Conditions: Advanced Renal Cell Carcinoma Metastatic Renal Cell Carcinoma
Keywords: renal cell carcinoma metastatic renal cell pazopanib checkpoint inhibitor therapy RCC hypernephroma renal adenocarcinoma kidney cancer renal cancer adult
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 62
Healthy volunteers: no

Brief summary:
The main purpose of this study was to assess the progression-free survival (PFS) based on local investigator assessment of pazopanib in participants with advanced and/or metastatic renal cell carcinoma (mRCC) following prior treatment with immune checkpoint inhibitors (ICI).

Detailed description:
This was a multi-center, open-label, single-arm Phase II study to determine the efficacy, tolerability, safety and quality of life of treatment with pazopanib in subjects with advanced and/or metastatic renal cell carcinoma (RCC) following prior treatment with immune checkpoint inhibitors (ICI).

Subjects could have received prior systemic therapy with an ICI (monotherapy or combination) as 1st or 2nd line RCC treatment. However, they must not have received pazopanib previously. In this study, pazopanib could be administered in the 2nd or 3rd line setting. The therapeutic line for individual subjects was assigned at the time of screening.

Subjects received 800 mg of pazopanib daily until disease progression, unacceptable toxicity, death, pregnancy, start of a new anti-neoplastic therapy, discontinuation at the discretion of the investigator or patient, lost to follow-up or end of study, whichever came first.

Arms:
arm 1: Participants received pazopanib as 2nd line treatment arm 2: Participants received pazopanib as 3rd line treatment

Interventions: intervention 1: Pazopanib
Intervention descriptions: intervention 1: Participants received 800mg of pazopanib once daily orally. Pazopanib was supplied as aqueous film-coated tablets containing 200 mg or 400 mg.

Protocol document:
Prot_000.pdf: 


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
P a g e 9 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
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

SAP_001.pdf: 


N o v arti s
C o nfi d e nti al
P a g e 2
S A P a m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
D o c u m e nt Hi st or y  – C h a n g e s c o m p ar e d t o pr e vi o u s fi n al v er si o n of S A P
D at e
Ti m e 
p oi nt
R e a s o n f or 
u p d at e
O ut c o m e f or u p d at e
S e cti o n a n d titl e 
i m p a ct e d ( C urr e nt)
1 - Se p- 2 0 1 7 
Pri or t o
F P F V 
a n d D B 
l oc k
Creati o n 
of 
i nitial versi o n
N/ A - First versi o n
N A
2 4 -A u g -
2 0 1 8
Pri or 
t o 
D B l oc k
T o 
i m ple me nt 
c ha n ges 
i n 
Pr ot oc ol 
a me n d me nt 1
Secti o n 2. 2 ( Ta ble 2-
3) :  Per pr ot oc ol set 
deifi niti o n 
has 
bee n 
re m o ve d.
Secti o n  
2. 2. 1 
:  
S u b gr o u p of I nterest
has bee d u p date d
Secti o n  
2. 5. 4 
:  
S u p p orti ve 
a nal ys is 
base d o n P P S has bee d 
re m o ve d. F orest pl ot 
als o re m o ve d.
Secti o n  
2. 7. 1 
Sec o n dar y  
en d p oi nts
( S u b-gr o u p 
a nal ys is 
a d de d 
f or O S 
a n d 
O R R)
Secti o n 
2. 8: 
Safet y 
a nal ys is:
( S u b-gr o u p 
a nal ys is a d de d f or A E 
a n d L A B)
Secti o n 
2. 8. 1: A E SI 
listi n g 
ha ve 
bee n 
re m o ve d. 
Secti o n 
2. 8. 3: 
La b  
s hift ta bles a n d o verall 
patie nt listi n gs ha ve 
bee n re m o ve d.


N o v arti s
C o nfi d e nti al
P a g e 3
S A P a m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
D at e
Ti m e 
p oi nt
R e a s o n f or 
u p d at e
O ut c o m e f or u p d at e
S e cti o n a n d titl e 
i m p a ct e d ( C urr e nt)
Secti o n 2. 8. 4: Ot her 
safety 
data: 
O verall 
patie nt listi n gs ha ve 
bee n re m o ve d.
Secti o n 2. 9 : Patie nt 
re p orte d o utc o me ( T he 
E Q - 5 D-5 L  in de x sc ore 
a n d 
patie nt 
listi n gs 
ha ve bee n re m o ve d)
Secti o n 3:  Sa m ple size 
calc ulati o n
Secti o n 5. 3. 1: 
A d de d 
t o defi ne t he M S K C C
a n d I MD C
ris k  ro u p 
i m p utati o n
1 1 -Fe b -
2 0 2 0
Pri or 
t o 
D B l oc k
T o 
ma ke 
c ha n ges 
i n 
s u b gr o u p 
p o p ulati o n c ut-
off 
f or fi nal 
a nal ys is
Secti o n  
2. 2. 1 
:  
S u b gr o u p c ut-off has 
bee d u p date d


N o v arti s
C o nfi d e nti al
P a g e 4
S A P a m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
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 .................................................................................................................4
1
I ntr o d ucti o n .........................................................................................................................8
1. 1
St u d y  desi g n.............................................................................................................8
1. 2
St u d y  o bjecti ves a n d e n d p oi nts ...............................................................................9
2
Statistical met h o ds .............................................................................................................1 1
2. 1
Data a nal y sis ge neral i nf or mati o n .........................................................................1 1
2. 1. 1
Ge neral defi niti o ns ................................................................................1 1
2. 2
A nal y sis sets ..........................................................................................................1 5
2. 2. 1
S u b gr o u p of i nterest ..............................................................................1 5
2. 3
Patie nt dis p ositi o n, de m o gra p hics a n d ot her baseli ne c haracteristics ...................1 6
2. 4
Treat me nts (st u d y treat me nt, resc ue me dicati o n, c o nc o mita nt t hera pies, 
c o m plia nce) ............................................................................................................1 8
2. 4. 1
St u d y  treat me nt / c o m plia nce................................................................1 8
2. 4. 2
Pri or, c o nc o mita nt a n d p ost t hera pies ...................................................1 9
2. 5
A nal y sis of t he pri mar y o bjecti ve..........................................................................2 0
2. 5. 1
Pri mar y  e n d p oi nt...................................................................................2 0
2. 5. 2
Statistical h y p ot hesis, m o del, a n d met h o d of a nal y sis ..........................2 1
2. 5. 3
Ha n dli n g of missi n g val ues/ce ns ori n g/ disc o nti n uati o ns .......................2 1
2. 5. 4
S u p p orti ve a nal y ses...............................................................................2 2
2. 6
A nal y sis of t he ke y sec o n dar y o bjecti ve ...............................................................2 3
2. 7
A nal y sis of sec o n dar y efficac y o bjecti ve(s)..........................................................2 3
2. 7. 1
Sec o n dar y  e n d p oi nts .............................................................................2 3
2. 7. 2
Statistical h y p ot hesis, m o del, a n d met h o d of a nal y sis ..........................2 5
2. 7. 3
Ha n dli n g of missi n g val ues/ce ns ori n g/ disc o nti n uati o ns .......................2 6
2. 8
Safet y  a nalys es .......................................................................................................2 6
2. 8. 1
A d verse e ve nts ( A Es) ............................................................................2 6
2. 8. 2
Deat hs ....................................................................................................2 7
2. 8. 3
La b orat or y  data .....................................................................................2 7
2. 8. 4
Ot her safet y  data ...................................................................................2 8
2. 9
Patie nt- re p orte d o utc o mes .....................................................................................3 0
3 1
2. 1 1
Ot her E x pl orat or y  a nalys es ....................................................................................3 1
2. 1 2
I nteri m a nalys is......................................................................................................3 2
3
Sa m ple size calc ulati o n ................................ .....................................................................3 2


N o v arti s
C o nfi d e nti al
P a g e 5
S A P a m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
3. 1
Pri mar y  a nalys is.....................................................................................................3 2
3. 2
P o wer f or a nal ys is of ke y sec o n dar y varia bles......................................................3 3
4
C ha n ge t o pr ot oc ol s pecifie d a nal ys es ..............................................................................3 3
5
A p pe n di x ...........................................................................................................................3 4
5. 1
I m p utati o n r ules .....................................................................................................3 4
5. 1. 1
St u d y  dr u g.............................................................................................3 4
5. 1. 2
A E, C o n Me ds a n d safet y assess me nt date i m p utati o n ..........................3 5
5. 1. 3
I m p utati o n f or M S K C C ris k gr o u p a n d I M D C ris k gr o u p....................3 6
5. 1. 4
Ot her i m p utati o ns.................................................................................. 3 7
5. 2
A Es c o di n g/ gra di n g ...............................................................................................3 8
5. 3
La b orat or y  para meters deri vati o ns ........................................................................3 8
5. 4
Statistical m o dels ...................................................................................................3 9
5. 4. 1
Pri mar y  a nalys is....................................................................................3 9
6
Refere nce ...........................................................................................................................4 0


N o v arti s
C o nfi d e nti al
P a g e 6
S A P a m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
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 E SI
A d v er s e e v e nt of s p e ci al i nt er e st
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 m i n otr a n sf er a s e
A S T
A s p art at e A mi n otr a n sf er a s e
A T C
A n at o mi c al T h er a p e uti c Cl a s sifi c ati o n
bi d
bi s i n di e m/t wi c e a d a y
B MI 
B o d y M a s s I n d e x
B O R
B e st O v er all R e s p o n s e
C B R
C li ni c al B e n efit R at e
CI
C o nfi d e n c e I nt er v al
C R
C o m pl et e R e s p o n s e
C R O
C o ntr a ct R e s e ar c h Or g a ni z ati o n
C R S
C a s e R etri e v al Str at e g y
C S R
Cli ni c al St u d y r e p ort
C T
C o m p ut e d T o m o gr a p h y 
C T C
C o m m o n T o xi cit y Crit eri a
C T C A E
C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s
C V
C o effi ci e nt of v ari ati o n
D A R
D o s a g e A d mi ni str ati o n R e c or d
D B
D at a b a s e L o c k
D D
Dr u g Di cti o n ar y 
DI
D o s e I nt e n sit y
D O R
D ur ati o n of R e s p o n s e
D R L
Dr u g R ef er e n c e Li sti n g
F A S
F ull A n al y si s S et
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 ym p t o m s
F P F V
Fir st P ati e nt Fir st Vi sit
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 F or m
E O T
E n d of Tr e at m e nt
H R
H e art R at e
I WR
I nt er a cti v e W e b R e s p o n s 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
K P S
K ar n of s k y P erf or m a n c e S t at u s
L L O Q
L o w er Li mit of Q u a ntifi c ati o n
L P F V
L a st P ati e nt Fir st Vi sit
L P L V
L a st P ati e nt L a st Vi sit


N o v arti s
C o nfi d e nti al
P a g e 7
S A P a m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
L V E F
L eft V e ntri c ul ar Ej e cti o n Fr a cti o n
M e d D R A
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s
m R C C
M et a st a si 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 U G A
M ulti g at e d A c q ui siti o n S c a n
N CI
N ati o n al C a n c er I n stit ut e
o. d.
O n c e D ail y
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 o n Di s e a s e
P DI
Pl a n n e d D o s e I nt e n sit y
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
P T
Pr ef er e d T er m
q d
Q u a’ q u e di’ e / o n c e a d a y
Q o L
Q u alit y of Lif e
R A P
R e p ort a n d A n al y si s P r o c e s s
R C C
R e n al C ell C ar ci n o m a
R DI
R el ati v e D o s e I nt e n sit y
R E CI S T
R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s 
S A E
S eri o u s A d v er s e E v e nt
S A P
St ati sti c al A n al y si s Pl a n
S A S
St ati sti c al A n al y si s S y st e m
S D
St a bl e Di s e a s e
S O C
S y st e m Or g a n Cl a s s
T B L
T ot al Bilir u bi n
T F L s
T a bl e s, Fi g ur e s, Li sti n g s
U L O Q
U p p er Li mit of Q u a ntifi c ati o n
U N K
U n k n o w n
W B C
W h it e Bl o o d C ell 
W H O
W o rl d H e alt h Or g a ni z ati o n


N o v arti s
C o nfi d e nti al
P a g e 8
S A P a m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
1
I ntr o d u cti o n
T his statistical a nal ys is pla n ( S A P) descri bes all pla n ne d a nal ys es f or t he cli nical st u d y re p ort(s)
( C S R) of st u d y CP Z P 0 3 4 A 2 4 1 0, a pr os pecti ve i nter nati o nal m ultice nter p hase II st u d y to 
e val uate t he efficac y, safet y an d q ualit y o f life of oral dail y  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 after pre vi o us t hera p y wit h c hec k p oi nt i n hi bit or 
treat me nt.
T he c o nte nt of t his S A P is base d o n pr ot oc ol P Z P 0 3 4 A 2 4 1 0 v 0 1 . All decisi o ns re gar di n g fi nal 
a nal ys is, as defi ne d i n t he S A P d oc u me nt, ha ve bee n ma de pri or t o data base l oc k of t he st u d y 
data.
1. 1
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 dy t o deter mi ne t he efficac y, safet y 
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 ( R C C) 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. A 
t otal of a p pr o xi matel y 1 0 0 patie nts are pla n ne d t o be e nr olle d (wit h a n a p pr o xi matel y 4 0 
patie nts recei ve paz o pa ni b as 2 n d li ne treat me nt.) a n d treate d i n t his st u d y.
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 wh 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).
Pr o gressi o n free s ur vi val ( P F S) as assesse d b y l ocal i n vesti gat or re vie w of t u m or assess me nts 
a n d usi n g R E CI S T v 1. 1 criteria is t he pri mar y e n d p oi nt i n t his st u d y.  
T he pri mar y a nal ys is f or P F S is pla n ne d after all patie nts ha ve recei ve d a mi ni m u m of 6 c ycles 
of st u d y  treat me nt or ha ve disc o nti n ue d st u d y treat me nt early. 
N o f or mal i nteri m a nal ys is is pla n ne d f or t his trial.
T he c ut-off date f or t he pri mar y  anal y sis will be esta blis he d after all patie nts ha ve recei ve d a 
mi ni m u m of 6 c ycles of st u d y treat 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 nalys is data will be s u mmarize d i n t he pri mar y  cli nical st u d y re p ort ( C S R).


N o v arti s
C o nfi d e nti al
P a g e 9
S A P a m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
Fi g ur e 1- 1
St u d y  d e si g n
1. 2
St u d y 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 1- 1 bel o w.


N o v arti s
C o nfi d e nti al
P a g e 1 0
S A P a m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
T a bl e 1- 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
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
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 m i 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
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 ory 
t o xi citi e s p er N CI-C T C A E v 4. 0 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 s.


N o v arti s
C o nfi d e nti al
P a g e 1 1
S A P A m e n d m e nt 1. 0
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
2
St ati sti c al m et h o d s
2. 1
D at a a n al y si s g e n er al i nf or m ati o n
T he pri mar y  an d fi nal a nal yses will be perf or me d b y  No vartis a n d/ or a desi g nate d C R O . S A S 
versi o n 9. 4 or later s oft ware will be us e d t o perf or m all data a nal yses a n d t o ge nerate ta bles, 
fi g ures a n d listi n gs.
D at a i n cl u d e d i n t h e a n al y si s
T he c ut-off date f or the pri mar y  anal ys is of st u d y data will be esta blis he d after all e nr olle d 
patie nts ha ve c o m plete d 6 c ycles of treat me nt or ha ve disc o nti n ue d st u d y. T he fi nal a nal ys is 
c ut-off date will be esta blis he d 2 years after t he last patie nt has starte d treat me nt. A ll statistical 
a nal y s es will be perf or me d usi n g all data c ollected i n t he data base u p t o t he data c ut -off date.
All data wit h a n assess me nt date or e ve nt start date (e. g. vital si g n assess me nt date or start date
of a n a d verse e ve nt) pri or t o or o n t he c ut-off date will b e i ncl u de d i n t he a nal ysis. A n y data
c ollecte d b e y o n d t he c ut-off date will n ot be i ncl u de d i n t he a nal ysis a n d will n ot be use d f or 
a n y deri vati o ns.
All e ve nts wit h start date bef ore or o n t he c ut -off date a n d e n d date after t he c ut -off date will be 
re p orte d as ‘o n g oi n g ’. T he sa me r ule will be a p plie d t o e ve nts starti n g bef ore or o n t he c ut-off 
date a n d n ot ha vi n g d oc u me nte d e n d date. T his a p pr oac h a p plies, i n partic ular, t o a d verse e ve nt 
a n d c o nc o mita nt me dicati o n re p orts. F or t hese e ve nts, t he e n d date will n ot be i m p ute d a n d 
t heref ore will n ot a p pear i n t he listi n gs.
G e n er al a n al y si s c o n v e nti o n s
P o oli n g of ce nters: U nless s pecifie d ot her wise, data fr o m all st u d y ce nters will be p o ole d f or 
t he a nalys is. D ue t o e x pecte d s mall n u m ber of patie nts e nr olle d at
ce nters, n o ce nter effect 
will be assesse d. 
Q u alit ati ve d at a (e. g., ge n der, race, etc.) will be s u m marize d b y  mea ns of c o nti n ge nc y 
ta bles; a missi n g cate g or y will be i ncl u de d as a p plica ble. Perce nta ges will be
calc ulate d usi n g t he n u m ber of patie nts i n t he rele va nt p o p ulati o n or s u b gr o u p as t he
de n o mi nat or.
Q u a ntit ati ve d at a (e. g., a ge, b o dy wei g ht, etc.) will be s u m marize d b y a p pr o priate
descri pti ve statistics (i.e. 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 a n d i n 
a d diti o n w he n s pecifie d 2 5 t h a n d 7 5 t h perce ntiles ).
2. 1. 1
G e n er al d efi niti o n s
I n v e sti g ati o n al dr u g a n d st u d y  tr e at m e nt
I nvesti g ati o n al dr u g , st u dy tre at me nt a n d st u dy dr u g will refer t o t he paz o pa ni b o nl y . 
S t u dy tre at me nt will be use d t hr o u g h o ut t his d oc u me nt.


N o v arti s
C o nfi d e nti al
P a g e 1 2
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
D at e of fir st a d mi ni str ati o n of st u d y  tr e at m e nt
T he date of first a d mi nistrati o n of st u d y treat me nt is defi ne d as t he first date w he n a n o n- zer o 
d ose of st u d y treat me nt is a d mi nistere d a n d rec or de d o n t he D osa ge A d mi nistrati o n Rec or d 
( D A R) eC R F . The date of first a d mi nistrati o n of st u d y treat me nt will als o be referre d as st art 
of st u dy tre at me nt.
D at e of l a st a d mi ni str ati o n of st u d y  tr e at m e nt
T he date of last a d mi nistrati o n of st u d y treat me nt is defi ne d as t he last date w he n a n o n- zer o 
d ose o f st u d y treat me nt is a d mi nistere d a n d rec or de d o n D A R e C R F. T he date of last
a d mi nistrati o n of st u d y treat me nt will als o be referre d t o as e n d of st u d y treat me nt.
St u d y d a y
T he st u d y da y, descri bes t he da y of t he e ve nt or assess me nt date, relati ve t o t he refere nce start 
date. 
T he st u d y  d a y is defi ne d as:

T he date of t he e ve nt ( visit date, o nset date of a n e ve nt, assess me nt date etc.) − 
refere nce start date + 1 if e ve nt is o n or after t he refere nce start date;

T he date of t he e ve nt ( visit date, o nset date of a n e ve nt, assess me nt date etc.) − 
refere nce start date if e ve nt prece des t he refere nce start date.
T he refere nce date f or all ass ess me nts (safet y, efficac y, Q o L/ P R O , etc.) is t he start of st u dy 
treat me nt. 
T he st u d y da y will be dis pla ye d i n t he data listi n gs. If a n e ve nt starts bef ore t he refere nce start 
date, t he st u dy d a y dis pla y e d o n t he listi n g will be ne gati ve.
Ti m e u nit
A year le n gt h is defi ne d as 3 6 5. 2 5 d a y s. A m o nt h le n gt h is 3 0. 4 3 7 5 d a y s ( 3 6 5. 2 5/ 1 2). If d urati o n 
is re p orted i n m o nt hs, d urati o n i n d a y s will be di vi de d b y 3 0. 4 3 7 5.  If d urati o n is re p orte d i n 
ye ars, d urati o n i n da ys will be di vi de d b y 3 6 5. 2 5.
T he c y cle le n gt h is 2 8 da ys fr o m da y 1 t o da y 2 8.
B a s eli n e
F or safety a n d efficac y eval uati o ns, t he last a vaila ble assess me nt o n or bef ore t he date of start 
of st u d y  treat me nt is defi ne d as “ baseli ne” assess me nt.
If patie nts ha ve n o val ue as defi ne d a b o ve, t he baseli ne res ult will be missi n g.
O n -tr e at m e nt a s s e s s m e nt/ e v e nt a n d o b s er v ati o n p eri o d s
F or a d verse e ve nt re p orti n g the 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 -tre at 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 d a y  bef ore first 
a d mi nistrati o n of st u d y treat me nt


N o v arti s
C o nfi d e nti al
P a g e 1 3
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
2.
o n- tre at me nt peri o d : fr om date of first a d mi nistrati o n of st u d y treat me nt t o 3 0 da y s after 
date of last act ual a d mi nistrati o n of a n y st u d y treat me nt (i ncl u di n g start a n d st o p date)
3.
p ost -tre at me nt peri o d: starti n g at da y 3 0+ 1 after last a d mi nistrati o n of st u d y treat me nt.
S afet y su m maries (ta bles, fi g ures) i ncl u de o nl y data fr o m t he o n- treat me nt peri o d wit h t he 
e xce pti o n of baseli ne data w hic h will als o be s u m marize d w here a p pr o priate (e. g. c ha n ge fr o m 
baseli ne s u m maries). I n a d diti o n, a se parate s u m mar y for deat h i ncl u di n g o n- treat me nt a n d 
p ost -treat me nt deat hs will be pr o vi de d. I n partic ular, su m mar y  ta bles f or a d verse e ve nts ( A Es)
will s u m marize o nl y  on -treat me nt e ve nts, wit h a start date d uri n g t he o n- treat me nt peri o d 
(tre at me nt-e m er ge nt A Es ).  
H o we ver, all safety data (i ncl u di n g t h ose fr o m t he p ost -treat me nt peri o d) 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.
Wi n d o w s f or m ulti pl e a s s e s s m e nt s
of P R O
I n or der t o s u m marize P R O meas ures a n d perf or ma nce stat us ( P S) c ollecte d o ver ti me 
(i ncl u di n g u nsc he d ule d visits), t he assess me nts will be ti me sl otte d. T he f oll o wi n g ge neral r ule 
will be a p plie d i n creati n g t he assess me nt wi n d o ws: If m ore t ha n o ne assess me nt is d o ne wit hi n
t he sa me ti me wi n d o w, t he assess me nt perf or me d cl osest t o t he tar get date will be use d. If t w o
assess me nts wit hi n a ti me wi n d o w are e q ui dista nt fr o m t he tar get date, t he n t he w orst of t he 
t w o assess me n ts will be use d. If m ulti ple assess me nts o n t he sa me date t he n t he w orst case will 
be use d. Data o btai ne d at t he e n d of treat me nt will be classifie d as ot her assess me nt i n t he 
c orres p o n di n g ti me wi n d o w.
Data fr o m all assess me nts (sc he d ule d a n d u nsc he d ule d), i ncl u di n g 
m ulti ple assess me nts, will be liste d.
N ote t hat o nl y  data c ollecte d u n der treat me nt (i.e. w hile t he patie nt is treate d) will be i ncl u de d
i n t he ti me t o defi niti ve deteri orati o n. T he e n d of treat me nt assess me nt will be i ncl u de d if 
c ollecte d wit hi n 3 0 d a y s of t he last d ose i nta ke.  
T a bl e 2 - 1
Ti m e w i n d o w s f or E Q -5 D -5 L, K P S a n d F K SI -D R S a s s e s s m e nt s 
A s s e s s m e nt
T ar g et d a y of
T i m e I nt er v al
B a s eli n e
        
≤ D a y 1 
        C y cl e 2 D a y  1
2 9
D a y 2 t o d a y 4 2
C y cl e 3 D a y 1
5 7
D a y 4 3 t o d a y 7 0
C y cl e 4 D a y 1
8 5
D a y 7 1 t o d a y 9 8
C y cl e 5 D a y  1
1 1 3
D a y 9 9 t o d a y 1 2 6
C y cl e 6 D a y 1
1 4 1
D a y 1 2 7 t o d a y 1 5 4
C y cl e 7 D a y 1
1 6 9
D a y 1 5 5 t o d a y 1 9 6
C y cl e 9 D a y 1
2 2 5
D a y 1 9 7 t o d a y 2 5 2
C y cl e 1 1 D a y 1
2 8 1
D a y 2 5 3 t o d a y 3 0 8
C y cl e 1 3 D a y 1
3 3 7
D a y 3 0 9 t o d a y 3 7 8
C y cl e 1 6 D a y 1
4 2 1
D a y 3 7 9 t o d a y 4 6 2


N o v arti s
C o nfi d e nti al
P a g e 1 4
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
E v er y 3 r d c y cl e u ntil 
E O T 
C y cl e k D a y 1 ( k ≥1 9 )
d =( k -1)* 2 8 + 1
D a y d -4 2 t o d a y d +4 1
E n d of Tr e at m e nt
A s s e s s m e nt t a k e n at t h e e n d of 
tr e at m e nt vi sit
N ot e: E O T d at a vi sit ar e i n cl u d e d 
if o bt ai n e d wit hi n 3 0 d a y s of l a st 
n o n -0 d o s e i nt a k e.
St u d y D a y 1 = st art d at e of st u d y tr e at m e nt
P o st tr e at m e nt st u d y d a y 1 = e n d of tr e at m e nt d at e + 1 d a y
3 0 d a y s i s c o n si d er e d t o b e t h e ti m e u ntil t ot al dr u g eli mi n ati o n
L a st c o nt a ct d at e 
T he last c o ntact date will be deri ve d f or patie nts n ot k n o w n t o ha ve die d at t he a n al ys is c ut-off 
usi n g t he last c o m plete date a m o n g t he f oll o wi n g:
T a bl e 2- 1
L a st c o nt a ct d at e d at a s o ur c e s
S o ur c e d at a
C o n diti o n s
St art d at e of st u d y tr e at m e nt
N o c o n diti o n
L a st c o nt a c t d at e/l a st d at e p ati e nt w a s k n o w n t o 
b e ali v e fr o m ‘S ur vi v al I nf or m ati o n’ p a g e 
P ati e nt st at u s i s r e p ort e d t o b e ali v e.
St art/ E n d d at e s fr o m f urt h er a nti n e o pl a sti c 
t h er a p y
N o n -mi s si n g m e di c ati o n/ pr o c e d ur e t er m.
St art/ E n d d at e s fr o m dr u g a d mi ni str ati o n r e c or d 
N o n -mi s si n g d o s e. D o s e s of 0 ar e all o w e d.
E n d of tr e at m e nt d at e fr o m e n d of tr e at m e nt p a g e
N o c o n diti o n.
T u m o r ( R E CI S T) a s s e s s m e nt d at e
E v al u ati o n i s m ar k e d a s ‘ d o n e’.
L a b or at or y c oll e cti o n d at e s
S a m pl e c oll e cti o n m ar k e d a s ‘ d o n e’. 
Vit al si g n s d a t e
At l e a st o n e n o n -mi s si n g p ar a m et er v al u e
P erf or m a n c e St at u s d at e
N o n -mi s si n g p erf or m a n c e st at u s
St art/ E n d d at e s of A E 
N o n -mi s si n g v er b ati m t er m
T he last c o ntact date is defi ne d as t he latest c o m plete date fr o m t he a b o ve list o n or bef ore t he 
data c ut-off date . T he c ut-off date will n ot be use d f or last c o ntact date, u nless t he patie nt was 
see n or c o ntacte d o n t hat dat e. N o d at e p ost c ut -off d at e will b e us e d. C o m pl et el y  i m p ute d
dates (e. g. t he a nal y sis c ut-of f dat e pr o gra m maticall y i m p ute d t o re place t he missi n g e n d date
of a d ose a d mi nistrati o n rec or d) will n ot b e use d t o deri ve t he last c o ntact dat e. Partial date 
i m p utati o n is all o we d o nl y  f or e ve nt ( deat h)/ce ns ori n g if c o mi n g fr o m ‘ S ur vi val i nf or mati o n’ 
e C R F. 
T he last c o ntact date will be use d f or ce ns ori n g of patie nts i n t he a nal ys is of o verall s ur vi val.




N o v arti s
C o nfi d e nti al
P a g e 1 6
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0

M S K C C ris k gr o u ps : p o or (≥ 2 ris k fact ors), i nter me diate ( 1ris k fact ors), fa v ora ble 
( 0 ris k fact or)

I M D C ris k gr o u ps: p oor ( > 2 ris k fact ors), i nter me diate ( 1 -2 ris k fact ors), fa v ora ble 
( 0 ris k fact or)

Li ne of t hera p y ( 2n d / 3r d ):
o
Sec o n d -Li ne t hera p y:  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 start of t he st u d y  treat me nt
o
T hir 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 pies bef ore start of t he st u d y treat me nt 
N o f or mal statistical test of h y p ot heses will be perf or me d f or t he su b gr o u ps, o nl y  poi nt esti mate 
of t he treat me nt effect a n d 9 5 % c o nfi de nce i nter vals will be pr o vi de d (see Secti o ns 2. 5 . 4 a n d 
2. 7 .1 f or f urt her a nalys is details). T he o bjecti ve of t he efficac y s u b gr o u p a nal ysis is t o e val uate 
h o m o ge neit y  of treat me nt effect i n t he a b o ve s u b gr o u ps. 
S u m mar y  ta bles will o nl y be perf or me d if at least 2 0 % of patie nts are prese nt i n eac h s u b gr o up. 
S o me gr o u pi n g of classes ma y be c o nsi dere d f or s o me s u bgr o u ps (e. g. t hera p y  ty p e).
2. 3
P ati e nt di s p o siti o n, 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 ull A nal ys is Set ( F A S) will be use d f or all baseli ne a n d de m o gra p hic s u m maries a n d 
listi n gs u nless ot her wise s pecifie d . 
B a si c d e m o gr a p hi c a n d b a c k gr o u n d d at a
All de m o gra p hic a n d baseli ne disease c haracteristics data will be s u m marize d a n d liste d.
Cate g orical data (e. g. ge n der, a ge gr o u ps: < 6 5 a n d ≥6 5 ye ars, race, et h nicit y, Kar n ofs k y 
perf or ma nce stat us, M S K C C, I M D C ris k gr o u p 
etc.) will be s um marize d b y  fre q ue nc y c o u nts 
a n d perce nta ges ; t he n u m ber a n d perce nta ge of patie nts wit h missi n g data will be pr o vi de d.
C o nti n u o us data (e. g. a ge, wei g ht, hei g ht, b o d y  mass i n de x etc.) will be s u m marize d b y  
descri pti ve statistics ( N, mea n, me dia n, sta n dar d de viati o n, mi ni m u m a n d ma xi m u m , 2 5t h a n d 
7 5t h perce ntiles ). B M I ( k g/ m 2) will be calc ulate d as wei g ht[ k g] / ( hei g ht[ m] 2) usi n g wei g ht at 
Baseli ne.  
B a s eli n e str atifi c ati o n f a ct or s
N ot a p plica ble.
Di a g n o si s a n d e xt e nt of c a n c er 
S u m mar y  statistics will
be ta b ulate d f or dia g n osis a n d e xte nt of ca ncer. T his a nal ysis will 
i ncl u de t he f oll o wi n g: details of t u m or hist ol o g y / c yt ol o g y, hist ol o gical gra de, sta ge at i nitial 
dia g n osis, ti me si nce i nitial dia g n osis , sta ge at ti me of st u d y entr y , prese nce/a bse nce of tar get 


N o v arti s
C o nfi d e nti al
P a g e 1 7
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
a n d n o n -tar get lesi o ns, metastatic sites i n v ol ve d.  N ote: Prese nce/a bse nce of tar get a n d n o n-
tar get lesi o ns will be base d o n t he data c ollecte d o n R E CI S T tar get/ n o n-tar get lesi o n assess me nt 
e C R F pa ges. Pr ese nce/a bse nce of m etastatic sites will be base d o n dia g n osis pa ge.
M e di c al hi st or y
Me dical hist or y  an d o n g oi n g c o n diti o ns, i ncl u di n g ca ncer-relate d c o n diti o ns a n d s ym pt o ms 
e ntere d o n (e) C R F will be s u m marize d a n d liste d. Se parate s u m maries will be prese n te d f or 
o n g oi n g a n d hist orical me dical c o n diti o ns.  The s u m maries will be prese nte d b y  pri mar y sys te m 
or ga n class ( S O C) a n d preferre d ter m ( P T). Me dical hist or y  an d c urre nt me dical c o n diti o ns 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. T he 
Me d D R A versi o n use d f or re p orti n g will be s pecifie d i n t he C S R a n d as a f o ot n ote i n t he 
a p plica ble ta bles/listi n gs.
Ot h er
Ot her data c ollecte d at baseli ne i ncl u di n g c hil d beari n g p ote ntial will be liste d.
P ati e nt di s p o siti o n
T he n u m ber ( %) of treate d patie nt s i ncl u de d i n t he F A S will be prese nte d. T he n u m ber ( %) of 
patie nt s i n t he F A S w h o are still o n treat me nt, w h o disc o nti n ue d t he st u d y phases a n d t he reas o n 
f or disc o nti n uati o n will be prese nte d.
T he f oll o wi n g s u m maries will be pr o vi de d ( wit h % base d o n t he t otal n u m ber of F A S patie nt s):

N u m ber ( %) of patie nt s w h o are still o n-treat me nt (base d o n t he ‘ E n d of Treat me nt 
P hase Dis p ositi o n ’ pa ge n ot c o m plete d); 

N u m ber ( %) of patie nt s w h o disc o nti n ue d t he st u d y treat me nt p hase ( base d o n t he 
‘ E n d of Treat me nt P hase Dis p ositi o n ’ pa ge) 

Pri mar y  reas o n f or st u d y treat me nt p hase disc o nti n uati o n ( base d o n t he ‘ E n d of 
Treat me nt P hase Dis p ositi o n ’ pa ge)

N u m ber ( %) of patie nt s w h o ha ve e ntere d t he p ost -treat me nt f oll o w- u p ( base d o n 
t he ‘E n d of Treat me nt P hase Dis p ositi o n ’ pa ge);

N u m ber ( %) of patie nt s w h o ha ve disc o nti n ue d fr o m t he p ost -treat me nt f oll o w- u p
( base d o n t he ‘E n d of P ost -treat me nt p hase dis p ositi o n’ pa ge);

Reas o ns f or disc o nti n uati o n fr o m t he p ost- treat me nt f oll o w- u p ( base d o n ‘E n d of 
P ost -treat me nt p hase dis p ositi o n ’ pa ge) ;

N u m ber ( %) of patie nt s w h o ha ve e ntere d t he s ur vi val f oll o w- u p ( base d o n t he 
‘E n d of P ost-treat me nt p hase dis p ositi o n’ pa ge a n d ‘ E n d of Treat me nt P hase 
Dis p ositi o n’ pa ge ).
Pr ot o c ol d e vi ati o n s
T he n u m ber ( %) of patie nts i n t he F A S wit h a n y pr ot oc ol de viati o n will be ta b ulate d b y  
de viati o n cate g or y (as s pecifie d i n t he st u d y St u d y  Specificati o n D oc u me nt ). All pr ot oc ol 
de viati o ns will be liste d.


N o v arti s
C o nfi d e nti al
P a g e 1 8
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
A n al y si s s et s
T he n u m ber ( %) of patie nts i n eac h a nal ys is set ( defi ne d i n Secti o n 2. 2 ) will be s u m marize d.
2. 4
Tr e at m e nt s ( st u d y  tr e at m e nt, r e s c u e m e di c ati o n, c o n c o mit a nt 
t h er a pi e s, c o m pli a n c e)
2. 4. 1
St u d y tr e at m e nt / c o m pli a n c e
D urati o n of e x p os ure t o paz o pa ni b (e x presse d i n m o nt hs) , act ual c u m ulati ve d ose, d ose 
i nte nsit y ( DI) a n d relati ve d ose i nte nsit y ( R DI) will be s u m marize d . D urati o n of e x p os ure will 
be cate g orize d i nt o ti me i nter vals; fre q ue nc y co u nts a n d perce nta ges will be prese nte d f or t he 
n u m ber ( %) of patie nt s i n eac h i nter val. T he n u m ber ( %) of patie nts w h o ha ve d ose re d ucti o ns
or i nterr u pti o ns, a n d t he reas o ns, will be s u m marize d. 
Patie nt le vel listi n gs of all d oses a d mi nistere d o n treat me nt al o n g wit h d ose c ha n ge reas o ns will 
be pr o d uce d.  
T he safet y set will be use d f or all s u m maries a n d listi n gs of st u d y treat me nt. 
D ur ati o n of e x p o s ur e t o st u d y  tr e at m e nt
D urati o n of e x p os ure t o st u d y treat me nt is c o nsi dere d b y  ta ki n g i nt o acc o u nt t he d urati o n of 
e x p os ure t o paz o pa ni b:
D urati o n of e x p os ure t o paz o pa ni b ( m o nt hs ) =((last date of e x p os ure t o paz o pa ni b ) – ( date of 
first a d mi nistrati o n of paz o pa ni b ) + 1) / ( 3 6 5. 2 5/ 1 2).
T he last date of e x p os ure t o paz o pa ni b is t he latest of t he last dates of e x p os ure t o paz o pa ni b 
(see secti o n 2. 1. 1.)
S u m mar y  of d urati o n of e x p os ure of paz o pa ni b i n a p pr o priate ti me u nits will i ncl u de cate g orical 
s u m maries ( <3 m o nt hs, 3- < 6 m o nt hs, 6- < 1 2 m o nt hs , 1 2- < 1 8 m o nt hs, ≥1 8 m o nt hs ) a n d 
c o nti n u o us s u m maries (i.e. mea n, sta n dar d de viati o n etc.) usi n g a p pr o priate u nits of ti me.
C u m ul ati v e d o s e
C u m ulati ve d ose of a st u d y treat me nt is defi ne d as t he t otal d ose gi ve n d uri n g t he st u d y 
treat me nt e x p os ure a n d will be s u m marize d .
T he pl a n ne d c u m ul ati ve d ose f or a st u d y treat me nt refers t o t he t otal pla n ne d d ose as per t he 
pr ot oc ol u p t o t he last date of st u d y treat me nt a d mi nistrati o n. 
T he act u al c u m ul ati ve d ose refers t o t he t otal act ual d ose a d mi nistere d, o ver t he d urati o n f or 
w hic h t he patie nt is o n t he st u d y treat me nt as d oc u me nte d i n t he D ose A d mi nistrati o n e C R F.
F or patie nts w h o di d n ot ta ke a n y dr u g t he c u m ulati ve d ose is b y  defi niti o n e q ual t o zer o.
F or c o nti n u o us d osi n g, t he act ual c u m ulati ve d ose is t he s u m of t he n o n-z er o d oses rec or de d 
o ver t he d osi n g peri o d a n d t he pla n ne d c u m ulati ve d ose is t he pla n ne d starti n g d ose s u m me d 
o ver t he sa me d osi n g peri o d.


N o v arti s
C o nfi d e nti al
P a g e 1 9
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
D o s e i nt e n sit y  a n d r el ati v e d o s e i nt e n sit y
D ose i nte nsit y ( DI) f or patie nts wit h n o n-zer o d urati o n of e x p os ure is defi ne d as f oll o ws: 
DI  (m g /d a y ) = Act ual C u m ulati ve d ose ( m g ) / D urati o n of e x p os ure t o st u d y treat me nt (d a y ).
F or patie nts w h o di d n ot ta ke a n y dr u g t he DI is b y defi niti o n e q ual t o zer o . 
Pla n ne d d ose i nte nsit y  ( PDI ) is defi ne d as f oll o ws:
P DI  (m g /d a y ) = Pla n ne d C u m ulati ve d ose ( m g ) / D urati o n of e x p os ure (d a y ).
Rel ati ve d ose i nte nsit y ( R DI) is defi ne d as f oll o ws:
R DI  = DI (m g /d a y )  / P DI (m g/ da y ).  
DI  an d R DI will be s u m marize d. R DI will als o be s u m marize d b y  the f oll o wi n g cate g ories: 
≤7 5 %, > 7 5 -9 0 %, > 9 0 -1 1 0 % a n d > 1 1 0 %.
D o s e r e d u cti o n s, i nt err u pti o n s or p er m a n e nt di s c o nti n u ati o n s
T he n u m ber of patie nt s w h o ha ve d ose re d ucti o ns or i nterr u pti o ns, a n d t he reas o ns, will be 
s u m marize d. 
‘ D ose i nterr u pte d’ a n d ‘ D ose c ha n ge d’ fiel ds fr o m t he D osa ge A d mi nistra ti o n C R F pa ges
( D A R) will be use d t o deter mi ne t he d ose re d ucti o ns a n d d ose i nterr u pti o ns .
T he c orres p o n di n g fiel ds ‘ Reas o n f o r d ose c ha n ge/ d ose i nterr u pte d’ will be use d t o s u m marize 
t he reas o ns.
F or t he p ur p ose of s u m marizi n g i nterr u pti o ns a n d reas o ns, i n case m ulti ple e ntries f or 
i nterr u pti o n t hat are e ntere d o n c o nsec uti ve da ys wit h differe nt reas o ns will be c o u nte d as 
se parate i nterr u pti o ns. H o we ver, if t he reas o n is t he sa me i n t his me nti o ne d m ulti ple e ntries o n 
c o nsec uti ve da ys, t he n it will be c o u nte d as o ne i nterr u pti o n. 
Re d ucti o n : A d ose c ha n ge w here t he prescri be d d ose le vel is l o wer t ha n t he pre vi o us prescri be d 
d ose le vel. T heref ore a n y dose c ha n ge t o c orrect a d osi n g err or will n ot be c o nsi dere d a d ose 
re d ucti o n.  O nl y d o se c ha n ge is c ollecte d i n t he C R F, n u m ber of re d ucti o ns will be deri ve d 
pr o gra m maticall y  base d o n t he c ha n ge a n d t he  directi o n of t he c ha n ge.
Missi n g data: If d ose is rec or de d b ut re gi me n is missi n g or e ntere d as ‘ n o ne’, it is ass u me d t hat 
t he st u d y treat me nt was ta ke n as per-pr ot oc ol.
2. 4. 2
Pri or , c o n c o mit a nt a n d p o st t h er a pi e s
Pri or a nti -c a n c er t h er ap y
T he n u m ber a n d perce nta ge of patie nts w h o recei ve d a n y pri or a nti-ne o plastic me dicati o ns, 
pri or a nti-ne o plastic ra di ot hera py or pri or a nti-ne o plastic s ur ger y will be s u m marize d. Pri or 
a nti-ne o plastic me dicati o ns will be s u m marize d b y l o west A T C class a n d preferre d ter m. 
S e parat e listi n gs will be pr o d uce d f or pri or a nti-ne o plastic me dicati o ns a n d s ur ger y . 
A nti- ne o plastic me dicati o ns will be c o de d usi n g t he W H O Dr u g Dicti o nar y  ( W H O-D D); a nti-
ne o plastic s ur ger y will be c o de d usi n g Me d D R A. Details re gar di n g Me d D R A a n d W H O-D D 
versi o n will be i ncl u de d i n t he f o ot n ote i n t he ta bles/listi n gs. 


N o v arti s
C o nfi d e nti al
P a g e 2 0
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
T he a b o ve a nal ys es will be perf or me d usi n g t he F ull A nal y sis Set.
P o st tr e at m e nt a nti -c a n c er t h er a p y
A nti- ne o plastic t hera pies si nce disc o nti n uati o n of st u d y treat me nt will be liste d a n d s u m marize d 
b y  A T C class a n d preferre d ter m b y  mea ns of fre q ue nc y c o u nts a n d perce nta ges usi n g t he F ull 
A nal y sis Set.
C o n c o mit a nt m e di c ati o n s
C o nc o mita nt t hera p y is defi ne d as all i nter ve nti o ns (t hera pe utic treat me nts a n d pr oce d ures) 
ot her t ha n t he st u d y treat me nt a d mi nistere d t o a patie nt c oi nci di n g wit h t he st u d y treat me nt 
peri o d. C o nc o mita nt t hera p y incl u de m e dicati o ns ( ot her t ha n st u d y dr u gs) starti n g o n or after 
t he start date of st u dy t reat me nt or me dicati o ns starti n g pri or t o t he start date of st u d y t reat me nt 
a n d c o nti n ui n g after t he start date of st u d y treat me nt. 
C o nc o mita nt me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n (W H O) Dr u g 
Ref ere nce  Listi n g  (D R L ) dicti o nar y   that  em pl o y s t he W H O 
A nat o mical T hera pe utic 
C he mical ( A T C) classificati o n s yste m a n d s u m marize d b y  l o west A T C class a n d preferre d ter m
usi n g fre q ue nc y co u nts a n d perce nta ges . S ur gical a n d me dical pr oce d ures will be c o de d usi n g 
Me d D R A a n d s u m marize d b y  S O C a n d preferre d ter m. T hese s u m maries will i ncl u d e:
1.
Me dicati o ns starti n g o n or after t he start of st u d y treat me nt b ut n o later t ha n 3 0 da y s 
after start of last d ose of st u d y  treat me nt a n d
2.
Me dicati o ns starti n g pri or t o start of st u d y  treat me nt a n d c o nti n ui n g after t he start of 
st u d y treat me nt.
All c o nc o mita nt t hera pies will be liste d. A n y co nc o mita nt t hera pies starti n g a n d e n di n g pri or 
t o t he start of st u dy t reat me nt or starti n g m or e t ha n 3 0 da ys after t he last date of st u d y treat me nt 
will be fla g ge d i n t he listi n g. T he safet y s et will be use d f or all c o nc o mita nt me dicati o n ta bles 
a n d listi n gs.
2. 5
A n al y si s of t h e pri m ar y  o bj e cti v e
T he pri mar y  objecti 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  
pr o gressi o n -free s ur vi val ( P F S) i n patie nts wit h l ocall y rec urre nt or 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 py wit h i m m u ne c hec k p oi nt i n hi bit or 
treat me nt.
2. 5. 1
Pri m ar y  e n d p oi nt
T he pri mar y  en d p oi nt of t he st u dy is P F S, defi ne d as t he ti me fr o m t he date of start of st u d y 
treat me nt 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 a n y ca use. F or t h e 
pri mar y  efficac y anal ys is, P F S will be base d o n l ocal i n vesti gat ors re vie w of t u m or assess me nts 
usi n g R E CI S T v 1. 1 criteria (see A p pe n di x 2 of t he st u d y  pr ot oc ol). T he pri mar y  a nalys is will 
be base d o n F A S a n d will i ncl u de all data o bser ve d u p- t o t he c ut-off date. If a patie nt has n ot 
pr o gresse d or die d at t he a nal ys is c ut-off date, 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 e val uati o n date bef ore t he c ut-off date . P F S e ve nts d oc u me nte d after t he 
i nitiati o n of ne w a nti -ne o plastic t hera py (i.e. R E CI S T v 1. 1. d oc u me nte d disease pr o gressi o n or 


N o v arti s
C o nfi d e nti al
P a g e 2 1
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
deat h) will be c o nsi dere d f or t he pri mar y  anal ys is pr o vi de d t u m or assess me nts c o nti n ue after 
i nitiati o n of ne w ca ncer t hera py ( See Secti o n 2. 5. 3 f or a d diti o nal details re gar di n g ce ns ori n g 
r ules a n d deter mi nati o n of date of last a de q uate t u m or assess me nt).  Disc o n ti n uati o n d ue t o
disease pr o gressi o n (c ollecte d o n t he ‘ E n d of treat me nt’ a n d ‘E n d of p ost treat me nt f oll o w u p’
dis p ositi o n pa g es) wit h o ut
s u p p orti n g o bjecti ve e vi de nce satisfyi n g pr o gressi o n criteria per
R E C IS T v 1. 1 will n ot be c o nsi dere d disease pr o gressi o n f or P F S deri vati o n. 
2. 5. 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. 
T he s ur vi val distri b uti o n of P F S will be esti mate d usi n g t he Ka pla n -Meier met h o d. T he res ults 
will be pl otte d gra p hicall y . T he me dia n , 2 5t h a n d 7 5 t h perce ntiles of P F S al o n g wit h 9 5 % 
c o nfi de nce i nter vals will be prese nte d . T he s ur vi val pr o ba bilities at e ver y 2 m o nt hs u p t o1 2 
m o nt hs, a n d t he ass ociate d 9 5 % c o nfi de nce i nter vals will be s u m marize d .
T he pri mar y  efficac y a nal ysis will be perf or me d o n t he F A S.
2. 5. 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 a n y ca use) is o bser ve d pri or t o t he a nal ysis 
c ut-off date.
P F S e ve nts d oc u me nte d after t he i nitiati o n of ne w a nti-ne o plastic t hera py (i.e. R E CI S T v 1. 1. 
d oc u me nte d disease pr o gressi o n or deat h) will be c o nsi dere d f or t he pri mar y a nal ys is pr o vi de d 
t u m or assess ments c o nti n ue after i nitiati o n of ne w ca ncer t hera p y .
T he date of last a de q uate t u m or assess me nt is t he date of 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 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 will be 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 urre d) t he n t he date of start date of 
treat me nt will be use d .
I n partic ular, P F S will be ce ns ore d at t he last a de q uate t u m or assess me nt if o ne of t he f oll o wi n g 
occ urs: a bse nce of e ve nt ; t he e ve nt occ urre d after t w o or m ore missi n g t u m or assess me nts. T he 
ter m “ missi n g a de q uate t u m or assess me nt” is defi ne d as a t u m or assess me nt ( T A) n ot 
perf or me d or t u m or assess me nt wit h o verall lesi o n res p o nse of “ U N K”. T he r ule t o deter mi ne 
n u m ber of missi n g T As is base d o n t he ti me i nter val bet wee n t he date of last a de q uate t u m or 
assess me nt a n d t he date of a n e ve nt. If t he i nter val is greater t ha n t wice t he pr ot oc ol-s pecifie d
i nter val bet wee n t he T As a n d 2 ti mes t he pr ot oc ol -all o we d ti me wi n d o w ar o u n d assess me nts, 
t he n t he n u m ber of missi n g assess me nts will be 2 or m ore .
Refer t o Ta ble 2 - 4 f or ce ns ori n g a n d e ve nt date o pti o ns a n d o utc o mes f or P F S.
T a bl e 2- 4
O ut c o m e a n d e v e nt/ c e n s or d at e s f or P F S a n al y si s
Sit uati o n
Date
O utc o me
N o b a s eli n e a s s e s s m e nt
D at e of st art of st u d y tr e at m e nt
C e n s or e d
Pr o gr e s si o n or d e at h 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
D at e of pr o gr e s si o n ( or d e at h)
Pr o gr e s s e d


N o v arti s
C o nfi d e nti al
P a g e 2 2
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
Sit uati o n
Date
O utc o me
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
D at e of pr o gr e s si o n ( or d e at h)
Pr o gr e s s e d
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
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 mi s s e d a s s e s s m e nt 
C e n s or e d
N o pr o gr e s si o n ( or d e at h)
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
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
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
N e w a nti c a n c er t h er a p y gi v e n pri or t o 
pr ot o c ol d efi n e d pr o gr e s si o n 
I g n or e t h e n e w a nti c a n c er t h er a p y 
a n d f oll o w sit u ati o n s a b o v e 
A s p er a b o v e 
sit u ati o n s
D e at h b ef or e fir st P D a s s e s s m e nt
D at e of d e at h
Pr o gr e s s e d
2. 5. 4
S u p p orti v e a n al y s e s
N A
S u b gr o u p a n al y s e s f or t h e pri m ar y  e n d p oi nt
T he pri mar y  e n d p oi nt of P F S will be s u m marize d f or t he s u b gr o u ps s pecifie d i n Secti o n 2. 2. 1
a n d usi n g t he sa me c o n ve nti o ns as f or t he pri mar y a nal ysis. 
F or eac h of t he s u b gr o u ps, t he f oll o wi n g a nal ys es will be perf or me d usi n g t he F A S :

Ka pla n -Meier esti mates of t he s ur vi val distri b uti o n of P F S
Efficac y  anal ys es i n s u b gr o u ps are i nte n de d t o e x pl ore t he c o nsiste nc y ( h o m o ge neit y) of 
treat me nt effect. N o i nfere ntial statistics ( p-val ues) will be pr o d uce d f or t he s u b gr o u ps .
C e n s ori n g p att er n of P F S
N u m ber of patie nts wit h a P F S e ve nt a n d n u m ber of patie nts ce ns ore d f or t he P F S a nal ysis will 
be s u m marize d. I n a d diti o n, a s u m mar y of reas o ns f or P F S ce ns ori n g will be pr o vi de d base d o n 
t he f oll o wi n g reas o ns:
1 : O n g oi n g wit h o ut e ve nt
2 : L o st t o f oll o w- u p
3 : Wit h dre w c o nse n t
4 : A de q uate assess me nt n o l o n ger a vaila ble
5 : E ve nt after > = 2 missi n g t u m or assess me nts
T he P F S ce ns or i n g reas o ns are defi ne d i n t he f oll o wi n g wa y. 
If t he ti me i nter val bet wee n t he last a de q uate T A date a n d t he earliest of t he f oll o wi n g dates is 
s maller or e q ual t o i nter val of 2 missi n g t u m or assess me nts (see Secti o n 2. 5. 3 f or defi niti o n):
1.
A nal y sis c ut-off date, 
2.
Date of c o nse nt wit h dra wal,
3.
Visit date of st u d y  treat me nt disc o nti n uati o n or e n d of p ost-treat me nt f oll o w- u p 
disc o nti n uati o n d ue t o l ost t o f oll o w - u p.


N o v arti s
C o nfi d e nti al
P a g e 2 3
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
T he n t he P F S ce ns ori n g reas o n will be:
1.
‘ O n g oi n g wit h o ut e ve nt ’, 
2.
‘ Wit h dre w c o nse nt’,
3.
‘ Lost t o f oll o w -u p’,  
If t he ti me i nter val is lar ger t ha n t he i nter val of 2 missi n g t u m or assess me nts wit h n o e ve nt 
o bser ve d t he n t he P F S ce ns ori n g reas o n will al wa ys defa ult t o ‘ A de q uate assess me nt n o l o n ger 
a vaila ble’.  If t he ti me i nter val bet wee n t he last a de q uate t u m or assess me nt date a n d t he P F S 
e ve nt date is lar ger t ha n t he i nter val of 2 missi n g t u m or assess me nts t he n t he patie nt will be 
ce ns ore d a n d t he ce ns ori n g reas o n will be ' E ve nt d oc u me nte d after t w o or m o re missi n g t u m or 
assess me nts'.
T hese s u m maries o n ce ns ori n g reas o ns will be pr o d uc e d. 
2. 6
A n al y si s of t h e k e y  se c o n d ar y  o bj e cti v e
T here is n ot ke y sec o n dar y  o bjecti ve i n t his si n gle ar m st u d y.
2. 7
A n al y si s of s e c o n d ar y  effi c a c y  o bj e cti v e ( s)
T he ot her sec on dar y  efficac y o bjecti ves are t o:

E val uate paz o pa ni b effect o n o verall s ur vi val ( O S )

E val uate paz o pa ni b effect wit h res pect t o o verall res p o nse rate ( O R R) a n d cli nical 
be nefit rate ( C B R) 

Descri be t he d urati o n of res p o nse ( D O R) i n t he s u bset of patie nts wit h c o nfir me d 
C R / P R

E val uate paz o pa ni b effect wit h res pect t o P R O assess me nts b y  EQ- 5 D- 5 L a n d 
F K SI -D R S q uesti o n naires.
2. 7. 1
S e c o n d ar y  e n d p oi nt s
O v er all S ur vi v al ( O S)
O verall S ur vi val ( O S ) is defi ne d as t he ti me fr o m date of start of treat me nt t o date of deat h d ue
t o a n y ca use. A c ut -off date will be esta blis he d f or eac h a nal ysis of O S. All deat hs occ urri n g o n 
or bef ore t he c ut -off date i n t he F A S will be use d i n t he O S a nal ys is. 
If a patie nt is n ot k n o w n t o ha ve die d at t he ti me of a nal ys is c ut-off, O S will be ce ns ore d at t he
date of last c o ntact . 
T he O S a nal ys es will als o be pr o vi de d b y  the li ne of t hera p y s u b gr o u ps defi ne d i n Secti o n 2. 2. 1 .
O v er all R e s p o n s e R at e ( O R R)
O R R is defi ne d as t he pr o p orti o n of patie nts wit h best o verall res p o nse ( B O R) of c o m plete 
res p o nse ( C R) or partial res p o nse ( P R) acc or di n g t o R E CIS T 1. 1 (see A p pe n di x 2 of t he st u d y  
pr ot oc ol). O R R will be calc ulate d base d o n t he F A S usi n g l ocal i n vesti gat ors re vie w of t u m or 
assess me nt data. T u m or asses s me nts perf or me d bef ore t he start of a n y f urt her a nti ne o plastic 
t hera py (i.e. a n y a d diti o nal sec o n dar y anti ne o plastic t hera py or s ur ger y) will be c o nsi dere d i n 


N o v arti s
C o nfi d e nti al
P a g e 2 4
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
t he assess me nt of B O R. P alliati ve ra di ot hera p y is n ot all o we d as per pr ot oc ol a n d t h ose will be 
c onsi dere d as a nti-ne o plastic t hera p y usa ge. 
T he O R R a nal yses will als o be pr o vi de d b y  th e li ne of t hera py s u b gr o u ps defi ne d i n Secti o n 
2. 2. 1 .
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 ( B O R) of c o nfir me d 
C R or P R, or S D or N o n -C R/ N o n -P D lasti n g 2 4 wee ks or l o n ger, acc or di n g t o R E CI S T v 1. 1 
criteria.  A patie nt will be c o nsi dere d t o ha ve S D f or 2 4 wee ks or l o n ger if a S D res p o nse is 
rec or de d at ( 2 4 - 1) wee ks or later fr o m start of st u d y treat me nt, all o wi n g f or t he ± 1 wee k visit 
wi n d o w f or t u m or assess me nts. C B R
will be calc ulate d usi n g t he F A S base d o n t he 
i n vesti gat ors’ t u m or assess me nts. 
D ur ati o n of r e s p o n s e ( DO 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 m plete res p o nse ( C R) or partial 
res p o nse ( P R) acc or di n g t o R E CI S T v 1. 1 base d o n l ocal i n vesti gat ors re vie w of t u m or 
assess me nt data . T he start date is 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 date of res p o nse, n ot t he date w he n res p o nse was c o nfir me d), a n d t he e n d date is defi ne d 
as 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 yi n g ca ncer. 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 de rl yi n g ca ncer will be ce ns ore d at t he date 
of t heir last a de q uate t u m or assess me nt usi n g t he ce ns ori n g r ule descri be d f or P F S a nalys is. 
Ti m e t o r e s p o n s e
Ti me t o res p o nse ( C R or P R) is t he ti me fr o m date of start of treat me nt t o first d oc u me nte d 
res p o nse o f C R or P R (w hic h m ust be c o nfir me d s u bse q ue ntl y) usi n g l ocal i n vesti gat ors re vie w 
of t u m or assess me nt data a n d acc or di n g t o R E CI S T v 1. 1. All patie nts i n t he F A S will be 
i ncl u de d i n t he ti me t o res p o nse calc ulati o n. Patie nts w h o di d n ot ac hie ve a c o nfir me d P R or 
C R will be ce ns ore d at:

t he ma xim u m f oll o w -u p ti me (i.e. F P F V - 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. eit her pr o gresse d or die d d ue t o a n y ca use);

t he last a de q uate t u m or assess me nt date f or all ot her patie nts.
W at erf all pl ot t o d e pi ct a nti -t u m or a cti vit y
Waterfall gra p hs will be use d t o de pict t he a nti-t u m or acti vit y usi n g F A S . T hese pl ots will 
dis pla y t he best perce nta ge c ha n ge fr o m baseli ne i n t he s u m of dia mete rs of all tar get
lesi o ns f or eac h patie nt. O nl y patie nts wit h meas ura ble
disease at baseli ne will be i ncl u de d
i n t he waterfall gra p hs.
S pecial c o nsi derati o n is nee de d f or assess me nts w her e t he tar get
lesi o n res p o nse is C R , P R or S D, b ut t he a p peara nc e of a ne w lesi o n or a w orse ni n g of n o n-
tar get lesi o ns res ults i n a n o verall lesi o n res p o nse of P D. As a c o nser vati ve a p pr oac h, s uc h
assess me nts will n ot be c o nsi dere d  f or  dis pla y a s  bars  i n  t he gra p h,  si nce  t he  perce nta ge  
c ha n ge  i n  t he  s u m  of dia meters of tar get lesi o ns reflects t he n on- P D tar get lesi o n res p o nse, 
b ut t he o verall lesi o n res p o nse is P D. A patie nt wit h o nl y s uc h assess me nts will be re prese nte d
b y a s pecial sy m b ol (e. g. ) i n t he waterfall gra p h. Assess me nts wit h “u n k n o w n” tar get lesi o n


N o v arti s
C o nfi d e nti al
P a g e 2 5
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
res p o nse a n d assess me nts wit h u n k n o w n o verall res p o nse will be e xcl u de d fr o m t he waterfall 
pl o ts. Patie nts wit h o ut a n y vali d assess me nts will be c o m pletel y e xcl u de d fr o m t he gra p hs.

T he t otal n u m ber of patie nts dis pla y e d i n t he gra p h will be s h o wn a n d t his n u m ber will
be use d as t he de n o mi nat o r f or calc ulati n g t he perce nta ges of patie nts wit h
t u m or
s hri n ka ge a n d t u m or gr o wt h. F o ot n ote will e x plai n t he reas o n f or e xcl u di n g s o me 
patie nts ( d ue t o a bse nce of a n y vali d assess me nt).

All p ossi ble assess me nt sce nari os are descri be d i n Ta ble 2 - 5.
T a bl e 2- 5
I n cl u sio n /e x cl u s io n of a s s e s s m e n t s u s e d i n w ater f all gr a p h
Cr it eria f or i ncl u s i o n/ ex c l usi o n
P o s s i bl e so u r ce s of
c o nt ra di ct i o n s
c a s e 
T ar g et r e sp o n s e  
O v er all l esi o n
r e sp o n s e
I ncl u d e
i n w at erfal l ?
N o n -t ar get
r e sp o n s e
N e w l e si o n ?
1
C R/ P R / S D
P D
Y e s b ut a s ‘o nl y
P D
a n y
2
C R/ P R / S D
P D
Y e s b ut a s ‘o nl y 
a n y
Y e s
3
U N K
U N K or P D
N o
a n y 
a n y
4
C R/ P R/ S D
U N K
N o
U N K  
N o
5
C R/ P R/ S D
C R/ P R/ S D 
Y e s a s a b ar
S D/I R
N o
6
P D
P D
Y e s a s a b ar
a n y 
a n y
P ati e nt -r e p ort e d o ut c o m e s ( P R O)
Statistical a nal y ses are descri be d i n Secti o n 2. 9 .
2. 7. 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
O v er all S ur vi v al
T he s ur vi val distri b uti o n of 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 prese 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 nf i de nce i nter vals
[ Br o o k me ye r a n d Cr o wle y 1 9 8 2] al o n g wit h t he pr o p orti o n of patie nts ali ve at 6, 1 2 a n d 2 4 
m o nt hs a n d t he ass ociate d 9 5 % c o nfi de nce i nter vals will be prese nte d .
O R R ( s a m e f or C B R)
O R R a n d C B R will be s u m marize d usi n g descri pti ve statistics ( N, %) al o n g wit h t w o-si de d 
e xact bi n o mial 9 5 % CI s [Cl o p per a n d Pears o n 1 9 3 4] .
D O R ( s a m e f or ti m e t o r e s p o n s e)
D O R will be s u m marize d f or all patie nts i n t he F A S wit h c o nfir me d B O R of C R or P R. D O R 
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 
prese nte d a n d 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.


N o v arti s
C o nfi d e nti al
P a g e 2 6
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
2. 7. 3
H a n dli n g of mi s si n g v al u e s/ c e n s ori n g/ di s c o nti n u ati o n s
O v er all S ur vi v al
If a patie nt is n ot k n o w n t o ha ve die d at t he ti me of a nal ys is c ut-off , t he n O S will be ce ns ore d 
at t he date of last k n o w n date patie nt was ali ve, i.e., last c o ntact date (see Secti o n 2. 1. 1 ).
O R R ( s a m e f or C B R)
Patie nts wit h u n k n o w n or missi n g best o verall res p o nse ( B O R) will be c o u nte d as fail ures. If 
t here is n o baseli ne t u m or assess me nt, all p ost -baseli ne o verall lesi o n res p o nses are e x pecte d t o 
be ‘ U n k n o w n’. If n o vali d p ost -baseli ne t u m or assess me nts are a vaila ble, t he best o verall 
res p o nse m ust be “ U n k n o w n” u nless pr o gressi o n is re p orte d. F or t he c o m p utati o n of O R R, 
t hese patie nts will be i ncl u de d i n t he F A S a n d will be c o u nte d as ‘fail ures’.
2. 8
S af et y a n al y s e s
All safet y a nal ys es will be bas e d o n t he safet y set. 
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 safety 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 -treat me 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.
2. 8. 1
A d v er s e e v e nt s ( A E s)
A E s u m maries will i ncl u de all A Es occ urri n g d uri n g o n treat me nt peri o d. All A Es c ollecte d i n 
t he A E e C R F pa ge will be liste d al o n g wit h t he i nf or mati o n c ollecte d o n t h ose A Es e. g. A E 
relati o ns hi p t o st u d y dr u g, A E o utc o me etc. A Es wit h start date o utsi de of o n-treat me nt peri o d 
will be fla g ge d i n t h e listi n gs. 
A Es will be s u m marize d b y  n u m ber a n d perce nta ge of patie nt s ha vi n g at least o ne A E, ha vi n g 
at least o ne A E i n eac h pri mar y  sys te m or ga n class ( S O C) a n d f or eac h preferre d ter m ( P T)
usi n g Me d D R A c o di n g. A patie nt wit h m ulti ple occ urre nces of a n A E will be c o u nte d o nl y 
o nce i n t he res pecti ve A E cate g or y. A patie nt wit h m ulti ple C T C A E gra des f or t he sa me 
preferre d ter m will be s u m marize d u n der t he ma xi m u m C T C A E gra de rec or de d f or t he e ve nt.
A E wit h missi n g C T C A E gra de will be i ncl u de d i n t he ‘ All gra des’ c ol u m n of t he s u m mar y 
ta bles.
I n AE s u m maries, t he pri mar y  sys te m or ga n class will be prese nte d al p ha beticall y a n d t he 
preferre d ter ms will be s orte d wit hi n pri mar y S O C i n desce n di n g fre q ue nc y. T he s ort or der f or 
t he preferre d ter m will be base d o n t heir fre q ue nc y .
T he f oll o wi n g a d verse e ve nt s u m maries will be pr o d uce d; o ver vie w of a d verse e ve nts a n d 
deat hs, A Es b y  SO C a n d P T, s u m marize d b y  relati o ns hi p, seri o us ness ( S A Es a n d n o n- S A Es) , 
lea di n g t o treat me nt disc o nti n uati o n, lea di n g t o d ose i nterr u pti o n/a dj ust me nt, re q uiri n g 
a d diti o nal t hera p y a n d lea di n g t o fatal o utc o me.
T he s u m mar y of o ver vie w of all a d verse e ve nts will be prese nte d f or li ne of t hera p y s u b gr o u ps 
as s pecifie d i n Secti o n 2. 2. 1 .


N o v arti s
C o nfi d e nti al
P a g e 2 7
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
2. 8. 1. 1
A d v er s e e v e nt s of s p e ci al i nt er e st / gr o u pi n g of AE s
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 
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 ba sis 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 Br oc h ure. T he latest Case Retrie val 
S trate g y ( C R S) a vaila ble at t he ti me of t he Pri mar y/Fi nal a nal ys is will be use d.
A E SI s f or t his trial i ncl u de he patic t o xicit y, h y perte nsi o n, t h yr oi d-relate d dis or ders  
( hy p ot h yr oi dis m) a n d car diac d y sf u ncti o n.
D at a a n al y si s of A E SI s
A n a d verse e ve nt of s pecial i nterest is a gr o u pi n g of a d verse e ve nts t hat are of scie ntific a n d 
me dical c o ncer n s pecific t o c o m p o u n d paz o pa ni b. T hese gr o u pi n gs are defi ne d usi n g Me d D R A 
ter ms, S M Qs (sta n dar dize d Me d D R A q ueries), H G L Ts ( hi g h le vel gr o u p ter ms), H L T ( hi g h 
le vel ter ms) a n d P Ts ( preferre d ter ms). C ust o mize d S M Qs ( N o vartis Me d D R A q ueries , N M Q)
ma y als o be use d . A N M Q is a c ust o mize d gr o u p of searc h ter ms w hic h defi nes a me dical 
c o nce pt f or w hic h t here is n o official S M Q a vaila ble or t he a vaila ble S M Q d oes n ot c o m pletel y 
fit t he nee d. It m a y  incl u de a c o m bi nati o n of si n gle ter ms a n d/ or a n e xisti n g S M Q, narr o w or 
br oa d. F or eac h s pecifie d A E SI , n u m ber a n d perce nta ge of patie nts wit h at least o ne e ve nt of 
t he A E SI occ urri n g d uri n g o n treat me nt peri o d will be s u m marize d.
S u m maries of t hese A E SIs will be pr o vi de d, (s pecif yi n g gra de, S A E, relati o ns hi p, lea di n g t o 
treat me nt disc o nti n uati o n, lea di n g t o d ose a dj ust me nt /i nterr u pti o n etc.).
2. 8. 2
D e at h s
Se parate s u m maries f or o n -treat me nt a n d all deat hs will be pr o d uce d b y  s yste m or ga n class a n d 
preferre d ter m. 
All deat hs will be liste d, p ost treat me nt deat hs will be fla g ge d. A se parate listi n g of deat hs pri or 
t o starti n g treat me nt will be pr o vi de d f or all scree ne d patie nt s.
2. 8. 3
L a b or at or y  d at a
O n a nal yz i n g la b orat or y, data fr o m all s o urces (ce ntral a n d l ocal la b orat ories) will be c o m bi ne d. 
T he s u m maries will i ncl ude all assess me nts a vaila ble f or t he la b para meter c ollecte d n o later 
t ha n 3 0 d a y s after t he last st u d y treat me nt a d mi nistrati o n date (see Secti o n 2. 1. 1 ).
T he f oll o wi n g s u m maries will be pr o d uce d f or he mat ol o g y  an d b i oc he mistr y la b orat or y data 
( b y la b orat or y para meter a n d treat me nt ):


N o v arti s
C o nfi d e nti al
P a g e 2 8
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0

W orst p ost -baseli ne C T C gra de (re gar dless of t he baseli ne stat us) will be prese nte d f or 
safety p o p ulati o n . Eac h patie nt will be c o u nte d o nl y  f or t he w orst gra de o bser ve d p ost-
baseli ne.
T he f oll o wi n g listi n g will be pr o d uce d f or t he la b orat or y  data:

Listi n g of all C T C gra de 3 or 4 la b orat or y  t o xicities.
Li v er f u n cti o n p ar a m et er s 
Li ver f u ncti o n para meters of i nterest are t otal bilir u bi n ( T B L), A L T, A S T a n d al kali ne 
p h os p hatase ( A L P). T he n u m ber ( %) of patie nts wit h w orst p ost -baseli ne val ues as per 
N o vartis L i ver T o xicit y g ui deli nes will be s u m marize d:
T he f oll o wi n g s u m maries will be pr o d uce d:

A L T or A S T > 3 x U L N 

A L T or A S T > 5 x U L N

A L T or A S T > 8 x U L N

A L T or A S T > 1 0 x U L N

A L T or A S T > 2 0 x U L N

T B L > 2 x U L N

T B L > 3 x U L N

A L T or A S T > 3 x U L N & T B L > 2 x U L N

A L T or A S T > 3 x U L N & T B L > 2 x U L N & A L P < 2 x U L N  ( p ote ntial H y’s la w)   
P ote ntial H y ’s La w e ve nts are defi ne d as t h ose patie nt s wit h c o nc urre nt occ urre nce of A S T or 
A L T > 3 x U L N a n d T B L > 2 x U L N a n d A L P < 2 x U L N  i n t he sa me assess me nt sa m ple d uri n g 
t he o n -treat me nt peri o d. F urt her me dical re vie w has t o be c o n d ucte d t o assess p ote ntial 
c o nf o u n di n g fact or s uc h as, li ver metastases , li ver f u ncti o n at baseli ne etc.
2. 8. 4
Ot h er s af et y  d at a
N A
2. 8. 4. 1
E C G a n d c ar di a c i m a gi n g d at a
D at a h a n dli n g
I n case t he st u d y re q uires E C G re plicates at a n y a ssess me nt, t he a vera ge of t he E C G para meters 
at t hat assess me nt s h o ul d be use d i n t he a nal ys es.
D at a a n al y si s
L ocal 1 2- lea d E C Gs i ncl u di n g H R, P R, Q R S, a n d Q T i nter vals will be o btai ne d f or eac h patie nt
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.


N o v arti s
C o nfi d e nti al
P a g e 2 9
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
T he n u m ber a n d perce nta ge of patie nt s wit h n ota ble E C G val ues will be prese nte d. 

Q T or Q Tc F
-
Ne w val ue of > 4 5 0 a n d ≤ 4 8 0 ms
-
Ne w val ue of > 4 8 0 a n d ≤ 5 0 0 ms
-
Ne w val ue of > 5 0 0 ms
-
I ncrease fr o m Baseli ne of > 3 0 ms t o ≤  6 0 ms
-
I ncrease fr o m Baseli ne of > 6 0 ms

H R
-
I ncrease fr o m baseli ne > 2 5 % a n d t o a val ue > 1 0 0 b p m
-
Decrease fr o m baseli ne > 2 5 % a n d t o a val ue < 5 0 b p m

P R
-
I ncrease fr o m baseli ne > 2 5 % a n d  t o a val ue > 2 0 0 ms
-
Ne w val ue of > 2 0 0 ms

Q R S
-
I ncrease fr o m baseli ne > 2 5 % a n d  t o a val ue > 1 2 0 ms 
-
Ne w val ues of Q R S > 1 2 0 ms 
A listi n g of n ota ble va uel of E C G pare meters will be pr o d uce d a n d t he assess me nts c ollecte d 
d uri n g t he p ost -treat me nt peri o d will be fla g ge d .
2. 8. 4. 2
Vit al si g n s
Vital si g n assess me nts are perf or me d i n or der t o c haracterize basic b o d y  fu ncti o n. T he 
f oll o wi n g para meters were c ollecte d: hei g ht (c m), wei g ht ( k g), b o d y  te m perat ure (° C), heart 
rate ( beats per mi n ute), s yst olic a n d diast olic bl o o d press ure ( m m H g).
D at a h a n dli n g
Vital si g ns c ollecte d o n treat me nt will be s u m marize d. Val ues meas ure d o utsi de of o n treat me nt 
peri o d will be fla g ge d i n t he listi n gs.
D at a a n al y si s
F or a nal ysis of vital si g ns t he cli nicall y nota ble vital si g n criteria are pr o vi de d i n Ta ble 2- 6
bel o w.
T a bl e 2- 6
Cli ni c all y  n ot a bl e c h a n g e s i n vit al si g n s
Vit al si g n 
( u nit)
Cli ni c all y n ot a bl e crit eri a
a b o v e n or m al v al u e 
b el o w n or m al v al u e
W e i g ht ( k g)
i n cr e a s e > 1 0 % fr o m B a s eli n e
d e cr e a s e  > 1 0 % fr o m B a s eli n e
S y st oli c bl o o d 
pr e s s ur e 
( m m H g)
> = 1 5 0 wit h i n cr e a s e fr o m b a s eli n e 
of > = 2 0
< = 9 0 wit h d e cr e a s e fr o m b a s eli n e 
of > = 2 0


N o v arti s
C o nfi d e nti al
P a g e 3 0
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
Vit al si g n 
( u nit)
Cli ni c all y n ot a bl e crit eri a
a b o v e n or m al v al u e 
b el o w n or m al v al u e
Di a st oli c bl o o d 
pr e s s ur e 
( m m H g)
> = 1 0 0 wit h i n cr e a s e fr o m b a s eli n e 
of > = 1 5
< = 5 0 wit h d e cr e a s e fr o m b a s eli n e 
of > = 1 5
P ul s e r at e 
( b p m)
> = 1 0 0 wi t h i n cr e a s e fr o m b a s eli n e 
of > 2 5 %
< = 5 0 wit h d e cr e a s e fr o m b a s eli n e of 
> 2 5 %
B o d y 
t e m p er at ur e
> = 3 9. 1
-
T he n u m ber a n d perce nta ge of patie nt s wit h n ota ble vital si g n val ue s ( hi g h/l o w) will be 
prese nte d .         
A listi n g of n ota ble val ues of vital si g n para meters will be pr o d uce d a n d t he assess me nts 
c ollecte d o utsi de of o n-treat me nt peri o d will be fla g ge d. 
2. 8. 4. 3
A d diti o n al A n al y s e s : E c h o c ar di o gr a m/ M U G A
D at a h a n dli n g
I n case t he st u d y re q uires E C H O/ M U G A re plicates at a n y assess me nt, t he a vera ge of t he L V E F 
at t hat assess me nt s h o ul d be use d i n t he a nal ys es.
D at a a n al y si s
L ocal ec h ocar di o gra m or M U G A will be o btai ne d f or eac h patie nt will be o btai ne d 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. T he n u m ber a n d perce nta ge of 
patie nts wit h n ota ble p ost -baseli ne val ues of left ve ntric ular ejecti o n fracti o n (L V E F) base d o n 
N CI -C T C A E v 4. 0 3 will be s u m marize d o n t he Safet y  Set: 

Gra de 2 : L V E F bet wee n > = 4 0 a n d < = 5 0 % a n d/ or decrease fr o m baseli ne bet wee n > = 1 0 
a n d < 2 0 %

Gra de 3: L V E F bet wee n < 4 0 a n d < = 2 0 % a n d/ or decrease fr o m baseli ne bet wee n > 2 0 %

Gra de 4: L V E F < 2 0 % 
I n a d diti o n, t he f oll o wi n g n ota ble p ost-baseli ne val ues will als o be descri be d o n t he Safet y Set:

N u m ber of patie nts wit h ne w L V E F ( %) < 5 0 %

N u m ber of patie nts wit h ne w L V E F ( %) < 5 0 % a n d decrease > 1 0 %

N u m ber of patie nts wit h ne w L V E F ( %) < 5 0 % a n d decrease > 2 0 %
2. 9
P ati e nt -r e p ort e d o ut c o m e s
T his st u d y is a si n gle ar m st u d y. T he ref ore, t he P R O a nal ys es will be descri pti ve a n d n o 
statistical m o dels will be pr o vi de d.




N o v arti s
C o nfi d e nti al
P a g e 3 2
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
T a bl e 2- 8
K ar n of s k y  P erf or m a n c e S c al e
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, n o e vi d e n c e of di s e a s e
9 0
A bl e t o c arr y o n n or m al a cti vit y; mi n or s y m p t o m s
8 0
N or m al a cti vit y wit h eff ort; s o m e s y m p t o ms
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 viti e s
6 0
R e q uir e s o c c a si o n al a s si st a n c e; c ar e s f or m o st 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 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 e d b ut d e at h n ot i m mi n e nt
2 0
V er y si c k: a cti v e s u p p orti v e c ar e n e e d e d
1 0
M ori b u n d: f at al pr o c e s s e s ar e pr o gr e s si n g r a pi dl y 
0
D e a d
All c ollecte d data will be prese nte d i n data listi n gs.
D ur ati o n of f oll o w -u p
St u d y f oll o w-u p will be s u m marize d usi n g t he f oll o wi n g met h o ds:
     S u m mar y of d urati o n bet wee n start date of treat me nt a n d c ut-off date, a n d f oll ow- u p
ti mes f or P F S/ O S, w hic h are defi ne d as f oll o ws:
o
D urati o n bet wee n start date of treat me nt a n d data c ut-off date = ( C ut-off date –
Date of start of treat me nt
+ 1) / 3 0. 4 3 7 5 ( m o nt hs).   T his ite m will be s u m marize d 
o ve rall.
o
F oll o w- u p ti me = ( Date of e ve nt or ce ns ori n g – Date of start of treat me nt + 1) / 
3 0. 4 3 7 5 ( m o nt hs) re gar dless of ce ns ori n g. Date of ce ns ori n g is defi ne d as t he last 
a de q uate t u m or assess me nt date f or P F S or last c o ntact date f or O S. T his ite m will 
be s u m marize d.
All s u m maries will be re p orte d i n m o nt hs. T he calc ulati o ns f or P F S wil l be base d o n l o c al
assess me nt. Date of ce ns ori n g is t he sa me as defi ne d f or t he P F S a n d O S a nal y sis.
2. 1 2
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.
3
S a m pl e si z e c al c ul ati o n
3. 1
Pri m ar y  a n al ysi s
Si n gl e ar m st u d y  wit h P F S a s pri m ar y  e n d p oi nt
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 00 patie nts ( wit h a p pr o xi matel y 40 
patie nts recei vi n g paz o pa ni b as 2 n d-li ne t hera p y) 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 wi t h V E G F R -T KI t hera p y after a n y PD -1c o m bi nati o n 


N o v arti s
C o nfi d e nti al
P a g e 3 3
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
(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 in hi bit ors is ass u me d 
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 l i n e ,  a n d  
3 r d
l i n e  p a t i e n t s  w i t h differe nt sa m ple sizes are pre se nte d i n Ta ble 3- 1 .
T a bl e 3- 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
S a m pl e 
si z e
9 5 % CI of 
me dia n
P F S ( m o nt h)
Wi dt h ( mo nt h s)
O v er all
5 m o nt h s
9 0
3. 9 6, 6. 3 1 2. 3 5 
3. 9 6, 6. 3 1 2. 3 5
1 0 0
4. 0 1, 6. 2 4 2. 2 3 
4. 0 1, 6. 2 4 2. 2 3
1 1 0
4. 0 5, 6. 1 7 2. 1 2 
4. 0 5, 6. 1 7 2. 1 2
2 n d li n e
6 m o nt h s
3 0
3. 9 5, 9. 1 2 5. 1 8 
3. 9 5, 9. 1 2 5. 1 8
4 0
4. 1 7, 8. 6 2 4. 4 5 
4. 1 7, 8. 6 2 4. 4 5
5 0
4. 3 4, 8. 3 0 3. 9 6 
4. 3 4, 8. 3 0 3. 9 6
3 r d li n e
4 m o nt h s
5 0
2. 9 6, 5. 4 0 2. 4 4 
2. 9 6, 5. 4 0 2. 4 4
6 0
3. 0 4, 5. 2 6 2. 2 2 
3. 0 4, 5. 2 6 2. 2 2
7 0
3. 1 0, 5. 1 6 2. 0 5 
3. 1 0, 5. 1 6 2. 0 5
3. 2
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.
4
C h a n g e t o pr ot o c ol s p e cifi e d a n al y s e s
T o f oll o w t he N o vartis sta n dar d, pri or, c o nc o mita nt a n d p ost t hera pies will be pr o vi de d o n t he 
F ull A nal ys is Set i nstea d of t he Safety Set as per pr ot oc ol. 
Per Pr ot oc ol Set ( P P S) was defi ne d i n t he ori gi nal pr ot oc ol, h o we ver, a nal ys is b y  PP S 
p o p ulati o n (i ncl u di n g P P S defi niti o n) will n ot be c o n d ucte d d ue t o t he fact t hat (i) sa m ple size 
re d ucti o n a n d (ii) S A P lea ni n g pri nci pal.
A E SI  mai n ris k na mes were u p date d acc or di n g t o t he last C R S a vaila ble at t he ti me of t he S A P 
fi nalizati o n.


N o v arti s
C o nfi d e nti al
P a g e 3 4
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
5
A p p e n di x
5. 1
I m p ut ati o n r ul e s
5. 1. 1
St u d y dr u g
T he f oll o wi n g r ule s h o ul d be use d f or t he i m p utati o n of t he d ose e n d date f or a gi ve n st u d y 
treat me nt c o m p o ne nt:
Sce n ari o 1 : If t he d ose e n d date is c o m pletely missi n g a n d t here is n o E O T pa ge a n d n o deat h 
date , t he patie nt is c o nsi dere d as o n -g oi n g :
T he p atie nt s h o ul d be treate d as o n-g oi n g a n d t he c ut -off date s h o ul d be use d as t he d ose e n d
date . 
Sce nari o 1 s h o ul d n ot a p plica ble f or fi nal C S R . All patie nts s h o ul d ha ve E O T pa ge c o m plete 
bef ore t he Data base l oc k f or Fi nal C S R .
Sce n ari o 2 : If t he d ose e n d date is c o m pletely or partiall y missi n g a n d t he E O T pa ge is 
a vaila ble:
Case 1: T he d ose e n d date is c o m pletel y  missi n g, a n d t he E O T c o m pleti o n date is c o m plete, 
t he n t his latter date s h o ul d be use d.  
Case 2: O nl y  Year( yy y y)  of t he d ose e n d date is availa ble a n d y y y y < t he year of E O T date:  
Use Dec 3 1 y y y y
Case 3: O nl y  Year( yy y y)  of t he d ose e n d date is availa ble a n d y y y y  = t he year of E O T date:
Use E O T d ate
Case 4: B ot h Year ( yy y y) a n d M o nt h ( m m) are a vaila ble f or d ose e n d date, a n d y y y y  = t he 
ye ar of E O T date a n d m m < t he m o nt h of  E O T date: 
Use l ast d a y of t he M o nt h ( m m)
All ot her cases s h o ul d be c o nsi dere d as a data iss ue a n d t he statisticia n s h o ul d c o ntact t he data 
ma na ger of t he st u d y .
After i m p utati o n, c o m pare t he i m p ute d date wit h start date of treat me nt, if t he i m p ute d date is 
< start date of treat me nt:
Use t he tre at me nt st art d ate
Patie nts wit h missi n g start dates are t o be c o nsi dere d missi n g f or all st u d y treat me nt c o m p o ne nt 
relate d calculati o ns a n d n o i m p utati o n will be ma de. If start date is missi n g t he n e n d-date s h o ul d 
n ot be i m p ute d.


N o v arti s
C o nfi d e nti al
P a g e 3 5
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
5. 1. 2
A E , C o n M e d s a n d s af et y  a s s e s s m e nt d at e i m p ut ati o n
T a bl e 5 - 1
I m p ut ati o n of st art d at e s ( AE, C M) a n d a s s e s s m e nt s ( L B, E G, V S)
Missi n g 
Ele me nt
R ule
da y , m o nt h, 
a n d year

N o i m p utati o n will be d o ne f or c o m pletel y  missi n g dates
da y , m o nt h

If a vaila ble year = ye ar of st u d y treat me nt start date t he n 
o
If st o p date c o ntai ns a f ull date a n d st o p date is earlier t ha n 
st u d y treat me nt start date t he n set start date = 0 1Ja n Y Y Y Y
o
Else set start date = st u d y treat me nt start date. 

If a vaila ble year > ye ar of st u d y treat me nt start date t he n 0 1Ja n Y Y Y Y

If a vaila ble year < ye ar of st u d y treat me nt start date t he n 0 1J ul Y Y Y Y
da y

If a vaila ble m o nt h a n d ye ar = m o nt h a n d ye ar of st u d y treat me nt start 
date t he n 
o
If st o p date c o ntai ns a f ull date a n d st o p date is earlier t ha n 
st u d y treat me nt start date t he n set start date = 0 1 M O N Y Y Y Y. 
o
Else set start date = st u d y treat me nt start date.

If a vaila ble m o nt h a n d ye ar > m o nt h a n d ye ar of st u d y treat me nt start 
date t he n 0 1 M O N Y Y Y Y  

If a vaila ble m o nt h a n d ye ar < m o nt h year of st u d y treat me nt start date 
t he n 1 5 M O N Y Y Y Y  


N o v arti s
C o nfi d e nti al
P a g e 3 6
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
T a bl e 5 - 2
I m p ut ati o n of e n d d at e s ( AE, C M) 
Missi n g 
Ele me nt
R ule
( * =last treat me nt date pl us 3 0 da y s n ot > ( deat h date, c ut -off date, 
wit h dra wal of c o nse nt date))
da y , m o nt h, 
a n d year

C o m pletel y  missi n g e n d dates (i ncl. o n g oi n g e ve nts) will be i m p ute d 
b y  t he e n d date of t he o n-treat me nt peri o d * 
da y , m o nt h

If partial e n d date c o ntai ns year o nl y, set e n d date = earliest of 
3 1 D ecY Y Y Y or e n d date of t he o n-treat me nt peri o d * 
da y

If partial e n d date c o ntai ns m o nt h a n d year, set e n d date = earliest of 
last da y of t he m o nt h or e n d date of t he o n -treat me nt peri o d*
A n y  A Es a n d C o n Me ds wit h partial/ missi n g dates will be dis pla ye d as s uc h i n t he data listi n gs .
A n y  AEs a n d C o n Me ds w hic h are c o nti n ui n g as per data c ut-off will be s h o w n as ‘ o n g oi n g’ 
rat her t ha n t he e n d date pr o vi de d. 
T he a b o ve i m p utati o ns are o nl y use d f or a nal yses of ti me t o a n d d urati o n of A Es an d 
c o nc o mita nt me dicati o ns. 
5. 1. 3
I m p ut ati o n f or M S K C C ri s k gr o u p a n d I M D C ri s k gr o u p
If a n y of t he f oll o wi n g 3 fact ors are missi n g t he r ule bel o w will be use f or assi g n t he M S K C C 
ris k gr o u p.
1.
Kar n ofs k y perf or ma nce stat us ( < 8 0 %)
2.
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)
3.
Hi g h c orrecte d ser u m calci u m ( ≥1 0 m g/ d L)
N u m ber 
of missi n g 
fact or(s)
Res p o nse fr o m n o n -missi n g fact or(s)
[ Yes = > patie nt met t he criteria ]
Ris k gr o u p
0
As c ollecte d i n data base
Use pr ot oc ol 
defi ne criteria
1 
2 Yes 
P o or
1
1 Yes a n d
1 N o
Missi n g 
1
2 N o
Missi n g
2
1 Yes 
Missi n g
2
1 N o
Missi n g
3
N A
Missi n g
If a n y o f t he f oll o wi n g 6 fact ors are missi n g t he r ule bel o w will be use f or assi g n t he I D MC ris k 
gr o u p.


N o v arti s
C o nfi d e nti al
P a g e 3 7
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
1.
Hae m o gl o bi n < L L N ,
2.
Platelet > U L N ,
3.
Ne utr o p hil > U L N ,
4.
C orrecte d ser u m c alci u m > U L N,
5.
Kar n ofs k y perf or ma nce stat us [ K P S] < 8 0 a n d 
6.
< 1 y ear fr o m dia g n osis t o first -li ne tar gete d t hera p y 
N u m ber of 
missi n g fact or(s)
Res p o nse fr o m n o n -missi n g 
fact or(s)
[ Yes = > patie nt met t he criteria ]
Ris k gr o u p
0
As c ollecte d i n data base
·
If t he patie nt has 0 fact or : 
Fa v ora ble pr o g n osis 
·
If t he patie nt has 1-2 fact ors : 
I nter me diate pr o g n osis
·
If t he patie nt has 3-6 fact ors : 
P o or pr o g n osis
5 fact ors missi n g
           1 or 0 Yes 
Missi n g
4 fact ors missi n g
           2, 1 or 0 Yes 
Missi n g
3 fact ors missi n g
           2, 1 or 0 Yes
Missi n g
3 fact ors missi n g
           3 Yes 
P o or
2 fact or missi n g
           ≥3 Yes 
P o or       
2 fact or missi n g
           2, 1 or 0 Yes
Missi n g   
1 fact or missi n g
           ≥3 Yes
P o or  
1 fact or missi n g
           2 Yes
Missi n g  
1 fact or missi n g
           1 Yes
I nter me diate
1 fact or missi n g
           0 Yes
Missi n g  
5. 1. 4
Ot h er i m p ut ati o n s
I n c o m pl et e d at e of i niti al di a g n o si s of c a n c er a n d d at e of m o st r e c e nt 
r e c urr e n c e
Missi n g da y is defa ulte d t o t he 1 5
t h of t he m o nt h a n d missi n g m o nt h a n d da y is defa ulte d t o 0 1 -
Ja n. 
I n c o m pl et e a s s e s s m e nt d at e s f or t u m or a s s e s s m e nt
All i n vesti gati o n dates (e. g. M RI sca n, 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 assess me nt 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 t he lates t of all i n vesti gati o n dates (e. g. M RI sca n, C T sca n ) if 


N o v arti s
C o nfi d e nti al
P a g e 3 8
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
t he o verall 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 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 i n vesti gati o n dates at 
t hat e val uati o n n u m ber.  If all meas ure me nt dates ha ve n o da y rec or de d, t he 1st of t he m o nt h is 
use d. If t he m o nt h is n ot c o m plete d, f or a n y o f 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  bet wee n pre vi o us a n d f oll o wi n g assess me nt. If 
a pre vi o us a n d f oll o wi n g assess me nt is n ot a vaila ble, t his assess me nt will n ot be use d f or a n y 
calc ulati o n.
A p pl yi n g t h e c ut -off t o t u m or a s s e s s m e nt
F or t u m or relate d assess me nts, if a n e val uati o n has s o me assess me nts d o ne pri or t o c ut-off date 
a n d ot hers after t he c ut-off date , t he n t he e val uati o n is c o nsi dere d p ost -c ut-off date a n d will 
be e xcl u de d fr o m a nal y sis.
5. 2
A E s c o di n g/ gr a di n g
A d verse e ve nts are c o de d usi n g t he Me dical dicti o nar y  for re g ulat or y acti vities ( Me d D R A) 
ter mi n ol o g y.
N ote: T he latest a vaila ble Me d D R A versi o n at t he ti me of t he a nal yses s h o ul d be use d. T he 
Me d D R A versi o n use d s h o ul d be s pecifie d i n t he f o ot n ote of rele va nt ta bles.  
A Es will be assesse d acc or di n g t o t he C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts 
( C T C A E) versi o n 4. 0 3.
T he C T C A E re prese nts a c o m pre he nsi ve gra di n g s yste m f or re p orti n g t he ac ute a n d late effects 
of ca ncer treat me nts. C T C A E gra di n g is b y  d efi niti o n a 5- p oi nt scale ge nerall y  corres p o n di n g 
t o mil d, m o derate, se vere, life t hreate ni n g, a n d deat h. T his gra di n g s yste m i n here ntl y places a 
val ue o n t he i m p orta nce of a n e ve nt, alt h o u g h t here is n ot necessaril y pr o p orti o nalit y  am o n g 
gra des (a gra de 2 is n ot nece ssaril y t wice as ba d as a gra de 1). 
5. 3
L a b or at or y  p ar a m et er s d eri v ati o n s
Gra de cate g orizati o n of la b val ues will be assi g ne d pr o gra m maticall y as per N CI  C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E) versi o n 4. 0 3 (s pecif y versi o n use d i n t he 
R A P). T h e calc ulati o n of C T C A E gra des will be base d o n t he o bser ve d la b orat or y val ues o nl y , 
cli nical assess me nts will n ot be ta ke n i nt o acc o u nt. T he criteria t o assi g n C T C A E gra des are 
gi ve n i n N o vartis i nter nal criteria f or C T C A E gra di n g of la b orat or y para meters. T he latest 
a vaila ble versi o n of t he d oc u me nt base d o n t he u n derl y i n g C T C A E versi o n 4. 0 3 at t he ti me of 
a nal ys is will be use d. F or la b orat or y tests w here gra des are n ot defi ne d b y  CT C A E v 4. 0 3 , res ults 
will be gra de d b y t he l o w/ n or mal/ hi g h   classificati o ns base d o n la b orat or y  n or mal ra n ges.
A se verit y  gra de of 0 will be assi g ne d f or all n o n-missi n g la b val ues n ot gra de d as 1 or hi g her. 
Gra de 5 will n ot be use d. F or la b orat or y tests t hat are gra de d f or b ot h l o w a n d hi g h val ues, 
s u m maries will be d o ne se paratel y an d la belle d b y  directi o n, e. g., s o di u m will be s u m marize d 
as h yp o natre mia a n d h y per natre mia.


N o v arti s
C o nfi d e nti al
P a g e 3 9
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
I m p ut ati o n R ul e s  
C T C gra di n g f or bl o o d differe ntials is base d o n a bs ol ute val ues. H o we ver, t his data ma y n ot be 
re p orte d as a bs ol ute c o u nts b ut rat her as perce nta ge of W B C. 
If la b orat or y val u es are pr o vi de d as ‘ < X’ (i.e. bel o w li mit of detecti o n) or ‘ > X’, pri or t o 
c o n versi o n of la b orat or y  val ues t o SI u nit, t hese n u meric val ues are set t o X. 
T he f oll o wi n g r ules will be a p plie d t o deri ve t he W B C 
differe ntial c o u nts w he n o nl y 
perce nta ges are a vaila ble f or a x x x differe ntial
x x x c o u nt = ( W B C c o u nt) * ( x x x % val ue / 1 0 0)
F urt her deri vati o n of la b orat or y para meters mi g ht be re q uire d f or C T C A E gra di n g. F or i nsta nce, 
c orrecte d calci u m ca n be deri ve d usi n g t he re p orte d t otal calci u m val ue a n d al b u mi n at t he sa me 
assess me nt usi n g t he f oll o wi n g f or m ula:
C orrecte d Calci u m ( m g/ d L) = Calci u m ( m g/ d L) – 0. 8 [ Al b u mi n ( g/ d L )- 4]
I n or der t o a p pl y t he a b o ve f or m ula, al b u mi n val ues i n g/ L will be c o n verte d t o g/ d L b y  
m ulti pl y i n g b y  0. 1), calci u m val ues i n m m ol/ L  will be c o n verte d t o m g/ d L by di vi di n g b y  
0. 2 4 9 5. F or calc ulati o n of la b orat or y CT C gra des 0 a n d 1, t he n or mal ra n ge f or deri ve d 
c orrecte d calci u m is set t o t he sa me li mits (i n m g/ d L ) as f or calci u m.
C T C gra des f or t he deri ve d a bs ol ute W B C differe ntial c o u nts ( ne utr o p hils, l ym p h oc y tes) a n d 
c orrecte d calci u m will be assi g ne d as descri be d a b o ve f or gra di n g
5. 4
S t ati sti c al m o d el s
5. 4. 1
Pri m ar y  a n al ysi s
A n al y si s of ti m e t o e v e nt s D at a
H y p o th e si s a n d t e s t st ati sti c
N ot a p plica ble.
K a pl a n -M ei er e sti m at e s
A n esti mate of t h e s ur vi val f u ncti o n i n eac h treat me nt gr o u p w ill be c o nstr ucte d usi n g Ka pla n -
Meier
( pro d u ct- li mit) m e t h od as i m ple me nte d i n P R O C LI F E T E S T wit h
M E T H O D = K M
o pti o n. T he P R O C LI F E T E S T state me nt will use t he o pti o n C O N F T Y P E = L O G L O G.
Me dia n 
s ur vi val f or ea c h treat me nt gr o u p will
be o bt ai ne d al o n g wi th 9 5 % c o nfi den ce 
i ntervals cal c ulate d fr o m P R O C LI F E T E S T o ut p ut usi n g t he met h o d
of [ Br o o k me ye r a n d 
Cr o wl e y 1 9 8 2] . Ka p la n-Mei er esti mat es of t he
s ur vival f un c tio n
w ith
9 5 %
c o nf i de nce
i nter vals at s pecifi c ti me p oi nt s wil l be s um m arize d. T h e stan da r d error of t h e
Ka pl a n-
Me ier esti mate wil l be calc ulate d usi n g Gr een w o o d’s f or m ula [ Collett 1 9 9 4 ].
Tr e at m e nt of ti es
T he S T R A T A state me nt i n LI F E T E S T pr oce d ure will be use d t o a nal yz e ti me t o e ve nt data 
wit h ties. 


N o v arti s
C o nfi d e nti al
P a g e 4 0
S A P A m e n d m e nt 2
1 1 -F e b -2 0 2 0 ( 7: 5 2)
C P Z P 0 3 4 A 2 4 1 0
A n al y si s of Bi n ar y  D at a
Si n gle ar m st u d y
C o nfi de nc e i nt e rv al f or res p o n se r ate
Res p o nses will
be s um m ariz e d i n ter ms of per ce nta ge rates wit h
1 0 0( 1 −α) % c o nfide n ce 
i nter val usi n g e xact bi n o mial c o nfi de nce i nter val (i m ple me nte d usi n g S A S pr oce d ur e F R E Q
wit h
E X A C T state me nt f or o ne- w a y t a ble [Cl o p per a n d Pears o n 1 9 3 4] .
M ulti pli cit y  a dj u st m e nt
N ot a p plica ble.
K e y  s e c o n d ar y a n al y si s
N ot a p plica ble.
6
R ef er e n c e
1.
Br o o k me y er R a n d Cr o wle y J ( 1 9 8 2). A C o nfi de nce I nter val f or t he Me dia n S ur vi val 
Ti me . Bi o metrics, 3 8, 2 9 - 4 1. 
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
3.
Cl o p per CJ a n d Pears 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 metrical , 2 6, 4 0 4-4 1 3.
4.
C ollet D ( 1 9 9 4). M o delli n g s ur vi val data i n me dical researc h. L o n d o n, C ha p ma n & Hall.
5.
F D A briefi n g D oc u me nt O nc ol o gic Dr u gs A d vis or y  C o m mittee Meeti n g, J ul y 2 4, 2 0 1 2, 
E val uati o n of ra di ol o gic re vie w of pr o gressi o n -free s ur vi val i n N o n-he mat ol o gic 
mali g na ncies. 
htt p:// w w w.f da. g o v/ d o w nl oa ds/a d vis or y c o m mittees/c o m mittees meeti n g materials/ dr u gs/ o n
c ol o gic dr u gsa d vis or y c o m mittee/ uc m 3 1 1 1 4 1. p df
6.
Na dal, et al ( 2 0 1 6) Safet y a n d cli nical acti vit y 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
7.
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