:

W hat pr otecte d healt h i nf or mati o n ( P HI) will be c ollecte d fr o m s u bjects i n t his st u d y

W h o will ha ve access t o t hat i nf or mati o n a n d w h y

W h o will use or d iscl ose t hat i nf or mati o n

T he ri g hts of a researc h s u bject t o re v o ke t heir a ut h orizati o n f or use of t heir P HI .
I n t he e ve nt t hat a s u bject re v o kes a ut h orizati o n t o c ollect or use P HI , t he i n vesti gat or, b y  
re g ulati o n, retai ns t he a bilit y t o use all i nf or matio n c ollecte d pri or t o t he re v ocati o n of s u bject 
a ut h orizati o n. F or s u bjects t hat ha ve re v o ke d a ut h orizati o n t o c ollect or use P HI , atte m pts 
s h o ul d be ma de t o o btai n per missi o n t o c ollect f oll o w-u p safety i nf or mati o n (e. g., has t he 
s u bject e x perie nce d a ny n e w or w orse ne d A Es) at t he e n d of t heir sc he d ule d st u d y  peri o d.
T he data c ollecti o n s yste m f or t his st u d y uses b uilt -i n sec urit y feat ures t o e ncr ypt all data f or 
tra ns missi o n i n b ot h directi o ns, pre ve nti n g u na ut h orize d access t o c o nfi de ntial partici pa nt 
i nf or mati o n. Access t o t he s yste m will be c o ntr olle d b y  a se q ue nce of i n di vi d uall y assi g ne d 

N o v arti s
C o nfi d e nti al
P a g e 7 4
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
user i de ntificati o n c o des a n d pass w or ds, ma de a vaila ble o nl y  to a ut h orize d pers o n nel w h o ha ve 
c o m plete d prere q uisite trai ni n g.
Year of birt h will be s olicite d (i n t he place of e xact date of birt h) t o esta blis h t hat t he s u bject 
satisfies pr ot oc ol a ge re q uire me nts a n d t o e na ble a p pr o priate a ge-relate d n or mal ra n ges t o be 
use d i n assessi n g la b orat or y  test res ults.
9. 2 
Sit e m o nit ori n g
Bef ore st u d y initiati o n, at a site i nitiati o n visit or at a n i n vesti gat or’s meeti n g, N o vartis 
pers o n nel ( or desi g nate d C R O) will re vie w t he pr ot oc ol a n d C R Fs wit h t he i n vesti gat ors a n d 
t heir staff. D uri n g t he st u d y, t he fiel d m o nit or will visit t he site re g ularl y t o c hec k t he 
c o m plete ness o f patie nt rec or ds, t he acc urac y of e ntries o n t he C R Fs, t he a d here nce t o t he 
pr ot oc ol t o G o o d Cli nical Practice, t he pr o gress of e nr oll me nt, a n d t o e ns ure t hat st u d y 
treat me nt is bei n g st ore d, dis pe nse d, a n d acc o u nte d f or acc or di n g t o s pecificati o ns. Ke y  st u dy 
pers o n nel m ust be a vaila ble t o assist t he fiel d m o nit or d uri n g t hese visits.
T he i n vesti gat or m ust mai ntai n s o urce d oc u me nts f or eac h patie nt i n t he st u d y, c o nsisti n g of 
case a n d visit n otes ( h os pital or cli nic me dical rec or ds) c o ntai ni n g de m o gra p hic a n d me dical 
i nf or mati o n, la b orat or y data, electr ocar di o gra ms, a n d t he res ults of a n y ot her tests or 
assess me nts. All i nf or mati o n rec or de d o n C R Fs m ust be tracea ble t o s o urce d oc u me nts i n t he 
patie nt's file. T he i n vesti gat or m ust als o kee p t he ori gi nal si g ne d i nf or me d c o nse nt f or m (a 
si g ne d c o py is gi ve n t o t he patie nt).
T he i n vesti gat or m ust gi ve t he m o nit or access t o all rele va nt s o urce d oc u me nts t o c o nfir m t heir 
c o nsiste nc y wit h t he C R F e ntries. N o vartis m o nit ori n g sta n dar ds re q uire f ull verificati o n f or t he 
prese nce of i nf or me d c o nse nt, a d here nce t o t he i ncl usi o n/e xcl usi o n criteria a n d d oc u me ntati o n 
of S A Es. A d diti o nal c hec ks of t he c o nsiste nc y  of t he s o urce data wit h t he C R Fs are perf or me d 
acc or di n g t o t he st u d y- s pecific m o nit ori n g pla n.
9. 3 
D at a c oll e cti o n
F or st u dies usi n g Electr o nic Data Ca pt ure ( E D C), t he desi g nate d i n vesti gat or staff will e nter 
t he data re q uire d b y  the pr ot oc ol i nt o t he Electr o nic Case Re p ort F or ms (e C R F). T he e C R Fs 
ha ve bee n b uilt usi n g f ull y vali date d sec ure we b -e na ble d s oft ware t hat co nf or ms t o 2 1 C F R Part 
1 1 re q uire me nts, I n vesti gat or site staff will n ot be gi ve n access t o t he E D C s yste m u ntil t he y 
ha ve bee n trai ne d. A ut o matic vali dati o n pr o gra ms c hec k f or data discre pa ncies i n t he e C R Fs 
a n d, all o w m o dificati o n or verificati o n of t he e ntere d data b y t he i n vesti gat or staff.
T he Pri nci pal I nvesti gat or is res p o nsi ble f or ass uri n g t hat t he data e ntere d i nt o e C R F is c o m plete, 
acc urate, a n d t hat e ntr y a n d u p dates are perf or me d i n a ti mel y  ma n ner.
Safet y  la b orat or y assess me nts 
 (bl o o d a n d tiss ue) sa m ples dra w n d uri n g t he 
c o urse of t he st u d y will be c ollecte d fr o m t he i n vesti gat or sites a n d se nt t o t he N o vartis 
desi g nate d ce ntral la b orat or y for pr ocessi n g. T he site staff desi g nate d b y  the i n vesti gat or will 
e nter t he i nf or mati o n re q uire d b y t he pr ot oc ol o nt o t he sa m ple c ollecti o n e C R F, as well as o nt o 
t he desi g nate d C R O’s re q uisiti o n f or m. O ne c o p y of t he re q uisiti o n f or m will be f or war de d t o 
t he ce ntral la b al o n g wit h t he c orres p o n di n g sa m ples wit h re q uire d i nf or mati o n (i ncl u di n g stu d y 
n u m ber, s u bject I D, etc.) a n d o ne c o p y will be retai ne d b y t he site.

N o v arti s
C o nfi d e nti al
P a g e 7 5
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
P R O data m ust be rec or de d b y  patie nts o nt o t he electr o nic ta blet de vice mai ntai ne d at st u d y site. 
T he site will e nter i nf or mati o n re gar di n g e P R O c ollecti o n i n t he e C R F.
9. 4 
D at a b a s e m a n a g e m e nt a n d q u alit y  c o ntr ol
F or st u dies usi n g e C R Fs, N o vartis pers o n nel ( or desi g nate d C R O) will re vie w t he data e ntere d 
b y  in vesti gati o nal staff f or c o m plete ness a n d acc urac y. Electr o nic data q ueries stati n g t he nat ure 
of t he pr o ble m a n d re q uesti n g clarific ati o n will be create d f or discre pa ncies a n d missi n g val ues 
a n d se nt t o t he i n vesti gati o nal site via t he E D C s yste m. Desi g nate d i n vesti gat or site staff are 
re q uire d t o res p o n d pr o m ptl y t o q ueries a n d t o ma ke a n y necessar y c ha n ges t o t he data.
C o nc o mita nt treat me nts a n d pri or me dicati o ns e ntere d i nt o t he data base will be c o de d usi n g t he 
W H O Dr u g Refere nce Li st, w hic h e m pl o ys t he A nat o mical T hera pe utic C he mical classificati o n 
s yste m. Me dical hist or y/c urre nt me dical c o n diti o ns a n d a d verse e ve nts will be c o de d usi n g t he 
Me dical dicti o nar y  f or re g ulat or y acti vities ( Me d D R A) ter mi n ol o g y.
Sa m ples a n d/ or data (e. g., safety la b orat or y assess me nt 
 sa m ples) will be 
pr ocesse d ce ntrall y an d t he res ults will be se nt electr o nicall y t o N o vartis ( or a desi g nate d C R O).
P R O data c ollecte d usi n g a n electr o nic ta blet de vice will be d oc u me nte d i nt o a se parate st u d y 
s pecific data base s u p plie d a n d ma na ge d b y  a desi g nate d ve n d or. All P R O data will be se nt 
electr o nicall y t o N o vartis pers o n nel ( or a desi g nate d C R O).
Data a bo ut patie nt e nr oll me nt, disc o nti n uati o n of st u d y  treat me nt, a n d me dicati o n n u m bers (if 
a p plica ble) f or st u d y treat me nt dis pe nse d via I RT (i n c o u ntries t hat are s u p plie d b y  No vartis 
D S M) will be trac ke d usi n g a n I nteracti ve Res p o nse Tec h n ol o g y. T he s yste m will be s u p plie d 
b y  a ve n d or(s), w h o will als o ma na ge t he data base. T he data will be se nt electr o nicall y t o 
N o vartis pers o n nel ( or desi g nate d C R O).
T he occ urre nce of a n y pr ot oc ol vi olati o ns will be deter mi ne d. After t hese acti o ns ha ve bee n 
c o m plete d a n d t he data ha ve bee n verifie d t o be c o m plete a n d acc urate, t he data base will be 
declare d l oc ke d a n d ma de a vaila ble f or data a nal ysis. A ut h orizati o n is re q uire d pri or t o ma ki n g 
a n y data base c ha n ges t o l oc ke d data, b y  joi nt writte n a gree me nt bet wee n t he Gl o bal He a d of 
Bi ostatistics a n d Data Ma na ge me nt a n d t he Gl o bal Hea d of Cli nical De vel o p me nt.
F or E D C st u dies, after data base l oc k, t he i n vesti gat or will recei ve a C D -R O M or pa per c o pies 
of t he patie nt data f or arc hi vi n g at t he i n vesti gati o nal site.
1 0 
St ati sti c al m et h o d s a n d d at a a n al y si s
T he pri mar y  efficac y a n d safet y a nal yses will be c o n d ucte d after all patie nts ha ve c o m plete d 6 
c ycles of st u d y treat me nt or ha ve disc o nti n ue d earl y. T he pri mar y a nal ysis will be s u m marize d 
i n t he pri mar y C S R base d o n t he F ull A nal ys is Set ( F A S). T he fi nal a nalys is will be perf or me d 
at t he e n d of t he st u d y an d will be s u m marize d i n t he fi nal st u d y CS R. Data a nal ys is c ut-off 
dates will be deter mi ne d a n d t he pri mar y  an d t he fi nal a nal ys es, a n d all data ca pt ure d i n t he 
st u d y u p t o t he respecti ve c ut -off date will be a nal y ze d a n d re p orte d.

T he pri mar y  efficac y a n d selecte d safet y a nal yses will als o be perf or me d f or t he f oll o wi n g 
s u b gr o u ps:

Li ne of t hera py ( 2n d / 3r d).

N o v arti s
C o nfi d e nti al
P a g e 7 6
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0

2 n d li ne t hera py:  all patie nts w h o recei ve d o nl y o ne li ne of pri or a nti ne o plastic t hera p y 
bef ore t he start of st u d y t reat me nt

3 r d li ne t hera p y: all patie nts w h o recei ve d t w o li nes of pri or a nti ne o plastic t hera py 
bef ore t he start of st u d y t reat me nt (treat me nt wit h i m m u ne c hec k p oi nt i n hi bit or m ust 
ha ve bee n t he last treat me nt pri or t o st u d y  e ntr y) 

A ge cate g or y  

M S K C C a n d I M D C ris k gr o u ps
F urt her details will be i ncl u de d i n t he Statistical A nal y sis Pla n ( S A P).
1 0. 1 
A n al y si s s et s
1 0. 1. 1 
F ull A n al y si s S et
T he F 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 a n d w h o recei ve d 
at least o ne d ose of paz o pa ni b .
1 0. 1. 2 
S af et y  Set
T he Safet y Set i ncl u des all patie nts w h o recei ve d at least o ne d ose of paz o pa ni b. T he safet y set 
a n d t he F A S are t he sa me f or t his si n gle ar m p hase II st u d y.
1 0. 1. 3 
P er -Pr ot o c ol S et
T he Per- Pr ot oc ol Set ( P P S) c o nsists of a s u bset of t he patie nts i n t he F A S w h o are c o m plia nt 
wit h re q uire me nts of t he pr ot oc ol.
T he pr ot oc ol de viati o ns p ote nti all y lea di n g t o e xcl usi o n fr o m t he P P S are:

Dia g n osis at scree ni n g differe nt fr o m hist ol o gicall y c o nfir me d l ocall y  rec urre nt or 
metastatic pre d o mi na ntl y clear cell re nal cell carci n o ma.

N o pre vi o us s ys te mic t hera p y wit h a n i m m u ne c hec k p oi nt i n hi bit or eit her as m o n ot hera py 
or i n c o m bi nati o n t hera p y , or m ore t ha n t w o pre vi o us li ne of a nti-ca ncer s yste mic t hera p y.

N o meas ur a ble lesi o ns at baseli ne.

A n ot her a nti -ne o plastic t hera p y a d mi nistere d after start of st u d y  treat me nt a n d pri or t o t he 
first t u m or assess me nt.
1 0. 1. 4 
Ot h er a n al y si s s et s
N ot a p plica ble.
1 0. 2 
P ati e nt d e m o gr a p hi c s/ ot h er b a s eli n e c h ar a ct eri sti c s
De m o gra p hic a n d ot her bas eli 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 f or all patie nts i n t he F A S.
Cate g orical data will be prese nte d as fre q ue ncies a n d perce nta ges. F or c o nti n u o us data, mea n, 
sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m will be prese nte d.
Rele va nt me dical hist ories a n d c urre nt me dical at baseli ne will be s u m marize d b y  sys te m or ga n 
class a n d preferre d ter m.

N o v arti s
C o nfi d e nti al
P a g e 7 7
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
1 0. 3 
Tr e at m e nt s ( st u d y  tr e at m e nt, c o n c o mit a nt t h er a pi e s, 
c o m pli a n c e)
T he Safet y set will i n ge neral be use d f or t he a nal yses of treat me nts. Cate g orical data will be 
s u m marize d as fre q ue ncies a n d perce nta ges. F or c o nti n u o us data, mea n, sta n dar d de viati o n, 
me dia n, 2 5t h a n d 7 5t 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 t o paz o p a ni b (e x presse d i n m o nt hs), t he d ose i nte nsit y  (c o m p ute d as 
t he rati o of act ual c u m ulati 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 ve 
d ose i nte nsit y (c o m p ute d as t he rati o of d ose i nte nsit y an d pla n ne d d ose i nte nsit y) will be 
s u m marized b y  mea ns of descri pti ve statistics.
T he n u m ber of patie nts wit h d ose a dj ust me nts (re d ucti 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 c orres p o n di n g reas o ns will be s u m marize d f or t he st u d y treat me nt. All 
paz o pa ni b d osi n g data will be liste d.
C o nc o mita nt me dicati o ns a n d si g nifica nt n o n -dr u g t hera pies pri or t o a n d after t he start of t he 
st u d y treat me nt will be liste d a n d s u m marize d acc or di n g t o t he A nat o mical T hera pe utic 
C he mical ( A T C) classificati o n s y ste m i n t he Safet y set.
A ntica ncer t hera pie s a d mi nistere d after t he disc o nti n uati o n of t he st u dy t reat me nt will be liste d 
a n d s u m marize d acc or di n g t o t he A T C classificati o n s y ste m.
1 0. 4 
Pri m ar y  o bj e cti v e
T he pri mar y  o bjecti ve of t he st u d y is t o e val uate t he efficac y of paz o pa ni b as assesse d b y P F S 
base d o n l ocal i n vesti gat or assess me nt per R E CI S T v 1. 1 i n patie nts wit h l ocall y ad va nce d/ 
metastatic R C C wit h pre d o mi na ntl y  clear cell c o m p o ne nt after pre vi o us t hera p y wit h i m m u ne 
c hec k p oi nt i n hi bit or treat me nt.
1 0. 4. 1 
V ari a bl e
T he pri mar y  efficac y varia ble of t he st ud y  is P F S, defi ne d as t he ti me fr o m t he date of start of 
paz o pa ni b treat me nt t o t he date of t he first d oc u me nte d pr o gres si o n or deat h d ue t o a n y ca use. 
P F S will be assesse d via l ocal re vie w acc or di n g t o R E CI S T 1. 1 (see A p pe n di x 2 f or f urt her 
details).
1 0. 4. 2 
St ati sti c al h y p ot h e si s, m o d el, a n d m et h o d of a n al y si s
N o f or mal h y p ot hesis will be teste d i n t he st u d y. A n esti mati o n of t he me dia n P F S wit h 9 5 % 
c o nfi de nce i nter vals will be pr o vi de d i n t he F A S p o p ulati o n. T he Ka pla n -Meier esti mate of t he 
P F S s ur vi val f u ncti o n will be esti mate d a n d dis pla y e d. T he res ulti n g me dia n P F S ti me will be 
gi ve n wit h 9 5 % c o nfi de nce i nter vals, as well as 2 5t h a n d 7 5t h perce ntiles will be re p orte d.
P F S pr o ba bilit y  at selecte d ti me-p oi nts (e. g., 3, 6 a n d 1 2 m o nt hs) will als o be esti mate d.
1 0. 4. 3 
H a n dli n g of mi s si n g v al u e s/ c e n s ori n g/ di s c o nti n u ati o n s
I n t he pri mar y a nalys is, P F S will be ce ns ore d at t he date of t he last a de q uate t u m or assess me nt 
if n o P F S e ve nt ( disease pr o gressi o n or deat h d ue t o an y  ca use) is o bser ve d pri or t o t he a nal ysis 
c ut-off date.

N o v arti s
C o nfi d e nti al
P a g e 7 8
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
O nl y  tu m or assess me nts wit h a re p orte d t u m or res p o nse stat us of C R, P R or S D will be 
c o nsi dere d a de q uate t o deter mi ne t he ce ns ori n g date.
If a P F S e ve nt is o bser ve d after t w o or m ore missi n g or n o n -a de q uate t u m or assess me nts, t he n 
P F S will be ce ns ore d at t he last a de q uate t u m or assess me nt bef ore t he P F S e ve nt. If a P F S e ve nt 
is o bser ve d after a si n gle missi n g or n o n- a de q uate t u m or assess me nt, t he act ual date of t he e ve nt 
will be use d.
1 0. 4. 4 
S u p p orti v e a n d s e n siti vit y a n al y s e s
As a s u p p orti ve a nal ys is, P F S m a y  be a nal yz e d base d o n t he Per Pr ot oc ol Set, usi n g t he sa me 
a nal ys is c o n ve nti o ns as i n t he pri mar y efficac y a nal ysis.
I n a d diti o n, s u b gr o u p a nal ysis b y  li ne of t hera py s u b gr o u p ( 2 n d/ 3r d), a ge cate g ory a n d M S K C C 
a n d I M D C ris k gr o u ps will be perf or me d i n t he F A S f or P F S as a p pr o priate. Details will be 
pr o vi de d i n t he S A P.
1 0. 5 
S e c o n d ar y  o bj e cti v e s
T he sec o n dar y  efficac y a n d safet y o bjecti ves t hat will be e val uate d i n t he st u d y i ncl u de:

O R R a n d C B R base d o n l oca l i n vesti gat or assess me nt as per R E CIS T 1. 1

O S

D O R i n t he s u bset of patie nts wit h c o nfir me d C R / P R;

safety a n d t olera bilit y

P R O assesse d b y  E Q-5 D a n d F K SI -D R S q uesti o n naires.
1 0. 5. 1 
K e y  s e c o n d ar y o bj e cti v e( s)
N ot a p plica ble
1 0. 5. 2 
Ot h er s e c o n d ar y  effi c a c y o bj e cti v e s
O v er all r e s p o n s e r at e ( O R R)
O R R is defi ne d as t he pr o p orti o n of patie nts wit h best o verall res p o nse ( B O R) of C R or P R 
base d o n l ocal i n vesti gat or’s assess me nt acc or di n g t o R E CI S T 1. 1 (see A p pe n di x 2 f or details). 
Deter mi nati o n of B O R of P R or C R will be base d o n c o nfir me d P R/ C R as per R E CI S T 1. 1.
O R R will be calc ulate d base d o n t he F A S a n d its e xact 9 5 % c o nfi de nce i nter val (Cl o p per a n d 
Pears o n 1 9 3 4 ) will be prese nte d.
Cli ni c al b e n efit r at e ( C B R)
C B R is defi ne d as t he pr o p orti o n of patie nts wit h a best o verall res p o nse of c o nfir me d C R, or 
P R or a n o verall lesi o n res p o nse of S D or N o n -C R/ N o n -P D lasti n g ≥2 4 wee ks base d o n l ocal 
i n vesti gat or’s assess me nt accor di n g t o R E CI S T 1. 1.
C B R a n d its e xact 9 5 % c o nfi de nce i nter val will be pr o vi de d usi n g F A S p o p ulati o n.

N o v arti s
C o nfi d e nti al
P a g e 7 9
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
O v er all s ur vi v al ( O S)
O S is defi ne d as t he ti me fr o m date of start of paz o pa ni b treat me nt t o date of deat h d ue t o a n y 
ca use. If a patie nt is n ot k n o w n t o ha ve die d, t he n O S will be ce ns ore d at t he latest date t he 
patie nt was k n o w n t o be ali ve ( o n or bef ore t he c ut- off date).
O S will be a nal yz e d i n t he F A S p o p ulati o n. T he O S distri b uti o n will be esti mate d usi n g t he 
Ka pla n -Meier met h o d. T he Ka pla n -Meier c ur ve will be gra p hicall y p rese nte d, a n d t he me dia n, 
2 5 t h a n d 7 5 t h perce ntiles will be s h o w n al o n g wit h t he c orres p o n di n g 9 5 % c o nfi de nce i nter vals. 
O S pr o ba bilit y  at selecte d ti me-p oi nts (e. g. , 6, 1 2 a n d 2 4 m o nt hs) will als o be esti mate d.
D ur ati o n of r e s p o n s e ( D O R)
D O R o nl y  a p plies t o patie nts, w h ose best o verall res p o nse is c o nfir me d C R or P R, as per l ocal 
i n vesti gat or’s assess me nt, acc or di n g t o R E CI S T 1. 1. D O R is defi ne d as t he ti me fr o m t he date 
of first d oc u me nte d res p o nse of C R or P R (i.e., t he start da te of res p o nse, n ot t he date w he n 
res p o nse was c o nfir me d), t o t he date of t he first d oc u me nte d pr o gressi o n or deat h d ue t o 
u n derl y i n g ca ncer, w hic he ver c o mes first. I n patie nts c o nti n ui n g wit h o ut pr o gressi o n or deat h 
d ue t o u n derl yi n g ca ncer D O R will be cens ore d at t he date of t heir last a de q uate t u m or 
assess me nt. D O R will be esti mate d usi n g t he Ka pla n -Meier met h o d. T he me dia n, 2 5
t h a n d 7 5 t h
perce ntiles, a n d t he c orres p o n di n g 9 5 % c o nfi de nce i nter vals will be pr o vi de d.
1 0. 5. 3 
S af et y  o bj e cti v e s
1 0. 5. 3. 1
A n al y si s s et a n d gr o u pi n g f or t h e a n al y s e s
F or all safet y a nal ys es, t he safet y set will be use d. S u m mar y ta ble a n d patie nt data listi n gs will 
be use d t o a nal yz e a n d prese nt safet y data.
T he o verall o bser vati o n peri o d will be di vi de d i nt o t hree m ut uall y  e xcl usi ve se g me nts:
1.
pre -treat me nt peri o d: fr o m da y of patie nt’s i nf or me d c o nse nt t o t he da y bef ore first d ose 
of st u d y  me dicati o n;
2.
o n- treat me nt i ncl u di n g safet y f oll o w-u p peri o d: fr o m da y  of first d ose of st u d y me dicati o n 
t o 3 0 da ys after last d ose of st u d y me dicati o n;
3.
p ost -treatme nt peri o d: starti n g at da y  3 1 after last d ose of st u d y me dicati o n.
If dates are i nc o m plete i n a wa y t hat clear assi g n me nt t o pre -, o n-, p ost-treat me nt peri o d ca n n ot 
be ma de, t he n t he res pecti ve data will be assi g ne d t o t he o n -treat me nt peri o d.
F or t he safety e val uati o ns ( wit h t he e xce pti o n of A Es), t he last a vaila ble assess me nt perf or me d 
o n or bef ore t he date of st u d y  treat me nt start will be c o nsi dere d as t he “ baseli ne” assess me nt.
1 0. 5. 3. 2
A d v er s e e v e nt s ( A E s)
S u m mar y  ta bles f or a d verse e ve 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 peri o d, t he tre at me nt-e mer ge nt A Es .
T he i nci de nce of treat me nt -e mer ge nt a d verse e ve nts ( ne w or w orse ni n g fr o m baseli ne) will be 
s u m marize d b y  sys te m or ga n class a n d or preferre d ter m, se verit y (ba se d o n N CI -C T C A E 
gra des), relati o n t o st u d y  treat me nt.

N o v arti s
C o nfi d e nti al
P a g e 8 0
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Seri o us a d verse e ve nts, n o n -seri o us a d verse e ve nts, a d verse e ve nts of s pecial i nterest ( A E SI) 
(see Secti o n 8. 1. 3 ) a n d a d verse e ve nts lea di n g t o st u dy t reat me nt disc o nti n uati o n d uri n g t he o n-
treat me nt peri o d will be ta b ulate d f or safety s et as well as b y li ne of t hera p y s u b gr o u p ( 2 n d/ 3 r d), 
a ge cate g or y a n d M S K C C a n d IM D C ris k gr o u ps .
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 verse e ve nts (i ncl u di n g t h ose fr o m t he pre a n d p ost -treat me nt 
peri o ds) will be liste d a n d t h ose c ollecte d d uri n g t he pre -treat me nt a n d p ost -treat me nt peri o d 
will be fla g ge d.
1 0. 5. 3. 3
L a b or at or y  a b n or m aliti e s
Gra di n g of la b orat or y val ues w ill be assi g ne d pr o gra m maticall y as per N CI  C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts ( N CI-C T C A E) versi o n 4. 0 3. T he calc ulati o n of N CI -
C T C A E gra des will be base d o n t he o bser ve d la b orat or y  val ues o nl y, cli nical assess me nts will 
n ot be ta ke n i nt o acc o u nt.
N CI -C T C A E G ra de 0 will be assi g ne d f or all n o n-missi n g val ues n ot gra de d as 1 or hi g her.
F or la b orat or y tests w here gra des are n ot defi ne d b y  NCI -C T C A E v 4. 0 3, results will be 
cate g orize d as l o w/ n or mal/ hi g h base d o n la b orat or y  n or mal ra n ges.
F or la b orat or y  tests w here gra des are defi ne d b y N CI -C T C A E v 4. 0 3:

W orst p ost -baseli ne N CI -C T C A E gra de (re gar dless of t he baseli ne stat us). Eac h patie nt 
will be c o u nte d o nl y o nce f or t he w orst gra de o bser ve d p ost-baseli ne.

S hift ta bles usi n g N CI - C T C A E gra des t o c o m pare baseli ne t o t he w orst o n-treat me nt 
val ue
F or la b orat or y  tests w here gra des are n ot defi ne d b y N CI-C T C A E v 4. 0 3:

S hift ta bles usi n g t he l o w/ n or mal/ hi g h/ (l o w a n d hi g h ) classificati o n t o c o m pare baseli ne 
t o t he w orst o n- treat me nt val ue.

La b orat or y  ab n or malities will be s u m marize d f or safety set as well as b y  li ne of t hera py 
s u b gr o u p ( 2 n d/ 3r d), a ge a n d M S K C C a n d ID M C ris k gr o u ps, as a p pr o priate .
Listi n g of all la b orat ory data wit h val ues fla g ge d t o s h o w t he c orres p o n di n g N CI -C T C A E v 4. 0 3 
gra de if a p plica ble a n d t he classificati o ns relati ve t o t he la b orat or y nor mal ra n ges will be 
ge nerate d.
1 0. 5. 3. 4
Ot h er s af et y  d at a
E C G

L ocal 1 2 -lea d E C Gs i ncl u di n g H R, P R, Q R S, Q T, a n d Q Tc F i nter vals will be o btai ne d f or 
eac h s u bject at baseli ne, d uri n g t he st u d y treat me nt peri o d a n d at t he e n d of treat me nt. 
E C G data will be rea d a n d i nter prete d l ocall y .

T he n u m ber a n d perce nta ge of patie nts wit h n ota ble E C G i nter val val ues a n d c ha n ge fr o m 
baseli ne E C G para meters b y  ti me p oi nt will be s u m marize d i n t he Safet y set.

All c ollecte d data will be prese nte d i n data listi n gs; n ota ble val ues a n d a b n or malit y  
fi n di n g will be fla g ge d i n t he listi n g.

N o v arti s
C o nfi d e nti al
P a g e 8 1
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
E c h o c ar di o gr a m/ M U G A

L ocal ec h ocar di o gra m or M U G A will be o btai ne d f or eac h s u bject at baseli ne, d uri n g t he 
st u d y treat me nt peri o d a n d at t he e n d of treat me nt.

Ejecti o n fracti o n val ues will be classifie d base d o n N CI -C T C A E v 4. 0 3 a n d a s hift ta ble 
will be pre pare d f or t he Safet y set t o s u m marize t he distri b uti o n of i n di vi d ual w orst o n -
treat me nt val ues vs. t he c orres p o n di n g baseli ne val ues.

All c ollecte d data will be prese nte d i n data listi n gs a n d n ota ble v al ues will be fla g ge d.
Vit al si g n s

Data o n vital si g ns will be ta b ulate d a n d liste d, n ota ble val ues will be fla g ge d.
1 0. 5. 3. 5
S u p p orti v e a n al y s e s f or s e c o n d ar y  o bj e cti v e s
N ot a p plica ble.
1 0. 5. 3. 6
T ol er a bilit y
T olera bilit y  will be assesse d b y  eval uati n g t he i nci de nce of dr u g -relate d a d verse e ve nts b y  NCI -
C T C A E gra de a n d t he i nci de nce of e ve nts lea di n g t o st u d y treat me nt disc o nti n uati o n (see 
Secti o n 1 0. 5. 3. 2 ).
1 0. 5. 4 
R e s o ur c e utili z ati o n
N ot a p plica ble.
1 0. 5. 5 
P ati e nt -r e p ort e d o ut c o m e s
T he F A S will be use d f or a nal y zi n g t he P R O data u nless s pecifie d differe ntl y . T he E Q- 5 D-5 L  
a n d F S KI -D R S will be use d t o c ollect P R O data o n t he s u bject’s healt h -relate d q ualit y  of life 
a n d disease-relate d s ym pt o ms.
T he E Q - 5 D-5 L  is a ge neral healt h stat us a n d healt h utilit y meas ure (Ra bi n 2 0 0 1 ) a n d meas ures 
5 di me nsi o n of healt h state: m o bilit y , self-care, us ual acti vities, pai n/ disc o mf ort, a n d 
a n xiet y/ de pressi o n eac h assesse d b y  a si n gle q uesti o n o n a fi ve- p oi nt or di nal scale E Q -5 D 
Vis ual A nal o g Scale ( V A S) is als o i ncl u de d. T he F K SI -Disease Relate d S y m pt o ms ( F K SI-D R S) 
is a 9- ite m q uesti o n naire s pecificall y desi g ne d t o e val uate s ym pt o ms 
t hat are directl y 
attri b uta ble t o ki d ne y  ca ncer (Cella 2 0 0 7 ) a n d i ncl u des patie nt’s s ym pt o ms i n t he past se ve n 
da y s s uc h as lac k of e ner g y, pai n, b o ne -pai n, s h ort ness of breat h, fati g ue, bl o o d i n uri ne, etc. 
T he sc ori n g of t hese i nstr u me nts will be d o ne i n acc or da nce wit h t he res pecti ve user’s ma n ual 
of t he i nstr u me nt.
Ha n dli n g of missi n g data a n d ge nerati o n of sta n dar d sc ores f or t he a nal ys is will be perf or me d 
i n acc or da nce wit h t he res pecti ve sc ori n g ma n ual.
Descri pti ve statistics ( mea n, sta n dar d de viati o n, me dia n, mi ni m u m, an d ma xi m u m) will be use d 
t o s u m marize t he sc ore d scales at eac h sc he d ule d assess me nt ti me p oi nt. A d diti o nall y, c ha n ges 
fr o m baseli ne i n t he sc ores at t he ti me of eac h assess me nt will be descri pti vel y  anal yz e d. 
A d diti o nal statistical a nal yses s uc h as re peate d meas ures a nal ys is f or c ha n ges of t he mea n 
sc ores o ver ti me will be perf or me d as a p pr o priate. Patie nts wit h a n e val ua ble baseli ne sc ore a n d 

N o v arti s
C o nfi d e nti al
P a g e 8 2
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
at least o ne e val ua ble p ost baseli ne sc ore d uri n g t he treat me nt peri o d will be i ncl u de d i n t he 
a nal ys is of t he c han ges fr o m baseli ne. S u m mar y  ta bles a n d pl ots will be re p orte d. All re p orte d 
data will be prese nte d i n data listi n g.

N o v arti s
C o nfi d e nti al
P a g e 8 3
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
1 0. 7 
I nt eri m a n al ysi s
N o f or mal i nteri m a nal ys is is pla n ne d f or t his trial.
1 0. 8 
S a m pl e si z e c al c ul ati o n
Si nce t here is n o f or mal h y p ot hesis testi n g, sa m ple size f or t his st u d y is n ot base d o n a n y 
statistical p o wer c o nsi derati o n. A t otal of a p pr o xi matel y 1 0 0 patie nts ( wit h a p pr o xi matel y 4 0 
patie nts recei vi n g paz o pa ni b as 2 n d-li ne t hera py)  are pla n ne d t o be e nr olle d a n d treate d i n t his 
st u d y. I n a retr os pecti ve st u d y, Na dal et al. re p orte d me dia n P F S ( m P F S) of 6. 9 m o nt hs ( 9 5 % 
Cl: 3. 7 t o 1 0. 1) i n m R C C patie nts treate d wit h V E G F R -T KI t hera p y after a n y PD- 1c o m bi nati o n 
(Na dal et al 2 0 1 6 ). Base d o n t his data, t he me dia n P F S f or t his patie nt p o p ulatio n treate d wit h 
paz o pa ni b f oll o wi n g pri or treat me nt wit h
i m m u ne c hec k p oi nt i n hi bit ors is ass u me d t o be 
a p pr o xi matel y 6 mo nt hs or less. C o nsi deri n g a recr uit me nt peri o d of 1 2 m o nt hs a n d 6 m o nt hs 
of f oll o w u p after L P F V, t he e x pecte d 9 5 % CI s f or a me dia n P F S f or o verall, 2 n d li ne, a n d 3 r d
li ne patie nts wit h diffe re nt sa m ple sizes are prese nte d i n Ta ble 1 0 - 1.
T a bl e 1 0 - 1 
S a m pl e si z e a n d e sti m at e d 9 5 % CI f or m e di a n P F S
P ati e nt p o p ul ati o n
M e di a n P F S 
( m o nt h s)
S a m pl e si z e
( N)
9 5 %  CI of m e di a n 
P F S ( m o nt h)
Wi dt h
( m o nt h)
O v er all 
5
9 0
3. 9 6, 6. 3 1 
2. 3 5
1 0 0
4. 0 1, 6. 2 4
2. 2 3
1 1 0
4. 0 5, 6. 1 7  
2. 1 2

N o v arti s
C o nfi d e nti al
P a g e 8 4
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
P ati e nt p o p ul ati o n
M e di a n P F S 
( m o nt h s)
S a m pl e si z e
( N)
9 5 %  CI of m e di a n 
P F S ( m o nt h)
Wi dt h
( m o nt h)
2 n d li n e 
6
3 0
3. 9 5, 9. 1 2
5. 1 8
4 0
4. 1 7, 8. 6 2
4. 4 5
5 0
4. 3 4, 8. 3 0
3. 9 6
3 r d li n e
4
5 0
2. 9 6 , 5.4 0
2. 4 4
6 0
3. 0 4, 5. 2 6 
2. 2 2
7 0
3. 1 0, 5. 1 6
2. 0 5
1 0. 9 
P o w er f or a n al y si s of k e y s e c o n d ar y  vari a bl e s
N ot a p plica ble.
1 1 
Et hi c al c o n si d er ati o n s a n d a d mi ni str ati v e pr o c e d ur e s
1 1. 1 
R e g ul at or y  a n d et hi c al c o m pli a n c e
T his cli nical st u d y was desi g ne d, s hall be i m ple me nte d a n d re p orte d i n acc or da nce wit h t he 
I C H Har m o nize d Tri partite G ui deli nes f or G o o d Cli nical Practice, wit h a p plica ble l ocal 
re g ulati o ns (i ncl u di n g E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C a n d U S C o de of Fe deral Re g ulati o ns 
Title 2 1), a n d wit h t he et hic al pri nci ples lai d d o w n i n t he Declarati o n of Helsi n ki.
1 1. 2 
R e s p o n si biliti e s of t h e i n v e sti g at or a n d I R B/I E C/ R E B
T he pr ot oc ol a n d t he pr o p ose d i nf or me d c o nse nt f or m m ust be re vie we d a n d a p pr o ve d b y  a 
pr o perl y c o nstit ute d I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee/ Researc h 
Et hics B oar d (IR B/I E C/ R E B) bef ore st u d y start. Pri or t o st u d y start, t he i n vesti gat or is re q uire d 
t o si g n a pr ot oc ol si g nat ure pa ge c o nfir mi n g his/ her a gree me nt t o c o n d uct t he st u d y in 
acc or da nce wit h t hese d oc u me nts a n d all of t he i nstr ucti o ns a n d pr oce d ures f o u n d i n t his 
pr ot oc ol a n d t o gi ve access t o all rele va nt data a n d rec or ds t o N o vartis m o nit ors, a u dit ors, 
N o vartis 
Cli nical 
Q ualit y  
Ass ura nce re prese ntati ves, desi g nate d a ge nts of N o vartis, 
I RBs/I E Cs/ R E Bs a n d re g ulat or y  a ut h orities as re q uire d.
1 1. 3 
I nf or m e d c o n s e nt pr o c e d ur e s
Eli gi ble patie nts ma y  onl y  be i ncl u de d i n t he st u d y after pr o vi di n g writte n ( wit nesse d, w here 
re q uire d by la w or re g ulati o n), I R B/I E C/ R E B -a p pr o ve d i nf or me d c o nse nt
I nf or me d c o nse nt m ust be o btai ne d bef ore c o nd ucti n g a n y st u d y- s pecific pr oce d ures (i.e. all of 
t he pr oce d ures descri be d i n t he pr ot oc ol). T he pr ocess of o btai ni n g i nf or me d c o nse nt s h o ul d be 
d oc u me nte d i n t he patie nt s o urce d oc u me nts. T he date w he n a s u bject’s I nf or me d C o nse nt was 
act uall y o btai ne d w ill be ca pt ure d i n t heir C R Fs.
N o vartis will pr o vi de t o i n vesti gat ors, i n a se parate d oc u me nt, a pr o p ose d i nf or me d c o nse nt 
f or m (IC F) t hat is c o nsi dere d a p pr o priate f or t his st u d y an d c o m plies wit h t he I CH G C P 
g ui deli ne a n d re g ulat or y re q uire me nts. A n y c han ges t o t his I CF s u g geste d b y  the i n vesti gat or 
m ust be a gree d t o b y  No vartis bef ore s u b missi o n t o t he I RB/I E C/ R E B, a n d a c o p y of t he 
a p pr o ve d versi o n m ust be pr o vi de d t o t he N o vartis m o nit or after I R B/ I E C/ R E B a p pr o val.

N o v arti s
C o nfi d e nti al
P a g e 8 6
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
1 1. 6 
St u d y d o c u m e nt ati o n, r e c or d k e e pi n g a n d r et e nti o n of 
d o c u m e nt s
Eac h partici pati n g site will mai ntai n a p pr o priate me dical a n d researc h rec or ds for t his trial, i n 
c o m plia nce wit h Secti o n 4. 9 of t he I C H E 6 G C P, a n d re g ulat or y a n d i nstit uti o nal re q uire me nts 
f or t he pr otecti o n of c o nfi de ntialit y of s u bjects. As part of partici pati n g i n a N o vartis -s p o ns ore d 
st u d y, eac h site will per mit a ut h orize d re prese ntati ves of t he s p o ns or(s) a n d re g ulat or y a ge ncies 
t o e xa mi ne (a n d w he n re q uire d b y ap plica ble la w, t o c o p y ) cli nical rec or ds f or t he p ur p oses of 
q ualit y  ass ura nce re vie ws, a u dits a n d e val uati o n of t he st u d y safety a n d pr o gress.
S o urce data are all i nf ormati o n, ori gi nal rec or ds of cli nical fi n di n gs, o bser vati o ns, or ot her 
acti vities i n a cli nical trial necessar y  for t he rec o nstr ucti o n a n d e val uati o n of t he trial. E xa m ples 
of t hese ori gi nal d oc u me nts a n d data rec or ds i ncl u de, b ut are n ot li mite d t o, h os pit al rec or ds, 
cli nical a n d office c harts, la b orat or y notes, me m ora n da, 
s u bjects’ diaries or e val uati o n 
c hec klists, p har mac y  dis pe nsi n g rec or ds, rec or de d data fr o m a ut o mate d i nstr u me nts, c o pies or 
tra nscri pti o ns certifie d after verificati o n as bei n g acc urate a n d c o m plete, micr ofic hes, 
p h ot o gra p hic ne gati ves, micr ofil m or ma g netic me dia, x- ra ys, a n d s u bject files a n d rec or ds ke pt 
at t he p har mac y, at t he la b orat ories, a n d me dic o-tec h nical de part me nts i n v ol ve d i n t he cli nical 
trial.
Data c ollecti o n is t he res p o ns i bilit y of t he cli nical trial staff at t he site u n der t he s u per visi o n of 
t he site Pri nci pal In vesti gat or. T he st u d y  case re p ort f or m ( C R F) is t he pri mar y data c ollecti o n 
i nstr u me nt f or t he st u d y. T he i n vesti gat or s h o ul d e ns ure t he acc urac y, c o m plete ness, le gi bilit y, 
a n d ti meli ness of t he data re p orte d i n t he C R Fs a n d all ot her re q uire d re p orts. Data re p orte d o n 
t he C R F, t hat are deri ve d fr o m s o urce d oc u me nts, s h o ul d be c o nsiste nt wit h t he s o urce 
d oc u me nts or t he discre pa ncies s h o ul d be e x plai ne d. All data re q ueste d o n t he C R F m ust be 
rec or de d. A n y m issi n g data m ust be e x plai ne d. A n y c ha n ge or c orrecti o n t o a pa per C R F s h o ul d 
be date d, i nitiale d, a n d e x plai ne d (if necessar y ) a n d s h o ul d n ot o bsc ure t he ori gi nal e ntr y. F or 
electr o nic C R Fs a n a u dit trail will be mai ntai ne d b y  t he s yste m. T he i n vesti gat or s h o ul d retai n 
rec or ds of t he c ha n ges a n d c orrecti o ns t o pa per C R Fs.
T he i n vesti gat or/i nstit uti o n s h o ul d mai ntai n t he trial d oc u me nts as s pecifie d i n Esse ntial 
D oc u me nts f or t he C o n d uct of a Cli nical Trial (I C H E 6 Secti o n 8) a n d as re q uire d b y  ap plica ble 
re g ulati o ns a n d/ or g ui deli nes. T he i n vesti gat or/i nstit uti o n s h o ul d ta ke meas ures t o pre ve nt 
acci de ntal or pre mat ure destr ucti o n of t hese d oc u me nts.
Esse ntial d oc u me nts ( writte n a n d electr o nic) s h o ul d be retai ne d f or a peri o d of n ot less t ha n 
fiftee n ( 1 5) ye ars fr o m t he c o m pleti o n of t he Cli nical Trial u nless S p o ns or pr o vi des writte n 
per missi o n t o dis p ose of t he m or, re q uires t heir rete nti o n f or a n a d diti o nal peri o d of ti me 
beca use of a p plica ble la ws, re g ulati o ns a n d / or g ui deli nes.
1 1. 7 
C o nfi d e nti alit y  of st u d y d o c u m e nt s a n d p ati e nt r e c or d s
T he i n vesti gat or m ust e ns ure a n o n y m it y of t he patie nts; patie nts m ust n ot be i de ntifie d b y  na mes 
i n a n y doc u me nts s u b mitte d t o N o vartis. Si g ne d i nf or me d c o nse nt f or ms a n d patie nt e nr ollme nt 
l o g m ust be ke pt strictly c o nfi de ntial t o e na ble patie nt i de ntificati o n at t he site.

N o v arti s
C o nfi d e nti al
P a g e 8 7
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
1 1. 8 
A u dit s a n d i n s p e cti o n s
S o urce data/ d oc u me nts m ust be a vaila ble t o i ns pecti o ns b y  No vartis or desi g nee or Healt h 
A ut h orities.
1 1. 9 
Fi n a n ci al di s cl o s ur e s
Fi na ncial discl os ur es s h o ul d be pr o vi de d b y  st u d y pers o n nel w h o are directl y  in v ol ve d i n t he 
treat me nt or e val uati o n of patie nts at t he site - pri or t o st u d y  start.
1 2 
Pr ot o c ol a d h er e n c e
I n vesti gat ors ascertai n t he y will a p pl y due dili ge nce t o a v oi d pr ot oc ol de viati o ns. U n der n o 
circ u msta nces s h o ul d t he i n vesti gat or c o ntact N o vartis or its a ge nts, if a n y, m o nit ori n g t he st u d y 
t o re q uest a p pr o val of a pr ot oc ol de viati o n, as n o a ut h orize d de viati o ns are per mitte d. If t he 
i n vesti gat or feels a pr ot oc ol de viati o n w o ul d i m pr o ve t he c on d uct of t he st u d y this m ust be 
c o nsi dere d a pr ot oc ol a me n d me nt, a n d u nless s uc h a n a me n d me nt is a gree d u p o n b y  No vartis 
a n d a p pr o ve d b y  the I R B/I E C/ R E B it ca n n ot be i m ple me nte d. All si g nifica nt pr ot oc ol 
de viati o ns will be rec or de d a n d re p orte d i n t he C S R.
1 2. 1 
A m e n d m e nt s t o t h e pr ot o c ol
A n y  c ha n ge or a d diti o n t o t he pr ot oc ol ca n o nly be ma de i n a writte n pr ot oc ol a me n d me nt t hat 
m ust be a p pr o ve d b y  N o vartis, Healt h A ut h orities w here re q uire d, a n d t he I R B/I E C/ R E B. O nl y 
a me n d me nts t hat are re q uire d f or patie nt safet y ma y  be i m ple me nte d pri or t o I RB/I E C/ R E B 
a p pr o val. N ot wit hsta n di n g 
t he nee d f or a p pr o val of f or mal pr ot oc ol a me n d me nts, t he 
i n vesti gat or is e x pecte d t o ta ke a n y i m me diate acti o n re q uire d f or t he safet y of a n y patie nt 
i ncl u de d i n t his st u d y, e ve n if t his acti o n re prese nts a de viati o n fr o m t he pr ot oc ol. I n 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 (e. g., U K re q uires t he n otificati o n of ur ge nt safet y meas ures 
wi t hi n 3 da ys) b ut n ot later t ha n 1 0 w or ki n g da ys.

N o v arti s
C o nfi d e nti al
P a g e 8 8
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
1 3 
R ef er e n c e s ( a v ail a bl e u p o n r e q u e st)
Al bi ges, et al ( 2 0 1 5) Efficac y  of tar gete d t hera pies after P D-1/ P D -L 1 bl oc ka ge i n metastatic 
re nal cell carci n o ma. E ur o pea n J o ur nal of Ca ncer; 5 1, 2 5 8 0- 2 5 8 6
At ki ns, et al ( 2 0 1 6) A xiti ni b i n c o m bi nati o n wit h pe m br oliz u ma b i n patie nts ( pts) wit h 
a d va nce d re nal cell carci n o ma (a R C C): Preli mi nar y  safety a n d efficac y res ults. A n nals of 
O nc ol o g y 2 7 ( S u p ple me nt 6): vi 2 6 6 -vi 2 9 5
Bille m o nt , et al ( 2 0 0 8) Bl o o d gl uc ose le vels i n patie nts wit h metastatic re nal cell carci n o ma 
treate d wit h s u niti ni b. Britis h J o ur nal of Ca ncer 9 9: 1 3 8 0- 1 3 8 2
Cella, et al ( 2 0 0 7) De vel o p me nt a n d Vali dati o n of a Scale t o Meas ure Disease -Relate d 
S y m pt o ms of Ki d ne y  Ca ncer. Val ue i n Healt h; V ol. 1 0
C h o ueiri, et al ( 2 0 1 5) Ca b oza nti ni b vers us E ver oli m us i n A d va nce d Re nal -Cell Carci n o ma. N 
E n gl J Me d; 3 7 3: 1 8 1 4 - 2 3
C h o w, et al ( 2 0 1 0) E pi de mi ol o g y  a n d ris k fact ors f or ki d ne y ca ncer. Nat. Re v. Ur ol. 7, 2 4 5-
2 5 7
Cl o p per CJ, Pear s o n E S ( 1 9 3 4) T he Use of C o nfi de nce or Fi d ucial Li mits Ill ustrate d i n t he 
Case of t he Bi n o mial. Bi o metri ka. V ol. 2 6, N o. 4, p p. 4 0 4 - 4 1 3
C o he n, et al ( 2 0 0 5) Re nal -Cell Carci n o ma. N E n gl J Me d; 3 5 3 : 2 4 7 7-9 0
Esc u dier, et al ( 2 0 0 7) Be vaciz u ma b pl us i nterfer o n alfa- 2a f or treat me nt of metastatic re nal 
cell carci n o ma: a ra n d o mise d, d o u ble- bli n d p hase III trial. La ncet; 3 7 0: 2 0 1 3 - 1 1
Esc u dier, et al ( 2 0 1 6) Re nal cell carci n o ma: E S M O Cli nical Practice G ui deli nes f or dia g n osis, 
treat me nt a n d f oll o w-u p. A n nals of O nc o l o g y 2 7 ( S u p ple me nt 5): v 5 8- v 6 8
G u pta, et al ( 2 0 0 8) E pi de mi ol o gic a n d s oci oec o n o mic b ur de n of metastatic re nal cell 
carci n o ma ( m R C C): a literat ure re vie w. Ca ncer Treat Re v; 3 4( 3): 1 9 3 - 2 0 5
Ha m mers H ( 2 0 1 6) I m m u n ot hera p y i n ki d ne y ca ncer: t he past, prese nt a n d f ut ure. C urr O pi n 
Ur ol. 2 6: 5 4 3- 5 4 7
H u des, et al ( 2 0 0 7) Te msir oli m us, I nterfer o n Alfa, or B ot h f or A d va nce d Re nal -Cell 
Carci n o ma. N E n gl J Me d; 3 5 6: 2 2 7 1 - 2 2 8 1
Lar ki n, et al ( 2 0 1 6) P hase 1 b d ose -fi n di n g st u d y of a vel u ma b (a nti-P D - L-1) + a xiti ni b i n 
treat me nt-naï ve patie nts wit h a d va nce d re nal cell carci n o ma. A n nals of O nc ol o g y  2 7 
( S u p ple me nt 6): vi 2 6 6-vi 2 9 5
M otzer, et al ( 2 0 0 4) Pr o g n ostic Fact ors f or S ur vi val i n Pre vi o usl y  Treate d Patie nts Wit h 
Metastatic Re nal Cell Carci n o ma. J Cli n O nc ol; 2 2, 4 5 4- 4 6 3
M otze r, et al ( 2 0 0 7) S u niti ni b vers us Interfer o n Alfa i n Metastatic Re nal -Cell Carci n o ma. N 
E n gl J Me d; 3 5 6: 1 1 5 - 2 4
M otzer, et al ( 2 0 0 8) Efficac y  of e ver oli m us i n a d va nce d re nal cell carci n o ma: a d o u ble-bli n d, 
ra n d o mise d, place b o-c o ntr olle d p hase III trial. La nc et; 3 7 2: 4 4 9 - 5 6
M otzer, et al ( 2 0 1 3) Paz o pa ni b vers us S u niti ni b i n Metastatic Re nal -Cell Carci n o ma. N E n gl J 
Me d; 3 6 9: 7 2 2 - 3 1
M otzer, et al ( 2 0 1 5) Ni v ol u ma b vers us E ver oli m us i n A d va nce d Re nal -Cell Carci n o ma. N 
E n gl J Me d; 3 7 3: 1 8 0 3 - 1 3

N o v arti s
C o nfi d e nti al
P a g e 8 9
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Na dal, et al ( 2 0 1 6) S afet y a n d cli nical acti vity of vasc ular e n d ot helial gr o wt h fact or rece pt or 
( V E G F R)-t yr osi ne ki nase i n hi bit ors after pr o gra m me d cell deat h 1 i n hi bit or treat me nt i n 
patie nts wit h metastatic clear cell re nal cell carci n o ma. A n nals of O nc ol o g y  2 7: 1 3 0 4- 1 3 1 1
Pic kar d, A Si m o n, et al ( 2 0 0 7) Esti mati o n of mi ni mall y  i m p orta nt differe nces i n E Q-5 D 
utilit y  a n d V A S sc ores i n ca ncer. Healt h a n d Q ualit y of Life O utc o mes, 5: 7 0
Ra bi n R, de C harr o F ( 2 0 0 1) E Q- 5 D: a meas ure of healt h stat us fr o m t he E ur o Q ol Gr o u p. 
A n n Me d. 3 3 : 3 3 7– 3 4 3
Ri ni, et al ( 2 0 1 1) C o m parati ve effecti ve ness of a xiti ni b vers us s orafe ni b i n a d va nce d re nal 
cell carci n o ma ( A XIS): a ra n d o mise d p hase 3 trial. La n cet 2 0 1 1; 3 7 8: 1 9 3 1- 3 9
Sie gel, et al ( 2 0 1 7) Ca ncer Statistics, 2 0 1 7. C A Ca ncer J Cli n; 6 7: 7 - 3 0
Ster n b er g, et al ( 2 0 1 0) Paz o pa ni b i n L ocall y  A d va nce d or Metastatic Re nal Cell Carci n o ma: 
Res ults of a Ra n d o mize d P hase III Trial. J Cli n O nc ol 2 8: 1 0 6 1- 1 0 6 8
Ster n ber g, et al ( 2 0 1 3) A ra n d o mise d, d o u ble- bli n d p hase III st u d y  of paz o pa ni b i n patie nts 
wit h a d va nce d a n d/ or metastatic re nal cell carci n o ma: fi nal o verall s ur vi val res ults a n d safet y  
u p date. E ur o pea n J o ur nal of Ca ncer; 4 9: 1 2 8 7 -1 2 9 6

N o v arti s
C o nfi d e nti al
P a g e 9 0
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
1 4 
A p p e n di c e s
1 4. 1 
A p p e n di x 1: Str o n g C Y P 3 A 4 i n hi bit or s a n d i n d uc er s
Str o n g i n hi bit or s of C Y P 3 A 4 1
b o c e pr e vir, cl arit hr o m y ci n, c o ni v a pt a n, gr a p efr uit j ui c e 2 , i n di n a vir, itr a c o n a z ol e, 
k et o c o n a z ol e, l o pi n a vir/rit o n a vir, mi b efr a dil, n ef a z o d o n e, n elfi n a vir, 
p o s a c o n a z ol e, rit o n a vir, s a q ui n a vir, s e q ui n a vir/rit o n a vir, t el a pr e vir, 
t elit hr o m y ci n, v ori c o n a z ol e, i n di n a vir/rit o n a vir, ti pr a n o avir/rit o n a vir, c o bi ci st at, 
tr ol e a n d o m y ci n, d a n o pr e vir/rit o n a vir, elt e gr a vir/rit o n a vir,
1. 
A str o n g i n hi bit or f or a s p e cifi c C Y P i s d efi n e d a s a n i n hi bit or t h at i n cr e a s e s t h e A U C of a s e n siti v e s u b str at e 
f or t h at C Y P b y e q u al or m or e t h a n 5-f ol d.
2. 
Eff e ct s e e m s t o b e d u e t o C Y P 2 C 1 9 i n hi biti o n b y et hi n yl e str a di ol
Str o n g i n d u c er s of 
C Y P 3 A 4 1
a v a si mi b e, c ar b a m a z e pi n e, p h e n yt oi n, rif a m pi n, St. J o h n’ s w ort 5 , rif a b uti n, 
p h e n o b ar bit al, mit ot a n e, e n z al ut a mi d e
M o d er at e i n d u c er s of 
C Y P 3 A 4 2
b o s e nt a n, ef a vir e n z, etr a viri n e, m o d afi nil, n af cilli n, rit o n a vir, t hi ori d a zi n e, ti pr a n a vir, 
s e m a g a c e st at 4 , t al vir ali n e4 , l o pi n a vir, l er si viri n e
W e a k i n d u c er s of C Y P 3 A 4 3
a m pr e n a vir, a pr e pit a nt, ar m o d afi nil b e x ar ot e n e, cl o b a z a m, d a n s h e n 5 , 
d e x a m et h a s o n e, e c hi n a c e a 5 , gi n g k o ( gi n kg o bil o b a) 5 , gl y c yrr hi zi n5 , 
m et h yl pr e d ni s ol o n e, n e vir a pi n e, o x c ar b a z e pi n e, pi o glit a z o n e, pr e d ni s o n e, 
pl e c o n aril 4 , pri mi d o n e, r alt e gr a vir, r ufi n a mi d e, s or af e ni b, t el a pr e vir, t er bi n afi n e, 
t o pir a m at e, tr o glit a z o n e4 , vi n bl a sti n e, e sli c ar b a z e pi n e, gi n s e n g5 , v e mur af e ni b, 
b o c e pr e vir, s ulfi n p yr a z o n e, ti c a gl er or, vi cri vir o c/rit o n a vir, rit o n a vir, ti cl o pi di n e, 
bri v a c et a m, Stri bil d ( c o m b o of el vit e gr a vir, c o bi ci st at, e mtri cit a bi n e, a n d t e n of o vir)
1. 
A str o n g i n d u c er f or a s p e cifi c C Y P i s d efi n e d a s a n i n hi bit or t h at d e cr e a s e s t h e A U C of a s e n siti v e s u b str at e 
f or t h at C Y P b y e q u al or m or e t h a n 8 0 %
2. 
A m o d er at e i n d u c er f or a s p e cifi c C Y P i s d efi n e d a s a n i n d u c er t h at d e cr e a s e s t h e A U C of a s u b str at e f or t h at 
C Y P b y 5 0 -8 0 %.
3. 
A w e a k i n d u c er f or a s p e cifi c C Y P i s d efi n e d a s a n i n d u c er t h at d e cr e a s e s t h e A U C of a s u b str at e f or t h at 
C Y P b y 2 0 -5 0 %.
4. 
Dr u g s n ot a v ail a bl e i n t h e U S M ar k et.
5. 
H er b al pr o d u ct

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

N o v arti s
C o nfi d e nti al
P a g e 9 2
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Gl o s s ar y
C R
C o m pl et e r e s p o n s e
C R F
C a s e R e p ort F or m
C S R
Cli ni c al St u d y R e p ort
C T
C o m p ut e d t o m o gr a p h y
D F S
Di s e a s e -fr e e s ur vi v al
e C R F
El e ctr o ni c C a s e R e p ort F or m
F P F V
Fir st p ati e nt fir st vi sit
G B M
Gli o bl a st o m a m ultif or m e
M RI
M a g n eti c r e s o n a n c e i m a gi n g
L P L V
L a st p ati e nt l a st vi sit
O S
O v er all s ur vi v al
P D
Pr o gr e s si v e di s e a s e
P F S
Pr o gr e s si o n -fr e e s ur vi v al
P R
P arti al r e s p o n s e
R A P
R e p orti n g a n d A n al y si s Pl a n
R E CI S T
R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s
S D
St a bl e di s e a s e
S O D
S u m of Di a m et er
T T F
Ti m e t o tr e at m e nt f ail ur e
T T P
Ti m e t o pr o gr e s si o n
U N K
U n k n o w n

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

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

N o v arti s
C o nfi d e nti al
P a g e 9 5
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0

A c ha n ge i n met h o d ol o g y  ca n be defi ne d as eit her a c ha n ge i n c o ntrast use (e. g., kee pi n g 
the sa me tec h ni q ue, li ke C T, b ut s witc hi n g fr o m wit h t o wit h o ut c o ntrast use or vice - versa, 
re gar dless of t he j ustificati o n f or t he c ha n ge) or a maj or c ha n ge i n tec h ni q ue (e. g., fr o m 
C T t o M RI , or vice-versa), or a c ha n ge i n a n y ot her i ma gi n g m o dalit y. A c h a n ge fr o m 
c o n ve nti o nal t o s piral C T or vice versa will n ot c o nstit ute a maj or “c ha n ge i n met h o d” f or 
t he p ur p oses of res p o nse assess me nt. A cha n ge i n met h o d ol o g y  will r es ult b y  defa ult i n a 
U N K o verall lesi o n res p o nse assess me nt as per N o vartis calc ulate d res p o nse. H o we ver, 
a n ot her res p o nse assess me nt t ha n t he N o vartis calc ulate d U N K res p o nse ma y be acce pte d 
fr o m t he i n vesti gat or or t he ce ntral bli n de d re vie wer if a defi niti ve res p o nse assess me nt 
ca n be j ustifie d, base d o n t he a vaila ble i nf or mati o n.

F D G -P E T : ca n c o m ple me nt C T sca ns i n assessi n g pr o gressi o n ( partic ularly p ossi ble f or 
‘ ne w’ disease). Ne w lesi o ns o n t he basis of F D G-P E T i ma gi n g ca n be i de ntifie d acc or di n g 
t o t he f oll o wi n g al g orit h m:

Ne gati ve F D G -P E T at baseli ne, wit h a p ositi ve F D G -P E T at f oll o w - u p is a si g n of P D 
base d o n a ne w lesi o n.

N o F D G - P E T at baseli ne wit h a p ositi ve F D G-P E T at f oll o w - u p:

If ne w disease is i n dicate d b y a p ositi ve P E T sca n b ut is n ot c o nfir me d b y C T ( or s o me 
ot her c o n ve nti o nal tec h ni q ue s uc h as M RI) at t he sa me assess me nt , t he n f oll o w- u p 
assess me nts b y C T will be nee de d t o deter mi ne if t here is tr uly pr o gressi o n occ urri n g at 
t hat site. In all cases P D will be t he date of c o nfir mati o n of ne w disease b y C T ( or s o me 
ot her c o n ve nti o nal tec h ni q ue s uc h as M RI) rat her t ha n t he da te of t he p ositi ve P E T sca n. 
If t here is a p ositi ve P E T sca n wit h o ut a ny c o nfir me d pr o gressi o n at t hat site b y C T, t he n a 
P D ca n n ot be assi g ne d.

If t he p ositi ve F D G-P E T at f oll o w -u p c orres p o n ds t o a pre -e xisti n g site of disease o n 
C T t hat is n ot pr o gressi n g o n t he basis of t he a nat o mic i ma ges, t his is n ot P D.

C hest x -ra y: Lesi o ns o n c hest x-ra y are acce pta ble as meas ura ble lesi o ns w he n t he y 
are clearl y defi ne d a n d s urr o u n de d b y aerate d l u n g. H o we ver, C T is prefera ble.

P h y sical e xa ms: E val uati o n of lesi o ns b y p h ysical e xa mi nati o n is acce pte d w he n 
lesi o ns are s u perficial, wit h at least 1 0 m m size, a n d ca n be assesse d usi n g cali pers.

Ultras o u n d: W he n t h e pri mar y e n d p oi nt of t he st u d y is o bjecti ve res p o nse e val uati o n, 
ultras o u n d ( U S) s h o ul d n ot be use d t o meas ure t u m or lesi o ns, u nless pre -s pecifie d b y 
t he pr ot oc ol. It is, h o we ver, a p ossi ble alter nati ve t o cli nical meas ure me nts of 
s u perficial pal pa ble ly m p h n o des, s u bc uta ne o us lesi o ns a n d t h y r oi d n o d ules. U S 
mi g ht als o be usef ul t o c o nfir m t he c o m plete disa p peara nce of s u perficial lesi o ns 
us uall y  assesse d b y cli nical e xa mi nati o n.

E n d osc o p y  a n d la par osc o p y: T he utilizati o n of e n d osc o p y a n d la par osc o p y f or 
o bjecti ve t u m or e val uati o n has n ot y et bee n f ull y a n d wi del y vali date d. T heir uses i n 
t his s pecific c o nte xt re q uire s o p histicate d e q ui p me nt a n d a hi g h le vel of e x pertise t hat 
ma y  o nly be a vaila ble i n s o me ce nters. T heref ore, t he utilizati o n of s uc h tec h ni q u es 
f or o bjecti ve t u m or res p o nse s h o ul d be restricte d t o vali dati o n p ur p oses i n s pecialize d 
ce nters. H o we ver, s uc h tec h ni q ues ca n be usef ul i n c o nfir mi n g c o m plete pat h ol o gical 
res p o nse w he n bi o psies are o btai ne d.

N o v arti s
C o nfi d e nti al
P a g e 9 6
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0

T u m or mar kers: T u m or mar kers al o ne ca n n ot be use d t o assess res p o nse. H o we ver, 
s o me disease s pecific a n d m ore vali date d t u m or mar kers (e. g., C A -1 2 5 f or o varia n 
ca ncer, P S A f or pr ostate ca ncer, al p ha - F P, L D H a n d Beta- h C G f or testic ular ca ncer) 
ca n be i nte grate d as n o n -tar get disease. If mar kers are initiall y  a b o ve t he u p per 
n or mal li mit t he y  m ust n or malize f or a patie nt t o be c o nsi dere d i n c o m plete cli nical 
res p o nse w he n all lesi o ns ha ve disa p peare d.

C yt ol o g y a n d hist ol o g y : C y t ol o g y a n d hist ol o g y ca n be use d t o differe ntiate bet wee n P R 
a n d C R i n rare cases (i.e., after treat me nt t o differe ntiate bet wee n resi d ual be ni g n lesi o ns 
a n d resi d ual mali g na nt lesi o ns i n t u m or t ypes s uc h as ger m cell t u m ors). C yt ol o gic 
c o nfir mati o n of ne o plastic nat ure of a n y eff usi o n t hat a p pears or w orse ns d uri n g treat me nt 
is re q uire d w he n t he meas ura ble t u m or has met t he criteria f or res p o nse or sta ble disease. 
U n der s uc h circ u msta nces, t he c y t ol o gic e xa mi nati o n of t he fl ui d c ollecte d will per mit 
differe ntiati o n bet wee n res p o nse a n d sta ble disease (a n eff usi o n ma y  be a si de effect of t he 
treat me nt) or pr o gressi ve disease (if t he ne o plastic ori gi n of t he fl ui d is c o nfir me d).

Cli nic al e x a mi n ati o n : Cli nical lesi o ns will o nl y  be c o nsi dere d meas ura ble w he n t he y are 
s u perficial (i.e., s ki n n o d ules a n d pal pa ble ly m p h n o des). F or t he case of s ki n lesi o ns, 
d oc u me ntati o n b y  c ol or p h ot o gra p h y, i ncl u di n g a r uler t o esti mate t he size of t he lesi o n, is 
rec o m me n de d.
2. 3 
B a s eli n e d o c u m e nt ati o n of t ar g et a n d n o n -t ar g et l e si o n s
F or t he e val uati o n of lesi o ns at baseli ne a n d t hr o u g h o ut t he st u d y, t he lesi o ns are classifie d at 
baseli ne as eit her tar get or n o n -tar get lesi o ns:

Tar get lesi o ns: All meas ura ble lesi o ns ( n o dal a n d n o n - n o dal) u p t o a ma xi m u m of fi ve 
lesi o ns i n t otal (a n d a ma xi m u m of t w o lesi o ns per or ga n), re prese ntati ve of all i n v ol ve d 
or ga ns s h o ul d be i de ntifie d as tar get lesi o ns a n d rec or de d a n d meas ure d at baseli ne. Tar get 
lesi o ns s h o ul d be selecte d o n t he basis of t heir size (lesi o ns wit h t he l o n gest dia meter) a n d 
t heir s uita bilit y f or acc urate re peate d meas ure me nts (eit her b y i ma gi n g tec h ni q ues or 
cli nicall y). Eac h tar get lesi o n m ust be u ni q uel y a n d se q ue ntiall y n u m bere d o n t he C R F 
(e ve n if it resi des i n t he sa me or ga n).
Mi ni m u m t ar g et l e si o n si z e at b a s eli n e

N o n -n o d al t ar get: N o n -n o dal tar get lesi o ns i de ntifie d b y  met h o ds f or w hic h slice 
t hic k ness is n ot a p plica ble (e. g., cli nical e xa mi nati o n, p h ot o gra p h y) s h o ul d be at least 1 0 
m m i n l o n gest dia meter. See Secti o n 2. 1. 1 .

N o d al t ar get: See Secti o n 2. 1. 1 .
A s u m of dia meters (l o n g a xis f or n o n -n o dal lesi o ns, s h ort a xis f or n o dal) f or all tar get lesi o ns 
will be calc ulate d a n d re p orte d as t he baseli ne s u m of dia meters ( S O D). T he baseli ne s u m of 
dia meters will be use d as refere nce b y  whic h t o c haracterize t he o bjecti ve t u m or res p o nse. Eac h 
tar get lesi o n i de ntifie d at baseli ne m ust be f oll o we d at eac h s u bse q ue nt e val uati o n a n d 
d oc u me nte d o n e C R F.

N o n -t ar get lesi o ns: All ot her lesi o ns are c o nsi dere d n o n -tar get lesi o ns, i.e. lesi o ns n ot 
f ulfillin g t he criteria f or tar get lesi o ns at baseli ne. Prese nce or a bse nce or w orse ni n g of 
n o n- tar get lesi o ns s h o ul d be assesse d t hr o u g h o ut t he st u d y; meas ure me nts of t hese lesi o ns 
are n ot re q uire d. M ulti ple n o n -tar get lesi o ns i n v ol ve d i n t he sa me or ga n ca n be assesse d as 

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

N o v arti s
C o nfi d e nti al
P a g e 9 8
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
f or all lesi o ns lar ger t ha n 5 m m i n s h ort a xis irres pecti ve of slice t hic k ness/rec o nstr ucti o n 
i nter val.
H o we ver, o nce a tar get n o dal lesi o n s hri n ks t o less t ha n 1 0 m m i n its s h ort a xis, it will be 
c o nsi dere d n or mal f or res p o nse p ur p ose deter mi nati o n. T he l ym p h n o de meas ure me nts will 
c o nti n ue t o be rec or ded t o all o w t he val ues t o be i ncl u de d i n t he s u m of dia meters f or tar get 
lesi o ns, w hic h ma y be re q uire d s u bse q ue ntly f or res p o nse deter mi nati o n.
2. 4. 2
D et er mi n ati o n of t ar g et l e si o n r e s p o n s e
T a bl e 2 - 1   
R e s p o n s e crit eri a f or t ar g et l e si o n s
R e s p o n s e Crit eri a
E v al u ati o n of t ar g et l e si o n s
C o m pl et e R e s p o n s e ( C R):
Di s a p p e ar a n c e of all n o n -n o d al t ar g et l e si o n s. I n a d diti o n, a n y 
p at h ol o gi c al l y m p h n o d e s a s si g n e d a s t ar g et l e si o n s m u st h a v e a 
r e d u cti o n i n s h ort a xi s t o < 1 0 m m 1
P arti al R e s p o n s e ( P R):
At l e a st a 3 0 % d e cr e a s e i n t h e s u m of di a m et er of all t ar g et l e si o n s, 
t a ki n g a s r ef er e n c e t h e b a s eli n e s u m of di a m et er s.
Pr o gr e s si v e Di s e a s e ( P D):
At l e a st a 2 0 % i n cr e a s e i n t h e s u m of di a m et er of all m e a s ur e d t ar g et 
l e si o n s, t a ki n g a s r ef er e n c e t h e s m all e st s u m of di am e t er of all t ar g et 
l e si o n s r e c or d e d at or aft er b a s eli n e. I n a d diti o n t o t h e r el ati v e i n cr e a s e 
of 2 0 %, t h e s u m m u st al s o d e m o n str at e a n a b s ol ut e i n cr e a s e of at l e a st 
5 m m 2 .
St a bl e Di s e a s e ( S D):
N eit h er s uffi ci e nt s hri n k a g e t o q u alif y f or P R or C R n or a n i n cr e a s e i n 
l e si o n s w hi c h w o ul d q u alif y f or P D.
U n k n o w n ( U N K)
Pr o gr e s si o n h a s n ot b e e n d o c u m e nt e d a n d o n e or m or e t ar g et l e si o n s 
h a v e n ot b e e n a s s e s s e d or h a v e b e e n a s s e s s e d u si n g a diff er e nt 
m e t h o d t h a n b a s eli n e.3
1.
S O D f or C R m a y  n ot b e z er o w h e n n o d al l e si o n s ar e p art of t ar g et l e si o n s
2.
F oll o wi n g a n i niti al C R, a P D c a n n ot b e a s si g n e d if all n o n -n o d al t ar g et l e si o n s ar e still n ot pr e s e nt 
a n d all n o d al l e si o n s ar e < 1 0 m m i n si z e. I n t hi s c a s e, t h e t ar g et l e si o n r e s p o n s e i s C R
3.
I n e x c e pti o n al cir c u m st a n c e s a n U N K r e s p o n s e d u e t o c h a n g e i n m et h o d c o ul d b e o v er -r ul e d b y 
t h e i n v e sti g at or or c e ntr al r e vi e w er u si n g e x p ert j u d g m e nt b a s ed o n t h e a v ail a bl e i nf or m ati o n ( s e e 
N ot e s o n t ar g et l e si o n r e s p o n s e a n d m et h o d ol o g y c h a n g e i n S e cti o n 2. 2 ).
N ot e s o n t ar g et l e si o n r e s p o n s e
Re a p pe ar a nce of lesi o ns : If t he lesi o n a p pears at t he sa me a nat o mical l ocati o n w here a tar get 
lesi o n ha d pre vi o usl y dis a p peare d, it is a d vise d t hat t he ti me p oi nt of lesi o n disa p peara nce (i.e. , 
t he “ 0 m m” rec or di n g) be re-e val uate d t o ma ke s ure t hat t he lesi o n was n ot act uall y prese nt 
a n d/ or n ot vis ualize d f or tec h nical reas o ns i n t his pre vi o us assess me nt. If it is n ot p ossi ble t o 
c ha n ge t he 0 val ue, t he n t he i n vesti gat or/ra di ol o gist has t o dec i de bet wee n t he f oll o wi n g 
p ossi bilities:

T he lesi o n is a ne w lesi o n, i n w hic h case t he o verall t u m or assess me nt will be c o nsi dere d 
as pr o gressi ve disease

T he lesi o n is clearl y a rea p peara nce of a pre vi o usl y  disa p peare d lesi o n, i n w hic h case t he 
size of t he lesi o n has t o be e ntere d i n t he C R F a n d t he t u m or assess me nt will re mai n base d 
o n t he s u m of t u m or meas ure me nts as prese nte d i n Ta ble 2 - 1 a b o ve (i.e., a P D will be 
deter mi ne d if t here is at least 2 0 % i ncrease i n t he s u m of dia m eters of all meas ure d tar get 

N o v arti s
C o nfi d e nti al
P a g e 9 9
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
lesi o ns, ta ki n g as refere nce t he s mallest s u m of dia meters of all tar get lesi o ns rec or de d at 
or afte r baseli ne wit h at least 5 m m i ncrease i n t he a bs ol ute s u m of t he dia meters). Pr o per 
d oc u me ntati o n s h o ul d be a vaila ble t o s u p p ort t his decisi o n. T his a p plies t o patie nts w h o 
ha ve n ot ac hie ve d tar get res p o nse of C R. F or patie nts w h o ha ve ac hie ve d C R, please refer 
t o last b ullet i n t his secti o n.

F or t h ose patie nts w h o ha ve o nl y o ne tar get lesi o n at baseli ne, t he rea p peara nce of t he 
tar get lesi o n w hic h disa p peare d pre vi o usly, e ve n if still s mall, is c o nsi dere d a P D.

Missi n g meas ure me nts: I n cases w here meas ure me nts are missi n g f or o ne or m ore tar get 
lesi o ns it is s o meti mes still p ossi ble t o assi g n P D base d o n t he meas ure me nts of t he 
re mai ni n g lesi o ns. F or e xa m ple, if t he s u m of dia meters f or 5 tar get lesi o ns at baseli ne is 
1 0 0 m m at baseli ne a n d t he s u m of dia m eters f or 3 of t h ose lesi o ns at a p ost - baseli ne visit 
is 1 4 0 m m ( wit h data f or 2 ot her lesi o ns missi n g) t he n a P D s h o ul d be assi g ne d. H o we ver, 
i n ot her cases w here a P D ca n n ot defi nitely be attri b ute d, t he tar get lesi o n res p o nse w o ul d 
be U N K.

N o dal lesi o n decrease t o n or mal size: W he n n o dal disease is i ncl u de d i n t he s u m of tar get 
lesi o ns a n d t he n o des decrease t o “ n or mal” size t he y s h o ul d still ha ve a meas ure me nt 
rec or de d o n sca ns. T his meas ure me nt s h o ul d be re p orte d e ve n w he n t he n o des are n or mal 
i n or der n ot t o o verstate pr o gressi o n s h o ul d it be base d o n i ncrease i n t he size of n o des.

Lesi o ns s plit: I n s o me circ u msta nces, disease t hat is meas ura ble as a tar get lesi o n at 
baseli ne a n d a p pears t o be o ne mass ca n s plit t o bec o me t w o or m ore s maller s u b -lesi o ns. 
W he n t his occ urs, t he dia meters (l o n g a xis - n o n-n o dal lesi o n, s h ort a xis - n o dal lesi o ns) 
of t he t w o s plit lesi o ns s h o ul d be a d de d t o get her a n d t he s u m rec or de d i n t he dia meter 
fiel d o n t he case re p ort f or m u n der t he ori gi nal lesi o n n u m ber. T his val ue will be i ncl u de d 
i n t he s u m of dia meters w he n deri vi n g tar get lesi o n res p o nse. T he i n di vi d ual s plit lesi o ns 
will n ot be c o nsi dere d as ne w lesi o ns, a n d will n ot a ut o maticall y  tri g ger a P D desi g nati o n.

Lesi o ns c oalesce d: C o n versel y, it is als o p ossi ble t hat t w o or m ore lesi o ns w hic h were 
disti nctl y  se parate at baseli ne bec o me c o nfl ue nt at s u bse q ue nt visits. W he n t his occ urs a 
pla ne bet wee n t he ori gi nal lesi o ns ma y  be mai ntai ne d t hat w o ul d ai d i n o btai ni n g dia meter 
meas ure me nts of eac h i n di vi d ual lesi o n. I f t he lesi o ns ha ve tr ul y c oalesce d s uc h t hat t he y 
are n o l o n ger se para ble, t he ma xi mal dia meters (l o n g a xis - n o n- n o dal lesi o n, s h ort a xis -
n o dal lesi o ns) of t he “ mer ge d lesi o n” s h o ul d be use d w he n calc ulati n g t he s u m of 
dia meters f or tar get lesi o ns. O n t he case re p ort f or m, t he dia meter of t he “ mer ge d lesi o n” 
s h o ul d be rec or de d f or t he size of o ne of t he ori gi nal lesi o ns w hile a size of “ 0” m m s h o ul d 
be e ntere d f or t he re mai ni n g lesi o n n u m bers w hic h ha ve c oalesce d.

T he me as ure me nts f or n o d al lesi o ns , e ve n if less t ha n 1 0 m m i n size, will c o ntri b ute t o 
t he calc ulati o n of tar get lesi o n res p o nse i n t he us ual wa y wit h sli g ht m o dificati o ns.

Si nce lesi o ns less t ha n 1 0 m m are c o nsi dere d n or mal, a C R f or tar get lesi o n res p o nse 
s h o ul d be assi g ne d w he n all n o dal tar get lesi o ns s hri n k t o less t ha n 1 0 m m a n d all n o n -
n o dal tar get lesi o ns ha ve disa p peare d.

O nce a C R tar get lesi o n res p o nse has bee n assi g ne d a C R will c o nti n ue t o be a p pr o priate 
(i n t he a bse nce of missi n g data) u ntil pr o gressi o n of tar get lesi o ns.

F oll o wi n g a C R, a P D ca n s u bse q ue ntl y  o nly be assi g ne d f or tar get lesi o n res p o nse if 
eit her a n o n -n o dal tar get lesi o n “rea p pears” or if a n y  si n gle n o dal lesi o n is at least 1 0 m m 

N o v arti s
C o nfi d e nti al
P a g e 1 0 0
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
a n d t here is at least 2 0 % i ncrease i n s u m of t he dia meters of all n o dal tar get lesi o ns 
relati ve t o na dir wit h at least 5 m m i ncrease i n t he a bs ol ute s u m of t he dia meters.

A c ha n ge i n met h o d f or t he e val uati o n of o ne or m ore lesi o ns will us uall y lea d t o a n U N K 
tar get lesi o n res p o nse u nless t here is pr o gressi o n i n dicate d by t he re mai n i n g lesi o ns w hic h 
ha ve bee n e val uate d b y t he sa me met h o d. I n e xce pti o nal circ u msta nces a n i n vesti gat or or 
ce ntral re vie wer mi g ht o ver -r ule t his assi g n me nt t o p ut a n o n- U N K res p o nse usi n g e x pert 
j u d g me nt base d o n t he a vaila ble i nf or mati o n. E. g., a c ha n ge t o a m ore se nsiti ve met h o d 
mi g ht i n dicate s o me t u m or s hri n ka ge of tar get lesi o ns a n d defi nitel y r ule o ut pr o gressi o n 
i n w hic h case t he i n vesti gat or mi g ht assi g n a n S D tar get lesi o n res p o nse; h o we ver, t his 
s h o ul d be d o ne wit h ca uti o n a n d c o nser vati vel y as t he res p o nse cate g ories ha ve well 
defi ne d criteria.
2. 4. 3
D et er mi n ati o n of n o n -t ar g et l e si o n r e s p o n s e
T a bl e 2 - 2 
R e s p o n s e crit eri a f or n o n -t ar g et l e si o n s
R e s p o n s e Crit eri a
E v al u ati o n of n o n -t ar g et l e si o n s
C o m pl et e R e s p o n s e ( C R):
Di s a p p e ar a n c e of all n o n -t ar g et l e si o n s. I n a d diti o n, all l ym p h n o d e s 
a s si g n e d a n o n -t ar g et l e si o n s m u st b e n o n-p at h ol o gi c al i n si z e ( < 1 0 m m 
s h ort a xi s)
Pr o gr e s si v e Di s e a s e ( P D):   
U n e q ui v o c al pr o gr e s si o n of e xi sti n g n o n -t ar g et l e si o n s.1
N o n -C R/ N o n -P D:
N eit h er C R n or P D
U n k n o w n ( U N K)
Pr o gr e s si o n h a s n ot b e e n d o c u m e nt e d a n d o n e or m or e n o n -t ar g et 
l e si o n s h a v e n ot b e e n a s s e s s e d or h a v e b e e n a s s e s s e d u si n g a diff er e nt 
m e t h o d t h a n b a s eli n e.2
1.
T h e a s si g n m e nt of P D s ol el y b a s e d o n c h a n g e i n n o n -t ar g et l e si o n s i n li g ht of t ar g et l e si o n 
r e s p o n s e of C R, P R or S D s h o ul d b e e x c e pti o n al. I n s u c h cir c u m st a n c e s, t h e o pi ni o n of t h e 
i n v e sti g at or or c e ntr al r e vi e w er d o e s pr e v ail.
2.
It i s r e c o m m e n d e d t h at t h e i n v e sti g at or a n d/ or c e ntr al r e vi e w er s h o ul d u s e e x p ert j u d g m e nt t o 
a s si g n a N o n -U N K r e s p o n s e w h er e v er p o s si bl e ( s e e n ot e s s e cti o n f or m or e d et ail s)
N ot e s o n n o n -t ar g et l e si o n r e s p o n s e

T he i n vesti gat or a n d/ or ce ntral re vie wer ca n use e x pert j u d g me nt t o assi g n a n o n -U N K 
res p o nse w here ver p ossi ble, e ve n w here lesi o ns ha ve n ot bee n f ull y assesse d or a differe nt 
met h o d has bee n use d. I n ma n y of t hese sit uati o ns it ma y still be p ossi ble t o i de ntif y 
e q ui v ocal pr o gressi o n ( P D) or defi niti vel y  r ule t his o ut ( n o n-C R/ N o n -P D) base d o n t he 
a vaila ble i nf or mati o n. I n t he s pecific case w here a m ore se nsit i ve met h o d has bee n use d 
i n dicati n g t he a bse nce of a n y n o n-tar get lesi o ns, a C R res p o nse ca n als o be assi g ne d.

T he res p o nse f or n o n -tar get lesi o ns is C R o nl y if all n o n -tar get n o n-n o dal lesi o ns w hic h 
were e val uate d at baseli ne are n o w all a bse nt a n d wit h a ll n o n-tar get n o dal lesi o ns 
ret ur ne d t o n or mal size (i.e. < 1 0 m m). If a ny of t he n o n -tar get lesi o ns are still prese nt, or 
t here are a ny a b n or mal n o dal lesi o ns (i.e. 1 0 m m) t he res p o nse ca n o nl y be ‘ N o n -
C R/ N o n -P D ’ u nless t here is u ne q ui v ocal pr o gressi o n of t he n o n -tar get lesi o ns (i n w hic h 
case res p o nse is P D ) or it is n ot p ossi ble t o deter mi ne w het her t here is u ne q ui v ocal 
pr o gressi o n (i n w hic h case res p o nse is U N K).

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

N o v arti s
C o nfi d e nti al
P a g e 1 0 2
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
T a bl e 2 - 3 
O v er all l e si o n r e s p o n s e at e a c h a s s e s s m e nt
T ar g et l e si o n s
N o n -t ar g et l e si o n s 
N e w L e si o n s
O v er all
l e si o n r e s p o n s e
C R
C R
N o
C R 1
C R
N o n -C R/ N o n -P D 3
N o
P R
C R, P R, S D
U N K
N o
U N K
P R
N o n -P D a n d n ot U N K 
N o
P R 1
S D
N o n -P D a n d n ot U N K 
N o
S D 1, 2
U N K
N o n -P D or U N K
N o
U N K 1
P D
A n y
Y e s or N o
P D
A n y
P D
Y e s or N o
P D
A n y
A n y
Y e s
P D
1.
T hi s o v er all l e si o n r e s p o n s e al s o a p pli e s w h e n t h er e ar e n o n o n -t ar g et l e si o n s i d e ntifi e d at 
b a s eli n e.
2.
O n c e c o nfir m e d P R w a s a c hi e v e d, all t h e s e a s s e s s m e nt s ar e c o n si d er e d P R.
3.
A s d efi n e d i n S e cti o n 2. 4 .
If t here are n o baseli ne sca ns a vaila ble at all, t he n t he o verall lesi o n res p o nse at eac h assess me nt 
s h o ul d be c o nsi dere d U n k n o w n ( U N K).
I n s o me circ u msta nces it ma y  be diffic ult t o disti n g uis h resi d ual disease fr o m n or mal tiss ue. 
W he n t he e val uati o n of c o m plete res p o nse de pe n ds o n t his deter mi nati o n, it is rec o m me n de d 
t hat t he resi d ual lesi o n be i n vesti gate d (fi ne nee dle as pirate/ bi o ps y) t o c o nfir m t he C R.
3 
Effi c a c y  d efi niti on s
T he f oll o wi n g defi niti o ns pri maril y relate t o patie nts w h o ha ve meas ura ble disease at baseli ne. 
Secti o n 3. 2. 8 o utli nes t he s pecial c o nsi derati o ns t hat nee d t o be gi ve n t o patie nts wit h n o 
meas ura ble d isease at baseli ne i n or der t o a p ply t he sa me c o nce pts.
3. 1 
B e st o v er all r e s p o n s e
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he treat me nt u ntil 
disease pr o gressi o n/rec urre nce (ta ki n g as refere nce f or P D t he s mallest meas ure m e nts rec or de d 
si nce t he treat me nt starte d). I n ge neral, t he patie nt's best res p o nse assi g n me nt will de pe n d o n 
t he ac hie ve me nt of b ot h meas ure me nt a n d c o nfir mati o n criteria.
T he best o verall res p o nse will us uall y  be deter mi ne d fr o m res p o nse assess me nts u n de rta ke n 
w hile o n treat me nt. H o we ver, if a n y assess me nts occ ur after treat me nt wit h dra wal t he pr ot oc ol 
s h o ul d s pecifically descri be if t hese will be i ncl u de d i n t he deter mi nati o n of best o verall 
res p o nse a n d/ or w het her t hese a d diti o nal assess me nts will be req uire d f or se nsiti vit y or 
s u p p orti ve a nal ys es. As a defa ult, a n y assess me nts ta ke n m ore t ha n 3 0 da ys after t he last d ose 
of st u d y treat me nt will n ot be i ncl u de d i n t he best o verall res p o nse deri vati o n. If a n y alter nati ve 
ca ncer t hera p y is ta ke n w hile o n stu d y  an y  su bse q ue nt assess me nts w o ul d or di naril y  be 
e xcl u de d fr o m t he best o verall res p o nse deter mi nati o n. If res p o nse assess me nts ta ke n after 
wit h dra wal fr o m st u d y treat me nt a n d/ or alter nati ve t hera py are t o be i ncl u de d i n t he mai n 
e n d p oi nt deter mi nati o n, t he n t his s h o ul d be descri be d a n d j ustifie d i n t he pr ot oc ol.

N o v arti s
C o nfi d e nti al
P a g e 1 0 3
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
W here a st u d y  re q uires c o nfir mati o n of res p o nse ( P R or C R), c ha n ges i n t u m or meas ure me nts 
m ust be c o nfir me d b y  re peat assess me nts t hat s h o ul d be perf or me d n ot less t ha n 4 wee ks after 
t he criteria f or res p o nse are first met.
L o n ger i nter vals ma y  als o be a p pr o priate. H o we ver, t his m ust be clearly state d i n t he pr ot oc ol. 
T he mai n g oal of c o nfir mati o n of o bjecti ve res p o nse is t o a v oi d o veresti mati n g t he res p o nse 
rate o bser ve d. I n cases w here c o nfir mat i o n of res p o nse is n ot feasi ble, it s h o ul d be ma de clear 
w he n re p orti n g t he o utc o me of s uc h st u dies t hat t he res p o nses are n ot c o nfir me d.

F or n o n -ra n d o mize d trials w here res p o nse is t he pri mar y e n d p oi nt, c o nfir mati o n is nee de d.

F or trials i nte n de d t o s u p p o rt accelerate d a p pr o val, c o nfir mati o n is nee de d

F or all ot her trials, c o nfir mati o n of res p o nse ma y  be c o nsi dere d o pti o nal.
T he best o verall res p o nse f or eac h patie nt is deter mi ne d fr o m t he se q ue nce of o verall (lesi o n) 
res p o nses acc or di n g t o t he f oll o wi n g rules:

C R = at least t w o deter mi nati o ns of C R at least 4 wee ks a part bef ore pr o gressi o n w here 
c o nfir mati o n re q uire d or o ne deter mi nati o n of C R pri or t o pr o gressi o n w here c o nfir mati o n 
n ot re q uire d

P R = at least t w o deter mi nati o ns of P R or better at least 4 w ee ks a part bef ore pr o gressi o n 
(a n d n ot q ualif yi n g f or a C R) w here c o nfir mati o n re q uire d or o ne deter mi nati o n of P R 
pri or t o pr o gressi o n w here c o nfir mati o n n ot re q uire d

S D = at least o ne S D assess me nt ( or better) > 6 wee ks start of treat me nt (a n d n ot 
q ualif yi n g f or C R or P R).

P D = pr o gressi o n 1 2 wee ks after start of treat me nt (a n d n ot q ualif y i n g f or C R, P R or 
S D).

U N K = all ot her cases (i.e. n ot q ualif y i n g f or c o nfir me d C R or P R a n d wit h o ut S D after 
m ore t ha n 6 wee ks or earl y  pr o gressi o n wit hi n t he first 12 wee ks)
T he ti me d urati o ns s pecifie d i n t he S D/ P D/ U N K defi niti o ns a b o ve are defa ults base d o n a 6 
wee k t u m or assess me nt fre q ue nc y. H o we ver t hese m a y  be m o difie d f or s pecific i n dicati o ns 
w hic h are m ore or less a g gressi ve. I n a d diti o n, it is e n visa ge d t hat t he ti me d urati o n ma y  als o 
ta ke i nt o acc o u nt assess me nt wi n d o ws. E. g. , if t he assess me nt occ urs e ver y 6 wee ks wit h a ti me 
wi n d o w of ± 7 da y s, a B O R of S D w o ul d re q uire a S D or better res p o nse l o n ger t ha n 5 wee ks 
after ra n d o mizati o n/start of treat me nt.
O verall lesi o n res p o nses of C R m ust sta y t he sa me u ntil pr o gressi o n sets i n, wit h t he e xce pti o n 
of a U N K stat us. A patie nt w h o ha d a C R ca n n ot s u bse q ue ntl y  ha ve a l o wer stat us ot her t ha n a 
P D, e. g.,P R or S D, as t his w o ul d i m pl y a pr o gressi o n base d o n o ne or m ore lesi o ns rea p peari n g, 
i n w hic h case t he stat us w o ul d bec o me a P D.
O nce a n o verall lesi o n res p o nse of P R is o bser ve d ( w hic h m a y  ha ve t o be a c o nfir me d P R 
de pe n di n g o n t he st u d y) t his assi g n me nt m ust sta y the sa me or i m pr o ve o ver ti me u ntil 
pr o gressi o n sets i n, wit h t he e xce pti o n of a n U N K stat us. H o we ver, i n st u dies w here 
c o nfir mati o n of res p o nse is re q uire d, if a patie nt has a si n gle P R (3 0 % re d ucti o n of t u m or 
b ur de n c o m pare d t o baseli ne) at o ne assess me nt, f oll o we d b y a <3 0 % re d ucti o n fr o m baseli ne
at t he ne xt assess me nt ( b ut n ot 2 0 % i ncrease fr o m pre vi o us s mallest s u m), t he o bjecti ve stat us 
at t hat assess me nt s h o ul d be S D. O nce a c o nfir me d P R was see n, t he o verall lesi o n res p o nse 
s h o ul d be c o nsi dere d P R ( or U N K) u ntil pr o gressi o n is d oc u me nte d or t he lesi o ns t otall y 

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

N o v arti s
C o nfi d e nti al
P a g e 1 0 5
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
u n k n o w n ( U N K) assess me nt at t hat ti me p oi nt a n d n o P D bef ore, will n ot be c o u nte d as earl y 
pr o gress ors i n t he a nal ys is b ut ma y be i ncl u de d i n t he de n o mi nat or of t he E P R rate, de pe n di n g 
o n t he a nal ysis p o p ulati o n use d. Si milarl y  whe n e xa mi ni n g o verall res p o nse a n d disease c o ntr ol, 
patie nts wit h a best o ve rall res p o nse assess me nt of u n k n o w n ( U N K) will n ot be re gar de d as 
“res p o n ders” b ut m a y  be i ncl u de d i n t he de n o mi nat or f or O R R a n d D C R calc ulati o n de pe n di n g 
o n t he a nal ys is p o p ulati o n (e. g., p o p ulati o ns base d o n a n I T T a p pr oac h).
3. 2 
Ti m e t o e v e nt v ari a bl e s
3. 2. 1
Pr o gr e s si o n -fr e e s ur vi v al
Us uall y  in all O nc ol o g y  st u dies, patie nts are f oll o we d f or t u m or pr o gressi o n after 
disc o nti n uati o n of st u d y me dicati o n f or reas o ns ot her t ha n pr o gressi o n or deat h. If t his is n ot 
use d, e. g., i n P hase I or II st u dies, t his sh o ul d be clearl y state d i n t he pr ot oc ol. N ote t hat 
ra n d o mize d trials ( prefera bl y bli n de d) are rec o m me n de d w here P F S is t o be t he pri mar y 
e n d p oi nt.
Pr o gressi o n -free s ur vi v al ( P F S) is t he ti me fr o m date of ra n d o mizati o n/start of treat me nt t o 
t he date of e ve nt defi ne d as t he first d oc u me nte d pr o gressi o n or deat h d ue t o a n y ca use. If a 
patie nt has n ot ha d a n e ve nt, pr o gressi o n -free s ur vi val is ce ns ore d at t he date of last a de q uate 
t u m or assess me nt.
P F S rate at x wee ks is a n a d diti o nal meas ure use d t o q ua ntif y PF S e n d p oi nt. It is rec o m me n de d 
t hat a Ka pla n Meier esti mate is use d t o assess t his e n d p oi nt.
3. 2. 2
O v er all s ur vi v al
All patie nts s h o ul d be f oll o we d u ntil deat h or u ntil patie nt has ha d a de q uate f oll o w -u p ti me as 
s pecifie d i n t he pr ot oc ol w hic he ver c o mes first. T he f oll o w-u p data s h o ul d c o ntai n t he date t he 
patie nt was last see n ali ve / last k n o w n date patie nt ali ve, t he date of deat h a n d t he reas o n of 
deat h (“ St u d y i n dicati o n” or “ Ot her”).
O ver all s ur vi v al ( O S) is defi ne d as t he ti me fr o m date of ra n d o mizati o n/start of treat me nt t o 
date of deat h d ue t o a n y ca use. If a patie nt is n ot k n o w n t o ha ve die d, s ur vi val will be ce ns ore d 
at t he date of last k n o w n date patie nt ali ve.
3. 2. 3
Ti m e t o pr o gr e s si o n
S o me st u dies mi g ht c o nsi der o nl y  deat h relate d t o u n derl y i n g ca ncer as a n e ve nt w hic h i n dicates 
pr o gressi o n. I n this case t he varia ble “ Ti me t o pr o gressi o n” mi g ht be use d. T T P is defi ne d as 
P F S e xce pt f or deat h u nrelate d t o u n derl yi n g ca ncer.
Ti me t o pr o gressi o n ( T T P) is t he ti me fr o m date of ra n d o mizati o n/start of treat me nt t o t he 
date of e ve nt defi ne d as t he first d oc u me nte d pr o gressi o n or deat h d ue t o u n derl y i n g ca ncer. If 
a patie nt has n ot ha d a n e ve nt, ti me t o pr o gressi o n is ce ns ore d at t he date of last a de q uate t u m or 
assess me nt.
3. 2. 4
P F S 2
A rece nt E M A g ui da nc e (E M A 2 0 1 2 ) rec o m me n ds a s u bstit ute e n d p oi nt i nter me diate t o P F S 
a n d O S calle d P F S 2, a s urr o gate f or O S w he n O S ca n n ot be meas ur e d relia bl y, w hic h assesses 

N o v arti s
C o nfi d e nti al
P a g e 1 0 6
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
t he i m pact of t he e x peri me ntal t hera p y on ne xt -li ne treat me nt. T he mai n p ur p ose of t his 
e n d p oi nt is t o assess l o n g ter m mai nte na nce strate gies, partic ularl y  of rese nsitizi n g a ge nts a n d 
w here it is necessar y  t o e xa mi ne t he o verall “fiel d of i nfl ue nce”.
P F S 2 , w hic h c o ul d be ter me d P F S deferre d, P F S dela y e d, ta n de m P F S, or P F S versi o n 2. 0, is 
t he ti me fr o m date of ra n d o mizati o n/start of treat me nt t o t he date of e ve nt defi ne d as t he first 
d oc u me nte d pr o gressi o n o n ne xt -li ne treat me nt or deat h fr o m a n y ca use. T h e ce ns ori n g r ules 
f or t his e n d p oi nt will i nc or p orate t he sa me pri nci ples as t h ose c o nsi dere d f or P F S i n t his 
d oc u me nt, a n d i n a d diti o n ma y  in v ol ve ot her c o nsi derati o ns w hic h will nee d t o be detaile d i n 
t he pr ot oc ol.
Please n ote t hat data c ollecti o n f or t he P F S 2 is li mite d t o t he date of pr o gressi o n a n d n ot s pecific 
rea d of t he t u m or assess me nts.
It is str o n gly rec o m me n de d t hat t he tea ms c o ns ult re g ulat or y age ncies f or scie ntific a d vice gi ve n 
t he li mite d e x perie nce wit h t he use of t his e n d p oi nt i n re g ulat or y setti n g i n li g ht of 
met h o d ol o gical iss ues w.r.t. ce ns ori n g f oresee n.
3. 2. 5
Ti m e t o tr e at m e nt f ail ur e
T his e n d p oi nt is ofte n a p pr o priate i n st u dies of a d va nce d disease w here earl y disc o nti n uati o n is 
t ypicall y relate d t o i nt olera nce of t he st u d y dr u g. I n so me pr ot oc ols, ti me t o treat me nt fail ure 
ma y  be c o nsi dere d as a se nsiti vit y anal ys is f or ti me t o pr o gressi o n. T he list of disc o nti n uati o n 
reas o ns t o be c o nsi dere d or n ot as treat me nt fail ure ma y  be a da pte d acc or di n g t o t he s pecificities 
of t he st u d y  or t he disease.
Ti me t o tre at me nt f ail ure ( T T F) is t he ti me fr o m date of ra n d o mizati o n/start of treat me nt t o 
t he earliest of date of pr o gressi o n, date of deat h d ue t o a n y c a use, or date of disc o nti n uati o n d ue 
t o reas o ns ot her t ha n ‘ Pr ot oc ol vi olati o n’ or ‘ A d mi nistrati ve pr o ble ms’. T he ti me t o treat me nt 
fail ure f or patie nts w h o di d n ot e x perie nce treat me nt fail ure will be ce ns ore d at last a de q uate 
t u m or assess me nt.
3. 2. 6
D ur ati o n of r e s p o n s e
T he a nal ysis of t he f oll o wi n g varia bles s h o ul d be perf or me d wit h m uc h ca uti o n w he n restricte d 
t o res p o n ders si nce treat me nt bias c o ul d ha ve bee n i ntr o d uce d. T here ha ve bee n re p orts w here 
a treat me nt wit h a si g nifica ntl y hi gher res p o nse rate ha d a si g nifica ntl y s h orter d urati o n of 
res p o nse b ut w here t his pr o ba bl y pri maril y reflecte d selecti o n bias w hic h is e x plai ne d as 
f oll o ws: It is p ost ulate d t hat t here are t w o gr o u ps of patie nts: a g o o d ris k gr o u p a n d a p o or ris k 
gr o u p. G o o d ris k patie nts te n d t o get i nt o res p o nse rea dil y (a n d relati vely q uic kl y ) a n d te n d t o 
re mai n i n res p o nse after t he y ha ve a res p o nse. P o or ris k patie nts te n d t o be diffic ult t o ac hie ve 
a res p o nse, m a y  ha ve a l o n ger ti me t o res p o n d, a n d te n d t o rela pse q uic kl y  whe n t he y do res p o n d. 
P ote nt a ge nts i n d uce a res p o nse i n b ot h g o o d ris k a n d p o or ris k patie nts. Less p ote nt a ge nts 
i n d uce a res p o nse mai nl y i n g o o d ris k patie nts o nl y . T his is descri be d i n m ore detail b y  M or ga n 
( 1 9 8 8).
It is rec o m me n de d t hat a n a nal ys is of all patie nts ( b ot h res p o n ders a n d n o n- res p o n ders) be 
perf or me d w het her or n ot a “res p o n ders o nl y”  descri pti ve a nalys is is prese nte d. A n a nal ysis of 
res p o n ders s h o ul d o nl y be perf or me d t o pr o vi de descri pti ve statistics a n d e ve n t he n i nter prete d 
wit h ca uti o n b y  eval uati n g t he res ults i n t he c o nte xt of t he o bser ve d res p o nse rates…
If a n 

N o v arti s
C o nfi d e nti al
P a g e 1 0 7
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
i nfere ntial c o m paris o n bet wee n treat me nts is re q uire d t his s h o ul d o nl y  be perf or me d o n all 
patie nts (i.e. n ot restricti n g t o “res p o n ders” o nl y) usi n g a p pr o priate statistical met h o ds s uc h as 
t he tec h ni q ues descri be d i n Ellis et al ( 2 0 0 8) . It s h o ul d als o be state d i n t he pr ot oc ol if d urati o n 
of res p o nse is t o be calc ulate d i n a d diti o n f or u nc o nfir me d res p o nse.
F or s u m mar y statistics o n “res p o n ders” o nl y  the f oll o wi n g defi niti o ns are a p pr o priate. ( S pecific 
defi niti o ns f or a n all-patie nt a nal ys is of t hese e n d p oi nts are n ot a p pr o priate si nce t he stat us of 
patie nts t hr o u g h o ut t he st u d y  is us ually ta ke n i nt o acc o u nt i n t he a nal ys is).
D ur ati o n of o ver all res p o nse ( C R or P R) : F or patie nts wit h a C R or P R ( w hic h ma y  ha ve t o 
be c o nfir me d t he start date is t he date of first d oc u me nte d res p o nse ( C R or P R) a n d t he e n d date 
a n d ce ns ori n g is defi ne d t he sa me as t hat f or ti me t o pr o gressi o n.
T he f oll o wi n g t w o d urat i o ns mi g ht be calc ulate d i n a d diti o n f or a lar ge P hase III st u d y in w hic h 
a reas o na ble n u m ber of res p o n ders is see n.
D ur ati o n of o ver all c o m plete res p o nse ( C R) : F or patie nts wit h a C R ( w hic h ma y  ha ve t o be 
c o nfir me d) t he start date is t he date of first d oc u me nte d C R a n d t he e n d date a n d ce ns ori n g is 
defi ne d t he sa me as t hat f or ti me t o pr o gressi o n.
D ur ati o n of st a ble dise ase ( C R/ P R/ S D) : F or patie nts wit h a C R or P R ( w hic h ma y ha ve t o be 
c o nfir me d) or S D t he start a n d e n d date as well as ce ns ori n g is defi ne d t he sa me as t hat f or ti me 
t o pr o gressi o n.
3. 2. 7
Ti m e t o r e s p o n s e
Ti me t o o ver all res p o nse ( C R or P R) is t he ti me bet wee n date of ra n d o mizati o n/start of 
treat me nt u ntil first d oc u me nte d res p o nse ( C R or P R). T he res p o nse ma y nee d t o be c o nfir me d 
de pe n di n g o n t h e t y pe of st u d y  an d its i m p orta nce. W here t he res p o nse nee ds t o be c o nfir me d 
t he n ti me t o res p o nse is t he ti me t o t he first C R or P R o bser ve d.
Alt h o u g h a n a nal ys is o n t he f ull p o p ulati o n is preferre d a descri pti ve a nal ys is ma y  be perf or me d 
o n t he “res po n ders” s u bset o nl y , i n w hic h case t he res ults s h o ul d be i nter prete d wit h ca uti o n 
a n d i n t he c o nte xt of t he o verall res p o nse rates, si nce t he sa me ki n d of selecti o n bias ma y  be 
i ntr o d uce d as descri be d f or d urati o n of res p o nse i n Secti o n 3. 2. 5 . It is rec o m me n de d t hat a n 
a nal ys is of all patie nts ( b ot h res p o n ders a n d n o n- res p o n ders) be perf or me d w het her or n ot a 
“res p o n ders o nl y” d escri pti ve a nal ys is is prese nte d. W here a n i nfere ntial statistical c o m paris o n 
is re q uire d, t he n all patie nts s h o ul d defi nitel y  be i ncl u de d i n t he a nal ys is t o e ns ure t he statistical 
test is vali d. F or a nalys is i ncl u di n g all patie nts, patie nts w h o di d n ot ac hie ve a res p o nse ( w hic h 
ma y  ha ve t o be a c o nfir me d res p o nse) will be ce ns ore d usi n g o ne of t he f oll o wi n g o pti o ns.

at ma xi m u m f oll o w-u p (i.e. F P F V t o L P L V use d f or t he a nal ys is) f or patie nts w h o ha d a 
P F S e ve nt (i.e. pr o gresse d or die d d ue t o a n y ca use). I n t his case t he P F S e ve nt is t he 
w orst p ossi ble o utc o me as it mea ns t he patie nt ca n n ot s u bse q ue ntl y res p o n d. Si nce t he 
statistical a nal ysis us uall y ma kes use of t he ra n ki n g of ti mes t o res p o nse it is s ufficie nt t o 
assi g n t he w orst p ossi ble ce ns ori n g ti me w hic h c o ul d be o bser ve d i n t he st u d y  w hic h is 
e q ual t o t he ma xi m u m f oll o w -u p ti m e (i.e. ti me fr o m F P F V t o LP L V)

at last a de q uate t u m or assess me nt date ot her wise. I n t his case patie nts ha ve n ot y et 
pr o gresse d s o t he y  t he oreticall y still ha ve a c ha nce of res p o n di n g

N o v arti s
C o nfi d e nti al
P a g e 1 0 8
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
Ti me t o o ver all c o m plete res p o nse ( C R) is t he ti me bet wee n dates of ra n do mizati o n/start of 
treat me nt u ntil first d oc u me nte d C R. Si milar a nal ysis c o nsi derati o ns i ncl u di n g (if a p pr o priate) 
ce ns ori n g r ules a p pl y f or t his e n d p oi nt descri be d f or t he ti me t o o verall res p o nse e n d p oi nt.
3. 2. 8
D efi niti o n of st art a n d e n d d at e s f or ti m e t o e v e nt v ari a bl e s
A s s e s s m e nt d at e
F or eac h assess me nt (i.e. e val uati o n n u m ber), t he assess me nt d ate is calc ulate d as t he latest of 
all meas ure me nt dates (e. g. , X-r a y, C T-sca n) if t he o verall lesi o n res p o nse at t hat assess me nt is 
C R/ P R/ S D/ U N K. Ot her wise - if o verall lesi o n res p o nse is pr o gressi o n - t he assess me nt date is 
calc ulate d as t he earliest date of all meas ure me nt dates at t hat e val uati o n n u m ber.
I n the calc ulati o n of t he assess me nt date f or ti me t o e ve nt varia bles, a n y u nsc he d ule d 
assess me nt s h o ul d be treate d si milarl y  t o ot her e val uati o ns.
St art d at e s
F or all “ti me t o e ve nt” varia bles, ot her t ha n d urati o n of res p o nse, t he ra n d o mizati o n/ date of 
treat me nt start will be use d as t he start date.
F or t he calc ulati o n of d urati o n of res p o nse t he f oll o wi n g start date s h o ul d be use d:

Date of first d oc u me nte d res p o nse is t he assess me nt date of t he first o verall lesi o n 
res p o nse of C R (f or d urati o n of o verall c o m plete res p o nse) or C R / P R (f or d urati o n of 
o verall res p o nse) res pecti vel y , w he n t his stat us is later c o nfir me d.
E n d d at e s
T he e n d dates w hic h are use d t o calc ulate ‘ti me t o e ve nt’ varia bles are defi ne d as f oll o ws:

Date of deat h ( d uri n g treat me nt as rec or de d o n t he treat me nt c o m pleti o n pa ge or d uri n g 
f oll o w-u p as rec or de d o n t he st u d y  e val uati o n c o m pletio n pa ge or t he s ur vi val f oll o w - u p 
pa ge).

Date of pr o gressi o n is t he first assess me nt date at w hic h t he o verall lesi o n res p o nse was 
rec or de d as pr o gressi ve disease.

Date of last a de q uate t u m or assess me nt is t he date t he last t u m or assess me nt wit h o verall 
lesi o n res p o nse of C R, P R or S D w hic h was ma de bef ore a n e ve nt or a ce ns ori n g reas o n 
occ urre d. I n t his case t he last t u m or e val uati o n date at t hat assess me nt is use d. If n o p ost -
baseli ne assess me nts are a vaila ble ( bef ore a n e ve nt or a ce ns ori n g reas o n occ urr e d) t he 
date of ra n d o mizati o n/start of treat me nt is use d.

Date of ne xt sc he d ule d assess me nt is t he date of t he last a de q uate t u m or assess me nt pl us 
t he pr ot oc ol s pecifie d ti me i nter val f or assess me nts. T his date ma y be use d if bac k- dati n g 
is c o nsi dere d w he n t he e ve nt occ urre d be yo n d t he acce pta ble ti me wi n d o w f or t he ne xt 
t u m or assess me nt as per pr ot oc ol (see Secti o n 3. 2. 8 ).
E x a m ple (if pr ot oc ol defi ne d sc he d ule of assess me nts is 3 m o nt hs): t u m or assess me nts at 
baseli ne - 3 m o nt hs - 6 m o nt hs - missi n g - missi n g - P D. Date of ne xt sc he d ule d assess me nt 
w o ul d t he n c orres p o n d t o 9 m o nt hs.

Date of disc o nti n uati o n is t he date of t he e n d of treat me nt visit.

N o v arti s
C o nfi d e nti al
P a g e 1 0 9
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0

Date of last c o ntact is defi ne d as t he last date t he patie nt was k n o w n t o be ali ve. T his 
c orres p o n ds t o t he latest date f or eit her t he visit date, la b sa m ple date or t u m or assess me nt 
date. If a vaila ble, t he last k n o w n date patie nt ali ve f r o m t he s ur vi val f oll o w-u p pa ge is 
use d. If n o s ur vi val f oll o w- u p is a vaila ble, t he date of disc o nti n uati o n is use d as last 
c o ntact date.

Date of sec o n dar y  a nti-ca ncer t hera p y is defi ne d as t he start date of a n y a d diti o nal 
(sec o n dar y) a nti ne o plastic t hera py or s ur ger y .
3. 2. 9
H a n dli n g of p ati e nt s wit h n o n -m e a s ur a bl e di s e a s e o nl y  at b a s eli n e
It is p ossi ble t hat patie nts wit h o nl y n o n-meas ura ble disease prese nt at baseli ne are e ntere d i nt o 
t he st u d y, eit her beca use of a pr ot oc ol vi olati o n or b y  desi g n (e. g., i n P hase III st u dies wit h P F S 
as t he pri mar y  en d p oi nt). I n suc h cases t he ha n dli n g of t he res p o nse data re q uires s pecial 
c o nsi derati o n wit h res pect t o i ncl usi o n i n a n y anal y sis of e n d p oi nts base d o n t he o verall 
res p o nse e val uati o ns.
It is rec o m me n de d t hat an y  patie nts wit h o nl y  no n- meas ura ble disease at baseli ne s h o ul d be 
i ncl u de d i n t he mai n (I T T) a nalys is of eac h of t hese e n d p oi nts.
Alt h o u g h t he te xt of t he defi niti o ns descri be d i n t he pre vi o us secti o ns pri maril y relates t o 
patie nts wit h meas ura ble disease at baseli ne, patie nts wit h o ut meas ura ble disease s h o ul d als o 
be i nc or p orate d i n a n a p pr o priate ma n ner. T he o verall res p o nse f or patie nts wit h n o n-
meas ura ble disease is deri ve d sli g htl y  differe ntl y acc or di n g t o Ta ble 3 - 1.
T a bl e 3 -1 
O v er all l e si o n r e s p o n s e at e a c h a s s e s s m e nt: p ati e nt s wit h n o n -
t ar g et di s e a s e o nl y
N o n -t ar g et l e si o n s
N e w L e si o n s
O v er all l e si o n r e s p o n s e
C R
N o
C R
N o n -C R/ N o n -P D 1
N o
N o n -C R/ n o n -P D
U N K
N o
U N K
P D
Y e s or N o
P D
A n y
Y e s
P D
1 A s d efi n e d i n S e cti o n 2. 4 .
I n ge neral, t he n o n -C R/ n o n -P D res p o nse f or t hese patie nts is c o nsi dere d e q ui vale nt t o a n S D 
res p o nse i n e n d p oi nt deter mi nati o n. I n su m mar y  ta bles f or best o verall res p o nse pa tie nts wit h 
o nl y  n o n-meas ura ble disease ma y be hi g hli g hte d i n a n a p pr o priate fas hi o n e. g. , i n partic ular b y  
dis pla y i n g t he s pecific n u m bers wit h t he n o n-C R/ n o n -P D cate g or y .
I n c o nsi deri n g h o w t o i nc or p orate data fr o m t hese patie nts i nt o t he a nal ysis t he i mp orta nce t o 
eac h e n d p oi nt of bei n g a ble t o i de ntif y a PR a n d/ or t o deter mi ne t he occ urre nce a n d ti mi n g of 
pr o gressi o n nee ds t o be ta ke n i nt o acc o u nt.
F or O R R it is rec o m me n de d t hat t he mai n (IT T) a nal ysis i ncl u des data fr o m patie nts wit h o nl y 
n o n- meas ura bl e disease at baseli ne, ha n dli n g patie nts wit h a best res p o nse of C R as “res p o n ders” 
wit h res pect t o O R R a n d all ot her patie nts as “ n o n -res p o n ders”.
F or P F S , it is a gai n rec o m me n de d t hat t he mai n I TT a nal ys es o n t hese e n d p oi nts i ncl u de all 
patie nts wit h o nl y n o n -meas ura ble disease at baseli ne, wit h p ossi ble se nsiti vit y a nal yses w hic h 

N o v arti s
C o nfi d e nti al
P a g e 1 1 0
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
e xcl u de t hese partic ular patie nts. E n d p oi nts s uc h as P F S w hic h are relia nt o n t he deter mi nati o n 
a n d/ or ti mi n g of pr o gressi o n ca n i nc or p orate data fr o m patie nts wit h o nl y  no n- mea s ura ble 
disease.
3. 2. 1 0 S e n siti vit y a n al y s e s
T his secti o n o utli nes t he p ossi ble e ve nt a n d ce ns ori n g dates f or pr o gressi o n, as well as a d dresses 
t he iss ues of missi n g t u m or assess me nts d uri n g t he st u d y. F or i nsta nce, if o ne or m ore 
assess me nt visits are misse d pri or t o t he pr o gressi o n e ve nt, t o w hat date s h o ul d t he pr o gressi o n 
e ve nt be assi g ne d? A n d s h o ul d pr o gressi o n e ve nt be i g n ore d if it occ urre d after a l o n g peri o d 
of a patie nt bei n g l ost t o f oll o w-u p? It is i m p orta nt t hat t he pr ot oc ol a n d R A P s pecif y th e 
pri mar y  anal y sis i n detail wit h res pect t o t he defi niti o n of e ve nt a n d ce ns ori n g dates a n d als o 
i ncl u de a descri pti o n of o ne or m ore se nsiti vit y a nal yses t o be perf or me d.
Base d o n defi niti o ns o utli ne d i n Secti o n 3. 2. 7 , a n d usi n g t he draft F D A g ui deli ne o n e n d p oi nts 
(Cli nical Trial E n d p oi nts f or t he A p pr o val of Ca ncer Dr u gs a n d Bi ol o gics -A pril 2 0 0 5 ) as a 
refere nce, t he f oll o wi n g a nalys es ca n be c o nsi de re d:

N o v arti s
C o nfi d e nti al
P a g e 1 1 1
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
T a bl e 3 - 2 
O pti o n s f or e v e nt d at e s u s e d i n P F S, T T P, d ur ati o n of r e s p o n s e
Sit u ati o n
O pti o n s f or e n d -d at e ( pr o gr e s si o n or 
c e n s ori n g) 1
( 1) = d ef a ult u nl e s s s p e cifi e d diff er e ntl y 
i n t h e pr ot o c ol or R AP
O ut c o m e
A 
N o b a s eli n e a s s e s s m e nt
( 1) D at e of r a n d o mi z ati o n/ st art of tr e at m e nt3
C e n s or e d
B
Pr o gr e s si o n at or b ef or e n e xt 
s c h e d ul e d a s s e s s m e nt
( 1) D at e of pr o gr e s si o n
( 2) D at e of n e xt s c h e d ul e d a s s e s s m e nt2
Pr o gr e s s e d
Pr o gr e s s e d
C 1
Pr o gr e s si o n or d e at h aft er 
e x a ctl y o n e mi s si n g a s s e s s m e nt
( 1) D at e of pr o gr e s si o n ( or d e at h)
( 2) D at e of n e xt s c h e d ul e d a s s e s s m e nt2
Pr o gr e s s e d
Pr o gr e s s e d
C 2
Pr o gr e s si o n or d e at h aft er t w o or 
m or e
mi s si n g a s s e s s m e nt s
( 1) D at e of l a st a d e q u at e a s s e s s m e nt2
( 2) D at e of n e xt s c h e d ul e d a s s e s s m e nt2
( 3) D at e of pr o gr e s si o n ( or d e at h)
C e n s or e d
Pr o gr e s s e d
Pr o gr e s s e d
D 
N o pr o gr e s si o n
( 1) D at e of l a st a d e q u at e a s s e s s m e nt 
C e n s or e d
E
Tr e at m e nt di s c o nti n u ati o n d u e t o 
‘ Di s e a s e pr o gr e s si o n’ wit h o ut 
d o c u m e nt e d pr o gr e s si o n, i. e. 
cli ni c al pr o gr e s si o n b a s e d o n 
i n v e sti g at or cl ai m
( 1) I g n or e cli ni c al pr o gr e s si o n a n d f oll o w 
sit u ati o n s a b o v e
( 2) D at e of di s c o nti n u ati o n ( vi sit d at e at 
w hi c h cli ni c al pr o gr e s si o n w a s 
d et er mi n e d)
A s p er 
a b o v e 
sit u ati o n s
Pr o gr e s s e d
F 
N e w a nti c a n c er t h er a p y gi v e n
( 1) I g n or e t h e n e w a nti c a n c er t h er a p y a n d 
f oll o w situ ati o n s a b o v e (I T T a p pr o a c h)
( 2) D at e of l a st a d e q u at e a s s e s s m e nt pri or 
t o n e w a nti c a n c er t h er a p y
( 3) D at e of s e c o n d ar y a nti-c a n c er t h er a p y
( 4) D at e of s e c o n d ar y a nti-c a n c er t h er a p y
A s p er 
a b o v e 
sit u ati o n s
C e n s or e d
C e n s or e d
E v e nt
G
D e at h s d u e t o r e a s o n ot h er t h a n 
d et eri or ati o n of ‘ St u d y i n di c ati o n’
( 1) D at e of l a st a d e q u at e a s s e s s m e nt
C e n s or e d 
( o nl y T T P 
a n d d ur ati o n 
of r e s p o n s e)
1.
= D efi niti o n s c a n b e f o u n d i n S e cti o n 3. 2. 7 .
2.
= Aft er t h e l a st a d e q u at e t u m or a s s e s s m e nt. “ D at e of n e xt s c h e d ul e d a s s e s s m e nt” i s d efi n e d i n 
S e cti o n 3. 2. 7 .
3.
= T h e r ar e e x c e pti o n t o t hi s i s if t h e p ati e nt di e s n o l at er t h a n t h e ti m e of t h e s e c o n d s c h e d ul e d 
a s s e s s m e nt a s d efi n e d i n t h e pr ot o c ol i n w hi c h c a s e t hi s i s a P F S e v e nt at t h e d at e of d e at h.
T he pri mar y  anal ys is a n d t he se nsiti vit y anal ys es m ust be s pecifie d i n t he pr ot oc ol. Clearl y 
defi ne if a n d w h y o pti o ns ( 1) are n ot use d f or sit uati o ns C, E a n d (if a p plica ble) F.
Sit uati o ns C ( C 1 a n d C 2): Pr o gressi o n or deat h after o ne or m ore missi n g assess me nts: T he 
pri mar y  a nalys is is us uall y usi n g o pti o ns ( 1) f or sit uati o ns C 1 a n d C 2, i.e.

( C 1) ta ki n g t he act ual pr o gressi o n or deat h date, i n t he case of o nl y  o ne missi n g 
assess me nt.

( C 2) ce ns ori n g at t he date of t he last a de q uate assess me nt, i n t he case of t w o or m ore 
c o nsec uti ve missi n g assess me nts.

N o v arti s
C o nfi d e nti al
P a g e 1 1 2
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
I n t he case of t w o or missi n g assess me nts (sit uati o n C 2), o pti o n ( 3) ma y be c o nsi dere d j oi ntl y 
wit h o pt i o n ( 1) i n sit uati o n C 1 as se nsiti vit y anal y sis. A varia nt of t his se nsiti vit y anal y sis 
c o nsists of bac k dati n g t he date of e ve nt t o t he ne xt sc he d ule d assess me nt as pr o p ose d wit h 
o pti o n ( 2) i n sit uati o ns C 1 a n d C 2.
Sit u ati o n E: Tre at me nt disc o nti n u ati o n d u e t o ‘ Dise ase pr o gressi o n’ wit h o ut d oc u me nte d 
pr o gressi o n: B y  defa ult, o pti o n ( 1) is use d f or sit uati o n E as patie nts wit h o ut d oc u me nte d P D 
s h o ul d be f oll o we d f or pr o gressi o n after disc o nti n uati o n of treat me nt. H o we ver, o pti o n ( 2) ma y 
be use d as se nsiti vit y a nal ysis. If pr o gressi o n is clai me d base d o n cli nical deteri orati o n i nstea d 
of t u m or assess me nt b y  e. g., C T -sca n, o pti o n ( 2) ma y  be use d f or i n dicati o ns wit h hi g h earl y 
pr o gressi o n rate or diffic ulties t o assess t he t u m or d ue t o cli nical deteri orati o n.
S it u ati o n F: Ne w c a ncer t her a p y gi ve n: t he ha n dli n g of t his sit uati o n m ust be s pecifie d i n 
detail i n t he pr ot oc ol. H o we ver, o pti o n ( 1) (I T T) is t he rec o m me n de d a p pr oac h; e ve nts 
d oc u me nte d after t he i nitiati o n of ne w ca ncer t hera py will be c o nsi dere d f or t he pri mar y 
a nal ys is i.e. pr o gressi o ns a n d deat hs d oc u me nte d after t he i nitiati o n of ne w ca ncer t hera p y 
w o ul d be i ncl u de d as e ve nts. T his will re q uire c o nti n ue d f oll o w- u p f or pr o gressi o n after t he 
start of t he ne w ca ncer t hera p y . I n s uc h cases, it is rec o m me n de d t hat a n a d diti o nal se nsiti vit y  
a nal ys is be perf or me d b y  ce ns ori n g at last a de q uate assess me nt pri or t o i nitiati o n of ne w ca ncer 
t hera py.
O pti o n ( 2), i.e. ce ns ori n g at last a de q uate assess me nt ma y be use d as a se nsiti vit y  a nal ysis. If a 
hi g h ce ns ori n g r ate d ue t o start of ne w ca ncer t hera p y is e x pecte d, a wi n d o w of a p pr o xi matel y 
8 wee ks perf or me d after t he start of ne w ca ncer t hera p y ca n be use d t o calc ulate t he date of t he 
e ve nt or ce ns ori n g. T his s h o ul d be clearl y s pecifie d i n t he a nal ys is pla n.
I n s o me s pecific setti n gs, l ocal treat me nts (e. g., ra diati o n/s ur ger y) m a y  not be c o nsi dere d as 
ca ncer t hera pies f or assess me nt of e ve nt/ce ns ori n g i n P F S/ T T P/ D o R a nal ysis. F or e xa m ple, 
palliati ve ra di ot hera py gi ve n i n t he trial f or a nal gesic p ur p oses or f or l ytic lesi o ns at ris k of 
fract ure will n ot be c o nsi dere d as ca ncer t hera py f or t he assess me nt of B O R a n d P F S a nal yses. 
T he pr ot oc ol s h o ul d clearl y state t he l ocal treat me nts w hic h are n ot c o nsi dere d as a nti ne o plastic 
t hera pies i n t he P F S/ T T P/ D o R a nal ysis.
T he p r ot oc ol s h o ul d state t hat t u m or assess me nts will be perf or me d e ver y x wee ks u ntil 
ra di ol o gical pr o gressi o n irres pecti ve of i nitiati o n of ne w a nti ne o plastic t hera p y. It is str o n gly 
rec o m me n de d t hat a t u m or assess me nt is perf or me d bef ore t he patie nt is s witche d t o a ne w 
ca ncer t hera p y.
A d diti o n al s u g g e sti o n s f or s e n siti vit y a n al y s e s
Ot her s u g gesti o ns f or a d diti o nal se nsiti vit y anal y ses ma y  incl u de a nal yses t o c hec k f or p ote ntial 
bias i n f oll o w- u p sc he d ules f or t u m or assess me nts, e. g., b y  assi g ni n g t he dates for ce ns ori n g 
a n d e ve nts o nl y  at sc he d ule d visit dates. T he latter c o ul d be ha n dle d b y re placi n g i n Ta ble 3- 2
t he “ Date of last a de q uate assess me nt” b y  the “ Date of pre vi o us sc he d ule d assess me nt (fr o m 
bas eli ne)”, wit h t he f oll o wi n g defi niti o n:

D ate of pre vi o us sc he d ule d assess me nt (fr o m b aseli ne) is t he date w he n a t u m or 
assess me nt w o ul d ha ve ta ke n place, if t he pr ot oc ol assess me nt sc he me was strictl y  
f oll o we d fr o m baseli ne, i m me diatel y bef ore or o n t he date of t he last a de q uate t u m or 
assess me nt.

N o v arti s
C o nfi d e nti al
P a g e 1 1 3
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
I n a d diti o n, a nal yses c o ul d be re peate d usi n g t he I n vesti gat ors’ assess me nts of res p o nse rat her 
t ha n t he calc ulate d res p o nse. T he nee d f or t hese t ypes of se nsiti vit y a nalys es will de pe n d o n t he 
i n di vi d ual re q uire ments f or t he s pecific st u d y an d disease area a n d ha ve t o be s pecifie d i n t he 
pr ot oc ol or R A P d oc u me ntati o n.
4 
D at a h a n dli n g a n d pr o gr a m mi n g r ul e s
T he f oll o wi n g secti o n s h o ul d be use d as g ui da nce f or de vel o p me nt of t he pr ot oc ol, data 
ha n dli n g pr oce d ures or p r o gra m mi n g re q uire me nts (e. g., o n i nc o m plete dates).
4. 1 
St u d y/ pr oj e ct s p e cifi c d e ci si o n s
F or eac h st u d y  ( or pr oject) vari o us iss ues nee d t o be a d dresse d a n d s pecifie d i n t he pr ot oc ol or 
R A P d oc u me ntati o n. A n y  de viati o ns fr o m pr ot oc ol m ust be disc usse d a n d defi ne d at t he latest 
i n t he R A P d oc u me ntati o n.
T he pr o p ose d pri mar y  anal y sis a n d p ote ntial se nsiti vit y anal ys es s h o ul d be disc usse d a n d 
a gree d wit h t he healt h a ut h orities a n d d oc u me nte d i n t he pr ot oc ol ( or at t he latest i n t he R A P 
d oc u me ntati o n bef ore da ta base l oc k).
4. 2 
E n d of tr e at m e nt p h a s e c o m pl eti o n
Patie nts m a y
v ol u ntaril y wit h dra w fr o m t he st u d y treat me nt or m a y  be ta ke n off t he st u d y 
treat me nt at t he discreti o n of t he i n vesti gat or at a n y ti me. F or patie nts w h o are l ost t o f oll o w-
u p, t he i n vesti gator or desi g nee s h o ul d s h o w " d ue dili ge nce" b y  doc u me nti n g i n t he s o urce 
d oc u me nts ste ps ta ke n t o c o ntact t he patie nt, e. g., dates of tele p h o ne calls, re gistere d letters, etc.
T he e n d of treat me nt visit a n d its ass ociate d assess me nts s h o ul d occ ur wit hi n 7 d a ys of t he last 
st u d y treat me nt.
Patie nts ma y  disc o nti n ue st u d y treat me nt f or a ny of t he f oll o wi n g reas o ns:

A d verse e ve nt(s)

L ost t o f oll o w - u p

P h y sicia n decisi o n

Pre g na nc y

Pr ot oc ol de viati o n

Tec h nical pr o ble ms

Patie nt / g uar dia n decisi o n

Pr o gressi ve disease

St u d y  ter mi nate d b y t he s p o ns or

N o n -c o m plia nt wit h st u d y treat me nt

N o l o n ger re q uires treat me nt

Treat me nt d urati o n c o m plete d as per pr ot oc ol ( o pti o nal, t o be use d if o nl y  a fi xe d n u m ber 
of c y cles is gi ve n)
Deat h is a reas o n w hic h “ m ust ” lea d t o disc o nti n ua ti o n of patie nt fr o m trial.

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

N o v arti s
C o nfi d e nti al
P a g e 1 1 5
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
4. 5 
Pr o gr a m mi n g r ul e s
T he f oll o wi n g s h o ul d be use d f or pr o gra m mi n g of efficac y  res ults:
4. 5. 1
C al c ul ati o n of ‘ti m e t o e v e nt’ v ari a bl e s
T i me t o e ve nt = e n d date - start date + 1 (i n da ys)
W he n 
n o p ost -baseli ne t u m or assess me nts are a vaila ble, t he date of ra n d o mizati o n/start of 
treat me nt will be use d as e n d date ( d urati o n = 1 da y) w he n ti me is t o be ce ns ore d at last t u m or 
assess me nt, i.e. ti me t o e ve nt varia bles ca n ne ver be ne gati ve.
4. 5. 2
I n c o m pl et e a s s e s s m e nt d at e s
All i n vesti gati o n dates (e. g. , X-ra y, C T sca n) m ust be c o m plete d wit h da y, m o nt h a n d year.
If o ne or m ore i n vesti gati o n dates are i nc o m plete b ut ot her i n vesti gati o n dates are a vaila ble, 
t his/t hese i nc o m plete date(s) are n ot c o nsi dere d f or calc ulati o n of t he assess me nt date (a n d 
assess me nt date is calc ulate d as o utli ne d i n Secti o n 3. 2. 7 ). If all meas ure me nt dates ha ve n o d a y  
recor de d, t he 1 st of t he m o nt h is use d.
If t he m o nt h is n ot c o m plete d, f or a n y of t he i n vesti gati o ns, t he res pecti ve assess me nt will be 
c o nsi dere d t o be at t he date w hic h is e xactl y b et wee n pre vi o us a n d f oll o wi n g assess me nt. If a 
pre vi o us a n d f oll o wi n g assessme nt is n ot a vaila ble, t his assess me nt will n ot be use d f or a n y 
calc ulati o n.
4. 5. 3
I n c o m pl et e d at e s f or l a st k n o w n d at e p ati e nt ali v e or d e at h
All dates m ust be c o m plete d wit h da y , m o nt h a n d year. If t he da y  is missi n g, t he 1 5 t h of t he 
m o nt h will be use d f or i nc o m plete deat h dates or dates of last c o ntact.
4. 5. 4
N o n -t ar g et l e si o n r e s p o n s e
If n o n o n- tar get lesi o ns are i de ntifie d at baseli ne (a n d t heref ore n ot f oll o we d t hr o u g h o ut t he 
st u d y), t he n o n- tar get lesi o n res p o nse at eac h assess me nt will be c o nsi dere d ‘ n ot a p plica ble 
( N A)’.
4. 5. 5
St u d y/ pr oj e ct s p e cifi c pr o gr a m mi n g
T he sta n dar d a nal ys is pr o gra ms nee d t o be a da pte d f or eac h st u d y/ pr oject.
4. 5. 6
C e n s ori n g r e a s o n
I n or der t o s u m marize t he vari o us reas o ns f or ce ns ori n g, t he f oll o wi n g cate g ories will be 
calc ulate d f or eac h ti me t o e ve nt varia ble base d o n t he treat me nt c o m pleti o n pa ge, t he st u d y 
e val uati o n c o m pleti o n pa ge a n d t he s ur vi val pa ge.
F or s ur vi val t he f oll o wi n g ce ns ori n g reas o ns are p ossi ble:

Ali ve

L ost t o f oll o w -u p
F or P F S a n d T T P (a n d t heref ore d urati o n of res p o nses) t he f oll o wi n g ce ns ori n g reas o ns are 
p ossi ble:

N o v arti s
C o nfi d e nti al
P a g e 1 1 6
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0

O n g oi n g wit h o ut e ve nt

L ost t o f oll o w - u p

Wit h dre w c o nse nt

A de q uate assess me nt n o l o n ger a vaila ble *

E ve nt d oc u me nte d after t w o or m ore missi n g t u m or assess me nts ( o pti o nal, see Ta ble 3 - 2)

Deat h d ue t o reas o n ot her t ha n u n derl yi n g ca ncer ( o nly use d f or T T P a n d d ur ati o n of 
res p o nse)

I nitiati o n of ne w a nti-ca ncer t hera p y
* A de q uate assess me nt is defi ne d i n Secti o n 3. 2. 7 . T his reas o n is a p plica ble w he n a de q uate 
e val uati o ns are missi n g f or a s pecifie d peri o d pri or t o data c ut-off ( or pri or t o a n y ot her 
ce ns ori n g reas o n) c orres p o n di n g t o t he u na vaila bilit y  of tw o 
or m ore 
pla n ne d t u m or 
assess me nts pri or t o t he c ut-off date. T he f oll o wi n g clarificati o ns c o ncer ni n g t his reas o n s h o ul d 
als o be n ote d:

T his ma y  be w he n t here has bee n a defi nite decisi o n t o st o p e val uati o n (e. g.,
reas o n =“ S p o ns or decisi o n” o n st u d y e val uati o n c o m pleti o n pa ge), w he n patie nts are n ot 
f oll o we d f or pr o gressi o n after treat me nt c o m pleti o n or w he n o nly U N K assess me nts are 
a vaila ble j ust pri or t o data c ut -off).

T he reas o n " A de q uate assess me nt n o l o n ger a vaila ble" als o pre vails i n sit uati o ns w he n 
a n ot her ce ns ori n g reas o n (e. g. , wit h dra wal of c o nse nt, l ost t o f oll o w-u p or alter nati ve a nti -
ca ncer t hera p y) has occ urre d m ore t ha n t he s pecifie d peri o d f oll o wi n g t he last a de q uate 
assess me nt.

T his reas o n will als o be use d t o ce ns or i n case of n o baseli ne assess me nt.

N o v arti s
C o nfi d e nti al
P a g e 1 1 7
A m e n d e d Pr ot o c ol v 0 2 ( Cl e a n )
Pr ot o c ol N o. C P Z P 0 3 4 A 2 4 1 0
5 
R ef er e n c e s ( a v ail a bl e u p o n r e q u e st)
De nt S, Zee ( 2 0 0 1) a p plicati o n of a ne w m ulti n o mial p hase II st o p pi n g r ule usi n g res p o nse 
a n d earl y pr o gressi o n, J Cli n O nc ol; 1 9: 7 8 5- 7 9 1
Eise n ha uer E, et al ( 2 0 0 9) Ne w res p o nse e val uati o n criteria i n s oli d t u m ors: re vise d R E CI S T 
g ui deli ne ( versi o n 1. 1). E ur o pea n J o ur nal of Ca ncer, V ol. 4 5: 2 2 8 - 4 7
Ellis S, et al ( 2 0 0 8) A nal ysis of d urati o n of res p o nse i n o nc ol o g y  trials. C o nte m p Cli n Trials 
2 0 0 8; 2 9: 4 5 6 - 4 6 5
E M A G ui da nce: 2 0 1 2 G ui deli ne o n t he e val uati o n of a ntica ncer me dici nal pr o d ucts i n ma n
F D A G ui deli nes: 2 0 0 5 Cli nical Trial E n d p oi nts f or t he A p pr o val of Ca ncer Dr u gs a n d 
Bi ol o gics, A pril 2 0 0 5
F D A G ui deli nes: 2 0 0 7 Cli nical Trial E n d p oi nts f or t he A p pr o val of Ca ncer Dr u gs a n d 
Bi ol o gics, Ma y  2 0 0 7
M or ga n T M ( 1 9 8 8) A nal y sis of d urati o n of res p o nse: a pr o ble m of o nc ol o g y trials. C o nt Cli n 
Trials; 9: 1 1 - 1 8
T herasse P, Ar b uc k S, Eise n ha uer E, et al ( 2 0 0 0) Ne w G ui deli nes t o E val uate t he Res p o nse t o 
Treat me nt i n S oli d T u m ors, J o ur nal of Nati o nal Ca ncer I nstit ute, V ol. 9 2; 2 0 5 - 1 6