Clinical trial NCT02276027
Conditions: Adenocarcinoma Lung Cancer; Squamous Cell Lung Carcinoma
Keywords: adenocarcinoma lung cancer, squamous cell lung carcinoma, NSCLC
Sponsor: Novartis Pharmaceuticals
Start date: 2015-01-20; Completion date: 2019-10-15
Enrollment: 66 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the anti-tumor activity of single agent BYL719, INC280, LDK378 and MEK162 in advanced NSCLC patients carrying specific molecular alterations.

There is a great unmet medical need in NSCLC patients with advanced or metastatic disease. Novel approaches using targeted therapeutic agents for these patient populations with molecular characterization could potentially identify subsets of advanced NSCLC patients who would benefit from targeted kinase inhibition. Study treatments, BYL719, INC280, LDK378 and MEK162, which target PIK3CA, c-MET, ALK/ROS1 and MEK respectively, have shown promising data in either preclinical or clinical lung cancer settings.

Detailed description:
To enter the screening phase of the study, the subjects' molecular alterations were determined using locally validated methodologies from a newly obtained tumor sample (preferred) or the most recent archival tumor sample available. Based on the molecular alterations of the tumor, subjects were assigned to one of the treatment arms. Subjects with multiple molecular alterations in epidermal growth factor receptor (EGFR) and the relevant pathways were excluded, except under the conditions described in Inclusion criteria.

The treatment period began on Cycle 1 Day 1 and continued in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of informed consent, death or the subject transferred to another Novartis study that could continue to provide the study drug.

All subjects were required to be followed up for 30 days for safety after receiving the last dose of study treatment. Subjects who discontinued study treatment for any reason other than disease progression were followed up for progression of disease. All subjects were required to be followed for survival. For subjects transferred to another Novartis study, an end of treatment visit (EOT) was required to be performed and the subject would not enter the follow-up period.

Arms: arm 1: Patient's tumor must have molecular alteration of the PIK3CA gene. arm 2: Patient's tumor must have molecular alteration of the c-MET gene. arm 3: Patient's tumor must have ALK or ROS1 gene rearrangement. arm 4: Patient's tumor must have KRAS, NRAS or BRAF mutation.
Interventions: intervention 1: BYL719 intervention 2: INC280 intervention 3: LDK378 intervention 4: MEK162
Intervention descriptions: intervention 1: BYL719 was dosed as 350 mg once daily. On the first day of each cycle, patient received a prescription of adequate drug supply for self-administration at home. The investigator must emphasized compliance and instructed the patient to take BYL719 exactly as prescribed. intervention 2: INC280 was dosed as 600 mg (tablet) or 400mg(Capsule) twice daily. On the first day of each cycle, patient received a prescription of adequate drug supply for self-administration at home. The investigator must emphasized compliance and instructed the patient to takeINC280 exactly as prescribed. intervention 3: LDK378 was dosed as 750 mg once daily. On the first day of each cycle, patient received a prescription of adequate drug supply for self-administration at home. The investigator must emphasized compliance and instructed the patient to take LDK378 exactly as prescribed. intervention 4: MEK162 was dosed as 45 mg twice daily. On the first day of each cycle, patient received a prescription of adequate drug supply for self-administration at home. The investigator must emphasized compliance and instructed the patient to take MEK162 exactly as prescribed.

Protocol documents:
Prot_000.pdf: 
Cli ni c al  D e v el o p m e nt  
I N C 2 8 0 
Pr ot o c ol  CI N C 2 8 0 X 2 2 0 5 / N C T 0 2 2 7 6 0 2 7
A  Ph a s e  II, o p e n  la b el,  multi pl e  ar m  st u d y of si n gl e ag e nt  
A U Y 9 2 2,  B Y L 7 1 9,  IN C 2 8 0,  LD K 3 7 8 a n d  ME K 1 6 2 i n  C hi n e s e  
p ati e nt s wit h  a dv a n c e d  no n -s m all  c ell lu n g  c a n c er  ( N S C L C) 
D o c u m e nt  t y p e  
A m e n d e d  Pr ot o c ol  V er si o n 
E U D R A C T  n u m b er   
N ot  a p pli c a bl e  
V er si o n  n u m b er   
0 7  ( Cl e a n) 
D e v el o p m e nt  p h a s e   
II 
D o c u m e nt  st at u s   
Fi n al  
R el e a s e  d at e   
2 2 -M a y -2 0 1 9
Pr o p ert y  of  N o v arti s 
C o nfi d e nti al  
M a y  n ot  b e  u s e d,  di v ul g e d,  p u bli s h e d,  or  ot h er wi s e  di s cl o s e d 
wit h o ut t h e  c o n s e nt  of  N o v arti s  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  2  
Pr ot o c ol  N o.  CI N C 2 8 0 X 2 2 0 5  
 
 
 
T a bl e  of  c o nt e nt s 
T a bl e  of   c o nt e nts ............................................................................................................. 2  
List   of t a bl es.................................................................................................................... 7  
List   of fi g ur es .................................................................................................................. 8  
List   of  a b br e vi ati o ns ........................................................................................................ 9  
Gl oss ar y   of t er ms .......................................................................................................... 1 2  
A m e n d m e nt  7 ( 2 2- M a y - 2 0 1 9) ....................................................................................... 1 3  
A m e n d m e nt  6 ( 2 6- J a n- 2 0 1 7) ......................................................................................... 1 4  
A m e n d m e nt  5 ( 0 1- J ul- 2 0 1 6) .......................................................................................... 1 7  
A m e n d m e nt  4  ................................................................................................................ 1 9  
A m e n d m e nt  3  ................................................................................................................ 2 3  
A m e n d m e nt  2  ................................................................................................................ 2 4  
A m e n d m e nt  1  ................................................................................................................ 2 5  
Pr ot o c ol s u m m ar y  ......................................................................................................... 2 9  
1   B a c k gr o u n d  ................................................................................................................... 3 1  
1. 1   
O v er vi e w  of  dis e as e  p at h o g e n esis,  e pi d e mi ol o g y  a n d  c urr e nt  tr e at m e nt ............. 3 1  
1. 2   
I ntr o d u cti o n t o i n v esti g ati o n al tr e at m e nt(s)  a n d  ot h er st u d y tr e at m e nt(s) ............ 3 2  
1. 2. 1   
O v er vi e w   of  B Y L 7 1 9......................................................................... 3 2  
1. 2. 2   
O v er vi e w   of I N C 2 8 0 .......................................................................... 3 5  
1. 2. 3   
O v er vi e w   of L D K 3 7 8  ........................................................................ 3 8  
1. 2. 4   
O v er vi e w   of  M E K 1 6 2 ........................................................................ 4 1  
2   R ati o n al e  ....................................................................................................................... 4 4  
2. 1   
St u d y r ati o n al e  a n d  p ur p os e  ............................................................................... 4 4  
2. 2   
R ati o n al e f or t h e  st u d y  d esi g n ............................................................................ 4 7  
2. 3   
R ati o n al e f or  d os e  a n d  r e gi m e n s el e cti o n ........................................................... 4 7  
3   O bj e cti v es  a n d   e n d p oi nts ............................................................................................... 4 8  
4   St u d y  d esi g n .................................................................................................................. 4 9  
4. 1   
D es cri pti o n  of  st u d y  d esi g n ................................................................................ 4 9  
4. 2   
Ti mi n g  of i nt eri m  a n al ys es  a n d   d esi g n  a d a pt ati o ns ............................................. 5 0  
4. 3   
D efi niti o n  of  e n d  of t h e st u d y  ............................................................................. 5 0  
4. 4   
E arl y  st u d y t er mi n ati o n ...................................................................................... 5 0  
5   P o p ul ati o n ..................................................................................................................... 5 0  
5. 1   
P ati e nt   p o p ul ati o n .............................................................................................. 5 0  
5. 2   
I n cl usi o n crit eri a  ................................................................................................ 5 1  
5. 3   
E x cl usi o n  crit eri a  ............................................................................................... 5 2  
6   Tr e at m e nt  ...................................................................................................................... 5 7  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  3  
Pr ot o c ol  N o.  CI N C 2 8 0 X 2 2 0 5  
 
6. 1   
St u d y  tr e at m e nt .................................................................................................. 5 7  
6. 1. 1   
D osi n g  r e gi m e n .................................................................................. 5 7  
6. 1. 2   
Tr e at m e nt   d ur ati o n ............................................................................. 5 9  
6. 2   
D os e  m o difi c ati o ns  ............................................................................................ 5 9  
6. 2. 1   
D os e  m o difi c ati o n  a n d  d os e  d el a y  ...................................................... 5 9  
6. 2. 2   
F oll o w- u p f or  t o xi citi es ...................................................................... 6 0  
6. 2. 3   
A nti ci p at e d ris ks  a n d s af et y  c o n c er ns  of t h e  st u d y tr e at m e nt .............. 6 0  
6. 3   
C o n c o mit a nt  m e di c ati o ns  ................................................................................... 6 0  
6. 3. 1   
P er mitt e d   c o n c o mit a nt t h er a p y ........................................................... 6 0  
6. 3. 2   
P er mitt e d  c o n c o mit a nt t h er a p y r e q uiri n g  c a uti o n  a n d/ or a cti o n ........... 6 1  
6. 3. 3   
Pr o hi bit e d  c o n c o mit a nt  t h er a p y .......................................................... 6 4  
6. 4   
P ati e nt  n u m b eri n g, tr e at m e nt  assi g n m e nt   or r a n d o mi z ati o n ................................ 6 5  
6. 4. 1   
P ati e nt   n u m b eri n g .............................................................................. 6 5  
6. 4. 2   
Tr e at m e nt  assi g n m e nt  or r a n d o mi z ati o n  ............................................. 6 5  
6. 4. 3   
Tr e at m e nt   bli n di n g ............................................................................. 6 5  
6. 5   
St u d y tr e at m e nt  pr e p ar ati o n  a n d  dis p e ns ati o n  ..................................................... 6 6  
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  ............................................. 6 6  
6. 5. 2   
Dr u g s u p pl y  a n d st or a g e  ..................................................................... 6 6  
6. 5. 3   
St u d y tr e at m e nt  c o m pli a n c e  a n d  a c c o u nt a bilit y  .................................. 6 7  
6. 5. 4   
Dis p os al  a n d   d estr u cti o n .................................................................... 6 7  
7   Visit s c h e d ul e  a n d  ass ess m e nt s  ...................................................................................... 6 7  
7. 1   
St u d y fl o w  a n d  visit s c h e d ul e  ............................................................................. 6 7  
7. 1. 1   
M o l e c ul ar  pr e-s cr e e ni n g  ..................................................................... 7 5  
7. 1. 2   
S cr e e ni n g  ........................................................................................... 7 5  
7. 1. 3   
Tr e at m e nt   peri o d  ................................................................................ 7 6  
7. 1. 4   
E n d  of tr e at m e nt  visit i n cl u di n g st u d y  c o m pl eti o n  a n d  pr e m at ur e 
wit h dr a w al  ......................................................................................... 7 6  
7. 1. 5   
Wit h dr a w al   of  C o ns e nt ...................................................................... 7 7  
7. 1. 6   
F oll o w  u p  p eri o d ................................................................................ 7 8  
7. 1. 7   
L ost  t o f oll o w- u p ............................................................................... 7 8  
7. 2   
Ass e ss m e nt  t y p es ............................................................................................... 7 9  
7. 2. 1   
Effi c a c y  ass ess m e nts  .......................................................................... 7 9  
7. 2. 2   
S af et y  a n d  t ol er a bilit y ass ess m e nts  ..................................................... 8 0  
7. 2. 3   
P h ar m a c o ki n eti cs  ............................................................................... 8 3  
 
 8 8  
8   S af et y  m o nit ori n g  a n d r e p orti n g  .................................................................................... 8 8  
8. 1   
A d v ers e  e v e nts  ................................................................................................... 8 8  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  4  
Pr ot o c ol  N o.  CI N C 2 8 0 X 2 2 0 5  
 
8. 1. 1   
D efi niti o ns  a n d r e p orti n g  ................................................................... 8 8  
8. 1. 2   
L a b or at or y  t est  a b n or m aliti es ............................................................. 9 0  
8. 2   
S eri o us  a d v ers e  e v e nts  ....................................................................................... 9 0  
8. 2. 1   
D efi niti o ns  ......................................................................................... 9 0  
8. 2. 2   
R e p orti n g  ........................................................................................... 9 1  
8. 3   
E m er g e n c y  u n bli n di n g  of  tr e at m e nt  assi g n m e nt ................................................. 9 2  
8. 4   
Pr e g n a n ci es  ........................................................................................................ 9 2  
8. 5   
W ar ni n gs  a n d  pr e c a uti o ns  .................................................................................. 9 2  
8. 6   
D at a   M o nit ori n g C o m mitt e e  .............................................................................. 9 3  
9   D at a  c oll e cti o n  a n d  m a n a g e m e nt  ................................................................................... 9 3  
9. 1   
D at a  c o nfi d e nti alit y  ............................................................................................ 9 3  
9. 2   
Sit e  m o nit ori n g  .................................................................................................. 9 4  
9. 3   
D at a  c oll e cti o n  ................................................................................................... 9 4  
9. 4   
D at a b as e  m a n a g e m e nt  a n d  q u alit y   c o ntr ol .......................................................... 9 4  
1 0   St atisti c al  m et h o ds  a n d  d at a  a n al ysis  ............................................................................. 9 5  
1 0. 1   A n al ysis  s ets  ...................................................................................................... 9 6  
1 0. 1. 1   
F ull  A n al ysis  S et  ................................................................................ 9 6  
1 0. 1. 2   
S af et y  S et  ........................................................................................... 9 6  
1 0. 1. 3   
P er - Pr ot o c ol S et  ................................................................................. 9 6  
1 0. 1. 4   
P h ar m a c o ki n eti c  a n al ysis s et  .............................................................. 9 6  
1 0. 2   P ati e nt  d e m o gr a p hi cs/ ot h er  b as eli n e  c h ar a ct eristi cs  ............................................ 9 7  
1 0. 3   Tr e at m e nts (st u d y tr e at m e nt,  c o n c o mit a nt  t h er a pi es, c o m pli a n c e)  ...................... 9 7  
1 0. 3. 1   
St u d y  tr e at m e nt .................................................................................. 9 7  
1 0. 3. 2   
C o n c o mit a nt  t h er a pi es........................................................................ 9 7  
1 0. 3. 3   
C o m pli a n c e  ........................................................................................ 9 7  
1 0. 4   Pri m ar y  o bj e cti v e  ............................................................................................... 9 7  
1 0. 4. 1   
V ari a bl e  ............................................................................................. 9 7  
1 0. 4. 2   
St atisti c al  h y p ot h esis,  m o d el,  a n d  m et h o d  of  a n al ysis  ......................... 9 8  
1 0. 4. 3   
H a n dli n g  of  missi n g  v al u es/ c e ns ori n g/ dis c o nti n u ati o ns  ...................... 9 9  
1 0. 4. 4   
S u p p orti v e  a n al ys es  ........................................................................... 9 9  
1 0. 5   S e c o n d ar y  o bj e cti v es .......................................................................................... 9 9  
1 0. 5. 1   
S e c o n d ar y  effi c a c y  o bj e cti v es  ............................................................ 9 9  
1 0. 5. 2   
S af et y  o bj e cti v es  .............................................................................. 1 0 0  
1 0. 5. 3   
P h ar m a c o ki n eti cs  ............................................................................. 1 0 3  
 
 1 0 3  
 
 
 1 0 3  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  5  
Pr ot o c ol  N o.  CI N C 2 8 0 X 2 2 0 5  
 
 
 1 0 4  
 
 1 0 4  
1 0. 7   I nt eri m a n al ysis  ................................................................................................ 1 0 4  
1 0. 8   S a m pl e  si z e c al c ul ati o n  .................................................................................... 1 0 4  
1 1   Et hi c al  c o nsi d er ati o ns  a n d  a d mi nistr ati v e   pr o c e d ur es .................................................. 1 0 5  
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  ................................................................... 1 0 5  
1 1. 2   R es p o nsi biliti es  of t h e i n v esti g at or  a n d  I R B/I E C/ R E B ..................................... 1 0 5  
1 1. 3   I nf or m e d c o ns e nt  pr o c e d ur es  ........................................................................... 1 0 6  
1 1. 4   Dis c o nti n u ati o n  of t h e st u d y ............................................................................. 1 0 6  
1 1. 5   P u bli c ati o n  of st u d y  pr ot o c ol  a n d r es ults  .......................................................... 1 0 6  
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 nts .................... 1 0 7  
1 1. 7   C o nfi d e nti alit y  of st u d y  d o c u m e nts  a n d  p ati e nt r e c or ds  .................................... 1 0 8  
1 1. 8   A u dits  a n d  i ns p e cti o ns ..................................................................................... 1 0 8  
1 1. 9   Fi n a n ci al   dis cl os ur es ........................................................................................ 1 0 8  
1 2   Pr ot o c ol  a d h er e n c e  ...................................................................................................... 1 0 8  
1 2. 1   A m e n d m e nts t o  t h e  pr ot o c ol............................................................................. 1 0 8  
1 3   R ef er e n c es ( a v ail a bl e   u p o n r e q u est) ............................................................................. 1 0 9  
1 4   A p p e n di x  .................................................................................................................... 1 1 2  
1 4. 1   G ui d eli n es f or  R es p o ns e  E v al u ati o n  Crit eri a i n  S oli d  T u m ors ( R E CI S T)  v. 1. 1  .1 1 2  
1 4. 1. 1   
I ntr o d u cti o n  ..................................................................................... 1 1 4  
1 4. 1. 2   
Effi c a c y  ass ess m e nts  ........................................................................ 1 1 4  
1 4. 1. 3   
D efi niti o ns  ....................................................................................... 1 1 4  
1 4. 1. 4   
Dis e as e  m e a s ur a bilit y  ...................................................................... 1 1 4  
1 4. 1. 5   
Eli gi bilit y  b as e d  o n  m e as ur a bl e  dis e as e  ............................................ 1 1 5  
1 4. 1. 6   
M et h o ds  of t u m or  m e as ur e m e nt  - g e n er al   g ui d eli n es ........................ 1 1 5  
1 4. 1. 7   
B as 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 esi o ns ................... 1 1 7  
1 4. 1. 8   
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 esi o ns ....................... 1 1 7  
1 4. 1. 9   
F oll o w- u p  & r e c or di n g   of l esi o ns ..................................................... 1 1 8  
1 4. 1. 1 0   N o n - n o d al l esi o ns ............................................................................ 1 1 8  
1 4. 1. 1 1   N o d al l esi o ns  ................................................................................... 1 1 8  
1 4. 1. 1 2   D et er mi n ati o n  of t ar g et  l esi o n r es p o ns e ............................................ 1 1 9  
1 4. 1. 1 3   D et er mi n ati o n  of  n o n -t ar g et l esi o n r es p o ns e ..................................... 1 2 1  
1 4. 1. 1 4   N e w  l esi o ns ..................................................................................... 1 2 1  
1 4. 1. 1 5   E v al u ati o n  of  o v er all  l esi o n r es p o ns e ............................................... 1 2 2  
1 4. 1. 1 6   Effi c a c y   d efi niti o ns .......................................................................... 1 2 3  
1 4. 1. 1 7   B est  o v er all  r es p o ns e ....................................................................... 1 2 3  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  6  
Pr ot o c ol  N o.  CI N C 2 8 0 X 2 2 0 5  
 
1 4. 1. 1 8   Ti m e t o  e v e nt  v ari a bl es  .................................................................... 1 2 5  
1 4. 1. 1 9   Pr o gr essi o n- fr e e s ur vi v al ................................................................. 1 2 5  
1 4. 1. 2 0   O v er all  s ur vi v al ............................................................................... 1 2 5  
1 4. 1. 2 1   Ti m e  t o  pr o gr essi o n ......................................................................... 1 2 5  
1 4. 1. 2 2   Ti m e t o  tr e at m e nt f ail ur e .................................................................. 1 2 5  
1 4. 1. 2 3   D ur ati o n  of  r es p o ns e ........................................................................ 1 2 5  
1 4. 1. 2 4   Ti m e  t o r es p o ns e .............................................................................. 1 2 6  
1 4. 1. 2 5   D efi niti o n  of st art  a n d  e n d  d at es f or ti m e t o  e v e nt  v a ri a bl es .............. 1 2 6  
1 4. 1. 2 6   H a n dli n g  of  p ati e nts  wit h  n o n -m e as ur a bl e  dis e as e  o nl y  at  b as eli n e  ... 1 2 8  
1 4. 1. 2 7   S e nsiti vit y  a n al ys es  .......................................................................... 1 2 9  
1 4. 1. 2 8   D at a  h a n dli n g  a n d   pr o gr a m mi n g r ul es .............................................. 1 3 1  
1 4. 1. 2 9   St u d y/ pr oj e ct  s p e cifi c  d e cisi o ns ....................................................... 1 3 1  
1 4. 1. 3 0   Tr e at m e nt  a n d st u d y  c o m pl eti o n  C R Fs  ............................................. 1 3 1  
1 4. 1. 3 1   St u d y  e v al u ati o n  c o m pl eti o n  ............................................................ 1 3 2  
1 4. 1. 3 2   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 esi o n r es p o ns e .............. 1 3 3  
1 4. 1. 3 3   Pr o gr a m mi n g  r ul es ........................................................................... 1 3 3  
1 4. 1. 3 4   C al c ul ati o n  of ‘ti m e t o  e v e nt’  v ari a bl es  ............................................ 1 3 3  
1 4. 1. 3 5   I n c o m pl et e ass ess m e nt  d at e s  ............................................................ 1 3 3  
1 4. 1. 3 6   I n c o m pl et e  d at es f or l ast  c o nt a ct or  d e at h  ......................................... 1 3 3  
1 4. 1. 3 7   N o n -t ar g et l esi o n r es p o ns e ............................................................... 1 3 4  
1 4. 1. 3 8   St u d y/ pr oj e ct  s p e cifi c  pr o gr a m mi n g ................................................. 1 3 4  
1 4. 1. 3 9   C e ns ori n g  r e as o n ............................................................................. 1 3 4  
1 4. 1. 4 0   R ef er e n c e ( a v ail a bl e   u p o n r e q u est) ................................................... 1 3 5  
1 4. 2   R e vi e w  of  crit eri a f or i nt err u pti o n  a n d r e -i niti ati o n  of st u d y tr e at m e nt ............. 1 3 6  
1 4. 3   A nti ci p at e d ris ks  a n d  n otifi c ati o n  t o i n v esti g at ors ............................................ 1 5 6  
1 4. 3. 1    
B Y L 7 1 9 ........................................................................................... 1 5 6  
1 4. 3. 2   
I N C 2 8 0 ............................................................................................ 1 6 1  
1 4. 3. 3  
L D K 3 7 8 ........................................................................................... 1 6 3  
1 4. 3. 4    
M E K 1 6 2 .......................................................................................... 1 6 6  
1 4. 3. 5  
R ef er e n c es ( a v ail a bl e  u p o n r e q u est)  ................................................. 1 6 8  
1 4. 4   C o n c o mit a nt  M e di c ati o ns  Pr o hi bit e d  or  P er mitt e d  wit h   C a uti o n....................... 1 6 9  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  7  
Pr ot o c ol  N o.  CI N C 2 8 0 X 2 2 0 5  
 
 
Li st  of t a bl e s 
T a bl e   3- 1  
O bj e cti v es  a n d  r el at e d  e n d p oi nts ........................................................ 4 8  
T a bl e   6- 1  
D os e  a n d  tr e at m e nt s c h e d ul e .............................................................. 5 7  
T a bl e   6- 2  
D os e r e d u cti o n st e ps f or  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  a n d   M E K 1 6 2 ... 6 0  
T a bl e   6- 3  
S u p pl y  a n d st or a g e  of  st u d y tr e at m e nts .............................................. 6 6  
T a bl e   7- 1  
Visit  e v al u ati o n  s c h e d ul e.................................................................... 6 9  
T a bl e   7- 2   
I m a gi n g c oll e cti o n  pl a n  ...................................................................... 7 9  
T a bl e   7- 3  
E C O G  p erf or m a n c e  st at us .................................................................. 8 0  
T a bl e   7- 4  
L o c al  Cli ni c al l a b or at or y  p ar a m et ers  c oll e cti o n  pl a n  .......................... 8 1  
T a bl e   7- 5  
I nt e nsi v e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g f or  B Y L 7 1 9 .............. 8 4  
T a bl e   7- 6  
I nt e nsi v e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g f or I N C 2 8 0 ............... 8 5  
T a bl e   7- 7  
I nt e nsi v e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g f or L D K 3 7 8  .............. 8 5  
T a bl e   7- 8  
I nt e nsi v e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g f or  M E K 1 6 2 ............. 8 6  
T a bl e   7- 9  
S p ars e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g  f or  B Y L 7 1 9 .................. 8 6  
T a bl e   7- 1 0  
S p ars e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g  f or I N C 2 8 0 ................... 8 6  
T a bl e   7- 1 1  
S p ars e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g  f or L D K 3 7 8  .................. 8 7  
T a bl e   7- 1 2  
S p ars e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g  f or  M E K 1 6 2 ................. 8 7  
 
 8 8  
T a bl e   1 0- 1  
P ar a m et ers  of  pri or  distri b uti o ns  a n d t hr es h ol ds f or  p ost eri or 
distri b uti o ns  of  O R R  .......................................................................... 9 9  
T a b l e  1 0- 2    
N o n c o m p art m e nt al  p h ar m a c o ki n eti c p ar a m et ers  .............................. 1 0 3  
T a bl e   1 0- 3  
B a y esi a n  d esi g n  p ar a m et ers  a n d  s a m pl e si z e  .................................... 1 0 5  
T a bl e   1 0- 4  
Pr o b a biliti es  of  c orr e ctl y  d e cl ari n g  pr eli mi n ar y  a cti vit y ( A i)  u n d er 
3 s c e n ari os  of tr u e  o v er all r es p o ns e  r at es ( Pi) .................................... 1 0 5  
T a bl e   1 4- 1  
R es p o ns e  crit eri a f or t ar g et l esi o ns  ................................................... 1 1 9  
T a bl e   1 4- 2  
R es p o ns e  crit eri a f or   n o n-t ar g et l esi o ns ............................................ 1 2 1  
T a bl e   1 4- 3  
O v er all l esi o n r es p o ns e  at  e a c h  ass ess m e nt ....................................... 1 2 2  
T a bl e   1 4- 4  
O v er all l esi o n r es p o ns e  at  e a c h  ass ess m e nt:  p ati e nts  wit h   n o n- 
t ar g et dis e as e   o nl y ............................................................................ 1 2 8  
T a bl e   1 4- 5  
O pti o ns f or  e v e nt  d at es  us e d i n  P F S,  T T P,  d ur ati o n  of r es p o ns e ........ 1 2 9  
T a bl e   1 4- 6  
Crit eri a f or i nt err u pti o n  a n d r e -i niti ati o n  of  B Y L 7 1 9 ........................ 1 3 6  
T a bl e   1 4- 7  
Crit eri a f or i nt err u pti o n  a n d r e -i niti ati o n  of I N C 2 8 0 ......................... 1 4 5  
T a bl e   1 4- 8  
Crit eri a f or i nt err u pti o n  a n d r e -i niti ati o n  of L D K 3 7 8 ........................ 1 4 8  
T a bl e   1 4- 9  
Crit eri a f or i nt err u pti o n  a n d r e -i niti ati o n of  M E K 1 6 2  ....................... 1 5 2  
T a bl e   1 4- 1 0  
Gr a di n g f or  r eti n al d et a c h m e nt  ......................................................... 1 5 5  
T a bl e   1 4- 1 1   
F oll o w-u p  e v al u ati o ns f or  s el e ct e d t o xi citi es * .................................. 1 6 2  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  8  
Pr ot o c ol  N o.  CI N C 2 8 0 X 2 2 0 5  
 
 
T a bl e   1 4- 1 2   
F oll o w-u p  e v al u ati o ns f or  s el e ct e d t o xi citi es .................................... 1 6 6  
T a bl e   1 4- 1 3  
P er mitt e d  c o n c o mit a nt  m e di c ati o ns  r e q uiri n g c a uti o n  ...................... 1 6 9  
T a bl e   1 4- 1 4   
Pr o hi bit e d c o n c o mit a nt  m e di c ati o ns  ................................................. 1 7 0  
T a bl e   1 4- 1 5  
M e di c ati o ns  wit h ris k  of  T d P/ Q T  ..................................................... 1 7 1  
Li st  of fi g ur e s 
Fi g ur e  2- 1  
M ol e c ul ar  a b n or m aliti es i n  h u m a n  l u n g  a d e n o c ar ci n o m a ................... 4 5  
Fi g ur e  4- 1   
St u d y  D esi g n ...................................................................................... 4 9  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 9 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
 Li st  of  a b b r e vi ati o n s 
A S C O  
A m eri c a n  S o ci et y  of  Cli ni c al  O n c ol o g y  
A D A  
A m eri c a n  Di a b et e s  A s s o ci ati o n  
A D L  
A cti viti e s  of  D ail y  Li vi n g  
A D M E  
A b s or pti o n,  Di stri b uti o n,  M et a b oli s m  a n d  E x cr eti o n  
A E  
A d v er s e  E v e nt  
A h R  
Ar o m ati c  h y dr o c ar b o n  R e c e pt or  
A kt  
s e e  P K B  
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 L K  
A n a pl a sti c  L y m p h o m a  Ki n a s e  
A L P  
Al k ali n e  P h o s p h at a s e  
A MI  
A c ut e  M y o c ar di al I nf ar cti o n  
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 U C  
Ar e a  U n d er t h e  c o n c e ntr ati o n -ti me  C ur v e  
B C R P  
Br e a st  C a n c er  R e si st a n c e  Pr ot ei n  
B P  
Bl o o d   Pr e s s ur e 
C F D A  
C hi n a  F o o d  a n d  Dr u g  A d mi ni str ati o n  
CI  
C o nfi d e n c e I nt er v al  
C K  
Cr e ati n e  Ki n a s e  
C L  
Cl e ar a n c e  
C m a x  
M a xi m u m  pl a s m a  c o n c e ntr ati o n  
C N S  
C e ntr al  N er v o u s  S y st e m  
C R  
C o m pl et e  R e s p o n s e  
C R F  
C a s e  R e p ort/ R e c or d  F or m; t h e t er m  C R F  c a n  b e  a p pli e d t o  eit h er  E D C  or  P a p er 
C S P  
Cli ni c al  St u d y  Pr ot o c ol  
C S R  
Cli ni c al  St u d y  R e p ort  
C S R  a d d e n d u m   
A n  a d d e n d u m t o  Cli ni c al  St u d y  R e p ort ( C S R) t h at  c a pt ur e s  all t h e  a d diti o n al i nf or m ati o n t h at 
i s  n ot i n cl u d e d i n t h e  C S R 
C 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  
C V A  
C er e br o v a s c ul ar  A c ci d e nt  
C Y P  
C yt o c hr o m e  P 4 5 0  
D C R  
Di s e a s e  C o ntr ol  R at 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 L T  
D o s e  Li miti n g  T o xi cit y  
D TI s  
Dir e ct  T hr o m bi n i n hi bit or s  
E C G  
El e ctr o c ar di o gr a m  
E G F R  
E pi d er m al  Gr o wt h  F a ct or  R e c e pt or  
E M L 4 -A L K   
E c hi n o d er m  mi cr ot u b ul e  a s s o ci at e d  pr ot ei n li k e  4 -a n a pl a sti c l y m p h o m a  ki n a s e 
E R G  
El e ctr o -R eti n o gr a m s  
F A S  
F ull  A n al y si s  S et  
FI H  
Fir st -i n-H u m a n  
F P G  
F a sti n g  Pl a s m a  Gl u c o s e  
G G T  
G a m m a -gl ut a m yl  Tr a n s p e pti d a s e  
G L P  
G o o d  L a b or at or y  Pr a cti c e  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 0
0  Pr ot o c ol  N o. 
 
 
 
 
H b A 1 c  
Gl y c o s yl at e d  H e m o gl o bi n  
H G F  
H e p at o c yt e  Gr o wt h  F a ct or  
H S P 9 0  
H e at  S h o c k  Pr ot ei n  9 0  
i. v. 
i ntr a v e n o u s 
I C 5 0 
C o n c e ntr ati o n  pr o d u ci n g  5 0 %  i n hi biti o n 
I C H 
I nt er n ati o n al  C o nf er e n c e  o n H ar m o ni z ati o n  
I E C 
I n d e p e n d e nt  Et hi c s C o m mitt e e  
I L D 
I nt er stiti al  L u n g Di s e a s e  
I R B 
I n stit uti o n al  R e vi e w B o ar d  
I N 
I n v e sti g at or  N otifi c ati o n 
L F T  
Li v er  F u n cti o n  T e st s  
Ki  
M et a b oli c i n hi biti o n r at e  c o n st a nt  
Ki n a ct  
M a xi m al i n a cti v ati o n  r at e 
L B B B  
L eft  B u n dl e  Br a n c h  Bl o c k  
L C -M S/ M S   
li q ui d  c hr o m at o gr a p h y-t a n d e m  m a s s s p e ctr o m etr y 
L L N  
L o w er  Li mit  of  N or m al  
L L O Q  
L o w er  Li mit  of  Q u a ntit ati o n  
L P L V  
L a st  P ati e nt  L a st  Vi sit  
L V E F  
L eft  V e ntri c ul ar  Ej e cti o n  Fr a cti o n  
M A P  
M et a  A n al yti c al  Pr e di cti v e  
M D R  
M ulti -dr u g  R e si st a n c e  
M E K  
Mit o g e n -a cti v at e d  pr ot ei n ( M A P)  Ki n a s e  
M R P  
M ulti dr u g r e si st a n c e -a s s o ci at e d  pr ot ei n  
M T D  
M a xi m u m  T ol er at e d  D o s e  
m T O R  
M a m m ali a n  T ar g et  of  R a p a m y ci n  
N S C L C  
N o n -S m all  C ell  L u n g  C a n c er  
O A T P  
Or g a ni c  a ni o n -tr a n s p orti n g p ol y p e pti d e  
O R R  
O bj e cti v e  R e s p o n s e  R at e  
O S  
O v er all  S ur vi v al  
P A S  
P h ar m a c o ki n eti c  A n al y si s  S et  
P F S  
Pr o gr e s si o n  Fr e e  S ur vi v al  
P- g p  
P- gl y c o pr ot ei n  
PI 3 K  
P h o s p h ati d yli n o sit ol - 3-Ki n a s e  
PI K 3 C A  
G e n e  w hi c h  e n c o d e s t h e  p 1 1 0 al p h a  c at al yti c  s u b u nit  of  PI 3 K 
P K  
P h ar m a c o ki n eti c s  
P D  
P h ar m a c o d y n a mi c s  
P K B  
Pr ot ei n  Ki n a s e  B  
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 T X  
P ati e nt  d eri v e d t u m or  x e n o gr aft  
P X R  
Pr e g n a n e  X  R e c e pt o r 
R a c c  
A c c u m ul ati o n r ati o  
R A P  
R e p ort  a n d  A n al y si s  Pl a n  
R A S/ R A F/ M E K   
mit o g e n -a cti v at e d  a n d  e xtr a c ell ul ar  si g n al – r e g ul at e d  ki n a s e 
R B B B  
Ri g ht  B u n dl e  Br a n c h  Bl o c k  
R E B  
R e s e ar c h  Et hi c s  B o ar d  
R E CI S T  
R e s p o n s e  E v al u ati o n  Crit eri a i n  S oli d  T u m or s  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 1
5  Pr ot o c ol  N o. 
 
 
 
 
R P 2 D  
R e c o m m e n d e d  P h a s e II  D o s e  
R  V al u e  
A L T/ A L P i n  x  U L N  
R V O  
R eti n al  V ei n  O c cl u si o n  
S A E  
S eri o u s  A d v er s e  E v e nt  
S C C  
S q u a m o u s  c ell  c ar ci n o m a  
S D  
St a bl e  Di s e a s e  
S E C  
S af et y  E v e nt  C at e g ori e s  
T 1/ 2  
T er mi n al  eli mi n ati o n  h alf -lif e 
T d P  
T or s a d e s  d e  P oi nt e s  
T KI  
T yr o si n e  Ki n a s e I n hi bit or s  
T m a x  
Ti m e t o r e a c h  p e a k  pl a s m a  c o n c e ntr ati o n  
T T P  
Ti m e t o  Pr o gr e s si o n  
U G T  
U D P -gl u c ur o n o s yltr a n sf er a s e  
U L N  
U p p er  Li mit  of  N or m al  
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  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 2
5  Pr ot o c ol  N o. 
 
 
 
 
Gl o s s ar y  of t er m s 
A s s e s s m e nt  
A  pr o c e d ur e  u s e d t o  g e n er at e  d at a r e q uir e d  b y t h e  st u d y  
Bi ol o gi c  S a m pl e s   
A  bi ol o gi c al  s p e ci m e n i n cl u di n g, f or  e x a m pl e,  bl o o d ( pl a s m a,  s er u m),  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)  
E nr oll m e nt  
P oi nt/ti m e  of  p ati e nt  e ntr y i nt o t h e  st u d y; t h e  p oi nt  at  w hi c h i nf or m e d  c o n s e nt  m u st  b e 
o bt ai n e d (i. e.  pri or t o  st arti n g  a n y  of t h e  pr o c e d ur e s  d e s cri b e d i n t h e  pr ot o c ol)  
I n v e sti g ati o n al  dr u g  
T h e  st u d y 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  
P eri o d  
A  s u b di vi si o n  of t h e  st u d y ti m eli n e;  di vi d e s  st a g e s i nt o  s m all er f u n cti o n al  s e g m e nt s 
s u c h  a s  s cr e e ni n g,  b a s eli n e, titr ati o n,  w a s h o ut,  et c.  
St a g e i n  c a n c er  
T h e  e xt e nt  of  a  c a n c er i n t h e  b o d y.  St a gi n g i s  u s u all y  b a s e d  o n t h e  si z e  of t h e t u m or, 
w h et h er l y m p h  n o d e s  c o nt ai n  c a n c er,  a n d  w h et h er t h e  c a n c er  h a s  s pr e a d fr o m t h e 
ori gi n al  sit e t o  ot h er  p art s  of t h e  b o 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  co 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 ati o n al tr e at m e nt s i n  c o m bi n ati o n. 
St u d y tr e at m e nt 
di s c o nti n u ati o n  
P oi nt/ti m e  w h e n  a  p ati e nt  p er m a n e ntl y  di s c o nti n u e s  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  
Wit h dr a w al  of  C o n s e nt   
Wit 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  a n 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  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 3
5  Pr ot o c ol  N o. 
 
 
 
 
A m e n d m e nt  7 ( 2 2- M a y -2 0 1 9)  
A m e n d m e nt r ati o n al e  
T h e  m ai n  p ur p os e  of t his  a m e n d m e nt is t o  a d d t h e  o pti o n f or  p ati e nts still  o n st u d y tr e at m e nt 
at t h e ti m e  of st u d y  e n d t o tr a nsf er i nt o  a n ot h er  N o v artis  st u d y. 
I n  a d diti o n, t h e  d efi niti o n  of  e n d  of t h e st u d y  h as  b e e n  cl arifi e d t o  pr o vi d e s uffi ci e nt  d at a f or 
a n al ysis  of s e c o n d ar y  effi c a c y  o bj e cti v es.  
T y p o gr a p hi c al  err ors  a n d i n c o nsist e n ci es  h a v e  b e e n  c orr e ct e d  as  n e e d e d t hr o u g h o ut t h e 
d o c u m e nt. 
 
St u d y  U p d at e:  
T h e   e nr oll m e nt   of  t his  st u d y   h as   b e e n   h alt e d  si n c e   0 1 -A u g -2 0 1 7   d u e  t o   diffi c ult y  i n  
i d e ntif yi n g  p atie nts  w h o  m et t h e  eli gi bilit y  crit eri a  of t h e st u d y.  A t ot al  of  6 6  p ati e nts  h a v e 
b e e n tr e at e d  o n t h e st u d y  wit h  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  or  M E K 1 6 2.  As  of  0 1 -M ar - 2 0 1 9, 
8  p ati e nts  ar e  o n g oi n g i n  L D K 3 7 8  ar m  a n d  h a v e  b e e n  o n tr e at m e nt f or  m or e t h a n  4 0  c y cl es. 
O n e  of t h e  8  p ati e nts  a c hi e v e d st a bl e  dis e as e  a n d t h e  ot h er  p ati e nts  a c hi e v e d  p arti al  r es p o ns e. 
 
C h a n g e s t o t h e  pr ot o c ol  
C h a n g es t o s p e cifi c s e cti o ns  of  t h e  pr ot o c ol   ar e s h o w n i n t h e tr a c k  c h a n g es  v ersi o n  of t h e 
pr ot o c ol  usi n g stri k e t hr o u g h r e d f o nt f or  d el eti o ns  a n d r e d  u n d erli n e f or i ns erti o ns.  
List   of   A b br e vi ati o ns:   A b br e vi ati o ns   d el et e d  f or  I n v esti g at or -I niti at e d   Tri al,  I nt er a cti v e  
R es p o ns e   T e c h n ol o g y,   M a xi m al  i n a cti v ati o n  r at e,   R e d   Bl o o d   C ells,   St a n d ar d   O p er ati n g  
Pr o c e d ur e  a n d  V ol u m e  of  distri b uti o n  at  St e a d y  St at e.   D efi niti o n  of   a b br e vi ati o n  f or  M A P  
w as   u p d at e d. 
S e cti o n  4. 1  w as  u p d at e d t o i n cl u d e t h e  o pti o n t o tr a nsf er  p ati e nts t o  a n ot h er  N o v artis st u d y. 
S e cti o ns  4. 3  a n d  7. 1. 6  w er e  u p d at e d t o  c orr e ctl y  r efl e ct t h e  d efi niti o n  of  e n d  of st u d y. 
I R B s/I E C s 
A   c o p y   of  t his   a m e n d e d   pr ot o c ol   will   b e  s e nt  t o  t h e  I nstit uti o n al   R e vi e w   B o ar d  
(I R Bs)/I n d e p e n d e nt  Et hi cs  C o m mitt e e (I E Cs)  a n d  H e alt h  A ut h oriti es. 
T h e   c h a n g es   d es cri b e d  i n  t his   a m e n d e d   pr ot o c ol  r e q uir e  I R B/I E C   a p pr o v al   pri or  t o  
i m pl e m e nt ati o n. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 4
5  Pr ot o c ol  N o. 
 
 
 
 
A m e n d m e nt  6 ( 2 6- J a n -2 0 1 7)  
CI N C 2 8 0 X 2 2 0 5 st art e d  e nr oll m e nt  o n  2 0 J a n u ar y  2 0 1 5.  As  of  1 5  N o v e m b er  2 0 1 6,  a t ot al  of 
5 0  p ati e nts  h a v e  b e e n tr e at e d  o n t h e st u d y  wit h  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  or  M E K 1 6 2.  
T h e  m ai n  p ur p os e  of t his  a m e n d m e nt is t o  u p d at e t h e  pr ot o c ol  wit h  n e w r e c o m m e n d ati o ns f or 
B Y L 7 1 9  A E  m a n a g e m e nt  a n d  d osi n g  a d mi nistr ati o n,  w hi c h  w er e  p u blis h e d i n t h e  m ost r e c e nt 
I n v esti g at or’s  Br o c h ur e. 
T h e  m o difi c ati o ns t o  A E  m a n a g e m e nt  ar e  b as e d  o n  a  pr o gr a m -wi d e  ass ess m e nt  a n d  a d vis or y 
b o ar d  i n p ut  r e g ar di n g   B Y L 7 1 9  i n d u c e d   h y p er gl y c e mi a   a n d  s ki n  t o xi cit y.   T h e  
i n cl usi o n/ e x cl usi o n   crit eri a   as   w ell   as   m a n a g e m e nt   g ui d eli n es   h a v e   b e e n   m o difi e d  i n  t his  
pr ot o c ol,   b as e d   o n   d e v el o p e d  g ui d a n c e  fr o m  t his   pr o gr a m  r e vi e w.   T h es e  r e c o m m e n d ati o ns 
a p pl y t o t h e  B Y L 7 1 9  ar m  a n d i n cl u d e:  a  m o difi c ati o n t o  e x cl u d e  p ati e nts  wit h  H b A 1 c  ≥  6. 5 %; 
u p d at e d  tr e at m e nt   g ui d a n c e   wit h  r e g ar d  t o   h y p er gl y c e mi a,  s ki n  t o xi cit y,   a n d   el e v at e d  
tr a ns a mi n as es. 
T h e  m o difi c ati o ns t o  B Y L 7 1 9  d osi n g  a d mi nistr ati o n  ar e  b as e d  o n  cli ni c al  d at a fr o m  a f o o d 
eff e ct  st u d y   a n d   dr u g -dr u g  i nt er a cti o n  st u d y.   B as e d   o n  t h es e   d at a,  t h e   pr ot o c ol   h as   b e e n  
u p d at e d  t o  i n cl u d e  r e q uir e d   a d mi nistr ati o n   of   B Y L 7 1 9   wit h  f o o d   a n d  t h e  r e m o v al   of   a  
r estri cti o n  o n  a d mi nistr ati o n  of  a ci d r e d u ci n g  a g e nts.  I n  a d diti o n,  t h e  a m e n d m e nt   h as  b e e n  
u p d at e d t o:  
•   All o w  c e ntr al r e vi e w f or  E C Gs f or  c o m p aris o n  of l o c al  E C G  a n al ysis;  
•   All o w  p ati e nts  wit h  o v erl a p pi n g  m ol e c ul ar  alt er ati o ns t o  b e  e nr oll e d;  
•   R e m o v e t h e  c o a g ul ati o n t est  d uri n g  pr e -s cr e e ni n g  as  p ati e nts  ar e  e x p e ct e d t o  b e  m o nit or e d 
f or  bl e e di n g ris k  d uri n g  bi o ps y  as  p er l o c al pr a cti c e;  
•   I m pl e m e nt  n e w str e n gt h  of  1 5 0 m g I N C 2 8 0 t a bl et  d e p e n di n g  o n t h e  a v ail a bilit y  of t h e 
s u p pli es  a n d f oll o wi n g t h e r e g ul at or y  r e q uir e m e nts; 
•   I n cr e as e t h e  mi ni m al  p ati e nt  n u m b er f or  P K s a m pl e  c oll e cti o n f or  B Y L 7 1 9  ar m t o  g et 
m or e  k n o wl e d g e  a b o ut t h e  P K  pr ofil e f or  B Y L 7 1 9  c o nsi d eri n g t his is t h e first st u d y f or 
B Y L 7 1 9 i n l u n g  c a n c er.  S p e cif y t h e  mi ni m al  p ati e nt  n u m b er f or  P K s a m pl e  c oll e cti o n  f or 
I N C 2 8 0  ar m  as  b ot h  c a ps ul e  a n d t a bl et  h a v e  b e e n  us e d i n t his  ar m  a n d  o nl y  o n e  p ati e nt 
w as tr e at e d  wit h  c a ps ul e.  
•   M a k e  ot h er  mi n or  cl arifi c ati o ns/  e dit ori al  c h a n g es  w hi c h  ar e i n cl u d e d i n t h e list  of 
c h a n g es   b el o w. 
 
C h a n g e s t o t h e  pr o t o c ol 
•   Pr ot o c ol s u m m ar y  a n d  S e cti o n  5. 1  h a v e  h as  b e e n  u p d at e d t o i n cl u d e  p ati e nts  wit h l u n g 
s q u a m o us  c ell  c ar ci n o m a f or  B Y L 7 1 9  ar m t o  e ns ur e t h e  p ati e nt  p o p ul ati o n is  c o nsist e nt 
wit h t h e  o n e i n t h e  S e cti o n  5. 2 . 
•   S e cti o n  2. 1  h as  b e e n  u p d at e d t o  c orr e ct t h e  y e ar  of  p u bli c ati o n f or  o n e  r ef er e n c e. 
•   S e cti o n   5. 2   h as   b e e n   u p d at e d  t o   cl arif y  t h e   pr o c ess  t o   e nr oll   p ati e nt   wit h   o v erl a p pi n g  
m ol e c ul ar  alt er ati o ns t est e d i n t h e  st u d y. 
•   S e cti o n   5. 3   h as   b e e n   u p d at e d  t o   e x cl u d e  f e m al e   p ati e nts   wit h   a   Q T c F > 4 6 0   ms e c  f or  
B Y L 7 1 9  ar m  a n d t o  e x cl u d e  p ati e nts  wit h  H b A 1 c  ≥  6. 5 % f or  B Y L 7 1 9  ar m.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 5
5  Pr ot o c ol  N o. 
 
 
 
•   S e cti o n  6. 1. 1  B Y L 7 1 9  d osi n g i nstr u cti o ns  a n d r e c o m m e n d ati o ns  h a v e  b e e n  u p d at e d  b as e d 
o n t h e r es ults  of  a f o o d  eff e ct  a n d  A R A  D DI  st u d y. 
•   S e cti o n  6. 2. 1  h as  b e e n r e or g a ni z e d  a n d  u p d at e d t o s p e cif y t h e r estri cti o n  of s e c o n d  d os e 
r e d u cti o n  o nl y a p pli es t o r e c urr e nt  Gr a d e  3/ 4  t o xi cit y. 
•   S e cti o n  6. 2. 2 , T a bl e  6 - 3 h as  b e e n  m o v e d t o  S e cti o n  1 4. 3. 2  t o  c o m bi n e  wit h t h e f oll o w u p 
g ui d eli n e f or li v er  a b n or m alit y f or I N C 2 8 0  ar m.  
•   S e cti o n   6. 2. 3   h as   b e e n   u p d at e d  t o  i n cl u d e   g e n er al   m e as ur es  t o   mi ni mi z e  ris ks  t o  t h e  
p ati e nts.  M a n a g e m e nt  of  P n e u m o nitis f or  B Y L 7 1 9  h as  b e e n r e m o v e d t o  S e cti o n  1 4. 3  t o 
e ns ur e   all  t h e  ris k   m a n a g e m e nt   g ui d eli n e  is  i n cl u d e d  i n  t h e  s a m e  s e cti o n.   D os e  
m o difi c ati o n   g ui d eli n e  f or   ot h er   A Es  f or   L D K 3 7 8   ar m   h as   b e e n  i n c or p or at e d  i nt o  t h e  
T a bl e   1 4- 8. 
•   S e cti o n   6. 3. 1   h as   b e e n   u p d at e d  t o  i n cl u d e  t h e   p er mitt e d   c o n c o mit a nt   m e di c ati o ns  f or  
B Y L 7 1 9  ar m.  
•   S e cti o n   6. 3. 2   h as   b e e n   u p d at e d  t o  i n cl u d e   n e w   p er mitt e d   c o n c o mit a nt   m e di ati o ns   us e d  
wit h  c a uti o n f or  B Y L 7 1 9  ar m  a n d t o  a d d  h er b al  m e di c ati o n  as  c o n c o mit a nt  m e di c ati o ns 
us e d  wit h  c a uti o n f or  all t h e  ar ms.  
•   S e cti o n  6. 3. 3  h as  b e e n  u p d at e d t o i n cl u d e t h e  ot h er  a nti c a n c er t h er a p y  as t h e  pr o hi bit e d 
c o n c o mit a nt   m e di c ati o n.   R estri cti o n   of   us e   A R A  i n   B Y L 7 1 9   ar m   h as   b e e n  r e m o v e d. 
C Y P 2 C 8/ 9  s u bstr at e   wit h   N TI   h as   b e e n   m o v e d  t o  t h e   p er mitt e d   m e di c ati o n   us e d   wit h  
c a uti o n.  H er b al  m e di c ati o n  h as  b e e n  cl arifi e d t o  b e  pr o hi bit e d f or  dis e as e tr e at m e nt f or  all 
t h e ar ms.  
•   S e cti o n  6. 5. 2 , T a bl e  6 - 3 h as  b e e n  u p d at e d t o  a d d  1 5 0 m g  as  a  n e w str e n gt h f or  I N C 2 8 0. 
•   S e cti o n  7. 1 , T a bl e  7 - 1  h as  b e e n  u p d at e d t o r e m o v e t h e  c o a g ul ati o n t est  d uri n g  m ol e c ul ar 
s cr e e ni n g.  A p art ti m e  b et w e e n tri pl et  E C Gs  h as  b e e n  u p d at e d.  A n d t h e r ef er e n c e t a bl e f or 
t h e  P K  a n al ysis  h as  b e e n c orr e ct e d.  
•   S e cti o n  7. 1. 2  h as  b e e n  u p d at e t o  cl arif y t h at st a n d ar d  c ar e  of  ass ess m e nt  p erf or m e d  b ef or e 
writt e n  i nf or m   c o ns e nt   o bt ai n e d   c a n   b e   us e d   c o nsi d eri n g  it   w as   wit hi n  t h e  s cr e e ni n g  
wi n d o w.  
•   S e cti o n  7. 2. 2. 6  h as  b e e n  u p d at e d t o i ntr o d u c e t h e  p ot e nti al  c e ntr al  E C G r e vi e w.  U p d at e  of 
t h e  a p art ti m e  b et w e e n tri pl et  E C Gs  h as  b e e n r efl e ct e d i n t his s e cti o n. 
•   S e cti o n  7. 2. 3. 1  h as  b e e n  u p d at e d t h e  mi ni m al  p ati e nt  n u m b er f or  P K s a m pl e  c oll e cti o n f or 
e a c h  ar m.  
•   S e cti o n  8. 2. 1  h as  b e e n  u p d at e d t o  cl arif y t h e  pr ot o c ol  e x e m pt  S A E.  
•   S e cti o n  9. 4  h as  b e e n  u p d at e d t o r efl e ct t h e  p ot e nti al  us e  of  c e ntr al  E C G  r e vi e w. 
•   S e cti o n  1 0  h as  b e e n  c orr e ct e d t h e  n u m b er  of tr e at m e nt  ar ms.  
•   S e cti o n  1 0. 5. 2. 4  h as  b e e n  u p d at e d t o i n cl u d e t h e  c e ntr al  E C G  d at a  i n t h e fi n al a n al ysis.  
•   S e cti o n  1 1. 5  h as  b e e n  u p d at e d t o  ali g n  wit h t h e  N o v artis  p u bli c ati o n   g ui d a n c e. 
•   S e cti o n  1 3  h as  b e e n  a d d e d  wit h  n e w  r ef er e n c es. 
•   S e cti o n  1 4. 2 , T a bl e  1 4 - 6 h as  b e e n  u p d at e d t o  pr o vi d e  m or e  d os e  m o difi c ati o n  g ui d a n c e f or 
h y p er gl y c e mi a  a n d s ki n t o xi cit y  a n d t o  u p d at e  d os e  m o difi c ati o n  g ui d a n c e  o n  di arr h e a,  
li v er  a b n or m alit y,  c ar di a c  e v e nts, st o m atitis,  a n d i n  c as e  of  ac ut e  p a n cr e atitis f or  B Y L 7 1 9 
ar m.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 6
5  Pr ot o c ol  N o. 
 
 
 
•   S e cti o n  1 4. 2 , T a bl e  1 4 - 8  h as  b e e n  u p d at e d t o  c orr e ct t h e  a d mi nistr ati o n  err or  a n d t o  a d d 
t h e  g e n er al  m a n a g e m e nt  g ui d a n c e f or  ot h er A Es.  
•   S e cti o n  1 4. 3. 1  h as  b e e n  a d d e d t h e s ki n t o xi cit y,  a m yl as e/ li p as e  e v al u ati o n, li v er t o xi cit y 
as  t h e  s el e ct e d  t o xi cit y  f or   B Y L 7 1 9   a n d   pr o vi d e d   m or e   g ui d a n c e  t o   m a n a g e  
h y p er gl y c e mi a, s ki n t o xi cit y  a n d  di arr h e a.  
•   S e cti o n   1 4. 3. 2   h as   b e e n   u p d at e d  t o  r efl e ct  t h e   m o v e   of  I N C 2 8 0  f oll o w   u p   of  s el e ct e d  
t o xi cit y. 
•   S e cti o n  1 4. 3. 3  h as  b e e n  u p d at e d t o r ef er t h e  DI LI f oll o w  u p  g ui d a n c e f or  L D K 3 7 8  ar m t o 
t h e  o n e f or I N C2 8 0  ar m.  
•   S e cti o n  1 4. 3. 5  h as  b e e n  u p d at e d  wit h  n e w r ef er e n c e   a d d e d. 
•   S e cti o n  1 4. 4  h as  b e e n  u p d at e d t o r efl e ct t h e  c h a n g es  wit h r es p e ct t o t h e  c o -a d mi nistr ati o n 
C Y P 2 C 8.  C Y P 2 C 9,  C Y P 3 A 4  a n d  B C R P.  
C h a n g es t o s p e cifi c s e cti o ns  of  t h e  pr ot o c ol   ar e s h o w n i n t h e tr a c k  c h a n g es  v ersi o n  of t h e 
pr ot o c ol  usi n g stri k e t hr o u g h r e d f o nt f or  d el eti o ns  a n d r e d  u n d erli n e d f or i ns erti o ns.  
 
I R B/I E C/ H A 
A   c o p y   of  t his   a m e n d e d   pr ot o c ol   will   b e  s e nt  t o  t h e  I nstit uti o n al   R e vi e w   B o ar d  
(I R Bs)/I n d e p e n d e nt  Et hi cs  C o m mitt e e (I E Cs)  a n d  H e alt h  A ut h oriti es. 
T h e   c h a n g es   d es cri b e d  i n  t his   a m e n d e d   pr ot o c ol  r e q uir e  I R B/I E C   a p pr o v al   pri or  t o  
i m pl e m e nt ati o n. 
T h e  c h a n g es  h er ei n  aff e ct t h e I nf or m e d  C o ns e nt.  Sit es  ar e r e q uir e d t o  u p d at e  a n d  s u b mit f or 
a p pr o v al   a  r e vis e d  I nf or m e d  C o ns e nt  t h at  t a k es  i nt o   a c c o u nt  t h e   c h a n g es   d es cri b e d  i n t his  
pr ot o c ol  a m e n d m e nt.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 7
5  Pr ot o c ol  N o. 
 
 
 
 
A m e n d m e nt  5 ( 0 1- J ul -2 0 1 6)  
A m e n d m e nt r ati o n al e  
T h e  CI N C 2 8 0 X 2 2 0 5 st u d y st art e d  e nr oll m e nt  o n  2 0 J a n u ar y  2 0 1 5.  As  of  2 3  M a y  2 0 1 6,  a t ot al 
of  4 0  p ati e nts  h a v e  b e e n tr e at e d i n t h e st u d y  wit h  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  or  M E K 1 6 2. 
T h e  e nr oll m e nt f or  L D K 3 7 8  ar m  w as  c o m pl et e d  o n  1 5 -A pr -2 0 1 6  b e c a us e t h e  s a m pl e si z e  as 
d efi n e d i n t h e  pr ot o c ol  w as  r e a c h e d. 
T h e  m ai n  p ur p os e  of t his  a m e n d m e nt is t o  u p d at e t h e  c o n c o mit a nt  m e di c ati o n i nf or m ati o n f or 
I N C 2 8 0 tr e at m e nt  ar m  a n d  L D K 3 7 8 tr e at m e nt  ar m,  a n d t o  cl arif y t h e  Q T i nt er v al  c orr e cti o n 
m et h o d f or  L D K 3 7 8 tr e at m e nt  ar m.  
A m e n d m e nt  R ati o n al es f o r I N C 2 8 0  a r m:  
•   B as e d  o n  n e w  P K  d at a it is s u g g est e d t h at t h e  c o n c o mit a nt  us e  of  Pr ot o n  P u m p I n hi bit ors 
( P PIs) is  u nli k el y t o i m p a ct t h e  effi c a c y  of I N C 2 8 0, t h er ef or e t h e  P PI r estri cti o n  c a n  b e 
r e m o v e d fr o m t his  pr ot o c ol f or  p ati e nts r e quiri n g  P PI  g astri c  pr ot e cti o n tr e at m e nt. 
M or e o v er, r e q uir e m e nts  o n  ot h er  a ci d r e d u ci n g  a g e nts ( g astri c  a ci d  m o d ul at ors  a n d  H 2 
r e c e pt or  a nt a g o nists)  c a n  als o  b e r e m o v e d. 
•   T h e list  of  pr o hi bit e d  a n d t o  b e  us e d  wit h  c a uti o n  m e di c ati o ns f or I N C 2 8 0  h as  als o  b e e n  
u p d at e d  b as e d  o n t h e l at est i nt er n al  D DI   g ui d a n c e. 
A m e n d m e nt  R ati o n al e f o r  L D K 3 7 8  a r m : 
•   F or  cl arifi c ati o n  p ur p os e, t o  e ns ur e t h e  Q T  c orr e cti o n  m et h o d is  c o nsist e nt  d uri n g t h e 
st u d y,  E C G  ass ess m e nt  a n d  d os e  m o difi c ati o n  g ui d a n c e  h as  b e e n  u p d at e d t o s p e cif y t h at 
Q T c F  w o ul d  b e  us e d t o  m o nit or  Q T   pr ol o n g ati o n. 
•   T h e list  of  p er mitt e d,  pr o hi bit e d  a n d t o  b e  us e d  wit h  c a uti o n  m e di c ati o ns f or  L D K 3 7 8  h as 
b e e n  u p d at e d  b as e d  o n t h e l at est i nt er n al  g ui d a n c e f or  L D K 3 7 8 tr e at m e nt.  N o n -e n z y m e 
i n d u ci n g  a nti-e pil e pti c  dr u gs  a n d  h er b al  m e di c ati o ns  h a v e  b e e n  a d d e d  as t h e  pr o hi bit e d 
c o n c o mit a nt  m e di c ati o ns.  E n z y m e i n d u ci n g  a nti -e pil e pti c  dr u gs,  bis p h os p h o n at e  a n d 
d e n os u m a b  h a v e  b e e n  a d d e d  as  p er mitt e d  c o n c o mit a nt  m e di c ati o ns.  C orti c ost er oi d  h as 
b e e n  a d d e d  as t h e  c o n c o mit a nt  m e di c ati o ns t o  b e  us e d  wit h  c a uti o n.  P alli ati v e 
r a di ot h er a p y  a n d  p alli ati v e s ur g er y  h a v e  b e e n a d d e d  as  all o w e d  c o n c o mit a nt  tr e at m e nts. 
 
C h a n g e s t o t h e  pr ot o c ol  
S e cti o n  1. 2. 2. 2. 2:  Cli ni c al  p h ar m a c o ki n eti cs  h as  b e e n  u p d at e d  wit h  n e w  P K  d at a f or I N C 2 8 0.  
S e cti o n   6. 3. 1:   P PIs   a n d   ot h er   a ci d  r e d u ci n g   a g e nts   h a v e   b e e n   a d d e d   as  t h e   p er mitt e d  
c o n c o mit a nt  m e di c ati o ns f or I N C 2 8 0.  E n z y m e i n d u ci n g  a nti -e pil e pti c  dr u gs , bis p h os p h o n at e 
a n d  d e n os u m a b  h a v e  b e e n  a d d e d  as  p er mitt e d  c o n c o mit a nt  m e di c ati o ns f or  L D K 3 7 8.  
S e cti o n  6. 3. 2:  C ort i c ost er oi d  h as  b e e n  a d d e d  as t h e  c o n c o mit a nt  m e di c ati o ns t o  b e  us e d  wit h 
c a uti o n  f or   L D K 3 7 8.   P alli ati v e  r a di ot h er a p y   a n d   p alli ati v e  s ur g er y   h a v e   b e e n   a d d e d   as  
all o w e d   c o n c o mit a nt  tr e at m e nts  f or   L D K 3 7 8.   R estri cti o ns   o n   a ci d  r e d u ci n g   a g e nts  ( g astri c 
a ci d  m o d ul at ors  a n d  H 2 r e c e pt or  a nt a g o nists)  h a v e  b e e n r e m o v e d f or  I N C 2 8 0. 
S e cti o n   6. 3. 3:   R estri cti o n   o n   P PIs   h as   b e e n  r e m o v e d  f or  I N C 2 8 0   b as e d   o n   n e w   P K   d at a.  
C Y P 2 C 8 s u bstr at e  wit h  n arr o w t h er a p e uti c i n d e x ( N TI)  h as  b e e n r e m o v e d f or  L D K 3 7 8  as  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 8
5  Pr ot o c ol  N o. 
 
 
 
L D K 3 7 8  is   n ot   a   p ot e nt  i n hi bit or   of   C Y P 2 C 8.  I n v esti g ati o n al  t h er a pi es   a n d   a nti -c a n c er 
t h er a pi es  e x c e pt t h e st u d y tr e at m e nt  a n d t h os e list e d i n t h e  S e cti o n  6. 3. 2  h a v e  b e e n  cl arifi e d t o 
b e   pr o hi bit e d   c o n c o mit a nt  t h er a pi es. T a bl e   7 -4  I N C 2 8 0   a r m:   L o c al   cli ni c al  l a b o r at or y 
p ar a m et ers  c oll e cti o n  pl a n  h as  b e e n  u p d at e d t o i n cl u d e t h e r e q uir e d l a b or at or y  e v al u ati o ns f or 
p ot e nti al  dr u g -i n d u c e d li v er i nj ur y  c as es. 
S e cti o n   1 4. 3. 2:   F oll o w- u p   e v al u ati o ns  f or  s el e ct e d   h e p ati c  t o xi citi es   h a v e   b e e n   u p d at e d  t o 
m a k e it  c o nsist e nt  wit h  T a bl e  6 -3.  A n d  R  v al u e  d efi niti o n  h as  b e e n  u p d at e d i n t h e f oll o w  u p 
of  p ot e nti al  DI LI  c as e  s e cti o n. 
S e cti o n   7. 2. 2. 6. 1:   T e xt   h as   b e e n   a d d e d  t o   cl arif y  t h at   Q T c F   will   b e   us e d  t o   c orr e ct   Q T  
i nt er v al  d uri n g t h e tr e at m e nt. 
T a bl e   1 4 -8   L D K 3 7 8   a r m:   T e xt   h as   b e e n   a d d e d  t o   cl arif y  t h at   Q T c F   will   b e   us e d   as  t h e  
c orr e cti o n  m et h o d f or t h e  m o nit ori n g  of  Q T  pr ol o n g ati o n.  
S e cti o n  1 4. 4 :  G ui d a n c e  h as  b e e n  a d d e d f or  h a n dli n g t h e sit u ati o n if  a  m e di c ati o n is list e d  b ot h 
i n  T a bl e  1 4-1 2  a n d  T a bl e  1 4 - 1 3. 
T a bl e  1 4 - 1 2:  T h e  s e nsiti v e  C Y P 2 D 6 s u bstr at e  h as  b e e n r e m o v e d  as it is  n ot  a p pli c a bl e t o  a n y 
ar m.  A n d  P PIs  h a v e  b e e n  a d d e d t o  e ns ur e it  c o nsist e nt  wit h t h e  S e cti o n  6. 3. 2. T a bl e  1 4 - 1 3: 
C Y P 2 D 6 s u bstr at es  wit h  N TI  a n d  P -g p tr a ns p ort ers  wit h  N TI  h a v e  b e e n r e m o v e d  as t h e y  ar e 
n ot  a p pli c a bl e t o  a n y  ar m.  C Y P 2 C 8 s u bstr at e  wit h  N TI  a n d  C Y P 2 C 9 s u bstr at e  wit h  N TI  h a v e 
b e e n   a d d e d  t o   e ns ur e  t h e  i nf or m ati o n  i n   T a bl e   1 4 -1 3  is   c o nsist e nt   wit h  t h e   S e cti o n   6. 3. 3.  
A d diti o n all y,   e a c h   pr o hi bit   c o n c o mit a nt   m e di c ati o n   h as   b e e n  s p e cifi e d   wit h  its   a p pli c a bl e 
tr e at m e nt  ar m(s). 
T a bl e  1 4 - 1 4:  M e di c ati o ns  wit h  k n o w n ris k  of  Q T  pr ol o n g ati o n  h a v e  b e e n  u p d at e d. 
C h a n g es t o s p e cifi c s e cti o ns  of  t h e  pr ot o c ol   ar e s h o w n i n t h e tr a c k  c h a n g es  v ersi o n  of t h e 
pr ot o c ol  usi n g stri k e t hr o u g h r e d f o nt f or  d el eti o ns  a n d r e d  u n d erli n e d f or i ns erti o ns.  
 
I R B/I E C/ H A 
A   c o p y   of  t his   a m e n d e d   pr ot o c ol   will   b e  s e nt  t o  t h e  I nstit uti o n al   R e vi e w   B o ar d  
(I R Bs)/I n d e p e n d e nt  Et hi cs  C o m mitt e e (I E Cs)  a n d  H e alt h  A ut h oriti es. 
T h e   c h a n g es   d es cri b e d  i n  t his   a m e n d e d   pr ot o c ol  r e q uir e  I R B/I E C   a p pr o v al   pri or  t o  
i m pl e m e nt ati o n. 
T h e  c h a n g es  h er ei n  aff e ct t h e I nf or m e d  C o ns e nt.  Sit es  ar e r e q uir e d t o  u p d at e  a n d s u b mit f or 
a p pr o v al   a  r e vis e d  I nf or m e d  C o ns e nt  t h at  t a k es  i nt o   a c c o u nt  t h e   c h a n g es   d es cri b e d  i n t his  
pr ot o c ol  a m e n d m e nt.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 9
5  Pr ot o c ol  N o. 
 
 
 
 
A m e n d m e nt  4 
A m e n d m e nt r ati o n al e  
T h e  m ai n  p ur p os e  of  t his  a m e n d m e nt is t o i n cl u d e s q u a m o us  c ell  c ar ci n o m a  p ati e nts i nt o t h e 
B Y L 7 1 9   ar m   a n d  t o   u p d at e  t h e   d os e   m o difi c ati o n   g ui d eli n es,  s af et y   m o nit ori n g   pl a n   a n d  
c ert ai n i n cl usi o n/ e x cl usi o n  crit eri a f or I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2 tr e at m e nt  ar ms  b as e d 
o n   a v ail a b l e  a n d  c urr e nt  i nf or m ati o n.   F or  t h e  p ati e nt   p o p ul ati o n,  t h e li mit ati o n  of  n o  m or e 
t h a n t w o  pri or li n es  of  a nti n e o pl asti c  w as r e m o v e d  pr o vi di n g tr e at m e nt  o p p ort u niti es f or t h os e 
p ati e nts  wit h  a d v a n c e d l u n g  c a n c er  dis e as e i n t h e l at e s etti n g,  c o nsi d eri n g r e c e nt  c h a n g es  of 
tr e at m e nt  l a n ds c a p e  i n  l u n g   c a n c er.   T his   a m e n d m e nt   als o  i ntr o d u c es  t h e   p ossi bilit y   of  
utili zi n g   a   c e ntr al  l a b or at or y  f or   m ol e c ul ar   pr es cr e e ni n g   p ur p os es.   T h e  r ati o n al e  f or  
m o difi c ati o n  of  e a c h  ar m  of t h e st u d y is list e d  as  b el o w.  
M ai n  C h a n g es i n  B Y L 7 1 9  a r m:  
•   PI K 3 C A -m ut at e d  n o n -s m all  c ell l u n g  c a n c er ( N S C L C) r e pr es e nts  a  cli ni c all y  a n d 
g e n eti c all y  h et er o g e n e o us s u b gr o u p i n  a d e n o c ar ci n o m as  as  w ell  as i n s q u a m o us  c ell 
c ar ci n o m as ( S C C)  wit h  a  hi g h er  pr e v al e n c e  of t h es e  m ut ati o ns i n  S C C ( 8. 9 %  vs  2. 9 % 
c o m p ari n g  wit h  a d e n o c ar ci n o m a) ( S c h effl er  et  al.  2 0 1 5).  PI K 3 C A  c o p y -n u m b er  g ai ns  als o 
o c c ur i n l u n g  c a n c ers,  wit h  hi g h er fr e q u e n c y i n s q u a m o us  c ell  c ar ci n o m as ( Y a m a m ot o  H 
et  al,  C a n c er  R es.  2 0 0 8;  K a w a n o  O  et  al,  L u n g  C a n c er.  2 0 0 7).  PI K 3 C A 
m ut ati o n/ a m pli fi c ati o n  m a y r e pr es e nt  a  g o o d  pr e di cti v e f e at ur e f or t h e  cli ni c al  a p pli c ati o n 
of s p e cifi c  PI 3 K i n hi bit ors i n  S C C l u n g  c a n c er  p ati e nts ( B o n elli  M A  et  al.  M ol  C a n c er 
T h er.  2 0 1 5  A u g). I nt er n al  P ati e nt  d eri v e d t u m or  x e n o gr aft ( P T X)  d at a s h o w e d t h at  3  o ut 
of  4  PI K 3 C A  m ut ati o n l u n g s q u a m o us  c ell  c ar ci n o m a  c ell li n e r es p o n d e d ( 2 st a bl e  a n d  1 
p arti al r es p o ns e, t h e n  pr o gr ess) t o t h e  B Y L 7 1 9 si n gl e  a g e nt tr e at m e nt.  B as e d  o n  his, t h e 
i n cl usi o n  crit eri a  of  B Y L 7 1 9  ar m is  e x p a n d e d fr o m  a d e n o c ar ci n o m a  N S C L C  p ati e nts t o 
a d e n o c ar ci n o m a  or s q u a m o us  c ell  c ar ci n o m a  N S C L C  p ati e nts.  
M ai n  c h a n g es i n I N C 2 8 0  a r m:  
•   T his  pr ot o c ol  a m e n d m e nt  pr o vi d es  a d diti o n al i nf or m ati o n  a n d  g ui d a n c e t o i n v esti g at ors 
f or t h e  m a n a g e m e nt  of li v er t o xi citi es.  Aft er t h e  c ut-off  d at e  of t h e  c urr e nt  I N C 2 8 0 
I n v esti g at or’s  Br o c h ur e ( 2 8-S e p -2 0 1 4),  a f e m al e  p ati e nt  e x p eri e n c e d  a s eri o us,  u n e x p e ct e d, 
p ossi bl y r el at e d  a d v ers e  e v e nt  of  a b n or m al li v er f u n cti o n t ests  d uri n g tr e at m e nt  wit h  a 
c o m bi n ati o n  of I N C 2 8 0  a n d  g efiti ni b  w hil e  e nr oll e d i n t h e  CI N C 2 8 0 X 2 2 0 2 st u d y.  T his 
a d v ers e  e v e nt  m et t h e l a b  crit eri a  of  H y’s  L a w  a n d t h e  h e p at ot o xi cit y  c o ul d  n ot  b e 
attri b ut e d s ol el y t o  eit h er  dr u g  al o n e  or t o t h e  c o m bi n ati o n.  T h er ef or e,  cl arifi c ati o ns i n t h e 
d os e  m o difi c ati o n  g ui d eli n es i n  c as e  of li v er t o xi cit y  a n d  u p d at e d r ul es  wit h r e g ar ds t o 
st u d y tr e at m e nt  dis c o nti n u ati o n f or  e v e nts t h at  m e et t h e  H y’s  L a w  crit eri a  ar e  a d d e d.  
F urt h er m or e,  ot h er  u p d at es  ar e  b ei n g i m pl e m e nt e d i n t his  pr ot o c ol  a m e n d m e nt  as 
d es cri b e d  b el o w:  
•   B as e d  o n t h e  pr e cli ni c al  d at a  w hi c h s u g g est  p h ot os e nsiti z ati o n  p ot e nti al f or I N C 2 8 0, 
pr e c a uti o n ar y  m e as ur es  a g ai nst  ultr a vi ol et  e x p os ur e  ar e  b ei n g i n cl u d e d i n t his  a m e n d m e nt, 
i n  a d diti o n t o t h e i nf or m ati o n  pr o vi d e d i n t h e  c urr e nt I N C 2 8 0 I n v esti g at or’s  Br o c h ur e. 
•   B as e d  o n t h e r e c e nt  pr eli mi n ar y  d at a fr o m t h e  o n g oi n g  cli ni c al st u di es  wit h I N C 2 8 0, t h e 
d efi niti o n  of  c -M E T  p ositi vit y is  u p d at e d.  Si n gl e  a g e nt I N C 2 8 0 s h o w e d  pr eli mi n ar y  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  2 0
5  Pr ot o c ol  N o. 
 
 
 
a ntit u m or  a cti vit y i n  p ati e nts  wit h  N S C L C.  As  of  2 1 -M ar -2 0 1 4,  3  o ut  of  6  p ati e nts  h a d  a 
c o nfir m e d  p arti al r es p o ns e;  all  p a ti e nts  h a d  hi g h  c-M E T st at us  b y I H C  or fl u or es c e n c e i n 
sit u  h y bri di z ati o n ( FI S H) ( B a n g  et  al  2 0 1 4).  T w o  of  3  p ati e nts  h a d  c -M E T  m ut ati o ns.  
M or e o v er,  as  of  2 1 -M ar -2 0 1 4, i n t h e  c o m bi n ati o n st u d y  of I N C 2 8 0  pl us  g efiti ni b,  p arti al 
r es p o ns es  w er e s e e n i n  8  o ut of  4 6 ( 1 7 %)  e v al u a bl e  N S C L C  p ati e nts.  All r es p o n d ers  h a d 
hi g h  c -M E T st at us ( a n al y z e d  b y I H C  or  FI S H):  p ati e nts  wit h  M E T  g e n e  c o p y  n u m b er  ≥  5 
d e m o nstr at e d  a n  o v er all r es p o ns e r at e  of  4 0 % ( n = 8/ 2 0)  a n d  p ati e nts  wit h  c -M E T I H C 
i nt e nsit y s c or e  3 +  d e m o nstr at e d  an  o v er all r es p o ns e r at e  of  3 3 % ( n = 7/ 2 1).  N o r es p o ns es 
h a v e  b e e n  o bs er v e d i n  p ati e nts  wit h  c -M E T I H C i nt e nsit y s c or e  2 +  or l o w  M E T  g e n e  c o p y 
n u m b er ( <  5) ( W u  et  al  2 0 1 4).  B as e d  o n t h es e  pr eli mi n ar y  d at a  o n t h e  a ntit u m or  a cti vit y 
of I N C 2 8 0  as  a si n gl e  a g e nt  a n d i n  c o m bi n ati o n  wit h  g efiti ni b i n  N S C L C  p ati e nts, t h e 
d efi niti o n  of t h e  c -M E T  p ositi v e st at us i n t his st u d y  will  b e  u p d at e d f or  p ati e nts  wit h  c - 
M E T I H C i nt e nsit y s c or e  3 + i n  ≥  5 0 %  of t u m or  c ells  or  c -M E T I H C i nt e nsit y s c or e  2 +  i n 
≥  5 0 %  of t u m or  c ells  a n d  M E T  g e n e  c o p y  n u m b er  ≥  5  as  d et e ct e d  b y  FI S H.  
•   T o  cl arif y t h e i niti al  d os a g e  a n d  d os e  m o difi c ati o n s c h e d ul e f or I N C 2 8 0 t a bl et  f or m ul ati o n. 
M ai n  c h a n g es i n  L D K 3 7 8  a r m:  
U n d er  t his  a m e n d m e nt,   a  c o nsist e nt   a p pr o a c h is  b ei n g i m pl e m e nt e d  a cr oss  o n g oi n g st u di es  
wit h  L D K 3 7 8 t o  m o nit or  a n d  m a n a g e s af et y si g n als i d e ntifi e d  as t h e  cli ni c al  e x p eri e n c e  wit h 
L D K 3 7 8  h as  gr o w n.  S p e cifi c all y,  c h a n g es  ar e  m a d e t h at  a d dr ess  h e p ati c t o xi cit y,  p a n cr e atitis 
a n d  p n e u m o nitis.  
•   t o  e x cl u d e  p ati e nts  wit h  hist or y  of  p a n cr e atitis  or  hist or y  of i n cr e as e d  a m yl as e  or li p as e 
t h at  w as  d u e t o  p a n cr e ati c dis e as e  
•   t o i n cl u d e  a d diti o n al  d os e  m o difi c ati o n  a n d f oll o w-u p  m o nit ori n g l a n g u a g e f or  p ati e nts 
w h o  m a y  e x p eri e n c e  p a n cr e ati c  e n z y m e  el e v at i o ns i n t h e  a bs e n c e  of  cli ni c al s y m pt o ms 
•   t o  u p d at e  d os e  m o difi c ati o n l a n g u a g e  a n d t h e  g ui d eli n es f or t h e  m a n a g e m e nt  of  h e p ati c 
t o xi cit y 
•   t o s p e cif y t h at f or  p ati e nts  m e eti n g  bi o c h e mi c al  crit eri a f or  H y’s l a w ( A S T  or  A L T  > 3. 0 x 
U L N  a n d t ot al  bilir u bi n  > 2. 0  x  U L N i n t h e  a bs e n c e  of  c h ol est asis  or  h e m ol ysis), st u d y 
tr e at m e nt  m ust  b e  p er m a n e ntl y  dis c o nti n u e d 
•   t o  u p d at e  a d v ers e  e v e nts  of s p e ci al int er est i n cl u di n g  h e p at ot o xi cit y, i nt erstiti al l u n g 
dis e as e/ p n e u m o nitis,  Q T i nt er v al  pr ol o n g ati o n,  br a d y c ar di a,  h y p er gl y c e mi a, 
g astr oi nt esti n al t o xi cit y ( n a us e a,  v o miti n g  a n d  di arr h e a)  a n d  p a n cr e atitis (i n cl u di n g li p as e 
a n d  a m yl as e  el e v ati o ns).  
•   H y p er gl y c e m i a  h as  als o  b e e n  o bs er v e d i n  p ati e nts tr e at e d  wit h  L D K 3 7 8.  P ati e nts  wit h 
a b n or m all y  hi g h  f asti n g  gl u c os e l e v els ar e   n o w e x cl u d e d  fr o m p arti ci p ati n g  i n t his st u d y. 
F or  c o nsist e n c y  a cr oss t h e  L D K 3 7 8  pr o gr a m  cli ni c al tri als,  ot h er  c h a n g es  as  o utli n e d 
b el o w  h a v e  b e e n  m a d e t o  d os e  m o difi c ati o ns f or  p ati e nts  w h o  e x p eri e n c e  t o xi cit y. 
M ai n  c h a n g es i n  M E K 1 6 2  a r m:  
T o  cl arif y t h e  d os e  m o difi c ati o n  g ui d eli n es  a n d t o  ali g n  wit h  ot h er  M E K 1 6 2  o n g oi n g st u di es, 
s p e cifi c all y f or r eti n al  e v e nts, l eft  v e ntri c ul ar s yst oli c  d ysf u n cti o n  a n d  cr e ati n e  ki n as e ( C K) 
el e v ati o n.  T h e r e c o m m e n d e d  d os e  m o difi c ati o ns  w er e  als o  m o difi e d  a n d  cl arifi e d f or:  ot h er 
e y e  dis or d ers, li v er -r el at e d  A Es,  Q T  pr ol o n g ati o n  a n d r as h. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  2 1
5  Pr ot o c ol  N o. 
 
 
 
•   T o  m o dif y t h e  gr a di n g  crit eri a  a n d  d os e  m o difi c ati o n f or r eti n al  e v e nts  
•   T o  cl arif y t h e  d os e  m o difi c ati o n t a bl e f or l eft  v e ntri c ul ar s yst oli c   d ysf u n cti o n 
•   T o  cl arif y t h e  g ui d a n c e f or  m o nit ori n g  a n d  d os e  m o difi c ati o n f or  C K  el e v ati o n  
C h a n g e s t o t h e  pr ot o c ol  
1.   S e cti o n  1. 2. 2. 2: I N C 2 8 0  cli ni c al s af et y: t h e  cli ni c al s af et y s e cti o n f or I N C 2 8 0  h as  b e e n 
u p d at e d  wit h t h e  m ost r e c e nt i nf or m ati o n  b as e d  o n t h e  c urr e nt I N C 2 8 0 I n v esti g at or’s 
Br o c h ur e ( e diti o n  5. 2) i n cl u di n g t h e  d es cri pti o n  of t h e  e v e nt  of  a b n or m al li v er f u n cti o n 
t ests  m e eti n g t h e  crit eri a  of  H y’s L a w.  
2.   S e cti o n  1. 2. 3:  u p d at e d t h e  F D A  a n d  E ur o p e a n  C o m missi o n  a p pr o v e d i n di c ati o n  a n d 
i nf or m ati o n  of  L D K 3 7 8 ( Z Y K A DI AT M ) 
3.  S e cti o n  1. 2. 3. 2:  u p d at e d t o  d eli n e at e  o v er all  A d v ers e  E v e nt  o c c urr e n c e  a n d t o  d e n ot e 
a d v ers e  e v e nts  of i nt er est f or  L D K 3 7 8  ar m.  
4.   S e cti o n  1. 2. 4. 2. 1:   u p d at e d t h e cli ni c al  i nf or m ati o n a c c or di n g  t o c urr e nt  N A M E  C O M P O U N D  I B 
e diti o n   1 1. 
5.   S e cti o n  2. 3  a n d  6. 1:  u p d at e d t h e i niti al  d os a g e f or I N C 2 8 0 t a bl et  f or m ul ati o n 
6.   S e cti o n  4. 1, s e cti o n  5. 1  a n d s e cti o n  7. 1. 1: i ntr o d u c e d t h e  p ossi bilit y  of  usi n g  c e ntr al 
l a b or at or y f or  m ol e c ul ar  pr es cr e e ni n g  p ur p os e. 
7.   S e cti o n  4. 3:  cl arifi e d t h e  d efi niti o n f or  e n d  of  st u d y. 
8.   S e cti o n  5. 2 - t o i n cl u d e s q u a m o us  c ell  c ar ci n o m a  p ati e nts i nt o t h e  B Y L 7 1 9 ar m  
9.   S e cti o n  5. 2 - I N C 2 8 0  ar m:  u p d at e d i n cl usi o n  crit eri a  8 t o  u p d at e t h e  c-M E T  p ositi v e 
d efi niti o n. 
1 0.  S e cti o n  5. 3 - E x cl usi o n  crit eri o n  9  h as  b e e n  u p d at e d t o  m o dif y  bilir u bi n  e x cl u d e d  v al u es  at 
s cr e e ni n g/ b as eli n e.  
1 1.  S e cti o n  5. 3 - L D K 3 7 8  ar m:  u p d at e d  e x cl usi o n  crit eri a  2 7 -3 4,  a n d  3 9 -4 0  wit h f urt h er 
l a b or at or y  e x a m  a n d t o  e x cl u d e  p ati e nts  wit h si g nifi c a nt  p a n cr eati c  hist or y f or  s af et y. 
1 2.  S e cti o n  5. 3 -M E K 1 6 2  ar m: i n cl u d e d  hist or y  of  Gil b ert’s  s y n dr o m e 
1 3.  S e cti o n  6. 1. 1: I nstr u cti o ns f or  a d mi nistr ati o n  of I N C 2 8 0:  pr e c a uti o n ar y  m e as ur es  a g ai nst 
ultr a vi ol et  e x p os ur e  h a v e  b e e n   a d d e d. 
1 4.  S e cti o n  6. 1. 1:  P ati e nts  w h o  h a v e  dis e as e  pr o gr essi o n  a n d  h a v e  e vi d e n c e  of  cli ni c al  b e n efit, 
s u c h  as  dis e as e s hri n k a g e  at  ot h er si t es  or s y m pt o m ati c i m pr o v e m e nt,  m a y  c o nti n u e 
tr e at m e nt  wit h  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2. I n  a d diti o n,  B Y L 7 1 9, I N C 2 8 0, 
L D K 3 7 8  a n d  M E K 1 6 2 tr e at m e nt  m a y  b e t e m p or aril y i nt err u pt e d t o  p er mit l o c al t h er a p y 
f or s y m pt o m ati c  m et ast as es  aft er  dis e as e  pr o gr essi o n  h as  b e e n  d o c u m e nt e d.  P ati e nts  w h o 
c o nti n u e  o n tr e at m e nt  aft er  dis e as e  pr o gr essi o n s h o ul d  dis c o nti n u e st u d y tr e at m e nt  o n c e 
t h e y  ar e  n o l o n g er  d eri vi n g  b e n efit  as  ass ess e d  b y t h e i n v esti g at or. 
1 5.  S e cti o n  6. 2:  u p d at e d t h e  d os e  m o difi c ati o n s c h e d ul e f or I N C 2 8 0 t a bl et  f or m ul ati o n. 
1 6.  S e cti o n  6. 2:  u p d at e d t h e  d os e  m o difi c ati o n  g ui d eli n e  a n d  a d d e d t h e  g e n er al  g ui d eli n e f or 
u nlist e d t o xi cit y  of  L D K 3 7 8  
1 7.  S e cti o n  6. 3. 2:  u p d at e t h e  m e di c ati o ns t o  b e  us e d  wit h  c a uti o n f or  I N C 2 8 0 
1 8.  S e cti o n  6. 3. 2:  a d d e d  U G T 1 A 1 i n hi bit ors  a n d i n d u c ers  as  p er mitt e d  c o n c o mit a nt 
m e di c ati o n  us e d  wit h  c a uti o n f or t h e  M E K 1 6 2  ar m  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  2 2
5  Pr ot o c ol  N o. 
 
 
 
1 9.  S e cti o n  6. 5. 2:  a d d e d  1 0 0 m g I N C 2 8 0 t a bl et f or m ul ati o n f or  cli ni c al  us e.  
2 0.  S e cti o n   7. 1. 4. 1:  pr o vi d e d f urt h er cl arit y  f or crit eri a  f or pr e m at ur e  p ati e nt  wit h dr a w al.  
2 1.  S e cti o n   7. 1. 7: a d d e d  t h e  d es cri pti o n t o cl arif y  t h e sit u ati o n f or wit h dr a w al  of   c o ns e nt. 
2 2.  S e cti o n  7. 1. 5:  a d d e d t h e  d es cri pti o n t o  cl arif y t h e sit u ati o n f or l ost t o f oll o w  u p.  
2 3.  S e cti o n  7. 2. 2. 5:  u p d at e d t h e l o c al  cli ni c al  c h e mistr y l a b or at or y  p ar a m et ers  a d di n g  s er u m 
a m yl as e, s er u m li p as e  a n d f asti n g  pl as m a   gl u c os e 
2 4.  S e cti o n  1 4. 2, t a bl e  1 4 -7,  D os e  m o difi c ati o n  g ui d eli n e f or I N C 2 8 0: t h e r e c o m m e n d e d  d os e 
m o difi c ati o ns f or I N C 2 8 0 i n  c as e  of  h e p ati c t o xi citi es  h a v e  b e e n   u p d at e d. 
2 5.  S e cti o n  1 4. 2, t a bl e  1 4 -8,  D os e  m o difi c ati o n  g ui d eli n e f or  L D K 3 7 8:  pr o vi d e d  a d diti o n al 
cl arit y  a n d  p ar a m et ers f or st u d y  dr u g  d os e  m o difi c ati o ns,  dis c o nti n u ati o n,  wit h s p e ci al 
f o c us  o n  p n e u m o nitis,  h e p ati c, r e n al  a nd  p a n cr e ati c  t o xi citi es 
2 6.  S e cti o n  1 4. 2, t a bl e  1 4 -9,  D os e  m o difi c ati o n  g ui d eli n e f or  M E K 1 6 2  a n d t a bl e  1 4 - 1 0, 
gr a di n g  of r eti n al  d et a c h m e nt:  pr o vi d e d  a d diti o n al  cl arit y  a n d  p ar a m et ers f or st u d y  dr u g 
d os e  m o difi c ati o ns,  dis c o nti n u ati o n,  wit h s p e ci al f o c us  o n r e ti n al  e v e nts,  h e p ati c,  c ar di a c 
a n d s ki n t o xi citi es.  T o  a d d t h e  m o difi e d  gr a di n g  d efi niti o n  of r eti n al  d et a c h m e nt t a bl e f or 
i m pr o v e d  a c c ur a c y  gr a di n g  of  a n y  ass o ci at e d r eti n al  e v e nts.  T his r e vis e d t a bl e is  a d a pt e d 
fr o m t h e  N CI  C T C A E,  V ersi o n  4. 0 3  Gr a di n g  of  R eti n o p at h y. 
2 7.  S e cti o n  1 4. 3. 2:  u p d at e d I N C 2 8 0  g ui d eli n e f or t h e f oll o w -u p  of l a b or at or y li v er 
a b n or m aliti es  
2 8.  S e cti o n  1 4. 3. 3:  u p d at e d  L D K 3 7 8  G ui d eli n es f or t h e f oll o w -u p  of l a b or at or y  h e m at ol o gi c 
a b n or m aliti es, l a b or at or y li v er  a b n or m aliti es, l a b or at or y r e n al  a b n or m aliti es, l a b or at or y 
p a n cr e ati c  a b n or m aliti es,  g ui d eli n e f or  m o nit ori n g  p n e u m o nitis  a n d  g ui d eli n e f or 
tr e at m e nt  of  h y p o p h os p h at e mi a. 
2 9.  S e cti o n  1 4. 4:  u p d at e d  wit h  c urr e nt i nf or m ati o n f or  c o n c o mit a nt  m e di c ati o ns  pr o hi bit e d  or 
us e d  wit h  c a uti o n, i n cl u di n g  U G T 1 A 1 i n hi bit ors  a n d i n d u c ers f or t h e  M E K 1 6 2  ar m  
C h a n g es t o s p e cifi c s e cti o ns  of t h e  pr ot o c ol  ar e s h o w n i n t h e tr a c k  c h a n g es  v ersi o n  of t h e 
pr ot o c ol  usi n g stri k e t hr o u g h r e d f o nt f or  d el eti o ns  a n d r e d  u n d erli n e d f or i ns erti o ns.  
 
I R B/I E C/ H A 
A   c o p y   of  t his   a m e n d e d   pr ot o c ol   will   b e  s e nt  t o  t h e  I nstit uti o n al   R e vi e w   B o ar d  
(I R Bs)/I n d e p e n d e nt  Et hi cs  C o m mitt e e (I E Cs)  a n d  H e alt h  A ut h oriti es. 
T h e   c h a n g es   d es cri b e d  i n  t his   a m e n d e d   pr ot o c ol  r e q uir e  I R B/I E C   a p pr o v al   pri or  t o  
i m pl e m e nt ati o n. 
T h e  c h a n g es  h er ei n  aff e ct t h e I nf or m e d  C o ns e nt.  Sit es  ar e r e q uir e d t o  u p d at e  a n d s u b mit f or 
a p pr o v al   a  r e vis e d  I nf or m e d  C o ns e nt  t h at  t a k es  i nt o   a c c o u nt  t h e   c h a n g es   d es cri b e d  i n t his  
pr ot o c ol  a m e n d m e nt.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  2 3
5  Pr ot o c ol  N o. 
 
 
 
A m e n d m e nt  3 
A m e n d m e nt r ati o n al e  
T h e  p ur p os e  of t his  a m e n d m e nt is t o r e m o v e t h e  A U Y 9 2 2 tr e at m e nt  ar m fr o m t h e st u d y  a n d 
t o i n cl u d e  g ui d eli n es f or t h e  m a n a g e m e nt  of  p n e u m o nitis i n t h e  B Y L 7 1 9 tr e at m e nt  ar m  of t h e 
st u d y. 
N o v artis  h as  a n n o u n c e d t h at  all  d e v el o p m e nt  w or k  o n t h e  A U Y 9 2 2  pr o gr a m  h as  b e e n  c e as e d 
b as e d   o n   a v ail a bl e s af et y   a n d   effi c a c y   cli ni c al   d at a.   T h er ef or e, t h e  A U Y 9 2 2 tr e at m e nt  ar m 
will  b e r e m o v e d fr o m t his st u d y  as  w ell.  
 
C h a n g e s t o t h e  pr ot o c ol  
D el eti o n   of  t h e   A U Y 9 2 2  r el e v a nt   p ar a gr a p hs  fr o m   S e cti o n   1. 2. 1,   S e cti o n   2. 1,   T a bl e   3 -1, 
Fi g ur e  4 -1,  S e cti o n  5. 2,  S e cti o n  6. 1,  S e cti o n  6. 3,  S e cti o n  7. 1,  T a bl e  7 -5,  T a bl e  7 -6,  T a bl e   7- 1 1, 
S e cti o n  1 0. 4. 2,  T a bl e  1 0 -1,  T a bl e  1 0 -3,  T a bl e  1 0 -4,  T a bl e  1 4 -6,  S e cti o n  1 4. 3. 1.  
A d diti o n   of   S e cti o n   6. 2. 3   M a n a g e m e nt   of   p n e u m o nitis   a n d   a d diti o n   of   g ui d eli n es  f or  t h e  
m a n a g e m e nt   of   p n e u m o nitis  t o   T a bl e   1 4 -7,   Crit eri a  f or  i nt err u pti o n   a n d  r e -i niti ati o n   of  
B Y L 7 1 9 tr e at m e nts.  
 
I R B/I E C 
A   c o p y   of  t his   a m e n d e d   pr ot o c ol   will   b e  s e nt  t o  t h e  I nstit uti o n al   R e vi e w   B o ar d  
(I R Bs)/I n d e p e n d e nt  Et hi cs  C o m mitt e e (I E Cs)  a n d  H e alt h  A ut h oriti es.  T h e  c h a n g es  d es cri b e d 
i n  t his   a m e n d e d   pr ot o c ol  r e q uir e  I R B/I E C   a p pr o v al   pri or  t o  i m pl e m e nt ati o n.  I n   a d diti o n,  
c h a n g es  h er ei n  aff e ct t h e I nf or m e d  C o ns e nt  a n d sit es  ar e r e q uir e d t o  u p d at e  a n d s u b mit f or 
a p pr o v al   a  r e vis e d  I nf or m e d  C o ns e nt  t h at  t a k es  i nt o   a c c o u nt  t h e   c h a n g es   d es cri b e d  i n t his  
a m e n d e d  pr ot o c ol.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  2 4
5  Pr ot o c ol  N o. 
 
 
 
 
A m e n d m e nt  2 
A m e n d m e nt r ati o n al e  
T h e  m ai n  p ur p os e  of t his  a m e n d m e nt is t o  u p d at e t h e s af et y  m o nit ori n g  pl a n  as r e c o m m e n d e d 
b y t h e  h e alt h  a ut h orit y,  C F D A, f or  A U Y 9 2 2  a n d I N C 2 8 0  ar ms  of t h e  pr ot o c ol.  
 
C h a n g e s t o t h e  pr ot o c ol  
C h a n g es t o s p e cifi c s e cti o ns  of t h e  pr ot o c ol  ar e s h o w n i n t h e tr a c k  c h a n g es  v ersi o n  of t h e 
pr ot o c ol  usi n g stri k e t hr o u g h r e d f o nt f or  d el eti o ns  a n d r e d  u n d erli n e d f or i ns erti o ns.  
S e cti o n  5. 3  e x cl usi o n  crit eri a  3 0,  h as  b e e n  u p d at e d t o  e x cl u d e t h e  p ati e nts  wit h  hi g hl y 
s us pi ci o us  p ul m o n ar y fi br osis  or i nt erstiti al l u n g  dis e as e.  
S e ct i o n  6. 1. 1  h as  b e e n  u p d at e d t o  e x pl ai n t h e  crit eri a t o s wit c h I N C 2 8 0 f or m ul ati o n fr o m 
c a ps ul es t o t a bl ets.  
S e cti o n  6. 2. 1  h as  b e e n  u p d at e d t o  cl arif y t h e  p ati e nt  dis c o nti n u ati o n  crit eri a f or  A U Y 9 2 2  ar m.  
S e cti o n  7. 2. 2. 6. 2  a n d t a bl e  7 -5,  h as  b e e n  u p d at e d t o  a d d t h e  u ns c h e d ul e d  E C G  visit i nt o t h e 
c ar di a c s af et y  m o nit ori n g  pl a n f or  A U Y 9 2 2  ar m.  
S e cti o n  7. 2. 2. 7,  h as  b e e n  u p d at e d t o  a d d t h e  u ns c h e d ul e d  o p ht h al m ol o gi c  e x a ms i nt o t h e 
o p ht h al m ol o gi c s af et y  m o nit ori n g  pl a n f or  A U Y 9 2 2  ar m.  
S e cti o n  7. 2. 3. 1  h as  b e e n  u p d at e d t o  a d d t h e  u ns c h e d ul e d  P K s a m pl e  c oll e cti o n  c orr el at e d  wit h 
t h e  u ns c h e d ul e d  E C G  visit. 
 
I R B/I E C/ H A 
A   c o p y   of  t his   a m e n d e d   pr ot o c ol   will   b e  s e nt  t o  t h e  I nstit uti o n al   R e vi e w   B o ar d  
(I R Bs)/I n d e p e n d e nt  Et hi cs  C o m mitt e e (I E Cs)  a n d  H e alt h  A ut h oriti es.  T h e  c h a n g es  d es cri b e d 
i n t his  a m e n d e d  pr ot o c ol r e q uir e I R B/I E C  a p pr o v al  pri or t o i m pl e m e nt atio n. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  2 5
5  Pr ot o c ol  N o. 
 
 
 
 
A m e n d m e nt  1 
A m e n d m e nt r ati o n al e  
T h e  m ai n  p ur p os e  of t his  a m e n d m e nt is t o r efi n e t h e  p ati e nt  crit eri a f or  p ati e nts  e nr oll e d i nt o 
t h e  A U Y 9 2 2,  B Y L 7 1 9,  a n d I N C 2 8 0  ar ms,  b as e d  o n r e c e nt  n e w  d at a. 
F or  A U Y 9 2 2  ar m, t h e i n cl usi o n  crit eri a is r efi n e d fr o m  E G F R  m ut ati o n t o  o nl y  E G F R  e x o n  
2 0  i ns erti o n   m ut ati o n   b as e d   o n  t h e   c urr e nt   o n g oi n g  tri al   C A U Y 9 2 2 A 2 2 0 6   a n d  
C A U Y 9 2 2 A 2 2 0 7 i nt eri m  a n al ysis r es ults.   A c c or di n g t o  pr eli mi n ar y  cli ni c al  effi c a c y  d at a i n 
C A U Y 9 2 2 A 2 2 0 6,  t h e   a nti -t u m or   a cti vit y   of   A U Y 9 2 2  si n gl e   a g e nt   h as   b e e n   o bs er v e d   
pri m aril y i n t h e  e x o n  2 0 i ns erti o n  m ut ati o n  p o p ul ati o n.  Si n c e t h e  e x o n  2 0 i ns erti o n i n  E G F R  
is  a  k n o w n i ntri nsi c/  pri m ar y r esist a n c e  m e c h a nis m t o  E G F R t yr osi n e  ki n as e i n hi bit ors ( T KIs), 
t h e i n cl usi o n  crit eri a f or  pri or tr e at me nt  wit h  T KIs is  n o w r e m o v e d. I n  a d diti o n, t his  p ati e nt 
p o p ul ati o n r e pr es e nts  a  hi g h  u n m et  m e di c al  n e e d  a m o n g  N S C L C  p ati e nts.  
F or  B Y L 7 1 9  ar m, t h e i n cl usi o n  crit eri a is f urt h er  cl arifi e d f or  PI K 3 C A  g e n e  a m plifi c ati o n  as 
c o p y  n u m b er  ≥ 4  w hi c h  w as  n ot  d efi n e d  i n t h e  c urr e nt  pr ot o c ol. 
F or  I N C 2 8 0  ar m, t h e i n cl usi o n  crit eri a is r estri ct e d fr o m  c M E T   FI S H (fl u or es c e n c e i n sit u 
h y bri di z ati o n)  g e n e  c o p y  n u m b er  of  ≥ 5  or  I H C  (i m m u n o hist o c h e mistr y)  st ai ni n g  2 +  or  3 +  ≥ 
5 0 %  t u m or  c ells  t o  o nl y  I H C  st ai ni n g  3 +   ≥ 5 0 %  t u m or  c ells    wit h  e x pl or ati o n  of  c -M E T 
m ut ati o n   a n d   a m plifi c ati o n  r etr os p e cti v el y.   T h e   pr eli mi n ar y   d at a  fr o m  t h e  si n gl e   a g e nt  
I N C 2 8 0 st u d y,  CI N C 2 8 0 X 2 1 0 2, s u g g est e d t h at  effi c a c y is r estri ct e d t o t h e  p ati e nt  p o p ul ati o n 
wit h  E G F R wt  a n d  hi g h  M E T st at us.  As  of  2 1  M ar c h  2 0 1 4,  3  o ut  of  6  p ati e nts  h a d  c o nfir m e d 
P R;  all  p ati e nts    w er e   E G F R wt  a n d  h a d  hi g h    M E T  st at us  b y  I H C  or  FI S H  ( B a n g    Y -J  et   al  
2 0 1 4).   T w o   of  t hr e e   p ati e nts   h a d   c M E T   m ut ati o ns.   T h e   a m e n d e d   crit eri a  is  t o   k e e p  
c o nsist e n c y  wit h t h e  o n g oi n g  CI N C 2 8 0 X 2 1 0 2  st u d y. 
F or t h e  p h ar m a c o ki n eti cs ( P K) s e cti o n, t h e  a m e n d m e nt is  m ai nl y t o  h ar m o ni z e  a n d  cl arif y t h e 
pr o c e d ur es   b y  r e d u ci n g  t h e   P K  s a m pli n gs   a n d   o pti mi zi n g  t h e  ti mi n g   p oi nt   wit h o ut   m aj or  
c h a n g es,   w hi c h   will   b e  i n  f a v or   of   p ati e nts   a n d  si m plifi e d  t h e   pr o c e d ur e  i n   cli ni c al  sit e  
o p er ati o n. 
A d d iti o n al  m o difi c ati o ns/  u p d at es t o t h e  pr ot o c ol i n cl u d e: 
T o  e x cl u d e  E G F R  m ut ati o n  p ati e nt  wit h  c o n c urr e nt  M E T  a m plifi c ati o n/ o v er e x pr essi o n  a n d/ 
or  PI K 3 C A  m ut ati o n/  a m plifi c ati o n f or  A U Y 9 2 2  ar m  a c c or di n g t o  a v ail a bl e  d at a.  
T o   a d d   a   n ot e  f or  I N C 2 8 0  t a bl ets  r e c o m m e n d e d   d osi n g  r e gi m e n  i nf or m ati o n   a n d   d os e  
r e d u cti o n st e ps i n st u d y tr e at m e nt s e cti o n  w hi c h  w as  n ot  d efi n e d i n t h e  c urr e nt  pr ot o c ol. 
T o   e x cl u d e  t h e   p ati e nt   h as   hist or y   of  i nt erstiti al l u n g   dis e as e   or  i nt erstiti al   p n e u m o nitis  i n  
L D K 3 7 8  ar m  a c c or di n g t o  a v ail a bl e s af et y i nf or m ati o n  a n d t o  c o m pl y  wit h  h e alt h  a ut h orit y’s 
r e q u est. 
T o  u p d at e  a n d  cl arif y t h e f asti n g ti m e f or  B Y L 7 1 9/I N C 2 8 0/ L D K 3 7 8  ar ms  b as e d  o n  c urr e nt 
a v ail a bl e  cli ni c al  p h ar m a c ol o gi c al i nf or m ati o n.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  2 6
5  Pr ot o c ol  N o. 
 
 
 
T o  r e m o v e  t h e  f asti n g  r e q uir e m e n t  f or   M E K 1 6 2   ar m   b as e d   o n  t h e  f o o d   eff e ct  st u di es,  
C M E K 1 6 2 A 2 1 0 3   a n d   A R R A Y  st u di e s,   w hi c h  s u g g est e d   n o   n e e d  f or  s p e cifi c ati o n   of  f o o d  
i nt a k e f or  M E K 1 6 2  a d mi nistr ati o n. 
T o   u p d at e   a n d  cl arif y t h e   p er mitt e d   a n d  pr o hi bit e d   m e di c ati o n  s e cti o n   a n d   als o   ali g n  wit h  
c urr e ntl y  a v ail a bl e i nf or m ati o n f or  c o m p o u n ds i n  all  ar ms.  
T o  r e m o v e  t h e   C 1 D 1   P K   c oll e cti o n  f or   A U Y 9 2 2/I N C 2 8 0/ L D K 3 7 8/ M E K 1 6 2   ar ms   a n d  
m o dif y  s e v er al   P K   c oll e cti o n  ti m e   p oi nts   wit h o ut   m aj or   c h a n g es   b e c a us e  f ull   h u m a n   P K  
pr ofil es  ar e  a v ail a bl e fr o m  pr e vi o us  st u di es  a n d l ess/s p ar s e s a m pli n g  will s er v e t h e  p ur p os e  of 
P K  c h ar a ct eri z ati o n 
 i n t his st u d y. 
T o i m pl e m e nt  t h e s af et y  d at a  a n d  effi c a c y  d at a r e vi e wi n g  pl a n f or  A U Y 9 2 2,   B Y L 7 1 9  a n d 
M E K 1 6 2  as  o n g oi n g  b asis i n s af et y  m o nit ori n g  a n d r e p orti n g s e cti o n.  
T o  u p d at e t h e  p ar a m et ers  of st atisti c al  m o d el  b as e d  o n  a v ail a bl e  A U Y 9 2 2  effi c a c y  d at a.  
T o   u p d at e t h e   crit eri a f or  i nt err u pti o n  a n d  r e -i niti ati o n   g ui d eli n e f or   p ul m o n ar y t o xi cit y  of  
L D K 3 7 8  ar m  a c c or di n g t o  a v ail a bl e s af et y i nf or m ati o n.  
A d diti o n al   e dit ori al   c h a n g es  h a v e  b e e n  m a d e t hr o u g h o ut  t h e  d o c u m e nt  i n  or d er t o i n cr e as e 
c o nsist e n c y  a n d  cl arit y.  
 
C h a n g e s t o t h e  pr ot o c ol  
C h a n g es t o s p e cifi c s e cti o ns  of  t h e  pr ot o c ol   ar e s h o w n i n t h e tr a c k  c h a n g es  v ersi o n  of t h e 
pr ot o c ol  usi n g stri k e t hr o u g h r e d f o nt f or  d el eti o ns  a n d r e d  u n d erli n e d f or i ns erti o ns.  
S e cti o n  1. 2  h as  b e e n  u p d at e d  wit h  c urr e nt  cli ni c al tri al  d at a i n  A U Y 9 2 2  ar m  a n d  wit h  n e w 
i nf or m ati o n  of f o o d  eff e ct st u d y i n  M E K 1 6 2  ar m. 
S e cti o n  2. 1  h as  b e e n  u p d at e d  wit h t h e r ati o n al e  a n d r el e v a nt r ef er e n c e f or s el e cti n g  p ati e nt 
p o p ul ati o n  of  E G F R  e x o n  2 0 i ns erti o n  m ut ati o n i n  A U Y 9 2 2  ar m.  
S e cti o n  2. 3  h as  b e e n  u p d at e d  wit h  c urr e nt i nf or m ati o n  of I N C 2 8 0  ar m f or t a bl et f or m ul ati o n.  
S e cti o n  3  T a bl e  3 -1  h as  b e e n  u p d at e d t o r e m o v e t h e  P K  p ar a m et er  R a c c  as  C 1 D 1  P K  will  n ot 
b e  o bt ai n e d.  
S e cti o n  4  Fi g ur e  4 -1  h as  b e e n  u p d at e d t o  ali g n  wit h t h e  n e w  m ol e c ul ar  alt er ati o n  crit eri a.  
S e cti o n  5. 2 i n cl usi o n  crit eri a  7 f or  A U Y 9 2 2  ar m  h as  b e e n  m o difi e d  a n d  c h a n g e d fr o m  E G F R 
g e n e  m ut ati o n  p o p ul ati o n t o  E G F R  g e n e  e x o n  2 0 i ns erti o n  m ut ati o n.  
S e cti o n  5. 2 i n cl usi o n  crit eri a  8  a n d  9 f or  A U Y 9 2 2  ar m  w er e r e m o v e d.  Si n c e t h e  E G F R  e x o n 
2 0  i ns erti o n  m ut ati o n is  o n e  of t h e  k n o w n i ntri nsi c r esist a n c e  m e c h a nis ms t o  E G F R t yr osi n e 
ki n as e  i n hi bit ors  ( T KIs),  t h e  r e q uir e d   T KI   as   pri or  tr e at m e nt  is  r e m o v e d  fr o m  i n cl usi o n  
crit eri a.  S e cti o n  5. 2 i n cl usi o n  crit eri a  1 0 f or  B Y L 7 1 9  ar m  h as  b e e n f urt h er  cl ar ifi e d f or t h e 
m ol e c ul ar  a m plifi c ati o n  wit h  PI K 3 C A  g e n e  c o p y  n u m b er  ≥  4.  
S e cti o n  5. 2  i n cl usi o n  crit eri a  1 1  f or  I N C 2 8 0  ar m  h as  b e e n  c h a n g e d  as  I H C  3 +  i n  ≥  5 0 %  of 
t u m or  c ells. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  2 7
5  Pr ot o c ol  N o. 
 
 
 
S e cti o n  5 i n cl usi o n  crit eri a  n ot e  w as  m o difi e d  wit h r e m o vi n g  “t h e  p a ti e nts  w h o  h a v e  E G F R 
m ut ati o n   a n d   c o n c urr e nt   wit h   c M E T   a m plifi c ati o n/   o v er e x pr essi o n   or   PI K 3 C A   m ut ati o n/  
a m plifi c ati o n ”.  
S e cti o n  5  e x cl usi o n  crit eri a  1 9 f or  A U Y 9 2 2  ar m  w as r e m o v e d t o  ali g n  wit h i n cl usi o n  crit eri a 
7,  8,  a n d  9  c h a n g es i n t h e  pr ot o c ol  
S e cti o n   5  e x cl usi o n   crit eri a  3 6  f or   L D K 3 7 8   ar m   w as   a d d e d t o  e x cl u d e  t h e  p ati e nts   wit h  a 
hist or y  of i nt erstiti al l u n g  dis e as e  or i nt erstiti al  p n e u m o nitis.  
S e cti o n   6. 1. 1,   T a bl e   6 -1   h as   b e e n   u p d at e d   wit h  t h e   d osi n g  r e gi m e n  i nf or m ati o n  f or  t a bl et  
f or m ul ati o n  of  I N C 2 80   ar m,   a n d  t h e  f asti n g  ti m e  f or   B Y L 7 1 9/I N C 2 8 0/ L D K 3 7 8   ar ms   w a s  
u p d at e d i n s e cti o n  6. 1. 1 t o  ali g n  wit h  c urr e nt i nf or m ati o n f or t h es e  c o m p o u n ds.  F or  M E K 1 6 2 
ar m, t h e f asti n g r e q uir e m e nt is r e m o v e d  b as e d  o n  c urr e nt  d at a  of  M E K 1 6 2.  
S e cti o n  6. 2. 1,  T a bl e  6 -2  h as  b e e n  cl arifi e d f or t h e  d os e r e d u cti o n st e ps f or I N C 2 8 0  ar m.  
S e cti o n  6. 3. 2  a n d  6. 3. 3  h as  b e e n  m o difi e d  a n d  u p d at e d f or t h e  p er mitt e d  c o n c o mit a nt t h er a p y 
r e q uiri n g  c a uti o n  a n d  pr o hi bit e d  c o n c o mit a nt t h er a p y t o  ali g n  wit h  a v ail a bl e  d at a  of  all  ar m 
c o m p o u n ds. 
S e cti o n  6. 5. 2,  T a bl e  6 -3 t h e  a v ail a bl e t a bl et str e n gt h  of  5 0 m g I N C 2 8 0  w as  a d d e d.  
S e cti o n  7. 1. 1  w as r e m o v e d  of t h e r e q uir e m e nt  of  p ost -T KI tr e at m e nt t u m or s a m pl e  c oll e cti o n 
t o  ali g n  wit h t h e i n cl usi o n  crit eri a  7  c h a n g es. 
S e cti o n  7. 1. 4. 1  w as  cl arifi e d t h e  d e fi niti o n  of  crit eri a f or  pr e m at ur e  p ati e nt  wit h dr a w al  a n d t o 
ali g n  wit h t h e  cli ni c al  d at a b as e s et  u p.  
S e cti o n  7. 2. 2. 6,  T a bl e  7 -5  w as  cl arifi e d  wit h t h e  E C G  c oll e cti o n ti m e  p oi nts.  
S e cti o n  7. 2. 3. 1,  T a bl es  7 -6 t o  7 -1 5  w er e  m o difi e d t o r e m o v e  C 1 D 1  P K  c oll e cti o n i n  A U Y 9 2 2, 
I N C 2 8 0,  L D K 3 7 8,  M E K 1 6 2  ar ms  a n d l ess/s p ars e  P K s a m pli n g i n  all t a bl es.  T h es e  u p d at es 
w er e f or  h ar m o ni z ati o n  of t h e  P K  c oll e cti o n s c h e d ul e i n  A U Y 9 2 2/I N C 2 8 0/ L D K 3 7 8/ M E K 1 6 2 
ar ms  wit h o ut  m aj or  c h a n g es s u bst a nti all y.  
S e cti o n  7. 2. 3. 2  w as  a d d e d  wit h  P K  a n al ysis  of t h e  m aj or  A U Y 9 2 2  m et a b olit e  BJ P 7 6 2. 
 
S e cti o n   8. 6  t o  i n di c at e  t h e  s af et y   a n d   effi c a c y   d at a  r e vi e w   pl a n  i n  t h e   pr ot o c ol.   T h e  
m o nit ori n g   of   p ati e nt   d at a   will   pr o vi d e  t h e   b asis  t o   N o v artis  f or   n e xt  st e ps   c o nsi d eri n g  
effi c a c y  a n d s af et y  d at a.  
S e cti o n  1 0. 4. 2 t o  u p d at e t h e  m ost  c urr e nt  effi c a c y  d at a f or  A U Y 9 2 2  ar m  a n d  T a bl e  1 0 -1  wit h 
p ar a m et er  of  pri or  distri b uti o ns  a n d t hr es h ol ds f or  p ost eri or  distri b uti o n  of  O R R.  
S e cti o n  1 0. 5. 3,  T a bl e  1 0 -2 s e v er al  P K  p ar a m et ers  w er e si m plifi e d.  
S e cti o n  1 0. 7 t o i n di c at e t h e s af et y  a n d  effi c a c y  d at a r e vi e w  pl a n i n t h e  pr ot o c ol  a n d  ali g n  wit h 
t h e  S e cti o n  8. 6. 
S e cti o n   1 0. 8,   T a bl e   1 0 -3   a n d   1 0 -4  t o   u p d at e   cli ni c all y  r el e v a nt   effi c a c y   c at e g or y ( Ri)   a n d 
pr o b a bilit y t o  ali g n  wit h t h e  u p d at e d  p ar a m et er i n  S e cti o n  1 0. 4. 2.  
S e cti o n  1 3 t o  a d d t hr e e  n e w  p u bli c ati o ns  as r ef er e n c es.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  2 8
5  Pr ot o c ol  N o. 
 
 
 
S e cti o n   1 4,   T a bl e   1 4 -9  t o   u p d at e  t h e   d os e  i nt err u pti o n   a n d  r e -i niti ati o n   g ui d eli n e  f or  
p ul m o n ar y t o xi cit y  i n  L D K 3 7 8  ar m. 
S e cti o n   1 4,   A p p e n di x   3,   A p p e n di x   4   a n d   A p p e n di x   5   w er e   cl arifi e d   a n d   u p d at e d   wit h  
p er mitt e d  c o n c o mit a nt  m e di c ati o n r e q uiri n g  c a uti o n,  pr o hi bit e d  c o n c o mit a nt  m e di c ati o n,  a n d 
dr u gs  wit h ris k  of  T d P/ Q T  pr ol o n g ati o n, r es p e cti v el y.  
 
I R B/I E C 
A   c o p y   of  t his   a m e n d e d   pr ot o c ol   will   b e  s e nt  t o  t h e  I nstit uti o n al   R e vi e w   B o ar d  
(I R Bs)/I n d e p e n d e nt  Et hi cs  C o m mitt e e (I E Cs)  a n d  H e alt h  A ut h oriti es.  T h e  c h a n g es  d es cri b e d 
i n  t his   a m e n d e d   pr ot o c ol  r e q uir e  I R B/I E C   a p pr o v al   pri or  t o  i m pl e m e nt ati o n.   T h e   ch a n g es 
h er ei n  aff e ct t h e I nf or m e d  C o ns e nt.   Sit es  ar e r e q uir e d t o  u p d at e  a n d s u b mit  f or  a p pr o v al  a 
r e vis e d  I nf or m e d   C o ns e nt  t h at  t a k es  i nt o   a c c o u nt  t h e   c h a n g es   d es cri b e d  i n  t his   pr ot o c ol  
a m e n d m e nt.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  2 9
5  Pr ot o c ol  N o. 
 
 
 
 
Pr ot o c ol  s u m m ar y: 
Pr ot o c ol  n u m b er  
CI N C 2 8 0 X 2 2 0 5  
Titl e  
A  P h a s e II,  o p e n l a b el,  m ulti pl e  ar m  st u d y  of  si n gl e  a g e nt  A U Y 9 2 2,  B Y L 7 1 9, 
I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2 i n  C hi n e s e  p ati e nt s  wit h  a d v a n c e d  n o n-s m all  c ell 
l u n g  c a n c er ( N S C L C) 
Bri ef titl e  
n/ a  
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 a s e II  
I n v e sti g ati o n t y p e  
Dr u g  
St u d y t y p e  
I nt er v e nti o n al 
P ur p o s e  a n d r ati o n al e  
T h e  p ur p o s e  of t hi s  st u d y i s t o  e v al u at e t h e  a nti -t u m or  a cti vit y  of  si n gl e  a g e nt 
B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2 i n  a d v a n c e d  N S C L C  p ati e nt s  c arr yi n g 
s p e cifi c  m ol e c ul ar  alt er ati o n s.  
T h er e i s  a  gr e at  u n m et  m e di c al  n e e d i n  N S C L C  p ati e nt s  wit h  a d v a n c e d  or 
m et a st ati c  di s e a s e.  N o v el  a p pr o a c h e s  u si n g t ar g et e d t h er a p e uti c  a g e nt s f or t h e s e 
p ati e nt  p o p ul ati o n s  wit h  m ol e c ul ar  c h ar a ct eri z ati o n  c o ul d  p ot e nti all y i d e ntif y 
s u b s et s  of  a d v a n c e d  N S C L C  p ati e nt s  w h o  w o ul d  b e n efit fr o m t ar g et e d  ki n a s e 
i n hi biti o n.  St u d y tr e at m e nt s,  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2,  w hi c h t ar g et 
PI K 3 C A,  c -M E T,  A L K/ R O S 1  a n d  M E K r e s p e cti v el y,  h a v e  s h o w n  pr o mi si n g  d at a i n 
eit h er  pr e cli ni c al  or  cli ni c al l u n g  c a n c er  s etti n g s.  
Pri m ar y  O bj e cti v e  
T o i n v e sti g at e t h e  a nti -t u m or  a cti vit y  of  si n gl e  a g e nt  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  a n d 
M E K 1 6 2  
S e c o n d ar y  O bj e cti v e s   
O bj e cti v e  1 :  T o f urt h er  a s s e s s t h e  cli ni c al  a cti vit y  of  si n gl e  a g e nt  B Y L 7 1 9, I N C 2 8 0, 
L D K 3 7 8  a n d  M E K 1 6 2  
O bj e cti v e  2 :  T o  c h ar a ct eri z e t h e  s af et y  a n d t ol er a bilit y  of  si n gl e  a g e nt  B Y L 7 1 9, 
I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2 
O bj e cti v e  3 :  T o  c h ar a ct eri z e t h e  p h ar m a c o ki n eti c  pr ofil e s of  si n gl e  a g e nt  B Y L 7 1 9,  
I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2 
St u d y  d e si g n  
T hi s i s  a  P h a s e II,  m ulti pl e  ar m,  o p e n -l a b el  st u d y  of  si n gl e  a g e nt  B Y L 7 1 9, I N C 2 8 0, 
L D K 3 7 8  a n d  M E K 1 6 2.  T hi s  st u d y  will  e nr oll  2 0 -2 5  a d v a n c e d  N S C L C  p ati e nt s t o 
e a c h tr e at m e nt  ar m  a c c or di n g t o t h eir  m ol e c ul ar  alt er ati o n s.  E a c h tr e at m e nt  ar m i s  
i n d e p e n d e nt fr o m  o n e  a n ot h er  a n d  will  b e  a n al y z e d  s e p ar at el y. 
P o p ul ati o n  
T h e  st u d y  will  e nr oll  p ati e nt s  w h o  h a v e  hi st ol o gi c all y  or  c yt ol o gi c all y  c o nfir m e d 
a d v a n c e d ( st a g e III B  or  st a g e I V) l u n g  a d e n o c ar ci n o m a ( all tr e at m e nt  ar m s)  or l u n g 
s q u a m o u s  c ell  c ar ci n o m a s ( B Y L 7 1 9  ar m  o nl y),  w h o  h a v e f ail e d  pri or tr e at m e nt  or  
p ati e nt s  w h o  ar e  d e e m e d  u n s uit a bl e f or  c h e m ot h er a p y i n t h e i n v e sti g at or’ s  o pi ni o n.  
K e y I n cl u si o n  crit eri a  
P ati e nt s  eli gi bl e f or i n cl u si o n i n t hi s  st u d y  h a v e t o  m e et  all  of t h e f oll o wi n g  crit eri a: 
Writt e n i nf or m e d  c o n s e nt  m u st  b e  o bt ai n e d  pri or t o  a n y  s cr e e ni n g  pr o c e d ur e s.  
1.   P ati e nt s  m u st  b e  1 8  y e ar s  or  ol d er  a n d  a bl e t o  si g n I nf or m e d  C o n s e nt.  
2.   Hi st ol o gi c all y  or  c yt ol o gi c all y  c o nfir m e d  a d v a n c e d ( st a g e III B  or  st a g e I V) l u n g 
a d e n o c ar ci n o m a.  F or  B Y L 7 1 9 tr e at m e nt  ar m, t h e  hi st ol o gi c all y  or  c yt ol o gi c all y 
c o nfir m e d  a d v a n c e d ( st a g e III B  or  st a g e I V) l u n g  a d e n o c ar ci n o m a  or l u n g 
s q u a m o u s  c ell  c ar ci n o m a.  
3.   P ati e nt s  w h o  h a v e f ail e d  at l e a st  o n e  pri or  a nti c a n c er tr e at m e nt r e gi m e n  or 
p ati e nt s  w h o  ar e  d e e m e d  u n s uit a bl e f or  c h e m ot h er a p y i n t h e i n v e sti g at or s  o pi ni o n 
(i n cl u di n g  p ati e nt s  w h o r ef u s e c h e m ot h er a p y)  
N ot e:  C h e m ot h er a p y  a d mi ni st er e d  a s  a dj u v a nt tr e at m e nt  m or e t h a n  si x  m o nt h s 
pri or t o  st u d y  e nr oll m e nt i s  n ot  c o n si d er e d  a  pri or li n e  of t h er a p y f or  p ur p o s e s  of 
t hi s  st u d y. 
4.   M e a s ur a bl e  di s e a s e  a c c or di n g t o  R E CI S T  v. 1. 1 (Irr a di at e d l e si o n s  ar e  n ot 
c o n si d er e d  m e a s ur a bl e  u nl e s s t h e y  h a v e  cl e arl y  pr o gr e s s e d  si n c e  r a di ot h er a p y) 
5.   E C O G  p erf or m a n c e  st at u s  ≤   2 
6.   P ati e nt s  m u st  b e  s uit a bl e  a n d  willi n g t o  u n d er g o  m a n d at or y  bi o p s y  a c c or di n g t o 
tr e ati n g i n stit uti o n’ s  g ui d eli n e s  a n d r e q uir e m e nt s f or  s u c h  pr o c e d ur e if t h er e i s  n o 
ar c hi v al  bi o p s y  a v ail a bl e.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  3 0
5  Pr ot o c ol  N o. 
 
 
 
 
I n  a d diti o n,  p ati e nt s  eli gi bl e f or  e a c h tr e at m e nt  ar m  m u st  m e et t h e  crit eri a f or t h e 
r e s p e cti v e  ar m. 
K e y  E x cl u si o n  crit eri a   
P ati e nt s  eli gi bl e f or t hi s  st u d y  m u st  n ot  m e et  a n y  of t h e f oll o wi n g  crit eri a:  
1.   S y m pt o m ati c  C N S  m et a st a s e s  w hi c h  ar e  n e ur ol o gi c all y  u n st a bl e  or r e q uiri n g 
i n cr e a si n g  d o s e s  of  st er oi d s  wit hi n t h e  4  w e e k s  pri or t o  st u d y  e ntr y t o  c o ntr ol t h eir 
C N S  di s e a s e  
2.   R a di at i o n t h er a p y  wit hi n  ≤  4  w e e k s  pri or t o  st u d y  e ntr y,  wit h t h e  e x c e pti o n  of 
li mit e d fi el d  p alli ati v e r a di ot h er a p y f or  b o n e  p ai n r eli ef.  A n y  p er si st e nt  si d e  eff e ct  of 
pri or r a di ot h er a p y  m u st  b e r e s ol v e d t o  ≤  C T C A E  gr a d e  1  pri or t o t h e fir st  d o s e  of 
st u d y tr e at m e nt.  
3.   A n y  ot h er  m ali g n a n ci e s  wit hi n t h e l a st  5  y e ar s  b ef or e  st u d y  e ntr y,  e x c e pt f or 
a d e q u at el y tr e at e d  c ar ci n o m a i n  sit u  of  c er vi x,  b a s al  or  s q u a m o u s  c ell  s ki n  c a n c er  
4.   M aj or  s ur g er y  ≤  2  w e e k s  pri or t o  st u d y  e ntr y  or  w h o  h a v e  n ot r e c o v er e d fr o m 
si d e  eff e ct s  of  s u c h t h er a p y  
5.   P ati e nt s  m u st  n ot  h a v e r e c ei v e d  pr e vi o u s  a nti -c a n c er t h er a pi e s  ≤  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 e x c e pt:  
●   
≤ 6  w e e k s f or  nitr o s o ur e a s  a n d   mit o m y ci n 
●   
≤ 5  h alf -lif e  of  c o nti n u o u s  or i nt er mitt e nt  s m all  m ol e c ul e t h er a p e uti c s  or 
i n v e sti g ati o n al  a g e nt s ( or  ≤  4  w e e k s  w h e n  h alf-lif e i s  u n k n o w n),  a n d  h a v e  n ot 
r e c o v er e d fr o m t h e  si d e  eff e ct s  of  s u c h tr e at m e nt ( C T C A E  gr a d e  ≤  1)  pri or t o 
t h e fir st  d o s e  of  st u d y tr eat m e nt,  e x c e pt f or  al o p e ci a.  
6.   A n y  of t h e f oll o wi n g l a b or at or y  v al u e s  at  b a s eli n e:  
●   
H e m o gl o bi n  <  9  g/ d L ( SI  U nit s:  9 0  g/ L)  
●   
Pl at el et  c o u nt  < 1 0 0  x  1 0 9/ L  
●   
A b s ol ut e  n e utr o p hil  c o u nt ( A N C)  <  1. 5  x  1 0 9/ L  
●   
S er u m  al b u mi n  <  2. 5  g/ dl  
●   
T ot al  bilir u bi n  >  1. 5  x  u p p er li mit  of  n or m al  ( U L N) 
●   
A S T/ S G O T  or  A L T/ S G P T   >  3  x u p p er  li mit of  n or m al  ( U L N) or   > 5. 0   x U L N 
if li v er  m et a st a s e s  ar e pr e s e nt  
●   
S er u m  cr e ati ni n e  >  1. 5  x  U L N  or  c al c ul at e d  cr e ati ni n e  cl e ar a n c e  b y 
C o c k cr oft- G a ult f or m ul a  <  5 0  m L/ mi n  
●   
S er u m  c al ci u m,  p ot a s si u m  a n d  m a g n e si u m < L L N  
P ati e nt s  eli gi bl e f or  e a c h tr e at m e nt  ar m  m u st  n ot  m e et  crit eri a f or r e s p e cti v e  ar m.  
I n v e sti g ati o n al  a n d 
r ef ere n c e t h er a p y  
B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8,  M E K 1 6 2  
Effi c a c y  a s s e s s m e nt s   
●   O R R  
●   O S  
●   P F S  
●   D C R  
●   D ur ati o n  of  o v er all r e s p o n s e  p er  R E CI S T  v 1. 1  
S af et y  a s s e s s m e nt s   
●   Fr e q u e n c y/ s e v erit y  of  A E s  a n d  S A E s  
●   L a b or at or y  a b n or m aliti e s  
●   D o s e i nt err u pti o n s  a n d  d o s e  r e d u cti o n s 
Ot h er  a s s e s s m e nt s  
●   P K  p ar a m et er s  
 
D at a  a n al y si s  
A  B a y e si a n  a p pr o a c h  will  b e  u s e d t o  e sti m at e  O R R  a n d t o  pr o vi d e i nf er e nti al 
st at e m e nt s f or  e a c h tr e at m e nt  ar m.  B a y e si a n  d e ci si o n r ul e s  will  b e  u s e d t o  d efi n e 
cli ni c all y  a n d  st ati c all y  si g nifi c a nt  a nti -t u m or  a cti vit y.  At t h e ti m e  of  a n al y si s  of  e a c h 
tr e at m ent  ar m t h e r e s p e cti v e  pri or  di stri b uti o n  will  b e  u p d at e d  wit h  all  a v ail a bl e 
d at a fr o m  p ati e nt s i n t h e r e s p e cti v e  F A S.  
All  d at a  will  b e li st e d  a n d  s u m m ari z e d  w h e n  a p pr o pri at e.  
K e y  w or d s  
n o n -s m all  c ell l u n g  c a n c er,  N S C L C,  st a g e III B  or  st a g e I V  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  3 1
5  Pr ot o c ol  N o. 
 
 
 
 
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 
L u n g  c a n c er is  a  c o m m o n t y p e  of  c a n c er t h at  aff e cts  m e n  a n d  w o m e n  ar o u n d t h e  gl o b e. I n 
2 0 1 2, t h er e  w er e  a n  esti m at e d  1 6 0, 0 0 0  d e at hs i n t h e  U S ( Si e g el  et  al  2 0 1 2 )  a n d  2 6 2, 0 0 0 i n t h e 
E ur o p e a n  U ni o n ( M al v e z zi  et  al  2 0 1 2 ). I n  C hi n a i n  2 0 0 5, t h er e  w er e  4 9 7, 9 0 8  n e w  c as es  a n d 
4 2 8, 9 3 6  d e at hs, t h e  hi g h est f or  a n y  m ali g n a nt t u m or ( W u  2 0 0 7 ).  N o n-s m all  c ell l u n g  c a n c er 
( N S C L C) is t h e  m ost  c o m m o n t y p e  of l u n g  c a n c er t h at  a c c o u nts f or r o u g hl y  8 5 %  of  all  c as es 
wit h  a p pr o xi m at el y  7 0 %  of  t h es e  p ati e nts  pr es e nti n g    wit h  a d v a n c e d  dis e as e  ( St a g e  III B  or 
St a g e I V)  at t h e ti m e  of  di a g n osis ( Al v ar e z  2 0 0 7 , R ui z  2 0 0 8 ). 
Pl ati n u m -b as e d  c h e m ot h er a p y is t h e st a n d ar d first -li n e tr e at m e nt f or  p ati e nts  wit h  a d v a n c e d 
N S C L C  ( S a n dl er   et   al   2 0 0 6 ).   T h es e   pl ati n u m   b as e d  t w o   dr u g   c yt ot o xi c   c o m bi n ati o ns  
( d o u bl ets) 
 i n cl u d e 
  cis pl ati n/ p a clit a x el, 
  cis pl ati n/ vi n or el bi n e, 
 cis pl ati n/ g e m cit a bi n e, 
cis pl ati n/ d o c et a x el,  a n d  c ar b o pl ati n/ p a clit a x el.  P e m etr e x e d  pl us  pl ati n u m  c h e m ot h er a p y i n t h e 
first-li n e s etti n g l e a d t o  a si g nifi c a nt s ur vi v al  a d v a nt a g e f or  a d v a n c e d  n o n-s q u a m o us  N S C L C 
p ati e nts   c o m p ar e d   wit h   ot h er   pl ati n u m -b as e d  r e g i m e ns  (Ri c h e y   et   al   2 0 1 2 ).   A d di n g   a nti- 
v as 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 R)   m o n o cl o n al 
  a nti b o d y  
B e v a ci z u m a b( A v asti n ® ) t o  c ar b o pl ati n/ p a clit a x el  h as  b e e n s h o w n t o i m pr o v e  pr o gr essi o n fr e e 
s ur vi v al ( P F S)  a n d  o v er all s ur vi v al ( O S)  b y t w o  m o nt hs ( S a n dl er  et  al  2 0 0 6 ). I n  a  m ulti-c e nt er 
r a n d o mi z e d  p h as e III st u d y  S a n dl er  a n d  c oll e a g u es s h o w e d t h at t h e  P F S  a n d  O S f or  p ati e nts 
r e c ei vi n g  B e v a ci z u m a b  pl us  c ar b o pl ati n  a n d  p a clit a x el  w as  6. 2  m o nt hs  a n d  O S  1 2. 3  m o nt hs, 
r es p e cti v el y  c o m p ar e d t o  4. 5  m o nt hs  a n d  1 0. 3  m o nt hs f or  p ati e nts r e c ei vi n g  c ar b o pl ati n  a n d 
p a clit a x el  o nl y.  
D uri n g t h e l ast f e w  y e ars, i m pr o v e d  k n o wl e d g e  of  N S C L C  bi ol o g y l e d t o t h e i d e ntifi c ati o n  of 
m ol e c ul ar  e v e nts  cr u ci al f or  m ali g n a nt tr a nsf or m ati o n  a n d  c a n c er  c ell s ur vi v al.  T h es e  a b err a nt 
m ol e c ul ar  e v e nts  ar e  criti c al  o n c o g e ni c  dri v ers  a n d, t h er ef or e, r e pr es e nt  p ot e nti al t h er a p e uti c 
t ar g ets  (G etti n g er   et   al   2 0 1 1 ).   As   a  r es ult,   n e w  t ar g et e d  tr e atm e nt   o pti o ns   ar e   e v ol vi n g.  
Erl oti ni b  a n d  g efiti ni b,  e pi d er m al   gr o wt h f a ct or  r e c e pt or  ( E G F R)  t yr osi n e  ki n as e i n hi bit ors 
( T KIs),   h a v e   b e e n   a p pr o v e d  f or  t h e  tr e at m e nt   of   N S C L C   p ati e nts   wit h  t u m ors   h ar b ori n g  
a cti v ati n g  m ut ati o ns i n t h e  E G F R  g e n e ( G etti n g er  et  al  2 0 1 1 ).  R e c e ntl y  c o m pl et e d  p h as e III 
st u di es  h a v e  c o nfir m e d t h at  p ati e nts  wit h  E G F R  m ut ati o ns s h o ul d r e c ei v e  E G F R  T KI  g efiti ni b 
or   erl oti ni b  as first li n e tr e at m e nt ( M o k  2 0 0 9 , M a e m o n d o  2 0 1 0 ,  Z h o u  2 0 1 1 ,  R os ell   2 0 1 2 ). 
T h es e st u di es s h o w e d  a  P F S  of  9 t o  1 3  m o nt hs i n first -li n e  p ati e nts  wit h  a d v a n c e d  dis e as e  a n d 
E G F R   m ut ati o ns   w h e n  tr e at e d   wit h   E G F R   T KI.   T h e   P F S  f or   p ati e nts  i n  t h es e  st u di es  
r a n d o mi z e d  t o  r e c ei v e   c h e m ot h er a p y   w as   4-6   m o nt hs.   T h e   o v er all  r es p o ns e  r at e  ( O R R)  i n  
p ati e nts r e c ei vi n g  E G F R  T KI r a n g e d fr o m  7 1 % t o  8 2 %.  T h e fr e q u e n c y  of  E G F R  m ut ati o ns is 
m or e   c o m m o n  i n   p ati e nts   of   Asi a n   d es c e nt  ( ar o u n d   3 0 -4 0 %)  i n  c o m p aris o n  t o    C a u c asi a n 
p ati e nts  ( ar o u n d   1 0 -1 5 %)  ( S e q uist   a n d   L y n c h   2 0 0 8 ),   h o w e v er  t h er e  is   n o  i n di c ati o n  t h at  
p ati e nts r es p o n d  diff er e ntl y t o  E G F R  T KI  b as e d  o n  et h ni cit y.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  3 2
5  Pr ot o c ol  N o. 
 
 
 
T h e  dis c o v er y  of  a n a pl asti c l y m p h o m a  ki n as e ( A L K) r e arr a n g e m e nt i n  N S C L C i n  2 0 0 7 ( S o d a  
et  al  2 0 0 7 ) r e pr es e nts  a n ot h er i m p ort a nt  mil est o n e i n t h e  er a  of  m ol e c ul ar t ar g et e d t h er a p y i n 
N S C L C.   M ost   r e c e ntl y  r e m ar k a bl e  r es p o ns es,  si mil ar  t o   E G F R   T KIs,   h a v e   b e e n   o bs er v e d  
wit h   cri z oti ni b,   a   d u al   A L K   a n d   c -M E T  i n hi bit or  i n   p ati e nts  t h at   h ar b or  t h e   e c hi n o d er m  
mi cr ot u b ul e  ass o ci at e d  pr ot ei n li k e  4 -a n a pl asti c l y m p h o m a  ki n as e ( E M L 4 -A L K) tr a nsf usi o n 
g e n e.  Cri z oti ni b  w as  ass o ci at e d  wit h  cli ni c all y  m e a ni n gf ul r es p o ns e r at es  of  5 0 %  a n d  6 1 % i n 
t w o  si n gl e-ar m  tri als  i n   2 5 5   p ati e nts   wit h  l o c all y   a d v a n c e d   or   m et ast ati c   A L K - p ositi v e 
N S C L C ( O u  et  al  2 0 1 1 ).  B as e d  o n t h es e  d at a,  cri z oti ni b r e c ei v e d  a p pr o v al f or t h e tr e at m e nt  of 
A L K -r e arr a n g e d   N S C L C.   As   of   M a y   2 0 1 2,   cri z oti ni b  is   a p pr o v e d  i n  s e v er al   c o u ntri es  
i n cl u di n g   b ut   n ot  li mit e d  t o   U S,  J a p a n   a n d   S wit z erl a n d.  I n  t h e   c o m pl et e d   p h as e  I  first  i n  
h u m a n st u d y,  a  p ot e nt  n e w i n hi bit or,  L D K 3 7 8 s h o w e d  7 5 %  O R R i n  a d v a n c e d  A L K  a cti v at e d 
N S C L C  p ati e nts,  a n d  e x hi bit e d  p ot e nt  a ntit u m or  a cti vit y i n  b ot h  Cri z oti ni b  n aï v e  a n d tr e at e d 
p o p ul ati o ns ( S h a w  et  al   2 0 1 3). 
H o w e v er,  d es pit e t h e  dr a m ati c r es p o ns es t o s u c h i n hi bit ors,  m ost  p ati e nts  ulti m at el y  h a v e  a 
r el a ps e.   M or e o v er,  i n   a d diti o n  t o   E G F R   a n d   A L K,   ot h er   m ol e c ul ar   alt er ati o ns  s u c h   as  
a m plifi c ati o ns  of  c -M E T,  m ut ati o ns  of  PI K 3 C A, t h e  g e n e  e n c o di n g f or  p h os p h ati d yli n osit ol - 
3- ki n as e ( PI 3 K)  al p h a,  a n d  m ut ati o ns  of  K R A S  h a v e  b e e n f o u n d i n  N S C L C.  T h e  m a n a g e m e nt 
of  a d v a n c e d  N S C L C  h as  e v ol v e d i nt o s u bt y pi n g  e a c h t u m or  b as e d  o n  dri v er  o n c o g e ni c  e v e nts 
i n v ol vi n g  t ar g et a bl e   ki n as e.   N o v el   a p pr o a c h es   usi n g  t ar g et e d  t h er a p e uti c   a g e nts  f or  t h es e  
p ati e nt  p o p ul ati o ns  wit h  m ol e c ul ar  c h ar a ct eri z ati o n  m a y i d e ntif y s u bs ets  of  a d v a n c e d  N S C L C 
p ati e nts  w h o  w o ul d  b e n efit fr o m t ar g et e d  ki n as e i n hi biti o n.  
 
1. 2  
I ntr o d u cti o n t o i n v e sti g ati o n al tr e at m e nt( s)  a n d  ot h er  st u d y 
tr e at m e nt( s) 
1. 2. 1   
O v er vi e w  of  B Y L 7 1 9  
B Y L 7 1 9 is  a n  or al  α -s p e cifi c  cl ass I  PI 3 K i n hi bit or.  It  p ot e ntl y i n hi bits  p 1 1 0 α ( b ot h  wil d t y p e 
a n d    m ut ati o ns)  b ut  l ess  str o n gl y  t h e  β,  δ,  a n d  γ  is of or ms  of  PI 3 K.    B Y L 7 1 9  is  als o  hi g hl y 
s el e cti v e f or  PI 3 K  al p h a  a n d  d o es  n ot  a ct  a g ai nst  V ps 3 4  a n d  m a m m ali a n t ar g et  of r a p a m y ci n 
( m T O R).  F or f urt h er  d et ails, r ef er  t o t h e  c urr e nt  v ersi o n  of  t h e I B [ B Y L 7 1 9 I n v esti g at or’s 
Br o c h ur e]. 
 
1. 2. 1. 1   N o n -cli ni c al  e x p eri e n c e  
 
1. 2. 1. 1. 1  N o n -cli ni c al  p h ar m a c o d y n a mi c s  
T h e  p ot e n c y  a n d s el e cti vit y  of  B Y L 7 1 9 is  c o nfir m e d  at t h e  c ell ul ar l e v el i n  m e c h a nisti c  a n d 
r el e v a nt  t u m or   c ell  li n es.   B Y L 7 1 9   p ot e ntl y  i n hi bits   p 1 1 0α   c ell ul ar   a cti vit y  ( C o n c e ntr ati o n  
pr o d u ci n g  5 0 % i n hi biti o n  (I C 5 0) = 7 4  n M)  a n d  s h o ws  si g nifi c a nt  s el e cti vit y  a g ai nst t h e  p 1 1 0β  
a n d   p 1 1 0 δ   is of or ms  ( a b o v e   1 5-f ol d).  Its   bi ol o gi c al   a cti vit y   c orr el at es   wit h  i n hi biti o n   of  
v ari o us  PI 3 K/ A kt  d o w nstr e a m si g n ali n g  p at h w a y  c o m p o n e nts.  I n  vi v o,  B Y L 7 1 9 s h o ws  d os e 
a n d ti m e -d e p e n d e nt i n hi biti o n  of t h e  PI 3 K/ A kt  p at h w a y i n r el e v a nt t u m or  x e n o gr aft  m o d els 
( p 1 1 0α -m e c h a nisti c  m o d el  a n d  p 1 1 0 α -m ut a nt  x e n o gr aft  m o d els) i n  n u d e  mi c e  a n d  r ats. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  3 3
5  Pr ot o c ol  N o. 
 
 
 
1. 2. 1. 1. 2  N o n -cli ni c al  p h ar m a c o ki n eti c s  a n d  m et a b oli s m  
I n  all s p e ci es, t h e  c o m p o u n d  w as r a pi dl y  a bs or b e d  wit h  T m a x  o c c urri n g  b et w e e n  0. 5 -2. 0  h. 
Or al  bi o a v ail a bilit y  w as  m o d er at e i n r ats  aft er s us p e nsi o n  d osi n g  a n d  c o m pl et e i n  mi c e  a n d 
d o gs   aft er   a  si n gl e   d os e   of   B Y L 7 1 9   as   a  s ol uti o n.  I n  r at   A D M E  st u d y,  t h e   dr u g  r el at e d  
r a di o a cti vit y  w as r a pi dl y  distri b ut e d t o  al m ost  all tiss u es,  b ut  n ot t h e  br ai n.  T h e  hi g h est tiss u e 
e x p os ur e  aft er  d osi n g  w as f o u n d i n t h e li v er,  bil e,  h ar d eri a n  gl a n d,  h air f olli cl es, t a ctil e  h air, 
a n d i n t h e  pr e p uti al  gl a n d.  Dr u g r el at e d r a di o a cti vit y  w as  als o f o u n d i n  m el a ni n  c o nt ai ni n g 
tiss u es s u c h  a s t h e  c h or oi d  a n d  cili ar y  b o d y  of t h e  e y e  b ut  d e cli n e d  wit h ti m e. 
B Y L 7 1 9 s h o w e d l o w  cl e ar a n c e  c o m p ar e d t o t h e  h e p ati c  bl o o d fl o w i n  e a c h s p e ci es t est e d.  
T h e   m ai n   bi otr a nsf or m ati o n   p at h w a y  t h at   w as   o bs er v e d   c o nsist e ntl y   a cr oss  s p e ci es   w a s  
h y dr ol ysis   of  t h e   pr oli n e   a mi d e   m oi et y,   w hi c h  is  t h e   o nl y   m et a b olit e  t h at   w as   d et e ct e d  i n  
h u m a n  a n d  d o g  h e p at o c yt e  i n c u b ati o ns. 
Aft er  t h e   or al   a d mi nistr ati o n   of  [ 1 4C] B Y L 7 1 9  i n  r ats,  t h e   dr u g -d eri v e d  r a di o a cti vit y  
u n d er w e nt  m ai nl y  bili ar y  e x cr eti o n  wit h  al m ost  c o m pl et e r e c o v er y  at  7  d a ys  p ost -d os e.  R e n al 
e x cr eti o n  of r a di o a cti vit y  w as r el ati v el y l o w ( 1 1 - 1 5 %).  
B Y L 7 1 9 s h o w e d r e v ersi bl e  w e a k i n hi biti o n  of  C Y P 2 C 8,  C Y P 2 C 9.  T h e  c o m p o u n d is  als o  a 
str o n g  ti m e-d e p e n d e nt  i n hi bit or   of   C Y P 3 A 4   i n  vitr o.   B Y L 7 1 9  is   a  s u bstr at e   of   B C R P   a n d 
m ulti -dr u g r esist e n c e -1 ( M D R -1) (l o w  affi nit y)  a n d s h o w e d  v er y  w e a k i n hi biti o n  of  M D R - 1. 
N o  i n hi biti o n   c o ul d   b e   o bs er v e d   o n   B C R P -  or   M R P 2 -m e di at e d  tr a ns p ort.   B Y L 7 1 9  is   n ot  
c o nsi d er e d   a   h u m a n   pr e g n a n e   X  r e c e pt or  ( P X R)   or   ar o m ati c   h y dr o c ar b o n  r e c e pt or  ( A h R)  
a cti v at or.  
F or  m or e i nf or m ati o n,  pl e as e r ef er t o t h e  c urr e nt [ B Y L 7 1 9 I n v esti g at or’s  Br o c h ur e].  
 
1. 2. 1. 1. 3  N o n -cli ni c al  s af et y  a n d  t o xi c ol o g y 
R o uti n e  s af et y   p h ar m a c ol o g y   a n d  t o xi c ol o g y  st u di es   w er e   c o n d u ct e d  i n  r ats   a n d   d o gs.  I n  
a d diti o n, f or  e x pl or at or y st u di es, s u c h  as i ns uli n/ gl u c os e t ol er a n c e t ests,  mi c e  w er e  als o  us e d. 
T h e   m aj orit y   of  t h e   o bs er v e d  t o xi c ol o gi c al   eff e cts   of   B Y L 7 1 9   w er e  r el at e d  t o  t h e  
p h ar m a c ol o gi c al  a cti vit y  of  B Y L 7 1 9  as  a  p 1 1 0 α  s p e cifi c i n hi bit or  of  PI 3 K  p at h w a y, s u c h  as 
a n i nfl u e n c e  o n i ns uli n ( a n d  p ot e nti all y  gl u c os e)  h o m e ost asis  a n d t h e ris k  of i n cr e as e d  bl o o d 
pr ess ur e.  T h e  p h ar m a c ol o gi c all y r el e v a nt t o xi cit y  w as  m ai nl y  o bs er v e d  at  d os a g es  cl os e t o  or 
at   M T D   aff e cti n g  t h e   b o n e   m arr o w   a n d  l y m p h oi d  tiss u e,   p a n cr e as,   a n d  s o m e  r e pr o d u cti v e 
or g a ns  of  b ot h  g e n d ers  b ei n g t h e  m ai n t ar g et  or g a ns  of t h e t o xi c  eff e cts.  I n  d o gs,  e pit h eli al 
eff e cts    w er e   s e e n  i n  t h e   c or n e a;   h o w e v er,  t h es e   eff e cts    w er e   n ot   d os e -d e p e n d e nt.   N o  
o p ht h al m ol o gi c  a b n or m aliti es ,  ass o ci at e d  wit h  B Y L 7 1 9 tr e at m e nt,  w er e  o bs er v e d i n r ats  or i n 
d o gs.   Cli ni c al   c h e mistr y  a n d  hist o p at h ol o gi c al   c h a n g es i n t h e  p a n cr e ati c isl ets i n di c at e d  a n 
alt er e d  gl u c os e  m et a b olis m,  c orr el ati n g  wit h si g ns  of i ns uli n i ns e nsiti vit y  as  w as  als o s e e n i n 
t h e  m o us e  i ns uli n/ gl u c os e   c h all e n g e  t est.   All  t o xi c   e v e nts   w er e  r e v ersi bl e   or  s h o w e d   a  
t e n d e n c y t o r e v ersi bilit y. 
B Y L 7 1 9  di d  n ot  s h o w  si g ns  of   Q T  pr ol o n g ati o n,  n e ur ol o gi c al  or  p ul m o n ar y  t o xi cit y;  it  di d  
n ot s h o w  a  p h ot ot o xi c  p ot e nti al  a n d  w as  n ot  g e n ot o xi c  i n vitr o . 
F or  m or e i nf or m ati o n,  pl e as e r ef er t o t h e  c urr e nt [ B Y L 7 1 9 I n v esti g at or’s  Br o c h ur e].  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  3 4
5  Pr ot o c ol  N o. 
 
 
 
1. 2. 1. 2   Cli ni c al  e x p eri e n c e  
 
1. 2. 1. 2. 1  Cli ni c al  st u di e s  
As  of t h e  c ut -off  d at e  of  2 0 -M a y -2 0 1 4,  5 4 3  p ati e nts  h a v e r e c ei v e d  B Y L 7 1 9  as  a si n gl e  a g e nt 
or i n  c o m bi n ati o n  wit h  a n ot h er tr e at m e nt.  
 
C B Y L 7 1 9 X 2 1 0 1  
B Y L 7 1 9  is   b ei n g  t est e d  i n   a   First -i n-H u m a n  ( FI H)   P h as e  I   d os e   es c al ati o n  st u d y  
[ C B Y L 7 1 9 X 2 1 0 1] i n  p ati e nts  with  a d v a n c e d s oli d t u m ors  c arr yi n g  a  m ut ati o n  of t h e  PI K 3 C A 
g e n e.  E nr oll m e nt  of t h e  d os e  es c al ati o n  p h as e  of t his st u d y is  c o m pl et e d.  D os e l e v els fr o m  3 0 
m g  q d t o  4 5 0  m g  q d  h a v e  b e e n t est e d.  T h e si n gl e  a g e nt  M T D  w as  d e cl ar e d  at  4 0 0  m g  q d.  A 
s af et y  e x p a nsi o n  c o h ort is  c urr e ntl y  o n g oi n g  at  a  d os e  of  4 0 0  m g  q d. I n  p ar all el,  a t wi c e  d ail y 
( bi d) s c h e d ul e is  b ei n g i n v esti g at e d. 
As  of  1 5 -F e b -2 0 1 3,  a t ot al  of  1 0 2  p ati e nts  wit h  a d v a n c e d  c a n c er  h a v e r e c ei v e d  at l e a st  o n e 
d os e  of  B Y L 7 1 9  a n d  h a v e  b e e n  e v al u at e d f or s af et y i n st u d y  [ C B Y L 7 1 9 X 2 1 0 1].  A t ot al  1 3  
o ut  of  1 0 2  e v al u a bl e  p ati e nts  e x p eri e n c e d  d os e li miti n g t o xi cit y,  8  aft er t h e  q d  a n d  5  aft er t h e 
bi d r e gi m e n.  D os e li miti n g t o xi citi es ( D L Ts) i n cl u d e d  gr a d e  3  or  4  h y p er gl y c e mi a ( 9  p ati e nts), 
gr a d e  3  n a us e a  ( 3 p ati e nt s), gr a d e   3  v o miti n g  ( 1 p ati e nt),  gr a d e   3  di arr h e a  ( 1 p ati e nt)  a n d  
gr a d e  3  h y p er p h os p h at e mi a ( 1  p ati e nt).  
O v er all,  1 0 1 ( 9 9 %)  p ati e nts  e x p eri e n c e d  A Es  w hi c h  w er e  s us p e ct e d t o  b e r el at e d t o  B Y L 7 1 9. 
T h e   m ost  fr e q u e ntl y  r e p ort e d  tr e at m e nt -r el at e d   A Es,  r e g ar dl ess   of   C T C A E   gr a d e   a n d   d os e 
w er e   h y p er gl y c e mi a   ( 4 9 %),   n a us e a   ( 4 3 %),   d e cr e as e d   a p p etit e   ( 3 7 %),   di arr h e a   ( 3 5 %), 
r as h/ h y p ers e nsiti vit y  ( 3 4 %),  a n d  ast h e ni a/f ati g u e  ( 3 4 %).  T h e  m ost  c o m m o n tr e at m e nt-r el at e d 
gr a d e  3  or  4  A Es  w er e  h y p er gl y c e mi a ( 2 5 %),  a n d r as h ( 8 %) . 
P arti al t u m or r es p o ns es  wit h si n gl e  a g e nt  B Y L 7 1 9  w er e  o bs er v e d i n  9  p ati e nts tr e at e d  at  d ail y 
d os es  ≥  2 7 0    m g  ( 4  c o nfir m e d,  5  u n c o nfir m e d).    M e di a n  pr o gr essi o n -fr e e  s ur vi v al   w as  1 5. 7 
w e e ks ( G o n z al e z -A n g ul o  et  al  2 0 1 3 ). 
 
1. 2. 1. 2. 2  Cli ni c al  P h ar m a c o ki n eti c s  
Aft er  or al  a d mi nistr ati o n,  B Y L 7 1 9 is  w ell  a bs or b e d.  M e di a n  T m a x  at t h e  M T D  d os e ( 4 0 0  m g 
o n c e  d ail y)   w as  2  h o urs.   Pl as m a  c o n c e ntr ati o ns  of   B Y L 7 1 9  g e n er all y  d e cli n e d i n  a  m o n o - 
e x p o n e nti al  m a n n er.  T 1/ 2  aft er  a  4 0 0  m g  or al  d os e  w as  7 t o  8  h o urs  a n d  g e n er all y  a p p e ar e d t o 
b e  i n d e p e n d e nt   of   d os e   a n d  ti m e.   Aft er   o n c e   d ail y   d osi n g,  t h e   dr u g   w as   mi ni m all y  
a c c u m ul at e d.   T h e  m e di a n   a c c u m ul ati o n r ati o ( R a c c)   of  B Y L 7 1 9   a cr oss  all   d os e l e v els  w as 
c al c ul at e d t o  b e  a b o ut  1. 3,  w hi c h is i n  a gr e e m e nt  wit h t h e s h ort  h alf -lif e  of  B Y L 7 1 9. St e a d y- 
st at e  B Y L 7 1 9  pl as m a l e v els  c a n  b e  e x p e ct e d t o  b e r e a c h e d  at  2 t o  3  d a ys f oll o wi n g  o ns et  of 
t h er a p y i n  m ost  p ati e nts. 
A   p h as e  I  st u d y  is   als o   o n g oi n g  i n  J a p a n es e  s oli d  t u m or   p ati e nts   [ B Y L 7 1 9 X 1 1 0 1]. 
Pr eli mi n ar y  P K  a n al ysis s h o w e d  B Y L 7 1 9  e x p os ur e i n J a p a n es e  p ati e nts  w as  c o m p ar a bl e t o 
W est er n  p ati e nts  [ B Y L 7 1 9 X 2 1 0 1]  at t h e t est e d  d os e l e v els  of  9 0  m g,  1 8 0  m g,  2 7 0  m g,  3 5 0 
m g  a n d  4 0 0  m g  q d.  
F or f urt h er  d et ails, r ef er t o t h e  c urr e nt [ B Y L 7 1 9 I n v esti g at or’s  Br o c h ur e].  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  3 5
5  Pr ot o c ol  N o. 
 
 
 
1. 2. 2   
O v er vi e w  of  I N C 2 8 0 
I N C 2 8 0  is   a  s m all   A T P   c o m p etiti v e,  r e v ersi bl e  i n hi bit or   of  t h e   c-M E T  r e c e pt or  t yr osi n e  
ki n as e.  T h e  pr ot o -o n c o g e n e  c -M E T  e n c o d es t h e  hi g h -affi nit y r e c e pt or f or  h e p at o c yt e  gr o wt h 
f a ct or ( H G F),  w hi c h is t h e  o nl y  k n o w n li g a n d f or t his r e c e pt or. 
 
1. 2. 2. 1   N o n -cli ni c al   ex p eri e n c e  
 
1. 2. 2. 1. 1  N o n -cli ni c al  p h ar m a c o d y n a mi c s  
I N C 2 8 0  p oss ess e s  p ot e nt i n hi bit or y  a cti vit y  a g ai nst t h e  c-M E T  ki n as e  i n  vitr o.  P ot e nt  a cti vit y 
(I C 5 0  v al u es:   0. 2 -  2  n M)   h as  b e e n  d e m o nstr at e d i n  c ell -b as e d  bi o c h e mi c al   a n d f u n cti o n al 
ass a y s t h at   m e as ur e  c -M E T -m e di a t e d si g n al tr a ns d u cti o n,   as  w ell  as  c-M E T -d e p e n d e nt   c ell  
pr olif er ati o n, s ur vi v al,  a n d  mi gr ati o n. I n  c -M E T/ H G F -dri v e n  x e n o gr aft  m o us e t u m or  m o d els, 
or al   d osi n g   of  I N C 2 8 0   d e m o nstr at e d  si g nifi c a nt   i n   vi v o  a cti vit y  i n   bl o c ki n g   b ot h   c -M E T 
p h os p h or yl ati o n  a n d t u m or  gr o wt h.  
 
1. 2. 2. 1. 2  N o n -cli ni c al  p h ar m a c o ki n eti c s  a n d  m et a b oli s m  
Aft er  a si n gl e  or al  d os e, I N C 2 8 0  w as  a bs or b e d r a pi dl y i n r ats  a n d  d o gs ( T m a x <  1 h).  T m a x i n 
m o n k e ys  w as l o n g er  a n d  r a n g e d  fr o m  2. 7 t o  7  h.  T h e  a bs ol ut e  or al  bi o a v ail a bilit y  ( F %)  w as 
l o w  i n  d o gs  ( 2 8 %),   m o d er at e  i n  t h e  r at  ( 6 6 %)  a n d  l o w  t o   m o d er at e  i n  t h e   m o n k e y  ( 2 4 %  t o 
4 4 %).  
I N C 2 8 0  is   wi d el y   a n d  r a pi dl y   distri b ut e d  i nt o   all  tiss u es.  I N C 2 8 0   p e n etr at e d  t h e   n or m al  
bl o o d- br ai n  b arri er  wit h  a  br ai n tiss u e t o  pl as m a r ati o  of  0. 1.  
I N C 2 8 0 is  pr e d o mi n a ntl y  m et a b oli z e d  b y  c yt o c hr o m es  P 4 5 0 i n  h u m a n  h e p ati c  mi cr os o m es. 
C Y P 3 A 4 is t h e  m aj or   P 4 5 0  e n z y m e t o  m et a b oli z e I N C 2 8 0.   I n  vitr o C Y P 3 A 4 is t h e  m aj or  
li v er  C Y P e n z y m es i n v ol v e d i n  o xi d ati v e  m et a b olis m  of I N C 2 8 0 i n  h u m a n li v er  mi cr os o m e 
( H L M) ( ~fm 9 9. 6 %)  wit h  v er y l o w  c o ntri b uti o n fr o m  ot h er  e n z y m es  ( ~ 0. 4 %). 
F oll o wi n g  i. v. a d mi nistr ati o n  of I N C 2 8 0 i n  r ats  a n d  m o n k e ys, l ess t h a n  1 %  of t ot al  d os e  w as 
e x cr et e d  as  p a r e nt  dr u g i n  uri n e, s u g g esti n g t h at t h e r e n al  p at h w a y is  n ot  a si g nifi c a nt r o ut e  of 
eli mi n ati o n. I n t h e r ats  A D M E st u d y, t ot al r a di o a cti vit y  w as  pri m aril y  eli mi n at e d  vi a  bili ar y 
s e cr eti o n.  
I N C 2 8 0  s h o w e d  i n hi bit or y   p ot e n c y  f or   C Y P 1 A 2,   C Y P 2 C 8,   C Y P 2 C 9,   C Y P 2 C 1 9   a n d  
C Y P 3 A 4/ 5.  Ti m e -d e p e n d e nt (irr e v ersi bl e) i n hi biti o n  b y I N C 2 8 0  w as  o bs er v e d f or  C Y P 1 A 2 
a n d   C Y P 3 A 4/ 5 -m e di at e d   mi d a z ol a m   1’ - h y dr o x yl ati o n.   P ot e nti al   D DI   d u e  t o  i n hi biti o n   of  
C Y P 1 A 2,  2 C 8,  2 C 9,  2 C 1 9  a n d  3 A 4/ 5 is  p ossi bl e  at  cli ni c all y r el e v a nt  d os es .  
I N C 2 80 i n hi bits  P -g p,  M X R/ B C R P,  O A T P 1 B 1  a n d  O A T P 1 B 3. I N C 2 8 0  m a y i n cr e as e  u pt a k e 
of  c o -m e di c ati o ns tr a ns p ort e d  b y  A B C  a n d  S L C -tr a ns p ort ers i n t h e  g astr o-i nt esti n al tr a ct  or 
d e cr e as e  eli mi n ati o n  of s o m e  dr u gs i nt o t h e  bil e  a n d/ or  uri n e.  
F or  m or e i nf or m ati o n,  pl e a s e r ef er t o t h e  c urr e nt [I N C 2 8 0 I n v esti g at or’s  Br o c h ur e].  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  3 6
5  Pr ot o c ol  N o. 
 
 
 
1. 2. 2. 1. 3  N o n -cli ni c al  s af et y  a n d  t o xi c ol o g y 
S af et y  p h ar m a c ol o g y st u di es  wit h I N C 2 8 0 i n di c at e d t h at I N C 2 8 0  h a d  n o si g nifi c a nt  eff e cts  o n 
c e ntr al   n er v o us  s yst e m  ( C N S)   a n d  r es pir at or y  f u n cti o ns  i n  r ats,   a n d   n o   eff e cts   o n  
c ar di o v as c ul ar f u n cti o n i n  m o n k e ys.  
T h e  t o xi c ol o g y  pr ofil es   of  I N C 2 8 0   w er e   c h ar a ct eri z e d  i n  si n gl e  a n d  r e p e at -d os e  st u di es  i n  
m o us e,  r at  a n d  C y n o m ol g us  m o n k e y.   T h e r e p e at -d os e st u di es r e v e al e d t h e f oll o wi n g t ar g et 
or g a ns  or s yst e ms:  ki d n e ys,  p a n cr e as,  C N S,  a n d  p ot e nti all y t h e li v er.  
D et ail e d  i nf or m ati o n is  a v ail a bl e i n t h e l at est  v ersi o n  of t h e [I N C 2 8 0 I n v esti g at or’s  Br o c h ur e]. 
 
1. 2. 2. 2   Cli ni c al  e x p eri e n c e  
As  of  2 8 -S e p -2 0 1 4 ( c ut -off  d at e  of t h e I N C 2 8 0 I n v esti g at or’s  Br o c h ur e,  e diti o n  5. 2),  a t ot al  of 
2 0 3  c a n c er  p ati e nts  h a v e  b e e n tr e at e d i n fi v e  cli ni c al tri als  wit h I N C 2 8 0  as  a si n gl e  a g e nt  a n d 
a  t ot al   of   1 0 3   c a n c er   p ati e nts   h a v e   b e e n  tr e at e d   wit h  I N C 2 8 0  i n   5   diff er e nt   c o m bi n ati o n  
t h er a pi es  wit h  a nti-c a n c er  a g e nts  at  v ari o us  d os es  a n d i n t w o f or m ul ati o ns,  c a ps ul e  a n d  t a bl et. 
Si n gl e  a g e nt I N C 2 8 0 is  g e n er all y t ol er a bl e (r e g ar dl ess  of t h e  d os e),  wit h t h e  m aj orit y  of t h e 
r e p ort e d  a d v ers e  e v e nts ( A Es)  b ei n g  of  mild  or  m o d er at e s e v erit y ( C T C A E  gr a d e  1  or  gr a d e 
2).  C T C A E  gr a d e  3  or  gr a d e  4  A Es s us p e ct e d t o  b e r el at e d t o I N C 2 8 0 i n si n gl e  a g e nt st u di es 
(r e g ar dl ess   of  t h e  d os e)  i n cl u d e d   h y p o p h os p h at e mi a,   p eri p h er al   e d e m a,  f ati g u e,  i n cr e as e  i n 
A S T,   A L T,   G G T,   a m yl as e,   bl o o d   bilir u bi n   a n d  li p as e,   v o miti n g,   c olitis   ul c er ati v e,  l u n g  
i nf e cti o n,   n a us e a,   a n e mi a,   n e utr o p e ni a,   h y p o p h a gi a,   d e cr e as e d   a p p etit e,   h y p o al b u mi n e mi a,  
m a c ul o -p a p ul ar r as h,  d e h y dr ati o n  a n d l y m p h o c yt e  d e cr e as e d.  
I n  t h e   c o m bi n ati o n  st u di es,  t h e   m ost  fr e q u e nt   A Es  s us p e ct e d  t o   b e  r el at e d  t o  I N C 2 8 0  
(r e g ar dl ess   of  t h e   d os e)   w er e   n a us e a   a n d   v o miti n g.   C T C A E   gr a d e   3   a n d   gr a d e   4   A Es  
s us p e ct e d  t o   b e  r el at e d  t o  I N C 2 8 0  (r e g ar dl ess   of  t h e   d os e)  i n cl u d e d   m ost  fr e q u e ntl y:  
as y m pt o m ati c i n cr e as e i n  a m yl as e, i n cr e as e i n li p as e,  A S T  a n d  A L T,  n a us e a  a n d  v o miti n g. 
O n e   S A E   wit h  f at al   o ut c o m e,   d et eri or at e d   c o u g h   a n d   d ys p n e a,   h as   b e e n  r e p ort e d   wit h   a  
s us p e ct e d  c a u s al r el ati o ns hi p t o  I N C 2 8 0. 
Aft er  t h e  c ut -off   d at e   of   2 8 -S e p -2 0 1 4,   a  f e m al e  p ati e nt   e x p eri e n c e d   a s eri o us,   u n e x p e ct e d,  
p ossi bl y  r el at e d   a d v ers e   e v e nt   of   a b n or m al  li v er  f u n cti o n  t ests   d uri n g  tr e at m e nt   wit h   a  
c o m bi n ati o n  of I N C 2 8 0  a n d  g efiti ni b  w hil e  e nr oll e d i n t h e  [ CI N C 2 8 0 X 2 2 0 2]  st u d y.  P ati e nt 
e x p eri e n c e d  c o n c urr e nt   el e v ati o ns  of  t ot al   bilir u bi n  > 2 × U L N  a n d  A L T/ A S T   > 3 × U L N  wit h  
a l k ali n e  p h os p h at as e ( A L P)  < 2 × U L N.  T h e  p ati e nt  p er m a n e ntl y  dis c o nti n u e d st u d y  dr u gs.  T h e 
li v er f u n cti o n  alt er ati o ns  w er e r e v ersi bl e  a n d i m pr o v e d  aft er t h e  dis c o nti n u ati o n  of  b ot h  dr u gs. 
At t h e ti m e  of t h e f oll o w -u p I n v esti g at or  N otifi c ati o n (I N), t h e  o ut c o m e  of t h e  a d v ers e  e v e nt 
of  a b n or m al li v er f u n cti o n t ests  w as r e p ort e d  as  c o m pl et el y r e c o v er e d.  T his  p ati e nt  m et t h e 
crit eri a  of  H y’s  L a w  a n d t h e  h e p at ot o xi cit y  c o ul d  n ot  b e  attri b ut e d s ol el y t o  eit h er  dr u g  al o n e 
or t o t h e  c o m bi n ati o n.  
T h e r e c o m m e n d e d  p h as e  II  d os e ( R P 2 D)  of I N C 2 8 0  m o n ot h er a p y  a n d i n  c o m bi n ati o n t h er a p y 
wit h  g efiti ni b is  4 0 0 m g  BI D i n t a bl et f or m ul ati o n.  T h e  m a xi m u m t ol er at e d  d os e ( M T D) f or 
si n gl e  a g e nt I N C 2 8 0  h as  n ot  b e e n  d efi n e d.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  3 7
5  Pr ot o c ol  N o. 
 
 
 
1. 2. 2. 2. 1  Cli ni c al  st u di e s  
 
CI N C 2 8 0 X 2 1 0 1  
As   of   2 8 -S e p - 2 0 12,  st u d y  I N C B 2 8 0 6 0 -1 0 1  ( N o v artis  st u d y   c o d e   [ CI N C 2 8 0 X 2 1 0 1]), 
c o n d u ct e d  b y I n c yt e  C or p or ati o n is  a si n gl e  a g e nt  P h as e I  FI H st u d y  d esi g n e d t o  c h ar a ct eri z e 
s af et y, t ol er a bilit y,  p h ar m a c o ki n eti cs,  p h ar m a c o d y n a mi cs,  a n d  a nti -t u m or  a cti vit y.  A t ot al  of 
4 5  p ati e nts  h a v e  b e e n tr e at e d  o n  el e v e n  d os e  c o h orts.  T h e  hi g h est  d os es t est e d  w er e  3 0 0  m g 
bi d  a n d  4 0 0  m g  q d. I N C 2 8 0  w as  w ell t ol er at e d  a n d t h e  M T D  h as  n ot  b e e n  est a blis h e d.  
 
CI N C 2 8 0 X 2 1 0 2  
[ CI N C 2 8 0 X 2 1 0 2]  st u d y  is   a   P h as e  I   d os e   es c al ati o n  st u d y  i n  s oli d  t u m or   wit h   c- M E T 
d ysr e g ul ati o n  c o n d u ct e d  b y  N o v artis.  
As  of J u n e  2 6,  2 0 1 3 I N C 2 8 0  6 0 0 m g  bi d is t h e  hi g h est s af e  d os e  b ei n g  e v al u at e d i n t his st u d y. 
2 5   p ati e nts   h a v e   b e e n   e nr oll e d  t o  si x   d os e  l e v els  ( 1 0 0 m g   bi d  ( 4   p ati e nts),   2 0 0 m g   bi d  ( 5  
p ati e nts),  2 5 0 m g  bi d ( 4  p ati e nts),  3 5 0 m g  bi d ( 3  p ati e nts),  4 5 0 m g  bi d ( 5  p ati e nts),  6 0 0  m g  bi d 
( 4  p ati e nts). I n t ot al t hr e e  D L Ts  h a v e  b e e n r e p ort e d i n t his st u d y,  o n e  C T C A E  gr a d e  3 t ot al 
bilir u bi n i n cr e as e  at  2 5 0 m g  bi d  d os e l e v el,  a n d t w o  C T C A E  gr a d e  3 f ati g u e,  o n e  at  2 0 0 m g  bi d 
a n d  o n e  at  4 5 0 m g  bi d  d os e l e v el.  
I n t h e  hi g h est  d os e l e v el ( 6 0 0  m g  bi d) t h er e  w er e  n o  D L Ts r e p ort e d. I n  a d diti o n,  as  of J u n e  2 6, 
2 0 1 3  n o  gr a d e  3  or  4 s us p e ct e d  A Es  h a v e  b e e n r e p ort e d f or t his  d os e l e v el.  Fi v e  S A Es i n  o n e 
p ati e nt  w er e r e p ort e d f or t his  c o h ort:  h y p er c al c a e mi a ( b ef or e  d osi n g), f e v er ( b ef or e  d os i n g), 
i nfl u e n z a  ( b ef or e   d osi n g),   cr e ati ni n e  i n cr e as e   a n d   h e p at or e n al  s y n dr o m e.   H o w e v er,   n o n e   of   
t h e  S A Es  w er e r el at e d t o t h e st u d y tr e at m e nt. 
T h er ef or e,   wit h   c o nsi d er ati o n   of   cli ni c al  s af et y,   P K   d at a  ( S e cti o n   1. 2. 2. 2. 2 ),   as  w ell   as  
pr e cli ni c al  P K/ P D  d at a,  6 0 0 m g  bi d  will s el e ct e d f or t his  p h as e II st u d y.  
T h e  pr eli mi n ar y  d at a fr o m  t h e si n gl e  a g e nt  I N C 2 8 0 st u d y,   CI N C 2 8 0 X 2 1 0 2,  s u g g est e d t h at  
effi c a c y is r estri ct e d t o t h e  p ati e nt  p o p ul ati o n  wit h  E G F R wt  a n d  hi g h  M E T st at us.  As  of  2 1 
M ar c h  2 0 1 4,  3  o ut  of  6  p ati e nts  h a d  c o nfir m e d  P R;  all  p ati e nts   w er e   E G F R wt  a n d  h a d  hi g h 
M E T  st at us   b y  I H C   or   FI S H  ( B a n g   Y -J   et   al   2 0 1 4).   T w o   of  t hr e e   p ati e nts   h a d   c M E T  
m ut ati o ns.  T h er ef or e, t his st u d y  will s el e ct t h e  hi g h  M E T st at us  as i n cl usi o n  crit eri a.  
 
CI N C 2 8 0 X 2 2 0 2  
[ CI N C 2 8 0 X 2 2 0 2]  is  a  P h as e I b/II st u d y i n  c o m bi n ati o n  wit h  g efiti ni b i n  a d ult  p ati e nts  wit h 
E G F R   m ut at e d,   c -M E T -p ositi v e   N S C L C   w h o   h a v e   pr o gr ess e d   aft er   E G F R  i n hi bit or  
tr e at m e nt. As  of J u n e  2 6,  2 0 1 3, t w e nt y si x  p ati e nts  w er e tr e at e d i n fi v e  d os e  c o h orts ( 1 0 0 m g 
q d ,  2 0 0 m g  q d,  4 0 0 m g  q d,  8 0 0 m g  q d,  2 0 0 m g  bi d)  of I N C 2 8 0.  N o  D L T  h as  b e e n  o bs er v e d. 
T w o  p ati e nts  h a v e r e p ort e d  c o nfir m e d  P Rs,  o n e i n  2 0 0  m g  q d  c o h ort  a n d t h e  ot h er i n  4 0 0  m g 
q d  c o h ort. 
 
1. 2. 2. 2. 2  Cli ni c al  P h ar m a c o ki n eti c s  
B y t h e  c ut -off  d at e  of J u n e  2 6,  2 0 1 3 t w e nt y  o n e  p ati e nts fr o m  [ CI N C 2 8 0 X 2 1 0 2]  st u d y  h a v e 
e v al u a bl e  P K  d at a  o n  C 1 D 1  a n d  C 1 D 1 5 fr o m  1 0 0  m g  bi d t o  6 0 0  m g  bi d.  T hr e e  p ati e nts  at  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  3 8
5  Pr ot o c ol  N o. 
 
 
 
6 0 0 m g  bi d  h a v e  e v al u a bl e  P K  d at a. I N C 2 8 0  e x p os ur e is i n cr e asi n g  b y  d os e  wit h  m o d er at e t o 
hi g h i nt er -s u bj e ct  v ari a bilit y.  Aft er  or al  a d mi nistr ati o n,  a bs or pti o n  of I N C 2 8 0 is f ast.  M e di a n 
T m a x r a n g es fr o m  1 t o  4  h o urs.  O bs er v e d t er mi n al  h alf -lif e is  a v er a g e d  of  2. 9 t o  7. 7 8  h o urs. 
T h e  m e a n  st e a d y  st at e  A U C 0 - 1 2h  at   3 5 0  m g  bi d,   4 5 0  m g  bi d  a n d  6 0 0  m g  bi d  ar e  2 0 1 1 6, 
1 7 0 7 7  a n d  3 7 1 4 2  n g * h/ m L, r es p e cti v el y.  St e a d y st at e  Ctr o u g h  c o n c e ntr ati o n  at  6 0 0  m g  bi d is 
a b o ut   3 5  f ol d   of  i n   vi v o  I C 9 0  f or   p - c-M E T  i n hi biti o n   m e as ur e d  fr o m   pr e cli ni c al   S 1 1 4  
x e n o gr aft  m o d el. 
I N C 2 8 0  e x hi bit e d  a  p H-d e p e n d e nt s ol u bilit y  pr ofil e  wit h  a l o w s ol u bilit y  at  hi g h  p H l e v el.  A 
st u d y t o  e v al u at e t h e  eff e ct  of l o n g  a cti n g  pr ot o n  p u m p i n hi bit or  o n t h e  P K  of  a si n gl e  d os e 
I N C 2 8 0  t a bl et  ( 6 0 0   m g)   w as   c o m pl et e d  i n   h e alt h y   v ol u nt e ers  [ CI N C 2 8 0 A 2 1 0 1].   D ail y 
tr e at m e nt   of   2 0  m g  r a b e pr a z ol e  f or   4  d a ys  r es ult e d  i n   a  m o d est  r e d u cti o n i n t h e   e xt e nt   of  
I N C 2 8 0   a bs or pti o n    wit h   a   2 5. 2 %   d e cr e as e  i n    A U Ci nf   a n d   a   3 7. 5 %   d e cr e as e  i n    C m a x. 
C o nsi d eri n g  t h e  4 2 %  a n d  6 5 %  v ari a bilit y  i n    A U C  o bs er v e d  i n  p ati e nt  si n gl e  a g e nt  st u di es 
[ CI N C 2 8 0 X 2 1 0 2] a n d  [ CI N C 2 8 0 X 1 1 0 1],  a  d e cr e as e  of  2 5 % i n  A U C  w h e n  a d mi nist er e d  wit h 
P PI  is   c o nsi d er e d   n ot  si g nifi c a nt.   T h e  i m p a ct   o n  t h e   1 2   h o ur   p ost -d os e   c o n c e ntr ati o n   of  
I N C 2 8 0 ( d efi n e d  as tr o u g h  c o n c e ntr ati o n f or  BI D  d osi n g)  w as  s m all  wit h  ~ 7 % r e d u ctio n  aft er 
r a b e pr a z ol e tr e at m e nt.  Pr eli mi n ar y  d at a i n  N S C L C  p ati e nts [ CI N C 2 8 0 X 2 2 0 2]  s u g g est e d t h at 
a nti -t u m or  a cti vit y is  c orr el at e d  m or e  wit h  Ctr o u g h t h a n  A U C  a n d C m a x.  
F or f urt h er  d et ails, r ef er t o t h e  c urr e nt [I N C 2 8 0 I n v esti g at or’s   Br o c h ur e]. 
 
1. 2. 3   
O v er vi e w  of  L D K 3 7 8  
L D K 3 7 8 ( c eriti ni b) is  a n  or all y  a v ail a bl e  A L K i n hi bit or.  L D K 3 7 8 is  a n  a p pr o xi m at el y  2 0 -f ol d 
m or e  p ot e nt  A L K i n hi bit or t h a n  cri z oti ni b, it is  m or e s el e cti v e f or  A L K  a n d  d o es  n ot i n hi bit 
M E T.  
I n  a d diti o n,  L D K 3 7 8 ( c eriti ni b) s h o ws  p ot e nt  a ntit u m or  a cti vit y i n  cri z oti ni b-r esist a nt  a ni m al 
m o d els  ( as   d es cri b e d   b el o w),   a n d  t h e  effi c a c y  s e e n  i n  t h e  o n g oi n g   P h as e  I   cli ni c al  tri al  i n  
p ati e nts  ( wit h   a n d   wit h o ut   pr e vi o us   cri z oti ni b  t h er a p y)  l e d  t o  t h e   a p pr o v al   of   L D K 3 7 8  
( c eriti ni b)  b y t h e  F D A  u n d er t h e tr a d e  n a m e  Z Y K A DI A ™  o n  2 9-A pr -2 0 1 4 f or t h e f oll o wi n g 
i n di c ati o n: 
•   Z Y K A DI A ™ is i n di c at e d f or t h e tr e at m e nt  of  p ati e nts  wit h  A L K -p ositi v e  m et ast ati c 
N S C L C  w h o  h a v e  pr o gr ess e d  o n  o r  ar e i nt ol er a nt t o cri z oti ni b.  
T his  i n di c ati o n  is   a p pr o v e d   u n d er   a c c el er at e d   a p pr o v al   b as e d   o n  t u m or  r es p o ns e  r at e   a n d  
d ur ati o n  of r es p o ns e.  A n i m pr o v e m e nt i n s ur vi v al  or  dis e as e -r el at e d s y m pt o ms  h a s  n ot  b e e n 
est a blis h e d.  C o nti n u e d  a p pr o v al f or t his i n di c ati o n  m a y  b e  c o nti n g e nt  u p o n  v erifi c ati o n  a n d 
d es cri pti o n  of  cli ni c al  b e n efit i n  c o nfir m at or y tri als.  
F urt h er m or e,  t h e   E ur o p e a n   C o m missi o n   a p pr o v e d   Z Y K A DI A   o n   0 6 -M a y -2 0 1 5  f or  t h e  
f oll o wi n g i n di c ati o ns: 
•   Z Y K A DI A is i n di c at e d f or t h e tr e at m e nt  of  a d ult  p ati e nts  wit h  a n a pl asti c l y m p h o m a 
ki n as e ( A L K)  p ositi v e  a d v a n c e d  n o n -s m all  c ell l u n g  c a n c er ( N S C L C)  pr e vi o usl y tr e at e d 
wit h  cri z oti ni b.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  3 9
5  Pr ot o c ol  N o. 
 
 
 
1. 2. 3. 1   N o n -cli ni c al  e x p eri e n c e  
 
1. 2. 3. 1. 1  N o n -cli ni c al  p h ar m a c o d y n a mi c s  
L D K 3 7 8  i n hi bits   a ut o p h os p h or yl ati o n   of   A L K,   A L K -m e di at e d   p h os p h or yl ati o n   of  
d o w nstr e a m si g n ali n g  pr ot ei ns,  a n d  pr olif er ati o n  of  A L K -d e p e n d e nt  c a n c er  c ells  b ot h  i n  vitr o 
a n d  i n   vi v o.   L D K 3 7 8  is   a p pr o xi m at el y   2 0-f ol d   m or e   p ot e nt  t h a n   cri z oti ni b  i n   e n z y m ati c  
in hi biti o n  ass a ys  of  t h e  A L K  ki n as e  a cti vit y (I C 5 0  of   0. 1 5  n M f or  L D K 3 7 8  a n d  3  n M f or 
cri z oti ni b).  
 
1. 2. 3. 1. 2  N o n -cli ni c al  p h ar m a c o ki n eti c s  a n d  m et a b oli s m  
L D K 3 7 8 s h o w e d  d el a y e d  a bs or pti o n  wit h  T m a x of  7 t o  1 3  h o urs  a cr oss  a ni m al s p e ci es.  G o o d 
or al  bi o a v ail a bilit y ( 4 8 -5 8 %)  w as  o bs er v e d i n t h e  m o us e,  r at  a n d  m o n k e y  w h e n  a d mi nist er e d 
as  a s ol uti o n  or s us p e nsi o n  u n d er f ast e d  c o n diti o n.  
I n r at  A D M E st u d y, t h e tiss u e  distri b uti o n  of t h e r a di o a cti vit y  w as  e xt e nsi v e  w h er e  m ost  of 
t h e tiss u e/ m atri c es  h a d  hi g h er  e x p os ur e t h a n t h at  of  bl o o d,  e x c e pt  e y e,  br ai n  a n d s pi n al  c or d. 
L D K 3 7 8  d eri v e d r a di o a cti vit y  h a d l o w  distri b uti o n i nt o t h e  br ai n  wit h  a n  A U C l ast br ai n/ bl o o d 
r ati o  of  0. 1 1. 
C Y P 3 A 4/ 5 is t h e  m aj or  h e p ati c  e n z y m e  m et a b oli zi n g  L D K 3 7 8 i n  a  h u m a n  i n  vitr o s yst e m. 
I n  r ats,  n e arl y  1 0 0 %  of  L D K 3 7 8-r el at e d r a di o a cti vit y  w as  eli mi n at e d vi a  t h e f e c es,  a n d r e n al 
e x cr eti o n  w as  mi n or,  a c c o u nti n g f or  < 1 %  of t h e  d os e.  
T h e  c o m p o u n d is  a ti m e -d e p e n d e nt  C Y P 3 A 4/ 5 i n hi bit or,  a n d  a  p ot e nt r e v ersi bl e i n hi bit or  of 
C Y P 2 A 6,   2 B 6,   2 C 8,   2 C 9   a n d   3 A 4/ 5.   T h es e   d at a  s u g g est   a   hi g h   p ot e nti al   of   dr u g - dr u g 
i nt er a cti o n   b et w e e n   L D K 3 7 8   a n d   c o m p o u n ds   m et a b oli z e d   b y  t h es e   C Y P  is of or ms  if  
s uffi ci e ntl y  hi g h  c o n c e ntr ati o ns  of  L D K 3 7 8  ar e  a c hi e v e d.  L D K 3 7 8 is li k el y  a  P -g p,  b ut  n ot 
B C R P  or  M R P 2 s u bstr at e. It  d o es  n ot i n hi bit  P -g p,  B C R P  or  M R P 2  u p t o  1. 5  μ M  i n  vitr o. 
F or  m or e i nf or m ati o n,  pl e as e r ef er t o t h e  c urr e nt [ L D K 3 7 8 I n v esti g at or’s  Br o c h ur e].  
 
1. 2. 3. 1. 3  N o n -cli ni c al  s af et y  a n d  t o xi c ol o g y 
L D K 3 7 8  w as  e v al u at e d  f or s af et y i n  2- a n d  4 -w e e k st u di es i n r ats  a n d  m o n k e ys.  T h e t o xi citi es 
i n d u c e d   b y   L D K 3 7 8   w er e  s yst e mi c  i nfl a m m ati o n,   g astr oi nt esti n al,  li v er  ( bil e   d u ct)   a n d  
p a n cr e as.  
D et ail e d  i nf or m ati o n  is   a v ail a bl e  i n  t h e  l at est   v ersi o n   of  t h e  [ L D K 3 7 8  I n v esti g at or’s  
Br o c h ur e]. 
 
1. 2. 3. 2   Cli ni c al  e x p eri e n c e  
 
1. 2. 3. 2. 1  Cli ni c al  st u di e s  
 
C L D K 3 7 8 X 2 1 0 1  
A  FI H  d os e  es c al ati o n  p h as e I st u d y  of  L D K 3 7 8,  [ C L D K 3 7 8 X 2 1 0 1], is  o n g oi n g i n  p ati e nts 
wit h   m ali g n a n ci es   c h ar a ct eri z e d   b y   g e n eti c   alt er ati o ns   of   A L K.   As   of   3 1 -O ct -2 0 1 3,   3 0 4  
p ati e nts  h a v e  b e e n tr e at e d  wit h  L D K 3 7 8  o n t h e first -i n-h u m a n st u d y [ C L D K 3 7 8 X 2 1 0 1].  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  4 0
5  Pr ot o c ol  N o. 
 
 
 
P ati e nts  h a v e  b e e n tr e at e d  o n  a  o n c e  d ail y s c h e d ul e  at t h e f oll o wi n g  d os e l e v els:  5 0  m g,  1 0 0 
m g,   2 0 0  m g,  3 0 0  m g,  4 0 0  m g,   5 0 0  m g,   6 0 0  m g,   7 0 0  m g  a n d  7 5 0  m g.   T h e  M T D i n  a d ult 
p ati e nts is  7 5 0  m g  q d,  d os e d  o n c e  d ail y.  
G astr oi nt esti n al  t o xi citi es i n cl u di n g  di arr h e a,   n a us e a,   a n d  v o miti n g  w er e t h e  m ost   c o m m o n  
a d v ers e  e v e nts,  o c c urri n g i n  7 2. 7 %,  7 2. 7 %  a n d  5 5. 5 %  of  p ati e nts, r es p e cti v el y.  Ot h er  a d v ers e 
e v e nts  o c c urri n g  i n    m or e  t h a n  2 0 %  of  p ati e nts  i n cl u d e d  f ati g u e  ( 3 0. 9 %),  a b d o mi n al  p ai n 
( 2 7. 3 %),  d e cr e as e d  a p p etit e  ( 2 5. 9 %),    A L T  i n cr e as e  ( 2 5. 0 %)  a n d  c o nsti p ati o n  ( 2 1. 4 %).   T h e 
i n ci d e n c e   of   gr a d e   3-4    A Es,  r e g ar dl ess  of  st u d y  dr u g  r el ati o ns hi p    w as  < 1 0 %  f or  all    A Es 
e x c e pt    A L T  i n cr e as e  ( 2 6. 7 %).    T h e  i n ci d e n c e  of  gr a d e  3 -4   A Es,  r e g ar dl ess   of  st u d y   dr u g  
r el ati o ns hi p    w as   < 5 %   f or   all    A Es   e x c e pt    A S T   i n cr e as e   ( 8. 2 %),   di arr h e a  ( 5. 9 %), 
h y p er gl y c e mi a ( 5. 5 %), li p as e i n cr e as e ( 5. 1 %),  a n d  bl o o d  al k ali n e  p h os p h at as e ( A L P) i n cr e as e 
( 5. 1 %).  Pr eli mi n ar y   E C G  d at a  fr o m  2 2 0  p ati e nts tr e at e d  at  d os es  of  5 0-7 5 0  m g s u g g est t h at 
L D K 3 7 8  m a y  h a v e  a n  eff e ct  o n t h e  Q T  i nt er v al. 
O n e  p ati e nt ( 7 0 0  m g  Q D  d os e;  < 1 %)  h a d  a  Q T c  >  5 0 0  ms e c  a n d  2  ( 1. 6 %)  p ati e nts  ( 1  at  7 0 0 
m g   Q D   d os e,   1   at   7 5 0   m g   Q D   d os e)   h a d   a n  i n cr e as e   of   >   6 0   ms e c  fr o m   b as eli n e   Q T c.  
P n e u m o nitis  or i nt erstiti al l u n g  dis e as e  h as  b e e n r e p ort e d  as  a n  S A E i n f o ur  p ati e nts.  
A d v ers e   e v e nts   of  s p e ci al  i nt er est  t o   b e   m o nit or e d  f or   L D K 3 7 8  ( c eriti ni b)   h a v e   als o   b e e n  
i d e ntifi e d   a n d  i n cl u d e:   h e p at ot o xi cit y,  i nt erstiti al  l u n g   dis e as e/ p n e u m o nitis,   Q T  i nt er v al  
pr ol o n g ati o n,   br a d y c ar di a,   h y p er gl y c e mi a,   g astr oi nt esti n al  t o xi cit y  ( n a us e a,   v o miti n g   a n d  
di arr h e a)   a n d   p a n cr e atitis  (i n cl u di n g  li p as e   a n d   a m yl as e   el e v ati o ns).   F or   a d diti o n al   d et ails,  
r ef er t o t h e  c urr e nt [ L D K 3 7 8 I n v esti g at or’s  Br o c h ur e]. 
A m o n g  1 1 4 r es p o ns e -e v al u a bl e  p ati e nts  wit h  at l e ast  1 8  w e e ks  of f oll o w -u p  pri or t o  2 8  F e b, 
2 0 1 3,  or  w h o  dis c o nti n u e d st u d y  e arli er,  a n d  w er e tr e at e d  wit h  L D K 3 7 8  d os es  of  4 0 0  m g  q d 
or  hi g h er,  6 6 ( 5 8 %)  p ati e nts  h a v e r es p o n d e d ( S h a w  et  al  2 0 1 3 ). I n a d diti o n, t h e r es p o ns e r at e 
t o   L D K 3 7 8  is  si mil ar  r e g ar dl ess   of   pri or   A L K  i n hi bit or  t h er a p y.  I n   p ati e nts   wit h   N S C L C  
tr e at e d  at  ≥ 4 0 0    m g  q d,   w h o  h a d  pr e vi o usl y  r e c ei v e d  cri z oti ni b,  t h e  r es p o ns e  r at e   w as  5 7 %, 
a n d i n t h os e  w h o  h a d  n ot  pr e vi o usl y r e c ei v e d  cri z ot i ni b it  w as  6 0 %.  T h e  m e di a n  d ur ati o n  of 
r es p o ns e i n  p ati e nts  w h o r es p o n d e d  a n d  w er e tr e at e d  at  ≥ 4 0 0  m g  q d  w as  8. 2  m o nt hs ( 9 5 %  CI: 
6. 9,  n ot  esti m a bl e),  a n d  7 1 %  h a d  a  d ur ati o n  of r es p o ns e  of  6  m o nt hs  or  l o n g er. 
 
1. 2. 3. 2. 2  Cli ni c al  P h ar m a c o ki n eti c s  
B as e d   o n   pr eli mi n ar y   cli ni c al   p h ar m a c o ki n eti c  ( P K)   d at a,  t h e   a p p ar e nt   T 1/ 2 of   L D K 3 7 8  is  
a p pr o xi m at el y   3 1 -3 9   h o urs   a cr oss  t h e   d os e  r a n g e   of   4 0 0 -7 5 0   m g.   F oll o wi n g   or al  
a d mi nistr ati o n,  t h e   m e di a n  ti m e  t o   m a xi m al   c o n c e ntr ati o n  is   a p pr o xi m at el y   6   h o urs.   Wit h  
m ulti pl e   d ail y   d osi n g,   t h e   a c c u m ul ati o n  r ati o  ( R a c c)  r a n g e d  fr o m   4-7  f ol d.   E v al u ati o n   of  
tr o u g h  c o n c e ntr ati o ns f oll o wi n g r e p e at e d  d ail y  a d mi nistr ati o n s u g g est e d t h at t h e st e a d y-st at e 
of  L D K 3 7 8  w as  a c hi e v e d  b y  a p pr o xi m at el y  C y cl e  1  D a y  1 5  a n d r e m ai n e d r el ati v el y st a bl e 
aft er  c y c l e  1.  T h e  P K  pr ofil e  of  L D K 3 7 8 s u p p orts  o n c e  d ail y  d osi n g. 
Pr eli mi n ar y  P K  a n al ysis fr o m  [ C L D K 3 7 8 X 2 1 0 1]  a n d  [ C L D K 3 7 8 X 1 1 0 1]  r e v e als si mil ar  P K 
pr ofil e  a m o n g  C a u c asi a n  a n d J a p a n es e fr o m  3 0 0 t o  7 5 0  m g  d os e l e v el.  
F or f urt h er  d et ails, r ef er t o t h e  c urr e nt [ L D K 3 7 8 I n v esti g at or’s  Br o c h ur e].  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  4 1
5  Pr ot o c ol  N o. 
 
 
 
1. 2. 4   
O v er vi e w  of  M E K 1 6 2  
M E K 1 6 2,   pr e vi o usl y   n a m e d   A R R Y   4 3 8 1 6 2,  is   a   p ot e nt   a n d  s el e c ti v e   all ost eri c,   A T P- 
u n c o m p etiti v e  i n hi bit or   of   M E K.   F or  f urt h er   d et ails,  r ef er  t o t h e  c urr e nt   v ersi o n   of  t h e I B 
[ M E K 1 6 2 I n v esti g at or’s  Br o c h ur e]. 
 
1. 2. 4. 1   N o n -cli ni c al  e x p eri e n c e  
 
1. 2. 4. 1. 1  N o n -cli ni c al  p h ar m a c o d y n a mi c s  
T h e   bi ol o gi c al   a cti vit y   of   M E K 1 6 2   h as   b e e n   e v al u at e d   i n   vitr o  ( b ot h   e n z y m ati c   a n d   c ell  
c ult ur e  ass a ys)   a n d i n  vi v o i n  m o us e  x e n o gr aft st u di es.   M E K 1 6 2  p ot e ntl y i n hi bits  M E K i n 
b ot h   bi o c h e mi c al   ass a y s   usi n g   p urifi e d   pr ot ei n,   a n d  i n   c ells.   M E K 1 6 2   h as   d e m o nstr at e d  
r o b ust,   b ut  s el e cti v e,   gr o wt h i n hi bit or y   a cti vit y  i n   a   wi d e  v ari et y   of   c a n c er   c ell  li n es.  I n   a 
c oll e cti o n  of  ~ 5 0 0  g e n eti c all y  a n n ot at e d  c ell li n es,  M E K 1 6 2 s h o w e d  a nti -pr olif er ati v e  a cti vit y 
pr ef er e nti all y i n  c ells  h ar b ori n g  a cti v ati n g  m ut ati o ns  of t h e  M A P  ki n as e  p at h w a y ( e. g.  B R A F, 
N R A S   a n d   K R A S),   a n d   i n   p arti c ul ar,   a cti v ati n g   m ut ati o ns  i n   B R A F   a n d   N R A S.  I n   vi v o,  
M E K 1 6 2  h as  d e m o nstr at e d  d os e  d e p e n d e nt t u m or  gr o wt h i n hi biti o n i n  v ari o us s u b c ut a n e o us 
t u m or  tr a ns pl a nts   h ar b ori n g   B R A F V 6 0 0 E   m ut ati o ns  ( H T 2 9,   C O L O 2 0 5,   A-3 7 5)   as   w ell   a s  
a cti v ati n g  m ut ati o ns i n  b ot h  N R A S ( Hs.  9 4 4 T)  a n d  K R A S ( Mi a P a C a 2,  A 5 4 9,  L o V o,  C al u 6). 
T h es e   d at a  s u g g est  t h at   M E K 1 6 2   m a y   pr o vi d e   a   p ot e nti al  t h er a p e uti c   b e n efit  i n   c a n c er  
i n di c ati o ns  h ar b ori n g t h es e  m ut ati o ns. 
 
1. 2. 4. 1. 2  N o n -cli ni c al  p h ar m a c o ki n eti c s  a n d  m et a b oli s m  
I n t h e r at  a n d  m o n k e y  A D M E st u d y,  aft er  or al  d osi n g  of  M E K 1 6 2, t h e  a v er a g e  a bs or pti o n i n 
b ot h  s p e ci es   w a s   m o d er at e  ( 4 9 %).  T h e  r at e  of  a bs or pti o n   w as  f ast  ( T m a x r a n g e d fr o m  0. 3 3 - 
0. 6 7 h). 
I n r at  A D M E st u d y,  dr u g-d eri v e d r a di o a cti vit y  w as  a bs or b e d  a n d  wi d el y  distri b ut e d t o  m ost 
tissu es.  T h e  hi g h est  c o n c e ntr ati o ns  w er e l o c at e d i n t h e  e x cr et a ( o v er  a  2 4 -h o ur ti m e  p eri o d f or 
b ot h str ai ns)  a n d i n cl u d e d t h e  g astr oi nt esti n al  c o nt e nts,  bil e  a n d  uri n e.  T h er e  w as  n o  e vi d e n c e 
of  m e a ni n gf ul  C N S  p e n etr ati o n.  
M E K 1 6 2   h as   m o d er at e   m e m br a n e   p er m e a bilit y   a n d  is   a  s u bstr at e   of   P -g P   a n d   B C R P.  
M E K 1 6 2  e x hi bits  hi g h  pl as m a  pr ot ei n  bi n di n g  i n  vitr o ( >  9 6 %,  e x c e pt  d o g  8 4 %).  N o n cli ni c al 
i n  vitr o a n d  i n  vi v o d at a i n di c at e t h at  M E K 1 6 2 is  m et a b oli z e d  b y  m ulti pl e r o ut es  b ut  pri m aril y 
b y  gl u c ur o ni d ati o n  p at h w a ys ( m ai nl y  vi a  U G T 1 A 1,  1 A 3  a n d  1 A 9)  a n d t o  a l ess er  e xt e nt  b y 
o xi d ati o n  p at h w a ys ( m ai nl y  vi a  C Y P 1 A 2  a n d  2 C 1 9).  I n  vitr o, t h e r el ati v e  c o ntri b uti o ns  of t h e 
gl u c ur o ni d ati o n,   h y dr ol ysis,   or  t h e   o xi d ati v e   p at h w a y  ( A R 0 0 4 2 6 0 3 2),  t o   o v er all   M E K 1 6 2  
m et a b olis m  i n  h u m a n  h e p at o c yt es   w er e  4 5. 1 %,  5. 1 %  a n d  2. 4 %,  r es p e cti v el y.   U G T 1 A 1   w as 
s h o w n t o  b e t h e  m aj or  c o ntri b ut or ( 9 0 %) t o t h e f or m ati o n  of t h e  dir e ct  gl u c ur o ni d e i n  h u m a n 
li v er  mi cr os o m es ( H L M).  U G T 1 A 3  a n d  U G T 1 A 9  c o ntri b ut e d  3 %  a n d  7 % r es p e cti v el y t o t h e 
gl u c ur o ni d ati o n  a cti vit y.  
M E K 1 6 2  p ot e ntl y i n hi bits  C Y P 2 B 6  a n d  w e a kl y i n hi bits  C Y P 1 A 2  a n d  2 C 9. It is  n ot  a ti m e 
d e p e n d e nt  i n hi bit or   of   C Y P 1 A 2,   C Y P 2 C 9,   C Y P 2 D 6   a n d   C Y P 3 A.   I n   vitr o  e vi d e n c e   als o  
s u g g ests t h at  M E K 1 6 2 i n d u c es  C Y P 3 A.  
F or  m or e i nf or m ati o n,  pl e as e r ef er t o t h e  c urr e nt [ M E K 1 6 2 I n v esti g at or’s  Br o c h ur e].  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  4 2
5  Pr ot o c ol  N o. 
 
 
 
1. 2. 4. 1. 3  N o n -cli ni c al  s af et y  a n d  t o xi c ol o g y 
T h e  t o xi c ol o gi c al   e v al u ati o ns   of   M E K 1 6 2  i n cl u d e  si n gl e   d os e,   a n d   2 8 -d a y   a n d   6 - m o nt h 
r e p e at-d os e st u di e s i n  S pr a g u e  D a wl e y r ats  a n d  2 8 -d a y  a n d  9 -m o nt h r e p e at -d os e st u di es i n  
c y n o m ol g us   m o n k e ys.  I n   all   of  t h e   g o o d  l a b or at or y   pri n ci pl e  ( G L P)  t o xi c ol o g y  st u di es  
c o n d u ct e d, t h er e  w as  n o si g nifi c a nt  eff e ct  of  M E K 1 6 2  o n  vit al  si g ns,  c o a g ul ati o n  p ar a m et ers, 
c o m pl e m e nt,  or g a n  w ei g hts  or  uri n al ysis  p ar a m et ers  wit h  d os es  u p t o  1 0 0  m g/ k g i n r ats  a n d 
1 0  m g/ k g i n   m o n k e ys. 
S af et y  p h ar m a c ol o g y st u di es  w er e  c o n d u ct e d t o  ass e ss t h e  eff e cts  of  M E K 1 6 2  o n  k e y  or g a n 
s yst e ms  ( c ar di o v as c ul ar,   r es pir at or y,   n e ur o b e h a vi or al,  r e n al   a n d   g astr oi nt esti n al  f u n cti o n).  
R ats r e c ei v e d si n gl e  or al  d os e s  of  1 0,  3 0  or  1 0 0  m g/ k g  a n d  m o n k e ys  w er e  gi v e n si n gl e  or al 
d os es  of  1,  3  a n d  1 0  m g/ k g.  T h er e  w er e  n o si g nifi c a nt i n  vi v o s af et y fi n di n gs  at  d os es  u p t o 
1 0 0  m g/ k g i n r ats  a n d  1 0  m g/ k g i n  m o n k e ys i n  a n y  of t h es e st u di es. I n t h e i n  vitr o  h E R G 
c h a n n el  ass a y,  M E K 1 6 2  w as  e v al u at e d  at  c o n c e ntr ati o ns  u p t o  3 0  µ M  a n d  d e m o nstr at e d  3 0 % 
i n hi biti o n  at  3 0  µ M ( a g ai n, i n  vi v o  c ar di o v as c ul ar t el e m etr y st u d y s h o w e d  n o  eff e cts). 
D et ail e d  i nf or m ati o n  is   a v ail a bl e  i n  t h e  l at est   v ersi o n   of  t h e  [ M E K 1 6 2  I n v esti g at or’s  
Br o c h ur e]. 
 
1. 2. 4. 2   Cli ni c al  e x p eri e n c e  
 
1. 2. 4. 2. 1  Cli ni c al  st u di e s  
As  of  0 7 -J a n u ar y -2 0 1 5,  a t ot al  of  2 4 3 0  h e alt h y s u bj e cts  a n d  p ati e nts  h a v e  b e e n  e nr oll e d i n 
M E K 1 6 2 st u di es  a n d  1 9 4 5  of  w h o m  h a v e r e c ei v e d  at l e ast  o n e  d os e  of  M E K 1 6 2,  eit h er  as  a 
si n gl e   a g e nt   or  i n   c o m bi n ati o n   a n d   h a v e   b e e n   e v al u at e d  f or  s af et y,  i n cl u di n g   2 0 4   h e alt h y  
s u bj e cts,  6 li v er  d ysf u n cti o n  p ati e nts,  1 6 4  p ati e nts  wit h r h e u m at oi d  art hritis  a n d  1 5 7 1  p ati e nts 
wit h   a d v a n c e d   c a n c er.   F or  f urt h er   d et ails,  r ef er  t o  t h e   c urr e nt   v ersi o n  of  t h e  I B  [ M E K 1 6 2 
I n v esti g at or’s  Br o c h ur e]. 
 
A R R A Y -1 6 2 -1 1 1  
T h e   o n g oi n g   cli ni c al  st u d y   A R R A Y - 1 6 2-1 1 1  is   a n   o p e n -l a b el   d os e-es c al ati o n  st u d y  i n  
p ati e nts  wit h  a d v a n c e d s oli d t u m ors  wit h  e x p a nsi o n  c o h orts i n  p ati e nts  wit h  bili ar y  c a n c er  or 
K R A S -  or  B R A F -m ut a nt  m et ast ati c  c ol or e ct al  c a n c er.  As  of  0 7 -J a n u ar y-2 0 1 3,  e nr ol l m e nt is 
cl os e d  a n d  a t ot al  of  9 3  p ati e nts  h a v e r e c ei v e d  at l e ast  1  d os e  of  M E K 1 6 2.  F o ur  d os e l e v els 
w er e  e v al u at e d:  3 0  m g  bi d,  4 5  m g  bi d,  6 0  m g  bi d  a n d  8 0  m g  bi d.  T w o  of  4  p ati e nts r e c ei vi n g 
8 0  m g  bi d  e x p eri e n c e d  D L Ts ( gr a d e  3  c h ori or eti n o p at h y  a n d  gr a d e  3  d er m atitis  a c n eif or m 
d es pit e  m a xi m al  tr e at m e nt   m e as ur es), t h us t h e  8 0   m g  bi d  d os e  w as  d e cl ar e d  n o n  t ol er a bl e. 
S e v e n  p ati e nts  w er e  e nr oll e d  at  6 0  m g  bi d  a n d  n o  D L Ts  w er e  o bs er v e d; t h er ef or e,  6 0  m g  bi d 
w as  d e cl ar e d t h e  M T D.   A d diti o n al   D L Ts  o bs er v e d i n t h e  e x p a nsi o n  c o h orts  h a v e i n cl u d e d 
gr a d e  3  p n e u m o ni a  a n d  gr a d e  3  bl o o d  cr e ati n e  ki n as e ( C K) i n cr e as e d ( o n e  p ati e nt  e a c h  at t h e 
4 5  m g  bi d  d os e l e v el)  a n d  gr a d e  3  m u c os al i nfl a m m ati o n  a n d  gr a d e  3  g e n er ali z e d  e d e m a ( o n e 
p ati e nt  e a c h  at t h e  6 0  m g  bi d  d os e l e v el).  T h e r e c o m m e n d e d  d os e f or t h e  pl a n n e d  P h as e III 
st u di es is  4 5  m g  bi d. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  4 3
5  Pr ot o c ol  N o. 
 
 
 
Fift e e n  o ut  of  9 3  p ati e nts  ( 1 6 %)  e x p eri e n c e d  at  l e ast  o n e  gr a d e  3  or  4    A E  s us p e ct e d  t o  b e 
tr e at m e nt  r el at e d.   T h e   m ost   c o m m o n  tr e at m e nt-r el at e d   gr a d e   3   or   4   A Es   w er e   bl o o d  C K 
i n cr e as e d, r as h,  d er m atitis  a c n eif or m,  h y p o k al e mi a  a n d  g e n er ali z e d  e d e m a.  M ost  of t h e  C K 
el e v ati o ns  w er e  as y m pt o m ati c  a n d r e v ersi bl e.  
R eti n al/ vis u al  e v e nts ( c o m bi n e d t er m  of r eti n al  a n d  vis u al  e v e nts  of  c h ori or eti n o p at h y,  visi o n 
bl urr e d,   p h ot o psi a,  r eti n o p at h y,  r eti n al   d et a c h m e nt,   vis u al  i m p air m e nt,   m a c ul ar   e d e m a,  
c h ori or eti n al   dis or d er,   m a c ul o p at h y,   m et a m or p h o psi a,   p h ot o p h o bi a,  r eti n al  is c h e mi a, r eti n al 
t el a n gi e ct asi a,  v e n o us  st asis  r eti n o p at h y  a n d  x a nt h o psi a)    w er e  r e p ort e d  i n  2 7/ 9 3  ( 2 9 %)  of 
p ati e nts,  a ll  of  w hi c h  w er e  c o nsi d er e d tr e at m e nt-r el at e d  e v e nts. I n  all  b ut  o n e  p ati e nt ( gr a d e  3 
at  8 0   m g  bi d)  t h es e  e v e nts   w er e  gr a d e  1  ( 1 4 %)  or  gr a d e  2  ( 1 4 %)  i n  s e v erit y.  T o  d at e,  t h es e 
r eti n al  e v e nts  h a v e  b e e n r e v ersi bl e i n  all  p ati e nts  u p o n  dis c o nti n u ati o n  or  d os e r e d u cti o n  of 
M E K 1 6 2. 
C ar di a c  e v e nts ( c o m bi n e d t er m  of  c ar di a c  e v e nts  of s y n c o p e,  ej e cti o n fr a cti o n  d e cr e as e d  a n d 
c ar di o m y o p at h y)  w er e  r e p ort e d i n  6/ 9 3  ( 6 %)  of  p ati e nts,  of t h os e  1/ 9 3 ( 1 %)  w er e  c o nsi d er e d 
tr e at m e nt r el at e d. 
As  of  0 7 -J a n u ar y-2 0 1 3,  a m o n g  9 3  p ati e nts tr e at e d,  st a bl e  dis e as e  w as  o bs er v e d i n  3 3  ( 3 5 %), 
wit h  a  m e di a n  d ur ati o n  of  3. 9  m o nt hs.  
 
C M E K 1 6 2 X 2 2 0 1  
[ C M E K 1 6 2 X 2 2 0 1]  is   a   p h as e  II  st u d y   ass essi n g  t h e  s af et y   a n d   effi c a c y   of   M E K 1 6 2  i n  
p ati e nts   wit h  l o c all y   a d v a n c e d   u nr es e ct a bl e   a n d   m et ast ati c   B R A F   a n d   N R A S   m ut at e d  
m el a n o m a.  
As  of  0 7 -J a n u ar y -2 0 1 3,  a t ot al  of  1 0 6  p ati e nts  h a v e r e c ei v e d  at l e ast  1  d os e  of  M E K 1 6 2.  F ort y 
si x  o ut  of  t h e  t ot al  1 0 6  e nr oll e d  p ati e nts  ( 4 3 %)  e x p eri e n c e d  at  l e ast  o n e  gr a d e  3  or  4    A E 
s us p e ct e d t o  b e tr e at m e nt -r el at e d.  T h e  m ost c o m m o n tr e at m e nt -r el at e d  gr a d e  3  or  4  A Es  w er e 
C K i n cr e as e d ( 2 0/ 1 0 6),  d er m atitis  a c n eif or m ( 4/ 1 0 6)  a n d  di arr h e a ( 3/ 1 0 6).  T h e  m aj orit y  of t h e 
C K   el e v ati o ns   w er e   a s y m pt o m ati c,   1 3/ 3 8   p ati e nts   wit h   C K   el e v ati o ns   als o   e x p eri e n c e d  
m y al gi a,   m us c ul ar   w e a k n ess   or   m us c ul os k el et al   p ai n   w hi c h   w as  j u d g e d  t o   b e  r el at e d  t o  
M E K 1 6 2.    C e ntr al  s er o us  r eti n o p at h y  li k e  e v e nts    w er e  r e p ort e d  b y  4 0/ 1 0 6  ( 3 8 %)  p ati e nts 
r e g ar dl ess  of r el ati o ns hi p t o  M E K 1 6 2 i n cl u di n g  gr a d e  3  or  4  e v e nts i n  3/ 1 0 6 ( 3 %)  of  p ati e nts. 
T h es e   e v e nts  i n cl u d e d   r eti n o p at h y  ( 1 3/ 1 0 6),   bl urr e d   visi o n  ( 9/ 1 0 6),  r eti n al   e d e m a  ( 8/ 1 0 6),  
g e n er ali z e d  e y e  dis or d er ( 4/ 1 0 6),  vitr e o us fl o at ers ( 4/ 1 0 6), r eti n al  d et a c h m e nt ( 3/ 1 0 6), r eti n al 
e pit h eli o p at h y ( 3/ 1 0 6),  vis u al i m p air m e nt ( 3/ 1 0 6).  M ost  C e ntr al s er o us r eti n o p at h y li k e  e v e nts 
w er e   gr a d e   1,  tr a nsi e nt  i n   n at ur e   a n d  r es ol v e d   wit h o ut  tr e at m e nt   m o difi c ati o n,   aft er   d os e  
r e d u cti o n,   or   aft er  i nt err u pti o n   of  tr e at m e nt.   C ar di a c   e v e nts  r e g ar dl ess   of  r el ati o ns hi p  t o  
M E K 1 6 2  w er e r e p ort e d  b y  4/ 1 0 6 ( 4 %)  p ati e nts.  All  w er e  gr a d e  3.  
A m o n g  t h e  3 5  p ati e nts  e v al u a bl e f or  effi c a c y  wit h  m ut a nt  B R A F  m el a n o m a  at  4 5  m g  bi d,  2 
c o nfir m e d   a n d   6   u n c o nfir m e d   p arti al  r es p o ns es   a n d   1 4   p ati e nts   wit h  st a bl e   dis e as e   w er e  
r e c or d e d.   T h er e  w er e  2 3   p ati e nts  wit h  B R A F   m ut a nt   m el a n o m a tr e at e d   at  6 0   m g  bi d  w er e 
e v al u a bl e f or  effi c a c y,  3  p ati e nts  wit h  c o nfir m e d  p arti al r es p o ns es  a n d  1  wit h  u n c o nfir m e d 
p arti al r es p o ns e  a n d  6  p ati e nts  wit h st a bl e  dis e as e  w er e r e p ort e d.  T h er e  w er e  3 5  p ati e nts  wit h 
N R A S   m ut a nt   m el a n o m a  tr e at e d   at   4 5   m g   bi d   e v al u a bl e  f or   effi c a c y,   6   c o nf ir m e d   a n d   2  
u n c o nfir m e d  p arti al r es p o ns es  a n d  1 5  p ati e nts  wit h st a bl e  dis e as e  w er e r e c or d e d.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  4 4
5  Pr ot o c ol  N o. 
 
 
 
1. 2. 4. 2. 2  Cli ni c al  p h ar m a c o ki n eti c s  
I n  h e alt h y s u bj e cts  a n d  p ati e nts  wit h r h e u m at oi d  art hritis, t h e  a n al ysis  of  P K  d at a  w as  d o n e 
usi n g  m o d el i n d e p e n d e nt  m et h o ds  o nl y.  T h es e  a n al ys es s u g g e st e d t h at  a bs or pti o n  w as r a pi d, 
t h er e  w as  e xt e nsi v e  distri b uti o n  a n d t h at t h e  a p p ar e nt t er mi n al  h alf-lif e w as s h ort.  C o ntr ar y t o 
e x p e ct ati o n,  gi v e n t h e s h ort  h alf -lif e,  a c c u m ul ati o n  gr e at er t h a n t h at  pr e di ct e d  b y li n e ar  P K 
w as   o bs er v e d.   O v er all   w h e n   gi v e n   bi d,   a c c u m ul ati o n   w as   ar o u n d   1. 5  t o   1. 7  f ol d.   T his  
a p p ar e nt   n o n -li n e arit y i n t h e  P K  of  M E K 1 6 2  m a y  h a v e  b ee n r el at e d t o  a  c o m bi n ati o n  of  a 
r el ati v el y  hi g h  L O Q  of t h e  ass a y  us e d ( 5  n g/ m L)  a n d t h e s c h e d ul e  of  bl o o d  c oll e cti o n f or  P K 
us e d.  I n   or d er   o v er c o m e  t h es e  li mit ati o ns   a n d  t o f ull y   c h ar a ct eri z e  t h e   P K   of   M E K 1 6 2  i n 
c a n c er   p ati e nts   a   m o d el   b as e d   a n al ysis   w a s   c o n d u ct e d   usi n g   a   p o p ul ati o n   P K   m et h o d.  
M E K 1 6 2   P K   w as   b est   d es cri b e d   b y   a  t w o   c o m p art m e nt   dis p ositi o n   m o d el   wit h first - or d er 
eli mi n ati o n   a n d  first   or d er   a bs or pti o n   wit h   a  l a g  ti m e.   T h e   esti m at e d   b et w e e n  s u bj e ct  
v ari a bilit y  o n  a p p ar e nt  cl e ar a n c e ( C L/ F)  w as  m o d er at e  ( 4 4 %)  a n d  v er y  hi g h  ( ~ 1 5 0 %)  f or t h e 
a p p ar e nt  c e ntr al  v ol u m e  of  distri b uti o n ( V c/ F)  a n d  a p p ar e nt  p eri p h er al  v ol u m e  of  distri b uti o n 
( V p/ F).  T h e  c o v ari at e  eff e ct  of  d os e  o n r el ati v e  bi o a v ail a bilit y  w as i d e ntifi e d  as si g nifi c a nt ( at 
a n  α  =  0. 0 0 1  si g ni fi c a n c e l e v el).  R el ati v e t o t h e  4 5  m g  d os e, t h e  bi o a v ail a bilit y  of t h e  3 0  m g 
d os e l e v el is  1 2 0 %;  w hil e t h e r el ati v e  bi o a v ail a bilit y  of  6 0  m g  a n d  8 0  m g  d os es  w er e  8 8 %  a n d 
7 7 %   T his  d os e  d e p e n d e n c e   w a s  n ot  s e e n  u si n g   m o d el  i n d e p e n d e nt   m et h o ds  b ut   m ost  li k el y 
r e pr es e nts   eit h er  s ol u bilit y  li mit e d   a bs or pti o n   of   M E K 1 6 2   or  t h e  i m p a ct   of   P-g p   or   a  
c o m bi n ati o n   of  t h e  t w o.   B as e d   o n  t h e   P K   p ar a m et ers   esti m at e d  i n  t his   a n al ysis   w h e n  
a d mi nist er e d  bi d,   M E K 1 6 2 st e a d y st at e is r e a c h e d  ar o u n d  D a y  1 5  a n d t h e  a c c u m ul ati o n is 
a r o u n d  1. 7 f ol d  w hi c h is  c o nsist e nt  wit h  o bs er v ati o n. 
P K  pr o p erti es  of  M E K 1 6 2  w er e i n  g e n er al  c o nsist e nt  a cr oss  et h ni citi es.  
T h e   eff e ct   of  f o o d   o n  t h e   P K   of   M E K 1 6 2   w as   ass e ss e d  i n   a   d efi niti v e  f o o d   eff e ct  st u d y  
[ C M E K 1 6 2 A 2 1 0 3]  a n d  cli ni c al st u d y  [ A R R A Y- 1 6 2- 1 0 4].  T h e r es ults  of [ C M E K 1 6 2 A 2 1 0 3] 
st u d y s h o w e d t h at  alt h o u g h t h e  mil d  eff e ct  of f o o d  o n t h e  a bs or pti o n  ki n eti cs  of  M E K 1 6 2  w as 
o bs er v e d, it  h o w e v er is  c o n cl u d e d  n ot  cli ni c all y r el e v a nt.  T h er e is  n o  n e e d f or s p e cifi c ati o n  of 
f o o d  i nt a k e  f or   M E K 1 6 2   a d mi nistr ati o n.   D at a  fr o m  t h e  t w o  st u di es  s u g g est e d  t h at   c a n c er  
p ati e nts  d o  n ot  n e e d t o  b e f ast e d  w h e n t a ki n g  M E K 1 6 2.  
 
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 
O n c o g e ni c si g n ali n g  p at h w a ys  c o m m o nl y  d ysr e g ul at e d i n l u n g  c a n c er i n v ol v e  a cti v ati o n  of  a 
r e c e pt or t yr osi n e  ki n as e, i n cl u di n g  E G F R  a n d  M E T,  at t h e  c ell s urf a c e  b y li g a n d  bi n di n g  a n d 
r e c e pt or   h o m o di m eri z ati o n   or   h et er o di m eri z ati o n  l ea di n g  t o   a ut o p h os p h or yl ati o n   of  t h e  
i ntr a c ell ul ar  t yr osi n e   ki n as e   d o m ai n,   w hi c h  i n  t ur n  tri g g ers   m ulti pl e  si g n al  tr a ns d u cti o n  
c as c a d e s i n cl u di n g t h e  R A S/ R A F/ M E K ( mit o g e n -a cti v at e d  a n d  e xtr a c ell ul ar si g n al – r e g ul at e d 
ki n as e  ki n as e)  a n d  PI 3 K/ A K T/ m T O R  p at h w a ys  (L ars e n  et  al  2 0 1 1 ).  T h es e  a b err a nt  p at h w a ys 
pr o vi d e  a  w e alt h  of  n e w  p ossi biliti es f or t ar g et e d t h er a p e uti cs.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  4 5
5  Pr ot o c ol  N o. 
 
 
 
Fi g ur e  2 - 1  
M ol e c ul ar  a b n or m aliti e s i n  h u m a n l u n g  a d e n o c ar ci n o m a  
Fi g ur e  2 -1  s h o w s  s o m e  of t h e  c o m m o n  m ol e c ul ar  a b n or m aliti e s i n  h u m a n l u n g  a d e n o c ar ci n o m a  a n d 
t h e  si g n ali n g  p at h w a y  at  w hi c h  st u d y tr e at m e nt  pr o p o s e d i n t hi s  st u d y  ar e t ar g eti n g.  T h e fr e q u e n ci e s 
of t h e s e  o n c o g e ni c  dri v er  g e n e s f o u n d i n  a d e n o c ar ci n o m a i n cl u di n g  E G F R,  PI K 3 C A,  c -M E T,  A L K/, 
R O S 1  a n d  K R A S/ N R A S/ B R A F  h a v e  b e e n r e p ort e d t o  b e  4 0. 3 %,  9. 2 %,  9. 5 %,  1 0. 3 %  a n d  1 0. 5 %, 
r e s p e cti v el y,  b a s e d  o n  d at a fr o m  G u a n g d o n g  L u n g  C a n c er I n stit ut e,  C hi n a (A n  et  al  2 0 1 2 )  a n d  ot h er 
p u bli c ati o n s ( W a n g  et  al  2 0 1 2 , S a s a ki  et  al  2 0 0 7 , B er g et h o n  et  al  2 0 1 2 ). 
T h e   p ur p os e   of  t his  st u d y  is  t o   e v al u at e  t h e   a nti -t u m or   a cti vit y   of  si n gl e   a g e nt   B Y L 7 1 9,  
I N C 2 8 0,   L D K 3 7 8   a n d   M E K 1 6 2  i n   a d v a n c e d   N S C L C   p ati e nts   c arr yi n g  s p e cifi c   m ol e c ul ar  
alt er ati o ns.  I n   a d diti o n,  t his  st u d y  is  t esti n g  t h e   m o d er n   p ar a di g m   of   all o c ati n g   p ati e nts  t o  
s p e cifi c tr e at m e nt  ar m  b as e d  o n t h eir i n di vi d u al  g e n eti c  pr ofil e.  M ost l u n g  a d e n o c ar ci n o m a 
p ati e nt   p o p ul ati o ns   wit h   m ol e c ul ar   c h ar a ct eri z ati o n   c o ul d  r e c ei v e  t ar g et e d  tr e at m e nt   a n d  
p ot e nti all y  b e n efit fr o m t ar g et e d  ki n as e i n hi biti o n.  
T h e  r ati o n al e f o r  e a c h  of t h e st u d y t r e at m e nts is  o utli n e d  b el o w:  
 
B Y L 7 1 9  
R e c e nt st u di es  h a v e s h o w n t h at t h e  PI 3 K si g n ali n g  c as c a d e is fr e q u e ntl y  o v er a cti v at e d  i n 
h u m a n  c a n c er ( Vi v a n c o  2 0 0 2 , Alt o m ar e  2 0 0 5 , C ar n er o  2 0 1 0 ),  a n d is  pl a yi n g a  criti c al r ol e   
b ot h i n t h e i niti ati o n  a n d  pr o gr essi o n  of  N S C L C ( M e m m ott  2 0 1 0 , X u  2 0 1 0 ).  PI K 3 C A  c o p y 
n u m b er  g ai n  h as  b e e n r e p ort e d i n  6. 2 %  a d e n o c ar ci n o m a l u n g  c a n c er ( Y a m a m ot o  2 0 0 8 )  T h e  pr e-
cli ni c al  d at a  d e m o nstr at e d t h at  B Y L 7 1 9  e x hi bits str o n g  a ntit u m or  eff e cts  at  w ell t ol er at e d  d os es 
i n t h e  PI K 3 C A  m ut at e d l u n g  c a n c er  m o d els s u c h  as  N CI-H 5 9 6,   H L U X 1 8 3 4,   H L U X 2 0 4 2  a n d 
H L U X 3 0 2 9 s u b c ut a n e o u s  x e n o gr aft  m o d el  i n  vi v o. Cli ni c al  e x p eri e n c e  wit h  B Y L 7 1 9 i n 
N S C L C is li mit e d s o f ar.  Tr e at m e nt  wit h  B Y L 7 1 9,  al p h a -s p e cifi c  PI 3 K i n hi bit or  m a y r e pr es e nt 
a n i m p ort a nt t h er a p e uti c  o pti o n f or  p ati e nts  wit h  m ol e c ul ar  alt er ati o n ( m ut ati o n  or 
a m plifi c ati o n)  of  PI K 3 C A.  PI K 3 C A -m ut at e d  N o n -s m all  c ell l u n g  c a n c er  ( N S C L C) r e pr es e nts  a 
cli ni c all y  a n d  g e n eti c all y  h et er o g e n e o us s u b gr o u p i n  a d e n o c ar ci n o m as  as  w ell  as   i n s q u a m o us 
c ell  c ar ci n o m as ( S C C)  wit h  a  hi g h er  pr e v al e n c e  of t h es e  m ut ati o ns i n  S C C  ( 8. 9 %  vs  2. 9 % 
c o m p ari n g  wit h  a d e n o c ar ci n o m a ) (S c h effl er  et   al.   2 0 1 5 ).   PI K 3 C A   c o p y-n u m b er  g ai ns  als o 
o c c ur i n l u n g  c a n c ers,  wit h  hi g h er fr e q u e n c y i n s q u a m o us  c ell  c ar ci n o m as ( Y a m a m ot o  H  2 0 0 8 ; 
K a w a n o  O  2 0 0 7 ).  PI K 3 C A  m ut ati o n/ a m plifi c ati o n  m a y r e pr es e nt  a  g o o d  pr e di cti v e f e at ur e f or 
t h e  cli ni c al  a p pli c ati o n  of s p e cifi c  PI 3 K i n hi bit ors i n  S C C l u n g c a n c er  p ati e nts ( B o n elli  M A  et 
al.  2 0 1 5  A u g ). 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  4 6
5  Pr ot o c ol  N o. 
 
 
 
I N C 2 8 0 
M E T  is  i n v ol v e d  i n   m a n y   m e c h a nis ms   of   c a n c er   pr olif er ati o n   a n d   m et ast asis.   M E T  
o v er e x pr essi o n   a n d   g e n eti c   alt er ati o ns   pl a y   a  r ol e  i n  t h e   p at h o g e n esis   of  s e v er al  t u m ors,  
i n cl u di n g l u n g  c a n c er (S attl er  et  al  2 0 1 1 ).  A stri ki n g  c orr el ati o n  b et w e e n  a m plifi c ati o n  of t h e 
c- M E T   g e n e  a n d r es p o ns e t o  c -M E T  i n hi bit ors  h as  b e e n   o bs er v e d  i n  r ar e  c a n c er   c ell  li n es 
ori gi n ati n g fr o m l u n g  a n d  ot h er tiss u es ( L utt er b a c h  2 0 0 7 , M c D er m ott  2 0 0 7 ).  A r an d o mi z e d 
p h as e II tri al  wit h  M et M A b s h o w e d  a  n e arl y  d o u bli n g (fr o m  6. 4 t o  1 2. 4  w e e ks) i n  pr o gr essi o n 
fr e e  s ur vi v al  ( h a z ar d  r ati o = 0. 5 6,  9 5 %    CI = 0. 3 1-2. 0 2,  p = 0. 0 5)    wit h    M et M A b  pl us  erl oti ni b 
v ers us  erl oti ni b  al o n e i n  p ati e nts  wit h  pr e vi o us tr e at m e nt  f or  a d v a n c e d  N S C L C  a n d  w h os e  
t u m ors   e x pr ess   hi g h  c-M E T  l e v els   ass ess e d   b y  I H C  ( S pi g el   et   al   2 0 1 1 ).  I N C 2 8 0,   a  hi g hl y 
s el e cti v e  a n d  p ot e nt  c-M E T i n hi bit or, is  e x p e ct e d t o  h a v e t h er a p e uti c  eff e ct i n  p ati e nts  w h os e 
t u m ors  b e ar  a b err ati o ns i n t his  p at h w a y. 
 
L D K 3 7 8  
A L K r e arr a n g e m e nts, si mil ar t o  ot h er  o n c o g e ni c  dri v ers s u c h  as  m ut a nt  E G F R  a n d  o n c o g e ni c 
R A S ,   ar e   g e n er all y   m ut u all y   e x cl usi v e.   C urr e ntl y,   cri z oti ni b  is  t h e   o nl y  t h er a p y   a p pr o v e d  
s p e cifi c all y  f or  t his s m all  s u bs et   of   p ati e nts   wit h  A L K   p ositi v e  N S C L C.   Cri z oti ni b is  als o  
eff e cti v e i n  R O S 1 tr a nsl o c ati o n  p ati e nts ( S h a w  et  al  2 0 1 2 ).  T h e i n v esti g ati o n  of  A L K-t ar g et e d 
t h er a pi es  t h at   m a y   h a v e   diff er e nti al   c h ar a ct eristi cs   v ers us   cri z oti ni b  i n  t er ms   of  r esist a n c e  
m e c h a nis m,   cli ni c al   a cti vit y   a n d/ or  s af et y   pr ofil e   a n d  t h at   m a y  r e pr es e nt   alt er n ati v e  a n d/ or  
c o m pli m e nt ar y t h er a p e u ti c  o pti o ns is  w arr a nt e d.  L D K 3 7 8 is  a  n o v el i n hi bit or  of  A L K t h at, i n 
pr e cli ni c al  st u di es,   w as  f o u n d  t o   b e   m or e   p ot e nt   a n d  s p e cifi c  (i. e.   d o es   n ot  i n hi bit   ot h er  
ki n as es, s u c h  as  M E T) t h a n  cri z oti ni b,  a n d is  a cti v e  a g ai nst  m ut at e d  v ersi o ns  of  A L K t h at  ar e 
k n o w n t o  c o nf er r esist a n c e t o  cri z oti ni b. I n t h e  o n g oi n g  p h as e I first i n  h u m a n st u d y,  L D K 3 7 8 
e x hi bit e d  p ot e nt  a ntit u m or  a cti vit y i n  b ot h  cri z oti ni b  n aï v e  a n d tr e at e d  p o p ul ati o ns.  L D K  w as 
d esi g n at e d  as  br e a kt hr o u g h t h er a p y  b y  F D A  o n  6 -M ar c h - 2 0 1 3. 
 
M E K 1 6 2  
K R A S is  o n e  of t h e  m ost fr e q u e ntl y  m ut at e d  o n c o g e n e i n  N S C L C,  wit h  m ut ati o ns  d et e ct e d i n 
a b o ut  3 0 %  of t u m ors i n  w hit e  p e o pl e ( D a vi es  et  al  2 0 0 2 , M al u m br es  2 0 0 3 ).  K R A S  m ut ati o ns 
als o   pr e di ct  f or   a bs e n c e   of   b e n efit  fr o m   E G F R  t yr osi n e   ki n as e  i n hi bit ors,   ar e   a   n e g ati v e  
pr o g n osti c f a ct or f or s ur vi v al ( Mits u d o mi  et  al  2 0 0 7 ; M as c a u x  et  al  2 0 0 5 ).  Alt h o u g h  K R A S 
m ut ati o ns  w er e i d e ntifi e d i n l u n g  c a n c er  n e arl y  2 0  y e ars  a g o,  n o  a p pr o v e d t h er a pi es  e xist f or 
K R A S  m ut a nt  N S C L C  a n d f e w tri als  h a v e s p e cifi c all y  a d dr ess e d t his  p o p ul ati o n  of  p ati e nts. 
U p t o  n o w,  dir e ct i n hi biti o n  of  K R A S  h as  pr o v e n  cli ni c all y  c h all e n gi n g ( S a nt os  et  al  1 9 8 4 ; 
Bl u m e ns c h ei n  et  al  2 0 0 5 ).  Eff orts t o i n hi bit  m ut a nt  K R A S i n  N S C L C  h a v e t h er ef or e t ar g et e d 
eff e ct or  pr ot ei ns  d o w nstr e a m i n t h e  R A S -R A F -M E K -E R K ( M A P K) si g n alli n g  p at h w a y.  T h e 
M A P K   p at h w a y   c o n v er g es   at  t h e   M E K 1/ M E K 2  ( als o   k n o w n   as   M A P 2 K 1   a n d   M A P 2 K 2)  
ki n as es, f or  w hi c h t h e  o nl y  k n o w n s u bstr at es  ar e t h e  E R K 1/ E R K 2 ( als o  k n o w n  as  M A P K 3 
a n d  M A P K 1)  ki n as es.  M E K i n hi biti o n is  e x p e ct e d t o  bl o c k  E R K si g n ali n g irr es p e cti v e  of t h e 
u pstr e a m si g n ali n g ( J a n n e  et  al  2 0 1 3 ).  T h er ef or e,  M E K r e pr es e nts  a  c o m p elli n g t ar g et f or t h e 
tr e at m e nt  of  c a n c er  a n d its i n hi bit or  M E K 1 6 2  m a y i n hi bit  gr o wt h-sti m ul at or y si g n als fr o m  a 
n u m b er  of  di v ers e s o ur c es.  T h e first st u d y t o  d e m o nstr at e t h e  cli ni c al  b e n efit f or  p ati e nts  wit h 
K R A S   m ut a nt N S C L C  is  a  p h as e II, r a n d o mi z e d tri al wit h  s el u m eti ni b,  a n  i n hi bit or  of M E K.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  4 7
5  Pr ot o c ol  N o. 
 
 
 
S el u m eti ni b s h o w e d i m pr o v e m e nt i n  m e di a n  O S  b y  4. 2  m o nt hs  w h e n  a d d e d t o  d o c et a x ol ( 9. 4 
m o nt hs  vs  5. 2  m o nt hs),  a n d i m pr o v e m e nt i n  m e di a n  P F S  b y  3. 2  m o nt hs ( 5. 3  m o nt hs  vs.  2. 1 
m o nt hs),  1 6  ( 3 7 %)  p ati e nts  i n  t h e  s el u m eti ni b  gr o u p  a n d  n o n e  i n  t h e  pl a c e b o  gr o u p  h a d  a n 
o bj e cti v e r es p o ns e ( J a n n e  et  al  2 0 1 3). 
 
2. 2  
R ati o n al e f or t h e  st u d y  d e si g n 
T h e  st u d y  is   d esi g n e d   as   a   P h as e  II,   m ulti pl e   ar m,   o p e n -l a b el  st u d y  i n   a d v a n c e d   N S C L C  
p ati e nts  w h o  h a v e f ail e d  pri or tr e at m e nt,  a n d  m ust  n ot  h a v e r e c ei v e d  m or e t h a n t w o  pri or li n es 
of  a nti n e o pl asti c t h er a p y.  T h es e  p ati e nts,  w h o  c urr e ntl y  h a v e  n o  eff e cti v e t h er a p e uti c  o pti o ns, 
will   b e   all o c at e d  t o   a  s p e cifi c  tr e at m e nt   ar m   a c c or di n g  t o  t h eir   c h ar a ct eri z e d   m ol e c ul ar  
alt er ati o ns,  aft er t h e  m ol e c ul ar  pr e -s cr e e ni n g  w hi c h  c a n  o pti mi z e t h e  p ati e nt s el e cti o n.  
T h e  m ulti pl e  ar m  d esi g n  w as  c h os e n,  wit h  o bj e cti v e r es p o ns e r at e ( O R R)  as  pri m ar y  e n d p oi nt, 
t o  e v al u at e t h e  effi c a c y  of si n gl e  a g e nt  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2 i n  a d v a n c e d 
N S C L C  p ati e nts. I n  a d diti o n, s af et y, t ol er a bilit y,  P K  a n d  g e n e  alt er ati o ns t h at  m a y  b e r el at e d 
wit h r esist a n c e  will  als o  b e  e v al u at e d f or  e a c h  a g e nt.  
Pr ot o c ol   will   b e  a m e n d e d if   n e w  n o n -o v erl a p pi n g t ar g et(s)   a n d  c o m p o u n d(s)   ar e i d e ntifi e d 
a n d  c o nsi d er e d t o  b e  a d d e d  as i n d e p e n d e nt  ar m(s) i n t h e  f ut ur e. 
F or  e a c h tr e at m e nt  ar m t h e s a m pl e si z e  w as  c al c ul at e d  b as e d  o n  a  B a y esi a n  a p pr o a c h  usi n g 
eit h er  a  mi ni m all y i nf or m ati v e  pri or ( B Y L 7 1 9, I N C 2 8 0  a n d  M E K 1 6 2)  or  a n i nf or m ati v e  pri or 
usi n g r el e v a nt  hist ori c al  d at a ( L D K 3 7 8).  T h e  pr o p os e d s a m pl e si z e  will  all o w  d et e cti n g  wit h 
hi g h li k eli h o o d st atisti c all y  a n d  cli ni c all y r el e v a nt  a nti -t u m or  a cti vit y. 
 
2. 3  
R ati o n al e f or  d o s e  a n d r e gi m e n  s el e cti o n  
T h e  s el e cti o n   of  t h e   d os es  ( 7 5 0 m g  q d  f or   L D K 3 7 8,   4 5 m g  bi d f or   M E K 1 6 2)   ar e   b as e d   o n 
M T D  or  R P 2 D i d e ntifi e d ( S e cti o n  1. 2 ).  T h e s a m e  M T D  or  R P 2 D f or  L D K 3 7 8  a n d  M E K 1 6 2 
ar e  est a blis h e d i n  p h as e I st u di es i n  J a p a n. 
F or   B Y L 7 1 9,   4 0 0   m g   q d  w as  t h e  M T D i d e ntifi e d  i n its   FI H  st u d y.   H o w e v er,  f urt h er   d at a 
s h o w e d t h at   3 5 0  m g  q d is  b ett er t ol er at e d,   a n d  3 5 0  m g  q d  h as  b e e n  d e cl ar e d  as  R P 2 D f or 
J a p a n es e  p o p ul ati o n.  T h er ef or e,  3 5 0  m g  q d  will  b e  us e d i n t his st u d y.  
F or I N C 2 8 0,  R P 2 D  of  6 0 0  m g  BI D  h as  b e e n  est a blis h e d  wit h  c a ps ul es.  T o i m pr o v e 
c o n v e ni e n c e  of st u d y  dr u g  a d mi nistr ati o n f or t h e  p ati e nts, I N C 2 8 0 t a bl et f or m ul ati o n  w as 
d e v el o p e d  wit h  hi g h er  d os a g e str e n gt hs  a n d  e v al u at e d i n  [ CI N C 2 8 0 X 2 1 0 2], [ CI N C 2 8 0 X 1 1 0 1] 
a n d  [ CI N C 2 8 0 X 2 2 0 2] st u di es.  Pr eli mi n ar y  P K  d at a s h o w e d t h at  m e a n  A U C  a n d  C m a x  at 
st e a d y-st at e f oll o wi n g  a d mi nistr ati o n  of I N C 2 8 0 t a bl ets  at  4 0 0  m g  BI D  w as  hi g h er t h a n t h at 
f oll o wi n g  c a ps ul es  at  6 0 0  m g  BI D ( R P 2 D i n [ CI N C 2 8 0 X 2 1 0 2]),  b ut i n t h e r a n g e  c o nsi d eri ng 
t h e  C V %.  B as e d  o n t h e t a bl et  P K  a n d s af et y  d at a fr o m t h es e st u di es, t h e  d os a g e  of I N C 2 8 0  at 
4 0 0  m g  BI D i n t a bl et  h as  b e e n  d e cl ar e d  as  R P 2 D i n  CI N C 2 8 0 X 2 1 0 2 st u d y.  4 0 0  m g  bi d is 
t h er ef or e t h e  d os e  of t a bl et f or m ul ati o n i n t his st u d y. 


 
 
 
N o v arti s  
C o nfi d e nti al  
 
P a g e  4 8 
A m e n d e d  Pr ot o c ol  V er si o n  0 7  ( Cl e a n) 
 
Pr ot o c ol  N o.  CI N C 2 8 0 X 2 2 0 5  
 
 
3  
O bj e cti v e s  a n d  e n d p oi nt s  
O bj e cti v es  a n d r el at e d  e n d p oi nts  ar e  d es cri b e d i n  T a bl e  3 - 1 b el o w. 
 
T a bl e   3- 1  
O bj e cti v e s  a n d  r el at e d  e n d p oi nt s  
 
O bj e cti v e  
E n d p oi nt  
A n al y si s  
Pri m ar y  
T o i n v e sti g at e t h e  a nti -t u m or  a cti vit y  of  si n gl e  a g e nt  B Y L 7 1 9, I N C 2 8 0, 
L D K 3 7 8  a n d  M E K 1 6 2  
O R R  p er  R E CI S T  v 1. 1  
R ef er t o  S e cti o n  1 0. 4  
S e c o n d ar y  
T o f urt h er  a s s e s s t h e  cli ni c al  a cti vit y  of  si n gl e  a g e nt  B Y L 7 1 9, I N C 2 8 0, 
L D K 3 7 8  a n d  M E K 1 6 2  
O S,  P F S,  D C R,  d ur ati o n  of  o v er all r e s p o n s e  p er  R E CI S T  v 1. 1   
R ef er t o  S e cti o n  1 0. 5. 1  
T o  c h ar a ct eri z e t h e  s af et y  a n d t ol er a bilit y  of  si n gl e  a g e nt  B Y L 7 1 9, 
I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2 
Fr e q u e n c y/ s e v erit y  of  A E s  a n d  S A E s; l a b or at or y  a b n or m aliti e s 
D o s e i nt err u pti o n s  a n d  d o s e r e d u cti o n s  
R ef er t o  S e cti o n  1 0. 5. 2  
T o  c h ar a ct eri z e t h e  p h ar m a c o ki n eti c  pr ofil e s  of  si n gl e  a g e nt  B Y L 7 1 9, 
I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2 
P K  p ar a m et er s i n cl u di n g  b ut  n ot li mit e d t o  A U C 0 -t,  C m a x,  T m a x, 
T 1/ 2,  C L/ F  a n d  V z/ F  
R ef er t o  S e cti o n  1 0. 5. 3  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  4 9
9  Pr ot o c ol  N o. 
 
 
 
 
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  P h as e II,  m ulti pl e  ar m,  o p e n -l a b el st u d y  of si n gl e  a g e nt  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8 
a n d  M E K 1 6 2.  T his st u d y  will  e nr oll  a p pr o xi m at el y  2 0 -2 5  a d v a n c e d  N S C L C  p ati e nts t o  e a c h 
tr e at m e nt   ar m   a c c or di n g  t o  t h eir   m ol e c ul ar   alt er ati o ns  (Fi g ur e   4 - 1).   E a c h  tr e at m e nt   ar m  is 
i n d e p e n d e nt fr o m  o n e  a n ot h er  a n d  will  b e  a n al y z e d s e p ar at el y. 
 
Fi g ur e  4 - 1  
St u d y  D e si g n  
 
 
 
M ol e c ul ar  pr e -s cr e e ni n g  
T o   e nt er  t h e  s cr e e ni n g   p h as e   of  t h e  st u d y,   p ati e nts   m ust   h a v e   writt e n   d o c u m e nt ati o n   of  
m ol e c ul ar  alt er ati o ns  as  d es cri b e d i n  Fi g ur e  4 - 1,  w hi c h s h o ul d  b e  o bt ai n e d l o c all y  or  c e ntr all y 
o n  eit h er  a  n e wl y  o bt ai n e d t u m or s a m pl e ( pr ef err e d)  or t h e  m ost r e c e nt  ar c hi v al t u m or s a m pl e 
a v ail a bl e.  
A  m ol e c ul ar  pr e -s cr e e ni n g I nf or m e d  C o ns e nt  all o wi n g f or t h e  c oll e cti o n  of  a  n e wl y  o bt ai n e d 
t u m or  s a m pl e   or   ar c hi v al  t u m or  s a m pl e  f or  l o c al   or   c e ntr al   ass ess m e nt   of  t h e   m ol e c ul ar  
alt er ati o n  st at us   will   b e  si g n e d   b ef or e   m ol e c ul ar   pr e -s cr e e ni n g.   F or   c e ntr al   ass ess m e nt,   a  
d esi g n at e d l a b or at or y  m a y  b e  us e d.  
 
S cr e e ni n g  
O n c e t h e  m ol e c ul ar  alt er ati o ns st at us is  k n o w n  or  d et er mi n e d, t h e  p ati e nt is  all o w e d t o si g n 
t h e  M ai n  St u d y I nf or m e d  C o ns e nt.  B as e d  o n t h e  m ol e c ul ar  alt er ati o ns  of t h e t u m or,  p ati e nts 
will  b e  all o c at e d t o  o n e  of t h e tr e at m e nt  ar ms.  P ati e nts  wit h  m ulti pl e  m ol e c ul ar  alt er ati o ns i n 
E G F R  a n d t h e r el e v a nt  p at h w a ys t h at  ar e i n di c at e d i n st u d y  d esi g n  Fi g ur e  4 - 1  will  g e n er all y 
b e  e x cl u d e d  e x c e pt  u n d er t h e  c o n diti o ns  d es cri b e d i n  S e cti o n  5. 2 .  P ati e nts  will  b e s cr e e n e d 
a g ai nst t h e i n cl usi o n/ e x cl usi o n  crit eri a  d es cri b e d i n  S e cti o n  5 .  All s cr e e ni n g  e v al u ati o ns  ar e 
r e q uir e d t o  b e  p erf or m e d  b ef or e  a d mi nistr ati o n  of st u d y tr e at m e nt. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  5 0
9  Pr ot o c ol  N o. 
 
 
 
Tr e at m e nt  p eri o d  
T h e tr e at m e nt  p eri o d  will  b e gi n  o n  C y cl e  1  D a y  1  a n d  will  c o nti n u e i n  2 8 -d a y  c y cl es  u ntil 
dis e as e   pr o gr essi o n,   u n a c c e pt a bl e  t o xi cit y,   wit h dr a w al   of  i nf or m e d   c o ns e nt,   d e at h,   or  t h e  
p ati e nt  h as  b e e n tr a nsf err e d t o  a n ot h er  N o v artis st u d y t h at  c a n  c o nti n u e t o  pr o vi d e st u d y  dr u g. 
(s e e  als o S e cti o n  7. 1. 4. 1  a n d  S e cti o n  7. 1. 5 ). 
 
3 0 -d a y  s af et y,  di s e a s e  pr o gr e s si o n,  s ur vi v al f oll o w -u p  a s s e s s m e nt s  
All  p ati e nts  will  b e f oll o w e d  u p f or s af et y  3 0  d a ys  aft er t h e l ast  d os e  of t h e st u d y tr e at m e nt. 
P ati e nts  w h o  dis c o nti n u e st u d y tr e at m e nt f or  a n y r e as o n  ot h er t h a n  dis e a s e  pr o gr essi o n  will  b e 
f oll o w e d  u p f or  pr o gr essi o n  of  dis e as e.  All  p ati e nts  will  b e f oll o w e d f or s ur vi v al (s e e  d et ails 
i n S e cti o n  7. 1. 6 ). 
F or  a n y  p ati e nt  h as  b e e n tr a nsf err e d t o  ot h er  N o v artis st u d y,  a n  e n d  of tr e at m e nt  visit  will  b e 
p erf or m e d  a n d t h e  p ati e nt  will  n ot  e nt er t h e f oll o w -u p  p eri o d.  
 
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 ot  a p pli c a bl e.  
 
4. 3  
D efi niti o n  of  e n d  of t h e  st u d y 
T h e  e n d  of st u d y is  d efi n e d  as t h e  e arli est  o c c urr e n c e  of  o n e  of t h e f oll o wi n g:  
•   All  p ati e nts  h a v e  c o m pl et e d  3 0 -d a ys s af et y f oll o w  u p  a n d  a  mi ni m u m  of  1 2  m o nt hs  h as 
el a ps e d si n c e l ast  p ati e nt first tr e at m e nt,  or  p ati e nts  h a v e  b e e n tr a nsf err e d t o  a n ot h er 
N o v artis st u d y t h at t h e y  c a n  c o nti n u e t o r e c ei v e st u d y   dr u g 
•   St u d y is t er mi n at e d  e arl y  
T h e fi n al  a n al ysis  of st u d y  d at a  will  b e  c o n d u ct e d  at t h e  e n d  of t h e st u d y.  
 
4. 4  
E arl y  st u d y t er mi n ati o n 
T h e st u d y  c a n  b e t er mi n at e d  at  a n y ti m e f or  a n y r e as o n  b y  N o v artis.  S h o ul d t his  b e  n e c ess ar y, 
t h e  p ati e nt s h o ul d  b e s e e n  a s s o o n  as  p o ssi bl e f or  a n  E O T  visit,  a n d t h e  ass ess m e nts f or  E O T 
as  d es cri b e d i n  S e cti o n  7  s h o ul d  b e  p erf or m e d f or  a  pr e m at ur el y  dis c o nti n u e d  or  wit h dr a w n 
p ati e nt.  T h e i n v esti g at or  m a y  b e i nf or m e d  of  a d diti o n al  pr o c e d ur es t o  b e f oll o w e d i n  or d er t o 
e ns ur e  t h at   a d e q u at e  c o nsi d er ati o n  is  gi v e n  t o  t h e   pr ot e cti o n  of  t h e  p ati e nt’s i nt er ests.   T h e  
i n v esti g at or  will  b e r es p o nsi bl e f or i nf or mi n g I R Bs  a n d/ or  E Cs  of t h e  e arl y t er mi n ati o n  of t h e 
tri al. 
 
5  
P o p ul ati o n  
5. 1  
P ati e nt  p o p ul ati o n 
T h e st u d y  will  e nr oll  p ati e nts  w h o  h a v e  hist ol o gi c all y  or  c yt ol o gi c all y  c o nfir m e d  a d v a n c e d 
(st a g e  III B   or  st a g e  I V)  l u n g   a d e n o c ar ci n o m a  ( all  tr e at m e nt   ar ms)   or  l u n g  s q u a m o us   c ell  
c ar ci n o m a  ( B Y L 7 1 9   ar m   o nl y),   w h o   pr o gr ess e d   d uri n g   or  f oll o wi n g   at  l e ast   o n e   pri or  
a nti c a n c er tr e at m e nt r e gi m e n  or  p ati e nts  w h o  ar e  d e e m e d  u ns uit a bl e f or  c h e m ot h er a p y i n t h e  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  5 1
9  Pr ot o c ol  N o. 
 
 
 
i n v esti g at ors’  o pi ni o n (i n cl u di n g  p ati e nts  w h o r ef us e  c h e m ot h er a p y).  E vi d e n c e  of  m ol e c ul ar 
alt er ati o ns  ( S e cti o n   4. 1 )   will   b e   d o c u m e nt e d  t hr o u g h  l o c al   or   c e ntr al  l a b or at or y  t esti n g.  
P ati e nts  wit h sil e nt  m ut ati o ns,  w hi c h  ar e  D N A  m ut ati o ns t h at  d o  n ot r es ult i n  a  c h a n g e t o t h e 
a mi n o  a ci d, s h o ul d  n ot  b e  e nr oll e d.  
P ati e nts   e nr oll e d  i n  t his  st u d y   ar e   n ot   p er mitt e d  t o   p arti ci p at e  i n   a d diti o n al   p ar all el  
i n v esti gati o n al  dr u g  or  d e vi c e st u di es.  
T h e  i n v esti g at or   or   d esi g n e e   m ust   e ns ur e  t h at   o nl y   p ati e nts   w h o   m e et   all  t h e  f oll o wi n g  
i n cl usi o n  a n d  n o n e  of t h e  e x cl usi o n  crit eri a  ar e  off er e d tr e at m e nt i n t h e st u d y.  D e p e n di n g  o n 
t h e st u d y tr e at m e nt s el e ct e d  b as e d  o n t h e  m ol e c ul ar  pr e-s cr e e ni n g r es ult,  b esi d es t h e  g e n er al 
i n cl usi o n  a n d  e x cl usi o n  crit eri a, t h e i n cl usi o n  a n d  e x cl usi o n  crit eri a s p e cifi c f or  e a c h  ar m  n e e d 
t o  b e  c o nsi d er e d  b ef or e t h e s u bj e ct  b ei n g  e nr oll e d. 
 
5. 2  
I n cl u si o n  crit eri a 
P ati e nts  eli gi bl e f o r i n cl usi o n i n t his st u d y  h a v e t o  m e et  all  of t h e f oll o wi n g  c rit e ri a:  
Writt e n i nf or m e d  c o ns e nt  m ust  b e  o bt ai n e d  pri or t o  a n y s cr e e ni n g  pr o c e d ur es.  
1.   P ati e nts  m ust  b e  1 8  y e ars  or  ol d er  a n d  a bl e t o si g n I nf or m e d   C o ns e nt. 
2.   Hist ol o gi c all y  or  c yt ol o gi c all y  c o nfir m e d,  a d v a n c e d (st a g e III B  or st a g e I V) l u n g 
a d e n o c ar ci n o m a.  F or  B Y L 7 1 9 tr e at m e nt  ar m, t h e  hist ol o gi c all y  or  c yt ol o gi c all y  c o nfir m e d 
a d v a n c e d (st a g e III B  or st a g e I V) l u n g  a d e n o c ar ci n o m a  or l u n g s q u a m o us  c ell  c ar ci n o m a.  
3.   P ati e nts  w h o  h a v e f ail e d  at l e ast  o n e  pri or  a nti c a n c er tr e at m e nt r e gi m e n  or  p ati e nts  w h o 
ar e  d e e m e d   u ns uit a bl e f or c h e m ot h er a p y  i n t h e i n v esti g at ors  o pi ni o n (i n cl u di n g p ati e nts 
w h o r ef us e   c h e m ot h er a p y). 
N ot e:  C h e m ot h er a p y  a d mi nist er e d  as  a dj u v a nt tr e at m e nt  m or e t h a n si x  m o nt hs  pri or t o 
st u d y  e nr oll m e nt is  n ot  c o nsi d er e d  a  pri or li n e  of t h er a p y f or  p ur p os es  of t his st u d y.  
4.   M e as ur a bl e  dis e a s e  a c c or di n g t o  R E CI S T  v. 1. 1 (Irr a di at e d l esi o ns  ar e  n ot  c o nsi d er e d 
m e as ur a bl e  u nl ess t h e y  h a v e  cl e arl y  pr o gr ess e d si n c e  r a di ot h er a p y) 
5.   E C O G  p erf or m a n c e st at us  ≤   2 
6.   P ati e nts  m ust  b e s uit a bl e  a n d  willi n g t o  u n d er g o  m a n d at or y t u m or  bi o ps y  a c c or di n g t o 
tr e ati n g i nstit uti o n’s  g ui d eli n es  a n d r e q uir e m e nts f or s u c h  pr o c e d ur e if t h er e is  n o  ar c hi v al 
bi o ps y  a v ail a bl e.  
P ati e nts  eli gi bl e f o r  e a c h t r e at m e nt  a r m  m ust  m e et t h e f oll o wi n g  c rit e ri a f o r  r es p e cti v e 
a r m:  
B Y L 7 1 9  
7.   P ati e nt's t u m or  m ust  h a v e  m ol e c ul ar  alt er ati o n ( m ut ati o n  a n d/ or  a m plifi c ati o n  wit h 
PI K 3 C A  g e n e  c o p y  n u m b er  ≥  4)  of t h e  PI K 3 C A  g e n e ( p ati e nts  wit h  ot h er  PI 3 K  p at h w a y 
alt er ati o ns  m a y  b e  e nr oll e d  aft er  a gr e e m e nt  b et w e e n s p o ns or  a n d  sit e). 
I N C 2 8 0  
8.   P ati e nt's t u m or  m ust  h a v e I H C i nt e nsit y  3 + i n  ≥  5 0 %  of t u m or  c ells  or  c -M E T I H C 
i nt e nsit y s c or e  2 + i n  ≥  5 0 %  of t u m or  c ells  a n d  c o n c urr e nt  h a v e  M E T  g e n e  c o p y  n u m b er  ≥ 
5  b y  FI S H.  P ati e nts  wit h  M E T  g e n e  c o p y  n u m b er  ≥  5 ( b y  FI S H)  wit h  u n k n o w n  c-M E T  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  5 2
9  Pr ot o c ol  N o. 
 
 
 
I H C r es ults  or  c-M E T  m ut ati o n  c a n  b e  e nr oll e d i n t h e st u d y f oll o wi n g  dis c ussi o n  a n d 
a gr e e m e nt  wit h  N o v artis.  
L D K 3 7 8 
9.   P ati e nt's t u m or  m ust  h a v e  A L K  or  R O S 1  g e n e  r e arr a n g e m e nt. 
1 0.  B ot h  cri z oti ni b  pr etr e at e d  a n d  cri z oti ni b  n ai v e  p ati e nts  w o ul d  b e  eli gi bl e.  
1 1.  P ati e nts’ t u m or s a m pl e  m ust  b e  o bt ai n e d  aft er  pr o gr essi o n  o n  cri z oti ni b if  p ati e nt is  pr e - 
tr e at e d  wit h  cri z oti ni b. If t u m or s a m pl e is  n ot  a v ail a bl e,  p ati e nts  m ust  b e s uit a bl e  a n d 
willi n g t o  u n d er g o  m a n d at or y  bi o ps y  a c c or di n g t o tr e ati n g i nstit uti o n’s  o w n  g ui d eli n es 
a n d r e q uir e m e nts f or s u c h  pr o c e d ur e.  
M E K 1 6 2 
1 2.  P ati e nt's t u m or  m ust  h a v e  K R A S,  N R A S  or  B R A F  m ut ati o n.  
N ot e:  P ati e nts  wit h  m ulti pl e  m ol e c ul ar  alt er ati o ns  w hi c h  ar e i n di c at e d i n  st u d y   d esi g n  
Fi g ur e  4 - 1 c a n  b e  e nr oll e d  aft er  dis c ussi o n  wit h   N o v artis. 
 
5. 3  
E x cl u si o n  crit eri a 
P ati e nts  eli gi bl e f o r t his st u d y  m ust  n ot  m e et  a n y  of t h e f oll o wi n g  c rit e ri a:  
1.   S y m pt o m ati c  C N S  m et ast as es  w hi c h  ar e  n e ur ol o gi c all y  u nst a bl e  or r e q uir e i n cr e asi n g 
d os es  of st er oi ds  wit hi n t h e  4  w e e ks  pri or t o st u d y  e ntr y t o  c o ntr ol t h eir  C N S  dis e as e 
N ot e :  P ati e nts  wit h  c o ntr oll e d  C N S  m et ast as es  m a y  p arti ci p at e i n t his tri al.  T h e  p ati ent 
m ust  h a v e  c o m pl et e d r a di ot h er a p y  or s ur g er y f or  C N S  m et ast as es  >  4  w e e ks  pri or t o  st u d y 
e ntr y.  P ati e nts  m ust  b e  n e ur ol o gi c all y st a bl e,  h a vi n g  n o  n e w  n e ur ol o gi c  d efi cits  o n  cli ni c al  
e x a mi n ati o n. 
2.   R a di ati o n t h er a p y  wit hi n  ≤  4  w e e ks  pri or t o st u d y  e ntr y,  wi t h t h e  e x c e pti o n  of li mit e d fi el d 
p alli ati v e r a di ot h er a p y f or  b o n e  p ai n r eli ef.  A n y  p ersist e nt si d e  eff e ct  of  pri or r a di ot h er a p y 
m ust  b e r es ol v e d t o  ≤  C T C A E  gr a d e  1  pri or t o t h e first  d os e  of st u d y  tr e at m e nt. 
3.   A n y  ot h er  m ali g n a n ci es  wit hi n t h e l ast  5  y e ars  b ef or e st u d y st art,  e x c e pt f or  a d e q u at el y 
tr e at e d  c ar ci n o m a i n sit u  of t h e  c er vi x,  b as al  or s q u a m o us  c ell s ki n c a n c er  
4.   P ati e nts  k n o w n t o  b e  HI V  p ositi v e.  HI V t esti n g is  n ot r e q uir e d i n t h e  a bs e n c e  of  cli ni c al 
si g ns  a n d s y m pt o ms s u g g esti n g  HI V  i nf e cti o n. 
5.   M aj or s ur g er y  ≤  2  w e e ks  pri or t o st u d y  e ntr y  or  w h o  h a v e  n ot r e c o v er e d fr o m si d e  eff e cts 
of s u c h  t h er a p y 
6.   A n y  dis e as e (i n cl u di n g  ps y c h oti c  dis or d ers,  dr u g  a b us e,  a cti v e i nf e cti o n,  u n c o ntr oll e d 
h y p ert e nsi o n,  cli ni c all y si g nifi c a nt  c ar di o v as c ul ar  dis e as e f or  e x a m pl e  c er e br o v as c ul ar 
a c ci d e nt ( C V A) ( ≤  6  m o nt hs  b ef or e st u d y  e ntr y),  m y o c ar di al i nf ar cti o n ( ≤  6  m o nt hs  b ef or e 
st u d y  e ntr y),  u nst a bl e  a n gi n a,  N e w  Y or k  h e art  ass o ci ati o n( N Y H A)  ≥  gr a d e  2  c hr o ni c  h e art 
f ail ur e ( C H F),  hist or y  or  pr es e n c e  of  cli ni c all y si g nifi c a nt  v e ntri c ul ar  arr h yt h mi as  or  atri al 
fi brill ati o n,  h e p ati c, r e n al  or  m et a b oli c  dis e as e,  m et a b oli c  d ysf u n cti o n),  p h ysi c al 
e x a mi n ati o n fi n di n g,  or  cli ni c al l a b or at or y fi n di n g  gi vi n g r e as o n a bl e s us pi ci o n  of  a 
dis e as e  or  c o n diti o n t h at  c o ntr a -i n di c at es t h e  us e of  a n i n v esti g ati o n al  dr u g  or  p uts t h e 
p ati e nt  at  hi g h ris k f or tr e at m e nt -r el at e d  c o m pli c ati o ns 
7.   P ati e nts  m ust  n ot  h a v e r e c ei v e d  pr e vi o us  a nti -c a n c er t h er a pi es  ≤  4  w e e ks  pri or t o t h e first 
d os e  of st u d y tr e at m e nt  e x c e pt:  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  5 3
9  Pr ot o c ol  N o. 
 
 
 
•   ≤ 6  w e e ks f or  nitr os o ur e as  a n d  mit o m y ci n  
•   ≤ 5  h alf -lif e  of  c o nti n u o us  or i nt er mitt e nt s m all  m ol e c ul e t h er a p e uti cs ( or  ≤ 4  w e e ks 
w h e n  h alf -lif e is  u n k n o w n), 
a n d  h a v e  n ot r e c o v er e d fr o m t h e si d e  eff e cts  of s u c h tr e at m e nt ( C T C A E  gr a d e  ≤  1) 
pri or t o t h e first  d os e  of st u d y tr e at m e nt,  e x c e pt f or  al o p e ci a.  
8.   C urr e ntl y r e c ei vi n g  a n y  pr o hi bit e d  m e di c ati o ns i n cl u di n g  vit a mi ns s u p pl e m e nts,  a n d 
h er b al   pr e p ar ati o ns m e di c ati o ns/s u p pl e m e nts.  R ef er  t o S e cti o n   6. 3 a n d  S e cti o n   1 4. 4 f or 
e x cl u d e d  m e di c ati o ns.  
9.   A n y  of t h e f oll o wi n g l a b or at or y  v al u es  at  b as eli n e:  
•   H e m o gl o bi n  <  9  g/ d L ( SI  U nits:  9 0  g/ L)  
•   Pl at el et  c o u nt  < 1 0 0  x   1 09/ L 
•   A bs ol ut e  n e utr o p hil  c o u nt ( A N C)  <  1. 5  x   1 09/ L 
•   S er u m  al b u mi n  <  2. 5  g/ dl  
•   T ot al  bilir u bi n  >  1. 5  x  u p p er li mit  of  n or m al  ( U L N) 
•   A S T/ S G O T  or  A L T/ S G P T  >  3. 0  x  u p p er li mit  of  n or m al ( U L N)  or  >  5. 0  x  U L N  if 
li v er  m et ast as es  ar e  pr es e nt 
•   S er u m  cr e ati ni n e  >  1. 5  x  U L N  or  c al c ul at e d  cr e ati ni n e  cl e ar a n c e  b y   C o c k cr oft-G a ult 
f or m ul a  <  5 0 m L/ mi n  
•   S er u m  c al ci u m,  p ot assi u m  a n d  m a g n esi u m  <  L L N (l o w er li mit  of   n or m al) 
1 0.  P ositi v e  uri n e  β -H C G t est (f e m al e  p ati e nts  of  c hil d b e ari n g  p ot e nti al  o nl y)  wit hi n  7 2  h o urs 
pri or t o first   d os e 
1 1.  Pr e g n a nt  or  n ursi n g (l a ct ati n g)  w o m e n,  w h er e  pr e g n a n c y is  d efi n e d  as t h e st at e  of  a  f e m al e 
aft er  c o n c e pti o n  a n d  u ntil t h e t er mi n ati o n  of  g est ati o n,  c o nfir m e d  b y  a  p ositi v e  h C G 
l a b or at or y t est. 
1 2.  W o m e n  of  c hil d -b e ari n g  p ot e nti al,  d efi n e d  as  all  w o m e n  p h ysi ol o gi c all y  c a p a bl e  of 
b e c o mi n g  pr e g n a nt,  u nl ess t h e y  ar e  usi n g  hi g hl y  eff e cti v e  m et h o ds  of  c o ntr a c e pti o n 
d uri n g  d osi n g  a n d f or  3 0  d a ys  aft er st o p pi n g  of st u d y  m e di c ati o n.  Hi g hl y  eff e cti v e 
c o ntr a c e pti o n  m et h o ds i n cl u d e:  
•   T ot al   a bsti n e n c e  ( w h e n  t his  is  i n  li n e   wit h  t h e   pr ef err e d   a n d   us u al  lif est yl e   of  t h e  
s u bj e ct.  P eri o di c  a bsti n e n c e ( e. g.,  c al e n d ar,  o v ul ati o n, s y m pt ot h er m al,  p ost - o v ul ati o n 
m et h o ds)  a n d  wit h dr a w al  ar e  n ot  a c c e pt a bl e  m et h o ds  of  c o ntr a c e pti o n  
•   F e m al e  st erili z ati o n  ( h a v e   h a d  s ur gi c al   bil at er al   o o p h or e ct o m y   wit h   or   wit h o ut  
h yst er e ct o m y)  or t ot al  h yst er e ct o m y  or t u b al li g ati o n  at l e ast si x  w e e ks  b ef or e t a ki n g 
st u d y tr e at m e nt. I n  c as e  of  o o p h or e ct o m y  al o n e,  o nl y  w h e n t h e r e pr o d u cti v e st at us  of 
t h e  w o m a n  h as  b e e n  c o nfir m e d  b y f oll o w  u p  h or m o n e l e v el ass ess m e nt  
•   M al e st erili z ati o n ( at l e ast  6  m o nt hs  pri or t o s cr e e ni n g).  F or f e m al e s u bj e cts  o n t h e 
st u d y t h e  v as e ct o mi z e d  m al e  p art n er s h o ul d  b e t h e s ol e  p art n er f or t h at  s u bj e ct. 
Us e  of  or al, i nj e ct e d  or i m pl a nt e d  h or m o n al  m et h o ds  of  c o ntr a c e pti o n  or  pl a c e m e nt  of  a n 
i ntr a ut eri n e  d e vi c e (I U D)  or i ntr a ut eri n e s yst e m (I U S),  or  ot h er f or ms  of  h or m o n al 
c o ntr a c e pti o n t h at  h a v e  c o m p ar a bl e  ef fi c a c y (f ail ur e r at e  < 1 %), f or  e x a m pl e  h or m o n e 
v a gi n al ri n g  or tr a ns d er m al  h or m o n e  c o ntr a c e pti o n.I n  c as e  of  us e  of  or al  c o ntr a c e pti o n  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  5 4
9  Pr ot o c ol  N o. 
 
 
 
w o m e n s h o ul d  h a v e  b e e n st a bl e  o n t h e s a m e  pill f or  a  mi ni m u m  of  3  m o nt hs  b ef or e t a ki n g 
st u d y tr e at m e nt. 
W o m e n  ar e  c o nsi d er e d  p ost -m e n o p a us al  a n d  n ot  of  c hil d  b e ari n g  p ot e nti al if t h e y  h a v e 
h a d  1 2  m o nt hs  of  n at ur al (s p o nt a n e o us)  a m e n orr h e a  wit h  a n  a p pr o pri a t e  cli ni c al  pr ofil e 
( e. g.  a g e  a p pr o pri at e,  hist or y  of  v as o m ot or s y m pt o ms)  or  h a v e  h a d s ur gi c al  bil at er al 
o o p h or e ct o m y ( wit h  or  wit h o ut  h yst er e ct o m y)  or t u b al li g ati o n  at l e ast si x  w e e ks  a g o. I n 
t h e  c as e  of  o o p h or e ct o m y  al o n e,  o nl y  w h e n t h e r e pr o d u cti v e st at us  of t h e  w o m a n  h as  b e e n 
c o nfir m e d  b y f oll o w  u p  h or m o n e l e v el  ass ess m e nt is s h e  c o nsi d er e d  n ot  of  c hil d  b e ari n g 
p ot e nti al.  
1 3.  S e x u all y  a cti v e  m al es  u nl ess t h e y  us e  a  c o n d o m  d uri n g i nt er c o urs e  w hil e t a ki n g  dr u g  a n d 
f or  3  m o nt hs  aft er st o p pi n g st u d y  m e di c ati o n a n d s h o ul d  n ot f at h er  a  c hil d i n t his  p eri o d. 
A  c o n d o m  is r e q uir e d t o  b e us e d  als o   b y v as e ct o mi z e d  m e n  i n  or d er t o pr e v e nt  d eli v er y  of 
t h e  dr u g  vi a s e mi n al fl ui d. 
P ati e nts  eli gi bl e f o r  e a c h t r e at m e nt  a r m  m ust  n ot  m e et  a n y  of t h e f oll o wi n g  c rit e ri a f o r 
r es p e cti v e  a r m:  
B Y L 7 1 9  
1 4.  I m p air e d  c ar di a c f u n cti o n  or  cli ni c all y si g nifi c a nt  c ar di a c  dis e as e, i n cl u di n g  a n y  o n e  of t h e 
f oll o wi n g: 
•   Hist or y  of  h e art f ail ur e  or l eft  v e ntri c ul ar ( L V)  d ysf u n cti o n ( L V E F  ≤  5 0 %)  b y  M U G A 
or  E C H O  
•   S T  d e pr essi o n  or  el e v ati o n  of  ≥  1. 5  m m i n  2  or  m or e  l e a ds 
•   M e a n  Q T c F > 4 5 0  ms e c f or  m al es  a n d  Q T c F >  4 6 0  ms e c f or f e m al es  usi n g  Fri d eri ci a’s 
c orr e cti o n  o n s cr e e ni n g  E C G.  P ati e nts  wit h  u nr e a d a bl e  or  u ni nt er pr e t a bl e  E C Gs  ar e 
als o  e x cl u d e d.  
•   C o n g e nit al l o n g  Q T  s y n dr o m e 
•   Hist or y  or  pr es e n c e  of  cli ni c all y si g nifi c a nt  v e ntri c ul ar  arr h yt h mi as  or  atri al 
fi brill ati o n 
•   Cli ni c all y si g nifi c a nt r esti n g  br a d y c ar di a ( <  5 0  b e ats /  mi n)  
•   C o m pl et e l eft  b u n dl e  br a n c h  bl o c k  ( L B B B) 
•   Ri g ht  b u n dl e  br a n c h  bl o c k ( R B B B)  + l eft  a nt eri or  h e mi bl o c k ( L A H B  - bif as ci c ul ar 
bl o c k) 
•   U nst a bl e  a n gi n a  p e ct oris  ≤  3  m o nt hs  pri or t o st u d y  e ntr y  
•   A c ut e  M y o c ar di al I nf ar cti o n ( A MI)  ≤  3  m o nt hs  pri or t o st u d y  e ntr y  
1 5.  F asti n g  pl as m a  gl u c os e ( F P G)  >  1 4 0  m g/ d L /  7. 7  m m ol/ L  or  Gl y c os yl at e d  H e m o gl o bi n 
( H b A 1 c)  ≥ 6. 5 % ( b ot h  crit eri a  h a v e t o  b e c h e c k e d)  
*  F or  p ati e nts  wit h  F P G  ≥  1 0 0  m g/ d L  a n d/ or  H b A 1 c  ≥ 5. 7 % (i. e . t hr es h ol d f or  pr e-di a b et es) 
at s cr e e ni n g,  r e c o m m e n d lif est yl e  c h a n g es  a c c or di n g t o  A D A  g ui d eli n es, i. e.  di et ar y 
a d vi c e ( e. g. s m all fr e q u e nt  m e als, l o w  c ar b o h y dr at e  c o nt e nt,  hi g h fi b er,  b al a n ci n g 
c ar b o h y dr at e i nt a k e  o v er t h e  c o urs e  of t h e  d a y, t hr e e s m al l  m e als  a n d  2 s m all s n a c ks 
r at h er t h a n  o n e l ar g e  m e al)  a n d  e x er cis e.  A  c o ns ult ati o n  wit h  a  di a b et ol o gist is  als o  hi g hl y 
r e c o m m e n d e d. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  5 5
9  Pr ot o c ol  N o. 
 
 
 
1 6.  I m p air e d  g astr oi nt esti n al ( GI) f u n cti o n  or  GI  dis e as e t h at  m a y si g nifi c a ntl y  alt er t h e 
a bs or pti o n  of  or al  B Y L 7 1 9 ( e. g. t ot al  g astr e ct o m y,  ul c er ati v e  dis e as e,  u n c o ntr oll e d  n a us e a, 
v o miti n g,  di arr h e a,  m al a bs or pti o n s y n dr o m e,  or s m all  b o w el r es e cti o n)  or  p ati e nts  u n a bl e 
t o t a k e  or al m e di c ati o n.  
1 7.  P ati e nts  w h o  ar e  c urr e ntl y r e c ei vi n g tr e at m e nt  wit h  m e di c ati o n t h at  h as  t h e  p ot e nti al t o 
pr ol o n g t h e  Q T i nt er v al  or i n d u ci n g  T ors a d es  d e  P oi nt es,  a n d t h e tr e at m e nt  c a n n ot  eit h er 
b e  dis c o nti n u e d  or s wit c h e d t o  a  diff er e nt  m e di c ati o n  pri or t o st arti n g st u d y  tr e at m e nt. 
1 8.  Tr e at m e nt  wit h t h er a p e uti c  d os es  of  c o u m ari n -b as e d  a nti c o a g u l a nts ( e. g.,  w arf ari n s o di u m, 
C o u m a di n ® ).  L o w  d os es  of  c o ur m ari n-b as e d  a nti c o a g ul a nts ( e. g.  ≤  2 m g/ d a y f or li n e 
p at e n c y)  ar e  p er mitt e d.  
1 9.  P ati e nts r e c ei vi n g  c hr o ni c  or  hi g h  d os e  c orti c ost er oi ds t h er a p y (i n h al e d st er oi ds  a n d s h ort 
c o urs es  of  or al st er oi ds f or  a nti -e m esis  or  as  a n  a p p etit e sti m ul a nt,  or si n gl e i. v.  d os es, i. e., 
f or  pr o p h yl a xis  of  c o ntr ast  m e di a  all er g y  ar e all o w e d)  
2 0.  A  hist or y  o f  a c ut e  or  c hr o ni c  p a n cr e atitis, s ur g er y  of t h e  p a n cr e as,  or  a n y ris k f a ct ors t h at 
m a y i n cr e as e t h e ris k  of  p a n cr e atitis  
2 1.  Pri or tr e at m e nt  wit h  PI 3 K  i n hi bit or 
I N C 2 8 0  
2 2.  A n y  of t h e f oll o wi n g l a b or at or y  v al u es  at  b as eli n e:  
•   As y m pt o m ati c s er u m  a m yl as e  >  gr a d e   2 
•   P at i e nts  wit h  gr a d e  1  or  gr a d e  2 s er u m  a m yl as e  at t h e  b e gi n ni n g  of st u d y  m ust  b e 
c o nfir m e d t o  h a v e  n o si g ns  a n d/ or s y m pt o ms  p a n cr e atitis  or  p a n cr e ati c i nj ur y  ( e. g. 
el e v at e d  P -a m yl as e,  a b n or m al i m a gi n g fi n di n gs  of  p a n cr e as,  et c.)  
•   S er u m li p as e  >  U L N  
•   F asti n g s er u m tri gl y c eri d e l e v el  >  5 0 0  m g/ d L  
2 3.  A  hist or y  of  a c ut e  or  c hr o ni c  p a n cr e atitis, s ur g er y  of t h e  p a n cr e as,  or  a n y ris k f a ct ors  t h at 
m a y i n cr e as e t h e ris k  of  p a n cr e atitis  
2 4.  A  hist or y  of  c ysti c  fi br osis. 
2 5.  P ati e nts  wit h  hi g hl y s us pi ci o us  p ul m o n ar y fi br osi s  or i nt erstiti al l u n g dis e as e.  
2 6.  Pri or tr e at m e nt  wit h  a  c -M E T i n hi bit or  or  H G F -t ar g eti n g t h er a p y 
L D K 3 7 8 
2 7.  S er u m  p ot assi u m,  m a g n esi u m,  p h os p h or us  a n d t ot al  c al ci u m ( c orr e ct e d f or s er u m  al b u mi n) 
w hi c h is  o ut  of  n or m al li mits  or  c o ul d  n ot  b e  c orr e ct e d t o  wit hi n  n or m al li mits  wit h 
s u p pl e m e nts  b ef or e t h e first  d os e  of  L D K 3 7 8  
2 8.  Al k ali n e  p h os p h at as e ( A L P)  > 5. 0  x  U L N  
2 9.  S e r u m  a m yl as e  > 2  x U L N  
3 0.  S er u m li p as e  > U L N  
3 1.  F asti n g  pl as m a  gl u c os e  > 1 7 5  m g/ d L ( > 9. 8  m m ol/ L)  
3 2.  I m p air e d  c ar di a c f u n cti o n  or  cli ni c all y si g nifi c a nt  c ar di a c  dis e as e, i n cl u di n g  a n y  o n e  of t h e 
f oll o wi n g: 
•   S u pr a v e ntri c ul ar  a n d  n o d al  arr h yt h mi as  n ot  c o ntr oll e d  wit h  m e di c ati o n  
•   Ot h er  c ar di a c  arr h yt h mi a  n ot  c o ntr oll e d  wit h  m e di c ati o n  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  5 6
9  Pr ot o c ol  N o. 
 
 
 
•   C orr e ct e d  Q T c F i nt er v al  ≥ 4 5 0  ms e c ( m al e  p ati e nts),  ≥  4 7 0  ms e c (f e m al e  p ati e nts) 
usi n g  Fri d eri ci a’s  c orr e cti o n  o n s cr e e ni n g  1 2 -l e a d  E C G ( as  m e a n  of tri pli c at e) 
•   R esti n g  h e art r at e  w hi c h is  o ut  of  5 0 -9 0  b p m  o n s cr e e ni n g  1 2 -l e a d  E C G ( as  m e a n of 
tri pli c at e) 
•   Hist or y  of  m y o c ar di al i nf ar cti o n,  a n gi n a  p e ct oris,  c or o n ar y  art er y  b y p ass  gr aft 
( C A B G)  wit hi n  6  m o nt hs  pri or t o st arti n g st u d y tr e at m e nt 
•   Cli ni c all y si g nifi c a nt  c ar di a c  arr h yt h mi as ( e. g.,  v e ntri c ul ar t a c h y c ar di a),  c o m pl et e l eft 
b u n dl e  br a n c h  bl o c k,  hi g h - gr ad e  A V  bl o c k ( e. g.,  bif as ci c ul ar  bl o c k,  M o bit z t y p e II 
a n d t hir d  d e gr e e  A V   bl o c k) 
3 3.  C o n g e nit al l o n g  Q T s y n dr o m e  or f a mil y  hist or y  of i di o p at hi c s u d d e n  d e at h ,  or  a n y  of  t h e 
f oll o wi n g: 
•   Ris k  f a ct ors f or T ors a d es   d e  P oi nt e ( T d P) i n cl u di n g u n c orr e ct e d   h y p o k al e mi a or 
h y p o m a g n es e mi a,  hist or y  of  c ar di a c f ail ur e,  or  hist or y  of  cli ni c all y 
si g nifi c a nt/s y m pt o m ati c  br a d y c ar di a 
•   C o n c o mit a nt  m e di c ati o n(s)  wit h  a  k n o w n ris k t o  pr ol o n g t h e  Q T i nt er v al  a n d/ or 
k n o w n t o  c a us e  T ors a d es  d e  P oi nt e t h at  c a n n ot  b e  dis 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 ( e. g.  wit hi n  5  h alf -li v es  or  7  d a ys  pri or t o st arti n g st u d y dr u g) 
•   I n a bilit y t o  d et er mi n e t h e  Q T c F i nt er v al 
3 4.  Hist or y  or  c urr e nt  di a g n osis  of  c ar di a c  dis e as e i n di c ati n g si g nifi c a nt ris k  of s af et y  f or 
p ati e nts  p arti ci p ati n g  i n t h e st u d y s u c h  as  u n c o ntr oll e d  or si g nifi c a nt  c ar di a c  dis e as e, 
i n cl u di n g  a n y  of t h e f oll o wi n g: 
•   U nst a bl e  a n gi n a  wit hi n  6  m o nt hs  pri or t o  s cr e e ni n g. 
•   R e c e nt  m y o c ar di al i nf ar cti o n  wit hi n  6  m o nt hs  pri or t o  s cr e e ni n g.  
•   U n c o ntr oll e d  c o n g esti v e  h e art  f ail ur e 
•   Cli ni c all y si g nifi c a nt (s y m pt o m ati c)  c ar di a c  arr h yt h mi as ( e. g., s ust ai n e d  v e ntri c ul ar 
t a c h y c ar di a,  a n d  cli ni c all y si g nifi c a nt s e c o n d  or t hir d  d e gr e e  A V  bl o c k  wit h o ut  a 
p a c e m a k er  
3 5.  Pri or tr e at m e nt  wit h  a n y  ot h er  A L K i n hi bit or  e x c e pt  cri z oti ni b  
3 6.  P ati e nt is  c urr e ntl y r e c ei vi n g tr e at m e nt  wit h  w arf ari n s o di u m ( C o u m a di n ®)  or  a n y   ot h er 
c o u m ari n - d eri v ati v e  a nti c o a g ul a nts. 
3 7.  P ati e nt is r e c ei vi n g tr e at m e nt  wit h  a n y  e n z y m e -i n d u ci n g  a nti c o n v uls a nt t h at  c a n n ot  b e 
dis c o nti n u e d  at l e ast  1  w e e k  b ef or e first  d os e  of st u d y tr e at m e nt,  a n d f or t h e  d ur ati o n  of 
t h e st u d y.  P ati e nt  o n  n o n  e n z y m e-i n d u ci n g  a nti c o n v uls a nts is eli gi bl e.  
3 8.  P ati e nt  h as  hist or y  of i nt erstiti al l u n g  dis e as e  or i nt erstiti al  p n e u m o nitis, i n cl u di n g 
cli ni c all y si g nifi c a nt r a di ati o n  p n e u m o nitis (i. e.,  aff e cti n g  a cti viti es  of  d ail y li vi n g  or 
r e q uiri n g t h er a p e uti c i nt er v e nti o n). 
3 9.  P ati e nt  h as  ot h er s e v er e,  a c ut e,  or  c hr o ni c  m e d i c al  c o n diti o ns i n cl u di n g  u n c o ntr oll e d 
di a b et es  m ellit us  or  ps y c hi atri c  c o n diti o ns  or l a b or at or y  a b n or m aliti es t h at, i n t h e  o pi ni o n 
of t h e i n v esti g at or,  m a y i n cr e as e t h e ris k  ass o ci at e d  wit h st u d y  p arti ci p ati o n  or  m a y 
i nt erf er e  wit h t h e i nt er pr et ati o n  of st u d y r es ults. 
4 0.  P ati e nt  h as  a  hist or y  of  p a n cr e atitis  or  hist or y  of i n cr e as e d  a m yl as e  or li p as e t h at  w as   d u e 
t o  p a n cr e ati c dis e as e.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  5 7
9  Pr ot o c ol  N o. 
 
 
 
M E K 1 6 2 
4 1.  I m p air e d  c ar di a c f u n cti o n  or  cli ni c all y si g nifi c a nt  c ar di a c  dis e as e, i n cl u di n g: 
•   Hist or y  of  h e art f ail ur e  or l eft  v e ntri c ul ar ( L V)  d ysf u n cti o n ( L V E F  ≤  5 0 %)  b y  M U G A 
or  E C H O  
•   U n c o ntr oll e d  art eri al  h y p ert e nsi o n,  d efi n e d  as  bl o o d  pr ess ur e  >  1 4 0/ 1 0 0  m m H g  
•   Hist or y  of  a c ut e  c or o n ar y s y n dr o m es (i n cl u di n g  m y o c ar di al i nf ar cti o n,  u nst a bl e 
a n gi n a,  C A B G,  c or o n ar y  a n gi o pl ast y,  or st e nti n g)  ≤ 6  m o nt hs  pri or t o st u d y  e ntr y  
•   S y m pt o m ati c  c hr o ni c  h e art f ail ur e,  hist or y  or  c urr e nt  e vi d e n c e  of  cli ni c all y si g nifi c a nt 
c ar di a c  arr h yt h mi a  a n d/ or  c o n d u cti o n  a b n or m alit y  ≤ 6  m o nt hs  pri or t o st u d y  e ntr y  
4 2.  Hist or y  or  c urr e nt  e vi d e n c e  of r eti n al  v ei n  o c cl usi o n ( R V O)  or  c urr e nt ris k f a ct ors f or  
R V O ( e. g.  u n c o ntr oll e d  gl a u c o m a  or  o c ul ar  h y p ert e nsi o n,  hist or y  of  h y p er vis c osit y  or 
h y p er c o a g ul a bilit y s y n dr o m es) 
4 3.  P ati e nts  w h o  h a v e  n e ur o m us c ul ar  dis or d ers t h at  ar e  ass o ci at e d  wit h  el e v at e d  C K ( e. g. 
I nfl a m m at or y  m y o p at hi es,  m us c ul ar  d ystr o p h y,  a m y otr o p hic l at er al s cl er osis, s pi n al 
m us c ul ar  atr o p h y);  
4 4.  Hist or y  of  Gil b ert’s  s y n dr o m e 
4 5.  Pri or t h er a p y  wit h  a  M E K  i n hi bit or 
 
6  
Tr e at m e nt  
6. 1  
St u d y tr e at m e nt 
I n v esti g ati o n al t r e at m e nt:  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2  ar e t h e i n v esti g ati o n al 
tr e at m e nt  or t h e  “st u d y tr e at m e nt ” f or t his st u d y. 
 
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  
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  
B Y L 7 1 9  
T a bl et s f or  or al  u s e  
3 5 0  m g  
O n c e  d ail y  
I N C 2 8 0 
C a p s ul e s/t a bl et s f or  or al  u s e   
6 0 0  m g  c a p s ul e/ 4 0 0  m g t a bl et   
T wi c e  d ail y  
L D K 3 7 8  
C a p s ul e s f or  or al  u s e   
7 5 0  m g  
O n c e  d ail y  
M E K 1 6 2  
T a bl et s f or  or al  u s e  
4 5  m g  
T wi c e  d ail y  
 
I n str u cti o n s f or  a d mi ni str ati o n  of  B Y L 7 1 9/I N C 2 8 0/ L D K 3 7 8/ M E K 1 6 2 
•   P ati e nts   will   b e  i nstr u ct e d  t o  s elf -a d mi nist er  t h e  st u d y  tr e at m e nt   wit h   at  l e ast   a   gl ass  
( a p pr o xi m at el y  2 5 0  m L)  of  w at er  at  a p pr o xi m at el y t h e s a m e ti m e  e a c h  d a y ( 2 4  ±  4  h o urs 
a p art f or  m or ni n g  d os e  of  Q D r e gi m e n  a n d  1 2  ±  2  h o urs  a p art f or  m or ni n g  a n d  e v e ni n g 
d os es  of  BI D r e gi m e n).  P ati e nts i n I N C 2 8 0 tr e at m e nt  ar m  ar e r e c o m m e n d e d t o  c o ns u m e 
a n ot h er  gl ass  of  w at er ( a b o ut  2 5 0  m L)  at  2  h o urs  aft er  e a c h I N C 2 8 0  a d mi nistr ati o n.  F or 
t h e  B Y L 7 1 9  ar m, if t h e  p ati e nt f or g ets t o t a k e  B Y L 7 1 9  d uri n g t h e  d a yti m e it s h o ul d b e 
t a k e n i n t h e  e v e ni n g  at t h e l at est  wit hi n  1  h o ur  aft er  a  m e al,  b ut  n ot l at er t h a n  6  p m. If  n ot 
t a k e n  b y t his ti m e, t h e  d os e s h o ul d  b e  wit h h el d t h at  d a y. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  5 8
9  Pr ot o c ol  N o. 
 
 
 
•   F or I N C 2 8 0  ar m, t h e  n e wl y  e nr oll e d  p ati e nts  will i niti at e tr e at m e nt  wit h I N C 2 8 0 t a bl ets  at  
4 0 0   m g   BI D  i n   c o m pli a n c e   wit h  t h e  l o c al  r e g ul ati o n.   T h e   o n g oi n g   p ati e nts   m a y   b e  
s wit c h e d  t o  t h e  t a bl et   aft er   dis c ussi o n   wit h   N o v artis   a n d  i n   c o m pli a n c e   wit h  l o c al  
r eg ul ati o n. 
•   B Y L 7 1 9  m ust   b e t a k e n  wit hi n  1  h o ur  aft er   a  m e al   or s n a c k ( pr ef er a bl y i n t h e  m or ni n g 
aft er  br e a kf ast). If, f or  a n y r e as o n,  a  br e a kf ast ( or  ot h er  m e al)  w as  n ot  c o ns u m e d, t h e n t h e 
p ati e nt s h o ul d t a k e st u d y tr e at m e nt  wit h  a  gl ass  of  w at er  wit hi n  1  h o ur  aft er  a s n a c k  at  a n y 
l at er  p oi nt i n ti m e. If t his  h a p p e ns  o n  d a ys  of  P K s a m pli n g, it s h o ul d  b e  d o c u m e nt e d i n t h e 
C R F.  
•   I N C 2 8 0/ L D K 3 7 8 s h o ul d  b e  a d mi nist er e d i n t h e f ast e d st at e,  at l e ast  1  h o ur  b ef or e  or  2 
h o urs  aft er  a  m e al.  
•   F or  all tr e at m e nt  ar ms,  p ati e nts  ar e fr e e t o  dri n k  w at er  d uri n g t h e f asti n g   p eri o d. 
•   P ati e nts s h o ul d  b e i nstr u ct e d t o s w all o w t h e  c a p s ul es/t a bl ets  w h ol e  a n d  n ot  t o  c h e w  or  
cr us h  t h e m. 
•   P ati e nts s h o ul d  b e i nstr u ct e d  n ot t o  m a k e  u p  miss e d  d os es  or  p arti al  d os es (i. e.  w h e n t h e 
e ntir e  d os e  is  n ot t a k e n  as i nstr u ct e d). If t h e  p ati e nt f or g ets t o t a k e  B Y L 7 1 9  d uri n g t h e 
d a yti m e it s h o ul d  b e t a k e n i n t h e  e v e ni n g  at t h e l at est  wit hi n  1  h o ur  aft er  a  m e al,  b ut  n ot 
l at er t h a n  6  p m. If  n ot t a k e n  b y t his ti m e, t h e  d os e s h o ul d  b e  wit h h el d t h at  d a y.  F or ot h er 
Q D r e gi m e n,  a  miss e d  or  p arti al  d os e  will  b e  d efi n e d  as  a  c as e  w h e n t h e f ull  d os e is  n ot 
t a k e n  wit hi n  8  h o urs  aft er t h e  a p pr o xi m at e ti m e  of t h e  us u all y  d ail y  d osi n g.  T h at  d a y’s 
d os e ( or  p art r e m ai ni n g  d os e) s h o ul d  b e  o mitt e d  a n d t h e  p ati e nt s h o ul d  c o nti n u e tr e at m e nt 
wit h t h e  n e xt s c h e d ul e d  d os e  o n t h e f oll o wi n g  d a y.  F or  a  BI D r e gi m e n,  a  miss e d  or  p arti al 
d os e is  d efi n e d  as t h e f ull  d os e is  n ot t a k e n  wit hi n  4  h o urs  aft er t h e  a p pr o xi m at e ti m e  of 
t h e  us u al  m or ni n g  or  e v e ni n g  d osi n g s c h e d ul e.  T h at  m or ni n g or  e v e ni n g  d os e s h o ul d  b e 
o mitt e d  a n d t h e  p ati e nt  will  c o nti n u e tr e at m e nt  wit h t h e  n e xt s c h e d ul e d   d os e. 
•   If  v o miti n g  o c c urs  d uri n g t h e  c o urs e  of tr e at m e nt,  n o r e-d osi n g  of t h e  p ati e nt is  all o w e d 
b ef or e  t h e   n e xt  s c h e d ul e d   d os e.   T h e   o c c urr e n c e   a n d  fr e q u e n c y   of   a n y   v o miti n g   a n d/ or  
di arr h e a ( or i n cr e as e d st o ol fr e q u e n c y)  m ust  b e  n ot e d i n t h e  A Es s e cti o n  of t h e  e C R F.  I n 
a d diti o n,  o n t h e  d a ys  of  P K s a m pli n g, t h e  o ns et ti m e  of  a n y  e pis o d es  of  v o miti n g  wit hi n 
t h e  first   4   h o urs   p ost-d osi n g   o n  t h at   d a y   m ust   b e   n ot e d  i n  t h e   c orr es p o n di n g   D os e  
A d mi nistr ati o n  R e c or d  P K  e C R F.  
•   P ati e nts  w h o  ar e  assi g n e d t o  L D K 3 7 8  or I N C 2 8 0 tr e at m e nt  ar ms  m ust  a v oi d  c o ns u m pti o n 
of  gr a p efr uit,  p o m e gr a n at es, st ar fr uits,  S e vill e  or a n g es  or  pr o d u cts  c o nt ai ni n g t h e j ui c e  of 
e a c h   d uri n g  t h e   e ntir e  st u d y   a n d   pr ef er a bl y   7   d a ys   b ef or e  t h e  first   d os e   of  st u d y  
m e di c ati o ns,   d u e t o  p ot e nti al   eff e ct   o n t h e  e x p os ur es  of  t h e st u d y  m e di c ati o ns.   N or m al 
or a n g e j ui c e is  all o w e d.  
•   O n  d a ys  w h e n  P K  bl o o d s a m pl es  ar e t o  b e  c oll e ct e d,  p ati e nts  will  b e i nstr u ct e d t o  h ol d 
t h eir  d os e  u ntil  arri v al  at t h e st u d y  c e nt er  a n d t a k e t h e  d os e  at  a n y l at er  p oi nt  of ti m e  aft er 
P K  bl o o d  c oll e cti o n.  T h e s a m e  di et ar y r estri cti o ns f or  d osi n g  will  b e i n  pl a c e  o n  d a ys  wit h 
P K  bl o o d s a m pli n g   d a ys. 
•   T h e i n v esti g at or  or r es p o nsi bl e sit e  p ers o n n el s h o ul d i nstr u ct t h e  p ati e nt t o t a k e t h e st u d y 
tr e at m e nts  as  p er  pr ot o c ol ( pr o m ot e  c o m pli a n c e).  All  d os a g es  pr es cri b e d  a n d  dis p e ns e d t o 
t h e  p ati e nt  a n d  all  d os e  c h a n g es  a n d  all  miss e d  d os es  d uri n g t h e st u d y  m ust  b e r e c or d e d  o n 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  5 9
9  Pr ot o c ol  N o. 
 
 
 
t h e  D os a g e  A d mi nistr ati o n  R e c or d  e C R F.  Dr u g  a c c o u nt a bilit y  m ust  b e  p erf or m e d  o n  a 
r e g ul ar  b asis. 
 
I n str u cti o n s f or  a d mi ni str ati o n  of I N C 2 8 0 
•   D uri n g t h e  e ntir e  d ur ati o n  of tr e at m e nt  wit h I N C 2 8 0, t h e  p ati e nt is r e c o m m e n d e d t o  us e 
pr e c a uti o n ar y  m e as ur es  a g ai nst  ultr a vi ol et  e x p os ur e ( e. g.,  us e  of s u ns cr e e n,  pr ot e cti v e 
cl ot hi n g,  a v oi d s u n b at hi n g  or  usi n g  a s u nl a m p  or t a n ni n g   b e d). 
 
6. 1. 2   
Tr e at m e nt  d ur ati o n 
P ati e nts  m a y  c o nti n u e tr e at m e nt  wit h si n gl e  a g e nt  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2 
u ntil t h e  p ati e nt  e x p eri e n c es  dis e as e  pr o gr essi o n,  d e at h,  u n a c c e pt a bl e t o xi cit y  a n d/ or tr e at m e nt 
is  dis c o nti n u e d  at  t h e  dis cr eti o n  of t h e i n v esti g at or   or t h e  p ati e nt   or  c o ns e nt   wit h dr a w al  as 
d es cri b e d  i n   S e cti o n   7. 1. 4. 1   a n d  S e cti o n   7. 1. 5 .   P ati e nts   w h o   h a v e   dis e a s e   pr o gr essi o n   a n d  
h a v e   e vi d e n c e   of   cli ni c al   b e n efit,  s u c h   as   dis e as e  s hri n k a g e   at   ot h er  sit es   or  s y m p t o m ati c 
i m pr o v e m e nt,   m a y   c o nti n u e  tr e at m e nt   wit h   B Y L 7 1 9,  I N C 2 8 0,   L D K 3 7 8   a n d   M E K 1 6 2.  I n 
a d diti o n,  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2 tr e at m e nt  m a y  b e t e m p or aril y i nt err u pt e d 
t o   p er mit  l o c al  t h er a p y  f or  s y m pt o m ati c   m et ast as es   aft er   dis e as e   pr o gr essi o n   h as   b e en 
d o c u m e nt e d.  P ati e nts  w h o  c o nti n u e  o n tr e at m e nt  aft er  dis e as e  pr o gr essi o n s h o ul d  dis c o nti n u e 
st u d y tr e at m e nt  o n c e t h e y  ar e  n o l o n g er  d eri vi n g  b e n efit  as  ass ess e d  b y t h e  i n v esti g at or. 
 
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  p ati e nts  w h o  d o  n ot t ol er at e t h e  pr ot o c ol -s p e cifi e d  d osi n g s c h e d ul e,  d os e  a dj ust m e nts  ar e 
p er mitt e d  i n   or d er  t o   all o w  t h e   p ati e nt  t o   c o nti n u e  t h e  st u d y  tr e at m e nt.   T h e  f oll o wi n g  
g ui d eli n es  n e e d t o  b e  a p pli e d.  
T h es e  c h a n g es  m ust  b e r e c or d e d  o n t h e  D os a g e  A d mi nistr ati o n  R e c or d  C R F.  
All   d os e   m o difi c ati o ns  s h o ul d   b e   b as e d   o n  t h e   w orst   pr e c e di n g  t o xi cit y.  I n   g e n er al,   e a c h  
p ati e nt is  o nl y  all o w e d  o n e  d os e r e d u cti o n. I n  a d diti o n,  a  p ati e nt s h o ul d  dis c o nti n u e tr e at m e nt 
wit h  st u d y  tr e at m e nt  if,   aft er  tr e at m e nt is  r es u m e d   at   a  l o w er   d os e,  t h e   Gr a d e   3/ 4 t o xi cit y 
r e c urs  wit h t h e s a m e  or  w ors e s e v erit y.   S e c o n d   d os e r e d u cti o ns  m a y  o nl y  b e  all o w e d  aft er 
dis c ussi o n  wit h  N o v artis.  
F or   e a c h   p ati e nt,   o n c e   a   d os e  l e v el  r e d u cti o n   h as   o c c urr e d,  t h e   d os e  l e v el   m a y   n ot   b e  r e - 
es c al at e d  d uri n g s u bs e q u e nt tr e at m e nt  c y cl es  wit h t h e st u d y tr e at m e nts.  
D os e r e d u cti o n l e v els f or st u d y tr e at m e nt  ar e list e d i n  T a bl e  6 - 2.  R e c o m m e n d ati o ns  of  crit eri a 
f or i nt err u pti o n  a n d r e-i niti ati o n  of st u d y tr e at m e nt  c a n  b e f o u n d i n S e cti o n  1 4. 2 . 
If   a   p ati e nt  r e q uir es   a   d os e  i nt err u pti o n   of   >   2 1   d a ys  fr o m  t h e  i nt e n d e d   d a y   of  t h e   n e xt  
s c h e d ul e d  d os e, t h e n t h e  p ati e nt  m ust  b e  dis c o nti n u e d fr o m t h e st u d y.  H o w e v er, if t h e  p ati e nt 
is  cl e arl y  b e n efiti n g fr o m t h e st u d y tr e at m e nt (i. e. st a bl e  dis e as e,  p arti al r es p o ns e,  c o m pl et e 
r es p o ns e),  a n d t h e  A Es  ar e r es ol v e d t o  gr a d e  ≤  1,  a n d,  aft er  dis c ussi o n  a n d  a gr e e m e nt  wit h t h e 
N o v artis  cli ni c al t e a m, t h e  p ati e nt  m a y r e m ai n  o n t h e st u d y tr e at m e nt  at  a  d os e l e v el  a dj ust e d 
b as e d  o n s af et y.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  6 0
9  Pr ot o c ol  N o. 
 
 
 
 
T a bl e   6- 2  
D o s e r e d u cti o n  st e p s f or  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2  
 
St u d y tr e at m e nt   
St arti n g  d o s e l e v el  - 0   
D o s e l e v el  - 1  
D o s e l e v el  -2*  
B Y L 7 1 9  
3 5 0  m g  q d  
3 0 0  m g  q d  
2 5 0  m g  q d  
I N C 2 8 0( c a p s ul e/t a bl et)  
6 0 0  m g  c a p s ul e  bi d/ 
4 0 0 m g t a bl et  bi d  
4 5 0  m g  c a p s ul e  bi d/  3 0 0 m g 
t a bl et  bi d 
3 5 0 m g  c a p s ul e  bi d/ 
2 0 0 m g t a bl et  bi d  
L D K 3 7 8  
7 5 0  m g  q d  
6 0 0  m g  q d  
4 5 0  m g  q d  
M E K 1 6 2  
4 5  m g  bi d  
3 0  m g  bi d  
N ot  all o w e d  
*  m a y  o nl y  b e  all o w e d  aft er  di s c u s si o n  a n d  a gr e e m e nt  wit h  N o v arti s  
 
6. 2. 2   
F oll o w -u p f or  t o xi citi e s 
P ati e nts  w h os e tr e at m e nt is i nt err u pt e d  or  p er m a n e ntl y  dis c o nti n u e d  d u e t o  a n  a d v ers e  e v e nt 
or  cli ni c all y si g nifi c a nt l a b or at or y  v al u e,  m ust  b e f oll o w e d  u p  u ntil  r es ol uti o n  or st a bili z ati o n 
of  t h e   e v e nt,   w hi c h e v er   c o m es  first.   A p pr o pri at e   cli ni c al   e x p erts  s u c h   as   o p ht h al m ol o gist,  
e n d o cri n ol o gist,   d er m at ol o gist,   ps y c hi atrists   et c.  s h o ul d   b e   c o ns ult e d   as   d e e m e d   n e c ess ar y.  
R e c o m m e n d e d   g ui d eli n es  f or  f oll o w   u p   of  s el e c t e d  t o xi citi es   of   e a c h  st u d y  tr e at m e nt   ar e  
pr o vi d e d i n  S e cti o n   1 4. 3. 
 
6. 2. 3   
A nti ci p at e d ri s k s  a n d  s af et y  c o n c er n s  of t h e  st u d y  tr e at m e nt 
A p pr o pri at e  eli gi bilit y  crit eri a  a n d s p e cifi c  d os e  m o difi c ati o n  a n d st o p pi n g r ul es  ar e i n cl u d e d 
i n  t his   pr ot o c ol.   R e c o m m e n d e d   g ui d eli n es  f or   pr o p h yl a cti c   or  s u p p orti v e  tr e at m e nt  f or  
e x p e ct e d  t o xi citi es,  i n cl u di n g   m a n a g e m e nt   of  st u d y -dr u g  i n d u c e d   a d v ers e   e v e nts,  i. e.,  
h y p er gl y c e mi a, s ki n t o xi cit y  a n d  di arr h e a  ar e  pr o vi d e d i n  S e cti o n  1 4. 3 .  T h e ris ks t o  p ati e nts i n 
t his tri al  m a y  b e  mi ni mi z e d  b y  c o m pli a n c e  wit h  eli gi bilit y  crit eri a  a n d st u d y  pr o c e d ur es,  as 
w ell   as,   cl os e  cli ni c al   m o nit ori n g.   T h er e  m a y  b e  u nf or es e e n ris ks  wit h  L D K 3 7 8,   B Y L 7 1 9,  
M E K 1 6 2  a n d I N C 2 8 0  w hi c h  m a y  b e s eri o us.  R ef er t o  pr e cli ni c al t o xi cit y  a n d/ or  cli ni c al  d at a 
i n t h e [I n v esti g at or’s  Br o c h ur e]. 
 
6. 3  
C o n c o mit a nt  m e di c ati o n s 
6. 3. 1   
P er mitt e d  c o n c o mit a nt t h er a p y  
P ati e nts  ar e  p er mitt e d t o  us e t h e f oll o wi n g  m e di c ati o ns  w hil e t a ki n g t h e st u d y  dr u gs,  e x c e pt 
w h e n s p e cifi c all y  pr o hi bit e d (s e e  S e cti o n  6. 3. 3 ): 
•   Or al  or t o pi c al  a nti bi oti cs  
•   M e di c ati o ns t o  pr e v e nt  or tr e at  n a us e a  or  v o miti n g  
•   A nti -di arr h e al  m e di c ati o ns ( e. g., l o p er a mi d e) f or s u bj e cts  w h o  d e v el o p  di arr h e a.  
B Y L 7 1 9  
T h e  us e  of  bis p h os p h o n at es/ d e n os u m a b r e g ar dl ess  of i n di c ati o n is  all o w e d  pr o vi d e d  p ati e nts 
h a v e  b e e n  o n st a bl e  d os es f or  at l e ast  2  w e e ks  pri or t o r a n d o mi z ati o n.  St a bl e  d os e s h o ul d  b e 
m ai nt ai n e d 
  d uri n g 
 t h e 
 tr e at m e nt 
  p eri o d. 
  P ati e nts 
 r e q uiri n g 
 i niti ati o n 
  of 
 
bis p h os p h o n at es/ d e n os u m a b   d uri n g  t h e   c o urs e   of  t h e  st u d y  s h o ul d   b e   dis c o nti n u e d   d u e  t o  
pr o gr essi v e  dis e as e  u nl ess  dis e as e  pr o gr essi o n  c a n  b e  c o m pl et el y r ul e d  o ut  a n d t his is  cl e arl y 
d o c u m e nt e d i n t h e  p ati e nts’ s o ur c e  d o c u m e nt ati o n.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  6 1
9  Pr ot o c ol  N o. 
 
 
 
P ati e nts  w h o  d e v el o p  di a b et es  m ellit us  d uri n g t h e st u d y s h o ul d  b e tr e at e d  a c c or di n g t o t h e 
A D A ( A m eri c a n  Di a b et es  Ass o ci ati o n)  g ui d a n c e. It is r e c o m m e n d e d t o st art tr e at m e nt  wit h 
m etf or mi n.   P ati e nts  r e c ei vi n g   or al   a nti di a b eti cs   w hi c h   ar e   pr e d o mi n a ntl y   m et a b oli z e d   b y  
C Y P 2 C 9  a n d  C Y P 2 C 8, i n cl u di n g  b ut  n ot li mit e d t o, r e p a gli ni d e, r osi glit a z o n e,  gli pi zi d e  a n d 
t ol b ut a mi d e,  s h o ul d   b e   m o nit or e d  f or   h y p o gl y c e mi a   as   B Y L 7 1 9   w as  f o u n d  t o   b e   w e a k  
r e v ersi bl e i n hi bit or  of t h es e  e n z y m es i n  vitr o. 
H e m at o p oi eti c   gr o wt h  f a ct ors   m a y   b e   us e d   a c c or di n g  t o   A m eri c a n   S o ci et y   of   Cli ni c al  
O n c ol o g y ( A S C O)  g ui d eli n es.  
B Y L 7 1 9  is   c h ar a ct eri z e d   b y   a   p H -d e p e n d e nt  s ol u bilit y.   T h er ef or e   a ci d  r e d u ci n g   a g e nts  
( A R As,  e. g.  pr ot o n-p u m p i n hi bit ors,  H 2 -a nt a g o nists  a n d  a nt a ci ds)  m a y  alt er t h e s ol u bi lit y  of 
B Y L 7 1 9   a n d   h e n c e  its   bi o a v ail a bilit y.   A   dr u g -dr u g  i nt er a cti o n  st u d y  i n   h u m a n   h e alt h y  
v ol u nt e ers   c o nfir m e d  t h at   c o -a d mi nistr ati o n   of   B Y L 7 1 9   wit h  t h e   H 2 -a nt a g o nist  r a niti di n e  
aft er  a    m e al  l e a d  t o  a  d e cr e as e  i n  e x p os ur e  b y  o nl y  ~ 2 0 %,  c o nsi d er e d  t o  b e  n ot  cli ni c all y 
r el e v a nt.  H e n c e  B Y L 7 1 9  c a n  b e  c o-a d mi nist er e d  wit h  a n y  A R As.  
C hr o ni c  d osi n g  of  hi g h l e v els  of  c orti c ost er oi ds s u c h  as  d e x a m et h as o n e  a n d  pr e d nis o n e  m a y 
pr ol o n g  or  a g gr a v at e  h y p er gl y c e mi a (st er oi d -i n d u c e d  di a b et es).  H y p er gl y c e mi a is  a  c o m m o n 
a d v ers e  e v e nt f or  PI 3 K i n hi bit ors li k e  B Y L 7 1 9  a n d s h o ul d t h er ef or e  b e  us e d  wit h  c a uti o n  a n d 
p ati e nts  cl os el y  m o nit or e d.  
 
I N C 2 8 0  ar m 
T h e   us e   of   P PIs   a n d   ot h er   a ci d  r e d u ci n g   a g e nts  ( g astri c   a ci d   m o d ul at ors   a n d   H 2  r e c e pt or  
a nt a g o nists) is  all o w e d.  
 
L D K 3 7 8  ar m  
T h e  us e  of  bis p h os p h o n at es i s  all o w e d r e g ar dl ess  of i n di c ati o n  pr o vi d e d  p ati e nts  h a v e  b e e n  o n 
st a bl e  d os es  o pti m all y f or  at l e ast  4  w e e ks  pri or t o t h e st art  of tr e at m e nt.  P ati e nts r e q uiri n g 
i niti ati o n  of  bis p h os p h o n at e tr e at m e nt  d uri n g t h e  c o urs e  of t h e st u d y s h o ul d  b e  e v al u at e d f or 
pr o gr essi v e   dis e as e   a n d  t h e  r es ult   of  t h e   e v al u ati o n  s h o ul d   b e   cl e arl y   d o c u m e nt e d  i n  t h e  
p ati e nts’ s o ur c e  d o c u m e nt ati o n.  N o  dr u g -dr u g i nt er a cti o n is  e x p e ct e d  b et w e e n  L D K 3 7 8  a n d 
bis p h os p h o n at es   a s  t h e  t w o   dr u gs   ar e   eli mi n at e d  t hr o u g h   diff er e nt   eli mi n ati o n   p at h w a ys.  
Bis p h os p h o n at e s  ar e  n ot i n hi bit ors  of  h u m a n  C Y P 4 5 0  e n z y m es i n v ol v e d i n t h e  m et a b olis m  of 
L D K 3 7 8  a n d  d o  n ot   u n d er g o  m et a b olis m   i n  vi v o.   T h e s a m e  g ui d eli n es  a p pl y t o t h e  us e  of 
d e n os u m a b f or t h e tr e at m e nt  of  b o n e  m et ast at i c  dis e as e. 
N o n -e n z y m e i n d u ci n g  a nti -e pil e pti c  m e di c ati o n ( N o n -EI A E D) is  all o w e d.  
T h e  p ati e nt  m ust  b e t ol d t o  n otif y t h e i n v esti g ati o n al sit e  a b o ut  a n y  n e w  m e di c ati o n s  h e/s h e 
t a k es  aft er t h e st art  of t h e st u d y  dr u gs.  All  m e di c ati o ns ( ot h er t h a n st u d y  dr u g) a n d si g nifi c a nt 
n o n- dr u g  t h er a pi es  (i n cl u di n g   p h ysi c al  t h er a p y,   h er b al/ n at ur al   m e di c ati o ns,   a n d   bl o o d  
tr a nsf usi o ns)  a d mi nist er e d  d uri n g t h e st u d y  m ust  b e list e d  o n t h e  C o n c o mit a nt  M e di c ati o ns 
e C R F  or t h e  Pr o c e d ur es  a n d  Si g nifi c a nt  N o n -Dr u g  T h er a pi es  e C R F,  r es p e cti v el y. 
 
6. 3. 2   
P er mitt e d  c o n c o mit a nt t h er a p y r e q uiri n g  c a uti o n  a n d/ or  a cti o n  
R ef er t o  S e cti o n  1 4. 4 , T a bl e  1 4 - 1 3 f or  a list  of t h e  m e di c ati o ns t h at r e q uir e  c a uti o n  w h e n 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  6 2
9  Pr ot o c ol  N o. 
 
 
 
c o n c o mit a ntl y   us e d   wit h   B Y L 7 1 9,  I N C 2 8 0,   L D K 3 7 8   or   M E K 1 6 2.  If   a  p ati e nt  r e q uir es  t h e 
c o n c o mit a nt   us e  of   a n y  m e di c ati o n  wit h  a  p ossi bl e  or   c o n diti o n al  ris k f or  Q T   pr ol o n g ati o n 
a n d/ or t ors a d e  d e  p oi nts ( R ef er t o  S e cti o n  1 4. 4 , T a bl e  1 4 - 1 5)  as  p er  dis cr eti o n  of i n v esti g at ors, 
t h es e  m e di c ati o ns  m a y  b e  all o w e d  h o w e v er  m ust  b e  m o nit or e d. 
H er b al  pr e p ar ati o ns/ m e di c ati o ns  ar e  n ot  e n c o ur a g e d t hr o u g h o ut t h e st u d y,  as  a  p ot e nti al  dr u g - 
dr u g i nt er a cti o n is  al w a ys  p ossi bl e.  
 
B Y L 7 1 9  ar m  
B Y L 7 1 9  is   a   p ot e nt   a n d  ti m e   d e p e n d e nt   C Y P 3 A 4/ 5  i n hi bit or   a n d   m o d er at e  i n hi bit or   of  
C Y P 2 C 8  a n d  C Y P 2 C 9  i n  vitr o.  C o n c o mit a nt  m e di c ati o ns t h at  ar e s e nsiti v e s u bstr at es  of t h es e 
e n z y m es ( e x c e pt t h os e  ar e  pr o hi bit e d  as st at e d i n  S e cti o n  6. 3. 3 ) s h all  b e  us e d  wit h  c a uti o n. I n 
vitr o  st u di es  s h o w e d  t h at    C Y P 3 A 4  is  t h e    m aj or  e n z y m e  i n v ol v e d  ( 9 2 %)  i n  t h e  pri m ar y 
o xi d ati v e   m et a b olis m   of   B Y L 7 1 9  i n   h u m a n  li v er   mi cr os o m es.   S e nsiti v e  s u bstr at es  f or  
C Y P 3 A 4,  C Y P 2 C 8  or  C Y P 2 C 9  a n d/ or  w hi c h  h a v e  a  n arr o w t h er a p e uti c i n d e x s h all t h e n  b e 
us e d  wit h  c a uti o n.  
 
B Y L 7 1 9  w as i d e ntifi e d  as  a s u bstr at e f or t h e  h u m a n  B C R P.   C o -a d mi nistr ati o n  of  B Y L 7 1 9 
wit h   B C R P  i n hi b it ors   m a y  i n cr e as e  s yst e mi c   e x p os ur e   a n d/ or   alt er  tiss u e   u pt a k e   of   or al  
B Y L 7 1 9  a n d s h o ul d t h er ef or e  b e  us e d  wit h  c a uti o n.  
T h er a p e uti c   d os es   of   w arf ari n  s o di u m  ( C o u m a di n ®)   or   a n y   ot h er   c o u m ari n -d eri v ati v e 
a nti c o a g ul a nts s h o ul d  b e  us e d  wit h  c a uti o n  a n d f ull y  a v oi d e d  w h e n e v er  p ossi bl e  b e c a us e  of its 
k n o w n i nt er a cti o n  wit h  m a n y  c o m m o nl y  us e d  m e di c ati o ns  a n d  c ert ai n f o o ds.  Alt er n ati v el y, 
t h er a p e uti c   a nti c o a g ul ati o n   m a y   b e   a c c o m plis h e d   usi n g  l o w-m ol e c ul ar   w ei g ht   h e p ari n   or  
Dir e ct  T hr o m bi n i n hi bit ors ( D TIs)  a n d  F a ct or  X a i n hi bit ors.  
L o c al r a di ot h er a p y f or  a n al g esi c  p ur p os es  or f or l yti c l esi o ns  at ris k  of fr a ct ur e  m a y  b e  c arri e d 
o ut  if  r e q uir e d.   W h e n e v er   p ossi bl e,  t h es e   p ati e nts  s h o ul d   h a v e   a  t u m or   ass ess m e nt   of  t h e  
l esi o n(s)   b ef or e  t h e y   a ct u all y  r e c ei v e  t h e  r a di oth er a p y  i n   or d er  t o  r ul e   o ut   pr o gr essi o n   of  
dis e as e.  I n   c as e   of   Pr o gr essi v e   Dis e a s e,   p ati e nts  s h o ul d   dis c o nti n u e  tr e at m e nt.   N o   d os e  
m o difi c ati o n  of st u d y tr e at m e nt is  n e e d e d  d uri n g r a di ot h er a p y.  
 
I N C 2 8 0  ar m 
M e di c ati o ns t h at  ar e  m o d er at e i n d u c ers  or i n hi bit ors  of  C Y P 3 A 4  ar e  n ot  pr o hi bit e d  b ut s h o ul d 
b e  a d mi nist er e d  wit h  c a uti o n.  S e nsiti v e s u bstr at es f or  C Y P 3 A 4,  C Y P 1 A 2,  C Y P 2 C 8,  C Y P 2 C 9 
a n d  C Y P 2 C 1 9,  e x c e pt t h os e  wit h  n arr o w t h er a p e uti c  wi n d o w  w hi c h  ar e  pr o hi bit e d, s h o ul d  b e 
a d mi nist er e d   wit h   c a uti o n.   S e nsiti v e  s u bstr at es  f or   P -g p,   B C R P,   M A T E   a n d   O A T P  
tr a ns p ort ers s h o ul d  als o  b e  a d mi nist er e d  wit h  c a uti o n. 
 
L D K 3 7 8  ar m  
L D K 3 7 8 is  a ti m e -d e p e n d e nt  C Y P 3 A 4/ 5 i n hi bit or  a n d is  als o  a  p ot e nt r e v ersi bl e i n hi bit or  of 
C Y P 2 A 6,  C Y P 2 E 1,   C Y P 2 C 9   a n d   C Y P 3 A 4/ 5.   C o n c o mit a nt   m e di c ati o ns  t h at   ar e  s e nsiti v e  
s u bstr at es    of   t h es e     e n z y m es    ( e x c e pt    t h os e     ar e     pr o hi bit e d     as    st at e d    i n   
S e cti o n  6. 3. 3 )  s h all  b e us e d  wit h  c a uti o n.  M et a b olis m   of L D K 3 7 8  is pri m aril y  m e di at e d  b y  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  6 3
9  Pr ot o c ol  N o. 
 
 
 
C Y P 3 A 4/ 5  i n  vitr o.  C o n c o mit a nt tr e at m e nt  of  L D K 3 7 8  wit h  w e a k i n hi bit ors  or  w e a k i n d u c ers 
of   C Y P 3 A 4/ 5 is  p er mitt e d.  C a uti o n s h o ul d  b e  us e d  w h e n  L D K 3 7 8 is  c o -a d mi nist er e d  wit h 
m o d er at e i n hi bit ors  or i n d u c ers.  D ur ati o n  of t h es e  c o n c o mit a nt tr e at m e nts s h o ul d  b e  k e pt  as 
s h ort  as  p ossi bl e ( e. g., l ess t h a n  1  w e e k)  or  a v oi d e d  w h e n e v er  p ossi bl e.  
C hr o ni c  d osi n g  of  c orti c ost er oi ds s u c h  as  d e x a m et h as o n e  a n d  pr e d nis o n e is  k n o w n t o i n d u c e 
C Y P 3 A   e n z y m es,  t h er e b y  i n cr e asi n g  t h e  ris k   of  r e d u ci n g   L D K 3 7 8   dr u g   e x p os ur e  t o  s u b - 
t h er a p e uti c l e v els. If  p ossi bl e, s yst e mi c  c orti c ost er oi d tr e at m e nt s h o ul d  n ot  b e  gi v e n  d uri n g 
t h e st u d y,  e x c e pt f or: 
•   T o pi c al  a p pli c ati o ns ( e. g., r as h), i n h al e d s pr a ys ( e. g.,  o bstr u cti v e  air w a ys  dis e as es),  e y e 
dr o ps  or l o c al i nj e cti o ns ( e. g.,  i ntr a-arti c ul ar);  
•   St a bl e   d os es  of c orti c ost er oi d  t h er a p y s u c h as   d e x a m et h as o n e a n d   pr e d nis o n e ( e. g., f or 
t u m or  ass o ci at e d s y m pt o ms)  ar e  p er mitt e d  d uri n g t h e  c o urs e  of t h e st u d y.  T h e 
c orti c ost er oi d  d os e  m ust  h a v e  b e e n st a bili z e d ( or  d e cr e asi n g) f or  at l e ast  5  d a ys  b ef or e 
i niti ati o n  of st u d y t h er a p y. 
L o c al r a di ot h er a p y f or  a n al g esi c  p ur p os es  or f or l yti c l esi o ns  at ris k  of fr a ct ur e  m a y  b e  c arri e d 
o ut if r e q uir e d. If  p alli ati v e r a di ot h er a p y is i niti at e d  aft er st art  of st u d y tr e at m e nt, t h e r e as o n 
f or its  us e  m ust  b e  cl e arl y  d o c u m e nt e d  a n d  pr o gr essi o n  as  p er  R E CI S T  1. 1  m ust  b e  ass ess e d 
a n d   d o c u m e nt e d.   P ati e nts   w h o   d e v el o p   pr o gr essi v e   dis e a s e   b ut   ar e  still   d eri vi n g   cli ni c al  
b e n efit fr o m  L D K 3 7 8 t h er a p y,  as  d et er mi n e d  b y t h e I n v esti g at or  m a y  u n d er g o r a di ot h er a p y 
a n d/ or  s ur gi c al r es e cti o n   as  p all i ati v e l o c ali z e d t h er a p y t o tr e at  m et ast ati c l esi o ns.   L D K 3 7 8 
s h o ul d  b e  h el d f or  at l e ast  4  d a ys  pri or t o r a di ot h er a p y  a n d  at l e ast  1  d a y  pri or t o  a n y s ur g er y. 
L D K 3 7 8    m a y  b e  r es u m e d  ≥ 3  d a ys  aft er  c o m pl eti n g  r a di ot h er a p y  or    mi n or  s ur g er y,  a n d  ≥ 2 
w e e ks  aft er  m aj or s ur g er y.  
T h e  us e  of  g astri c  pr ot e cti o n  a g e nts i n cl u di n g  a nt a ci ds,  H 2 -a nt a g o nists,  a n d  P PIs is  all o w e d. 
H o w e v er,  P PIs s h o ul d  b e  us e d  wit h  c a uti o n  d u e t o t h e t h e or eti c al  eff e cts  of l o n g -a cti n g  p H 
el e v ati n g  a g e nts (i. e.,  pr ol o n g e d  a ci d s u p pr essi o n)  o n r e d u ci n g  L D K 3 7 8  a bs or pti o n.  W h e n t h e 
c o n c urr e nt  us e  of  a  H 2 -a nt a g o nist  or  a n  a nt a ci d  wit h  L D K 3 7 8 is  n e c ess ar y, t h e  H 2  bl o c k er 
m ust  b e  a d mi nist er e d  1 0  h o urs  b ef or e  or  2  h o urs  aft er t h e  L D K 3 7 8  d os e,  a n d t h e  a nt a ci d  m ust 
b e  a d mi nist er e d  2  h o urs  b ef or e  or  2  h o urs  aft er t h e  L D K 3 7 8  d os e.  Ti m e r estri cti o ns f or t h e 
c o n c urr e nt  us e  of  P PIs  a n d  L D K 3 7 8  ar e  n ot  a p pli c a bl e  d u e t o t h e l o n g -a cti n g  eff e cts  of  P PIs 
o n  g astri c  p H (i. e., s e p ar ati o n  of  d os es  will  n ot li k el y i m p a ct t his i nt er a cti o n).  
 
M E K 1 6 2  ar m  
M E K 1 6 2 is  a  p ot e nt i n hi bit or  of  C Y P 2 B 6 ( Ki  of  1. 6 7  μ M)  i n  vitr o.  C o n c o mit a nt  m e di c ati o ns 
t h at  ar e s e nsiti v e s u bstr at e s  of  C Y P 2 B 6 s h all  b e  us e d  wit h  c a uti o n.  M E K 1 6 2 is  a  p ot e nti al 
i n d u c er  of  C Y P 3 A 4  m R N A  a n d  a cti vit y i n  vitr o.  C a uti o n s h o ul d  b e  us e d i n  p ati e nts r e c ei vi n g 
c o n c o mit a nt   m e di c ati o ns  t h at   ar e  s e n siti v e  s u bstr at es   of   C Y P 3 A 4   as  t h e   effi c a c y   of  t h es e  
dr u gs  c o ul d  b e r e d u c e d  w h e n  a d mi nist er e d  wit h   M E K 1 6 2. 
M E K 1 6 2  h as  b e e n i d e ntifi e d t o  b e  pri m aril y  m et a b oli z e d  b y  U G T 1 A 1 i n  vitr o. It is  a d vis e d 
t h at i n hi bit ors  a n d i n d u c ers  of  U G T 1 A 1 s h o ul d  b e t a k e n  wit h  c a uti o n  w h e n  c o-a d mi nist er e d 
wit h  M E K 1 6 2.  P ati e nts s h o ul d  b e  cl os el y  m o nit or e d f or t h e  o c c urr e n c e  of  a d v ers e  e v e nts.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  6 4
9  Pr ot o c ol  N o. 
 
 
 
T h e s ol u bilit y  of  M E K 1 6 2 is  p H  d e p e n d e nt  a n d  a  1 0 -f ol d  d e cr e as e i n s ol u bilit y is  o bs er v e d 
b et w e e n  p H  1  a n d  2.  S h ort  a cti n g  g astri c  a ci d  m o d ul at ors  c a n  b e t a k e n,  at l e ast  3  h o urs  b ef or e 
or  3  h o urs  aft er  M E K 1 6 2  a d mi nistr ati o n.  H 2 r e c e pt or  a nt a g o nists s h o ul d  b e  a v oi d e d.  
If  H 2 r e c e pt or  a nt a g o nists  ar e  us e d  d uri n g t h e  c o urs e  of t his st u d y,  M E K 1 6 2 s h all  b e t a k e n  at 
l e ast   2   h o urs   b ef or e   or   8   h o urs   aft er   H 2  r e c e pt or   a nt a g o nists.  I n   vitr o  d at a  s h o w e d  t h at  
M E K 1 6 2 is  a s u bstr at e  of  P -g p  a n d  B C R P  wit h  m o d er at e t o  hi g h  p er m e a bilit y  a n d t h us t h e 
us e  of  dr u gs t h at  ar e  p ot e nt i n hi bit ors  of t h es e  tr a ns p ort ers  m a y  b e  us e d  wit h  c a uti o n.  Pl e as e 
r ef er t o S e cti o n  1 4. 4 , T a bl e  1 4 - 1 3 f or  a list  of t h es e  dr u gs. 
 
6. 3. 3   
Pr o hi bit e d  c o n c o mit a nt  t h er a p y 
Dr u gs  wit h  k n o w n ris k  of  c a usi n g  T d P  ar e  pr o hi bit e d (r ef er t o  S e cti o n  1 4. 4 , T a bl e  1 4 - 1 5). 
St u d y  tr e at m e nt   m ust   b e  i nt err u pt e d   as  l o n g   as  t h e   p ati e nt  r e q uir es  t h er a p y   wit h   Q T  
pr ol o n gi n g  a g e nt.  
O t h er i n v esti g ati o n al t h er a pi es  m ust  n ot  b e  us e d  w hil e t h e  p ati e nt is  o n t h e st u d y. 
A nti c a n c er  t h er a p y  ( c h e m ot h er a p y,  t ar g et e d  t h er a p y,   bi ol o gi c  t h er a p y,  r a di ati o n  t h er a p y   or  
a nti -c a n c er  s ur g er y  [ e x c e pt   p alli ati v e  r a di ot h er a p y   a n d   p alli ati v e  s ur gi c al   as   d es cri b e d  i n  
S e cti o n  6. 3. 2 ]),  ot h er t h a n t h e st u d y tr e at m e nt,  m ust  n ot  b e  gi v e n t o  p ati e nts  w hil e t h e y  ar e 
e nr oll e d i n t h e tr e at m e nt  p orti o n  of t h e tri al. If s u c h  a g e nts  ar e r e q uir e d t h e n t h e  p ati e nt  m ust 
b e  p er m a n e ntl y  dis c o nti n u e d fr o m t h e tr e at m e nt  p orti o n  of t h e st u d y.  
H er b al  pr e p ar ati o ns/ m e di c ati o ns f or  dis e as e tr e at m e nt  ar e  n ot  all o w e d t hr o u g h o ut t h e st u d y. 
P ati e nts  s h o ul d  st o p   usi n g   h er b al   m e di c ati o ns   at  l e ast   7   d a ys   pri or  t o  first   d os e   of  st u d y  
tr e at m e nt. 
Ot h er   pr o hi bit e d   c o n c o mit a nt  t h er a p y  is  list e d  i n   S e cti o n   1 4. 4 ,  T a bl e   1 4 - 1 4  a n d  s p e cifi e d  
b el o w f or  e a c h tr e at m e nt  ar m.  
 
B Y L 7 1 9  ar m  
B Y L 7 1 9  is   a   p ot e nt   a n d  ti m e   d e p e n d e nt   C Y P 3 A 4/ 5  i n hi bit or   a n d   m o d er at e  i n hi bit or   of  
C Y P 2 C 8  a n d  C Y P 2 C 9  i n  vitr o.  C o n c o mit a nt  m e di c ati o ns t h at  ar e s e nsiti v e s u bstr at es  of t h es e 
e n z y m es   a n d   h a v e   n arr o w  t h er a p e uti c  i n d e x   ar e   pr o hi bit e d.   I n   vitr o  st u di es  s h o w e d  t h at  
C Y P 3 A 4  is  t h e    m aj or   e n z y m e  i n v ol v e d  ( 9 2 %)  i n  t h e   pri m ar y  o xi d ati v e   m et a b olis m   of  
B Y L 7 1 9  i n   h u m a n  li v er   mi cr os o m es.   Str o n g  i n hi bit ors   a n d  i n d u c ers   of   C Y P 3 A 4/ 5   ar e  
pr o hi bit e d. 
 
I N C 2 8 0  ar m 
I N C 2 8 0  is   m o d er at el y   m et a b oli z e d   b y   C Y P 3 A 4  i n   vitr o.  Str o n g  i n hi bit ors   or  i n d u c ers   of  
C Y P 3 A 4/ 5  ar e  pr o hi bit e d  d uri n g t h e  c o urs e  of t h e st u d y. I N C 2 8 0 is  a n irr e v ersi bl e i n hi bit or  
of  C Y P 1 A 2 a n d  C Y P 3 A 4.  All  a g e nts t h at  ar e  m et a b oli z e d  m ai nl y  b y  C Y P 1 A 2  or  C Y P 3 A 4/ 5 
a n d  h a v e  a  n arr o w t h er a p e uti c i n d e x  ar e  pr o hi bit e d  d uri n g t his  st u d y. 
 
L D K 3 7 8  ar m  
I n  vitr o m et a b olis m st u di es s u g g e st t h at  o xi d ati v e  m et a b olis m  of  L D K 3 7 8 is  pr e d o mi n a ntl y 
m e di at e d  b y  C Y P 3 A 4/ 5.  Str o n g i n hi bit ors  or i n d u c ers  of  C Y P 3 A 4/ 5  ar e  pr o hi bit e d.  P ati e nts  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  6 5
9  Pr ot o c ol  N o. 
 
 
 
r e c ei vi n g  c o n c o mit a nt  m e di c ati o ns  k n o w n t o str o n gl y i n hi bit   a n d/ or i n d u c e  C Y P 3 A 4/ 5 t h at 
ar e  d e e m e d  m e di c all y  n e c ess ar y s h o ul d  b e  e x cl u d e d fr o m t h e  st u d y. 
L D K 3 7 8  is   a   p ot e nt  i n hi bit or   of   dr u gs   m et a b oli z e d   b y  t h e   c yt o c hr o m es   C Y P 2 C 9   a n d  
C Y P 3 A 4/ 5  i n   vitr o.   C o n c o mit a nt   m e di c ati o ns   k n o w n  t o   b e   m ai nl y   m et a b oli z e d   b y  t h es e  
e n z y m es  a n d  h a vi n g  a l o w t h er a p e uti c i n d e x  ar e  pr o hi bit e d i n t h e st u d y.  T h er a p e uti c  d os es  of 
w arf ari n s o di u m  or  a n y  ot h er  c o u m ari n -d eri v ati v e  a nti c o a g ul a nts  ar e  n ot  p er mitt e d.  L D K 3 7 8 
is  a n in hi bit or  of  C Y P 2 C 9, t h e  m aj or  m et a b oli zi n g  e n z y m e  of  w arf ari n.  A  cli ni c all y r el e v a nt 
i n cr e as e i n  w arf ari n  e x p os ur e is  p ossi bl e. 
Us e  of  EI A E Ds is  n ot  p er mitt e d. If  a  p ati e nt is  c urr e ntl y t a ki n g  a n  EI A E D,  h e/s h e  m ust  h a v e 
dis c o nti n u e d t h e  EI A E D t h er a p y f or  at l e ast  1  w e e k  pri or t o st arti n g st u d y  dr u g. If  a  p ati e nt 
w as  pr e vi o usl y  o n  a  n o n -EI A E D  a n d  n e e ds t o  p er m a n e ntl y  c h a n g e  a nti c o n v uls a nt  a g e nt  b ut 
c a n n ot  c h a n g e t o  a n ot h er  n o n -EI A E D, t h e  p ati e nt  will  b e t a k e n  off  L D K 3 7 8.  
 
M E K 1 6 2  ar m  
T h e  s ol u bilit y   of   M E K 1 6 2  is   p H   d e p e n d e nt.   L o n g -a cti n g   pr ot o n   p u m p  i n hi bit ors   ar e  
pr o hi bit e d  a n d  m ust  b e  dis c o nti n u e d  at l e ast  3  d a ys  pri or t o t h e first  d os e  of st u d y  tr e at m e 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  
E a c h  p ati e nt is i d e ntifi e d i n t h e st u d y  b y  a  S u bj e ct   N u m b er  ( S u bj e ct  N o.), t h at is  assi g n e d 
w h e n t h e  p ati e nt is first  e nr oll e d f or  pr e -s cr e e ni n g  a n d is r et ai n e d  as t h e  pri m ar y i d e ntifi er f or 
t h e  p ati e nt t hr o u g h o ut  his/ h er  e ntir e  p arti ci p ati o n i n t h e tri al.  T h e  S u bj e ct  N o.  c o nsists  of t h e 
C e nt er   N u m b er  ( C e nt er   N o.)  ( as   assi g n e d   b y   N o v artis  t o  t h e  i n v esti g ati v e  sit e)   wit h   a  
s e q u e nti al  p ati e nt  n u m b er s uffi x e d t o it, s o t h at  e a c h s u bj e ct is  n u m b er e d  u ni q u el y  a cr oss t h e 
e ntir e  d at a b as e.  U p o n si g ni n g t h e  pr e -s cr e e nin g I nf or m e d  C o ns e nt, t h e  p ati e nt is  assi g n e d t o 
t h e  n e xt s e q u e nti al  S u bj e ct  N o.  a v ail a bl e t o t h e i n v esti g at or t hr o u g h t h e  Or a cl e  cli ni c al  R D C 
i nt erf a c e. 
 
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 
A p pr o xi m at el y   2 0 -2 5   p ati e nts   will   b e   assi g n e d  t o   e a c h  tr e at m e nt   ar m   a c c or di n g  t o  t h eir  
c h ar a ct eri z e d  m ol e c ul ar  alt er ati o n.  
 
6. 4. 3   
Tr e at m e nt  bli n di n g  
N ot  a p pli c a bl e.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  6 6
9  Pr ot o c ol  N o. 
 
 
 
 
6. 5  
St u d y tr e at m e nt  pr e p ar ati o n  a n d  di s p e n s ati o n 
T h e i n v esti g at or  or r es p o nsi bl e sit e  p ers o n n el  m ust i nstr u ct t h e  p ati e nt  or  c ar e gi v er t o t a k e t h e 
st u d y  tr e at m e nts   as   p er   pr ot o c ol.   St u d y  tr e at m e nt(s)   will   b e   dis p e ns e d  t o  t h e   p ati e nt   b y  
a ut h ori z e d  sit e   p ers o n n el   o nl y.   All   d os a g es   pr es cri b e d  t o  t h e   p ati e nt   a n d   all   d os e   c h a n g es  
d uri n g t h e st u d y  m ust  b e r e c or d e d  o n t h e  D os a g e  A d mi nistr ati o n  R e c or d  C R F.  
 
B Y L 7 1 9/I N C 2 8 0/ L D K 3 7 8/ M E K 1 6 2  ar m  
St u d y tr e at m e nt i n cl u di n g i nstr u cti o ns f or  a d mi nistr ati o n  ar e  dis p e ns e d  b y st u d y  p ers o n n el  o n 
d a y  1  of  e a c h  c y cl e.  P ati e nts  wi ll  b e  pr o vi d e d  wit h  a d e q u at e s u p pl y  of st u d y tr e at m e nts. 
 
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 h e  st u d y   m e di c ati o n   p a c k a gi n g   h as   a   2 -p art  l a b el  f or   B Y L 7 1 9,  I N C 2 8 0,   L D K 3 7 8   a n d  
M E K 1 6 2.  Sit e  p ers o n n el  will  a d d t h e  p ati e nt  n u m b er  o n t h e l a b el.  
I m m e di at el y  bef or e  dis p e nsi n g t h e  p a c k a g e t o t h e  p ati e nt, sit e  p ers o n n el  will  d et a c h t h e  o ut er 
p art  of t h e l a b el fr o m t h e  p a c k a gi n g  a n d  affi x it t o t h e s o ur c e  d o c u m e nt ( Dr u g  L a b el  F or m)  
f or t h at  p ati e nt’s  u ni q u e  p ati e nt  n u m b er. 
M e di c ati o n l a b els  will  b e i n t h e l o c al l a n g u a g e  a n d  c o m pl y  wit h t h e l e g al  r e q uir e m e nts  of  
e a c h  c o u ntr y.  T h e y  will i n cl u d e st or a g e  c o n diti o ns f or t h e   dr u g. 
 
6. 5. 2   
Dr u g  s u p pl y  a n d  st or a g e  
St u d y  tr e at m e nts   m ust   b e  r e c ei v e d   b y   d esi g n at e d   p ers o n n el   at  t h e  st u d y  sit e,   h a n dl e d   a n d  
st or e d s af el y  a n d  pr o p erl y,  a n d  k e pt i n  a s e c ur e d l o c ati o n t o  w hi c h  o nl y t h e i n v esti g at or  a n d 
d esi g n at e d  sit e   p ers o n n el   h a v e   a c c e ss.   U p o n  r e c ei pt,  t h e  st u d y  tr e at m e nt  s h o ul d   b e  st or e d  
a c c or di n g t o t h e i nstr u cti o ns s p e cifi e d  o n t h e  dr u g l a b els  a n d i n t h e [I n v esti g at or’s  Br o c h ur e].  
 
T a bl e   6- 3  
S u p pl y  a n d  st or a g e  of  st u d y  tr e at m e nt s 
 
St u d y tr e at m e nt s   
D o s e s t o  b e  s u p pli e d  
St or a g e r e q uir e m e nt  
B Y L 7 1 9  
2 0 0 m g,  5 0 m g  T a bl et s  
R ef er t o t h e l a b el  of t h e  cli ni c al 
s u p pli e s f or  e x pir ati o n  d at e  a n d 
pr o p er  st or a g e  c o n diti o n s  
I N C 2 8 0 
5 0 m g  C a p s ul e s /  2 0 0  m g,  1 0 0  m g*,  1 5 0  m g*,  5 0  m g 
T a bl et s  
D o  n ot  st or e  a b o v e  2 5° C  
L D K 3 7 8  
1 5 0 m g  C a p s ul e s  
D o  n ot  st or e  a b o v e  2 5 ° C  
M E K 1 6 2  
1 5 m g  T a bl et s  
D o  n ot  st or e  a b o v e  2 5° C 
Pr ot e ct fr o m li g ht  
* T h e I N C 2 8 0  1 0 0 m g t a bl et  a n d  1 5 0  m g t a bl et  u s a g e  will  d e p e n d  o n t h e  a v ail a bilit y  of  dr u g  s u p pli e s  a n d f oll o w  b y 
r e g ul at or y r e q uir e m e nt. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  6 7
9  Pr ot o c ol  N o. 
 
 
 
 
6. 5. 3   
St u d y tr e at m e nt  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 tr e at m e nt  c o m pli a n c e  
C o m pli a n c e  will  b e  ass ess e d  b y t h e i n v esti g at or  a n d/ or st u d y  p ers o n n el  at  e a c h  p ati e nt  visit 
a n d  i nf or m ati o n   pr o vi d e d   b y  t h e   p ati e nt   a n d/ or   c ar e gi v er   will   b e   c a pt ur e d  i n  t h e   Dr u g  
A c c o u nt a bilit y   F or m.   T his  i nf or m ati o n   m ust   b e   c a pt ur e d  i n  t h e  s o ur c e   d o c u m e nt   at   e a c h  
p ati e nt  visit.  
 
6. 5. 3. 2   St u d y tr e at m e nt  a c c o u nt a bilit y  
T h e i n v esti g at or  or  d esi g n e e  m ust  m ai nt ai n  a n  a c c ur at e r e c or d  of t h e s hi p m e nt  a n d  dis p e nsi n g 
of st u d y tr e at m e nt i n  a  dr u g  a c c o u nt a bilit y l o g.  Dr u g  a c c o u nt a bilit y  will  b e  n ot e d  b y t h e fi el d 
m o nit or  d uri n g sit e  visits  a n d  at t h e  c o m pl eti o n  of t h e st u d y.  P ati e nts  will  b e  as k e d t o r et ur n 
all  u n us e d st u d y tr e at m e nt  a n d  p a c k a gi n g  o n  a r e g ul ar  b asis,  at t h e  e n d  of t h e st u d y  or  at t h e 
ti m e  of st u d y tr e at m e nt  dis c o nti n u ati o n. 
At st u d y  cl os e -o ut,  a n d,  as  a p pr o pri at e  d uri n g t h e  c o urs e  of t h e st u d y, t h e i n v esti g at or  will 
r et ur n   all   us e d   a n d   u n us e d  st u d y  tr e at m e nt,   p a c k a gi n g,   dr u g  l a b els,   a n d   a   c o p y   of  t h e  
c o m pl et e d  dr u g  a c c o u nt a bilit y l o g t o t h e  N o v artis  m o nit or  or t o t h e  N o v artis  a d dr ess  pr o vi d e d 
i n t h e i n v esti g ator f ol d er  at  e a c h sit e.  
 
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 pli c a bl e.  
6. 5. 4   
Di s p o s al  a n d  d e str u cti o n  
T h e st u d y tr e at m e nt s u p pl y  c a n  b e  d estr o y e d  at t h e l o c al  N o v artis f a cilit y,  dr u g s u p pl y  gr o u p 
or t hir d  p art y,  as  a p pr o pri at e.  
St u d y tr e at m e nt  d estr u cti o n  at t h e i n v esti g ati o n al sit e  will  o nl y  b e  p er mitt e d if  a ut h ori z e d  b y 
N o v artis i n  a  pri or  a gr e e m e nt  a n d if  p er mitt e d  b y l o c al r e g ul ati o ns.  
 
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 
T a bl e   7 - 1  lists   all   of  t h e   ass ess m e nt s   a n d  i n di c at es   wit h   a n   “ X ”,  t h e   visits   w h e n  t h e y   ar e  
p erf or m e d.  All  d at a  o bt ai n e d fr o m t h es e  ass e ss m e nts  m ust  b e s u p p ort e d i n t h e  p ati e nt’s s o ur c e 
d o c u m e nt ati o n.   T h e  t a bl es  i n di c at e   w hi c h   ass ess m e nts   pr o d u c e   d at a  t o   b e   e nt er e d  i nt o 
d at a b as e ( D)  or r e m ai n i n s o ur c e  d o c u m e nts  o nl y ( S) ( “ C at e g or y ”   c ol u m n). 
N o  C R F  will  b e  us e d  as  a s o ur c e  d o c u m e nt.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  6 8
9  Pr ot o c ol  N o. 
 
 
 
 
Vi sit s  a n d  s c h e d ul e  wi n d o w s  
S cr e e ni n g/ b as eli n e   e v al u ati o ns  (i n cl u di n g   b as eli n e  r a di ol o gi c al   ass ess m e nt/s)   m ust   b e  
p erf or m e d   ≤   2 8   d a ys   of   c y cl e   1   d a y   1.    L a b or at or y   ass ess m e nt s  i n cl u di n g   h e m at ol o g y, 
c h e mistr y,   c o a g ul ati o n,   uri n al ysis,  i ns uli n/ gl u c os e   m o nit ori n g  ( B Y L 7 1 9   o nl y)   a n d   c ar di a c  
e n z y m es ( B Y L 7 1 9,   L D K 3 7 8  a n d  M E K 1 6 2)  p erf or m e d  as  p art  of  t h e s cr e e ni n g  e v al u ati o ns 
a n d  wit hi n  7 2  h o urs  of t h e first  d os e  of st u d y tr e at m e nt,  ar e  n ot r e q uir e d t o  b e r e p e at e d  o n t h e 
first  d osi n g  d a y. 
D uri n g  t h e   c o urs e   of  t h e  st u d y   visits,  t est   a n d/ or   pr o c e d ur es  s h o ul d   o c c ur   o n  s c h e d ul e  
w h e n e v er  p ossi bl e.  A  visit  wi n d o w  of  +/ - 3  d a ys is  all o w e d.  O n  d a ys t h at  P K is  c oll e ct e d t h e 
wi n d o w is  o nl y  +/ - 1  d a y.  P K s a m pl e  of  C 1 D 1  m ust  b e  c oll e ct e d  at t h e s a m e  d a y  of first  d os e.  
R a di ol o gi c al   ass e ss m e nt s   m ust   b e   p erf or m e d   +/ -7   d a ys   of  t h e  s c h e d ul e d   d at e   of  t h e  
ass e ss m e nt.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  6 9
9  Pr ot o c ol  N o. 
 
 
 
 
T a bl e   7- 1  
Vi sit  e v al u ati o n  s c h e d ul e  
 
 
C at e g or y  
 
 
Pr ot o c ol 
S e cti o n  
 
M ol e c ul ar  
Pr e -s cr e e ni n g  
S cr e e ni n g  
 
 
 
 
 
 
C y cl e  1  
 
 
 
 
 
 
C y cl e  2  
 
 
 
 
 
C y cl e  3  a n d 
S u b s e q u e nt  c y cl e s  
 
 
 
 
 
 
E O T  
 
 
 
 
3 0 -d a y 
s af et y  
F U  
 
 
 
 
Di s e a s e 
pr o gr e s si o  
n  F U  
 
 
 
 
 
S ur vi v al 
F U  
 
 
 
 
Vi sit  N a m e  
  
 
 
 
 
 
1  
 
 
 
 
2  
 
 
 
 
3  
 
 
 
 
4  
 
 
 
 
5  
 
 
 
 
6  
 
 
 
 
7  
 
 
 
 
8  
 
 
 
 
9  
 
 
 
1 
0  
 
 
 
1 
1  
1 2  
 
 
 
1 
3  
1 4  
 
Wit hi n  1 4 
d a y s  of 
t h e l a st 
d o s e  
 
3 0  d a y s 
aft er t h e 
l a st 
d o s e  
 
E v er y  8 
w e e k s 
aft er t h e 
l a st  d o s e 
 
E v er y  3 
m o nt h s 
aft er t h e 
l a st  d o s e 
 
 
B Y L 7 1 
9  
 
 
B Y L 7 1 
9  
 
 
D a y  of  c y cl e  
  
 
 
-2 8  
t o 
-1  
 
 
1  
 
 
8  
 
1 
5  
 
2 
2  
 
 
1  
 
 
8  
 
1 
5  
 
2 
2  
 
 
1  
 
 
8  
 
1 
5  
 
 
2 2  
 
 
N/ A  
 
 
N/ A  
 
 
N/ A  
 
 
N/ A  
O bt ai n I nf or m e d  C o n s e nt  
O bt ai n  m ol e c ul ar 
pr e -s cr e e ni n g  
I nf or m e d  C o n s e nt 
D  
7. 1. 1   
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
O bt ai n I nf or m e d 
C o n s e nt  
D  
7. 1. 2  
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
P ati e nt  hi st or y  
Ar c hi v al  or  n e wl y 
o bt ai n e d t u m or 
s a m pl e f or  
a s s e s s m e nt  
D  
7. 1. 1   
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
D e m o gr a p h y   
D   
7. 1. 2. 2  
 
X  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
I n cl u si o n/ e x cl u si o 
n  crit eri a  
D  
5  
 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  7 0
9  Pr ot o c ol  N o. 
 
 
 
 
C at e g or y  
 
 
Pr ot o c ol 
S e cti o n  
 
M ol e c ul ar  
Pr e -s cr e e ni n g  
S cr e e ni n g  
 
 
 
 
 
 
C y cl e  1  
 
 
 
 
 
 
C y cl e  2  
 
 
 
 
 
C y cl e  3  a n d 
S u b s e q u e nt  c y cl e s  
 
 
 
 
 
 
E O T  
 
 
 
 
3 0 -d a y 
s af et y 
F U  
 
 
 
 
Di s e a s e 
pr o gr e s si o 
n  F U  
 
 
 
 
 
S ur vi v al 
F U  
 
 
 
 
Vi sit  N a m e  
  
 
 
 
 
 
1  
 
 
 
 
2  
 
 
 
 
3  
 
 
 
 
4  
 
 
 
 
5  
 
 
 
 
6  
 
 
 
 
7  
 
 
 
 
8  
 
 
 
 
9  
 
 
 
1 
0  
 
 
 
1 
1  
1 2  
 
 
 
1 
3  
1 4  
 
Wit hi n  1 4 
d a y s  of 
t h e l a st 
d o s e  
 
3 0  d a y s 
aft er t h e 
l a st 
d o s e  
 
E v er y  8 
w e e k s 
aft er t h e 
l a st  d o s e 
 
E v er y  3 
m o nt h s 
aft er t h e 
l a st  d o s e 
 
B Y L 7 1 
9  
 
B Y L 7 1 
9  
 
 
D a y  of  c y cl e  
  
 
 
-2 8  
t o 
-1  
 
 
1  
 
 
8  
 
1 
5  
 
2 
2  
 
 
1  
 
 
8  
 
1 
5  
 
2 
2  
 
 
1  
 
 
8  
 
1 
5  
 
 
2 2  
 
 
N/ A  
 
 
N/ A  
 
 
N/ A  
 
 
N/ A  
R el e v a nt  m e di c al 
hi st or y  
D  
7. 1. 2. 2  
 
X 
  
  
  
  
  
  
  
  
  
 
  
 
 
 
 
 
Di a g n o si s  a n d 
e xt e nt  of  c a n c er  
D  
7. 1. 2. 2  
 
X 
  
  
  
  
  
  
  
  
  
 
  
 
 
 
 
 
Pri or 
a nti n e o pl a sti c 
t h er a p y 
D  
7. 1. 2. 2  
 
X 
  
  
  
  
  
  
  
  
  
 
  
 
 
 
 
 
Pri or/ c o n c o mit a nt 
m e di c ati o n s  
D  
7. 1. 2. 2  
 
X 
  
  
  
  
  
  
  
  
  
 
  
 
 
 
 
 
P h y si c al  e x a mi n ati o n s  
P h y si c al 
e x a mi n ati o n  
S  
7. 2. 2. 1  
 
X  
X 
  
  
 
X   
  
 
X 
 
  
 
X 
 
 
 
Vit al  si g n s   
D  
7. 2. 2. 2  
 
X  
X  
X  
X  
X  
X 
 
X 
 
X 
 
  
 
X 
 
 
 
H ei g ht  
D  
7. 2. 2. 3  
 
X 
  
  
  
  
  
  
  
  
  
 
  
 
 
 
 
 
W ei g ht  
D   
7. 2. 2. 3  
 
X   
X    
  
 
X    
  
 
X  
 
  
 
X  
 
 
 
P erf or m a n c e 
st at u s  
D  
7. 2. 2. 4  
 
X  
X 
  
  
 
X   
  
 
X 
 
  
 
X 
 
 
 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  7 1
9  Pr ot o c ol  N o. 
 
 
 
 
C at e g or y  
 
 
Pr ot o c ol 
S e cti o n  
 
M ol e c ul ar  
Pr e -s cr e e ni n g  
S cr e e ni n g  
 
 
 
 
 
 
C y cl e  1  
 
 
 
 
 
 
C y cl e  2  
 
 
 
 
 
C y cl e  3  a n d 
S u b s e q u e nt  c y cl e s  
 
 
 
 
 
 
E O T  
 
 
 
 
3 0 -d a y 
s af et y 
F U  
 
 
 
 
Di s e a s e 
pr o gr e s si o 
n  F U  
 
 
 
 
 
S ur vi v al 
F U  
 
 
 
 
Vi sit  N a m e  
  
 
 
 
 
 
1  
 
 
 
 
2  
 
 
 
 
3  
 
 
 
 
4  
 
 
 
 
5  
 
 
 
 
6  
 
 
 
 
7  
 
 
 
 
8  
 
 
 
 
9  
 
 
 
1 
0  
 
 
 
1 
1  
1 2  
 
 
 
1 
3  
1 4  
 
Wit hi n  1 4 
d a y s  of 
t h e l a st 
d o s e  
 
3 0  d a y s 
aft er t h e 
l a st 
d o s e  
 
E v er y  8 
w e e k s 
aft er t h e 
l a st  d o s e 
 
E v er y  3 
m o nt h s 
aft er t h e 
l a st  d o s e 
 
B Y L 7 1 
9  
 
B Y L 7 1 
9  
 
 
D a y  of  c y cl e  
  
 
 
-2 8  
t o 
-1  
 
 
1  
 
 
8  
 
1 
5  
 
2 
2  
 
 
1  
 
 
8  
 
1 
5  
 
2 
2  
 
 
1  
 
 
8  
 
1 
5  
 
 
2 2  
 
 
N/ A  
 
 
N/ A  
 
 
N/ A  
 
 
N/ A  
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  
1 
  
  
 
X   
  
 
X 
 
  
 
X 
 
 
 
C h e mi str y   
D  
7. 2. 2. 5. 2   
X 
X 
1 
  
  
 
X   
  
 
X 
 
  
 
X 
 
 
 
C o a g ul ati o n   
D  
7. 2. 2. 5. 3   
X 2 
X 
1 
  
  
  
  
  
  
  
  
 
  
 
X 2 
 
 
 
Uri n al y si s   
D  
7. 2. 2. 5. 4   
X 
X 
1 
  
  
  
  
  
  
  
  
 
  
 
X 
 
 
 
Pr e g n a n c y t e st   
D   
7. 2. 2. 5. 5    
 
X    
  
  
  
  
  
  
  
 
  
 
X  
 
 
 
F a sti n g  pl a s m a 
gl u c o s e, i n s uli n, 
c- p e pti d e,  
( B Y L 7 1 9) 
D  
7. 2. 2. 5. 6   
X 
X 
1 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
 
 
 
H e m o gl o bi n  A 1 c 
( B Y L 7 1 9) 
D  
7. 2. 2. 5. 6   
X 
X 
1 
  
  
  
  
  
  
 
D a y 1  e v er y t hr e e  c y cl e s   
X 
 
 
 
C ar di a c  e n z y m e s 
( B Y L 7 1 9/ 
L D K 3 7 8)  
D  
7. 2. 2. 6. 3   
X 
X 
1 
  
  
  
  
  
  
  
  
 
  
 
X 
 
 
 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  7 2
9  Pr ot o c ol  N o. 
 
 
 
 
C at e g or y  
 
 
Pr ot o c ol 
S e cti o n  
 
M ol e c ul ar  
Pr e -s cr e e ni n g  
S cr e e ni n g  
 
 
 
 
 
 
C y cl e  1  
 
 
 
 
 
 
C y cl e  2  
 
 
 
 
 
C y cl e  3  a n d 
S u b s e q u e nt  c y cl e s  
 
 
 
 
 
 
E O T  
 
 
 
 
3 0 -d a y 
s af et y 
F U  
 
 
 
 
Di s e a s e 
pr o gr e s si o 
n  F U  
 
 
 
 
 
S ur vi v al 
F U  
 
 
 
 
Vi sit  N a m e  
  
 
 
 
 
 
1  
 
 
 
 
2  
 
 
 
 
3  
 
 
 
 
4  
 
 
 
 
5  
 
 
 
 
6  
 
 
 
 
7  
 
 
 
 
8  
 
 
 
 
9  
 
 
 
1 
0  
 
 
 
1 
1  
1 2  
 
 
 
1 
3  
1 4  
 
Wit hi n  1 4 
d a y s  of 
t h e l a st 
d o s e  
 
3 0  d a y s 
aft er t h e 
l a st 
d o s e  
 
E v er y  8 
w e e k s 
aft er t h e 
l a st  d o s e 
 
E v er y  3 
m o nt h s 
aft er t h e 
l a st  d o s e 
 
B Y L 7 1 
9  
 
B Y L 7 1 
9  
 
 
D a y  of  c y cl e  
  
 
 
-2 8  
t o 
-1  
 
 
1  
 
 
8  
 
1 
5  
 
2 
2  
 
 
1  
 
 
8  
 
1 
5  
 
2 
2  
 
 
1  
 
 
8  
 
1 
5  
 
 
2 2  
 
 
N/ A  
 
 
N/ A  
 
 
N/ A  
 
 
N/ A  
C ar di a c  e n z y m e s 
( M E K 1 6 2) 
D  
7. 2. 2. 6. 3   
X 
X 
1 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
 
 
I m a gi n g  a n d  ot h er  a s s e s s m e nt 
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  b e gi n ni n g  at 
t h e  st art  of  c y cl e  3  a n d  a s 
n e e d e d t o  c o nfir m  pr e vi o u s 
r e s p o n s e 
X 
(if  n ot 
c o n d u ct e 
d  wit hi n 
3 0  d a y s 
pri or t o 
E O T)  
 
X 
 
E C G 
( B Y L 7 1 9/ L D K 3 7 8/ 
M E K 1 6 2)
3  
D  
7. 2. 2. 6. 1   
X  
X 
 
X 
 
X  
X 
 
X 
 
  
 
X 
 
 
 
E C G (I N C 2 8 0) 3  
D   
7. 2. 2. 6. 1   
X   
X    
  
 
X    
  
 
X  
 
  
 
X  
 
 
 
C ar di a c i m a gi n g 
( B Y L 7 1 9) 
D  
7. 2. 2. 6. 2   
X 
  
  
  
  
  
  
  
  
  
 
  
 
X 
 
 
 
C ar di a c i m a gi n g 
( M E K 1 6 2) 
D   
7. 2. 2. 6. 2   
X  
  
  
 
X  
  
  
 
X   
E v er y  8  w e e k s f oll o wi n g 
st art fr o m  C 2 D 2 2  
X  
 
 
 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  7 3
9  Pr ot o c ol  N o. 
 
 
 
 
C at e g or y  
 
 
Pr ot o c ol 
S e cti o n  
 
M ol e c ul ar  
Pr e -s cr e e ni n g  
S cr e e ni n g  
 
 
 
 
 
 
C y cl e  1  
 
 
 
 
 
 
C y cl e  2  
 
 
 
 
 
C y cl e  3  a n d 
S u b s e q u e nt  c y cl e s  
 
 
 
 
 
 
E O T  
 
 
 
 
3 0 -d a y 
s af et y 
F U  
 
 
 
 
Di s e a s e 
pr o gr e s si o 
n  F U  
 
 
 
 
 
S ur vi v al 
F U  
 
 
 
 
Vi sit  N a m e  
  
 
 
 
 
 
1  
 
 
 
 
2  
 
 
 
 
3  
 
 
 
 
4  
 
 
 
 
5  
 
 
 
 
6  
 
 
 
 
7  
 
 
 
 
8  
 
 
 
 
9  
 
 
 
1 
0  
 
 
 
1 
1  
1 2  
 
 
 
1 
3  
1 4  
 
Wit hi n  1 4 
d a y s  of 
t h e l a st 
d o s e  
 
3 0  d a y s 
aft er t h e 
l a st 
d o s e  
 
E v er y  8 
w e e k s 
aft er t h e 
l a st  d o s e 
 
E v er y  3 
m o nt h s 
aft er t h e 
l a st  d o s e 
 
B Y L 7 1 
9  
 
B Y L 7 1 
9  
 
 
D a y  of  c y cl e  
  
 
 
-2 8  
t o 
-1  
 
 
1  
 
 
8  
 
1 
5  
 
2 
2  
 
 
1  
 
 
8  
 
1 
5  
 
2 
2  
 
 
1  
 
 
8  
 
1 
5  
 
 
2 2  
 
 
N/ A  
 
 
N/ A  
 
 
N/ A  
 
 
N/ A  
O p ht h al m ol o g y 
e x a m s 
( M E K 1 6 2) 
D  
7. 2. 2. 7  
 
X 
  
 
X 
 
X   
  
 
X 
 
  
 
X 
 
 
 
S af et y  
A d v er s e  e v e nt s   
D  
8. 1  
X 
( pr o c 
e d ur e 
r el at e 
d 
S A E s  
o nl y)  
X  
C o nti n u o u s  m o nit ori n g  d uri n g tr e at m e nt  
X 
X 
 
 
C o n c o mit a nt 
m e di c ati o n  
D 
 
 
X  
C o nti n u o u s  m o nit ori n g  d uri n g tr e at m e nt  
X 
X 
 
 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  7 4
9  Pr ot o c ol  N o. 
 
 
 
 
C at e g or y  
 
 
Pr ot o c ol 
S e cti o n  
 
M ol e c ul ar  
Pr e -s cr e e ni n g  
S cr e e ni n g  
 
 
 
 
 
 
C y cl e  1  
 
 
 
 
 
 
C y cl e  2  
 
 
 
 
 
C y cl e  3  a n d 
S u b s e q u e nt  c y cl e s  
 
 
 
 
 
 
E O T  
 
 
 
 
3 0 -d a y 
s af et y 
F U  
 
 
 
 
Di s e a s e 
pr o gr e s si o 
n  F U  
 
 
 
 
 
S ur vi v al 
F U  
 
 
 
 
Vi sit  N a m e  
  
 
 
 
 
 
1  
 
 
 
 
2  
 
 
 
 
3  
 
 
 
 
4  
 
 
 
 
5  
 
 
 
 
6  
 
 
 
 
7  
 
 
 
 
8  
 
 
 
 
9  
 
 
 
1 
0  
 
 
 
1 
1  
1 2  
 
 
 
1 
3  
1 4  
 
Wit hi n  1 4 
d a y s  of 
t h e l a st 
d o s e  
 
3 0  d a y s 
aft er t h e 
l a st 
d o s e  
 
E v er y  8 
w e e k s 
aft er t h e 
l a st  d o s e 
 
E v er y  3 
m o nt h s 
aft er t h e 
l a st  d o s e 
 
B Y L 7 1 
9  
 
B Y L 7 1 
9  
 
 
D a y  of  c y cl e  
  
 
 
-2 8  
t o 
-1  
 
 
1  
 
 
8  
 
1 
5  
 
2 
2  
 
 
1  
 
 
8  
 
1 
5  
 
2 
2  
 
 
1  
 
 
8  
 
1 
5  
 
 
2 2  
 
 
N/ A  
 
 
N/ A  
 
 
N/ A  
 
 
N/ A  
P K  s a m pli n g   
D   
7. 2. 3  
  
 
R ef er t o  T a bl e  7 -5  t o T a bl e  7 -1 2  f or  P K  s a m pli n g  s c h e d ul e s 
 
 
 
 
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. 6  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
X  
X 
X 
S ur vi v al  st at u s 
F oll o w -u p  
D  
7. 1. 6  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
 
X 
1 L a b or at or y  a s s e s s m e nt s i n cl u di n g  h e m at ol o g y,  c h e mi str y,  c o a g ul ati o n,  uri n al y si s, i n s uli n/ gl u c o s e  m o nit ori n g ( B Y L 7 1 9  o nl y)  a n d  c ar di a c  e n z y m e s (  B Y L 7 1 9,  L D K 3 7 8  a n d 
M E K 1 6 2)  p erf or m e d  a s  p art  of t h e  s cr e e ni n g  e v al u ati o n s  a n d  wit hi n  7 2  h o ur s  of t h e fir st  d o s e  of  st u d y tr e at m e nt,  ar e  n ot r e q uir e d t o  b e r e p e at e d  at  C 1 D 1.  
2 C o a g ul ati o n  d uri n g  s cr e e ni n g  a n d  E O T  will  o nl y  b e  p erf or m e d if  a  n e wl y  o bt ai n e d t u m or  s a m pl e i s  c oll e ct e d.  
3 T hr e e  s e q u e nti al  1 2 -l e a d  E C G s,  s e p ar at e d  b y  ar o u n d  2  mi n ut e s,  m u st  b e  p erf or m e d  d uri n g  s cr e e ni n g 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  7 5
5  Pr ot o c ol  N o. 
 
 
 
 
7. 1. 1   
M ol e c ul ar  pr e -s cr e e ni n g  
E vi d e n c e  of  m ol e c ul ar  alt er ati o ns is r e q uir e d i n  or d er t o  b e gi n  cli ni c al s cr e e ni n g  a cti viti es. 
Writt e n  d o c u m e nt ati o n  of  m ol e c ul ar  alt er ati o ns s h o ul d  b e  o bt ai n e d fr o m:  
•   L o c al  ass ess m e nt  o n  eit h er  a  n e wl y  o bt ai n e d t u m or s a m pl e ( pr ef err e d)  or t h e  m ost r e c e nt 
a r c hi v al t u m or s a m pl e  a v ail a bl e;  c e ntr al  ass ess m e nt  m a y  b e  a p pli e d i n t h e f ut ur e. 
•   F or t h e  L D K 3 7 8  ar m,  p ati e nts’ t u m or s a m pl e  m ust  b e  o bt ai n e d  aft er  pr o gr essi o n  o n 
cri z oti ni b if  p ati e nt is  pr e -tr e at e d  wit h  cri z oti ni b. If t u m or s a m pl e is  n ot  a v ail a bl e,  p ati e nts 
m ust  b e s uit a bl e  a n d  willi n g t o  u n d er g o  m a n d at or y  bi o ps y  a c c or di n g t o tr e ati n g 
i nstit uti o n’s  o w n  g ui d eli n es  a n d r e q uir e m e nts f or s u c h  pr o c e d ur e. 
P ati e nts   m ust  si g n  t h e   m ol e c ul ar   pr e -s cr e e ni n g   c o ns e nt  t o   all o w  f or  t h e   c oll e cti o n   a n d  
s hi p m e nt   of   ar c hi v al   a n d/ or   a   n e wl y   o bt ai n e d  t u m or  s a m pl es  t o  t h e  l o c al  l a b or at or y   or  
N o v artis   d esi g n e d   c e ntr al  l a b or at or y  f or   m ol e c ul ar   pr es cr e e ni n g   p ur p os es.   T h e   m ol e c ul ar 
pr es cr e e ni n g  p ur p os es  c o ul d  b e  us e d f or  a n al ysis  of  g e n e  a m plifi c ati o n  a n d  m ut ati o n.  
M ol e c ul ar  pr e -s cr e e ni n g  d at a  c o nfir mi n g  p ati e nt  eli gi bilit y  will  b e  d o c u m e nt e d i n t h e  e C R F if 
t h e  p ati e nt  b e c o m es  eli gi bl e  a n d tr e at e d  as  pl a n n e d. 
I n  a d diti o n  a n d  w h er e v er  p ossi bl e t h e  ar c hi v al  a n d/ or  n e wl y  o bt ai n e d t u m or s a m pl es  m a y  b e 
us e d  t o   pr ofil e   g e n e   alt er ati o ns   a n d   e x pr essi o n   of   c a n di d at e   g e n es  r el at e d  t o   dr u g/s u bj e ct  
r es p o ns es,   d e v el o p m e nt   of  r esist a n c e   m e c h a nis ms,   or   h y p ot h esis   g e n er ati n g   a p pr o a c h es  t o  
d eli n e at e r es p o n d er/ n o n r es p o n d er  p o p ul ati o ns.  
 
7. 1. 2   
S cr e e ni n g  
P ati e nts   wit h   N C S L C   w h o   h a v e   a v ail a bl e  i nstit uti o n al   d at a   d e m o nstr ati n g   m ol e c ul ar  
alt er ati o ns  m a y  b e gi n  cli ni c al s cr e e ni n g  aft er t h e  m ai n st u d y I nf or m e d  C o ns e nt  F or m  h as  b e e n 
si g n e d. 
T h e  cli ni c al s cr e e ni n g  p eri o d st arts  o n c e  a  p ati e nt  h as  pr o vi d e d  writt e n i nf or m e d  c o ns e nt t o 
p arti ci p at e i n t h e st u d y.  S cr e e ni n g  ass ess m e nts  h a v e t o  b e  d o n e  wit hi n  2 8  d a ys  pri or t o t h e 
first  d os e  of st u d y  m e di c ati o n  wit h t h e  e x c e pti o n  of  pr e g n a n c y t est,  w hi c h  m ust  b e  p erf or m e d 
wit hi n   7 2  h o urs b ef or e  t h e first  d os e. Cli ni c al  a n d  r a di ol o gi c al t u m or ass ess m e nt   b y R E CI S T  
1. 1 ( S e cti o n  1 4. 1 ) s h o ul d  b e  c o n d u ct e d  pr ef er a bl y  wit hi n  1  w e e k ( 7  d a ys)  pri or t o t h e first 
d os e  of t h e  st u d y tr e at m e nt;  h o w e v er t u m or  ass ess m e nts  u p t o  4  w e e ks ( 2 8  d a ys)  pri or t o t h e 
first   d os e   will   b e   a c c e pt a bl e.   D uri n g  s cr e e ni n g  t h e   dis e as e   m ust   b e  st a g e d.   T h e  t u m or  
ass e ss m e nt  m a d e  d uri n g t h e s cr e e ni n g  p h as e  will  pr o vi d e t h e  b as eli n e t u m or  m e as ur e m e nts, 
w hi c h   will   b e   us e d  t o   d et er mi n e  f ut ur e  r es p o ns es   a n d/ or   pr o gr essi o n.   A   c o m pl et e  list   of  
s cr e e ni n g  e v al u ati o ns is  pr o vi d e d i n t h e  visit  of  ass e ss m e nt s t a bl e ( T a bl e  7 - 1).  Ass e ss m e nts 
w hi c h  ar e  p art  of t h e  p ati e nt’s  cli ni c al st a n d ar d  of  c ar e  m a y  b e  p erf or m e d  b ef or e  o bt ai ni n g t h e 
I C F, if  wit hi n t h e  a c c e pt a bl e s cr e e ni n g  wi n d o w. 
 
7. 1. 2. 1   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 
P ati e nts   w h o  si g n e d   a   m ol e c ul ar   pr e -s cr e e ni n g  I C F   b ut   ar e   c o nsi d er e d  i n eli gi bl e   aft er  
m ol e c ul ar  pr e -s cr e e ni n g,  as  w ell  as  p ati e nts  w h o  ar e f o u n d  n ot  eli gi bl e  aft er si g ni n g t h e  m ai n  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  7 6
5  Pr ot o c ol  N o. 
 
 
 
st u d y  c o ns e nt  will  b e  c o nsi d er e d  a s s cr e e ni n g f ail ur es,  a n d  d at a  will  b e  h a n dl e d i n t h e s a m e 
m a n n er.  
T h e  r e as o n  f or   m ol e c ul ar   pr e -s cr e e ni n g  f ail ur e   or  s cr e e ni n g  f ail ur e   will   b e   e nt er e d   o n  t h e  
S cr e e ni n g   P h as e   Dis p ositi o n   P a g e.   T h e   d e m o gr a p hi c  i nf or m ati o n,  i nf or m e d   c o ns e nt,   a n d  
I n cl usi o n/ E x cl usi o n  p a g es  m ust  als o  b e  c o m pl et e d f or  S cr e e n  F ail ur e  p ati e nts.  N o ot h er  d at a 
will   b e   e nt er e d  i nt o  t h e   cli ni c al   d at a b as e  f or   p ati e nts   w h o   ar e  s cr e e n  f ail ur es,   u nl ess  t h e  
s u bj e ct  e x p eri e n c e d  a  S eri o us  A d v er s e  E v e nt  d uri n g t h e  S cr e e ni n g  P h as e (s e e  S e cti o n  8  f or 
S A E r e p orti n g  d et ails).  F or  m ol e c ul ar  pr e -s cr e e ni n g f ail ur es,  o nl y  S A Es  p ossi bl y r el at e d t o  a 
st u d y  pr o c e d ur e  will  b e r e p ort e d. 
 
7. 1. 2. 2   P ati e nt  d e m o gr a p hi c s  a n d  ot h er  b a s eli n e  c h ar a ct eri sti c s  
D at a   will   b e   c oll e ct e d   o n   p ati e nt   c h ar a ct eristi cs  i n cl u di n g   d e m o gr a p hi c  i nf or m ati o n  ( a g e,  
g e n d er, r a c e )  a n d  ot h er  b a c k gr o u n d  or r el e v a nt  m e di c al  hist or y, i n cl u di n g  hist or y  of  dis e as e 
a n d   c urr e nt   dis e as e   st at us,  st a gi n g,  sit es   of   dis e as e,   pri or   a nti c a n c er  t h er a pi es,   pri or  
m e di c ati o n/  si g nifi c a nt   n o n -dr u g t h er a pi es   a n d  a n y   ot h er   ass ess m e nts  t h at   ar e   d o n e f or   t h e 
p ur p os es  of  d et er mi ni n g  eli gi bilit y f or i n cl usi o n i n t h e st u d y (i. e,  E C O G  p erf or m a n c e st at us, 
c o m pl et e   p h ysi c al   e x a mi n ati o n  i n cl u di n g   n e ur ol o gi c al   ass ess m e nt,  t u m or   ass ess m e nt   b y  
R E CI S T,  vit al si g ns,  h e m at ol o g y,  c h e mistr y,  1 2 -l e a d  E C G,  a n d  uri n e  pr e g na n c y  t est). 
 
7. 1. 3   
Tr e at m e nt  p eri o d  
A tr e at m e nt  c y cl e is  d efi n e d  as  2 8  d a ys ( 4  c al e n d ar   w e e ks)  f or  t h e  p ur p os es  of s c h e d uli n g 
pr o c e d ur es   a n d   e v al u ati o ns.   Pl e as e  r ef er  t o   T a bl e   7 - 1  f or   d et ails   of  t h e  ti mi n g   of  r e q uir e d 
ass e ss m e nt s  a n d  S e cti o n  7. 1  f or  visit  wi n d o ws. 
P ati e nts  will  b e tr e at e d  u ntil  o n e  of t h e  crit eri a  d es cri b e d i n  S e cti o n  7. 1. 4. 1  is  m et. 
 
7. 1. 4   
E n d  of tr e at m e nt  vi s it i n cl u di n g  st u d y  c o m pl eti o n  a n d  pr e m at ur e 
wit h dr a w al  
At  t h e  ti m e   p ati e nts   dis c o nti n u e  st u d y  tr e at m e nt,   a   visit  s h o ul d   b e  s c h e d ul e d   as  s o o n   as  
p ossi bl e   a n d   wit hi n   1 4   d a ys   of  t h e  l ast   d os e   of  st u d y  tr e at m e nt   or   wit hi n   1 4   d a ys   of  t h e  
d e cisi o n  t o   p er m a n e ntl y   dis c o nti n u e  st u d y  tr e at m e nt,   at   w hi c h  ti m e   all   of  t h e   ass ess m e nts  
list e d f or t h e  E n d  of  Tr e at m e nt ( E O T)  visit  will  b e  p erf or m e d. If t h e  d e cisi o n t o  wit h dr a w t h e 
p ati e nt  o c c urs  at  a r e g ul arl y s c h e d ul e d  visit, t h at  visit  m a y  b e c o m e t h e  E O T  visit r at h er t h a n  
h a vi n g t h e  p ati e nt r et ur n f or  a n  a d diti o n al  visit.  
A n  E n d  of  Tr e at m e nt  P h as e  Dis p ositi o n  P a g e s h o ul d  b e  c o m pl et e d,  gi vi n g t h e  d at e  a n d r e as o n 
f or st o p pi n g t h e st u d y tr e at m e nt. If  a  wit h dr a w al  o c c urs,  or if t h e  p ati e nt f ails t o r et ur n f or 
visits,  t h e  i n v es ti g at or   m ust   d et er mi n e  t h e   pri m ar y  r e as o n  f or   a   p ati e nt’s   pr e m at ur e   
wit h dr a w al fr o m t h e st u d y  a n d r e c or d t his i nf or m ati o n  o n t h e  E O T  e C R F  p a g e.  
E n d  of tr e at m e nt/ Pr e m at ur e  wit h dr a w al  visit is  n ot  c o nsi d er e d  as t h e  e n d  of t h e st u d y.  
 
7. 1. 4. 1   Crit eri a f or  pr e m at ur e  p ati e nt  wit h dr a w al  
P ati e nts  m a y  v ol u nt aril y  dis c o nti n u e fr o m t h e st u d y tr e at m e nt f or  a n y r e as o n  at  a n y ti m e. If  a 
p ati e nt  d e ci d es t o  dis c o nti n u e  fr o m t h e st u d y tr e at m e nt, t h e i n v esti g at or  m ust  m a k e  e v er y 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  7 7
5  Pr ot o c ol  N o. 
 
 
 
eff ort  ( e. g.  t el e p h o n e,   e -m ail,  l ett er)  t o   d et er mi n e  t h e   pri m ar y  r e as o n  f or  t his   d e cisi o n   a n d  
r e c or d t his i nf or m ati o n i n t h e  p ati e nt’s  c h art  a n d  o n t h e  a p pr o pri at e  C R F  p a g es.  T h ey  m a y  b e 
c o nsi d er e d  wit h dr a w n if t h e y st at e  a n i nt e nti o n t o  wit h dr a w, f ail t o r et ur n f or  visits,  or  b e c o m e 
l ost t o f oll o w-u p f or  a n y  ot h er r e as o n.  
T h e i n v esti g at or s h o ul d  dis c o nti n u e st u d y tr e at m e nt f or  a  gi v e n  p ati e nt if,  o n  b al a n c e,  h e/s h e 
b eli e v es t h at  c o nti n u ati o n  w o ul d  b e  d etri m e nt al t o t h e  p ati e nt’s  w ell - b ei n g. 
St u d y tr e at m e nt  m a y  b e  dis c o nti n u e d  u n d er t h e f oll o wi n g  cir c u mst a n c es:  
•   A d v ers e  e v e nt  
•   D e at h  
•   Pr o gr essi v e  Dis e as e  
•   Pr e g n a n c y  
•   Pr ot o c ol  d e vi ati o n  
•   St u d y t er mi n at e d  b y  s p o ns or 
•   T e c h ni c al   pr o bl e ms 
•   L ost t o  f oll o w- u p 
•   P h ysi ci a n  d e cisi o n  
•   S u bj e ct/  g u ar di a n  d e cisi o n  
P ati e nts  w h o  dis c o nti n u e st u d y tr e at m e nt s h o ul d  u n d er g o  a n  e n d  of tr e at m e nt  visit  a n d t h e n  
e nt er t h e f oll o w- u p  p eri o d. 
 
7. 1. 4. 2   R e pl a c e m e nt  p oli c y  
N o r e pl a c e m e nt  will  b e  n e e d e d.  
 
7. 1. 5   
Wit h dr a w al  of  C o n s e nt  
P ati e nts  m a y  v ol u nt aril y  wit h dr a w  c o ns e nt t o  p arti ci p at e i n t h e st u d y f or  a n y r e as o n  at  a n y 
ti m e.  Wit h dr a w al  of  c o ns e nt  o c c urs  o nl y  w h e n  a  p ati e nt  d o es  n ot  w a nt t o  p arti ci p at e i n t h e 
st u d y  a n y l o n g er,  a n d  d o es  n ot  w a nt  a n y f urt h er  visits  or  ass ess m e nts,  a n d  d o es  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 artis  will  c o nti n u e t o r et ai n  a n d  us e  all r es e ar c h r es ults t h at  h a v e  alr e a d y  b e e n  c oll e ct e d 
f or t h e st u d y  e v al u ati o n.  All  bi ol o gi c al s a m pl es t h at  h a v e  alr e a d y  b e e n  c oll e ct e d  m a y  b e 
r et ai n e d  a n d  a n al y z e d at  a l at er  d at e ( or  as r e q uir e d  b y l o c al r e g ul ati o ns).  
If  a  p ati e nt  wit h dr a ws  c o ns e nt, t h e i n v esti g at or  m ust  m a k e  e v er y  eff ort ( e. g. t el e p h o n e,  e-m ail, 
l ett er) t o  d et er mi n e t h e  pri m ar y r e as o n f or t his  d e cisi o n  a n d r e c or d t his i nf or m ati o n.  St u d y 
tr e at m e nt m ust  b e  dis c o nti n u e d  a n d  n o f urt h er  ass e ss m e nts  c o n d u ct e d.  
F urt h er  att e m pts t o  c o nt a ct t h e  p ati e nt  ar e  n ot  all o w e d  u nl ess s af et y fi n di n gs r e q uir e 
c o m m u ni c ati o n  or f oll o w  u p.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  7 8
5  Pr ot o c ol  N o. 
 
 
 
 
7. 1. 6   
F oll o w  u p  p eri o d  
 
3 0 -d a y  s af et y f oll o w -u p  
All   p ati e nts   m ust   h a v e  s af et y   e v al u ati o ns  f or   3 0   d a ys.   A Es   will   b e   ass ess e d  ( c o nt a ct   b y  
t el e p h o n e is  p er mitt e d)  u ntil  3 0  d a ys f oll o wi n g t h e l ast  d os e  of st u d y tr e at m e nt  or st art  of  n e w 
a nti c a n c er  t h er a p y.   All   c o n c o mit a nt   m e di c ati o ns   gi v e n  t o   a   p ati e nt   as   a  r es ult   of   a n   A E  
e x p eri e n c e  d uri n g t his  p eri o d  will  b e r e c or d e d  o n t h e  c o n c o mit a nt  m e di c ati o n  e C R F  p a g e.  All 
c a n c er  m e di c ati o ns/t h er a pi es  gi v e n t o  a  p ati e nt  ≤  3 0  d a ys  aft er t h e l ast  d os e  of  st u d y tr e at m e nt 
m ust   b e  r e c or d e d   o n  t h e   a nti n e o pl asti c  t h er a pi es  si n c e   dis c o nti n u ati o n   of  st u d y  tr e at m e nt  
e C R F.  
 
Di s e a s e  pr o gr e s si o n f oll o w -u p  
A n y  p ati e nt  w h o  dis c o nti n u es fr o m st u d y tr e at m e nt f or  a n y r e as o n ( e x c e pt f or  d e at h,  dis e as e 
pr o gr essi o n, l ost t o f oll o w -u p,  or st u d y t er mi n ati o n)  will  c o nti n u e t o  h a v e t u m or  ass ess m e nts 
p erf or m e d  e v er y  8  w e e ks i n t h e f oll o w -u p  p eri o d  u ntil   dis e as e  pr o gr essi o n  or  st art   of   n e w 
a nti c a n c er t h er a p y.  
 
S ur vi v al f oll o w -u p  
P ati e nts  will  b e  c o nt a ct e d (t el e p h o n e is  p er mitt e d) f or s ur vi v al st at us  e v er y  3  m o nt hs fr o m l ast 
d os e  u ntil  d e at h, l ost t o f oll o w -u p,  wit h dr a w al  of  c o ns e nt  or st u d y  e n d ( S e e  S e cti o n  4. 3  f or 
d et ails).  All  c a n c er  m e di c ati o ns/t h er a pi es  gi v e n t o  a  p ati e nt  d uri n g f oll o w -u p  p eri o d  will  b e 
c oll e ct e d.  
P ati e nts l ost t o f oll o w  u p s h o ul d  b e r e c or d e d  as s u c h  o n t h e  C R F.  F or  p ati e nts  w h o  ar e l ost t o 
f oll o w-u p,  t h e  i n v esti g at or  s h o ul d  s h o w   " d u e   dili g e n c e "   b y   d o c u m e nti n g  i n  t h e  s o ur c e  
d o c u m e nts st e ps t a k e n t o  c o nt a ct t h e  p ati e nt,  e. g.,  d at es  of t el e p h o n e  c alls, r e gist er e d l ett ers, 
et c.  
 
7. 1. 7   
L o st t o  f oll o w-u p  
F or  p ati e nts  w h os e st at us is  u n cl e ar  b e c a us e t h e y f ail t o  a p p e ar f or st u d y  visits  wit h o ut st ati n g 
a n i nt e nti o n t o  wit h dr a w  c o ns e nt, t h e i n v esti g at or s h o ul d s h o w  " d u e  dili g e n c e "  b y  c o nt a cti n g 
t h e  p ati e nt, f a mil y  or f a mil y  p h ysi ci a n  as  a gr e e d i n t h e i nf or m e d  c o ns e nt  a n d  b y  d o c u m e nti n g 
i n  t h e  s o ur c e   d o c u m e nts  st e ps  t a k e n  t o   c o nt a ct  t h e   p ati e nt,   e. g.   d at es   of  t el e p h o n e   c alls,  
r e gist er e d l ett ers,  et c.  A  p ati e nt s h o ul d  n ot  b e  c o nsi d er e d l ost t o f oll o w-u p  u ntil  d u e  dili g e n c e 
h as  b e e n  c o m pl et e d.  P ati e nts l ost t o f oll o w  u p s h o ul d  b e r e c or d e d  as s u c h  o n t h e  a p pr o pri at e 
Dis p ositi o n  C R F.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  7 9
5  Pr ot o c ol  N o. 
 
 
 
 
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 a bl e   7- 2  
I m a gi n g  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  T r e at m e nt/ F oll o w -u p  
C T  or  M RI  wit h  c o ntr a st  e n h a n c e m e nt 
( C h e st,  A b d o m e n,  P el vi s) 
M a n d at e d  
M a n d at e d,  e v er y  8  w e e k s 
( ± 7  d a y s) 
W h ol e  b o n e  s ci nti gr a p h y  
If  cli ni c all y i n di c at e d 
N ot  a p pli c a bl e  
Br ai n  C T  or  M RI  
M a n d at e d  
If  cli ni c all y i n di c at e d 
B o n e  X -r a y  or  C T /  M RI ( b o n e l e si o n s 
o nl y)  
If  h ot  s p ot s  o n  b o n e 
s ci nti gr a p h y  
If  b o n e l e si o n s  at  s cr e e ni n g 
e v er y  8  w e e k s ( ± 7  d a y s)  
S ki n  c ol or  P h ot o gr a p h y ( s ki n l e si o n s  o nl y)   
M a n d at e d if  s ki n l e si o n s  at 
s cr e e ni n g  
If  s ki n l e si o n s  at  s cr e e ni n g 
T u m or r es p o ns e  will  b e  d et er mi n e d l o c all y  a c c or di n g t o  R es p o ns e  E v al u ati o n  Crit eri a i n  S oli d 
T u m ors ( R E CI S T)  v ersi o n  1. 1 ( S e cti o n  1 4. 1 ).  T h e l o c al i n v esti g at or’s  ass e ss m e nt  will  b e  us e d 
f or t h e  pri m ar y  e n d p oi nt  a n al ysis  a n d f or tr e at m e nt  d e cisi o n  m a ki n g. 
C T/ M RI s c a ns  will  b e  p erf or m e d  at  b as eli n e  wit hi n  2 8  d a ys ( pr ef er a bl y  7  d a ys)  b ef or e st art  of 
tr e at m e nt  a n d s u bs e q u e ntl y  e v er y  8  w e e ks fr o m st art  of  c y cl e  3  u ntil  pr o gr essi o n  of  dis e as e. 
S e e  T a bl e   7 - 1  a n d  T a bl e   7 - 2  f or   d et ails.   C T/ M RI  s c a n   will   b e   p erf or m e d   at   E O T  if   n ot  
c o n d u ct e d  wit hi n  3 0  d a ys  pri or t o  E O T.  Dis e as e  pr o gr essi o n f oll o w -u p s h o ul d  b e  p erf or m e d 
as  d es cri b e d i n  S e cti o n  7. 1. 6 . 
Aft er  b as eli n e,  all  ass ess m e nt s s h o ul d  b e  p erf or m e d  wit hi n  ± 7  d a ys  of t h e s c h e d ul e d  d a y  of 
ass e ss m e nt. I m a gi n g  e v al u ati o ns s u bs e q u e nt t o  a n  off -s c h e d ul e  c o nfir m at or y s c a n, s h o ul d  b e 
p erf or m e d  a c c or di n g t o t h e  ori gi n al  ass ess m e nt s c h e d ul e.  T h e s a m e  m et h o d  of  ass ess m e nt  a n d 
t h e  s a m e  t e c h ni q u e  s h o ul d   b e   us e d  t o   c h ar a ct eri z e   e a c h  i n di vi d u al   a n d  r e p ort e d  l esi o n   at  
b as eli n e  a n d  d uri n g f oll o w  u p.  
All  p ati e nts  will  u n d er g o  C T/ M RI s c a n  of t h e  c h est,  a b d o m e n  a n d  p el vis  at s cr e e ni n g/ b as eli n e 
a n d  e v er y  8  w e e ks t h er e aft er. If  at  b as eli n e  a  p ati e nt  h as  a  m e di c al  c o ntr ai n di c ati o n t o  C T i. v. 
c o ntr ast   or   d e v el o ps   a   c o ntr ai n di c ati o n   d uri n g  t h e  tri al,   a   n o n -c o ntr ast   C T   of   c h est   pl us  
c o ntr ast -e n h a n c e d  M RI  of  a b d o m e n  a n d  p el vis is  a c c e pt a bl e.  
P ati e nts   wit h   cli ni c al   e vi d e n c e   of   b o n e   m et ast as es   m ust   h a v e   a   w h ol e   b o d y   b o n e  s c a n   at  
b as eli n e  p er l o c al i nstit uti o n al  pr a cti c e.  H ot s p ots i d e ntifi e d  o n t h e  w h ol e  b o d y s ci nti gr a p h y  at 
b as eli n e,  w hi c h  ar e  n ot  visi bl e  o n t h e  c h est,  a b d o m e n  a n d  p el vis  C T ( or  M RI) s c a n s h o ul d  b e 
i m a g e d  at  b as eli n e  a n d f oll o w e d  at s u bs e q u e nt s c h e d ul e d  visits  usi n g l o c ali z e d  C T,  M RI  or  X- 
r a y.  Aft er  b as eli n e,  w h ol e  b o d y s ci nti gr a p h y  n e e d  n ot  b e r e p e at e d,  u nl ess  cli ni c all y i n di c at e d. 
S ki n l esi o ns  pr es e nt  at  b as eli n e s h o ul d  b e  d o c u m e nt e d  usi n g  c ol or  p h ot o gr a p h y, i n cl u di n g  a 
r ul er,  s o  t h at  t h e  si z e   of  t h e  l esi o n(s)   c a n   b e   d et er mi n e d  fr o m  t h e   p h ot o gr a p h.   S ki n  
p h ot o gr a p hs s h o ul d  b e  c o nti n u e d  at s u bs e q u e nt t u m or  ass ess m e nts f or  a n y l esi o ns t h at  w er e 
p h ot o gr a p h e d  at  s cr e e ni n g. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  8 0
5  Pr ot o c ol  N o. 
 
 
 
B as eli n e   Br ai n   C T   or   M RI   will   b e   m a n d at e d  f or   all   p ati e nts   pri or  t o  st u d y  tr e at m e nt.  
S u bs e q u e nt   br ai n  s c a ns  s h o ul d   o nl y   b e   c o n d u ct e d  i n   p ati e nts  t h at   d e v el o p  s y m pt o ms  
i n di c ati v e  of  br ai n m et ast as es.  
All  C Rs  a n d  P R s  m ust  b e  c o nfir m e d  b y  a  s e c o n d  a ss e ss m e nt  n ot  e arli er t h a n  4  w e e ks l at er  a n d 
i d e all y  n o l at er t h a n  5  w e e ks  aft er t h e  crit eri a f or r es p o ns e  ar e first  m et. 
P E T/ C T   m a y   b e   us e d   o nl y  if  t h e   C T  is   of  si mil ar   di a g n osti c   q u alit y   as   a   C T   p erf or m e d  
wit h o ut  P E T, i n cl u di n g t h e  utili z ati o n  o f  or al  a n d i ntr a v e n o us  c o ntr ast m e di a.  
 
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  
 
7. 2. 2. 1   P h y si c al  e x a mi n ati o n  
A  c o m pl et e  p h ysi c al   e x a mi n ati o n  will  i n cl u d e t h e  e x a mi n ati o n  of   g e n er al   a p p e ar a n c e,  s ki n, 
n e c k (i n cl u di n g t h yr oi d),  e y es,  e ars,  n os e, t hr o at, l u n gs,  h e art,  a b d o m e n,  b a c k, l y m p h  n o d es, 
e xtr e miti es,  v as c ul ar  a n d  n e ur ol o gi c al. If i n di c at e d  b as e d  o n  m e di c al  hi st or y  a n d/ or s y m pt o ms, 
r e ct al,  e xt er n al  g e nit ali a,  br e ast,  a n d  p el vi c  e x a ms  will  b e  p erf or m e d. 
A  s h ort   p h ysi c al   e x a m   will  i n cl u d e  t h e   e x a mi n ati o n   of   g e n er al   a p p e ar a n c e   a n d   vit al  si g ns  
( bl o o d  pr ess ur e [ B P]  a n d  p uls e).  A s h ort  p h ysi c al  e x a m  will  b e  at  all  visits st arti n g fr o m  Visit 
3  e x c e pt  w h e n it is  cli ni c all y i n di c at e d.  
 
7. 2. 2. 2   Vit al  si g n s  
Vit al si g ns i n cl u di n g  bl o o d  pr ess ur e  a n d  p uls e  m e as ur e m e nts  will  b e  c oll e ct e d  b ef or e  d osi n g 
at t h e  cli ni c.  Aft er t h e  p ati e nt  h as  b e e n sitti n g f or fi v e  mi n ut es,  wit h  b a c k s u p p ort e d  a n d  b ot h 
f e et  pl a c e d  o n t h e fl o or, s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur e  will  b e  m e as ur e d. I n  c as e t h e 
c uff  si z es   a v ail a bl e   ar e   n ot  l ar g e   e n o u g h  f or  t h e   p ati e nt's   ar m   cir c u mf er e n c e,   a  
s p h y g m o m a n o m et er  wit h  a n  a p pr o pri at el y si z e d  c uff  m a y  b e   us e d. 
 
7. 2. 2. 3   H ei g ht  a n d  w ei g ht  
H ei g ht (s cr e e ni n g  o nl y) i n  c e nti m et ers ( c m)  a n d  b o d y  w ei g ht (t o t h e  n e ar est  0. 1  kil o gr a m [ k g] 
i n i n d o or  cl ot hi n g,  b ut  wit h o ut s h o es)  will  b e  m e as ur e d. 
 
7. 2. 2. 4   P erf or m a n c e  st at u s  
E C O G  p erf or m a n c e st at us  will  b e  ass ess e d.  
 
T a bl e   7- 3  
E C O G  p erf or m a n c e  st at u s  
Gr a d e  
E C O G  St at u s  
 
0 
F ull y  a cti v e,  a bl e t o  c arr y  o n  all  pr e -di s e a s e  p erf or m a n c e  wit h o ut  r e stri cti o n 
 
1 
R e stri ct e d i n  p h y si c all y  str e n u o u s  a cti vit y  b ut  a m b ul at or y  a n d  a bl e t o  c arr y  o ut  w or k  of  a li g ht 
or  s e d e nt ar y  n at ur e ( e. g., li g ht  h o u s e  w or k,  offi c e  w or k)  
 
2 
A m b ul at or y  a n d  c a p a bl e  of  all  s elf -c ar e  b ut  u n a bl e t o  c arr y  o ut  a n y  w or k  a cti viti e s.  U p  a n d 
a b o ut  m or e t h a n  5 0 %  of  w a ki n g  h o ur s  
 
3 
C a p a bl e  of  o nl y li mit e d  s elf -c ar e,  c o nfi n e d t o  b e d  or  c h air  m or e t h a n  5 0 %  of  w a ki n g  h o ur s  
 
4 
C o m pl et el y  di s a bl e d.  C a n n ot  c arr y  o n  a n y  s elf -c ar e.  T ot all y  c o nfi n e d t o  b e d  or  c h air  
 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  8 1
5  Pr ot o c ol  N o. 
 
 
 
7. 2. 2. 5   L a b or at or y  e v al u ati o n s  
 
T a bl e   7- 4  
L o c al  Cli ni c al l a b or at or y  p ar a m et er s  c oll e cti o n  pl a n  
 
T e st  C at e g or y   
T e st  N a m e  
H e m at ol o g y   
H e m at o crit,  H e m o gl o bi n,  Pl at el et s,  R e d  bl o o d  c ell s,  W hit e  bl o o d  c ell s,  W B C  M or p h ol o g y 
wit h  Diff er e nti al ( B a s o p hil s,  E o si n o p hil s,  L y m p h o c yt e s,  M o n o c yt e s,  N e utr o p hil s)  
C h e mi str y  
Al b u mi n,  Al k ali n e  p h o s p h at a s e,  A L T ( S G P T),  A S T ( S G O T),  C al ci u m,  M a g n e si u m, 
p h o s p h or o u s,  P ot a s si u m,  C hl ori d e,  Cr e ati ni n e,  Cr e ati n e  ki n a s e,  Dir e ct  Bilir u bi n, I n dir e ct 
Bilir u bi n,  T ot al  Bilir u bi n,  T ot al  C h ol e st er ol,  T ot al  Pr ot ei n,  Tri gl y c eri d e s,  Bl o o d  Ur e a  
Nit r o g e n ( B U N)  or  Ur e a,  S er u m  a m yl a s e,  S er u m li p a s e , f a sti n g  pl a s m a  gl u c o s e,  G G T 
Uri n al y si s  
Di p sti c k  m e a s ur e m e nt s f or  s p e cifi c  gr a vit y,  p H,  pr ot ei n,  gl u c o s e,  bilir u bi n,  k et o n e s, 
l e u k o c yt e s,  a n d  bl o o d  will  b e  p erf or m e d.  A n y  cli ni c all y  si g nifi c a nt fi n di n g s  o n  di p sti c k  will 
b e f oll o w e d  u p  wit h  a  mi cr o s c o pi c  e v al u ati o n.  
C o a g ul ati o n   
Pr ot hr o m bi n ti m e  ( P T)  or 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) 
Gl u c o s e  a n d i n s uli n 
m o nit ori n g  
( o nl y f or  B Y L 7 1 9) 
F a sti n g  pl a s m a  gl u c o s e, i n s uli n,  c -p e pti d e,  H e m o gl o bi n  A 1 c  
T e st s f or 
h e p at ot o xi cit y  f oll o w- 
u p (if  cli ni c all y 
i n di c at e d f or 
I N C 2 8 0) 
L F T s:  al b u mi n,  A L T,  A S T,  G G T, t ot al  bilir u bi n,  dir e ct  a n d i n dir e ct  bilir u bi n,  A L P  A L P 
fr a cti o n at e d ( q u a ntifi c ati o n  of i s of or m s) 
Cr e ati n e  ki n a s e,  pr ot hr o m bi n ti m e ( P T)/I N R  
T e sti n g f or  a c ut e  h e p atiti s  A,  B,  C  or  E i nf e cti o n,  ot h er  h e p at otr o pi c  vir al i nf e cti o n  a n d 
a ut oi m m u n e  h e p atiti s  a s  cli ni c all y i n di c at e d (r ef er t o  S e cti o n  1 4. 3. 2 ) 
A l o c al l a b or at or y  will  b e  us e d f or  a n al ysis  of  all s p e ci m e ns  c oll e ct e d.  
 
7. 2. 2. 5. 1  H e m at ol o g y  
H e m at ol o g y  p a n el  o utli n e d i n  T a bl e  7 - 4  will  b e  p erf or m e d  as  p er t h e  ass ess m e nt s c h e d ul e i n 
T a bl e  7 - 1. 
 
7. 2. 2. 5. 2  Cli ni c al   c h e mi str y 
C h e mistr y  p a n el  o utli n e d i n  T a bl e  7 - 4  will  b e  p erf or m e d  as  p er t h e  ass ess m e nt s c h e d ul e i n 
T a bl e  7 - 1. 
 
7. 2. 2. 5. 3  C o a g ul ati o n  
C o a g ul ati o n  p a n el  o utli n e d i n  T a bl e  7 - 4  will  b e  p erf or m e d  as  p er t h e  ass ess m e nt s c h e d ul e i n 
T a bl e  7 - 1.  A  c o a g ul ati o n  pr ofil e  m ust  b e  p erf or m e d  wit hi n  7 2  h o urs  pri or t o t u m or  bi o psi es. 
C o a g ul ati o n   d uri n g  s cr e e ni n g   a n d   E O T   will   o nl y   b e   p erf or m e d  if   a   n e wl y   o bt ai n e d  t u m or 
s a m pl e  will  b e  c oll e ct e d. 
 
7. 2. 2. 5. 4  Uri n al y si s  
Uri n al ysis  p a n el  o utli n e d i n  T a bl e  7 - 4  will  b e  p erf or m e d  as  p er t h e  ass ess m e nt s c h e d ul e i n  
T a bl e  7 - 1. 
 
7. 2. 2. 5. 5  Pr e g n a n c y  a n d  a s s e s s m e nt s  of  f ertilit y 
Pr e g n a n c y  t ests  will  b e  p erf or m e d  as  p er t h e  ass ess m e nt s c h e d ul e i n T a bl e  7 - 1. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  8 2
5  Pr ot o c ol  N o. 
 
 
 
All  w o m e n  of  c hil d b e ari n g  p ot e nti al  m ust  c o m pl et e  a  uri n e  pr e g n a n c y t est  at t h e s cr e e ni n g 
visit,  wit hi n  7 2  h o urs  pri or t o first  a d mi nist r ati o n  of t h e st u d y tr e at m e nt ( C y cl e  1  D a y  1)  a n d 
at  E O T.  
W o m e n  w h o  ar e  n ot  of  c hil d b e ari n g  p ot e nti al  d o  n ot r e q uir e  a  pr e g n a n c y t est,  b ut  m ust f ulfill 
t h e   c o n diti o ns  f or  t h e   n o n-c hil d b e ari n g  st at us   gi v e n  i n   S e cti o n   5. 3 ,   p oi nt   1 2.  I n   c as e   of  
pr e g n a n c y,  t h e  p ati e nt   m ust   p er m a n e ntl y st o p st u d y  tr e at m e nt  i m m e di at el y,   wit h dr a w fr o m   
t h e tri al,  a n d t h e  pr e g n a n c y  m ust  b e r e p ort e d  o n t h e  Cli ni c al  Tri al  Pr e g n a n c y  F or m. 
 
7. 2. 2. 5. 6   Gl u c o s e/i n s uli n  m o nit ori n g  ( B Y L 7 1 9) 
F asti n g s er u m i ns uli n, f asti n g s er u m  C -p e pti d e  a n d f asti n g  pl as m a  gl u c os e ( F P G) f or i ns uli n 
a n d  gl u c os e s af et y  m o nit ori n g  will  b e  ass ess e d  pr e -d os e  pri or t o t h e li g ht  br e a kf ast  at l e ast 
o n c e  w e e kl y.  P ati e nts  m ust  b e f asti n g  o v er ni g ht f or  at l e ast  8  h o urs.  A d diti o n al  m e as ur e m e nts 
m a y  b e  p erf or m e d  as  cli ni c all y i n di c at e d.  H e m o gl o bi n  A 1 c t esti n g f or  h y p er gl y c e mi a  will  b e 
ass e ss e d  at t h e s c h e d ul e i n  T a bl e  7 - 1. 
 
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)  
St a n d ar d  1 2 l e a d  E C G  will  b e  p erf or m e d  as  p er t h e  ass ess m e nt s c h e d ul e i n  T a bl e  7 - 1.  T h e 
u ns c h e d ul e d  E C G  will  b e  p erf or m e d i n  c as e  of  a n y si g ns  a n d/  or s y m pt o ms  as j u d g e d  b y t h e 
i n v esti g at or.   F or   all   p ati e nts,   3  s e q u e nti al   1 2-l e a d   E C Gs,  s e p ar at e d   b y   a p pr o xi m at el y   2  
mi n ut es,  m ust  b e  p erf or m e d  d uri n g s cr e e ni n g.  T his is  n e c ess ar y t o  g et  a n  a c c ur at e  b as eli n e 
Q T c F  c al c ul ati o n.  O n e si n gl e  E C G  will  b e  p erf or m e d f or t h e  ot h er ti m e -p oi nts  d uri n g t h e tri al 
a n d  Q T c F is  us e d t o  c orr e ct t h e  Q T i nt er v als.  
I nt er pr et ati o n  of t h e tr a ci n g  m ust  b e  m a d e  b y  a  q u alifi e d  p h ysi ci a n  a n d  d o c u m e nt e d  o n t h e 
E C G  C R F  p a g e.  E a c h  E C G tr a ci n g s h o ul d  b e l a b el e d  wit h t h e st u d y  n u m b er,  p ati e nt i niti als 
( w h er e  r e g ul ati o ns   p er mit),   p ati e nt   n u m b er,   d at e,   a n d   k e pt  i n  t h e  s o ur c e   d o c u m e nts   at  t h e  
st u d y  sit e.   E C Gs   m a y   b e s e nt  t o   a  N o v artis   d esi g n at e d  l a b or at or y  f or  r etr os p e cti v e   c e ntr al  
r e vi e w  i n   a d diti o n al  t o  t h e l o c al  r e vi e w  i n   c as e  it  is  n e e d e d  t o  f urt h er   c o nfir m  t h e  c ar di a c  
s af et y  of t h e st u d y tr e at m e nt(s).  All  eli gi b ilit y  a n d  p ati e nt  m a n a g e m e nt  d e cisi o ns s h o ul d  b e 
m a d e  b as e d  o n t h e l o c al r e a di n g  of t h e  E C G.  
 
7. 2. 2. 6. 2  C ar di a c i m a gi n g  - M U G A ( m ulti pl e  g at e d  a c q ui siti o n)  s c a n  or 
e c h o c ar di o gr a m ( B Y L 7 1 9/ M E K 1 6 2)  
 
F or  B Y L 1 7 9  ar m:  
A  M U G A  or  E C H O s c a n s h o ul d  b e  p erf or m e d  d uri n g s cr e e ni n g  a n d  at  E O T t o  ass ess t h e l eft 
v e ntri c ul ar   ej e cti o n  fr a cti o n  ( L V E F).   T h es e   c ar di a c  i m a gi n g   ass ess m e nts   m a y   b e  r e p e at e d  
d uri n g tr e at m e nt  o nl y if  cli ni c all y i n di c at e d.  
 
F or  M E K 1 6 2  ar m:  
A  M U G A  or  E C H O s c a n s h o ul d  b e  p erf or m e d  d uri n g s cr e e ni n g,  C 1 D 2 2,  C 2 D 2 2,   f oll o wi n g 
wit h  e v er y  8  w e e ks  at t h e  b e gi n ni n g  of  C 2 D 2 2  a n d  at  E O T t o  ass ess t h e l eft  v e ntri c ul ar  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  8 3
5  Pr ot o c ol  N o. 
 
 
 
ej e cti o n  fr a cti o n  ( L V E F).   T h es e   c ar di a c  i m a gi n g   ass ess m e nts   m a y   b e  r e p e at e d   d uri n g  
tr e at m e nt  o nl y if  cli ni c all y i n di c at e d. 
 
7. 2. 2. 6. 3  C ar di a c  e n z y m e s  ( B Y L 7 1 9/ L D K 3 7 8/ M E K 1 6 2) 
 
B Y L 7 1 9  a n d  L D K 3 7 8  
C ar di a c  e n z y m es tr o p o ni n -I   or  tr o p o ni n-T   will  b e  c oll e ct e d   p er  t h e  ass ess m e nt  s c h e d ul e i n  
T a bl e  7 - 1.  T h es e  p ar a m et ers s h o ul d  b e  ass ess e d  d uri n g tr e at m e nt  o nl y if  cli ni c all y i n di c at e d. 
 
M E K 1 6 2  
C K  a n d tr o p o ni n (tr o p o ni n -I  or tr o p o ni n-T)  will  b e  ass e ss e d  p er t h e  ass ess m e nt s c h e d ul e i n 
T a bl e  7 - 1.  If  C K  ≥ 3 x  U L N,  a  w e e kl y  f oll o w  u p  of is o e n z y m es,  a n d  m y o gl o bi n i n  bl o o d  a n d 
uri n e  will  b e  d o n e,  a n d tr o p o ni n  as  a p pli c a bl e.  
7. 2. 2. 7   O p ht h al m ol o g y  e x a m s ( M E K 1 6 2) 
M E K 1 6 2  
F ull   o p ht h al mi c   e x a mi n ati o n  i n cl u di n g  slit  l a m p   e x a mi n ati o n,   vis u al   a c uit y  t esti n g,   vis u al  
fi el d  t esti n g,  i ntr a o c ul ar   pr ess ur e  (I O P)   a n d  i n dir e ct  f u n d os c o p y   wit h   att e nti o n  t o  r eti n al  
a b n or m aliti es,   es p e ci all y   c e ntr al  s er o us  r eti n o p at h y   a n d   R V O,   will   b e   p erf or m e d   p er  t h e  
ass e ss m e nt s c h e d ul e i n  T a bl e   7- 1. 
F or   p ati e nts   wit h   cli ni c al  s us pi ci o n   of   c e ntr al  s er o us  r eti n o p at h y   or   R V O,   a d diti o n al  
ass e ss m e nt s   of  fl u or es c ei n   a n gi o gr a p h y   a n d/ or   o pti c al   c o h er e n c e  t o m o gr a p h y   a n d  
El e ctr or eti n o gr a m ( E R G)  ar e r e c o m m e n d e d.  
 
7. 2. 3   
P h ar m a c o ki n eti c s  
P K  p ar a m et ers  will  b e  esti m at e d fr o m  e a c h i n di vi d u al  pl as m a  c o n c e ntr ati o n -ti m e  pr ofil e  usi n g 
n o n- c o m p art m e nt al  a n al ysis ( P h o e ni x s oft w ar e  v ersi o n  6. 2  a n d  a b o v e).  P K  p ar a m et ers t o  b e 
e v al u at e d   ar e  i n cl u d e d  i n  t h e  st atisti c al   a n d   d at a   a n al ysis  s e cti o n   of  t hi s   pr ot o c ol  ( S e cti o n  
1 0. 5. 3 ). 
 
 
 
7. 2. 3. 1   P h ar m a c o ki n eti c  bl o o d  c oll e cti o n  a n d  h a n dli n g  
S eri al i nt e nsi v e  P K  bl o o d s a m pl es  will  b e  c oll e ct e d fr o m  at l e ast  1 2  p ati e nts fr o m  B Y L 7 1 9 
ar m,  at l e ast  6  p ati e nts tr e at e d  wit h I N C 2 8 0 t a bl et,  a n d  at l e ast  6  p ati e nts fr o m  ot h er tr e at m e nt 
ar ms f or t h e  a n al ysis  of t h e  pl as m a  c o n c e ntr ati o n  of  e a c h  dr u g.  S p ars e  P K  bl o o d s a m pl es  will 
b e  c oll e ct e d i n t h e r est  of  t h e  p ati e nts fr o m  e a c h tr e at m e nt  ar m.  3 ml  bl o o d s a m pl e  will  b e 
c oll e ct e d  o n  e a c h ti m e  p oi nt.  
If   p ati e nts   e x p eri e n c e   a  s eri o us   a d v ers e   e v e nt   or   a n   a d v ers e   e v ent  l e a di n g  t o  t h e  
dis c o nti n u ati o n  of t h e st u d y tr e at m e nt  as  p er  d efi niti o n i n  S e cti o n  7. 1. 4. 1 ,  a n  u ns c h e d ul e d  P K 
bl o o d s a m pl e s h o ul d  b e  o bt ai n e d  w h e n e v er  p ossi bl e  a n d t h e  d at e  a n d ti m e  of t h e l ast  d os e  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  8 4
4  Pr ot o c ol  N o. 
 
 
 
 
s h o ul d  b e r e c or d e d. I n  a d diti o n, t h e  u ns c h e d ul e d  P K s a m pl e s h o ul d  als o  b e  c oll e ct e d i n  c as e 
t h e  p ati e nt  p erf or ms t h e  u ns c h e d ul e d  E C G  as  p er t h e S e cti o n  7. 2. 2. 6. 1 . 
O n  t h e   d a y   of   P K  s a m pli n g,  if   v o miti n g   o c c urs   wit hi n   4   h o urs  f oll o wi n g   or al   dr u g  
a d mi nistr ati o n  of  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2, t h e  o c c urr e n c e  of  v o miti n g  a n d 
ti m e  will  b e r e c or d e d  o n t h e  P K s a m pli n g  p a g e  of  e C R F. 
Pl e as e r ef er t o  T a bl e  7 - 5 t o T a bl e  7 - 8 for i nt e nsi v e  bl o o d  c oll e cti o n s c h e d ul e,  a n d  T a bl e  7 - 9 t o 
T a bl e  7 - 1 2 f or s p ars e  P K  bl o o d  c oll e cti o n s c h e d ul e f or  e a c h tr e at m e nt  ar m. 
C o m pl et e i nstr u cti o ns f or   bl o o d  c oll e cti o n,  h a n dli n g  a n d s hi p m e nt   of   P K  s a m pl es f or   e a c h  
c o m p o u n d  will  b e  pr o vi d e d i n t h e  [ L a b or at or y  M a n u al]. 
 
T a bl e   7- 5  
I nt e n si v e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g f or B Y L 7 1 9  
 
Tr e at m e nt 
C y cl e  
 
D a y  
 
S c h e d ul e d  Ti m e  P oi nt  
D o s e  R ef er e n c e 
I D  B Y L 7 1 9 
P K  S a m pl e 
N o  B Y L 7 1 9  
 
D e s cri pti o n  
1 
1  
Pr e -d o s e  
2 0 1  
2 0 1  
B ef or e  d o s e  o n  C y cl e  1, 
D a y  1  
1 
1  
0. 5  h o ur s  ±  1 0  mi n ut e s   
2 0 1  
2 0 2  
 
1 
1  
1  h o ur s  ±  1 0 mi n ut e s   
2 0 1  
2 0 3  
 
1  
1   
2  h o ur s  ±  1 0  mi n ut e s   
2 0 1  
2 0 4  
 
1  
1   
4  h o ur s  ±  3 0  mi n ut e s   
2 0 1  
2 0 5  
 
1  
1   
6  h o ur s  ±  1  h o ur   
2 0 1  
2 0 6  
 
1 
1  
8  h o ur s  ±  1  h o ur   
2 0 1  
2 0 7  
 
1 
2  
2 4  h o ur s  ±  2  h o ur s c  
2 0 1 a /  2 0 0 1 b  
2 0 8  
B ef or e  d o s e  o n  C y cl e  1, 
D a y  2  
1  
1 5   
Pr e -d o s e c  
2 0 2 b /  2 0 0 2 a  
2 0 9  
B ef or e  d o s e  o n  C y cl e  1, 
D a y  1 5  
1  
1 5   
0. 5  h o ur s  ±  1 0  mi n ut e s   
2 0 2  
2 1 0  
 
1  
1 5   
1  h o ur s  ±  1 0  mi n ut e s   
2 0 2  
2 1 1  
 
1 
1 5   
2  h o ur s  ±  3 0  mi n ut e s   
2 0 2  
2 1 2  
 
1 
1 5   
4  h o ur s  ±  3 0  mi n ut e s   
2 0 2  
2 1 3  
 
1  
1 5   
6  h o ur s  ±  1  h o ur   
2 0 2  
2 1 4  
 
1  
1 5   
8  h o ur s  ±  1  h o ur   
2 0 2  
2 1 5  
 
1  
1 6   
2 4  h o ur s  ±  2  h o ur s c  
2 0 2 a /  2 0 0 3 b  
2 1 6  
B ef or e  d o s e  o n  C y cl e  1, 
D a y  1 6  
2 
1  
Pr e -d o s e c  
2 0 3 a /  2 0 0 4 b  
2 1 7  
B ef or e  d o s e  o n  C y cl e  2, 
D a y  1  
3 
1  
Pr e -d o s e c  
2 0 4 a /  2 0 0 5 b  
2 1 8  
B ef or e  d o s e  o n  C y cl e  3, 
D a y  1  
 
 
U n s c h e d ul e d  
 
2 1 0 1 + d  
 
I nt e n si v e  P K  bl o o d  c oll e cti o n  will  b e  p erf or m e d i n  at l e a st  1 2  p ati e nt s fr o m  B Y L 7 1 9 tr e at m e nt  ar m 
a d o s e  a d mi ni str ati o n r e c or d  b ef or e  P K  s a m pli n g;  
b d o s e  a d mi ni str ati o n r e c or d  aft er  P K  s a m pli n g;  
c P K  s a m pl e  s h o ul d  b e  c oll e ct e d  b ef or e  n e xt  d o s e  s c h e d ul e  
d U n s c h e d ul e d  P K  s a m pl e  n u m b er  st art s fr o m  2 1 0 1  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  8 5
4  Pr ot o c ol  N o. 
 
 
 
 
 
T a bl e   7- 6  
I nt e n si v e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g f or I N C 2 8 0 
 
Tr e at m e nt 
C y cl e  
 
D a y  
 
S c h e d ul e d  Ti m e  P oi nt  
D o s e  R ef er e n c e 
I D I N C 2 8 0 
P K  S a m pl e  N o 
I N C 2 8 0 
 
D e s cri pti o n  
1 
1 5   
Pr e -d o s e c  
3 0 1 b /  3 0 0 1a  
3 0 1  
B ef or e  m or ni n g  d o s e 
o n  C y cl e  1,  D a y  1 5  
1  
1 5   
0. 5  h o ur  ±  1 0  mi n ut e s   
3 0 1  
3 0 2  
 
1  
1 5   
1  h o ur  ±  1 0  mi n ut e s   
3 0 1  
3 0 3  
 
1  
1 5   
2  h o ur s  ±  1 0  mi n ut e s   
3 0 1  
3 0 4  
 
1  
1 5   
4  h o ur s  ±  3 0  mi n ut e s   
3 0 1  
3 0 5  
 
1  
1 5   
6  h o ur s  ±  1  h o ur   
3 0 1  
3 0 6  
 
1  
1 5   
8  h o ur s  ±  1  h o ur   
3 0 1  
3 0 7  
 
2 
1  
Pr e -d o s e c  
3 0 2 a /  3 0 0 2 b  
3 0 8  
B ef or e  m or ni n g  d o s e 
o n  C y cl e  2,  D a y  1  
3 
1  
Pr e -d o s e c  
3 0 3 a /  3 0 0 3 b  
3 0 9  
B ef or e  m or ni n g  d o s e 
o n  C y cl e  3,  D a y  1  
 
 
U n s c h e d ul e d  
 
3 1 0 1 + d  
 
I nt e n si v e  P K  bl o o d  c oll e cti o n  will  b e  p erf or m e d i n  at l e a st  6  p ati e nt s fr o m I N C 2 8 0 tr e at m e nt  ar m 
a d o s e  a d mi ni str ati o n r e c or d  b ef or e  P K  s a m pli n g;  
b d o s e  a d mi ni str ati o n r e c or d  aft er  P K  s a m pli n g;  
c P K  s a m pl e  s h o ul d  b e  c oll e ct e d  b ef or e  n e xt  d o s e  s c h e d ul e  
d U n s c h e d ul e d  P K  s a m pl e  n u m b er  st art s fr o m  3 1 0 1  
 
 
T a bl e   7- 7  
I nt e n si v e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g f or L D K 3 7 8  
 
Tr e at m e nt 
C y cl e  
 
D a y  
S c h e d ul e d  Ti m e 
P oi nt  
D o s e  R ef er e n c e 
I D  L D K 3 7 8 
P K  S a m pl e  N o 
L D K 3 7 8  
 
D e s cri pti o n  
1 
1 5   
Pr e -d o s e c  
4 0 1 b /  4 0 0 1a  
4 0 1  
B ef or e  d o s e  o n 
C y cl e  1,  D a y  1 5  
1  
1 5   
0. 5  h o ur  ±  1 0  mi n ut e s   
4 0 1  
4 0 2  
 
1  
1 5   
1  h o ur  ±  1 0  mi n ut e s   
4 0 1  
4 0 3  
 
1  
1 5   
2  h o ur  ±  1 0  mi n ut e s   
4 0 1  
4 0 4  
 
1  
1 5   
4  h o ur s  ±  3 0  mi n ut e s   
4 0 1  
4 0 5  
 
1 
1 5   
6  h o ur s  ±  1  h o ur   
4 0 1  
4 0 6  
 
1  
1 5   
8  h o ur s  ±  1  h o ur   
4 0 1  
4 0 7  
 
1 
1 6   
2 4  h o ur s  ±  2  h o ur s   
4 0 1 a /  4 0 0 2 b  
4 0 8  
B ef or e  d o s e  o n 
C y cl e  1,  D a y  1 6  
2 
1  
Pr e -d o s e c  
4 0 2 a /  4 0 0 3 b  
4 0 9  
B ef or e  d o s e  o n 
C y cl e  2,  D a y  1  
3 
1  
Pr e -d o s e c  
4 0 3 a /  4 0 0 4 b  
4 1 0  
B ef or e  d o s e  o n 
C y cl e  3,  D a y  1  
 
 
U n s c h e d ul e d  
 
4 1 0 1 + d  
 
I nt e n si v e  P K  bl o o d  c oll e cti o n  will  b e  p erf or m e d i n  at l e a st  6  p ati e nt s fr o m  L D K 3 7 8 tr e at m e nt  ar m 
a d o s e  a d mi ni str ati o n r e c or d  b ef or e  P K  s a m pli n g;  
b d o s e  a d mi ni str ati o n r e c or d  aft er  P K  s a m pli n g;  
c P K  s a m pl e  s h o ul d  b e  c oll e ct e d  b ef or e  n e xt  d o s e  s c h e d ul e  
d U n s c h e d ul e d  P K  s a m pl e  n u m b er  st art s fr o m  4 1 0 1  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 8 6 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
T a bl e   7- 8  
I nt e n si v e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g f or M E K 1 6 2  
Tr e at m e nt 
C y cl e   
D a y   
S c h e d ul e d  Ti m e  P oi nt  
D o s e  R ef er e n c e 
I D  M E K 1 6 2 
P K  S a m pl e  N o 
M E K 1 6 2   
D e s cri pti o n  
1 
1 5   
Pr e -d o s e c  
5 0 1 b /  5 0 0 1a  
5 0 1  
B ef or e  m or ni n g  d o s e 
o n  C y cl e  1,  D a y  1 5  
1  
1 5   
0. 5  h o ur  ±  1 0  mi n ut e s   
5 0 1  
5 0 2  
1  
1 5   
1  h o ur  ±  1 0  mi n ut e s   
5 0 1  
5 0 3  
1  
1 5   
2  h o ur s  ±  1 0  mi n ut e s   
5 0 1  
5 0 4  
1  
1 5   
4  h o ur s  ±  3 0  mi n ut e s   
5 0 1  
5 0 5  
1  
1 5   
6  h o ur s  ±  1  h o ur   
5 0 1  
5 0 6  
1  
1 5   
8  h o ur s  ±  1  h o ur   
5 0 1  
5 0 7  
2 
1  
Pr e -d o s e c  
5 0 2 a /  5 0 0 2 b  
5 0 8  
B ef or e  m or ni n g  d o s e 
o n  C y cl e  2,  D a y  1  
3 
1  
Pr e -d o s e c  
5 0 3 a /  5 0 0 3 b  
5 0 9  
B ef or e  m or ni n g  d o s e 
o n  C y cl e  3,  D a y  1  
U n s c h e d ul e d  
5 1 0 1 + d  
I nt e n si v e  P K  bl o o d  c oll e cti o n  will  b e  p erf or m e d i n  at l e a st  6  p ati e nt s fr o m  M E K 1 6 2 tr e at m e nt  ar m 
a d o s e  a d mi ni str ati o n r e c or d  b ef or e  P K  s a m pli n g;  
b d o s e  a d mi ni str ati o n r e c or d  aft er  P K  s a m pli n g;  
c P K  s a m pl e  s h o ul d  b e  c oll e ct e d  b ef or e  n e xt  d o s e  s c h e d ul e  
d U n s c h e d ul e d  P K  s a m pl e  n u m b er  st art s fr o m  5 1 0 1  
T a bl e   7- 9  
S p ar s e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g f or  B Y L 7 1 9  
Tr e at m e nt 
C y cl e   
D a y  
S c h e d ul e d  Ti m e 
P oi nt  
D o s e  R ef er e n c e 
N o  B Y L 7 1 9  
P K  S a m pl e  N o 
B Y L 7 1 9  
D e s cri pti o n  
1 
1 5   
Pr e -d o s e c  
2 5 1 b /  2 0 5 1a  
2 5 1  
B ef or e  d o s e  o n 
C y cl e  1,  D a y  1 5  
1 5   
2  h o ur s  ±  3 0  mi n ut e s   
2 5 1  
2 5 2  
1 5   
6  h o ur s  ±  1  h o ur   
2 5 1  
2 5 3  
1 6   
2 4  h o ur s  ±  2  h o ur s c  
2 5 1 a /  2 0 5 2 b  
2 5 4  
B ef or e  d o s e  of 
C y cl e  1,  D a y  1 6  
2 
1  
Pr e -d o s e c  
2 5 2 a /  2 0 5 3 b  
2 5 5  
B ef or e  d o s e  of 
C y cl e  2,  D a y  1  
3 
1  
Pr e -d o s e c  
2 5 3 a /  2 0 5 4 b  
2 5 6  
B ef or e  d o s e  of 
C y cl e  3,  D a y  1  
U n s c h e d ul e d  
2 5 0 1 + d  
a d o s e  a d mi ni str ati o n r e c or d  b ef or e  P K  s a m pli n g;  
b d o s e  a d mi ni str ati o n r e c or d  aft er  P K  s a m pli n g;  
c P K  s a m pl e  s h o ul d  b e  c oll e ct e d  b ef or e  n e xt  d o s e  s c h e d ul e  
d U n s c h e d ul e d  P K  s a m pl e  n u m b er  st art s fr o m  2 5 0 1  
T a bl e   7-1 0   
S p ar s e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g f or  I N C 2 8 0 
Tr e at m e nt 
C y cl e  
D a y   
S c h e d ul e d  Ti m e  P oi nt  
D o s e  R ef er e n c e 
N o I N C 2 8 0  
P K  S a m pl e  N o 
I N C 2 8 0 
D e s cri pti o n  
1 
1 5   
Pr e -d o s e c  
3 5 1 b /  3 0 5 1a  
3 5 1  
B ef or e  m or ni n g  d o s e 
o n  C y cl e  1,  D a y  1 5  
1  
1 5   
2  h o ur  ±  3 0  mi n ut e s   
3 5 1  
3 5 2  
1  
1 5   
6  h o ur s  ±  1  h o ur   
3 5 1  
3 5 3  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 8 7 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
Tr e at m e nt 
C y cl e   
D a y   
S c h e d ul e d  Ti m e  P oi nt  
D o s e  R ef er e n c e 
N o I N C 2 8 0  
P K  S a m pl e  N o 
I N C 2 8 0 
D e s cri pti o n  
2 
1  
Pr e -d o s e c  
3 5 2 a /  3 0 5 2 b  
3 5 4  
B ef or e  m or ni n g  d o s e 
o n  C y cl e  2,  D a y  1  
3 
1  
Pr e -d o s e c  
3 5 3 a /  3 0 5 3 b  
3 5 5  
B ef or e  m or ni n g  d o s e 
o n  C y cl e  3,  D a y  1  
U n s c h e d ul e d  
3 5 0 1 + d  
a d o s e  a d mi ni str ati o n r e c or d  b ef or e  P K  s a m pli n g;  
b d o s e  a d mi ni str ati o n r e c or d  aft er  P K  s a m pli n g;  
c P K  s a m pl e  s h o ul d  b e  c oll e ct e d  b ef or e  n e xt  d o s e  s c h e d ul e  
d U n s c h e d ul e d  P K  s a m pl e  n u m b er  st art s fr o m  3 5 0 1  
T a bl e   7-1 1   
S p ar s e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g f or  L D K 3 7 8  
Tr e at m e nt 
C y cl e   
D a y   
S c h e d ul e d  Ti m e  P oi nt  
D o s e  R ef er e n c e 
N o  L D K 3 7 8  
P K  S a m pl e  N o 
L D K 3 7 8  
D e s cri pti o n  
1 
1 5   
Pr e -d o s e c  
4 5 1 b /  4 0 5 1a  
4 5 1  
B ef or e  d o s e  o n  C y cl e 
1,  D a y  1 5  
1 
1 5   
2  h o ur s  ±  3 0  mi n ut e s   
4 5 1  
4 5 2  
1  
1 5   
6  h o ur s  ±  1  h o ur   
4 5 1  
4 5 3  
2 
1  
Pr e -d o s e c  
4 5 2 a /  4 0 5 2 b  
4 5 4  
B ef or e  d o s e  o n  C y cl e 
2,  D a y  1  
3 
1  
Pr e -d o s e c  
4 5 3 a /  4 0 5 3 b  
4 5 5  
B ef or e  d o s e  o n  C y cl e 
3,  D a y  1  
U n s c h e d ul e d  
4 5 0 1 + d  
a d o s e  a d mi ni str ati o n r e c or d  b ef or e  P K  s a m pli n g;  
b d o s e  a d mi ni str ati o n r e c or d  aft er  P K  s a m pli n g;  
c P K  s a m pl e  s h o ul d  b e  c oll e ct e d  b ef or e  n e xt  d o s e  s c h e d ul e  
d U n s c h e d ul e d  P K  s a m pl e  n u m b er  st art s fr o m  4 5 0 1  
T a bl e   7-1 2   
S p ar s e  p h ar m a c o ki n eti c  bl o o d  c oll e cti o n l o g f or  M E K 1 6 2  
Tr e at m e nt 
C y cl e  
D a y   
S c h e d ul e d  Ti m e  P oi nt  
D o s e  R ef er e n c e 
N o  M E K 1 6 2  
P K  S a m pl e  N o 
M E K 1 6 2  
D e s cri pti o n  
1  
1 5   
Pr e -d o s e c  
5 5 1 b / 5 0 5 1a  
5 5 1  
B ef or e  m or ni n g  d o s e 
o n  C y cl e  1,  D a y  1 5  
1  
1 5   
2  h o ur s  ±  3 0  mi n ut e s   
5 5 1  
5 5 2  
1 
1 5   
6  h o ur s  ±  1  h o ur   
5 5 1  
5 5 3  
2 
1  
Pr e -d o s e c  
5 5 2 a /  5 0 5 2 b  
5 5 4  
B ef or e  m or ni n g  d o s e 
o n  C y cl e  2,  D a y  1  
3 
1  
Pr e -d o s e c  
5 5 3 a /  5 0 5 3 b  
5 5 5  
B ef or e  m or ni n g  d o s e 
o n  C y cl e  3,  D a y  1  
U n s c h e d ul e d  
5 5 0 1 + d  
a d o s e  a d mi ni str ati o n r e c or d  b ef or e  P K  s a m pli n g;  
b d o s e  a d mi ni str ati o n r e c or d  aft er  P K  s a m pli n g;  
c P K  s a m pl e  s h o ul d  b e  c oll e ct e d  b ef or e  n e xt  d o s e  s c h e d ul e  
d U n s c h e d ul e d  P K  s a m pl e  n u m b er  st art s fr o m  5 5 0 1  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 8 8 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
7. 2. 3. 2   A n al yti c al  m et h o d  
C o n c e ntr ati o ns  of  B Y L 7 1 9,  L D K 3 7 8, I N C 2 8 0  a n d  M E K 1 6 2  will  b e  m e as ur e d i n  pl as m a  wit h 
v ali d li q ui d  c hr o m at o gr a p h y -t a n d e m   m ass s p e ctr o m etr y  ( L C-M S/ M S)   ass a ys.   L L O Q s  ar e   1 
n g/ m L  f or   B Y L 7 1 9,   L D K 3 7 8,  I N C 2 8 0   a n d   M E K 1 6 2.   A n y  r es ults   b el o w  t h e   L L O Q   a n d  
missi n g s a m p l es  will  b e l a b el e d  a c c or di n gl y. 
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 v ers e   e v e nt  is   d efi n e d   as  t h e   a p p e ar a n c e   of  ( or   w ors e ni n g   of   a n y   pr e - e xisti n g) 
u n d esir a bl e  si g n(s),  s y m pt o m(s),   or   m e di c al   c o n diti o n(s)  t h at   o c c ur   aft er   p ati e nt’s  si g n e d  
i nf or m e d  c o ns e nt  h as  b e e n  o bt ai n e d. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 8 9 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
A Es  w hi c h  o c c ur  aft er si g n at ur e  of  m ol e c ul ar  pr e -s cr e e ni n g I C F  will  o nl y  b e  c a pt ur e d if t h e y 
m e et t h e  d efi niti o n  of s eri o us  as  o utli n e d i n  S e cti o n  8. 2  a n d  ar e r e p ort e d t o  b e  c a us all y r el at e d 
wit h st u d y  pr o c e d ur es ( e. g.  a n i n v asi v e  pr o c e d ur e s u c h  as  bi o ps y).  O n c e t h e  m ai n st u d y I C F is 
si g n e d,  all  A Es  p er t h e  d es cri pti o ns  b el o w  will  b e  c a pt ur e d i n t h e  A d v ers e  E v e nt  C R F.  
A b n or m al l a b or at or y  v al u es  or t est r es ults  o c c urri n g  aft er i nf or m e d  c o ns e nt  c o nstit ut e  a d v ers e 
e v e nts  o nl y if t h e y i n d u c e  cli ni c al  si g ns  or s y m pt o ms,   ar e  c o nsi d er e d  cli ni c all y si g nifi c a nt, 
r e q uir e t h er a p y ( e. g.,  h e m at ol o gi c  a b n or m alit y t h at r e q uir es tr a nsf usi o n  or  h e m at ol o gi c al st e m 
c ell s u p p ort),  or r e q uir e  c h a n g es i n st u d y  m e di c ati o n(s).  
A d v ers e  e v e nts t h at  b e gi n  or  w ors e n  aft er i nf or m e d  c o ns e nt s h o ul d  b e r e c or d e d i n t h e  A d v ers e 
E v e nts  C R F.  C o n diti o ns t h at  w er e  alr e a d y  pr es e nt  at t h e ti m e  of i nf or m e d  c o ns e nt s h o ul d  b e 
r e c or d e d i n t h e  M e di c al  Hist or y  p a g e  of t h e  p ati e nt’s  C R F.  A d v ers e  e v e nt  m o nit ori n g s h o ul d 
b e  c o nti n u e d f or  at l e ast  3 0  d a ys f oll o wi n g t h e l ast  d os e  of st u d y tr e at m e nt.  A d v ers e  e v e nts 
(i n cl u di n g  l a b   a b n or m aliti es  t h at   c o nstit ut e   A Es)  s h o ul d   b e   d es cri b e d   usi n g   a   di a g n osis  
w h e n e v er   p ossi bl e,  r at h er  t h a n  i n di vi d u al   u n d erl yi n g  si g ns   a n d  s y m pt o ms.   W h e n   a   cl e ar  
di a g n osis   c a n n ot   b e  i d e ntifi e d,   e a c h  si g n   or  s y m pt o m  s h o ul d   b e  r e p ort e d   as   a    s e p ar at e  
A d v ers e  E v e nt. 
A d v ers e  e v e nts  will  b e  ass ess e d  a c c or di n g t o t h e  C o m m o n  T er mi n ol o g y  Crit eri a f or  A d v ers e 
E v e nts ( C T C A E)  v ersi o n  4. 0 3.  
If  C T C A E  gr a di n g  d o es  n ot  e xist f or  a n  a d v ers e  e v e nt, t he s e v erit y  of  mil d,  m o d er at e, s e v er e, 
a n d lif e -t hr e at e ni n g,  c orr es p o n di n g t o  gr a d es  1 - 4,  will  b e  us e d.  C T C A E  gr a d e  5 ( d e at h)  will 
n ot  b e  us e d i n t his  st u d y  b ut is  c oll e ct e d  a s  a  s eri o us n ess  crit eri a ;  r at h er, i nf or m ati o n  a b o ut 
d e at hs  will  b e  c oll e ct e d t h o u g h  a  D e at h f or m.  
T h e  o c c urr e n c e  of  a d v ers e  e v e nts s h o ul d  b e s o u g ht  b y  n o n -dir e cti v e  q u esti o ni n g  of t h e  p ati e nt 
(s u bj e ct)  d uri n g t h e s cr e e ni n g  pr o c ess  aft er si g ni n g i nf or m e d  c o ns e nt  a n d  at  e a c h  visit  d uri n g 
t h e  st u d y.   A d v ers e   e v e nts   als o   m a y   b e   d et e ct e d   w h e n  t h e y   ar e   v ol u nt e er e d   b y  t h e   p ati e nt  
(s u bj e ct)   d uri n g  t h e  s cr e e ni n g   pr o c ess   or   b et w e e n   visits,   or  t hr o u g h   p h ysi c al   e x a mi n ati o n,  
l a b or at or y  t est,   or   ot h er   ass ess m e nt s.   As  f ar   as   p ossi bl e,   e a c h   a d v ers e   e v e nt  s h o ul d   b e  
e v al u at e d t o  d et er mi n e:  
1. T h e s e v erit y  gr a d e ( C T C A E  Gr a d e   1- 4)
2. Its  d ur ati o n ( St art  a n d  e n d d at es)
3. Its r el ati o ns hi p t o t h e st u d y tr e at m e nt ( R e as o n a bl e  p ossi bilit y t h at  A E is r el at e d:  N o, Y es)
4. A cti o n t a k e n  wit h r es p e ct t o st u d y  or i n v esti g ati o n al tr e at m e nt ( n o n e,  d os e  a dj ust e d,
t e m p or aril y i nt erru pt e d,  p er m a n e ntl y  dis c o nti n u e d,  u n k n o w n,  n ot  a p pli c a bl e)
5. W h et h er  m e di c ati o n  or t h er a p y  w as  gi v e n ( n o  c o n c o mit a nt  m e di c ati o n/ n o n - dr u g t h er a p y,
c o n c o mit a nt  m e di c ati o n/ n o n - dr u g t h er a p y)
6. O ut c o m e ( n ot r e c o v er e d/ n ot r es ol v e d, r e c o v er e d/r es ol v e d, r e c o v eri n g/r es ol vi n g,
r e c o v er e d/r es ol v e d  wit h s e q u al a e, f at al,  u n k n o w n)
7. W h et h er it is s eri o us,  w h er e  a s eri o us  a d v ers e  e v e nt ( S A E) is  d efi n e d  as i n  S e cti o n  8. 2. 1 ,
a n d  w hi c h s eri o us n ess  crit eri a  h a v e  b e e n  m et.
All  a d v ers e  e v e nts s h o ul d  b e tr e at e d  a p pr o pri at el y. If  a  c o n c o mit a nt  m e di c ati o n  or  n o n - dr u g 
t h er a p y is  gi v e n, t his  a cti o n s h o ul d  b e r e c or d e d  o n t h e  A d v ers e  E v e nt  C R F. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 9 0 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
O n c e   a n   a d v ers e   e v e nt  is   d et e ct e d,  it  s h o ul d   b e  f oll o w e d   u ntil  its  r es ol uti o n   or   u ntil  it  is  
j u d g e d t o  b e  p er m a n e nt,  a n d  ass ess m e nt s h o ul d  b e  m a d e  at  e a c h  visit ( or  m or e fr e q u e ntl y, if 
n e c ess ar y)  of  a n y  c h a n g es i n s e v erit y, t h e s us p e ct e d r el ati o ns hi p t o t h e st u d y tr e at m e nt, t h e 
i nt erv e nti o ns r e q uir e d t o tr e at it,  a n d t h e   o ut c o m e. 
Pr o gr essi o n  of  m ali g n a n c y (i n cl u di n g f at al  o ut c o m es), if  d o c u m e nt e d  b y  us e  of  a p pr o pri at e 
m et h o d (f or  e x a m pl e,  as  p er  R E CI S T  crit eri a f or s oli d t u m ors  or  as  p er  C h es o n's  g ui d eli n es 
f or  h e m at ol o gi c al  m ali g n a n ci es), s h o ul d  n ot  b e r e p ort e d  as  a s eri o us  a d v ers e e v e nt.  
A d v ers e  e v e nts s e p ar at e fr o m t h e  pr o gr essi o n  of  m ali g n a n c y ( e x a m pl e,  d e e p  v ei n t hr o m b osis 
at t h e ti m e  of  pr o gr essi o n  or  h e m o pt ysis  c o n c urr e nt  wit h fi n di n g  of  dis e as e  pr o gr essi o n)  will 
b e  r e p ort e d   as   p er   us u al   g ui d eli n es   us e d  f or  s u c h   e v e nts   wit h   pr o p er   attri b uti o n  r e g ar di n g  
r el at e d n ess t o t h e  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  re p orti n g  
L a b or at or y  a b n or m aliti es t h at  c o nstit ut e  a n  A d v ers e  e v e nt i n t h eir  o w n ri g ht ( ar e  c o nsi d er e d 
cli n i c all y  si g nifi c a nt,  i n d u c e   cli ni c al  si g ns   or  s y m pt o ms,  r e q uir e   c o n c o mit a nt  t h er a p y   or  
r e q uir e   c h a n g es  i n  st u d y  tr e at m e nt),  s h o ul d   b e  r e c or d e d   o n  t h e   A d v ers e   E v e nts   C R F.  
W h e n e v er   p ossi bl e,   a   di a g n osis,  r at h er  t h a n   a  s y m pt o m  s h o ul d   b e   pr o vi d e d  ( e. g.   a n e mi a  
inst e a d   of  l o w   h e m o gl o bi n).   L a b or at or y   a b n or m aliti es  t h at   m e et  t h e   crit eri a  f or   A d v ers e  
E v e nts s h o ul d  b e f oll o w e d  u ntil t h e y  h a v e r et ur n e d t o  n or m al  or  a n  a d e q u at e  e x pl a n ati o n  of 
t h e   a b n or m alit y  is  f o u n d.   W h e n   a n   a b n or m al  l a b or at or y   or  t est  r es ult   c orr es p o n ds  t o   a  
si g n/s y m pt o m  of  a n  alr e a d y r e p ort e d  a d v ers e  e v e nt, it is  n ot  n e c ess ar y t o s e p ar at el y r e c or d t h e 
l a b/t est r es ult  as  a n  a d diti o n al e v e nt.  
L a b or at or y  a b n or m aliti es, t h at  d o  n ot  m e et t h e  d efi niti o n  of  a n  a d v ers e  e v e nt, s h o ul d  n ot  b e 
r e p ort e d   as   a d v ers e   e v e nts.   A   Gr a d e   3   or   4   e v e nt  (s e v er e)   as   p er   C T C A E   d o es   n ot  
a ut o m ati c all y i n di c at e  a  S A E  u nl ess it  m e ets t h e  d efi niti o n  of s eri o us  as  d efi n e d  b el o w  a n d/ or 
as  p er  i n v esti g at or’s  dis cr eti o n.   A  d os e  h ol d  or  m e di c ati o n f or t h e l a b  a b n or m alit y  m a y  b e 
r e q uir e d  b y t h e  pr ot o c ol i n  w hi c h  c as e t h e l a b  a b n or m alit y  w o ul d still,  b y  d efi niti o n,  b e  a n 
a d v ers e  e v e nt  a n d  m ust  b e r e p ort e d  as s u c h.  
8. 2  
S eri o u s  a d v er s e  e v e nt s  
8. 2. 1   
D efi niti o n s  
S eri o us  a d v ers e  e v e nt ( S A E) is  d efi n e d  as  o n e  of t h e f oll o wi n g:  
• 
Is f at al  or lif e-t hr e at e ni n g
• 
R es ults i n  p ersist e nt  or si g nifi c a nt  dis a bilit y/i n c a p a cit y
• 
C o nstit ut es  a  c o n g e nit al  a n o m al y/ birt h  d ef e ct
• 
Is  m e di c all y si g nifi c a nt, i. e.,  d efi n e d  as  a n  e v e nt t h at j e o p ar di z es t h e  p ati e nt  or  m a y
r e q uir e  m e di c al  or s ur gi c al i nt er v e nti o n t o  pr e v e nt  o n e  of t h e  o ut c o m es list e d a b o v e
• 
R e q uir es i n p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n,


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 9 1 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
• 
N ot e t h at  h os pit ali z ati o ns f or t h e f oll o wi n g r e as o ns s h o ul d  n ot  b e r e p ort e d  as s eri o us
a d v ers e  e v e nts:
• 
R o uti n e tr e at m e nt  or  m o nit ori n g  of t h e st u di e d i n di c ati o n,  n ot  ass o ci at e d  wit h  a n y
d et eri or ati o n i n   c o n diti o n
• 
El e cti v e  or  pr e -pl a n n e d tr e at m e nt f or  a  pr e -e xisti n g  c o n diti o n t h at is  u nr el at e d t o t h e
i n di c ati o n  u n d er st u d y  a n d  h as  n ot  w ors e n e d si n c e si g ni n g t h e i nf or m e d  c o ns e nt
• 
S o ci al r e as o ns  a n d r es pit e  c ar e i n t h e  a bs e n c e  of  a n y  d et eri or ati o n i n t h e  p ati e nt’s
g e n er al  c o n diti o n
• 
N ot e t h at tr e at m e nt  o n  a n  e m er g e n c y  o ut p ati e nt  b asis t h at  d o es  n ot r es ult i n  h os pit al
a d missi o n  a n d i n v ol v es  a n  e v e nt  n ot f ulfilli n g  a n y  of t h e  d efi niti o ns  of  a  S A E  gi v e n  a b o v e
is  n ot  a s eri o us  a d v ers e e v e nt
• 
Pr o gr essi o n   of   m ali g n a n c y  (i n cl u di n g  f at al   o ut c o m es),  if   d o c u m e nt e d   b y   us e   of
a p pr o pri at e   m et h o d  (f or   e x a m pl e,   as   p er   R E CI S T   crit eri a  f or  s oli d  t u m ors   or   as   p er
C h es o n's  g ui d eli n e s  f or  h e m at ol o gi c al  m ali g n a n ci es), s h o ul d  n ot  b e r e p ort e d  as  a s eri o us
a d v ers e   e v e nt.   A d v ers e   e v e nts  s e p ar at e  fr o m  t h e   pr o gr essi o n   of   m ali g n a n c y  ( e x a m pl e,
d e e p  v ei n t hr o m b osis  at t h e ti m e  of  pr o gr essi o n  or  h e m o pt ysis  c o n c urr e nt  wit h fi n di n g  of
dis e as e  pr o gr essi o n)   will   b e r e p ort e d  as  p er   us u al   g ui d eli n es  us e d f or  s u c h  e v e nts  wit h
pr o p er  attri b uti o n r e g ar di n g r el at e d n ess t o t h e  dr u g.
8. 2. 2   
R e p orti n g  
S A E  c oll e cti o n  will st art  u p o n si g ni n g t h e  m ol e c ul ar  pr e -s cr e e ni n g I C F.  S A Es  will  o nl y  b e 
r e p ort e d if t h e  e v e nt is s us p e ct e d t o  b e  c a us all y r el at e d t o  a st u d y  pr o c e d ur e  as  ass ess e d  b y t h e 
i n v esti g at or  ( e. g.   a n  i n v asi v e   pr o c e d ur e  s u c h   as   bi o ps y).   S A Es   will   b e  f oll o w e d   u ntil  
r es ol uti o n   or   u ntil   cli ni c all y  r el e v a nt  i m pr o v e m e nt   or  st a bili z ati o n.  If  t h e   m ai n  I C F  is   n ot  
si g n ed  ( m ol e c ul ar  s cr e e n  f ail ur e),   S A E   c oll e cti o n   e n ds   3 0   d a ys   aft er  t h e  l ast  st u d y  r el at e d  
pr o c e d ur e. 
T o   e ns ur e   p ati e nt  s af et y,   e v er y   S A E,  r e g ar dl ess   of  s us p e ct e d   c a us alit y,   o c c urri n g   aft er  t h e 
p ati e nt   h as  pr o vi d e d  m ai n i nf or m e d  c o ns e nt   a n d  u ntil   at l e ast   3 0  d a ys  aft er t h e  p ati e nt   h as 
st o p p e d  st u d y  tr e at m e nt   m ust   b e  r e p ort e d  t o   N o v artis   wit hi n   2 4   h o urs   of  l e ar ni n g   of  its  
o c c urr e n c e.  
A n y  S A Es  e x p eri e n c e d  aft er t his  3 0  d a ys  p eri o d s h o ul d  o nl y  b e r e p ort e d t o  N o v artis if t h e 
i n v esti g at or  s us p e cts   a   c a u s al  r el ati o nshi p  t o  t h e  st u d y  tr e at m e nt.   R e c urr e nt   e pis o d es,  
c o m pli c ati o ns,  or  pr o gr essi o n  of t h e i niti al  S A E  m ust  b e r e p ort e d  as f oll o w -u p t o t h e  ori gi n al 
e pis o d e   wit hi n   2 4   h o urs   of  t h e  i n v esti g at or  r e c ei vi n g  t h e  f oll o w -u p  i nf or m ati o n.   A n   S A E  
o c c urri n g   at   a   diff er e nt  ti m e  i nt er v al   or   ot h er wis e   c o nsi d er e d   c o m pl et el y   u nr el at e d  t o   a  
pr e vi o usl y r e p ort e d  o n e s h o ul d  b e r e p ort e d s e p ar at el y  as  a  n e w  e v e nt.  
I nf or m ati o n  a b o ut  all  S A Es is  c oll e ct e d  a n d r e c or d e d  o n t h e  S eri o us  A d v ers e  E v e nt  R e p ort 
F or m;  all  a p pli c a bl e  s e cti o ns  of  t h e f or m  m ust  b e  c o m pl et e d i n  or d er t o  pr o vi d e  a  cli ni c all y 
t h or o u g h r e p ort.  T h e i n v esti g at or  m ust  ass ess  a n d r e c or d t h e r el ati o ns hi p  of  e a c h  S A E t o  e a c h 
s p e cifi c st u d y tr e at m e nt (if t h er e is  m or e t h a n  o n e st u d y tr e at m e nt),  c o m pl et e t h e  S A E  R e p ort 
F or m i n  E n glis h,  a n d s u b mit t h e  c o m pl et e d f or m  wit hi n  2 4  h o urs  N o v artis.  D et ail e d  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 9 2 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
i nstr u cti o ns r e g ar di n g t h e s u b missi o n  pr o c ess  a n d r e q uir e m e nts f or si g n at ur es  ar e t o  b e f o u n d 
i n t h e i n v esti g at or f ol d er  pr o vi d e d t o  e a c h sit e. 
F oll o w- u p i nf or m ati o n is s u b mitt e d i n t h e s a m e  w a y  as t h e  ori gi n al   S A E   R e p ort.   E a c h r e - 
o c c urr e n c e,  c o m pli c ati o n ,  or  pr o gr essi o n  of t h e  ori gi n al  e v e nt s h o ul d  b e r e p ort e d  as  a f oll o w- 
u p  t o  t h at   e v e nt  r e g ar dl ess   of   w h e n  it   o c c urs.   T h e  f oll o w -u p  i nf or m ati o n  s h o ul d   d es cri b e  
w h et h er t h e  e v e nt  h as r es ol v e d  or  c o nti n u es, if  a n d  h o w it  w as tr e at e d,  w h et h er t h e  bli n d  w as 
br o k e n  or  n ot,  a n d  w h et h er t h e  p ati e nt  c o nti n u e d  or  wit h dr e w fr o m st u d y  p arti ci p ati o n.  
If t h e  S A E is  n ot  pr e vi o usl y  d o c u m e nt e d i n t h e [I n v esti g at or’s  Br o c h ur e]  or  P a c k a g e I ns ert 
( n e w  o c c urr e n c e)  a n d is t h o u g ht t o  b e r el at e d t o t h e  N o v artis st u d y tr e at m e nt,  a n  o n c ol o g y 
N o v artis  Dr u g  S af et y  a n d  E pi d e mi ol o g y ( D S & E)  d e p art m e nt  ass o ci at e  m a y  ur g e ntl y r e q uir e 
f urt h er i nf or m ati o n fr o m t h e i n v esti g at or f or  H e alt h  A ut h orit y r e p orti n g.  N o v artis  m a y  n e e d t o 
iss u e  a n I n v esti g at or  N otifi c ati o n (I N), t o i nf or m  all i n v esti gat ors i n v ol v e d i n  a n y st u d y  wit h 
t h e  s a m e   dr u g  t h at  t his   S A E   h as   b e e n  r e p ort e d.   S us p e ct e d   U n e x p e ct e d   S eri o us   A d v ers e  
R e a cti o ns ( S U S A Rs)  will  b e  c oll e ct e d  a n d r e p ort e d t o t h e  c o m p et e nt  a ut h oriti es  a n d r el e v a nt 
et hi cs   c o m mitt e es  i n   a c c or d a n c e   wit h   Dir e cti v e   2 0 0 1/ 2 0/ E C   or   as   p er   n ati o n al  r e g ul at or y  
r e q uir e m e nts i n  p arti ci p ati n g  c o u ntri es. 
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 pli c a bl e.  
8. 4  
Pr e g n a n ci e s 
T o   e ns ur e  p ati e nt  s af et y,   e a c h   pr e g n a n c y   o c c urri n g   w hil e t h e  p ati e nt  is   o n st u d y tr e at m e nt  
m ust   b e r e p ort e d t o  N o v artis  wit hi n  2 4  h o urs  of l e ar ni n g  of  its  o c c urr e n c e.  T h e  pr e g n a n c y 
s h o ul d  b e f oll o w e d  u p t o  d et er mi n e  o ut c o m e, i n cl u di n g s p o nt a n e o us  or  v ol u nt ar y t er mi n ati o n, 
d et ails  of t h e  birt h,  a n d t h e  pr es e n c e  or  a bs e n c e  of  a n y  birt h  d ef e cts,  c o n g e nit al  a b n or m aliti es, 
or  m at er n al  a n d/ or  n e w b or n  c o m pli c ati o ns.  
Pr e g n a n c y  s h o ul d   b e  r e c or d e d   o n   a   Cli ni c al   Tri al   Pr e g n a n c y   F or m   a n d  r e p ort e d   b y  t h e  
i n v esti g at or  t o t h e  o n c ol o g y  N o v artis  Dr u g  S af et y  a n d  E pi d e mi ol o g y  D e p art m e nt  ( D S & E). 
Pr e g n a n c y f oll o w -u p s h o ul d  b e r e c or d e d  o n t h e s a m e f or m  a n d s h o ul d i n cl u d e  a n  ass ess m e nt 
of  t h e   p ossi bl e  r el ati o ns hi p  t o  t h e  st u d y  tr e at m e nt   a n y   pr e g n a n c y   o ut c o m e.   A n y   S A E  
e x p eri e n c e d  d uri n g  pr e g n a n c y  m ust  b e r e p ort e d  o n t h e  S A E  R e p ort  F or m.  
Pr e g n a n c y  o ut c o m es  m ust  b e  c oll e ct e d f or t h e f e m al e  p art n ers  of  a n y  m al es  w h o t o o k st u d y 
tr e at m e nt  in t his st u d y.   C o ns e nt  t o r e p ort  i nf or m ati o n  r e g ar di n g t h es e   pr e g n a n c y   o ut c o m es  
s h o ul d  b e  o bt ai n e d fr o m t h e  m ot h er.  
8. 5  
W ar ni n g s  a n d  pr e c a uti o n s 
N o  e vi d e n c e  a v ail a bl e  at t h e ti m e  of t h e  a p pr o v al  of t his st u d y  pr ot o c ol i n di c at e d t h at s p e ci al 
w ar ni n gs  or  pr e c a uti o ns  w er e  a p pr o pri at e,  ot h er t h a n t h os e  n ot e d i n t h e  pr o vi d e d [I n v esti g at or 
Br o c h ur e].  A d diti o n al s af et y i nf or m ati o n  c oll e ct e d  b et w e e n I B  u p d at es  will  b e  c o m m u ni c at e d 
i n  t h e  f or m   of  I n v esti g at or   N otifi c ati o ns.   T his  i nf or m ati o n   will   b e  i n cl u d e d  i n  t h e   p ati e nt  
i nf or m e d  c o ns e nt  a n d s h o ul d  b e  dis c uss e d  wit h t h e  p ati e nt  d uri n g t h e st u d y  as  n e e d e d. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 9 3 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
8. 6  
D at a  M o nit ori n g  C o m mitt e e 
D u e  t o   t h e   e x pl or at or y   n at ur e   of  t his   p h as e  II  st u d y,   a n  i n d e p e n d e nt   d at a   m o nit ori n g  
c o m mitt e e  will  n ot  b e  c o nstit ut e d. I n di vi d u al  p ati e nt s af et y  d at a  a n d  a g gr e g at e s af et y  d at a  will 
b e r e vi e w e d  o n  a n  o n g oi n g  b asis.  M e a n w hil e, t h e  effi c a c y  d at a ( O R R  a n d t h e  ot h er  effi c a c y 
e n d p oi nts)  will  b e  m o nit or e d  b y t h e st u d y t e a m  a cr oss t h e  d ur ati o n  of t h e tri al.  T h e s af et y  a n d 
effi c a c y  d at a r e vi e w  will  b e  b as e d  o n t h e  a v ail a bl e i n v esti g at or r e p ort e d  d at a i n t h e  cli ni c al 
d at a b as e   at  t h e  r es p e cti v e  ti m es.   T h e   d at a   will   b e   dis c u ss e d   wit h  i n v esti g at ors  i n  
t el e c o nf er e n c es.  I n  c as e  of   h a vi n g s uffi ci e nt   e vi d e n c e  of  l a c k  of   effi c a c y f or   a st u d y  dr u g, 
N o v artis  a n d t h e i n v esti g at or  p arti es  m ust r e a c h  a  c o ns e ns us  o n  w h et h er t o t er mi n at e f urt h er 
p ati e nt  e nr ol m e nt i n t h e tr e at m e nt   gr o u p. 
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 m ati o n  a b o ut st u d y s u bj e cts  will  b e  k e pt  c o nfi d e nti al  a n d  m a n a g e d  u n d er t h e  a p pli c a bl e 
l a ws  a n d r e g ul ati o ns.  T h os e r e g ul ati o ns r e q uir e  a si g n e d s u bj e ct  a ut h ori z ati o n i nf or mi n g t h e 
s u bj e ct  of t h e f oll o wi n g: 
• 
W h at  pr ot e ct e d  h e alt h i nf or m ati o n ( P HI)  will  b e  c oll e ct e d fr o m s u bj e cts i n t his  st u d y
• 
W h o  will  h a v e  a c c ess t o t h at i nf or m ati o n  a n d  w h y
• 
W h o  will  us e  or  dis cl os e t h at  i nf or m ati o n
• 
T h e ri g hts  of  a r es e ar c h s u bj e ct t o r e v o k e t h eir  a ut h ori z ati o n f or  us e  of t h eir  P HI.
I n t h e  e v e nt  t h at  a s u bj e ct  r e v o k es  a ut h ori z ati o n t o  c oll e ct   or   us e  P HI,  t h e i n v esti g at or,  b y 
r e g ul ati o n, r et ai ns t h e  a bilit y t o  us e  all i nf or m ati o n  c oll e ct e d  pri or t o t h e r e v o c ati o n  of s u bj e ct 
a ut h ori z ati o n.   F or  s u bj e cts  t h at   h a v e  r e v o k e d   a ut h ori z ati o n  t o   c oll e ct   or   us e   P HI,   att e m pts 
s h o ul d   b e   m a d e  t o   o bt ai n   p er missi o n  t o   c oll e ct  f oll o w -u p  s af et y  i nf or m ati o n  ( e. g.   h as  t h e  
s u bj e ct  e x p eri e n c e d  a n y  n e w  or  w ors e n e d  A Es)  at t h e  e n d  of t h eir s c h e d ul e d st u d y  p eri o d.  
T h e  d at a  c oll e cti o n s yst e m f or t his st u d y  us es  b uilt -i n s e c urit y f e at ur es t o  e n cr y pt  all  d at a f or 
tr a ns missi o n  i n   b ot h   dir e cti o ns,   pr e v e nti n g   u n a ut h ori z e d   a c c ess  t o   c o nfi d e nti al   p arti ci p a nt  
i nf or m ati o n.  A c c ess t o t h e s yst e m  will  b e  c o ntr oll e d  b y  a s e q u e n c e  of i n di vi d u all y  assi g n e d 
us er  i d e ntifi c ati o n   c o d es   a n d   p ass w or d s,   m a d e   a v ail a bl e   o nl y  t o   a ut h ori z e d   p ers o n n el   w h o  
h a v e  c o m pl et e d  pr er e q uisit e tr ai ni n g.  
Pri or t o  e nt eri n g  k e y s e nsiti v e  p ers o n all y i d e ntifi a bl e i nf or m ati o n ( S u bj e ct I niti als  a n d  e x a ct 
D at e  of  Birt h), t h e s yst e m  will  pr o m pt sit e t o  v erif y t h at t his  d at a is  all o w e d t o  b e  c oll e ct e d. If 
t h e sit e i n di c at es t h at  c o u ntr y r ul es  or  et hi cs  c o m mitt e e st a n d ar ds  d o  n ot  p er mit  c oll e cti o n  of 
t h es e it e ms, t h e s yst e m  will  n ot s oli cit  S u bj e ct I niti als.  Y e ar  of  birt h  will  b e s oli cit e d (i n t h e 
pl a c e  of  e x a ct  d at e  of  birt h) t o  est a blis h t h at t h e s u bj e ct s atisfi es  pr ot o c ol  a g e r e q uir e m e nts 
a n d t o  e n a bl e  a p pr o pri at e  a g e -r el at e d  n or m al  r a n g es t o  b e  us e d i n  ass essi n g l a b or at or y t est 
r es ults. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 9 4 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
9. 2  
Sit e  m o nit ori n g 
B ef or e  st u d y  i niti ati o n,   at   a  sit e  i niti ati o n   visit   or   at   a n  i n v esti g at or’s   m e eti n g,   N o v artis  
p ers o n n el ( or  d esi g n at e d  C R O)  will r e vi e w t h e  pr ot o c ol  a n d  C R Fs  wit h t h e i n v esti g at ors  a n d 
t h eir  st aff.   D uri n g  t h e  st u d y,  t h e  fi el d   m o nit or   will   visit  t h e  sit e  r e g ul arl y  t o   c h e c k  t h e  
c o m pl et e n ess  of   p ati e nt  r e c or ds,  t h e  a c c ur a c y   of  e ntri es  o n  t h e  C R Fs,  t h e  a d h er e n c e t o  t h e 
pr ot o c ol  t o   G o o d   Cli ni c al   Pr a cti c e,  t h e   pr o gr ess   of   e nr oll m e nt,   a n d  t o   e ns ur e  t h at  st u d y  
tr e at m e nt is  b ei n g st or e d,  dis p e ns e d,  a n d  a c c o u nt e d f or  a c c or di n g t o s p e cifi c ati o ns.  K e y st u d y 
p ers o n n el  m ust  b e  a v ail a bl e t o  assist t h e fi el d  m o nit or  d uri n g t h es e  visits.  
T h e i n v esti g at or  m ust  m ai nt ai n s o ur c e  d o c u m e nts f or  e a c h  p ati e nt i n t h e st u d y,  c o nsisti n g  of 
c as e  a n d  visit  n ot es ( h os pit al  or  cli ni c  m e di c al r e c or ds)  c o nt ai ni n g  d e m o gr a p hi c  a n d  m e di c al 
i nf or m ati o n,  l a b or at or y   d at a,   el e ctr o c ar di o gr a ms,   a n d  t h e  r es ults   of   a n y   ot h er  t ests   or  
ass e ss m e nt s.  All i nf or m ati o n r e c or d e d  o n  C R Fs  m ust  b e tr a c e a bl e t o s o ur c e  d o c u m e nts i n t h e 
p ati e nt's fil e.  T h e i n v esti g at or  m ust  als o  k e e p t h e  ori gi n al si g n e d i nf or m e d  c o ns e nt f or m ( a 
si g n e d  c o p y is  gi v e n t o t h e  p ati e nt). 
T h e i n v esti g at or   m ust   gi v e t h e  m o nit or  a c c ess t o   all  r el e v a nt  s o ur c e  d o c u m e nts t o  c o nfir m 
t h eir  c o nsist e n c y  wit h t h e  C R F  e ntri es.  N o v artis  m o nit ori n g st a n d ar ds r e q uir e f ull  v erifi c ati o n 
f or  t h e   pr es e n c e   of  i nf or m e d   c o ns e nt,   a d h er e n c e  t o  t h e  i n cl usi o n/ e x cl usi o n   crit eri a   a n d  
d o c u m e nt ati o n   of   S A Es.   A d diti o n al   c h e c ks   of  t h e   c o nsist e n c y   of  t h e  s o ur c e   d at a   wit h  t h e  
C R F s  ar e  p erf or m e d  a c c or di n g t o t h e st u d y -s p e cifi c  m o nit ori n g  pl a n. 
9. 3  
D at a  c oll e cti o n 
T h e   d esi g n at e d  i n v esti g at or  st aff   will   e nt er  t h e   d at a  r e q uir e d   b y  t h e   pr ot o c ol  i nt o  t h e  
El e ctr o ni c   C as e   R e p ort   F or ms  ( e C R F).   T h e   e C R Fs   h a v e   b e e n   b uilt   usi n g  f ull y   v ali d at e d  
s e c ur e  w e b -e n a bl e d s oft w ar e t h at  c o nf or ms t o  2 1  C F R  P art  1 1 r e q uir e m e nts, I n v esti g a t or sit e 
st aff   will   n ot   b e   gi v e n   a c c ess  t o  t h e   E D C  s yst e m   u ntil  t h e y   h a v e   b e e n  tr ai n e d.   A ut o m ati c  
v ali d ati o n   pr o gr a ms   c h e c k  f or   d at a   dis cr e p a n ci es  i n  t h e   e C R Fs   a n d,   all o w   m o difi c ati o n  or  
v erifi c ati o n  of t h e  e nt er e d  d at a  b y t h e i n v esti g at or  st aff. 
T h e   Pri n ci p al  I n v esti g at or  is  r es p o nsi bl e  f or   ass uri n g  t h at  t h e   d at a   e nt er e d  i nt o   e C R F  is  
c o m pl et e,  a c c ur at e,  a n d t h at  e ntr y  a n d  u p d at es  ar e  p erf or m e d i n  a ti m el y  m a n n er.  
P K 
 s a m pl es  dr a w n  d uri n g t h e  c o urs e  of t h e st u d y  will   b e  c oll e c t e d 
fr o m t h e i n v esti g at or sit es  a n d  a n al y z e d  b y  d esi g n at e d  N o v artis  L a b or at ori es.  T h e sit e st aff 
d esi g n at e d  b y t h e i n v esti g at or  will  e nt er t h e i nf or m ati o n r e q uir e d  b y t h e  pr ot o c ol  o nt o t h e  P K 
  S a m pl e   C oll e cti o n   e C R Fs,  r es p e cti v el y,   as   w ell   as   t h e   d e si g n at e d   C R O’s  
r e q uisiti o n  f or ms.   T h e  fi el d   m o nit or   will  r e vi e w  t h e  r el e v a nt   e C R Fs  f or   a c c ur a c y   a n d  
c o m pl et e n ess  a n d  will  w or k  wit h t h e sit e st aff t o  a dj ust  a n y  dis cr e p a n ci e s  as r e q uir e d.  T h e 
fi el d  m o nit or  will  als o r e vi e w t h e r e q uisiti o n f or ms f or  co m pl et e n ess.  
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 nt r ol 
N o v artis  p ers o n n el ( or  d esi g n at e d  C R O)  will r e vi e w t h e  d at a  e nt er e d  b y i n v esti g ati o n al st aff 
f or  c o m pl et e n ess  a n d  a c c ur a c y.  El e ctr o ni c  d at a  q u eri es st ati n g t h e  n at ur e  of t h e  pr o bl e m  a n d 
r e q u esti n g  cl arifi c ati o n  will  b e  cr e at e d f or  dis cr e p a n ci es  a n d  missi n g  v al u es  a n d s e nt t o t h e 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 9 5 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
i n v esti g ati o n al  sit e   vi a  t h e   E D C  s yst e m.   D esi g n at e d  i n v esti g at or  sit e  st aff   ar e  r e q uir e d  t o  
r es p o n d  pr o m ptl y t o  q u eri es  a n d t o  m a k e  a n y  n e c ess ar y  c h a n g es t o t he  d at a.  
C o n c o mit a nt tr e at m e nts  a n d  pri or  m e di c ati o ns  e nt er e d i nt o t h e  d at a b as e  will  b e  c o d e d  usi n g 
t h e   W H O   Dr u g   R ef er e n c e   List,   w hi c h   e m pl o ys  t h e   A n at o mi c al   T h er a p e uti c   C h e mi c al  
cl assifi c ati o n s yst e m.  M e di c al  hist or y/ c urr e nt  m e di c al  c o n diti o ns  a n d  a d v ers e  e v e nts  will  b e 
c o d e d  usi n g t h e  M e di c al  di cti o n ar y f or r e g ul at or y  a cti viti es ( M e d D R A) t er mi n ol o g y.  
S a m pl es   a n d/ or   d at a  f or   P K  s a m pli n g  
  will   b e   pr o c ess e d   c e ntr all y   a n d  t h e  
r es ults  will  b e s e nt  el e ctr o ni c all y t o  N o v artis ( or  a  d esi g n at e d  C R O). E C Gs  m a y  b e r e vi e w e d 
r etr os p e cti v el y   b y   a   N o v artis   d esi g n at e d   E C G  l a b or at or y   a n d  t h e  r es ults   will   b e  s e nt  t o  
N o v artis.   At  t h e  c o n cl usi o n  of  t h e st u d y,  t h e  o c c urr e n c e  of   a n y  pr ot o c ol  vi ol ati o ns  will   b e 
d et er mi n e d.   Aft er  t h es e   a cti o ns   h a v e   b e e n   c o m pl et e d   a n d   t h e   d at a   h as   b e e n   v erifi e d  t o   b e  
c o m pl et e   a n d   a c c ur at e,  t h e   d at a b as e   will   b e   d e cl ar e d  l o c k e d   a n d   m a d e   a v ail a bl e  f or   d at a  
a n al ysis.  A ut h ori z ati o n is r e q uir e d  pri or t o  m a ki n g  a n y  d at a b as e  c h a n g es t o l o c k e d  d at a,  b y 
j oi nt  writt e n  a gr e e m e nt  b et w e e n t h e  Gl o b al H e a d  of  Bi ost atisti cs  a n d  D at a  M a n a g e m e nt  a n d 
t h e  Gl o b al  H e a d  of  Cli ni c al  D e v el o p m e nt. 
F or  E D C st u di es,  aft er  d at a b as e l o c k, t h e i n v esti g at or  will r e c ei v e  a  C D -R O M  or  p a p er  c o pi es 
of t h e  p ati e nt  d at a f or  ar c hi vi n g  at t h e i n v esti g ati o n al sit e.  
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  
D at a   will   b e   a n al y z e d   b y   N o v artis   a n d/ or   d esi g n at e d   C R O.   A n y   d at a   a n al ysi s   c arri e d   o ut  
i n d e p e n d e ntl y   b y  t h e  i n v esti g at or   m ust   b e  s u b mitt e d  t o   N o v artis   b ef or e   p u bli c ati o n   or  
pr es e nt ati o n. 
D at a  will  b e s u m m ari z e d  wit h r es p e ct t o  d e m o gr a p hi c  a n d  b as eli n e  c h ar a ct eristi cs,  effi c a c y  
a n d s af et y  o bs er v ati o ns  a n d  m e a s ur e m e nts  a n d  all r el e v a nt  P K  a n d  P D  m e as ur e m e nts  usi n g 
d es cri pti v e st atisti cs ( q u a ntit ati v e  d at a)  a n d  c o nti n g e n c y t a bl es ( q u alit ati v e  d at a).  
T h e  fi v e  tr e at m e nt   ar ms   will   b e   a n al y z e d  s e p ar at el y.   F or   e a c h  tr e at m e nt   ar m  t h e   pri m ar y  
a n al ysis  will  b e  c o n d u ct e d  o n  all  p ati e nt  d at a  at t h e ti m e  w h e n  all  p ati e nts  of t h e r es p e cti v e 
tr e at m e nt  ar m  h a v e  p ot e nti all y  c o m pl et e d  at l e ast si x  c y cl es  of tr e at m e nt  or  dis c o nti n u e d t h e 
st u d y.   T h e r es ults  of t h e  pri m ar y  a n al ys es  of  t h e f o ur tr e at m e nt  ar ms  will  b e r e p ort e d i n  a 
si n gl e  pri m ar y  C S R.   A n y  a d diti o n al   d at a f or   p ati e nts  c o nti n ui n g t o r e c ei v e st u d y tr e at m e nt 
p ast t h e  d at a  c ut -off  d at e f or t h e r es p e cti v e  pri m ar y  a n al ysis,  as  all o w e d  b y t h e  pr ot o c ol,  will 
b e r e p ort e d  o n  e n d  of st u d y ( 1 2  m o nt hs  aft er  L P L V) i n  a si n gl e fi n al  C S R.  
C at e g ori c al  d at a  will  b e  pr es e nt e d  as fr e q u e n ci es  a n d  p er c e nt a g es.  F or  c o nti n u o us  d at a,  m e a n, 
st a n d ar d   d e vi ati o n,   m e di a n,   2 5t h   a n d   7 5t h   p er c e ntil es,   mi ni m u m,   a n d   m a xi m u m   will   b e  
pr es e nt e d.  
S cr e e n f ail ur e  p ati e nts  ar e t h os e  w h o si g n e d t h e i nf or m e d  c o ns e nt,  b ut  n e v er st art e d t h e st u d y 
tr e at m e nt  f or   a n y  r e as o n.   F or  t h es e   p ati e nts,  t h e   e C R F   d at a     c oll e ct e d     as     d es cri b e d    i n  
S e cti o n  7. 1. 2. 2 , will   n ot  b e i n cl u d e d i n a n y  a n al ysis,   b ut will   b e r e p ort e d i n  a s e p ar at e listi n g. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 9 6 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
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  
F or  e a c h tr e at m e nt  ar m t h e  F ull  A n al ysis  S et ( F A S)  c o m pris es  all  p ati e nts  w h o r e c ei v e d  at 
l e ast  o n e  d os e  of t h e r es p e cti v e st u d y tr e at m e nt.  T h e  F A S  will  b e  us e d f or  all listi n gs  of r a w 
d at a.  U nl ess  ot h er wis e s p e cifi e d t h e  F A S  will  b e t h e  d ef a ult  a n al ysis s et  us e d f or  all  a n al ys es.  
1 0. 1. 2   
S af et y  S e t 
F or  e a c h tr e at m e nt  ar m t h e  S af et y  S et i n cl u d es  all  p ati e nts  w h o r e c ei v e d  at l e ast  o n e  d os e  of 
t h e r es p e cti v e st u d y  m e di c ati o n  a n d  h a d  at  l e ast   o n e  v ali d  p ost-b as eli n e  s af et y   ass ess m e nt.  
Pl e as e  n ot e:  A  “ n o ”  t o i n di c at e t h at t h e  p ati e nt  h a d  n o  A Es ( o n t h e  A E  e C R F)  c o nstit ut es  a 
v ali d s af et y  ass ess m e nt.  
P ati e nts  will  b e  cl assifi e d  a c c or di n g t o tr e at m e nt r e c ei v e d,  w h er e tr e at m e nt r e c ei v e d is  d efi n e d 
as:  
• 
T h e tr e at m e nt  assi g n e d if it  w as r e c ei v e d  at l e ast  o n c e,   or
• 
If t h e  assi g n e d tr e at m e nt  w as  n e v er r e c ei v e d, t h e n t h e first tr e at m e nt r e c ei v e d  w h e n
st arti n g t h er a p y  wit h st u d y tr e at m e nt  will  b e  us e d f or  cl assifi c ati o n
T h e s af et y s et  will  b e  us e d f or t h e s af et y s u m m ar y  of t h e st u d y.  
1 0. 1. 3   
P er -P r ot o c ol S et  
F or  e a c h tr e at m e nt  ar m t h e  P er -Pr ot o c ol  S et ( P P S)  c o nsists  of  a s u bs et  of t h e  p ati e nts i n t h e 
r es p e cti v e  F A S  w h o  ar e  c o m pli a nt  wit h r e q uir e m e nts  of t h e  cli ni c al st u d y  pr ot o c ol ( C S P). 
Pr ot o c ol  d e vi ati o ns  p ot e nti all y  l e a di n g t o  e x cl usi o n fr o m t h e  P P S  ar e: 
• 
t y p e  of i n di c ati o n  diff er e nt fr o m t h os e r e q uir e d i n S e cti o n  5  ( e. g., i n c orr e ct
hist ol o g y/ c yt ol o g y, i n c orr e ct  m ol e c ul ar  alt er ati o n  et c.)
• 
pri or t h er a p y  d o es  n ot  m at c h  wit h r e q uir e m e nts i n  S e cti o n  5  i n t er ms  of  n u m b er  a n d t y p es
of  pr e vi o us t h er a p y  r e gi m e ns
• 
missi n g  or i n c o m pl et e  d o c u m e nt ati o n  of st a g e  of  dis e as e
• 
E C O G > 2
• 
a n ot h er  a nti -n e o pl asti c t h er a p y  a d mi nist er e d  aft er st art  of st u d y tr e at m e nt  a n d  pri or t o first
t u m or ass ess m e nt
• 
st u d y tr e at m e nt r e c ei v e d  diff er e nt fr o m tr e at m e nt  assi g n e d
• 
p ati e nt  wit h o ut  m e as ur a bl e  l esi o ns
A n y  ot h er  pr ot o c ol  d e vi ati o ns l e a di n g t o  e x cl usi o n  fr o m t h e  P P S  will  b e  d es cri b e d i n t h e  R A P 
pri or t o  cli ni c al  d at a b as e l o c k.  
1 0. 1. 4   
P h ar m a c o ki n eti c  a n al y si s  s et  
F or  e a c h tr e at m e nt  ar m t h e  p h ar m a c o ki n eti c  a n al ysis s et ( P A S)  c o nsists  of  all  p ati e nts  w h o 
h a v e  at l e ast  o n e s a m pl e  pr o vi di n g  e v al u a bl e  P K.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 9 7 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
T h e  P A S  will  b e  us e d f or s u m m ari es  of  P K  d at a (t a bl es  a n d fi g ur es)  as  w ell  as f or listi n gs  of 
d eri v e d  p ar a m et ers.  
N ot e:  P ati e nts  will  b e r e m o v e d fr o m t h e  esti m ati o n  of  c ert ai n  P K  p ar a m et ers  o n  a n i n di vi d u al 
b asis  d e p e n di n g  o n t h e  n u m b er  of  a v ail a bl e  bl o o d s a m pl es.  T h es e  p ati e nts  will  b e i d e ntifi e d  at 
t h e ti m e  of t h e  a n al ysis  al o n g  wit h t h e r e as o n f or t h eir r e m o v al. 
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 
D e m o gr a p hi c   a n d   ot h er   b as eli n e   d at a,  i n cl u di n g   a g e,   g e n d er,   h ei g ht,   w ei g ht,   m e di c al  
c o n diti o n,  dis e as e  c h ar a ct eristi cs  et c.,  will  b e s u m m ari z e d  d es cri pti v el y  b y tr e at m e nt  ar m.  
1 0. 3  
T r 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) 
1 0. 3. 1   
St u d y tr e at m e nt  
F or  e a c h tr e at m e nt  ar m t h e  a ct u al  d os e  a n d  d ur ati o n i n  d a ys  of st u d y tr e at m e nt  as  w ell  as t h e 
d os e  i nt e nsit y  ( c o m p ut e d   as  t h e  r ati o   of   a ct u al   d os e  r e c ei v e d   a n d   a ct u al   d ur ati o n)   a n d  t h e  
r el ati v e   d os e  i nt e nsit y  ( c o m p ut e d   as  t h e  r ati o   of   a ct u al   d os e  i nt e nsity   a n d   pl a n n e d   d os e  
i nt e nsit y)   will   b e  list e d   a n d  s u m m ari z e d   b y   m e a ns   of   d es cri pti v e  st atisti c s  i n  t h e   C S R.  
C at e g ori es f or r el ati v e  d os e i nt e nsit y  will  b e s p e cifi e d  as  <  0. 5,  ≥  0. 5  - <  0. 7 5,  ≥  0. 7 5  - <  0. 9,  
≥  0. 9  -  <  1. 1  a n d  ≥  1. 1.  T h e  n u m b er  a n d  pr o p orti o n  of  p ati e nts  wit hi n  e a c h  c at e g or y  will  b e 
pr es e nt e d.  
1 0. 3. 2   
C o n c o mit a nt  th er a pi e s  
F or  e a c h tr e at m e nt  ar m  c o n c o mit a nt  m e di c ati o ns  a n d si g nifi c a nt  n o n -dr u g t h er a pi es  pri or t o 
a n d  aft er t h e st art  of t h e st u d y tr e at m e nt  will  b e list e d  b y  p ati e nt  a n d s u m m ari z e d  b y  A T C 
( a n at o mi c al t h er a p e uti c  c h e mi c al  cl assifi c ati o n s yst e m) t er m. 
1 0. 3. 3   
C o m pli a n c e  
C o m pli a n c e t o t h e  pr ot o c ol  will  b e  ass ess e d  b y t h e  n u m b er  a n d  pr o p orti o n  of  p ati e nts  wit h 
pr ot o c ol   d e vi ati o ns.   T h es e   will   b e  i d e ntifi e d   pri or  t o   d at a b as e  l o c k   a n d   will   b e  list e d   a n d 
s u m m ari z e d  b y tr e at m e nt  ar m.  C o m pli a n c e t o  e a c h  of t h e st u d y tr e at m e nts  will  b e  ass ess e d  b y 
t h e  n u m b er  of  d os e r e d u cti o ns  a n d  d os e i nt err u pti o ns, s e e S e cti o n  1 0. 5 . 
1 0. 4  
Pri m ar y  o bj e cti v e 
T h e   pri m ar y   o bj e cti v e  is  t o  i n v esti g at e   t h e   a nti-t u m or   a cti vit y   of  si n gl e   a g e nt   B Y L 7 1 9,  
I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2 i n  C hi n es e  p ati e nts  wit h  a d v a n c e d  N S C L C  c arr yi n g s p e cifi c 
m ol e c ul ar  alt er ati o ns.  
1 0. 4. 1   
V ari a bl e  
T h e  pri m ar y  e n d p oi nt is  O R R  p er  R E CI S T  v 1. 1 ( S e cti o n  1 4. 1 ). 
F or   e a c h  tr e at m e nt   ar m,  i n di vi d u al  l esi o n   m e as ur e m e nts   a n d   o v er all  r es p o ns e   at   e a c h  
ass e ss m e nt   will   b e  list e d   b y   p ati e nt,  fr o m   w hi c h  t h e   b est   o v er all  r es p o ns e  ( B O R)   will   b e  
d eri v e d f or  all  p ati e nts  a c c or di n g t o  R E CI S T  v 1. 1.  T h e  O R R is t h e  pr o p orti o n  of  p at i e nts  wit h 
B O R  of  eit h er  C R  or  P R  a m o n g  all  p ati e nts i n t h e r es p e cti v e  F A S.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 9 8 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
P ati e nts   wit h  s y m pt o ms  of  r a pi dl y  pr o gr essi n g   dis e as e   wit h o ut  r a di ol o gi c  e vi d e n c e   will   b e  
cl assifi e d   as   pr o gr essi o n   o nl y   w h e n   cl e ar   e vi d e n c e   of   cli ni c al   d et eri or ati o n  is   d o c u m e nt e d  
a n d/ or  p ati e nt  dis c o nti n u e d  d u e t o ‘ Dis e as e  pr o gr essi o n’  or  d e at h  d u e t o st u d y i n di c ati o n.  
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  
A  B a y esi a n  a p pr o a c h  will  b e  us e d t o  esti m at e  O R R  a n d t o  pr o vi d e i nf er e nti al st at e m e nts i n 
e a c h  ar m.  
F or  I N C 2 8 0,   B Y L 7 1 9   a n d   M E K 1 6 2,   a   mi ni m all y  i nf or m ati v e   u ni m o d al   B et a   pri or  
distri b uti o n f or  e a c h  ar m i  wit h  p ar a m et ers  a i a n d  b i (N e u e ns c h w a n d er  et  al.  2 0 1 0 ) t h at r efl e cts 
t h e  d e gr e e  of  u n c ert ai nt y  ar o u n d  O R R  b ef or e st arti n g t h e  c urr e nt tri al  w as  eli cit e d.  B as e d  o n 
pri or  cli ni c al  ass u m pti o n, t h e  pri or  m e di a n  of  O R R  of  e a c h tr e at m e nt  ar m is  o bt ai n e d. If t h e 
pri or   m e di a n   O R R  is  s m all er  t h a n  5 0 %,  b i= 1  a n d  a i=l n( 0. 5)/l n( m e di a n i);  ot h er wis e  ai= 1  a n d 
b i=l n( 0. 5)/l n( 1 -m e di a n i).  T h e  v al u es  of  pri or  m e di a ni,  ai a n d  b i f or t h e t hr e e tr e at m e nt  ar ms  ar e 
list e d i n T a bl e   1 0- 1. 
F or   B Y L 7 1 9   ar m,   b as e d   o n  t h e   ass u m pti o n  t h at  si mil ar  r es p o ns e  is   e x p e ct e d  i n  
a d e n o c ar ci n o m a  a n d s q u a m o us  c ell  c ar ci n o m a  p ati e nt s,  pri m ar y  a n al ys es  will  b e  d o n e  usi n g 
t h e  p o ol e d  d at a fr o m t h es e t w o s u b gr o u ps  of  p ati e nts. 
F or t h e  L D K 3 7 8 tr e at m e nt  ar ms,  a  mi xt ur e  of  pri or  distri b uti o ns  wit h t his  c o m p o n e nt ( als o 
list e d i n T a bl e  1 0 - 1)  will  b e  us e d: 
• 
[ C L D K 3 7 8 X 2 1 0 1], [ C L D K 3 7 8 X 1 1 0 1] a n d  [ C L D K 3 7 8 X 2 2 0 1] f or t h e  L D K 3 7 8 tr e at m e nt
a m); I n  or d er t o r efl e ct  p ot e nti al  v ari a bilit y  of t h e  h et er o g e n eit y  b et w e e n tri als, t h e
h et er o g e n eit y  p ar a m et er  τ  w as  gi v e n  a  h alf -n or m al  distri b uti o n  wit h s c al e  0. 5.  T his
distri b ut i o n is ri g ht s k e w e d  wit h  m e di a n  0.  3 4  a n d  9 5 %  pr o b a bilit y i nt er v al ( 0. 0 1 6- 1. 1 2).
It  all o ws t h e  h et er o g e n eit y t o  v ar y fr o m s m all t o l ar g e  b ut  at t h e s a m e ti m e  gi v es s m all
pr o b a bilit y t o  v er y l ar g e  v al u es  of t a u (t a u  >  1) . T his  c o m p o n e nt r e c ei v es  a  pri or  w ei g ht  of
8 0 %.
• 
T h e s e c o n d  mi ni m all y i nf or m ati v e  c o m p o n e nt is  d eri v e d  as  d es cri b e d  a b o v e f or I N C 2 8 0,
B Y L 7 1 9  a n d  M E K 1 6 2 tr e at m e nt  ar ms,  a n d r e c ei v es  a  pri or  w ei g ht  of  2 0 %.
At ti m e  of  a n al ysis f or  e a c h tr e at m e nt  ar m t h e r es p e cti v e  pri or  distri b uti o n  will  b e  u p d at e d 
wit h  all  a v ail a bl e  d at a fr o m  p ati e nts i n t h e r es p e cti v e  F A S.  O n c e  u p d at e d, t h e  p ost eri or ris ks 
t h at t h e tr u e  O R R li es i n t h e f oll o wi n g  effi c a c y i nt er v als  will  b e  pr o vi d e d: 
•
[ 0,  Li)  u n a c c e pt a bl e effi c a c y
•
[ Li,  Mi) li mit e d effi c a c y
•
[ Mi,  1 0 0 %]  cli ni c all y r el e v a nt effi c a c y
T h e  v al u es  of t hr es h ol ds  L i a n d  M i f or t h e fi v e tr e at m e nt  ar ms  ar e list e d i n T a bl e  1 0 - 1. If t h e 
esti m at e d  O R R i n  ar m i i s  e q u al t o  or  gr e at er t h a n  M i a n d t h e  p ost eri or ris k  of  b ei n g i n t h e 
u n a c c e pt a bl e  effi c a c y  c at e g or y  is  l o w er  t h a n  5 %,  t h e n  pr eli mi n ar y  a cti vit y  of  t h e  r es p e cti v e 
st u d y  tr e at m e nt   will   b e   d e cl ar e d.   Ot h er wis e,  t h e i nf er e nti al  s u m m ari es  f or  t h e  3   c at e g ori es  
a b o v e  will  b e  ass ess e d f or f urt h er  c h ar a ct eri z ati o n  of t h e  effi c a c y.  F or  e a c h tr e at m e nt  ar m, t h e 
esti m at e d  O R R  will  b e t a k e n fr o m t h e  m e di a n  v al u e  of t h e r es p e cti v e  p ost eri or  distri b uti o n.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e 9 9 
Pr ot o c ol N o.  CI N C 2 8 0 X 2 2 0 5 
T a bl e  1 0 - 1  
P ar a m et er s  of  pri or  di stri b uti o n s  a n d  t hr e s h ol d s f or  p o st eri or 
di stri b uti o n s  of  O R R  
Ar m  
Pri or  di stri b uti o n  
T hr e s h ol d  
i 
C o m p o n e nt   
a   
b   
M e di a n   
9 0 %  Cr e di bl e i nt er v al   
L i
M
i 
1.  L D K 3 7 8   
1 ** ( 8 0 %) 
6. 9 3 7 4   
5. 2 5 6 2   
5 7 %   
( 3 4 %,  7 9 %) 
4 0 %   
5 5 %  
2 ( 2 0 %)   
1   
0. 7 5 6 5   
6 0 %   
( 7 %,  9 8 %) 
Mi xt ur e  
5 8 %   
( 2 6 %,  8 7 %) 
2. I N C 2 8 0 
1  
0. 3 6 5 4   
1   
1 5 %   
( 0. 0 3 %,  8 7 %) 
7. 5 %   
1 7. 5 %  
3.   M E K 1 6 2   
1
0. 3 6 5 4   
1   
1 5 %   
( 0. 0 3 %,  8 7 %) 
7. 5 %   
1 7. 5 %  
4.   B Y L 7 1 9   
1
0. 3 6 5 4   
1   
1 5 %   
( 0. 0 3 %,  8 7 %) 
7. 5 %   
1 7. 5 %  
**  C o m p o n e nt  d eri v e d fr o m  M A P  a p pr o a c h.  B a s e d  o n  [ C L D K 3 7 8 X 1 1 0 1] d at a  wit h  2 r e s p o n d er s i n  5  p ati e nt s  at 
7 5 0  m g  Q D,  wit h  c ut -off  d at e  of  2 9 -A pr -2 0 1 3,  a n d  [ C L D K 3 7 8 X 2 1 0 1] d at a  wit h  4 7 r e s p o n d er s i n  7 8  p ati e nt s  at  7 5 0 
m g  Q D,  wit h  c ut -off  d at e  of  2 8 -F e b -2 0 1 3.  T hi s  c o m p o n e nt r e c ei v e d  8 0 %  w ei g ht  a n d  will  b e  u p d at e d  wit h 
a d diti o n al  d at a  pri or t o t h e fi n al  a n al y si s.  
I n  a d diti o n, f or  e a c h tr e at m e nt  ar m t h e  m e a n,  m e di a n,  a n d t w o-si d e d  9 0 %  cr e di bl e i nt er v al f or 
O R R fr o m t h e  p ost eri or  distri b uti o n  will  b e  pr es e nt e 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  
Missi n g   d at a   will  si m pl y   b e   n ot e d   as   missi n g   o n   a p pr o pri at e  t a bl es/listi n gs.   P ati e nts   wit h  
missi n g   b est   o v er all  r es p o ns e   will   b e   c o nsi d er e d   as   n o n -  r es p o n d ers  f or  t h e   pri m ar y   O R R  
a n al ysis.  
1 0. 4. 4   
S u p p orti v e  a n al y s e s  
• 
F or   e a c h  tr e at m e nt   ar m  t h e   B a y esi a n   p ost eri or   esti m at e   of   m e di a n   a n d  t w o -si d e d  9 0 %
cr e di bl e i nt er v al  of  O R R  will  b e  pr es e nt e d  usi n g  P P S, if  P P S is  diff er e nt fr o m  F A S.
• 
F or  e a c h tr e at m e nt  ar m, i n di vi d u al t u m or l esi o n  ass e ss m e nts  will  b e list e d  al o n g  wit h t h e
o v er all  r es p o ns e   b y   ass ess m e nt.   B O R   will   b e  list e d   b y   p ati e nt   a n d  s u m m ari z e d   wit h
fr e q u e n c y   a n d   p er c e nt a g e,  t o g et h er   wit h  t h e   o bs er v e d   O R R   a n d  fr e q u e ntist   e x a ct  t w o - 
si d e d  9 0 %  c o nfi d e n c e i nt er v al.
• 
F or  B Y L 7 1 9  ar m,  B O R s u m m ari es  m a y  als o  b e  pr o vi d e d  b y s u bt y p es  of  c a n c er ( e. g. l u n g
a d e n o c ar ci n o m a  a n d l u n g s q u a m o us  c ell  c ar ci n o m a)
1 0. 5  
S e c o n d ar y  o bj e cti v e s 
1 0. 5. 1   
S e c o n d ar y  effi c a c y  o bj e cti v e s  
T h e s e c o n d ar y  effi c a c y  o bj e cti v e  of t his st u d y is t o f urt h er  esti m at e  cli ni c al  a cti vit y  of si n gl e 
a g e nt  B Y L 7 1 9, I N C 2 8 0,  L D K 3 7 8  a n d  M E K 1 6 2 i n  C hi n es e  p ati e nts  wit h  a d v a n c e d  N S C L C 
c arr yi n g s p e cifi c  m ol e c ul ar  alt er ati o ns.  T u m or r es p o ns e  will  b e  e v al u at e d  b as e d  o n  R E CI S T 
v 1. 1 ( S e cti o n  1 4. 1 ).  Dis e as e  c o ntr ol r at e ( D C R),  d ur ati o n  of r es p o ns e,  P F S  a n d  O S  will b e 
ass e ss e d  a n d  a n al y z e d  as f oll o ws:  
• 
D C R is  d efi n e d  as t h e  pr o p orti o n  of  p ati e nts  wit h  a  B O R  of  C R,  P R  or  S D  at  a n y ti m e  o n
st u d y.  F or  e a c h tr e at m e nt  ar m t h e  o bs er v e d  D C R  wit h  e x a ct t w o -si d e d  9 0 %  c o nfi d e n c e
i nt er v al  will  b e pr es e nt e d.


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 0 0
0  Pr ot o c ol  N o. 
• 
D ur ati o n  of  o v er all r es p o ns e is  d efi n e d  as t h e ti m e fr o m t h e first  d o c u m e nt e d  C R  or  P R
( c o nfir m e d  b y t h e s u bs e q u e nt  ass ess m e nt) t o t h e  d at e  of t h e first  d o c u m e nt e d  pr o gr essi o n
or  d e at h  d u e t o  u n d erl yi n g  c a n c er.  W h e n t h er e is  n o  d o c u m e nt ati o n  of r a di ol o gi c  e vi d e n c e
of  pr o gr essi o n,  a n d t h e  p ati e nt  dis c o nti n u e d f or ‘ Dis e as e  pr o gr essi o n’  d u e t o  d o c u m e nt e d
cli ni c al  d et eri or ati o n  of  dis e as e, t h e  d at e  of  dis c o nti n u ati o n is  us e d  as  d at e  of  pr o gr essi o n.
If   a   p ati e nt   h as   n ot   e x p eri e n c e d   a   d o c u m e nt e d   pr o gr essi o n   or   d e at h   d u e  t o   u n d erl yi n g
c a n c er,   d ur ati o n   of   o v er all  r es p o ns e  is   c e ns or e d   at  t h e   d at e   of  t h e  l ast   a d e q u at e  t u m or
ass e ss m e nt.  If   a   p ati e nt   dis c o nti n u e d  tri al  tr e at m e nt   a n d  r e c ei v e d   a   n e w   a nti - n e o pl asti c
t h er a p y  pri or t o  dis e as e  pr o gr essi o n,  d ur ati o n  of  o v er all r es p o ns e is  c e ns or e d  at t h e st art
d at e  of t h e  n e w t h er a p y.  T h e  K a pl a n -M ei er  c ur v e,  m e di a n  a n d  q u artil e  will  b e  pr es e nt e d if
a s uffi ci e nt  n u m b er  of r es p o ns es is  o bs er v e d.  F or  e a c h tr e at m e nt  ar m t h e s u bs et  of  p ati e nts
wit h  d o c u m e nt e d  C R  or  P R i n  F A S  will  b e   us e d.
• 
P F S is  d efi n e d  as t h e ti m e fr o m st art  of st u d y tr e at m e nt t o t h e  d at e  of t h e first  d o c u m e nt e d
pr o gr essi o n   or   d e at h   d u e  t o   a n y   c a us e.   W h e n  t h er e  is   n o   d o c u m e nt ati o n   of  r a di ol o gi c
e vi d e n c e   of   pr o gr essi o n,   a n d  t h e   p ati e nt   dis c o nti n u e d  f or  ‘ Dis e as e   pr o gr essi o n’   d u e  t o
d o c u m e nt e d  cli ni c al  d et eri or ati o n  of  dis e as e, t h e  d at e  of  dis c o nti n u ati o n is  us e d  as  d at e  of
pr o gr essi o n. If  a  p ati e nt  h as  n ot  e x p eri e n c e d  a  d o c u m e nt e d  pr o gr essi o n  or  d e at h,  P F S is
c e ns or e d  at t h e  d at e  of t h e l ast  a d e q u at e t u m or  ass ess m e nt.  If  a  p ati e nt  dis c o nti n u e d tri al
tr e at m e nt  a n d r e c ei v e d  a  n e w  a nti-n e o pl asti c t h er a p y  pri or t o  dis e as e  pr o gr essi o n,  P F S is
c e ns or e d   at  t h e  st art   d at e   of  t h e   n e w  t h er a p y.   T h e   K a pl a n -M ei er   esti m at e   of   P F S
distri b uti o n f u n cti o n  will  b e  pr es e nt e d  gr a p hi c all y  usi n g  F A S.  T h e r es ulti n g  m e di a n  a n d
q u artil e  esti m at es  will  b e  pr o vi d e d  al o n g  wit h t w o -si d e d  9 0 %  c o nfi d e n c e i nt er v als.
• 
O S is  d efi n e d  as t h e ti m e fr o m st art  of st u d y tr e at m e nt t o  d at e  of  d e at h  d u e t o  a n y  c a us e. If
a  p ati e nt is  n ot  k n o w n t o  h a v e  di e d,  O S  will  b e  c e ns or e d  at t h e  d at e  of t h e l ast  c o nt a ct.  T h e
K a pl a n -M ei er  esti m at e  of  O S  distri b uti o n f u n cti o n  will  b e  pr es e nt e d  gr a p hi c all y  usi n g
F A S.  T h e r es ulti n g  m e di a n  a n d  q u artil e  esti m at es  will  b e  pr o vi d e d  al o n g  wit h t w o -si d e d
9 0 %  c o nfi d e n c e  i nt er v als.
F or   B Y L 7 1 9   ar m,   b as e d   o n  t h e   ass u m pti o n  t h at  si mil ar  r es p o ns e  is   e x p e ct e d  i n  
a d e n o c ar ci n o m a  a n d s q u a m o us  c ell  c ar ci n o m a  p ati e nts,  a n al ys es f or t h e s e c o n d ar y  e n d p oi nts 
will  b e  d o n e  usi n g t h e  p o ol e d  d at a fr o m t h es e t w o s u b gr o u ps  of  p ati e nts.  H o w e v er, s e p ar at e 
a n al ys es  b y t h es e t w o s u b gr o u ps  m a y  als o  b e  p erf or m e d.  
1 0. 5. 2   
S af et y  o bj e cti v e s  
T h e s af et y  o bj e cti v e  of t his st u d y is t o  c h ar a ct eri z e t h e s af et y  a n d t ol er a bilit y  of si n gl e  a g e nt 
B Y L 7 1 9,  I N C 2 8 0,   L D K 3 7 8   a n d   M E K 1 6 2  i n   C hi n es e   p ati e nts   wit h   a d v a n c e d   N S C L C  
c arr yi n g s p e cifi c  m ol e c ul ar  alt er ati o ns.  
1 0. 5. 2. 1   A n al y si s  s et  a n d  gr o u pi n g f or t h e  a n al y s e s  
Listi n gs  of  A Es  will  b e  pr o vi d e d  b as e d  o n t h e  F A S.  F or  all s af et y  a n al ys es, t h e s af et y s et  will 
b e  us e d  u nl ess  ot h er wis e s p e cifi e d.  All listi n gs  a n d t a bl es  will  b e  pr es e nt e d f or  e a c h tr e a t m e nt 
ar m s e p ar at el y.  
T h e  o v er all  o bs er v ati o n  p eri o d  will  b e  di vi d e d i nt o t hr e e  m ut u all y  e x cl usi v e s e g m e nts:  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 0 1
0  Pr ot o c ol  N o. 
 
 
 
1.   pr e- tr e at m e nt  p eri o d: fr o m  d a y  of  p ati e nt’s i nf or m e d  c o ns e nt t o t h e  d a y  b ef or e first  d os e 
of st u d y  m e di c ati o n  
2.   o n- tr e at m e nt  p eri o d: fr o m  d a y  of first  d os e  of st u d y  m e di c ati o n t o  3 0 d a ys  aft er l ast  d os e 
of st u d y  m e di c ati o n  or  u p o n  dis e as e  pr o gr essi o n  or i niti ati n g  a  n e w  a nti n e o pl asti c t h er a p y, 
w hi c h e v er  o c c urs  first. 
3.   p ost- tr e at m e nt  p eri o d: st arti n g  at  d a y  3 1  aft er l ast  d os e  of st u d y  m e di c ati o n,  or  at  d at e  of 
dis e as e  pr o gr essi o n  or i niti ati n g  a  n e w  a nti n e o pl asti c  t h er a p y. 
 
1 0. 5. 2. 2   A d v er s e  e v e nt s  ( A E s) 
S u m m ar y t a bl es f or  a d v ers e  e v e nts ( A Es)  h a v e t o i n cl u d e  o nl y  A Es t h at st art e d  or  w ors e n e d 
d uri n g t h e  o n -tr e at m e nt  p eri o d, t h e t r e at m e nt-e m e r g e nt  A Es,  usi n g s af et y s et.  
H o w e v er,   all  s af et y   d at a (i n cl u di n g t h os e  fr o m  t h e   pr e  a n d   p ost -tr e at m e nt   p eri o ds)   will  b e 
list e d  usi n g  F A S  a n d t h os e  c oll e ct e d  d uri n g t h e  pr e-tr e at m e nt  a n d  p ost-tr e at m e nt  p eri o d  ar e t o 
b e fl a g g e d.  
F or   e a c h  tr e at m e nt   ar m  t h e  i n ci d e n c e   of  tr e at m e nt -e m er g e nt   A Es  ( n e w   or   w ors e ni n g  fr o m  
b as eli n e)  will  b e s u m m ari z e d  b y s yst e m  or g a n  cl ass  a n d/ or  pr ef err e d t er m, s e v erit y ( b as e d  o n 
C T C A E  gr a d es), t y p e  of  A E, r el ati o n t o st u d y tr e at m e nt.  
D e at hs r e p ort a bl e  as  S A Es  a n d  n o n -f at al  S A Es  will  b e list e d  b y  p ati e nt  a n d t a b ul at e d  b y t y p e 
of  a d v ers e  e v e nt.  
S p e cifi c s af et y  e v e nt  c at e g ori es ( S E C)  mi g ht  b e  c o nsi d er e d.  S u c h  c at e g or i es  c o nsist  of  o n e  or 
m or e  w ell -d efi n e d s af et y  e v e nts  w hi c h  ar e si mil ar i n  n at ur e  a n d f or  w hi c h t h er e is  a s p e cifi c 
cli ni c al i nt er est i n  c o n n e cti o n  wit h t h e st u d y tr e at m e nt(s).  
F or  e a c h s p e cifi e d  S E C,  n u m b er  a n d  p er c e nt a g e  of  p ati e nts  wit h  at l e ast  o n e  e v e nt  p art  of t h e 
S E C  mi g ht  b e r e p ort e d.  
 
1 0. 5. 2. 3   L a b or at or y  a b n or m aliti e s  
F or  l a b or at or y  t ests   c o v er e d   b y  t h e   C T C A E   v ersi o n   4. 0 3,  t h e  st u d y’s   bi ost atisti c al   a n d  
r e p orti n g  t e a m   will   gr a d e  l a b or at or y   d at a   a c c or di n gl y.   F or  l a b or at or y  t ests   c o v er e d  b y 
C T C A E,   a   Gr a d e   0  will   b e  assi g n e d  f or   all   n o n -missi n g   v al u es   n ot   gr a d e d   as  1  or   hi g h er. 
Gr a d e  5  will  n ot  b e   us e d. 
F or l a b or at or y t ests  w h er e  gr a d es  ar e  n ot  d efi n e d  b y  C T C A E, r es ults  will  b e  gr a d e d  b y t h e 
l o w/ n or m al/ hi g h  cl assifi c ati o ns  b as e d  o n l a b or at or y  n or m al r a n g es. 
F or  e a c h tr e at m e nt  ar m t h e f oll o wi n g s u m m ari es  will  b e  g e n er at e d s e p ar at el y f or  h e m at ol o g y, 
bi o c h e mistr y,  uri n ar y  a n d  c o a g ul ati o n l a b or at or y t ests:  
•   fr e q u e n c y t a bl e f or  n e wl y  o c c urri n g  o n-tr e at m e nt  gr a d es  3  or  4  usi n g t h e s af et y s et 
•   s hift t a bl es  usi n g  C T C A E  gr a d es t o  c o m p ar e  b as eli n e t o t h e  w orst  o n -tr e at m e nt  v al u e 
usi n g t h e s af et y  s et 
•   f or l a b or at or y t ests  w h er e  C T C A E  gr a d es  ar e  n ot  d efi n e d, s hift t a bl es  usi n g t h e 
l o w/ n or m al/ hi g h/(l o w  a n d  hi g h)  usi n g t h e s af et y s et 
•   listi n g  of  all l a b or at or y  d at a  wit h  v al u es fl a g g e d t o s h o w t h e  c orr es p o n di n g  C T C A E 
gr a d es  a n d t h e  cl assifi c ati o ns r el ati v e t o t h e l a b or at or y  n or m al r a n g es  usi n g t h e  F A S.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 0 2
0  Pr ot o c ol  N o. 
 
 
 
I n  a d diti o n t o t h e  a b o v e  m e nti o n e d t a bl es  a n d listi n gs,  ot h er  e x pl or at or y  a n al ys es, f or  e x a m pl e 
fi g ur es  pl otti n g ti m e  c o urs e  of r a w  or  c h a n g e i n l a b or at or y t ests  o v er ti m e  or  b o x  pl ots  mi g ht 
b e s p e cifi e d i n t h e  R A P.  
1 0. 5. 2. 4   Ot h er  s af et y  d at a 
E C G  
If  a v ail a bl e,  c e ntr al  E C G  d at a  will  b e  us e d f or  all  E C G s u m m ar y t a bl es  a n d  a n al ys es. 
T h e f oll o wi n g r e p orts  will  b e  pr o d u c e d:  
•   s hift t a bl e  b as eli n e t o  w orst  o n -tr e at m e nt r es ult f or  o v er all ass ess m e nts  
•   listi n g  of  E C G  e v al u ati o ns f or  all  p ati e nts  wit h  at l e ast  o n e  a b n or m alit y. 
Vit al  si g n s  
D efi niti o ns  of  n ot a bl y  a b n or m al r es ults  will  b e  gi v e n i n t h e  R A P.  T h e f oll o wi n g r e p orts  will 
b e  pr o d u c e d: 
•   s hift t a bl e  b as eli n e t o  w orst  o n -tr e at m e nt r es ult 
•   t a bl e  wit h  d es cri pti v e st atisti cs  at  b as eli n e,  o n e  or s e v er al  p ost-b as eli n e ti m e  p oi nts  a n d 
c h a n g e fr o m  b as eli n e t o t his/t h es e  p ost -b as eli n e ti m e   p oi nts. 
•   B ot h l o c al  a n d  c e ntr al (if  c oll e ct e d)  E C G  d at a  will  b e  list e d. 
A d diti o n al  gl u c o s e/i n s uli n  m o nit ori n g f or  B Y L 7 1 9 tr e at m e nt  ar m  
A d diti o n al s af et y  ass ess m e nts i n cl u d e f asti n g s er u m i ns uli n, f asti n g s er u m  C -p e pti d e, f asti n g 
pl as m a  gl u c os e  a n d  h e m o gl o bi n  A 1 c ( S e cti o n  7. 2. 2. 5. 6 ).  T h e  d at a  will  b e list e d  wit h  n ot a bl e 
v al u es   b ei n g  fl a g g e d.   S u m m ar y  t a bl es   wi t h   d es cri pti v e  st atisti cs   will   b e   pr es e nt e d  f or  r a w  
ass e ss m e nt s  a n d f or  c h a n g es fr o m  b as eli n e  at  e a c h ti m e  p oi nts.  
 
A d diti o n al  s af et y  a s s e s s m e nt s f or  B Y L 7 1 9/ L D K 3 7 8/ M E K 1 6 2 tr e at m e nt  ar m s  
A d diti o n al  s af et y   ass ess m e nts i n cl u d e  c ar di a c i m a gi n g  ( S e cti o n  7. 2. 2. 6. 2 ),   c ar di a c  e n z y m es 
(S e cti o n  7. 2. 2. 6. 3 )  a n d  o p ht h al m ol o g y  e x a ms (S e cti o n  7. 2. 2. 7 ).  F or  e a c h tr e at m e nt  ar m, t h e 
d at a  will  b e list e d  wit h  n ot a bl e  v al u es  b ei n g fl a g g e d.  S u m m ar y t a bl es  will  b e  pr es e nt e d f or 
ass e ss m e nt s  a n d  c h a n g es fr o m  b as eli n e  at  e a c h ti m e  p oi nt.  
F urt h er  s af et y   d at a   will   b e   c oll e ct e d   as   a p pr o pri at e   a n d  list e d   wit h   n ot a bl e   v al u es   b ei n g  
fl a g g e d. 
 
1 0. 5. 2. 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  
A n y s u p p orti v e  a n al ys es t h at  ar e  c o nsi d er e d  a p pr o pri at e f or s e c o n d ar y  v ari a bl es  will  b e 
d es cri b e d i n t h e  R A P  pri or t o  D B L.  
 
1 0. 5. 2. 6   T ol er a bilit y  
F or  e a c h tr e at m e nt  ar m t h e t ol er a bilit y  of st u d y tr e at m e nt  will  b e  ass ess e d  b y s u m m ari zi n g t h e 
n u m b er   of   d os e  i nt err u pti o ns   a n d   d os e  r e d u cti o ns.   R e as o n s  f or   d os e  i nt err u pti o n   a n d   d os e  
r e d u cti o ns  will  b e list e d  b y  p ati e nt. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 0 3
0  Pr ot o c ol  N o. 
 
 
 
1 0. 5. 3   
P h ar m a c o ki n eti c s  
P A S  will  b e  us e d i n  all  p h ar m a c o ki n eti c  d at a  a n al ysis  a n d  P K s u m m ar y st atisti cs.  
F or   e a c h  tr e at m e nt   ar m   all   c o n c e ntr ati o n   d at a   will   b e  list e d   a n d  s u m m ari z e d   b y  ti m e.  
D es cri pti v e st atisti cs  will i n cl u d e  arit h m eti c  a n d  g e o m etri c  m e a n,  m e di a n, st a n d ar d  d e vi at i o n, 
a n d   c o effi ci e nt   of   v ari ati o n  ( C V),   g e o m etri c   C V,   mi ni m u m   a n d   m a xi m u m.   Missi n g  
c o n c e ntr ati o n  v al u es  will  b e r e p ort e d  as is i n  d at a listi n gs.  C o n c e ntr ati o n  v al u es  b el o w  L o w er 
Li mit  of  Q u a ntit ati o n ( L L O Q)  will  b e  h a n dl e d  as  z er o i n s u m m ar y st atisti cs,  a n d r e p ort e d  as is 
i n   d at a  listi n gs.  I n di vi d u al   c o n c e ntr ati o n-ti m e   pr ofil e   as   w ell   as   m e a n   c o n c e ntr ati o n-ti m e 
pr ofil e  will  b e  pl ott e d.  
P h ar m a c o ki n eti c   p ar a m et ers   as  list e d  i n   T a bl e   1 0 - 2  will   b e   a n al y z e d   a n d  s u m m ari z e d.   
Missi n g  d at a  will  n ot  b e i m p ut e d.  D es cri pti v e st atisti cs  of  all  p h ar m a c o ki n eti c  p ar a m et ers  will 
i n cl u d e  arit h m eti c  a n d  g e o m etri c  m e a n,  m e di a n, st a n d ar d  d e vi ati o n,  a n d  C V,  g e o m etri c  C V, 
mi ni m u m   a n d   m a xi m u m.   O nl y   m e di a n   v al u es   a n d  r a n g es   will   b e   gi v e n  f or   T m a x.   Z er o 
c o n c e ntr ati o ns  will  n ot  b e i n cl u d e d i n t h e  g e o m etri c  m e a n  c al c ul ati o n.  
 
T a bl e  1 0 -2           N o n c o m p art m e nt al  p h ar m a c o ki n eti c  p ar a m et er s  
 
A U Cl a st  
T h e  A U C fr o m ti m e  z er o t o t h e l a st  m e a s ur a bl e  c o n c e ntr ati o n  s a m pli n g ti m e (tl a st) ( m a s s  x ti m e  x 
v ol u m e -1)  
A U Ci nf   
T h e  A U C fr o m ti m e  z er o t o i nfi nit y ( m a s s  x ti m e  x  v ol u m e -1)  
A U Ct a u   
T h e  A U C  c al c ul at e d t o t h e  e n d  of  a  d o si n g i nt er v al (t a u) ( a m o u nt  x ti m e  x  v ol u m e -1)  
A U C 0 -t  
T h e  A U C  c al c ul at e d fr o m ti m e  z er o ( 0) t o t  h o ur s ( a m o u nt  x ti m e  x  v ol u m e -1)  
C m a x   
T h e  m a xi m u m ( p e a k)  o b s er v e d  pl a s m a  c o n c e ntr ati o n ( m a s s  x  v ol u m e -1)  
T m a x   
T h e ti m e t o r e a c h  m a xi m u m ( p e a k)  pl a s m a  c o n c e ntr ati o n (ti m e)  
L a m b d a _ z   
S m all e st ( sl o w e st)  di s p o siti o n ( h y bri d) r at e  c o n st a nt (ti m e -1)  m a y  al s o  b e  u s e d f or t er mi n al 
eli mi n ati o n r at e  c o n st a nt (ti m e -1)  
T 1/ 2   
T h e  eli mi n ati o n  h alf -lif e  a s s o ci at e d  wit h t h e t er mi n al  sl o p e ( L a m b d a  z)  of  a  s e mi l o g arit h mi c 
c o n c e ntr ati o n -ti m e  c ur v e (ti m e).  U s e  q u alifi er f or  ot h er  h alf-li v e s 
C L/ F   
T h e  a p p ar e nt t ot al  b o d y  cl e ar a n c e  of  dr u g fr o m t h e  pl a s m a ( v ol u m e  x ti m e -1) f or  or al  a d mi ni str ati o n  
V z/ F   
T h e  a p p ar e nt  v ol u m e  of  di stri b uti o n  d uri n g t er mi n al  p h a s e ( a s s o ci at e d  wit h  L a m b d a  z) ( v ol u m e)  
C L   
T h e t ot al  b o d y  cl e ar a n c e  of  dr u g fr o m t h e  pl a s m a ( v ol u m e  x ti m e -1) f or i ntr a v e n o u s  a d mi ni str ati o n  
V z   
T h e  v ol u m e  of  di stri b uti o n  d uri n g t er mi n al  p h a s e ( a s s o ci at e d  wit h  L a m b d a  z) ( v ol u m e) f or 
i ntr a v e n o u s  a d mi ni str ati o n 
 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 0 4
0  Pr ot o c ol  N o. 
 
 
 
 
 
1 0. 7  
I nt eri m a n al y si s  
N o i nt eri m  a n al ys es  will  b e  p erf or m e d.  H o w e v er, s af et y  a n d  effi c a c y  d at a  will  b e r e vi e w e d  o n 
a n  o n g oi n g  b asis  b y t h e st u d y t e a m  a cr oss t h e  d ur ati o n  of t h e tri al (r ef er t o  S e cti o n  8. 6 ).  T h e 
s af et y  m o nit ori n g  will  b e  d o n e  a c c or di n g t o  S e cti o n  7. 2. 2 . 
 
1 0. 8  
S a m pl e  si z e  c al c ul ati o n 
F or   e a c h  tr e at m e nt   ar m   a   B a y esi a n  si n gl e -st a g e  si n gl e-ar m   d esi g n  is   u s e d.   Gi v e n  t h e   pri or  
distri b uti o n   a n d   d e cisi o n  r ul es   d es cri b e d  i n  ( S e cti o n   1 0. 4. 2 ),  t h e  li k eli h o o d  t o  
wr o n gl y/ c orr e ctl y  d e cl ar e  pr eli mi n ar y  a cti vit y  u n d er  v ari o us s c e n ari os  of  effi c a c y  w as   d eri v e d. 
Gi v e n  t h e   pri or,  t h e   p ost eri or   distri b uti o n   a n d   p ost eri or   pr o b a biliti es   c a n   b e   d eri v e d   usi n g  
si m ul at e d  d at a (i. e.  ass u mi n g  n u m b er  of  p ati e nts  a n d  n u m b er  of r es p o n d ers).  T h er ef or e, f or  a 
p arti c ul ar  s a m pl e si z e i. e.  n u m b er  of  p ati e nts, t h e  mi ni m u m  n u m b er  of   p ati e nts r e q uir e d t o 
s atisf y t h e t w o  crit eri a  m e nti o n e d i n  S e cti o n  1 0. 4. 2  a n d  d e cl ar e  cli ni c all y r el e v a nt  effi c a c y  c a n 
t h e n   b e   d eri v e d.   T h us,   w h et h er  t h e   d o u bl e   crit eri a  t o   d e cl ar e   pr eli mi n ar y   a cti vit y   c a n   b e  
s atisfi e d  or  n ot is t h e n tr a nsl at e d i nt o t h e si n gl e  crit eri o n  wit h  o bs er v e d  n u m b er  of r es p o n d ers 
( Ri).   T h e   o p er ati n g   c h ara ct eristi cs  s h o w n  i n  t h e   T a bl e   1 0 - 3  a n d  T a bl e   1 0 - 4  b el o w   ar e  
c al c ul at e d  b as e d  o n t his  R i. 
T a bl e  1 0 - 3  b el o w lists f or  e a c h  ar m i t h e s a m pl e si z e,  m a xi m u m  O R R f or t h e  u n a c c e pt a bl e 
effi c a c y   c at e g or y  ( L i),   mi ni m u m   O R R  f or  t h e   cli ni c all y  r el e v a nt   effi c a c y   c at e g or y  ( Mi), 
mi ni m u m   n u m b er   of  r es p o ns es  f or  t h e   cli ni c all y  r el e v a nt   effi c a c y   c at e g or y  ( R
i),   a n d  
pr o b a bilit y  t o   wr o n gl y  d e cl ar e  pr eli mi n ar y  a cti vit y   w h e n   O R R = L i.  T h e  c h os e n s a m pl e si z es 
all  h a v e  < 7. 8 %  pr o b a bilit y  of  wr o n g  c o n cl usi o n  w h e n t h e tr u e  O R R is  wit hi n t h e  u n a c c e pt a bl e 
effi c a c y  i nt er v al. 
T a bl e   1 0 - 4  pr es e nts  t h e   pr o b a bilit y   of   c orr e ctl y   d e cl ari n g   pr eli mi n ar y   a cti vit y   u n d er   3  
s c e n ar i os  of  tr u e   O R R.   T h e  pr o p os e d  d esi g n  a c hi e v es  hi g h  p o w er  ( > = 8 8. 9 %)   w h e n  t h e  tr u e 
O R R is  > = 7 1. 0 %  a n d  2 9. 8 % i n  L D K 3 7 8  a n d t h e  ot h er  ar ms, r es p e cti v el y.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 0 5
0  Pr ot o c ol  N o. 
 
 
 
T a bl e  1 0 - 3  
B a y e si a n  d e si g n  p ar a m et er s  a n d  s a m pl e  si z e  
 
 
M a xi m u m   
Mi ni m u m  O R R   
Mi ni m u m  #  of  
 
O R R f or   
f or  cli ni c all y  
r e s p o n s e s  
Pr o b a bilit y t o  
u n a c c e pt a bl e   r el e v a nt 
f or  cli ni c all y  
wr o n gl y  d e cl ar e  
effi c a c y   
effi c a c y  
r el e v a nt 
pr eli mi n ar y  
 
S a m pl e  
 
 
effi c a c y  
a cti vit y  w h e n  
Ar mi  
si z e  
L i 
M
i 
R i 
tr u e  O R R = Li 
1.  L D K 3 7 8   
2 5   
4 0 %  
5 5 %  
1 4  
7. 8 %  
2. I N C 2 8 0   
2 0   
7. 5 %   
1 7. 5 %  
4  
5. 8 %  
3.  M E K 1 6 2   
2 0   
7. 5 %   
1 7. 5 %  
4  
5. 8 %  
4.  B Y L 7 1 9   
2 0   
7. 5 %   
1 7. 5 %  
4  
5. 8 %  
 
T a bl e  1 0 - 4  
Pr o b a biliti e s  of  c orr e ctl y  d e cl ari n g  pr eli mi n ar y  a cti vit y ( A i)  u n d er  3 
s c e n ari o s  of tr u e  o v er all r e s p o n s e r at e s  ( Pi) 
 
Ar m  
S c e n ari o  1  
 
S c e n ari o  2  
S c e n ari o  3  
i 
P i ( = Mi)  
A i 
P i ( = Ui 1*) 
A i 
P i ( = Ui 2**) 
A i 
1.  L D K 3 7 8   
5 5. 0 %   
5 4. 3 %   
6 4. 7 %   
8 6. 8 %   
7 1. 0 %   
9 6. 6 %  
2. I N C 2 8 0   
1 7. 5 %   
4 7. 4 %   
2 4. 1 %   
7 4. 6 %   
2 9. 8 %   
8 8. 9 %  
3.  M E K 1 6 2   
1 7. 5 %   
4 7. 4 %   
2 4. 1 %   
7 4. 6 %   
2 9. 8 %   
8 8. 9 %  
4.  B Y L 7 1 9   
1 7. 5 %   
4 7. 4 %   
2 4. 1 %   
7 4. 6 %   
2 9. 8 %   
8 8. 9 %  
*  d efi n e d  s o t h at  o d d s( U i 1)/ o d d s( Mi) = 1. 5 
**  d efi n e d  s o t h at  o d d s( Ui 2)/ o d d s( Mi) = 2. 0 
 
 
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 ni c al st u d y  w as  d esi g n e d, s h all  b e i m pl e m e nt e d  a n d r e p ort e d i n  a c c or d a n c e  wit h t h e 
I C H   H ar m o ni z e d   Tri p artit e   G ui d eli n es  f or   G o o d   Cli ni c al   Pr a cti c e,   wit h   a p pli c a bl e  l o c al  
r e g ul ati o ns (i n cl u di n g  E ur o p e a n  Dir e cti v e  2 0 0 1/ 2 0/ E C  a n d  U S  C o d e  of  F e d er al  R eg ul ati o ns 
Titl e  2 1),  a n d  wit h t h e  et hi c al  pri n ci pl es l ai d  d o w n i n t h e  D e cl ar ati o n  of  H elsi 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 h e  pr ot o c ol  a n d t h e  pr o p os e d i nf or m e d  c o ns e nt f or m  m ust  b e r e vi e w e d  a n d  a p pr o v e d  b y  a 
pr o p erl y   c o nstit ut e d   I nstit uti o n al   R e vi e w   B o ar d/I n d e p e n d e nt   Et hi cs   C o m mitt e e/ R es e ar c h  
Et hi cs   B o ar d  (I R B/I E C/ R E B)   b ef or e  st u d y  st art.   Pri or  t o  st u d y  st art,  t h e  i n v esti g at or  is  
r e q uir e d t o si g n  a  pr ot o c ol si g n at ur e  p a g e  c o nfir mi n g  his/ h er  a gr e e m e nt t o  c o n d u ct t h e st u d y 
i n  a c c ord a n c e  wit h t h es e  d o c u m e nts  a n d  all  of t h e i nstr u cti o ns  a n d  pr o c e d ur es f o u n d i n t his 
pr ot o c ol   a n d t o  gi v e  a c c ess t o  all  r el e v a nt   d at a  a n d r e c or ds t o  N o v artis  m o nit ors,   a u dit ors,  
N o v artis   Cli ni c al   Q u alit y   Ass ur a n c e  r e pr es e nt ati v es,   d esi g n at e d   a g e nts   of   N o v ar tis, 
I R Bs/I E Cs/ R E Bs  a n d r e g ul at or y  a ut h oriti es  as r e q uir e d. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 0 6
0  Pr ot o c ol  N o. 
 
 
 
 
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 bl e  p ati e nts  m a y  o nl y  b e i n cl u d e d i n t h e st u d y  aft er  pr o vi di n g  writt e n ( wit n ess e d,  w h er e 
r e q uir e d  b y l a w  or r e g ul ati o n), I R B/I E C/ R E B-a p pr o v e d i nf or m e d  c o ns e nt.  
I nf or m e d  c o ns e nt  m ust  b e  o bt ai n e d  b ef or e  c o n d u cti n g  a n y st u d y-s p e cifi c  pr o c e d ur es (i. e.  all 
of  t h e   pr o c e d ur es   d es cri b e d  i n  t h e   pr ot o c ol).   T h e   pr o c ess   of   o bt ai ni n g  i nf or m e d   c o ns e nt  
s h o ul d  b e  d o c u m e nt e d i n t h e  p ati e nt s o ur c e  d o c u m e nts.  T h e  d at e  w h e n  a s u bj e ct’s I nf or m e d 
C o ns e nt  w as  a ct u all y  o bt ai n e d  will  b e  c a pt ur e d i n t h eir  C R Fs.  
N o v artis  will  pr o vi d e t o i n v esti g at ors, i n  a s e p ar at e  d o c u m e nt,  a  pr o p os e d i nf or m e d  c o ns e nt 
f or m  (I C F)  t h at  is   c o nsi d er e d   a p pr o pri at e  f or  t his  st u d y   a n d   c o m pli es   wit h  t h e  I C H   G C P  
g ui d eli n e  a n d r e g ul at or y r e q uir e m e nts.  A n y  c h a n g es t o t his I C F s u g g est e d  b y t h e i n v esti g at or 
m ust   b e   a gr e e d  t o  b y   N o v artis  b ef or e  s u b missi o n  t o  t h e I R B/I E C/ R E B,   a n d   a  c o p y   of  t h e 
a p pr o v e d  v ersi o n  m ust  b e  pr o vi d e d t o t h e  N o v artis  m o nit or  aft e r I R B/I E C/ R E B  a p pr o v al. 
W o m e n  of  c hil d  b e ari n g  p ot e nti al s h o ul d  b e i nf or m e d t h at t a ki n g t h e st u d y  m e di c ati o n  m a y 
i n v ol v e  u n k n o w n ris ks t o t h e f et us if  pr e g n a n c y  w er e t o  o c c ur  d uri n g t h e st u d y  a n d  a gr e e t h at 
i n  or d er t o  p arti ci p at e i n t h e st u d y t h e y  m ust  a d h er e t o t h e  c o ntr a c e pti o n r e q uir e m e nt f or t h e 
d ur ati o n  of t h e st u d y. If t h er e is  a n y  q u esti o n t h at t h e  p ati e nt  will  n ot r eli a bl y  c o m pl y, t h e y 
s h o ul d  n ot  b e  e nt er e d i n t h e st u d y. 
 
1 1. 4  
Di s c o nti n u ati o n  of t h e  st u d y 
N o v artis  r es er v es  t h e  ri g ht  t o   dis c o nti n u e  t his  st u d y   u n d er  t h e   c o n diti o ns  s p e cifi e d  i n  t h e  
cli ni c al  st u d y   a gr e e m e nt.   S p e cifi c   c o n diti o ns  f or  t er mi n ati n g  t h e  st u d y   ar e   o utli n e d    i n   
S e cti o n   4. 4 
 
1 1. 5  
P u bli c ati o n  of  st u d y  pr ot o c ol  a n d  r e s ult s 
N o v artis is  c o m mitt e d t o f oll o wi n g  hi g h  et hi c al st a n d ar ds f or r e p orti n g st u d y r es ults f or its 
i n n o v ati v e   m e di ci n e,  i n cl u di n g  t h e  ti m el y   c o m m u ni c ati o n   a n d   p u bli c ati o n   of   cli ni c al  tri al  
r es ults,  w h at e v er t h eir  o ut c o m e.  N o v artis  ass ur es t h at t h e  ke y  d esi g n  el e m e nts  of t his  pr ot o c ol 
will  b e  p ost e d  o n t h e  p u bli cl y  a c c essi bl e  d at a b as e,  e. g. s u c h  as  w w w. cli ni c altri als. g o v,  b ef or e 
st u d y st art. I n  a d diti o n, r es ults  of i nt er v e nti o n al  cli ni c al tri als i n  a d u lt  p ati e nts  ar e  p ost e d  o n 
w w w. n o v artis cli ni c altri als. c o m,  a  p u bli cl y  a c c essi bl e  d at a b as e  of  cli ni c al st u d y r es ults  wit hi n 
1  y e ar  of  u p o n st u d y  c o m pl eti o n (i. e.,  L P L V),  a n d fi n ali z ati o n  of t h e st u d y r e p ort t h e r es ults  
of t his st u d y  will  b e  eit h er s u b mitt e d f or  p u bli c ati o n  a n d/ or  p ost e d i n t h os e f or i nt er v e nti o n al 
cli ni c al tri als i n v ol vi n g  p e di atri c  p ati e nts  wit hi n  6  m o nt hs  of st u d y  c o m pl eti o n  
N o v artis  f oll o ws  t h e  I C MJ E   a ut h ors hi p   g ui d eli n es  ( w w w.i c mj e. or g)   a n d   ot h er  s p e cifi c  
g ui d eli n es  of t h e j o ur n al  or  c o n gr ess t o  w hi c h t h e  p u bli c ati o n  will  b e s u b mitt e d  
A ut h ors  will  n ot r e c ei v e r e m u n er ati o n f or t h eir  writi n g  of  a  p u bli c ati o n,  eit h er  dir e ctl y fr o m 
N o v artis  or t hr o u g h t h e  pr of essi o n al  m e di c al  writi n g  a g e n c y.  A ut h or(s)  m a y  b e r e q u est e d t o 
pr es e nt   p ost er   or   or al   pr es e nt ati o n   at   s ci e ntifi c   c o n gr ess;   h o w e v er,   t h er e    will   b e   n o  
h o n or ari u m  pr o vi d e d f or s u c h  pr es e nt ati o ns.  
As   p art   of  its   c o m mit m e nt  t o  f ull  tr a ns p ar e n c y  i n   p u bli c ati o ns,   N o v artis  s u p p orts  t h e  f u ll 
dis cl os ur e  of  all f u n di n g s o ur c es f or t h e st u d y  a n d  p u bli c ati o ns,  as  w ell  as  a n y  a ct u al  a n d  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 0 7
0  Pr ot o c ol  N o. 
 
 
 
p ot e nti al   c o nfli cts  of i nt er est  of fi n a n ci al  a n d  n o n -fi n a n ci al   n at ur e  b y  all  a ut h ors, i n cl u di n g 
m e di c al  writi n g/ e dit ori al s u p p ort, if  a p pli c a b l e. 
F or t h e  N o v artis  G ui d eli n es f or t h e  P u bli c ati o n  of  R es ults fr o m  N o v artis -s p o ns or e d  R es e ar c h, 
pl e as e r ef er t o  w w w. n o v artis. c o m.  
 
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 
E a c h  p arti ci p ati n g sit e  will  m ai nt ai n  a p pr o pri at e  m e di c al  a n d r es e ar c h r e c or ds f or t his tri al, i n 
c o m pli a n c e   wit h   S e cti o n   4. 9   of  t h e  I C H   E 6   G C P,   a n d  r e g ul at or y   a n d  i nstit uti o n al  
r e q uir e m e nts  f or  t h e   pr ot e cti o n   of   c o nfi d e nti alit y   of  s u bj e cts.   As   p art   of   p arti ci p ati n g  i n   a  
N o v artis- s p o n s or e d st u d y,  e a c h sit e  will  p er mit  a ut h ori z e d r e pr es e nt ati v es  of t h e s p o ns or(s)  
a n d r e g ul at or y  a g e n ci es t o  e x a mi n e ( a n d  w h e n r e q uir e d  b y  a p pli c a bl e l a w, t o  c o p y)  cli ni c al 
r e c or ds  f or  t h e   p ur p os es   of   q u alit y   ass ur a n c e  r e vi e ws,   a u dits   a n d   e v al u ati o n   of  t h e  st u d y   
s af et y  a n d  pr o gr ess. 
S o ur c e   d at a   ar e   all  i nf or m ati o n,   ori gi n al  r e c or ds  of   cli ni c al  fi n di n gs,   o bs er v ati o ns,   or   ot h er  
a cti viti es  i n   a   cli ni c al  tri al   n e c ess ar y  f or  t h e  r e c o nstr u cti o n   a n d   e v al u ati o n   of  t h e  tri al.  
E x a m pl es  of t h es e  ori gi n al  d o c u m e nts  a n d  d at a r e c or ds i n cl u d e,  b ut  a r e  n ot li mit e d t o,  h os pit al 
r e c or ds,   cli ni c al   a n d   offi c e   c h arts,  l a b or at or y   n ot es,   m e m or a n d a,  s u bj e cts’   di ari es   or   
e v al u ati o n   c h e c klists,   p h ar m a c y   dis p e nsi n g  r e c or ds,  r e c or d e d   d at a  fr o m   a ut o m at e d  
i nstr u m e nts,  c o pi es  or tr a ns cri pti o ns  c ertifi e d  aft er  v erifi c ati o n  as  b ei n g  a c c ur at e  a n d  c o m pl et e, 
mi cr ofi c h es,   p h ot o gr a p hi c  n e g ati v es,   mi cr ofil m  or   m a g n eti c  m e di a,   x -r a ys,   a n d  s u bj e ct  fil es 
a n d  r e c or ds   k e pt   at  t h e   p h ar m a c y,   at  t h e  l a b or at ori es,   a n d   m e di c o -t e c h ni c al   d e p art m e nts  
i n v ol v e d i n t h e  cli ni c al tri al. 
D at a  c oll e cti o n is t h e r es p o nsi bilit y  of t h e  cli ni c al tri al st aff  at t h e sit e  u n d er t h e s u p er visi o n  of 
t h e sit e  Pri n ci p al I n v esti g at or.  T h e st u d y  c as e r e p ort f or m ( C R F) is t h e  pri m ar y  d at a  c oll e cti o n 
i nstr u m e nt f or t h e st u d y.  T h e i n v esti g at or s h o ul d  e ns ur e t h e a c c ur a c y,  c o m pl et e n ess, l e gi bilit y, 
a n d ti m eli n ess  of t h e  d at a r e p ort e d i n t h e  C R Fs  a n d  all  ot h er r e q uir e d r e p orts.  D at a r e p ort e d  
o n  t h e   C R F,  t h at   ar e   d eri v e d  fr o m  s o ur c e  d o c u m e nts,  s h o ul d   b e  c o nsist e nt   wit h  t h e s o ur c e 
d o c u m e nts  or t h e  dis cr e p a n ci es s h o ul d  b e  e x pl ai n e d.  All  d at a r e q u est e d  o n t h e  C R F  m ust  b e 
r e c or d e d.   A n y   missi n g   d at a   m ust   b e   e x pl ai n e d.   A n y   c h a n g e   or   c orr e cti o n  t o   a   p a p er   C R F  
s h o ul d   b e   d at e d,  i niti al e d,   a n d   e x pl ai n e d (if   n e c ess ar y)   a n d  s h o ul d   n ot   o bs c ur e t h e   ori gi n al  
e ntr y.  F or  el e ctr o ni c  C R Fs  a n  a u dit tr ail  will  b e  m ai nt ai n e d  b y t h e s yst e m.  T h e i n v esti g at or 
s h o ul d r et ai n r e c or ds  of t h e  c h a n g es  a n d  c orr e cti o ns t o  p a p er  C R Fs.  
T h e  i n v esti g at or/i nstit uti o n  s h o ul d   m ai nt ai n  t h e  tri al   d o c u m e nts   as  s p e cifi e d  i n   Ess e nti al  
D o c u m e nts  f or  t h e   C o n d u ct   of   a   Cli ni c al   Tri al  (I C H   E 6   S e cti o n   8)   a n d   as  r e q uir e d   b y  
a p pli c a bl e r e g ul ati o ns  a n d/ or  g ui d eli n es.  T h e i n v esti g at or/i nstit uti o n s h o ul d t a k e  m e as ur es t o 
pr e v e nt  a c ci d e nt al  or  pr e m at ur e  d estr u cti o n  of t h es e  d o c u m e nts.  
Ess e nti al  d o c u m e nts ( writt e n  a n d  el e ctr o ni c) s h o ul d  b e r et ai n e d f or  a  p eri o d  of  n ot l ess t h a n 
fift e e n ( 1 5)  y e ars fr o m t h e  c o m pl eti o n  of t h e  Cli ni c al  Tri al  u nl ess  S p o ns or  pr o vi d es  writt e n 
p er missi o n  t o   dis p os e   of  t h e m   or,  r e q uir es  t h eir  r et e nti o n  f or   a n   a d diti o n al   p eri o d   of  ti m e  
b e c a us e  of  a p pli c a bl e l a ws, r e g ul ati o ns  a n d/ or  g ui d eli n es.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 0 8
0  Pr ot o c ol  N o. 
 
 
 
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 h e  i n v esti g at or    m ust  e ns ur e  a n o n y mit y  of  t h e  p ati e nts;  p ati e nts    m ust  n ot  b e  i d e ntifi e d  b y 
n a m es i n  a n y  d o c u m e nts s u b mitt e d t o  N o v artis.  Si g n e d i nf or m e d  c o ns e nt f or ms  a n d  p ati e nt 
e nr oll m e nt l o g  m ust  b e  k e pt stri ctl y  c o nfi d e nti al t o  e n a bl e  p ati e nt i d e ntifi c ati o n  at t h e sit e.  
 
1 1. 8  
A u dit s  a n d i n s p e cti o n s 
S o ur c e  d at a/ d o c u m e nts  m ust   b e  a v ail a bl e t o i ns p e cti o ns  b y  N o v artis  or   d esi g n e e  or   H e alt h  
A ut h ori ti es. 
 
1 1. 9  
Fi n a n ci al  di s cl o s ur e s 
Fi n a n ci al  dis cl os ur es s h o ul d  b e  pr o vi d e d  b y st u d y  p ers o n n el  w h o  ar e  dir e ctl y i n v ol v e d i n t h e 
tr e at m e nt  or  e v al u ati o n  of  p ati e nts  at t h e sit e - pri or t o st u d y st art.  
 
1 2   
Pr ot o c ol  a d h er e n c e  
I n v esti g at ors  as c ert ai n t h e y  will  a p pl y  d u e  dili g e n c e t o  a v oi d  pr ot o c ol  d e vi ati o ns.  U n d er  n o 
cir c u mst a n c es s h o ul d t h e i n v e sti g at or   c o nt a ct   N o v artis  or  its  a g e nts,  if   a n y,  m o nit ori n g t h e 
st u d y t o r e q u est  a p pr o v al  of  a  pr ot o c ol  d e vi ati o n,  as  n o  a ut h ori z e d  d e vi ati o ns  ar e  p er mitt e d. If 
t h e i n v esti g at or f e els  a  pr ot o c ol  d e vi ati o n  w o ul d i m pr o v e t h e  c o n d u ct  of t h e st u d y t his  m ust  
b e   c o nsi d er e d   a   pr ot o c ol   a m e n d m e nt,   a n d   u nl ess  s u c h   a n   a m e n d m e nt  is   a gr e e d   u p o n   b y 
N o v artis   a n d   a p pr o v e d   b y  t h e  I R B/I E C/ R E B  it   c a n n ot   b e  i m pl e m e nt e d.   All  si g nifi c a nt  
pr ot o c ol  d e vi ati o ns  will  b e r e c or d e d  a n d r e p ort e d i n t h e  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 h a n g e  or  a d diti o n t o t h e  pr ot o c ol  c a n  o nl y  b e  m a d e i n  a  writt e n  pr ot o c ol  a m e n d m e nt t h at 
m ust   b e   a p pr o v e d   b y   N o v artis,   H e alt h   A ut h o riti es   w h er e  r e q uir e d,   a n d  t h e  I R B/I E C/ R E B.  
O nl y   a m e n d m e nts  t h at   ar e  r e q uir e d  f or   p ati e nt  s af et y   m a y   b e  i m pl e m e nt e d   pri or  t o  
I R B/I E C/ R E B   a p pr o v al.   N ot wit hst a n di n g  t h e   n e e d  f or   a p pr o v al   of  f or m al   pr ot o c ol  
a m e n d m e nts, t h e i n v esti g at or is  e x p e ct e d t o t a k e  a n y  i m m e di at e  a cti o n r e q uir e d f or t h e s af et y 
of   a n y   p ati e nt  i n cl u d e d  i n  t his  st u d y,   e v e n  if  t his   a cti o n  r e pr es e nts   a   d e vi ati o n  fr o m  t h e  
pr ot o c ol. I n s u c h  c as es,  N o v artis s h o ul d  b e  n otifi e d  of t his  a cti o n  a n d t h e I R B/I E C  at t h e st u d y 
sit e s h o ul d  b e i nf or m e d  a c c or di n g t o l o c al r e g ul ati o ns ( e. g.  U K r e q uir es t h e  n otifi c ati o n  of 
ur g e nt s af et y  m e as ur es  wit hi n  3  d a ys)  b ut  n ot l at er t h a n  1 0  w or ki n g  d a ys.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 0 9
0  Pr ot o c ol  N o. 
 
 
 
 
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 v ar e z  M,  R o m a n  E,  S a nt os  E S,  et  al ( 2 0 0 7)  N e w t ar g ets f or   n o n-s m all-c ell l u n g  c a n c er 
t h er a p y.  E x p ert  R e v  A nti c a n c er  T h er;  7( 1 0): 1 4 2 3- 3 7. 
Alt o m ar e  D A,  T est a J R ( 2 0 0 5)  P ert ur b ati o ns  of t h e  A K T si g n ali n g  p at h w a y i n  h u m a n  c a n c er. 
O n c o g e n e  2 4:  7 4 5 5 – 6 4. 
A n  SJ  et  al ( 2 0 1 2) I d e ntifi c ati o n  of  e nri c h e d  dri v er  g e n e  alt er ati o ns i n s u b gr o u ps  of  n o n -s m all 
c ell l u n g  c a n c er  p at eit ns  b as e d  o n  hist ol o g y  a n d s m o ki n g st at us.  P L o S  O n e,  V ol u m e  7, Iss u e  6.  
B a n g  YJ,  S u  W C,  N a m  D H,  et  al ( 2 0 1 4)  P h as e I st u d y  of t h e s af et y  a n d  effi c a c y  of I N C 2 8 0 i n 
p ati e nts  wit h  a d v a n c e d  M E T -d e p e n d e nt s oli d t u m ors. J  Cli n  O n c ol  3 2: 5s (s u p pl;  a bstr  2 5 2 0)  
B er g et h o n,  K.,  et  al.  R O S 1 r e arr a n g e m e nts  d efi n e  a  u ni q u e  m ol e c ul ar  cl ass  of l u n g  c a n c ers. 
J. Cli n. O n c ol.  3 0. 8 ( 2 0 1 2):  8 6 3 - 7 0. 
Bl u m e ns c h ei n,  G.  et  al.  A r a n d o mi z e d  p h as e III tri al  c o m p ari n g i o n af ar ni b/ c ar b o pl ati n/ 
p a clit a x el  v ers us  c ar b o pl ati n/ p a clit a x el ( C P) i n  c h e m ot h er a p y -n ai v e  p ati e nts  wit h  a d v a n c e d  or 
m et ast ati c  n o n -s m all  c ell l u n g  c a n c er ( N S C L C).  L u n g  C a n c er,  2 0 0 5;  4 9:  S 3 0  
B o n elli  M A.,  et  al. I n hi biti o n  of  PI 3 K  P at h w a y  R e d u c es I n v asi v e n ess  a n d  E pit h eli al -t o- 
M es e n c h y m al  Tr a nsiti o n i n  S q u a m o us  L u n g  C a n c er  C ell  Li n es  H ar b ori n g  PI K 3 C A  G e n e 
Alt er ati o ns.  M ol  C a n c er  T h er  2 0 1 5; 1 4: 1 9 1 6 - 1 9 2 7. 
C ar n er o  A ( 2 0 1 0)  T h e  P K B/ A K T  p at h w a y i n  c a n c er.  C urr  P h ar m  D es  1 6: 3 4 – 4 4. 
D a vi es  H,  Bi g n ell,  G R,  C o x  C,  et  al ( 2 0 0 2)  M ut ati o ns  of t h e  B R A F  g e n e i n  h u m a n  c a n c er. 
N at ur e.  4 1 7: 9 4 9 - 5 4. 
F eli p.  E ( 2 0 1 2),  P h as e II  a cti vit y  of t h e  H S P 9 0 i n hi bit or  A U Y 9 2 2 i n  p ati e nts  wit h  A L K - 
r e arr a n g e d ( A L K +)  or  E G F R-m ut at e d  a d v a n c e d  n o n -s m all  c ell l u n g  c a n c er ( N S C L C),  E S M O.  
G etti n g er  S,  L y n c h  T ( 2 0 1 1)  A  d e c a d e  of  a d v a n c es i n tr e at m e nt f or  a d v a n c e d  n o n -s m all  c ell 
l u n g  c a n c er.  Cli n  C h est  M e d;  3 2( 4): 8 3 9- 5 1. 
G o n z al e z -A n g ul o  et  al ( 2 0 1 3)  S af et y,  p h ar m a c o ki n eti cs  a n d  pr eli mi n ar y  a cti vit y  of t h e  al p h a - 
s p e cifi c i n hi bit or  B Y L 7 1 9:  R es ults fr o m t h e first -i n-h u m a n st u d y  A S C O.  
J a n n e,  P.  A.,  et  al.  S el u m eti ni b  pl us  d o c et a x el f or  K R A S -m ut a nt  a d v a n c e d  n o n -s m all-c ell 
l u n g  c a n c er:  a r a n d o mis e d,  m ulti c e ntr e,  pl a c e b o-c o ntr oll e d,  p h as e  2 st u d y.  L a n c et  O n c ol.   1 4. 1 
( 2 0 1 3):  3 8- 4 7. 
K a w a n o  O  et  al.  PI K 3 C A  g e n e  a m plifi c ati o n i n J a p a n es e  n o n -s m all  c ell l u n g  c a n c er.  L u n g 
C a n c er.  2 0 0 7;  5 8: 1 5 9 – 1 6 0. 
L ars e n  et  al.  T ar g et e d t h er a pi es f or l u n g  c a n c er:  cli ni c al  e x p eri e n c e  a n d  n o v el  a g e nts.  C a n c er 
J.  2 0 1 1  N o v-D e c;  1 7( 6):  5 1 2 – 5 2 7. 
L utt er b a c h  B,  et  al ( 2 0 0 7)  L u n g  c a n c er  c ell li n es  h ar b ori n g  M E T  g e n e  a m plifi c ati o n  ar e 
d e p e n d e nt  o n  M et f or  gr o wt h  a n d s ur vi v al.  C a n c er  R es e ar c h.  A pr  1 5; 6 7( 8): 3 9 8 7.  
M a e m o n d o  M, I n o u e  A,  K o b a y as hi  K,  S u g a w ar a  et  al ( 2 0 1 0)  G efiti ni b  or  c h e m ot h er a p y f or 
n o n- s m all -c ell l u n g  c a n c er  wit h  m ut at e d  E G F R.  N  E n gl J  M e d;  3 6 2( 2 5): 2 3 8 0 - 8. 
M al u m br es  M,  B ar b a ci d  M. ( 2 0 0 3)  R A S  o n c o g e n es: t h e first  3 0  y e ars.  N at  R e v 
C a n c er.; 3( 6): 4 5 9 -6 5.  Err at u m i n:  N at  R e v  C a n c er;  3( 9): 7 0 8.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 1 0
0  Pr ot o c ol  N o. 
 
 
 
M al v e z zi  M,  B ert u c ci o  P,  L e vi  F,  et  al ( 2 0 1 2)  E ur o p e a n  c a n c er  m ort alit y  pr e di cti o ns f or t h e 
y e ar  2 0 1 2.  A n n  O n c ol;  2 3( 4): 1 0 4 4 - 5 2. 
M as c a u x,  C.,  et  al.  T h e r ol e  of  R A S  o n c o g e n e i n s ur vi v al  of  p ati e nts  wit h l u n g  c a n c er:  a 
s yst e m ati c r e vi e w  of t h e lit er at ur e  wit h  m et a -a n al ysis.  Br.J. C a n c er  9 2. 1 ( 2 0 0 5):  1 3 1 - 3 9. 
M c D er m ott  U,  et  al ( 2 0 0 7) I d e ntifi c ati o n  of  g e n ot y p e -c orr el at e d s e nsiti vit y t o s el e cti v e  ki n as e 
i n hi bit ors  b y usi n g  hi g h -t hr o u g h p ut t u m or  c ell li n e  pr ofili n g.  Pr o c  N atl  A c a d  S ci  U. S. A.: 
1 0 4( 5 0): 1 9 9 3 6- 4 1. 
M e m m ott  R M,  D e n nis  P A ( 2 0 1 0)  T h e r ol e  of t h e  A kt/ m T O R  p at h w a y i n t o b a c c o  c ar ci n o g e n - 
i n d u c e d l u n g t u m ori g e n esis.  Cli n  C a n c er  R es  1 6:  4– 1 0. 
Mits u d o mi,  T.  a n d  Y.  Y at a b e.  M ut ati o ns  of t h e  e pi d er m al  gr o wt h f a ct or r e c e pt or  g e n e  a n d 
r el at e d  g e n es  as  d et er mi n a nts  of  e pi d er m al  gr o wt h f a ct or r e c e pt or t yr osi n e  ki n as e i n hi bit ors 
s e nsiti vit y i n l u n g  c a n c er.  C a n c er  S ci.  9 8. 1 2 ( 2 0 0 7):  1 8 1 7 - 2 4. 
M o k  T,  W u  Y L,  T h o n g pr as ert  S,  et  al ( 2 0 0 9)  G efiti ni b  or  c ar b o pl ati n -p a clit a x el i n  p ul m o n ar y 
a d e n o c ar ci n o m a.  N  E n gl J  M e d;  3 6 1:  9 4 7 - 5 7. 
M o k,  T.,  Y.  L.  W u,  a n d  L.  Z h a n g.  A s m all st e p t o w ar ds  p ers o n ali z e d  m e di ci n e f or  n o n -s m all 
c ell l u n g  c a n c er.  Dis c o v. M e d.  8. 4 3 ( 2 0 0 9):  2 2 7 -3 1.  
N e u e ns c h w a n d er  B,  C a p k u n -Ni g gli  G,  Br a ns o n  M,  S pi e g el h alt er  DJ ( 2 0 1 0)  S u m m ari zi n g 
hist ori c al i nf or m ati o n  o n  c o ntr ol s i n  cli ni c al tri als.  Cli ni c al  Tri als,  7,  5 - 1 8. 
O u  S H ( 2 0 1 1)  Cri z oti ni b:  a  n o v el  a n d first -i n-cl ass  m ultit ar g et e d t yr osi n e  ki n as e i n hi bit or f or 
t h e tr e at m e nt  of  a n a pl asti c l y m p h o m a  ki n as e r e arr a n g e d  n o n-s m all  c ell l u n g  c a n c er  a n d 
b e y o n d.  Dr u g  D es  D e v el  T h e r;  5: 4 7 1- 4 8 5. 
O x n ar d,  G.  R.,  et  al.  N e w str at e gi es i n  o v er c o mi n g  a c q uir e d r esist a n c e t o  e pi d er m al  gr o wt h 
f a ct or r e c e pt or t yr osi n e  ki n as e i n hi bit ors i n l u n g  c a n c er.  Cli n. C a n c er  R es.  1 7. 1 7 ( 2 0 1 1):  5 5 3 0- 
3 7. 
Ri c h e y,  S.  L.,  et  al.  " P h as e II  Tri al  of  P e m etr e x e d  Pl us  G e m cit a bi n e i n  P ati e nts  Wit h  L o c all y 
A d v a n c e d  a n d  M et ast ati c  N o n cl e ar  C ell  R e n al  C ell  C ar ci n o m a. "  A m.J. Cli n. O n c ol. ( 2 0 1 2).  
R os ell  R,  C ar c er e n y  E,  G er v als  R,  et  al.  Erl oti ni b  v ers us st a n d ar d  c h e m ot h er a p y  as first -li n e 
tr e at m e nt f or  E ur o p e a n  p ati e nts  wit h  a d v a n c e d  E G F R  m ut ati o n-p ositi v e  n o n -s m all-c ell l u n g 
c a n c er ( E U R T A C):  a  m ulti c e ntr e,  o p e n -l a b el, r a n d o mis e d  p h as e  3 tri al.  L a nc et  O n c ol.  2 0 1 2; 
1 3:  2 3 9 – 4 6. 
R ui z  M G,  Fl o or  K,  R o e p m a n  P,  et  al ( 2 0 0 8) I nt e gr ati o n  of  g e n e  d os a g e  a n d  g e n e  e x pr essi o n 
i n  n o n-s m all  c ell l u n g  c a n c er, i d e ntifi c ati o n  of  H S P 9 0  as  p ot e nti al t ar g et.  P L o S  O n e;  3( 3): 
0 0 0 1 7 2 2. 
S as a ki  H,  et  al.  M ut ati o n  of  e pi d er m a l  gr o wt h f a ct or r e c e pt or  g e n e i n  a d e n os q u a m o us 
c ar ci n o m a  of t h e l u n g.  L u n g  C a n c er.  2 0 0 7;  5 5:  1 2 9 - 1 3 0. 
S c h effl er  M.,  et  al. ( 2 0 1 5)  PI K 3 C A  m ut ati o ns i n  n o n -s m all  c ell l u n g  c a n c er ( N S C L C):  g e n eti c 
h et er o g e n eit y,  pr o g n osti c i m p a ct  a n d i n ci d e n c e  of  pri or  m ali g n a n ci es.  O n c ot ar g et.  2 0; 
6( 2): 1 3 1 5- 2 6. 
S a n dl er  A,  Gr a y  R,  P err y  M C,  et  al ( 2 0 0 6)  P a clit a x el -c ar b o pl ati n  al o n e  or  wit h  b e v a zi c u m a b 
f or  n o n-s m all-c ell l u n g  c a n c er.  N  E n gl J  M e d;  3 5 5: 2 5 4 2 - 2 5 5 0. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 1 1
0  Pr ot o c ol  N o. 
 
 
 
S a nt os,  E.,  et  al.  " M ali g n a nt  a cti v ati o n  of  a  K -r as  o n c o g e n e i n l u n g  c ar ci n o m a  b ut  n ot i n 
n or m al tiss u e  of t h e s a m e  p ati e nt. "  S ci e n c e  2 2 3. 4 6 3 7 ( 1 9 8 4):  6 6 1 - 6 4. 
S attl er,  M.,  et  al.  T h e r ol e  of t h e  c -M et  p at h w a y i n l u n g  c a n c er  a n d t h e  p ot e nti al f or t ar g et e d 
th er a p y.  T h er. A d v. M e d. O n c ol.  3. 4 ( 2 0 1 1):  1 7 1 - 8 4. 
S e q uist  L V,  L y n c h  TJ ( 2 0 0 8)  E G F R t yr osi n e  ki n as e i n hi bit ors i n l u n g  c a n c er:  a n  e v ol vi n g 
st or y.  A n n u  R e v  M e d;  5 9: 4 2 9 - 4 4 2. 
S h a w  et  al ( 2 0 1 2).  R es ults  of t h e first -i n-h u m a n  P h as e I st u d y  of t h e  A L K i n hi bit or  L D K 3 7 8 
i n  a d v a n c e d  m ali g n a n ci es,  A S C O. 
S h a w  et  al ( 2 0 1 3).  Cli ni c al  A cti vit y  of t h e  A L K I n hi bit or  L D K 3 7 8 i n  A d v a n c e d,  A L K - 
p ositi v e  N S C L C,  A S C O.  
Si e g el  R,  N ais h a d h a m  D, J e m al  A ( 2 0 1 2)  C a n c er  St atisti cs  2 0 1 2.  C A  C a n c er J  Cli n;  6 2( 1): 1 0 - 
2 9. 
S pi g el  et  al. ( 2 0 1 1)  Fi n al  effi c a c y r es ults fr o m  O A M 4 5 5 8 g,  a r a n d o mi z e d  p h as e II st u d y 
e v al u ati n g  M et M A b  or  pl a c e b o i n  c o m bi n ati o n  wit h  erl oti ni b i n  a d v a n c e d  N S C L C,  A S C O.  
S o d a,  M.,  et  al. I d e ntifi c ati o n  of t h e tr a nsf or mi n g  E M L 4 -A L K f usi o n  g e n e i n  n o n -s m all-c ell 
l u n g  c a n c er.  Nat ur e  4 4 8. 7 1 5 3 ( 2 0 0 7):  5 6 1 - 6 6. 
T a n n a pf el  A,  B e ni c k e  M,  K at ali ni c  A  et  al ( 2 0 0 0)  Fr e q u e n c y  of  p 1 6(I N K 4 A)  alt er ati o ns  a n d 
K- r as  m ut ati o ns i n i ntr a h e p ati c  c h ol a n gi o c ar ci n o m as  of t h e li v er.  G ut;  4 7: 7 2 1- 7. 
T a n n a pf el  A,  S o m m er er  F,  B e ni c k e  M  et  al.( 2 0 0 3)  M ut ati o ns  of t h e  B R A F  g e n e i n 
c h ol a n gi o c ar ci n o m a  b ut  n ot i n  h e p at o c ell ul ar  c ar ci n o m a.  G ut;  5 2: 7 0 6 - 1 2. 
Vi v a n c o I,  S a w y ers  C L.  T h e  p h os p h ati d yli n osit ol  3 -Ki n as e  A K T  p at h w a y i n  h u m a n  c a n c er. 
N at  R e v C a n c er.  2 0 0 2;  2: 4 8 9 – 5 0 1. 
W a n g  et  al ( 2 0 1 2)  P h os p h ati d yli n osit ol  3 -ki n as e  c o ul d  b e  a  pr o misi n g t ar g et i n l u n g  c a n c er 
t h er a p y. J  B U O N.  2 0 1 2  O ct-D e c; 1 7( 4): 7 2 9 - 3 4. 
W u  Y,  et  al ( 2 0 0 7)  L u n g  c a n c er  m a n a g e m e nt i n t h e  Asi a -P a cifi c r e gi o n:  W h at’s t h e  diff er e n c e 
c o m p ar e d  wit h t h e  U nit e d  St at es  a n d  E ur o p e ?  R es ults  of t h e  S e c o n d  Asi a  P a cifi c l u n g  c a n c er 
c o nf er e n c e. J o ur n al  of  T h or a ci c  O n c ol o g y J u n: 2( 6)  5 7 4 - 5 7 6. 
W u  Y L,  Y a n g J C H,  Ki m  D W,  et  al ( 2 0 1 4)  S af et y  a n d  effi c a c y  of I N C 2 8 0 i n  c o m bi n ati o n 
wit h  g efiti ni b i n  p ati e nts  wit h  E G F R -m ut at e d,  M E T - p ositi v e  N S C L C:  a si n gl e-ar m  P h as e 
I b/II st u d y. ( A S C O  a bstr a ct,  2 0 1 4) 
X u  C X, Ji n  H,  S hi n J Y ( 2 0 1 0)  R ol es  of  pr ot ei n  ki n as e  B/ A kt i n l u n g  c a n c er.  Fr o nt  Bi os ci  2: 
1 4 7 2 – 8 4. 
Y a m a m ot o  H,  S hi g e m ats u  H,  N o m ur a  M,  L o c k w o o d  W W,  S at o  M,  O k u m ur a  N,  S o h J, 
S u z u ki  M, Wist u b a II,  F o n g  K M,  et  al.  PI K 3 C A  m ut ati o ns  a n d  c o p y  n u m b er  g ai ns i n  h u m a n 
l u n g  c a n c ers. C a n c er  R es.  2 0 0 8;  6 8: 6 9 1 3– 6 9 2 1. 
Z h o u  C,  W u  Y L,  C h e n  G,  et  al ( 2 0 1 1)  Erl oti ni b  v ers us  c h e m ot h er a p y  as first -li n e tr e at m e nt 
f or  p ati e nts  wit h  a d v a n c e d  E G F R  m ut ati o n- p ositi v e  n o n-s m all-c ell l u n g  c a n c er ( O P TI M A L, 
C T O N G -0 8 0 2):  a  m ulti c e ntr e,  o p e n -l a b el, r a n d o mis e d,  p h as e  3 st u d y.  L a n c et  O n c ol; 
1 2( 8): 7 3 5- 4 2. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 1 2
0  Pr ot o c ol  N o. 
 
 
 
 
1 4   
A p p e n di x  
1 4. 1  
G ui d eli n e s f or  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 
( R E CI S T) v. 1. 1  
H ar m o ni z ati o n  of  effi c a c y  a n al y si s  of  s oli d t u m or  st u di e s  
 
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):  
 
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:  Fi n al, 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  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 1 3
0  Pr ot o c ol  N o. 
 
 
 
 
Gl o s s ar y  
C R  
C o m pl et e  re 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  
L P L V  
L a st  p ati e nt l a st   vi sit 
M RI  
M a g n eti c r e s o n a n c e i m a gi n g  
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 ort  A n al y si s  Pr e p ar ati o 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  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 1 4
0  Pr ot o c ol  N o. 
 
 
 
 
1 4. 1. 1   
I ntr o d u cti o n 
T h e  p ur p os e  of t his  d o c u m e nt is t o  pr o vi d e t h e  w or ki n g  d efi niti o ns  a n d r ul es  n e c ess ar y f or  a 
c o nsist e nt   a n d   effi ci e nt   a n al ysis   of   effi c a c y  f or   o n c ol o g y  st u di es  i n  s oli d  t u m ors.   T his  
d o c u m e nt is  b as e d  o n t h e  R E CI S T  crit eri a f or t u m or r es p o ns es ( T h er ass e  et  al  2 0 0 0 )  a n d t h e 
r e vis e d  R E CI S T  1. 1  g ui d eli n es (Eis e n h a u er  et  al  2 0 0 9 ). 
T his  d o c u m e nt  will  n ot  a d dr ess t h e  us e  of  R E CI S T  1. 1 f or  gli o bl ast o m a  m ultif or m e ( G B M).  
T h e  effi c a c y  ass ess m e nts  d es cri b e d   i n S e cti o n  1 4. 1. 2  a n d t h e  d efi niti o n  of  b est r es p o ns e i n 
S e cti o n  1 4. 1. 1 7  ar e  b as e d  o n t h e  R E CI S T  1. 1  crit eri a  b ut  als o  gi v e  m or e  d et ail e d i nstr u cti o ns 
a n d  r ul es  f or   d et er mi n ati o n   of   b est  r es p o n s e.  S e cti o n   1 4. 1. 1 8   is  s u m m ari zi n g  t h e   “ti m e  t o  
e v e nt ”  v ari a bl es  a n d r ul es  w hi c h  ar e  m ai nl y  d eri v e d fr o m i nt er n al  dis c ussi o ns  a n d r e g ul at or y 
c o ns ult ati o ns,  as t h e  R E CI S T  crit eri a  d o  n ot  d efi n e t h es e  v ari a bl es i n  d et ail.  S e cti o n  1 4. 1. 2 8   
of t his  g ui d eli n e  d es cri b es  d at a  h a n dli n g  a n d  pr o gr a m mi n g r ul es.  T his s e cti o n is t o  b e r ef err e d 
t o i n t h e  a n al ysis  pl a n(s) t o  pr o vi d e f urt h er  d et ails  n e e d e d f or  pr o gr a m mi n g. 
As f or  a  us u al  N o v artis t e m pl at e,  c o m m e nts  ar e  writt e n i n it ali c f o nt.  T h e  pr ot o c ol  a ut h ors 
m ust t a k e t h es e  c o m m e nts i nt o  c o n si d er ati o n  a n d  pr o vi d e  pr oj e ct  or st u d y s p e cifi c  d et ails i n 
t h e  pr ot o c ol.  S p e cifi c all y,  d efi niti o ns  hi g hli g ht e d i n r e d  m ust  b e  dis c uss e d,  d efi n e d  a n d t h e n 
d o c u m e nt e d i n t h e st u d y  pr ot o c ol.  A n y  d e vi ati o ns t o t h e  g ui d eli n e  m ust  b e  cl e arl y s p e cifi e d i n 
t h e  pr ot o c ol  wit h j ustifi c ati o n. 
 
1 4. 1. 2   
Effi c a c y  a s s e s s m e nt s  
T u m or  e v al u ati o ns  ar e  m a d e  b as e d  o n  R E CI S T  crit eri a ( T h er ass e  et  al  2 0 0 0 ),  N e w  G ui d eli n es 
t o  E v al u at e t h e  R es p o ns e t o  Tr e at m e nt i n  S oli d  T u m ors, J o ur n al  of  N ati o n al  C a n c er I nstit ut e, 
V ol.   9 2;   2 0 5 -1 6   a n d  r e vis e d   R E CI S T   g ui d eli n es  ( v ersi o n   1. 1)  ( Eis e n h a u er   et   al   2 0 0 9 ) 
E ur o p e a n J o ur n al  of  C a n c er;  4 5: 2 2 8 - 2 4 7. 
 
1 4. 1. 3   
D efi niti o n s  
 
1 4. 1. 4   
Di s e a s e  m e a s ur a bilit y  
I n  or d er  t o  e v al u at e t u m ors t hr o u g h o ut   a st u d y  d efi niti o ns  of   m e as ur a bilit y  ar e r e q uir e d i n 
or d er t o  cl assif y l esi o ns  a p pr o pri at el y  at  b as eli n e. I n  d efi ni n g  m e as ur a bilit y  a  disti n cti o n  als o 
n e e ds t o  b e  m a d e  b et w e e n  n o d al l esi o ns ( p at h ol o gi c al l y m p h  n o d es)  a n d  n o n -n o d al l esi o ns.  
•   M e as u r a bl e  dis e as e  -  t h e  pr es e n c e  of  at l e ast  o n e  m e as ur a bl e  n o d al  or  n o n-n o d al l esi o n. 
If t h e  m e as ur a bl e  dis e as e is r estri ct e d t o  a s olit ar y l esi o n, its  n e o pl asti c  n at ur e s h o ul d  b e 
c o nfir m e d  b y   c yt ol o g y/ hist ol o g y. 
F or  p ati e nts  wit h o ut  m e as ur a bl e  dis e as e s e e  S e cti o n  1 4. 1. 2 6  
M e as u r a bl e l esi o ns  ( b ot h  n o d al  a n d  n o n- n o d al) 
•   M e as ur a bl e  n o n - n o d al - As  a r ul e  of t h u m b, t h e  mi ni m u m si z e  of  a  m e as ur a bl e  n o n - n o d al 
t ar g et  l esi o n   at   b as eli n e  s h o ul d   b e   n o  l ess  t h a n   d o u bl e  t h e  sli c e  t hi c k n ess   or   1 0 m m  
w hi c h e v er  is  gr e at er - e. g. t h e  mi ni m u m  n o n -n o d al l esi o n si z e f or  C T/ M RI  wit h  5 m m  c uts 
will  b e  1 0  m m, f or  8  m m  c o nti g u o us  c uts t h e  mi ni m u m si z e  will  b e  1 6  m m.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 1 5
0  Pr ot o c ol  N o. 
 
 
 
•   L yti c  b o n e l esi o ns  or  mi x e d l yti c -bl asti c l esi o ns  wit h i d e ntifi a bl e s oft tiss u e  c o m p o n e nts, 
t h at  c a n  b e  e v al u at e d  b y  C T/ M RI,  c a n  b e  c o nsi d er e d  as  m e as ur a bl e l esi o ns. 
•   M e as ur a bl e  n o d al l esi o ns (i. e. l y m p h  n o d es)  -  L y m p h  n o d es  ≥ 1 5  m m i n s h ort  a xis  c a n  b e 
c o nsi d er e d f or  s el e cti o n  as t ar g et  l esi o n s.   L y m p h  n o d es  m e as uri n g  ≥ 1 0 m m   a n d  < 1 5 m m   
ar e  c o ns i d er e d  n o n-m e a s ur a bl e.  L y m p h  n o d es  s m all er t h a n  1 0  m m i n s h ort  a xis  at  b as eli n e, 
r e g ar dl ess  of t h e sli c e t hi c k n ess,  ar e  n or m al  a n d  n ot  c o nsi d er e d i n di c ati v e  of dis e as e.  
•   N o n -m e as ur a bl e l esi o n s  - all  ot h er l esi o ns  ar e  c o nsi d er e d  n o n -m e as ur a bl e, i n cl u di n g s m a ll 
l esi o ns (l o n g est  di a m et er  < 1 0  m m  wit h  C T s c a n  or  p at h ol o gi c al l y m p h  n o d es  wit h ≥   1 0 t o 
<   1 5   m m  s h ort   a xis),   e. g.,   bl asti c   b o n e  l esi o ns,  l e pt o m e ni n g e al   dis e as e,   as cit es,  
pl e ur al/ p eri c ar di al   eff usi o n,  i nfl a m m at or y   br e ast   dis e as e,  l y m p h a n gitis   c utis/ p ul m o nis,  
a b d o mi n al  m ass es t h at  ar e  n ot  c o nfir m e d  a n d f oll o w e d  b y i m a gi n g t e c h ni q u es,  a n d  c ysti c  
l esi o ns. 
 
1 4. 1. 5   
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  m e as ur a bl e l esi o ns  ar e i d e ntifi e d   at  b as eli n e,  t h e  p ati e nt   m a y  b e  all o w e d  t o   e nt er t h e 
st u d y  i n  s o m e  sit u ati o ns  ( e. g.  i n   P h as e  III  st u di es   w h er e   P F S  is  t h e   pri m ar y   e n d p oi nt).  
H o w e v er, it is r e c o m m e n d e d t h at  p ati e nts  b e  e x cl u d e d fr o m tri als  w h er e t h e  m ai n f o c us is  o n 
t h e   O v er all   R es p o ns e   R at e  ( O R R).   G ui d a n c e   o n   h o w   p ati e nts   wit h  j ust   n o n-m e as ur a bl e 
dis e as e  at  b as eli n e  will  b e  e v al u at e d f or r es p o ns e  a n d  als o  h a n dl e d i n t h e st atisti c al  a n al ys es is 
gi v e n i n  S e cti o n   1 4. 1. 2 6. 
 
1 4. 1. 6   
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  
T h e f oll o wi n g  c o nsi d er ati o ns  ar e t o  b e  m a d e  w h e n  e v al u ati n g t h e t u m or:  
•   All  m e as ur e m e nts s h o ul d  b e t a k e n  a n d r e c or d e d i n  m etri c  n ot ati o n ( m m),  usi n g  a r ul er  or 
c ali p ers.   All   b as eli n e   e v al u ati o ns  s h o ul d   b e   p erf or m e d   as   cl os el y   as   p ossi bl e  t o  t h e  
b e gi n ni n g  of tr e at m e nt  a n d  n e v er  m or e t h a n  4  w e e ks  b ef or e t h e  b e gi n ni n g  of t h e  tr e at m e nt. 
•   I m a gi n g-b as e d   e v al u ati o n  is   pr ef err e d  t o   e v al u ati o n   b y   cli ni c al   e x a mi n ati o n   w h e n   b ot h  
m et h o ds  h a v e  b e e n  us e d t o  ass ess t h e  a nti t u m or  eff e ct  of  a tr e at m e nt. 
•   F or  o pti m al  e v al u ati o n  of  p ati e nts t h e s a m e  m et h o ds  of  ass ess m e nt  a n d t e c h ni q u e s h o ul d 
b e  us e d t o  c h ar a ct eri z e  e a c h i d e ntifi e d  a n d r e p ort e d l esi o n  at  b as eli n e  a n d  d uri n g f oll o w - 
u p.  C o ntr ast -e n h a n c e d  C T  of  c h est,  a b d o m e n  a n d  p el vis s h o ul d  pr ef er a bl y  b e  p erf or m e d 
usi n g   a   5 m m  sli c e  t hi c k n ess   wit h   a   c o nti g u o us  r e c o nstr u cti o n   al g orit h m.   C T/ M RI  s c a n  
sli c e  t hi c k n ess  s h o ul d   n ot   e x c e e d   8   m m   c uts   usi n g   a   c o nti g u o us  r e c o nstr u cti o n  
al g orit h m.If  at  b as eli n e  a  p ati e nt is  k n o w n t o  b e  all er gi c  t o  C T  c o ntr ast  or  d e v el o ps  all er g y 
d uri n g t h e tri al, t h e f oll o wi n g  c h a n g e i n i m a gi n g  m o d alit y  will  b e  a c c e pt e d f or f oll o w  u p: 
a   n o n -c o ntr ast   C T   of   c h est  ( M RI   n ot  r e c o m m e n d e d   d u e  t o  r es pir at or y   artif a cts)   pl us  
c o ntr ast -e n h a n c e d  M RI  of  a b d o m e n  a n d   p el vis. 
•   A  c h a n g e i n  m et h o d ol o g y  c a n  b e  d efi n e d  as  eit h er  a  c h a n g e i n  c o ntr ast  us e ( e. g.  k e e pi n g 
t h e s a m e t e c h ni q u e, li k e  C T,  b ut s wit c hi n g fr o m  wit h t o  wit h o ut  c o ntr ast  us e  or  vi c e-v ers a, 
r e g ar dl ess  of t h e j ustifi c ati o n f or t h e  c h a n g e)  or  a  c h a n g e i n t e c h ni q u e ( e g.  fr o m  C T t o 
M RI,  or  vi c e -v ers a),  or  a  c h a n g e i n  a n y  ot h er i m a gi n g  m o d alit y.  A  c h a n g e i n  m et h o d ol o g y 
will  r es ult   b y   d ef a ult  i n   a   U N K   o v er all  l esi o n  r es p o ns e   ass ess m e nt.   H o w e v er   a n ot h er  
r es p o ns e  ass e ss m e nt  t h a n  t h e   N o v artis c al c ul at e d  U N K   r es p o ns e m a y   b e a c c e pt e d  fr o m 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 1 6
0  Pr ot o c ol  N o. 
 
 
 
t h e i n v esti g at or  or t h e  c e ntr al  bli n d e d r e vi e w er if  a  d efi niti v e r es p o ns e  ass e ss m e nt  c a n  b e 
j ustifi e d,  b as e d  o n t h e  a v ail a bl e i nf or m ati o n. " 
If  h e a d  a n d  n e c k t u m ors  a n d t h os e  of  e xtr e miti es  ar e  e v al u at e d i n t h e st u d y,  pl e as e s p e cif y t h e 
m et h o ds i n  d et ail i n  t h e  pr ot o c ol. 
•   F D G -P E T :  c a n  c o m pl e m e nt  C T s c a ns i n  ass essi n g  pr o gr essi o n ( p arti c ul arl y  p ossi bl e f or 
‘ n e w’  dis e as e).  N e w l esi o ns  o n t h e  b a sis  of  F D G-P E T i m a gi n g  c a n  b e i d e ntifi e d  a c c or di n g 
t o t h e f oll o wi n g  al g orit h m: 
•   N e g ati v e  F D G -P T  at  b as eli n e,  wit h  a  p osi ti v e  F D G-P E T  at f oll o w -u p is  a si g n  of  P D 
b as e d  o n  a  n e w  l esi o n. 
•   N o  F D G -P E T  at  b as eli n e  wit h  a  p ositi v e  F D G -P E T  at  f oll o w- u p: 
•   If t h e  p ositi v e  F D G-P T  at f oll o w -u p  c orr es p o n ds t o  a  n e w sit e  of  dis e as e  c o nfir m e d  b y  C T, 
t his is  P D. 
•   If t h e  p ositi v e  F D G-P E T  at f oll o w- u p is  n ot  c o nfir m e d  as  a  n e w sit e  of  dis e as e  o n  C T, 
a d diti o n al f oll o w -u p  C T  ar e  n e e d e d t o  d et er mi n e if t h er e is tr ul y  pr o gr essi o n  o c c urri n g  at 
t h at  Sit e (if s o, t h e  d at e  of  P D  will  b e t h e  d at e  of t h e i niti al  a b n or m al  C T s c a n). 
•   If t h e  p ositi v e  F D G-P E T  at f oll o w -u p  c orr es p o n ds t o  a  pr e -e xisti n g sit e  of  dis e as e  o n  C T 
t h at is  n ot  pr o gr essi n g  o n t h e  b asis  of t h e  a n at o mi c i m a g es, t his is  n ot P D.  
•   C h est  x -r a y :  L esi o ns  o n  c h est  x-r a y  ar e  a c c e pt a bl e  as  m e as ur a bl e l esi o n s  w h e n t h e y  ar e 
cl e arl y  d efi n e d  a n d s urr o u n d e d  b y  a er at e d l u n g.  H o w e v er,  C T is  pr ef er a bl e.  
•   Ult r as o u n d :   W h e n  t h e   pri m ar y   e n d p oi nt   of  t h e  st u d y  is   o bj e cti v e  r es p o ns e   e v al u ati o n,  
ultr as o u n d ( U S) s h o ul d  n ot  b e  us e d t o  m e as ur e t u m or l esi o ns.  It  is,  h o w e v er,  a  p ossi bl e 
alt er n ati v e  t o   cli ni c al   m e as ur e m e nts   of  s u p erfi ci al   p al p a bl e  l y m p h   n o d es,  s u b c ut a n e o us  
l esi o ns   a n d  t h yr oi d   n o d ul es.   U S   mi g ht   als o   b e   us ef ul  t o   c o nfir m  t h e   c o m pl et e  
dis a p p e ar a n c e  of s u p erfi ci al l esi o ns  us u all y  ass ess e d  b y  cli ni c al  e x a mi n ati o n.  
•   E n d os c o p y  a n d l a p a r os c o p y :  T h e  utili z ati o n  of  e n d os c o p y  a n d l a p ar os c o p y f or  o bj e cti v e 
t u m or  e v al u ati o n  h as  n ot  y et  b e e n f ull y  a n d  wi d el y  v ali d at e d.  T h eir  us es i n t his s p e cifi c 
c o nt e xt  r e q uir e s o p histi c at e d  e q ui p m e nt   a n d  a  hi g h l e v el   of   e x p ertis e t h at   m a y  o nl y  b e 
a v ail a bl e i n s o m e  c e nt ers.  T h er ef or e, t h e  utili z ati o n  of s u c h t e c h ni q u es f or  o bj e cti v e t u m or 
r es p o ns e s h o ul d  b e r estri ct e d t o  v ali d ati o n  p ur p os es i n s p e ci ali z e d  c e nt ers.  H o w e v er, s u c h 
t e c h ni q u es c a n  b e  us ef ul i n  c o nfir mi n g  c o m pl et e  p at h ol o gi c al r es p o ns e  w h e n  bi o psi es  ar e 
o bt ai n e d.  
•   T u m o r   m a r k e rs :   T u m or   m ar k ers   al o n e   c a n n ot   b e   us e d  t o   ass ess  r es p o ns e.   H o w e v er,  
s o m e  dis e as e s p e cifi c  a n d  m or e  v ali d at e d t u m or  m ar k ers ( e. g.  C A -1 2 5 f or  o v ari a n  c a n c er, 
P S A  f or   pr ost at e   c a n c er,   alf a -F P,   L D H   a n d   B et a -h C G  f or  t esti c ul ar   c a n c er)   c a n   b e  
i nt e gr at e d  as  n o n-t ar g et  dis e as e. If  m ar k ers  ar e i niti all y  a b o v e t h e  u p p er  n or m al li mit t h e y 
m ust   n or m ali z e  f or   a   p ati e nt  t o   b e   c o nsi d er e d  i n   c o m pl et e   cli ni c al  r es p o ns e   w h e n   al l 
l esi o ns  h a v e  dis a p p e ar e d. 
•   C yt ol o g y  a n d  hist ol o g y :  C yt ol o g y  a n d  hist ol o g y  c a n  b e  us e d t o  diff er e nti at e  b et w e e n  P R 
a n d  C R i n r ar e  c as es (i. e.,  aft er tr e at m e nt t o  diff er e nti at e  b et w e e n r esi d u al  b e ni g n l esi o ns 
a n d  r esi d u al   m ali g n a nt  l esi o ns  i n  t u m or  t y p es  s u c h   as   g er m   c ell  t u m ors).   C yt ol o gi c  
c o nfir m ati o n  of  n e o pl asti c  n at ur e  of  a n y  eff usi o n t h at  a p p e ars  or  w ors e ns  d uri n g tr e at m e nt 
is r e q uir e d  w h e n t h e  m e as ur a bl e t u m or  h as  m et t h e  crit eri a f or r es p o ns e  or st a bl e  dis e as e. 
U n d er  s u c h  cir c u mst a n c es,   t h e  c yt ol o gi c  e x a mi n ati o n   of  t h e  fl ui d  c oll e ct e d  will   p er mit  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 1 7
0  Pr ot o c ol  N o. 
 
 
 
diff er e nti ati o n  b et w e e n r es p o ns e  a n d st a bl e  dis e as e ( a n  eff usi o n  m a y  b e  a si d e  eff e ct  of t h e 
tr e at m e nt)  or  pr o gr essi v e  dis e as e (if t h e  n e o pl asti c  ori gi n  of t h e fl ui d is  c o nfir m e d). 
•   Cli ni c al  e x a mi n ati o n :  Cli ni c al l esi o ns  will  o nl y  b e  c o nsi d er e d  m e as ur a bl e  wh e n t h e y  ar e 
s u p erfi ci al  (i. e.,  s ki n   n o d ul es   a n d   p al p a bl e  l y m p h   n o d es).   F or  t h e   c as e   of  s ki n  l esi o ns,  
d o c u m e nt ati o n  b y  c ol or  p h ot o gr a p h y, i n cl u di n g  a r ul er t o  esti m at e t h e si z e  of t h e l esi o n, is 
r e c o m m e n d e d. 
 
1 4. 1. 7   
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 h e  e v al u ati o n  of l esi o ns  at  b as eli n e  a n d t hr o u g h o ut t h e st u d y, t h e l esi o ns  ar e  cl assifi e d  at 
b as eli n e  as  eit h er t ar g et  or  n o n -t ar g et l esi o ns: 
•   T a r g et  l esi o ns :  All  m e as ur a bl e l esi o ns ( n o d al  a n d  n o n-n o d al)  u p t o  a  m a xi m u m  of fi v e 
l esi o ns i n t ot al ( a n d  a  m a xi m u m  of t w o l esi o ns  p er  or g a n), r e pr es e nt ati v e  of  all i n v ol v e d 
or g a ns s h o ul d  b e i d e ntifi e d  as t ar g et l esi o ns  a n d r e c or d e d  a n d  m e as ur e d  at  b as eli n e.  T ar g et 
l esi o ns s h o ul d  b e s el e ct e d  o n t h e  b asis  of t h eir si z e (l esi o ns  wit h t h e l o n g est  di a m et er)  a n d 
t h eir  s uit a bilit y  f or   a c c ur at e  r e p e at e d   m e as ur e m e nts  ( eit h er   b y  i m a gi n g  t e c h ni q u es   or  
cli ni c all y).   E a c h t ar g et  l esi o n  m ust  b e  u ni q u el y  a n d s e q u e nti all y  n u m b er e d  o n t h e  C R F  
( e v e n if it r esi d es i n t h e s a m e  or g a 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 a r g et :  N o n-n o d al t ar g et l esi o ns i d e ntifi e d  b y  m et h o ds f or  w hi c h sli c e 
t hi c k n ess is  n ot  a p pli c a bl e ( e. g.  cli ni c al  e x a mi n ati o n) s h o ul d  b e  at l e ast  1 0 m m i n l o n g est 
di a m et er.  S e e  S e cti o n   1 4. 1. 4. 
•   N o d al t a r g et :  S e e S e cti o n   1 4. 1. 4. 
A s u m  of  di a m et ers (l o n g  a xis f or  n o n -n o d al l esi o ns, s h ort  a xis f or  n o d al) f or  all t ar g et l esi o ns 
will  b e  c al c ul at e d  a n d r e p ort e d  as t h e  b as eli n e s u m  of  di a m et ers ( S O D).  T h e  b as eli n e s u m  of 
di a m et ers  will   b e  us e d   as r ef er e n c e  b y  w hi c h  t o  c h ar a ct eri z e t h e  o bj e cti v e t u m or r es p o ns e. 
E a c h t ar g et l esi o n i d e ntifi e d  at  b as eli n e  m ust  b e f oll o w e d  at  e a c h s u bs e q u e nt  e v al u ati o n  a n d 
d o c u m e nt e d  o n  e C R F.  
•   N o n -t a r g et l esi o ns:  All  ot h er l esi o ns  ar e  c o nsi d er e d  n o n-t ar g et l esi o ns, i. e. l esi o ns  n ot 
f ulfilli n g t h e  crit eri a f or t ar g et l esi o ns  at  b as eli n e.  Pr es e n c e  or  a bs e n c e  or  w ors e ni n g  of 
n o n- t ar g et l esi o ns s h o ul d  b e  ass e ss e d t hr o u g h o ut t h e st u d y;  m e as ur e m e nts  of t h es e l esi o ns 
ar e  n ot r e q u ir e d.  M ulti pl e  n o n-t ar g et l esi o ns i n v ol v e d i n t h e s a m e  or g a n  c a n  b e  ass ess e d  as 
a  gr o u p  a n d r e c or d e d  as  a si n gl e it e m (i. e.  m ulti pl e li v er  m et ast asis).  E a c h  n o n -t ar g et 
l esi o n i d e ntifi e d  at  b as eli n e  m ust  b e f oll o w e d  at  e a c h s u bs e q u e nt  e v al u ati o n  a n d 
d o c u m e n t e d  o n e C R F.  
 
1 4. 1. 8   
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   ass ess  t u m or  r es p o ns e,  t h e  s u m   of   di a m et er  f or   all  t ar g et  l esi o ns   will   b e   c al c ul at e d  ( at  
b as eli n e  a n d t hr o u g h o ut t h e st u d y).  At  e a c h  ass ess m e nt r es p o ns e is  e v al u at e d first s e p ar at el y 
f or t h e t ar g et (T a bl e  1 4 - 1)  a n d  n o n-t arg et l esi o ns ( T a bl e  1 4 - 2) i d e ntifi e d  at  b as eli n e.  T h es e 
e v al u ati o ns  ar e t h e n  us e d t o  c al c ul at e t h e  o v er all l esi o n r es p o ns e  c o n si d eri n g  b ot h t h e t ar g et 
a n d  n o n -t ar g et l esi o ns t o g et h er (T a bl e  1 4 - 3)  as  w ell  as t h e  pr es e n c e  or  a bs e n c e  of  n e w l esi o ns. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 1 8
0  Pr ot o c ol  N o. 
 
 
 
1 4. 1. 9   
F oll o w -u p  & r e c or di n g  of  l e si o n s 
At  e a c h  visit  a n d f or  e a c h l esi o n t h e  a ct u al  d at e  of t h e s c a n  or  pr o c e d ur e  w hi c h  w as  us e d f or 
t h e  e v al u ati o n  of  e a c h s p e cifi c l esi o n s h o ul d  b e r e c or d e d.  T his  a p pli es t o t ar g et  a n d  n o n-t ar g et 
l esi o ns  as  w ell   as  n e w  l esi o ns t h at   ar e  d et e ct e d.   At  t h e  ass ess m e nt   visit   all   of  t h e s e p ar at e 
l esi o n   e v al u ati o n   d at a   ar e   e x a mi n e d   b y t h e  i n v esti g at or  i n   or d er  t o  d eri v e t h e   o v er all   visit  
r es p o ns e.  T h er ef or e all s u c h  d at a  a p pli c a bl e t o  a  p arti c ul ar  visit s h o ul d  b e  ass o ci at e d  wit h t h e 
s a m e  ass ess m e nt  n u m b er.  
 
1 4. 1. 1 0   N o n -n o d al  l e si o n s 
F oll o wi n g tr e at m e nt, l esi o ns  m a y  h a v e l o n g est  di a m et er  m e as ur e m e nts s m all er t h a n t h e i m a g e 
r e c o nstr u cti o n i nt er v al.  L esi o ns s m all er t h an t wi c e t h e r e c o nstr u cti o n i nt er v al  ar e s u bj e ct t o 
s u bst a nti al  “ p arti al  v ol u m e ”  eff e cts (i. e., si z e  m a y  b e  u n d er esti m at e d  b e c a us e  of t h e  dist a n c e 
of t h e  c ut fr o m t h e l o n g est  di a m et er; s u c h l esi o ns  m a y  a p p e ar t o  h a v e r es p o n d e d  or  pr o gr ess e d 
o n s u bs e q u e nt  e x a mi n ati o ns,  w h e n, i n f a ct, t h e y r e m ai n t h e s a m e  si z e). 
If t h e l esi o n  h as  c o m pl et el y  dis a p p e ar e d, t h e l esi o n si z e s h o ul d  b e r e p ort e d  as  0  m m. 
W h e n  a t u m or  d o es  n ot  dis a p p e ar   c o m pl et el y  a n d s hri n ks t o l ess t h a n t h e sli c e t hi c k n ess  a 
d ef a ult   v al u e s h o ul d   b e  assi g n e d   d e p e n di n g   o n t h e  sli c e  t hi c k n ess.   Wit h  5  m m   c o nti g u o us  
sli c e  t hi c k n ess,  t h e   d ef a ult   v al u e  will  b e  5  m m.   Si mil arl y,  f or   a  7   m m  sli c e t hi c k n ess,  t h e 
d ef a ult  v al u e  will  b e  7  m m.  A ct u al  m e as ur e m e nt s h o ul d  b e  gi v e n f or  all l esi o ns l ar g er t h a n t h e 
d ef a ul t v al u e.  
I n  ot h er  c as es  w h er e t h e l esi o n  c a n n ot  b e r eli a bl y  m e as ur e d f or r e as o ns  ot h er t h a n its si z e ( e. g., 
b or d ers  of t h e l esi o n  ar e  c o nf o u n d e d  b y  n ei g h b ori n g  a n at o mi c al str u ct ur es),  n o  m e as ur e m e nt 
s h o ul d  b e  e nt er e d  a n d t h e l esi o n  c a n n ot  b e  e v al u at e d.  
 
1 4. 1. 1 1   N o d al l e si o n s  
A  n o d al l esi o n l ess t h a n  1 0  m m i n si z e  b y s h ort  a xis is  c o nsi d er e d  n or m al.  L y m p h  n o d es  ar e 
n ot  e x p e ct e d t o  dis a p p e ar  c o m pl et el y, s o  a  “ n o n -z er o si z e ”  will  al w a ys  p ersist.  
If  a  n o d al l esi o n s hri n ks t o l ess t h a n t h e sli c e t hi c k n ess  a  d ef a ult  v al u e  s h o ul d  b e  assi g n e d 
d e p e n di n g  o n t h e sli c e t hi c k n ess.  Wit h  5  m m  c o nti g u o us sli c e t hi c k n ess, t h e  d ef a ult  v al u e  will 
b e   5   m m.   Si mil arl y,  f or   a   7   m m  sli c e  t hi c k n ess,  t h e   d ef a ult   v al u e   will   b e   7   m m.   A ct u al  
m e as ur e m e nt s h o ul d  b e  gi v e n f or  all l esi o ns l ar g er t h a n t h e  d ef a ult  v al u e.  
H o w e v er,  o n c e  a t ar g et  n o d al l esi o n s hri n ks t o l ess t h a n  1 0  m m i n its s h ort  a xis, it  will  b e 
c o nsi d er e d  n or m al f or r es p o ns e  p ur p os e  d et er mi n ati o n.  T h e l y m p h  n o d e  m e as ur e m e nts  will 
c o nti n u e t o  b e r e c or d e d t o  all o w t h e  v al u es t o  b e i n cl u d e d i n t h e s u m  of  di a m et ers f or t ar g et 
l esi o ns,  w hi c h  m a y  b e r e q uir e d s u bs e q u e ntl y f or r es p o ns e  d et er mi n ati o n. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 1 9
0  Pr ot o c ol  N o. 
 
 
 
 
1 4. 1. 1 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  1 4 - 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 a m et er  of  all t ar g et l e si o n s r e c or d e d  at  or 
aft er  b a s eli n e. I n  a d diti o n t o t h e r el ati v e i n cr e a s e  of  2 0 %, t h e  s u m  m u st  al s o 
d e m o n str at e  a n  a b s ol ut e i n cr e a s e  of  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 et h o d  t h a n b a s eli n e. 3  
 
1 S O D f or  C R  m a y  n ot  b e  z er o  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 M et h o d ol o g y  c h a n g e  S e e  S e cti o n  1 4. 1. 6 . 
 
 
N ot e s  o n t ar g et l e si o n  r e s p o n s e  
R e a p p e a r a n c e  of l esi o ns : If t h e l esi o n  a p p e ars  at t h e s a m e  a n at o mi c al l o c ati o n  w h er e  a t ar g et 
l esi o n  h a d  pr e vi o usl y  dis a p p e ar e d,  it  is  a d vis e d t h at  t h e ti m e  p oi nt  of l esi o n  dis a p p e ar a n c e 
(i. e.,  t h e  “ 0   m m ” r e c or di n g)   b e  r e-e v al u at e d  t o   m a k e  s ur e  t h at  t h e  l esi o n   w as   n ot   a ct u all y  
pr es e n t   a n d/ or   n ot   vis u ali z e d  f or  t e c h ni c al  r e as o ns  i n  t his   pr e vi o us   ass e ss m e nt.  If  it  is   n ot  
p ossi bl e  t o   c h a n g e  t h e   0   v al u e,  t h e n  t h e  i n v esti g at or/r a di ol o gist   h as  t o   d e ci d e   b et w e e n  t h e 
f oll o wi n g t hr e e  p ossi biliti es: 
•   T h e l esi o n is  a  n e w l esi o n, i n  w hi c h  c as e t h e  o v er all t u m or  ass ess m e nt  will  b e  c o nsi d er e d 
as  pr o gr essi v e  dis e a s e  
•   T h e l esi o n is  cl e arl y  a r e a p p e ar a n c e  of  a  pr e vi o usl y  dis a p p e ar e d l esi o n, i n  w hi c h  c as e t h e 
si z e  of t h e l esi o n  h as t o  b e  e nt er e d i n t h e  C R F  a n d t h e t u m or  ass ess m e nt  will r e m ai n  b as e d 
o n t h e  s u m  of t u m or  m e as ur e m e nts  as  pr es e nt e d i n  T a bl e  1 4 - 1  a b o v e (i. e.,  a  P D  will  b e 
d et er mi n e d if t h er e is  at l e ast  2 0 % i n cr e as e i n t h e  s u m  of  di a m et ers  of  all  m e as ur e d t ar g et 
l esi o ns, t a ki n g  as r ef er e n c e t h e s m all est s u m  of  di a m et ers  of  all t ar g et l esi o ns r e c or d e d  at 
or  aft er  b as eli n e).  Pr o p er  d o c u m e nt ati o n s h o ul d  b e  a v ail a bl e t o s u p p ort t his  d e cisi o n. 
•   F or  t h os e  p ati e nts  w h o  h a v e  o nl y  o n e t ar g et l esi o n  at   b as eli n e,  t h e r e a p p e ar a n c e  of  t h e 
t ar g et l esi o n  w hi c h  dis a p p e ar e d  pr e vi o usly,  e v e n if still s m all, is  c o nsi d er e d  a  P D.  
•   Missi n g  m e as u r e m e nts:  I n  c as es  w h er e  m e as ur e m e nts  ar e  missi n g f or  o n e  or  m or e t ar g et 
l esi o ns  it  is  s o m eti m es  still   p ossi bl e  t o   assi g n   P D   b as e d   o n  t h e   m e as ur e m e nts   of  t h e  
r e m ai ni n g l esi o ns.  F or  e x a m pl e, if t h e s u m of  di a m et ers f or  5 t ar g et l esi o ns  at  b as eli n e is 
1 0 0 m m  at  b as eli n e  a n d t h e s u m  of  di a m et ers f or  3  of t h os e l esi o ns  at  a  p ost -b a s eli n e  visit 
is  1 4 0 m m ( wit h  d at a f or  2  ot h er l esi o ns  missi n g) t h e n  a  P D s h o ul d  b e  assi g n e d.  H o w e v er, 
i n  ot h er  c as es  w h er e  a  P D  ca n n ot  d efi nit el y  b e  attri b ut e d t h e t ar g et l esi o n r es p o ns e  w o ul d 
b e  U N K.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 2 0
0  Pr ot o c ol  N o. 
 
 
 
•   N o d al  l esi o n   d e c r e as e  t o   n o r m al  si z e:   W h e n   n o d al   dis e as e  is  i n cl u d e d i n t h e s u m   of 
t ar g et  l esi o ns   a n d  t h e   n o d es   d e cr e as e  t o   “ n or m al ”  si z e  t h e y  s h o ul d  still   h a v e   a  
m e as ur e m e nt  r e c or d e d   o n  s c a ns.   T his   m e as ur e m e nt  s h o ul d   b e  r e p ort e d   e v e n   w h e n  t h e  
n o d es  ar e  n or m al i n  or d er  n ot t o  o v erst at e  pr o gr essi o n s h o ul d it  b e  b as e d  o n i n cr e as e i n t h e 
si z e  of  n o d es. 
•   L esi o ns  s plit:   I n  s o m e   cir c u mst a n c e s,   dis e as e  t h at  is   m e as ur a bl e   as   a  t ar g et  l esi o n   at  
b as eli n e  a n d  a p p e ars t o  b e  o n e  m ass  c a n s plit t o  b e c o m e t w o  or  m or e s m all er s u b -l esi o ns. 
W h e n t his  o c c urs, t h e  di a m et ers (l o n g  a xis  -  n o n-n o d al l esi o n, s h ort  a xis  -  n o d al l esi o ns) 
of  t h e t w o s plit l esi o ns s h o ul d  b e  a d d e d t o g et h er  a n d t h e s u m r e c or d e d i n t h e  di a m et er 
fi el d  o n t h e  c as e r e p ort f or m  u n d er t h e  ori gi n al l esi o n  n u m b er.  T his  v al u e  will  b e i n cl u d e d 
i n t h e s u m  of  di a m et ers  w h e n  d eri vi n g t ar g et l esi o n r es p o ns e.  T h e i n di vi d u al s plit lesi o ns 
will  n ot  b e  c o nsi d er e d  as  n e w l esi o ns,  a n d  will  n ot  a ut o m ati c all y tri g g er  a  P D   d esi g n ati o n. 
•   L esi o ns  c o al e s c e d:   C o n v ers el y, it is  als o  p ossi bl e t h at t w o  or  m or e l esi o ns  w hi c h  w er e 
disti n ctl y s e p ar at e  at  b as eli n e  b e c o m e  c o nfl u e nt  at s u bs e q u e nt  visits.  W h e n t his  o c c urs  a 
pl a n e  b et w e e n t h e  ori gi n al l esi o ns  m a y  b e  m ai nt ai n e d t h at  w o ul d  ai d i n  o bt ai ni n g  di a m et er 
m e as ur e m e nts  of  e a c h i n di vi d u al l esi o n. If t h e l esi o ns  h a v e tr ul y  c o al es c e d s u c h t h at t h e y 
ar e  n o l o n g er s e p ar a bl e, t h e  m a xi m al  di a m et ers (l o n g  a x is -  n o n-n o d al l esi o n, s h ort  a xis  - 
n o d al  l esi o ns)   of  t h e   “ m er g e d  l esi o n ”  s h o ul d   b e   us e d   w h e n   c al c ul ati n g  t h e   s u m   of  
di a m et ers f or t ar g et l esi o ns.  O n t h e  c as e r e p ort f or m, t h e  di a m et er  of t h e  “ m er g e d l esi o n ” 
s h o ul d  b r e c or d e d f or t h e si z e  of  o n e  of t h e  ori gi n al l esi o ns  w hil e  a si z e  of  “ 0 ” m m s h o ul d 
b e  e nt er e d f or t h e r e m ai ni n g l esi o n  n u m b ers  w hi c h  h a v e  c o al es c e d.  
•   T h e  m e as u r e m e nts f o r  n o d al l esi o ns ,  e v e n if l ess t h a n  1 0 m m i n si z e,  will  c o ntri b ut e t o 
t h e  c al c ul ati o n  of t ar g et l esi o n r es p o ns e i n t h e  us u al  w a y  wit h sli g ht m o difi c ati o ns.  
•   Si n c e l esi o ns l ess t h a n  1 0 m m  ar e  c o nsi d er e d  n or m al  a  C R f or t ar g et l esi o n r es p o ns e 
s h o ul d  b e  assi g n e d  w h e n  n o d al t ar g et l esi o ns s hri n k t o l ess t h a n  1 0 m m  a n d  all  n o n - 
n o d al t ar g et l esi o ns  h a v e  dis a p p e ar e d.  
•   O n c e   a   C R  t ar g et  l esi o n  r es p o ns e   h as   b e e n   assi g n e d   a   C R   will   c o nti n u e  t o   b e  
a p pr o pri at e (i n t h e  a bs e n c e  of  missi n g  d at a)  u ntil  pr o gr essi o n  of t ar g et l esi o ns.  
•   F oll o wi n g  a  C R,  a  P D  c a n s u bs e q u e ntl y  o nl y  b e  assi g n e d f or t ar g et l esi o n r es p o ns e if 
eit h er  a  n o n -n o d al t ar g et l esi o n  “r e a p p e ars ”  or if t h e  a bs ol ut e s u m  of t h e r e m ai ni n g 
n o d al  t ar g et  l esi o ns i n cr e as es  b y   at  l e ast   5 m m   a n d  at  l e ast   o n e  of  t h os e r e m ai ni n g 
l esi o ns   ar e   at l e ast   1 0 m m i n si z e.  i. e.  if  t h e s h ort   a xis  of   a r e m ai ni n g  n o d al t ar g et 
l esi o n i n cr e as es fr o m  5  m m t o  1 0  m m  or fr o m  7  m m t o  1 2. 5  m m t his is  c all e d  P D,  b ut 
if it i n cr e as es fr o m  7  m m t o  1 0  m m it  d o es  n ot  q u alif y f or P D.  
W h e n  b ot h  n o d al  a n d  n o n -n o d al l esi o ns  ar e still  pr es e nt t h er e  m a y  b e r ar e  o c c asi o ns  w h e n  a 
P D f or t ar g et l esi o n r es p o ns e is  pri m aril y  d u e t o i n cr e as es  i n  si z e  of  n o d al l esi o ns  b ut  w h er e 
t h e  t ar g et  l y m p h   n o d es   ar e  still   all  l ess  t h a n   1 0 m m  i n  si z e.   T his   ki n d   of  r ar e   a n o m al y  is  
a c c e pt a bl e si n c e  ot h er wis e t h e r ul es f or  d et er mi ni n g t ar g et l esi o n r es p o ns e  w o ul d  b e c o m e t o o 
c o m pl e x. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 2 1
0  Pr ot o c ol  N o. 
 
 
 
 
1 4. 1. 1 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  1 4 - 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 y m p h  n o d e s  a s si g n e d  a 
n o n -t ar g et l e si o n s  m u st  b e  n o n-p at h ol o gi c al i n  si z e ( <  1 0  m m  s h ort  a xi s)  
 
Pr o gr e s si v e  Di s e a s e ( P D):   
U n e q ui v o c al  pr o gr e s si o n  of  e xi sti n g  n o n -t ar g et l e si o n s.1  
I n c o m pl et e  R e s p o n s e/ 
St a bl e  Di s e a s e ( S 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 et h o d t h a n  b a s eli n e.  
 
1 Alt h o u g h  a  cl e ar  pr o gr e s si o n  of  “ n o n-t ar g et” l e si o n s  o nl y i s  e x 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 
tr e ati n g  p h y si ci a n  d o e s  pr e v ail  a n d t h e  pr o gr e s si o n  st at u s  s h o ul d  b e  c o nfir m e d l at er  o n  b y t h e r e vi e w  p a n el ( or 
st u d y  c h air).  
 
 
N ot e s  o n  n o n -t ar g et l e si o n r e s p o n s e 
•   T h e r es p o ns e f or  n o n -t ar g et l esi o ns is C R  o nl y if  all  n o n -t ar g et  n o n-n o d al l esi o ns  w hi c h 
w er e   e v al u at e d   at   b as eli n e   ar e   n o w   all   a bs e nt   a n d   wit h   all   n o n -t ar g et   n o d al  l esi o ns  
r et ur n e d t o  n or m al si z e (i. e.  <  1 0 m m). If  a n y  of t h e  n o n-t ar g et l esi o ns  ar e still  pr es e nt,  or 
t h er e  ar e  a n y  a b n or m al  n o d al l esi o ns (i. e.  ≥  1 0  m m) t h e r es p o ns e  c a n  o nl y  b e ‘ I n c o m pl et e 
r es p o ns e/ St a bl e   dis e as e ’   u nl ess   a n y   of  t h e  l esi o ns   w as   n ot   ass ess e d  (i n   w hi c h   c as e  
r es p o ns e is U N K )  or t h er e is  u n e q ui v o c al  pr o gr essi o n  of t h e  n o n-t ar g et l esi o ns (i n  w hi c h 
c as e r es p o ns e is  P D ). 
•   U n e q ui v o c al  pr o gr essi o n:  T o  a c hi e v e  “ u n e q ui v o c al  pr o gr essi o n ”  o n t h e  b asis  of  n o n -t ar g et 
dis e as e t h er e  m ust  b e  a n  o v er all l e v el  of s u bst a nti al  w ors e ni n g i n  n o n -t ar g et  dis e as e s u c h 
t h at,  e v e n i n  pr es e n c e  of  C R,  P R  or  S D i n t ar g et  dis e as e, t h e  o v er all t u m or  b ur d e n  h as 
i n cr e as e d s uffi ci e ntl y t o  m erit  dis c o nti n u ati o n  of t h er a p y.  A  m o d est  “i n cr e as e ” i n t h e si z e 
of   o n e   or   m or e   n o n -t ar g et  l esi o ns  is   us u all y   n ot  s uffi ci e nt  t o   q u alif y  f or   u n e q ui v o c al  
pr o gr essi o n st at us.  T h e  d esi g n ati o n  of  o v er all  pr o gr essi o n s ol el y  o n t h e  b asis  of  c h a n g e i n 
n o n- t ar g et  dis e as e i n t h e f a c e  of  C R,  P R  or  S D  of t ar g et  dis e as e is t h er ef or e  e x p e ct e d t o  b e 
r ar e.  E v e n i n  c as es  w h er e t h er e is  n o  m e as ur a bl e  dis e as e  at  b as eli n e, i n  or d er f or  a  P D t o 
b e  assi g n e d  o n t h e  b asis  of  n o n -t ar g et l esi o ns t h e i n cr e as e i n t h e  e xt e nt  of t h e  dis e as e  m ust 
b e s u bst a nti al.  I n st u di es  w h er e t h e  o v er all  n o n -t ar g et l esi o n r es p o ns e is  n ot r e c or d e d  b ut 
i nst e a d  t h e  i n di vi d u al  st at us   of  i n di vi d u al  l esi o ns  ( A bs e nt,   Pr es e nt   or   W ors e n e d)  is  
d et er mi n e d, if t h er e is  u n e q ui v o c al  pr o gr essi o n  of  n o n -t ar g et l esi o ns t h e n  at l e ast  o n e  of 
t h e  n o n-t ar g et l esi o ns  m ust  b e  assi g n e d  a st at u s  of  “ W ors e n e d ”.  Si mil arl y,  a n i n di vi d u al 
n o n- t ar g et  l esi o n  s h o ul d   o nl y   b e   assi g n e d   a   “ W ors e n e d ”  st at us  if  t h er e  is   u n e q ui v o c al  
pr o gr essi o n  of  n o n -t ar g et l esi o ns o v er all.  
•   W h er e   p ossi bl e,  si mil ar  r ul es  t o  t h os e   d es cri b e d  i n   S e cti o n   1 4. 1. 1 2   f or   assi g ni n g   P D  
f oll o wi n g  a  C R f or t h e  n o n-t ar g et  l esi o n r es p o ns e i n t h e  pr es e n c e  of   n o n-t ar g et l esi o ns  
n o d al l esi o ns s h o ul d  b e   a p pli e d. 
 
1 4. 1. 1 4   N e w l e si o n s  
T h e  a p p e ar a n c e  of  a  n e w l esi o n is  al w a ys  ass o ci at e d  wit h  Pr o gr essi v e  Dis e as e ( P D)  a n d  h as t o 
b e r e c or d e d  as  a  n e w l esi o n i n t h e  N e w  L esi o n  C R F  p a g e.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 2 2
0  Pr ot o c ol  N o. 
 
 
 
•   If  a  n e w l esi o n is e q ui v o c al , f or  e x a m pl e  b e c a us e  of its s m all si z e,  c o ntin u e d t h er a p y  a n d 
f oll o w-u p  e v al u ati o n  will  cl arif y if it r e pr es e nts tr ul y  n e w  dis e as e. If r e p e at s c a ns  c o nfir m 
t h er e is  d efi nit el y  a  n e w l esi o n, t h e n  pr o gr essi o n s h o ul d  b e  d e cl ar e d  usi n g t h e  d at e  of t h e 
first  o bs er v ati o n  of t h e l esi o n 1 
•   If  n e w  dis e as e is  o bs er v e d i n  a r e gi o n  w hi c h  w as n ot s c a n n e d  at  b as eli n e  or  w h er e t h e 
p arti c ul ar  b as eli n e s c a n is  n ot  a v ail a bl e f or s o m e r e as o n t h e n t his s h o ul d  b e  c o nsi d er e d  as 
a  P D.  T h e  o n e  e x c e pti o n t o t his is  w h e n t h er e  ar e  n o  b as eli n e s c a ns  at  all  a v a il a bl e f or  a 
p ati e nt i n  w hi c h  c as e t h e r es p o ns e s h o ul d  b e  U N K,  as f or  a n y  of t his  p ati e nt's  ass ess m e nt 
(s e e S e cti o n   1 4. 1. 1 5). 
•   A  l y m p h  n o d e is  c o nsi d e r e d  as  a  “ n e w l esi o n ” a n d, t h er ef or e, i n di c ati v e  of  pr o gr essi v e 
dis e as e if t h e s h ort  a xis i n cr e as es i n si z e t o  ≥  1 0 m m f or t h e first ti m e i n t h e st u d y  pl us 
5 m m  a bs ol ut e  i n cr e as e. 
F D G -P E T :  c a n  c o m pl e m e nt  C T s c a ns i n  ass essi n g  pr o gr essi o n ( p arti c ul arl y  p ossi bl e f or 
‘ n e w’  dis e as e).  S e e S e cti o n  1 4. 1. 6 . 
 
1 4. 1. 1 5     Ev al u ati o n  of  o v er all l e si o n  r e s p o n s e 
T h e   e v al u ati o n   of   o v er all  l esi o n  r es p o ns e   at   e a c h   ass e ss m e nt  is   a   c o m p o sit e   of  t h e  t ar g et  
l esi o n r es p o ns e,  n o n-t ar g et l esi o n r es p o ns e  a n d  pr es e n c e  of  n e w l esi o ns  as s h o w n  b el o w i n 
T a bl e   1 4- 3. 
 
T a bl e  1 4 - 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  
I n c o m pl et e r e s p o n s e/ S D3 
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  1 4. 1. 8 . 
 
If t h er e  ar e  n o  b as eli n e s c a ns t a k e n  at  all  at  b as eli n e t h e n t h e  o v er all l esi o n r es p o ns e  at  e a c h 
ass e ss m e nt s h o ul d  b e  c o nsi d er e d  U n k n o w n ( U N K).  
If t h e  e v al u ati o n  of  a n y  of t h e t ar g et  or  n o n-t ar g et l esi o ns i d e ntifi e d  at  b as eli n e  c o ul d  n ot  b e 
m a d e  d uri n g f oll o w -u p, t h e  o v er all st at us  m ust  b e ‘ u n k n o w n’  u nl ess  pr o gr essi o n  w as s e e n.  
I n s o m e  cir c u mst a n c es it  m a y  b e  diffi c ult t o  disti n g uis h r esi d u al  dis e as e fr o m  n or m al tiss u e. 
W h e n t h e  e v al u ati o n  of  c o m pl et e r es p o ns e  d e p e n ds  o n t his  d et er mi n ati o n, it is r e c o m m e n d e d 
t h at t h e r esi d u al l esi o n  b e i n v esti g at e d (fi n e  n e e dl e  as pir at e/ bi o ps y) t o  c o nfir m t h e  C R. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 2 3
0  Pr ot o c ol  N o. 
 
 
 
1 4. 1. 1 6   Effi c a c y  d efi niti o n s  
T h e f oll o wi n g  d efi niti o ns  pri m aril y r el at e t o  p ati e nts  w h o  h a v e  m e as ur a bl e  dis e as e  at  b as eli n e. 
S e cti o n  1 4. 1. 2 6  o utli n es t h e s p e ci al  c o nsi d er ati o ns t h at  n e e d t o  b e  gi v e n t o  p ati e nts  wit h  n o 
m e as ur a bl e  dis e as e  at  b as eli n e i n  or d er t o  a p pl y t h e s a m e  c o n c e pts.  
 
1 4. 1. 1 7   B e st  o v er all  r e s p o n s e 
T h e  b est  o v er all r es p o ns e is t h e  b est r es p o n s e r e c or d e d fr o m t h e st art  of t h e tr e at m e nt  u ntil 
dis e as e   pr o gr essi o n/r e c urr e n c e  (t a ki n g   as  r ef er e n c e  f or   P D  t h e  s m all est   m e as ur e m e nts  
r e c or d e d si n c e t h e tr e at m e nt st art e d). I n  g e n er al, t h e  p ati e nt's  b est r es p o ns e  assig n m e nt  will 
d e p e n d  o n t h e  a c hi e v e m e nt  of  b ot h  m e as ur e m e nt  a n d  c o nfir m ati o n  crit eri a.  
T h e  b est  o v er all r es p o ns e  will  us u all y  b e  d et er mi n e d fr o m r es p o ns e  ass e ss m e nts  u n d ert a k e n 
w hil e   o n  tr e at m e nt.   H o w e v er,  if   a n y   ass ess m e nts   o c c ur   aft er  tr e at m e nt   wit h dr a w al   t h e 
pr ot o c ol  s h o ul d  s p e cifi c all y   d es cri b e  if  t h es e   will   b e  i n cl u d e d  i n t h e   d et er mi n ati o n  of   b est  
o v er all r es p o ns e  a n d/ or  w h et h er t h es e  a d diti o n al  ass e ss m e nt s  will   b e r e q uir e d f or s e nsiti vit y 
or s u p p orti v e  a n al ys es.  As  a  d ef a ult,  a n y  ass ess m e nts t a k e n  m or e  t h a n  2 8  d a ys  aft er t h e l ast 
d os e   of  st u d y  t h er a p y   will   n ot   b e  i n cl u d e d  i n  t h e   b est   o v er all  r es p o ns e   d eri v ati o n.  If   a n y  
alt er n ati v e   c a n c er  t h er a p y  is  t a k e n   w hil e   o n  st u d y   a n y  s u bs e q u e nt   ass ess m e nt s   w o ul d  
or di n aril y  b e  e x cl u d e d fr o m t h e  b est  o v er all r es p o ns e  d et er mi n ati o n. If r es p o ns e  ass ess m e nts 
t a k e n  aft er  wit h dr a w al fr o m st u d y tr e at m e nt  a n d/ or  alt er n ati v e t h er a p y  ar e t o  b e i n cl u d e d i n 
t h e  m ai n  e n d p oi nt  d et er mi n ati o n t h e n t his s h o ul d  b e  d es cri b e d  a n d j ustifi e d i n t h e  pr ot o c ol. 
W h er e   a  st u d y  r e q uir es   a  r es p o ns e   P R   or   C R,   c h a n g es  i n  t u m or   m e as ur e m e nts   m ust   b e  
c o nfir m e d   b y r e p e at   ass ess m e nts  t h at  s h o ul d   b e  p erf or m e d  n ot  l ess  t h a n   4  w e e ks   aft er  t h e  
crit eri a f or r es p o ns e  ar e first  m et.  
T h e  b est  o v er all r es p o ns e f or  e a c h  p ati e nt is  d et er mi n e d fr o m t h e s e q u e n c e  of  o v er all (l esi o n) 
r es p o ns es  a c c or di n g t o t h e f oll o wi n g r ul es: 
•   C R  =  at l e ast t w o  d et er mi n ati o ns  of  C R  at l e ast  4  w e e ks  a p art  b ef or e  pr o gr essi o n  w h er e 
c o nfir m ati o n r e q uir e d  or  o n e  d et er mi n ati o n  of  C R  pri or t o  pr o gr essi o n  w h er e  c o nfir m ati o n 
n ot  r e q uir e d 
•   P R  =  at l e ast t w o  d et er mi n ati o ns  of  P R  or  b ett er  at l e ast  4  w e e ks  a p art  b ef or e  pr o gr essi o n 
( a n d  n ot  q u alif yi n g f or  a  C R)  w h er e  c o nfir m ati o n r e q uir e d  or  o n e  d et er mi n ati o n  of  P R 
pri or t o  pr o gr essi o n  w h er e  c o nfir m ati o n  n ot  r e q uir e d 
•   S D  =  at l e ast  o n e  S D  ass ess m e nt ( or  b ett er)  >  6  w e e ks  aft er r a n d o mi z ati o n/st art  of 
tr e at m e nt ( a n d  n ot  q u alif yi n g f or  C R  or P R).  
•   P D  =  pr o gr essi o n  ≤  1 2  w e e ks  aft er r a n d o mi z ati o n/ st art  of tr e at m e nt ( a n d  n ot  q u alif yi n g 
f or  C R,  P R  or S D).  
If  P D i n  a  diff er e nt f oll o w-u p  p eri o d is  c o nsi d er e d  o v er all r es p o ns e =’ pr o gr essi v e  dis e a s e’, t his 
m ust  b e s p e cifi e d i n t h e  pr ot o c ol.  
T h e  pr ot o c ol s h o ul d st at e if  dis c o nti n u ati o n  d u e t o ‘ Dis e as e  pr o gr essi o n’  or  d e at h  d u e t o st u d y 
i n di c ati o n is  c o nsi d er e d  P D  e v e n if t his  w as  n ot  a c c o m p a ni e d  b y  d o c u m e nt ati o n  of  P D  b as e d 
o n t u m or  m e as ur e m e nts.  T his  d e p e n ds  o n  P h as e  of t h e st u d y  a n d t h e  pri m ar y  e n d p oi nt ( e. g. 
P h as e III st u di es i n  w hi c h  pr o gr essi o n -fr e e s ur vi v al is  pri m ar y  e n d p oi nt s h o ul d  c o nsi d er  o nl y 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 2 4
0  Pr ot o c ol  N o. 
 
 
 
d o c u m e nt e d  P D ,  w h er e as  P h as e I  a n d II st u di es  m a y  c o nsi d er  all  cli ni c al  d et eri or ati o ns  P D). 
T h e f oll o wi n g s e nt e n c e t h er ef or e is  o nl y  a p pli c a bl e if t his is s p e cifi e d i n t h e  pr ot o c ol:  
•   P ati e nts  wit h s y m pt o ms  of r a pi dl y  pr o gr essi n g  dis e as e  wit h o ut r a di ol o gi c  e vi d e n c e  will  b e 
cl assifi e d  as  pr o gr essi o n  o nl y  w h e n  cl e ar  e vi d e n c e  of  cli ni c al  d et eri or ati o n is  d o c u m e nt e d 
a n d/ or  p ati e nt  dis c o nti n u e d  d u e t o ‘ Dis e as e  pr o gr essi o n’  or  d e at h  d u e t o st u d y  i n di c ati o n. 
•   U N K  =  all  ot h er  c as es (i. e.  n ot  q u alif yi n g f or  c o nfir m e d  C R  or  P R  a n d  wit h o ut  S D  aft er 
m or e t h a n  6  w e e ks  or  e arl y  pr o gr essi o n  wit hi n t h e first  1 2  w e e ks)  
O v er all  l esi o n  r es p o ns es   of   C R   m ust  st a y  t h e  s a m e   u ntil   pr o gr essi o n  s ets  i n,   wit h  t h e  
e x c e pti o n  of  a  U N K st at us.  A  p ati e nt  w h o  h a d  a  C R  c a n n ot s u bs e q u e ntl y  h a v e  a l o w er st at us 
ot h er  t h a 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 gr essi o n   b as e d   o n  o n e  or   m or e 
l esi o ns r e a p p e ari n g, i n  w hi c h  c as e t h e st at us  w o ul d  b e c o m e  a P D.  
O n c e  a n  o v er all l esi o n r es p o ns e  of  P R is  o bs er v e d ( w hi c h  m a y  h a v e t o  b e  a  c o nfir m e d  P R 
d e p e n di n g   o n  t h e  st u d y)  t his   assi g n m e nt   m ust  st a y  t h e  s a m e   or  i m pr o v e   o v er  ti m e   u ntil  
pr o gr essi o n  s ets  i n,   wit h  t h e   e x c e pti o n   of   a n   U N K  st at us.   H o w e v er,  i n  st u di es   w h er e  
c o nfir m ati o n  of r es p o ns e is r e q uir e d,  if  a  p ati e nt  h as  a  si n gl e  P R  ( ≥ 3 0 %  r e d u cti o n  of  t u m or 
b ur d e n  c o m p ar e d t o  b as eli n e)  at  o n e  ass ess m e nt, f oll o w e d  b y  a  < 3 0 % r e d u cti o n fr o m  b as eli n e 
at  t h e  n e xt  ass e ss m e nt  ( b ut  n ot  ≥ 2 0 %  i n cr e as e  fr o m  pr e vi o us  s m all est  s u m),  t h e  o bj e cti v e 
st at us  at t h at ass ess m e nt  s h o ul d   b e  S D.   O n c e  a  c o nfir m e d   P R  w as s e e n,  t h e  o v er all  l esi o n  
r es p o ns e s h o ul d  b e  c o n si d er e d  P R ( or  U N K)  u ntil  pr o gr essi o n is  d o c u m e nt e d  or t h e l esi o ns 
t ot all y  dis a p p e ar i n  w hi c h  c as e  a  C R  assi g n m e nt is  a p pli c a bl e. I n st u di es  w h er e  c o nfir m ati o n 
of  r es p o ns e  is   n ot  r e q uir e d   aft er   a  si n gl e   P R  t h e   o v er all  l esi o n  r es p o ns e  s h o ul d  still   b e  
c o nsi d er e d  P R ( or  U N K)  u ntil  pr o gr essi o n is  d o c u m e nt e d  or t h e l esi o n t ot all y  dis a p p e ars i n 
w hi c h  c as e  a  C R  assi g n m e nt is  a p pli c a bl e.  
If  t h e   p ati e nt   pr o gr ess e d   b ut   c o nti n u es  st u d y   m e di c ati o n,  f urt h er   ass ess m e nt s   ar e   n ot  
c o nsi d er e d f or t h e  d et er mi n ati o n  of  b est  o v er all r es p o ns e.  
T h e  b est  o v er all r es p o ns e f or  a  p ati e nt is  al w a ys  c al c ul at e d,  b as e d  o n t h e s e q u e n c e  of  o v er all 
l esi o n r es p o ns es.  H o w e v er, t h e  o v er all l esi o n r es p o ns e  at  a  gi v e n  ass ess m e nt  m a y  b e  pr o vi d e d 
fr o m  diff er e nt s o ur c es: 
•   I n v esti g at or  o v er all l esi o n r es p o ns e 
•   C e ntr al  Bli n d e d  R e vi e w  o v er all l esi o n  r es p o ns e 
•   N o v artis  c al c ul at e d  o v er all l esi o n r es p o ns e ( b as e d  o n  m e as ur e m e nts fr o m  eit h er 
I n v esti g at or  or  C e ntr al R e vi e w)  
T h e   pri m ar y   a n al ysis   of  t h e   b est   o v er all  r es p o ns e   will   b e   b as e d   o n  t h e  s e q u e n c e   of  
i n v esti g at or/ c e ntr al  bli n d e d r e vi e w/ c al c ul at e d (i n v esti g at or)/ c al c ul at e d ( c e ntr al)  o v er all l esi o n 
r es p o ns es. 
B as e d   o n  t h e   p ati e nts’   b est   o v er all  r es p o ns e   d uri n g  t h e  st u d y,  t h e f oll o wi n g r at es   ar e t h e n 
c al c ul at e d:  
O v e r all  r es p o ns e  r at e ( O R R)  is t h e  pr o p orti o n  of  p ati e nts  wit h  a  b est  o v er all r es p o n s e  of  C R 
or  P R.  T his is  als o r ef err e d t o  as ‘ O bj e cti v e r es p o ns e r at e’ i n s o m e  pr ot o c ols  or  p u bli c ati o ns.  
Dis e as e  c o nt r ol  r at e ( D C R)  is t h e  pr o p orti o n  of  p ati e nts  wit h  a  b est  o v er all r es p o ns e  of  C R 
or  P R  or  S D.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 2 5
0  Pr ot o c ol  N o. 
 
 
 
A n ot h er  a p pr o a c h is t o s u m m ari z e t h e  pr o gr essi o n r at e  at  a  c ert ai n ti m e  p oi nt  aft er  b as eli n e. I n 
t his  c as e, t h e f oll o wi n g  d efi niti o n is  us e d: 
E a rl y  p r o g r essi o n  r at e ( E P R)  is t h e  pr o p orti o n  of  p ati e nts  wit h  pr o gr essi v e  dis e as e  wit hi n  8 
w e e ks  of t h e st art  of  tr e at m e nt. 
 
1 4. 1. 1 8   Ti m e t o  e v e nt  v ari a bl e s  
 
1 4. 1. 1 9   Pr o gr e s si o n -fr e e s ur vi v al  
P r o g r essi o n -f r e e s u r vi v al ( P F S) is t h e ti m e fr o m  d at e  of r a n d o mi z ati o n/st art  of tr e at m e nt t o 
t h e  d at e  of  e v e nt  d efi n e d  as t h e first  d o c u m e nt e d  pr o gr essi o n  or  d e at h  d u e t o  a n y  c a us e. If  a 
p ati e nt  h as  n ot  h a d  a n  e v e nt,  pr o gr essi o n -fr e e s ur vi v al is  c e ns or e d  at t h e  d at e  of l ast  a d e q u at e 
t u m or  ass ess m e nt. 
 
1 4. 1. 2 0   O v er all  s ur vi v al  
O v e r all s u r vi v al ( O S)  is  d efi n e d  as t h e ti m e fr o m  d at e  of r a n d o mi z ati o n/st art  of tr e at m e nt t o 
d at e   of   d e at h   d u e  t o   a n y   c a us e.  If   a   p ati e nt  is   n ot   k n o w n  t o   h a v e   di e d,  s ur vi v al   will   b e  
c e ns or e d  at t h e  d at e  of l ast  c o nt a ct.  
 
1 4. 1. 2 1   Ti m e t o  pr o gr e s si o n  
Ti m e t o  p r o g r essi o n ( T T P)  is t h e ti m e fr o m  d at e  of r a n d o mi z ati o n/st art  of tr e at m e nt t o t h e 
d at e  of  e v e nt  d efi n e d  as t h e first  d o c u m e nt e d  pr o gr essi o n  or  d e at h  d u e t o  u n d erl yi n g  c a n c er. If 
a  p ati e nt  h as  n ot  h a d  a n  e v e nt, ti m e t o  pr o gr essi o n  is  c e ns or e d   at t h e  d at e  of l ast   a d e q u at e 
t u m or  ass ess m e nt. 
 
1 4. 1. 2 2   Ti m e t o tr e at m e nt  f ail ur e 
Ti m e t o t r e at m e nt f ail u r e ( T T F)  is t h e ti m e fr o m  d at e  of r a n d o mi z ati o n/st art  of tr e at m e nt t o 
t h e  e arli est  of  d at e  of  pr o gr essi o n,  d at e  of  d e at h  d u e t o  a n y  c a us e,  or  d at e  of  dis c o nti n u ati o n 
d u e  t o  r e as o ns   ot h er  t h a n  ‘ Pr ot o c ol   vi ol ati o n’   or  ‘ A d mi nistr ati v e   pr o bl e ms’.   T h e  ti m e  t o  
tr e at m e nt f ail ur e f or  p ati e nts  w h o  di d  n ot  e x p eri e n c e tr e at m e nt f ail ur e  will  b e  c e ns or e d  at l ast 
a d e q u at e t u m or  ass ess m e nt.  
 
1 4. 1. 2 3   D ur ati o n  of r e s p o n s e  
D u r ati o n  of  o v e r all  r es p o ns e ( C R  o r  P R) :  F or  p ati e nts  wit h  a  C R  or  P R ( w hi c h  m a y  h a v e t o 
b e  c o nfir m e d t h e st art  d at e is  t h e  d at e  of first  d o c u m e nt e d r es p o ns e ( C R  or  P R)  a n d t h e  e n d 
d at e  a n d  c e ns ori n g is  d efi n e d t h e s a m e  as t h at f or ti m e t o  pr o gr essi o n.  
T h e f oll o wi n g t w o  d ur ati o ns  mi g ht   b e  c al c ul at e d i n  a d diti o n f or   a l ar g e  P h as e III  st u d y i n 
w hi c h  a r e as o n a bl e  n u m b er  of r es p o n d ers is s e e n.  
D u r ati o n  of  o v e r all  c o m pl et e  r es p o ns e ( C R) :  F or  p ati e nts  wit h  a  C R ( w hi c h  m a y  h a v e t o  b e 
c o nfir m e d) t h e st art  d at e is t h e  d at e  of first  d o c u m e nt e d  C R  a n d t h e  e n d  d at e  a n d  c e ns ori n g is 
d efi n e d t h e s a m e  as t h at f or ti m e t o  pr o gr essi o n.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 2 6
0  Pr ot o c ol  N o. 
 
 
 
D u r ati o n  of st a bl e  dis e as e ( C R/ P R/ S D) :  F or  p ati e nts  wit h  a  C R  or  P R ( w hi c h  m a y  h a v e t o 
b e  c o nfir m e d)  or  a n  S D t h e st art  a n d  e n d  d at e  as  w ell  as  c e ns ori n g is  d efi n e d t h e s a m e  as t h at 
f or ti m e t o  pr o gr essi o n. 
 
1 4. 1. 2 4   Ti m e t o r e s p o n s e  
Ti m e  t o   o v e r all   r es p o ns e  ( C R   o r   P R)   is t h e ti m e  b et w e e n  d at e  of  r a n d o mi z ati o n/st art  of 
tr e at m e nt   u ntil  first   d o c u m e nt e d  r es p o ns e  ( C R   or   P R).   T h e  r es p o ns e   m a y   n e e d  t o   b e  
c o nfir m e d  d e p e n di n g  o n t h e t y p e  of st u d y  a n d its i m p ort a n c e.  W h er e t h e r es p o ns e  n e e ds t o  b e 
c o nfir m e d t h e n ti m e t o r es p o ns e is t h e ti m e t o t h e first  C R  or  P R   o bs er v e d. 
Alt h o u g h   a n   a n al ysis   o n  t h e  f ull   p o p ul ati o n  is   pr ef err e d   a   d es cri pti v e   a n al ysis   m a y   b e  
p erf or m e d  o n t h e  “r es p o n d ers ” s u bs et   o nl y,  i n  w hi c h  c as e t h e r es ults s h o ul d  b e i nt er pr et e d 
wit h  c a ut i o n  a n d i n t h e  c o nt e xt  of t h e  o v er all r es p o ns e r at es, si n c e t h e s a m e  ki n d  of s el e cti o n 
bi as   m a y   b e  i ntr o d u c e d   as   d e s cri b e d  f or   d ur ati o n   of  r es p o ns e  i n   S e cti o n   1 4. 1. 2 3 .  It  is 
r e c o m m e n d e d  t h at   a n   a n al ysis   of   all   p ati e nts  ( b ot h  r es p o n d ers   a n d   n o n-r es p o n d ers)   b e  
p erf or m e d   w h et h er   or   n ot   a  r es p o n d ers   o nl y   d es cri pti v e   a n al ysis  is   pr es e nt e d.   W h er e   a n  
i nf er e nti al st atisti c al  c o m p aris o n is r e q uir e d t h e n  all  p ati e nts s h o ul d  d efi nit el y  b e i n cl u d e d i n 
t h e  a n al ysis t o  e ns ur e t h e st atisti c al t est is  v ali d.  F or  a n al ysis i n cl u di n g  all  p ati e nts,  p ati e nts 
w h o  di d  n ot  a c hi e v e  a r es p o ns e ( w hi c h  m a y  h a v e t o  b e  a  c o nfir m e d r es p o ns e)  will  b e  c e ns or e d 
usi n g  o n e  of t h e f oll o wi n g   o pti o ns. 
•   at  m a xi m u m f oll o w -u p (i. e.  F P F V t o  L P L V  us e d f or t h e  a n al ysis) f or  p ati e nts  w h o  h a d  a 
P F S   e v e nt  (i. e.   pr o gr ess e d  or   di e d  d u e t o  a n y  c a us e).  I n t his  c as e t h e  P F S is t h e  w orst 
p ossi bl e   o ut c o m e   a s  it   m e a ns  t h e   p ati e nt  t h at  t h e   p ati e nt   c a n n ot  s u bs e q u e ntl y  r es p o n d. 
Si n c e t h e st atisti c al  a n al ysis  us u all y  m a k es  us e  of t h e r a n ki n g  of ti m es t o r es p o ns e it is 
s uffi ci e nt t o  assi g n t h e  w orst  p ossi bl e  c e ns ori n g ti m e  w hi c h  c o ul d  b e  o bs er v e d i n t h e st u d y 
w hi c h is  e q u al t o t h e  m a xi m u m f oll o w -u p ti m e (i. e. ti m e fr o m  F P F V t o  L P L V)  
•   at  l ast   a d e q u at e  t u m or   ass ess m e nt   d at e   ot h er wis e.  I n  t his   c as e   p ati e nts   h a v e   n ot   y et 
pr o gr ess e d s o t h e y t h e or eti c all y still  h a v e  a  c h a n c e  of  r es p o n di n g 
Ti m e t o  o v e r all  c o m pl et e  r es p o ns e ( C R)  is t h e ti m e  b et w e e n  d at es  of r a n d o mi z ati o n/st art  of 
tr e at m e nt  u ntil first  d o c u m e nt e d  C R.  Si mil ar  a n al ysis  c o nsi d er ati o ns i n cl u di n g (if  a p pr o pri at e) 
c e ns ori n g r ul es  a p pl y f or t his  e n d p oi nt  d es cri b e d f or t h e ti m e t o  o v er all r es p o ns e  e n d p oi nt.  
I n di c at e i n t h e pr ot o c ol  w h et h er  a s u b gr o u p  a n al ysis  of r es p o n d ers  o nl y  will  b e  p erf or m e d i n 
a d diti o n t o t h e f ull  p o p ul ati o n  a n al ysis ( w hi c h s h o ul d  b e i n cl u d e d  as  d ef a ult).  
 
1 4. 1. 2 5   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  e a c h  ass ess m e nt  (i. e.  e v al u ati o n  n u m b er), t h e ass ess m e nt  d at e  is  c al c ul at e d  as t h e l at est 
of   all   m e as ur e m e nt   d at es  ( e. g.   X -r a y,   C T-s c a n)  if  t h e   o v er all  l esi o n  r es p o ns e   at  t h at  
ass e ss m e nt is  C R/ P R/ S D/ U N K.  
Ot h er wis e  - if  o v er all l esi o n r es p o ns e is  pr o gr essi o n - t h e  ass ess me nt  d at e is  c al c ul at e d  as t h e 
e arli est  d at e  of  all  m e as ur e m e nt  d at es  at t h at  e v al u ati o n  n u m b er.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 2 7
0  Pr ot o c ol  N o. 
 
 
 
St art  d at e s  
St at e i n t h e  pr ot o c ol if  d at e  of r a n d o mi z ati o n  or  d at e  of st art  of tr e at m e nt is t o  b e  us e d f or  all 
d efi niti o ns.  F or r a n d o mi z e d st u di es s p e cif y  e x a ctl y  w h er e t h e r a n d o mi z ati o n  d at e  c o m es fr o m,  
e. g. fr o m I V R S,  or if st art  of tr e at m e nt is  us e d  as r a n d o mi z ati o n  d at e.  F or  n o n -r a n d o mi z e d 
st u di es  pl e as e s p e cif y  w hi c h tr e at m e nt st art  d at e is t a k e n if  m or e t h a n  o n e tr e at m e nt is t o  b e 
gi v e n. 
F or  all  “ti m e t o  e v e nt ”  v ari a bl es,  ot h er t h a n t h e  d ur ati o n  of r es p o ns es, t h e r a n d o mi z ati o n/  d at e 
of tr e at m e nt st art  will  b e  us e d  as t h e st art  d at e.  
F or t h e  c al c ul ati o n  of  d ur ati o n  of r es p o ns es t h e f oll o wi n g st art  d at e s h o ul d  b e  us e d:  
•   D at e   of  first   d o c u m e nt e d  r es p o ns e  is  t h e   ass ess m e nt   d at e   of  t h e  first   o v er all  l esi o n  
r es p o ns e  of  C R (f or  d ur ati o n  of  o v er all  c o m pl et e r es p o ns e)  or  C R /  P R (f or  d ur ati o n  of 
o v er all r es p o ns e) r es p e cti v el y,  w h e n t his st at us is l at er   c o nfir m e d. 
 
E n d  d at e s  
T h e  e n d  d at es  w hi c h  ar e  us e d t o  c al c ul at e ‘ti m e t o  e v e nt’  v ari a bl es  ar e  d efi n e d  as f oll o ws:  
•   D at e  of  d e at h ( d uri n g tr e at m e nt  as r e c or d e d  o n t h e tr e at m e nt  c o m pl eti o n  p a g e  or  d uri n g 
f oll o w-u p  as r e c or d e d  o n t h e st u d y  e v al u ati o n  c o m pl eti o n  p a g e  or t h e s ur vi v al f oll o w -u p 
p a g e).  
•   D at e  of  pr o gr essi o n is t h e first  ass ess m e nt  d at e  at  w hi c h t h e  o v er all l esi o n r es p o ns e  w as 
r e c or d e d  as  pr o gr essi v e dis e as e.  
W h e n  t h er e  i s   n o   d o c u m e nt ati o n   of  r a di ol o gi c   e vi d e n c e   of   pr o gr essi o n,   a n d  t h e   p ati e nt  
dis c o nti n u e d f or ‘ Dis e as e  pr o gr essi o n’  d u e t o  d o c u m e nt e d  cli ni c al  d et eri or ati o n  of  dis e as e, t h e 
d at e  of  dis c o nti n u ati o n is  us e d  as  d at e  of  pr o gr essi o n.  
•   D at e  of l ast  a d e q u at e t u m or  ass ess m e nt is t h e  d at e t h e l ast t u m or  ass ess m e nt  wit h  o v er all 
l esi o n r es p o ns e  of  C R,  P R  or  S D  w hi c h  w as  m a d e  b ef or e  a n  e v e nt  or  a  c e ns ori n g r e as o n 
o c c urr e d. I n t his  c as e t h e l ast t u m or  e v al u ati o n  d at e  at t h at  ass ess m e nt is  us e d.  If  n o  p ost- 
b as eli n e  ass e ss m e nt s  ar e  a v ail a bl e ( b ef or e  a n   e v e nt   or  a  c e ns ori n g  r e as o n   o c c urr e d)  t h e 
d at e  of r a n d o mi z ati o n/st art  of tr e at m e nt is   us e d. 
•   D at e  of  n e xt s c h e d ul e d  ass ess m e nt is t h e  d at e  of t h e l ast  a d e q u at e t u m or  ass e ss m e nt  pl u s 
t h e  pr ot o c ol s p ecifi e d ti m e i nt er v al f or  ass ess m e nt s.  T his  d at e  m a y  b e  us e d if  b a c k - d ati n g 
is  c o nsi d er e d  w h e n t h e  e v e nt  o c c urr e d  b e y o n d t h e  a c c e pt a bl e ti m e  wi n d o w f or t h e  n e xt 
t u m or  ass ess m e nt  as  p er  pr ot o c ol (s e e S e cti o n  1 4. 1. 2 6 ). 
E x a m pl e  (if   pr ot o c ol   d efi n e d  s c h e d ul e   of   ass ess m e nts  is   3   m o nt hs):  t u m or   ass ess m e nts   at  
b as eli n e  -  3  m o nt hs  -  6  m o nt hs  -  missi n g  -  missi n g  -  P D.  D at e  of  n e xt s c h e d ul e d  ass ess m e nt 
w o ul d t h e n  c orr es p o n ds t o  9  m o nt hs.  
•   D at e  of  dis c o nti n u ati o n is t h e  d at e  of t h e  e n d  of  tr e at m e nt visit.  
•   D at e  of  l ast   c o nt a ct  is  d efi n e d   as t h e l ast   d at e t h e  p ati e nt   w as  k n o w n  t o   b e  ali v e.   T his 
c orr es p o n ds t o t h e l at est  d at e f or  eit h er t h e  visit  d at e, l a b s a m pl e  d at e  or t u m or  ass ess m e nt 
d at e.  If  a v ail a bl e,  t h e l ast  c o nt a ct  d at e fr o m t h at s ur vi v al f oll o w -u p  p a g e is  us e d. If  n o 
s ur vi v al f oll o w-u p is  a v ail a bl e, t h e  d at e  of  dis c o nti n u ati o n is  us e d  as l ast  c o nt a ct  d at e.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 2 8
0  Pr ot o c ol  N o. 
 
 
 
•   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 is  d efi n e d  as t h e st art  d at e  of  a n y  a d diti o n al 
(s e c o n d ar y)  a nti n e o pl asti c t h er a p y  or s ur g er y. 
 
1 4. 1. 2 6   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 bl e t h at  p ati e nts  wit h j ust  n o n-m e as ur a bl e  dis e as e  pr e s e nt  at  b as eli n e  ar e  e nt er e d i nt o 
t h e st u d y,  eit h er  b e c a us e  of  a  pr ot o c ol  vi ol ati o n  or  b y  d esi g n ( e. g. i n  P h as e III st u di es  wit h 
P F S  as t h e  pri m ar y  e n d p oi nt).  I n s u c h  c as es t h e  h a n dli n g  of t h e r es p o ns e  d at a r e q uir es s p e ci al 
c o nsi d er ati o n   wit h  r es p e ct  t o  i n cl usi o n  i n   a n y   a n al ysis   of   e n d p oi nts   b as e d   o n  t h e   o v er all  
r es p o ns e  e v al u ati o ns. 
T h e   pr ot o c ol  s h o ul d  st at e   cl e arl y   w h et h er   p ati e nts   wit h   n o n -m e as ur a bl e   dis e as e   o nl y   at  
b as eli n e   will   b e   all o w e d  i nt o  t h e  st u d y.  If   p ati e nts   wit h   n o n -m e as ur a bl e   dis e as e   o nl y   ar e  
all o w e d t o  b e  e nr oll e d t h e n t h e st atisti c al s e cti o n s h o ul d  d es cri b e  cl e arl y  h o w  d at a fr o m t h es e 
p ati e nts  will  b e i n c or p or at e d i nt o t h e  pri m ar y  a n al ysis  a n d  m ai n  a n al ys es  of t h e  k e y s e c o n d ar y 
e n d p oi nts. I n st u di es  w h er e  pr es e n c e  or  ot h er wis e  of  m e as ur a bl e  dis e as e is  e x p e ct e d t o  h a v e  a 
r el ati v el y  l ar g e  i m p a ct   o n  t h e   pri m ar y   e n d p oi nt,  this  f a ct or   c a n   e v e n   b e   c o nsi d er e d   as   a  
str atifi c ati o n f a ct or i n t h e r a n d o mi z ati o n  pr o c ess.  
It is r e c o m m e n d e d t h at  a n y  p ati e nts  wit h  o nl y  n o n-m e as ur a bl e  dis e a s e  at  b as eli n e s h o ul d  b e 
i n cl u d e d i n t h e  m ai n (I T T)  a n al ysis  of  e a c h  of t h es e  e n d p oi nts. 
F or st u di es  w hi c h s p e cifi c all y  e x cl u d e  p ati e nts  wit h  n o n -m e as ur a bl e  dis e as e  o nl y  at  b as eli n e 
t h e  pr e-s p e cifi e d  a n al y sis  pl a n s h o ul d  d e s cri b e  h o w t o  h a n dl e  d at a fr o m t h es e t y p es  of  p ati e nts 
if t h e y  ar e  e nr oll e d  b y  err or. It is r e c o m m e n d e d f or t h es e t y p es  of st u di es th at  p ati e nts  wit h 
n o n- m e as ur a bl e  dis e a s e i d e ntifi e d t hr o u g h t h e l o c al sit e  e v al u ati o n  b e i n cl u d e d i n t h e list  of 
pr ot o c ol   vi ol ati o ns.   H o w e v er,   d e cisi o ns   o n   e x cl usi o n  fr o m   a   p er   pr ot o c ol   a n al ysis  s h o ul d  
r el at e t o  w h et h er t h e  p ati e nt  h as  m e as ur a bl e  dis e as e  ac c or di n g t o t h e  pri m ar y  d at a s o ur c e.  F or 
e x a m pl e, if t h e  pri m ar y  d at a s o ur c e is fr o m  a  c e ntr al i n d e p e n d e nt r e vi e w t h e n  p ati e nts  wit h 
n o n- m e as ur a bl e   dis e a s e   o nl y   a c c or di n g t o t his   c e ntr al  r e vi e w s h o ul d   b e  e x cl u d e d  fr o m  t h e 
r el e v a nt  p er  pr ot o c ol a n al ys es.  
Al t h o u g h  t h e  t e xt   of  t h e   d efi niti o ns   d es cri b e d  i n  t h e   pr e vi o us  s e cti o ns   pri m aril y  r el at es  t o  
p ati e nts  wit h  m e as ur a bl e  dis e as e  at  b as eli n e,  p ati e nts  wit h o ut  m e as ur a bl e  dis e as e s h o ul d  als o 
b e i n c or p or at e d i n  a n  a p pr o pri at e  m a n n er.  T h e  o v er all r es p o ns e f or  p ati e nts  wit h  m e as ur a bl e 
dis e as e is  d eri v e d sli g htl y  diff er e ntl y  a c c or di n g t o  T a bl e  1 4 - 4. 
 
T a bl e  1 4 - 4  
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  
I n c o m pl et e r e s p o n s e/ S D1  
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  1 4. 1. 8  
 
 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 2 9
0  Pr ot o c ol  N o. 
 
 
 
I n  g e n er al, t h e n o n- C R/ n o n -P D  r es p o ns e  f or t h es e  p ati e nts is  c o nsi d er e d  e q ui v al e nt t o  a n  S D 
r es p o ns e i n  e n d p oi nt  d et er mi n ati o n. I n s u m m ar y t a bl es f or  b est  o v er all r es p o ns e  p ati e nts  wit h 
j ust  n o n-m e as ur a bl e  dis e as e  m a y  b e  hi g hli g ht e d i n  a n  a p pr o pri at e f as hi o n  e. g. i n  p arti c ul ar  b y 
dis pl a yi n g t h e  s p e cifi c  n u m b ers  wit h t h e  n o n -C R/ n o n -P D  c at e g or y.  
I n  c o nsi d eri n g  h o w t o i n c or p or at e  d at a fr o m t h es e  p ati e nts i nt o t h e  a n al ysis t h e i m p ort a n c e t o 
e a c h  e n d p oi nt  of  b ei n g  a bl e t o i d e ntif y  a  P R  a n d/ or t o  d et er mi n e t h e  o c c urr e n c e  a n d ti mi n g  of 
pr o gr essi o n  n e e ds t o  b e t a k e n i nt o  a c c o u nt.  
F o r  O R R  it is r e c o m m e n d e d t h at t h e  m ai n (I T T)  a n al ysis i n cl u d es  d at a fr o m  p ati e nts  wit h 
o nl y   n o n -m e as ur a bl e   dis e a s e   at   b as eli n e,   h a n dli n g   p ati e nts   wit h   a   b est  r es p o ns e   of   C R   as  
“r es p o n d ers ”   wit h  r es p e ct  t o   O R R   a n d   all   ot h er   p ati e nts   as   “ n o n -r es p o n d ers ”.   St u d y t e a ms  
m a y  als o  w a nt t o  p erf or m s e nsiti vit y  a n al ys es  e x cl u di n g  p ati e nts fr o m t h e  a n al ysis  of  O R R 
( e. g.  p ossi bl y  as  p art  of  a  p er-pr ot o c ol t y p e  a n al ysis).  Si mil ar  c o nsi d er ati o ns s h o ul d  b e  gi v e n 
t o   ot h er   e n d p oi nts   w hi c h r el y   o n  a  cl e ar   disti n cti o n   b ei n g   m a d e   b et w e e n   a   P R   a n d   a n   S D  
r es p o ns e. 
F o r  P F S , it is  a g ai n r e c o m m e n d e d t h at t h e  m ai n I T T a n al ys es  o n t h es e  e n d p oi nts i n cl u d e  all 
p ati e nts  wit h j ust  n o n -m e as ur a bl e  dis e as e  at  b a s eli n e,  wit h  p ossi bl e s e nsiti vit y  a n al ys es  w hi c h 
e x cl u d e  t h es e   p arti c ul ar   p ati e nts.   E n d p oi nts  s u c h   as   P F S   w hi c h   ar e  r eli a nt   o n  t h e  
d et er mi n ati o n  a n d/ or ti mi n g  of  pr o gr essi o n  c a n i n c or p or at e  d at a fr o m  p ati e nts  
 
1 4. 1. 2 7   S e n siti vit y  a n al y s e s  
T his  s e cti o n   o utli n es  t h e   p ossi bl e   e v e nt   a n d   c e ns ori n g   d at es  f or   pr o gr essi o n,   as   w ell  is  
a d dr essi n g t h e iss u es  of  missi n g t u m or  ass ess m e nts  d uri n g t h e st u d y.  F or i nst a n c e, if  o n e  or 
m or e   ass ess m e nt   visits   ar e   miss e d   pri or  t o  t h e   pr o gr essi o n   e v e nt,  t o   w h at   d at e  s h o ul d  t h e  
pr o gr essi o n  e v e nt  b e  assi g n e d ?  A n d s h o ul d  pr o gr essi o n  e v e nt  b e  i g n or e d if it  o c c urr e d  aft er  a 
l o n g  p eri o d  of  a  p ati e nt  b ei n g l ost t o f oll o w-u p ? It is i m p ort a nt t h at t h e  pr ot o c ol  a n d  a n al ysis 
pl a n s p e cif y t h e  pri m ar y  a n al ysis i n  d et ail  wit h r es p e ct t o t h e  d efi niti o n  of  e v e nt  a n d  c e ns ori n g 
d at es  a n d  als o i n cl u d e  a  d es c ri pti o n  of  o n e  or  m or e s e nsiti vit y  a n al ys es t o  b e  p erf or m e d. 
B as e d   o n   d efi niti o ns   o utli n e d  i n   S e cti o n   1 4. 1. 2 5 ,   a n d   usi n g  t h e   dr aft   F D A   g ui d eli n e   o n  
e n d p oi nts ( Cli ni c al   Tri al  E n d p oi nts f or t h e  A p pr o v al   of  C a n c er   Dr u gs  a n d  Bi ol o gi cs,  A pril 
2 0 0 5)  as  a r ef er e n c e, t h e f oll o wi n g  a n al ys es  c a n  b e  c o nsi d er e d:  
 
T a bl e  1 4 -5  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  a n al y si s  pl a n 
 
 
 
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 nt 2  
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 nt 2  
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 nt 2  
( 2) D at e  of  n e xt  s c h e d ul e d  a s s e s s m e nt 2  
( 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  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 3 0
0  Pr ot o c ol  N o. 
 
 
 
 
 
 
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  a n al y si s  pl a n 
 
 
 
O ut c o m e  
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) N/ A  
( 2) D at e  of  di s c o nti n u ati o n ( vi sit  d at e  at  w hi c h 
cli ni c al  pr o gr e s si o n  w a s  d et er mi n e d)  
I g n or e d 
Pr o gr e s s e d  
F  
N e w  a nti c a n c er t h er a p y  gi v e n  
( 1) D at e  of l a st  a d e q u at e  a s s e s s m e nt  
( 2) D at e  of  s e c o n d ar y  a nti -c a n c er  t h er a p y 
( 3) D at e  of  s e c o n d ar y  a nti -c a n c er  t h er a p y 
( 4) N/ A  
C e n s or e d 
C e n s or e d 
E v e nt 
I g n or e d 
G   
D e at h s  d u e t o r e a s o n  ot h er t h a n 
d et eri or ati o n  of ‘ St u d y i n di c ati o n’  
( 1)  D at e  of l a st  a d e q u at e  a s s e s s m e nt 
C e n s or e d 
( o nl y  T T P  a n d 
d ur ati o n  of  
r e s p o n s e) 
1 = D efi niti o n s  c a n  b e f o u n d i n  S e cti o n  1 4. 1. 2 5  
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  1 4. 1. 2 5  
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 h e  pri m ar y  a n al ysis  a n d t h e s e nsiti vit y  a n al ys es  m ust  b e s p e cifi e d i n t h e  pr ot o c ol.  Cl e arl y 
d efi n e i f  a n d  w h y  o pti o ns ( 1)  ar e  n ot  us e d f or sit u ati o ns  C,  E  a n d (if  a p pli c a bl e)  F. 
Sit u ati o ns  C ( C 1  a n d  C 2):  Pr o gr essi o n  or  d e at h  aft er  o n e  or  m or e  missi n g  ass ess m e nts:  T h e 
pri m ar y  a n al ysis is  us u all y  usi n g  o pti o ns ( 1) f or sit u ati o ns  C 1  a n d  C 2, i. e.  
•   ( C 1) t a ki n g t h e  a ct u al  pr o gr essi o n  or  d e at h  d at e, i n t h e  c as e  of  o nl y  o n e  missi n g 
ass e ss m e nt.  
•   ( C 2)  c e ns ori n g  at t h e  d at e  of t h e l ast  a d e q u at e  ass ess m e nt, i n t h e  c as e  of t w o  or  m or e 
c o ns e c uti v e  missi n g  ass ess m e nts.  
I n t h e  c as e  of t w o  or  missi n g  ass ess m e nts (sit u ati o n  C 2),  o pti o n ( 3)  m a y  b e  c o nsi d er e d j oi ntl y 
wit h  o pti o n ( 1)  i n sit u ati o n  C 1  as s e nsiti vit y  a n al ysis.   A  v ari a nt  of  t his s e nsiti vit y  a n al ysis 
c o nsists  of  b a c k d ati n g t h e  d at e  of  e v e nt t o t h e  n e xt s c h e d ul e d  ass e ss m e nt  as  pr o p os e d  wit h 
o pti o n ( 2) i n sit u ati o ns  C 1  a n d  C 2.  
Sit u ati o n   E:   T r e at m e nt   dis c o nti n u ati o n   d u e  t o  ‘ Dis e as e   p r o g r essi o n’   w it h o ut 
d o c u m e nt e d  p r o g r essi o n :  B y  d ef a ult,  o pti o n ( 1) is  us e d f or sit u ati o n  E  as  p ati e nts  wit h o ut 
d o c u m e nt e d   P D  s h o ul d   b e  f oll o w e d  f or   pr o gr essi o n   aft er   dis c o nti n u ati o n   of  tr e at m e nt.  
H o w e v er,  o pti o n ( 2)  m a y  b e  us e d  as s e nsiti vit y  a n al ysis. If  pr o gr essi o n i s  cl ai m e d  b as e d  o n 
cli ni c al  d et eri or ati o n i nst e a d  of t u m or  ass ess m e nt  b y  e. g.  C T -s c a n,  o pti o n ( 2)  m a y  b e  us e d f or 
i n di c ati o ns  wit h  hi g h  e arl y  pr o gr essi o n r at e  or  diffi c ulti es t o  ass ess t h e t u m or  d u e t o  cli ni c al 
d et eri or ati o n. 
Sit u ati o n  F:  N e w  c a n c e r t h e r a p y  gi v e n : t h e  h a n dli n g  of t his sit u ati o n  m ust  b e s p e cifi e d i n 
d et ail i n t h e  pr ot o c ol.  H o w e v er,  o pti o n ( 1), i. e.  c e ns ori n g  at l ast  a d e q u at e  ass ess m e nt  m a y  b e 
us e d  as  a  d ef a ult i n t his  c as e.  
 
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 h er  s u g g esti o ns  f or   a d diti o n al  s e nsiti vit y   a n al ys es   m a y  i n cl u d e   a n al ys es  t o   c h e c k  f or  
p ot e nti al  bi as i n f oll o w -u p s c h e d ul es f or t u m or  ass ess m e nt s,  e. g.  b y  assi g ni n g t h e  d at es f or  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 3 1
0  Pr ot o c ol  N o. 
 
 
 
c e ns ori n g  a n d  e v e nts  o nl y  at s c h e d ul e d  visit  d at es.  T h e l att er  c o ul d  b e  h a n dl e d  b y r e pl a ci n g i n 
T a bl e   1 4 - 5  t h e   “ D at e   of  l ast   a d e q u at e   a ss e ss m e nt ”   b y  t h e   “ D at e   of   pr e vi o us  s c h e d ul e d  
ass e ss m e nt (fr o m  b as eli n e) ”,  wit h t h e f oll o wi n g  d efi niti o n:  
•   D at e  of  p r e vi o us s c h e d ul e d  ass ess m e nt (f r o m  b as eli n e)  is t h e  d at e  w h e n  a t u m or 
ass e ss m e nt  w o ul d  h a v e t a k e n  pl a c e, if t h e  pr ot o c ol  ass ess m e nt s c h e m e  w as stri ctl y 
f oll o w e d fr o m  b as eli n e, i m m e di at el y  b ef or e  or  o n t h e  d at e  of t h e l ast  a d e q u at e t u m or 
ass e ss m e nt.  
I n  a d diti o n,  a n al ys es  c o ul d  b e r e p e at e d  usi n g t h e I n v esti g at ors’  ass ess m e nts  of r es p o ns e r at h er 
t h a n t h e  c al c ul at e d r es p o ns e.  T h e  n e e d f or t h es e t y p es  of s e nsiti vit y  a n al ys es  will  d e p e n d  o n 
t h e i n di vi d u al r e q uir e m e nts f or t h e s p e cifi c st u d y  a n d dis e as e  ar e a  a n d  h a v e t o  b e s p e cifi e d i n 
t h e  pr ot o c ol  or  R A P  d o c u m e nt ati o n. 
 
1 4. 1. 2 8   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 h e  f oll o wi n g  s e cti o n  s h o ul d   b e   us e d   as   g ui d a n c e  f or   d e v el o p m e nt   of  t h e   pr ot o c ol,   d at a  
h a n dli n g  pr o c e d ur es  or  pr o gr a m mi n g r e q uir e m e nts ( e. g.  o n i n c o m pl et e  d at es).  
 
1 4. 1. 2 9   St u d y/ pr oj e ct  s p e cifi c  d e ci si o n s  
F or  e a c h st u d y ( or  pr oj e ct)  v ari o us iss u es  n e e d t o  b e  a d dr ess e d  a n d  s p e cifi e d i n t h e  pr ot o c ol  or 
R A P  d o c u m e nt ati o n.  A n y  d e vi ati o ns fr o m  pr ot o c ol  m ust  b e  dis c uss e d  a n d  d efi n e d  at t h e l at est 
i n t h e  R A P  do c u m e nt ati o n. 
T h e   pr o p os e d   pri m ar y   a n al ysis   a n d   p ot e nti al  s e nsiti vit y   a n al ys es  s h o ul d   b e   dis c uss e d   a n d  
a gr e e d  wit h t h e  h e alt h  a ut h oriti es  a n d  d o c u m e nt e d i n t h e  pr ot o c ol ( or  at t h e l at est i n t h e  R A P 
d o c u m e nt ati o n  b ef or e  d at a b as e l o c k).  
 
1 4. 1. 3 0   Tr e at m e nt  a n d  st u d y  c o m pl eti o n  C R F s  
If st u d y tr e at m e nt is  dis c o nti n u e d, t h e E n d  of  T r e at m e nt  P a g e  is t o  b e  c o m pl et e d  wit h  a  visit 
d at e r efl e cti n g t h e  d at e t h e  dis c o nti n u ati o n  d e cisi o n  w as  m a d e,  a n d  wit h t h e ‘ L ast  k n o w n  d at e 
s u bj e ct t o o k st u d y tr e at m e nt’  a n d  o n e  of t h e f oll o wi n g r e as o ns:  
•   A d v ers e  e v e nt(s)  
•   A b n or m al l a b or at or y  v al u e(s)  
•   A b n or m al t est  pr o c e d ur e  r es ults(s) 
•   Pr ot o c ol  vi ol ati o n  
•   S u bj e ct  wit h dr e w   c o ns e nt 
•   L ost t o  f oll o w- u p 
•   A d mi nistr ati v e   pr o bl e ms 
•   D e at h  
•   Dis e as e   pr o gr essi o n 
•   Tr e at m e nt  d ur ati o n  c o m pl et e d  as  p er   pr ot o c ol 
F or  r e as o ns  ot h er  t h a n  pr o gr essi o n ( a n d  d e at h) it s h o ul d  b e  c h e c k e d if t his  w as  n ot i n f a ct 
pr o gr essi o n  ( es p e ci all y  r e as o ns   A d v ers e   E v e nts,   A b n or m al  l a b or at or y   v al u e  (s),   A b n or m al   
t est  pr o c e d ur e r es ult  a n d s u bj e ct  wit h dr e w  c o ns e nt).  Als o it s h o ul d  b e  c h e c k e d if  p ati e nt  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 3 2
0  Pr ot o c ol  N o. 
 
 
 
wit h dr e w  c o ns e nt  b e c a us e  of s af et y iss u es, i n  w hi c h  c as e r e as o ns  A d v ers e  E v e nts,  A b n or m al 
l a b or at or y  v al u e (s),  A b n or m al t est  pr o c e d ur e r es ult s h o ul d  b e  us e d. I n s u c h  c as es  w h ere t h e 
r e as o n f or  dis c o nti n u ati o n is  A d v ers e  E v e nt, t h e  a d v ers e  e v e nt  C R F  p a g e  m ust  b e  c o nsist e nt 
wit h t h e  E O T r e as o n  pr o vi d e d  
All  p ati e nts  w h o  dis c o nti n u e d st u d y tr e at m e nt  will  b e f oll o w e d f or  p ost  a tr e at m e nt  e v al u ati o n 
u ntil   pr o gr essi o n   or   u ntil   a   n e w   a n ti c a n c er  t h er a p y  is  i niti at e d.   P ati e nts   w h o   dis c o nti n u e d  
st u d y tr e at m e nt f or r e as o ns  ot h er t h a n  d o c u m e nt e d  pr o gr essi o n,  d e at h  or l ost t o f oll o w -u p  will 
b e f oll o w e d f or  pr o gr essi o n t h er e aft er ( p ati e nts  w h o  wit h dr e w  c o ns e nt  mi g ht  n ot  b e f oll o w e d 
wit h  r e g ul ar   t u m or   ass ess m e nt s   at  t h e  st u d y  sit e,   b ut  s h o ul d  i d e all y   b e  f oll o w e d   u ntil  
pr o gr essi o n  o utsi d e t h e st u d y sit e). I d e all y,  all  p ati e nts  w h o  dis c o nti n u e d st u d y tr e at m e nt f or 
pr o gr essi o n   wit h o ut   d o c u m e nt e d   pr o gr essi o n   will  still   b e  f oll o w e d   wit h  r e g ul ar  t u m or  
ass e ss m e nt s ( e. g. i n  c as e  of  c e ntr al r a di ol o g y r e vi e w).If  p ati e nt  wit h dr a ws  c o ns e nt, it  m ust  b e 
cl e arl y st at e d if  p ati e nt is  als o  wit h dr a wi n g  c o ns e nt  fr o m   p ost tr e at m e nt  e v al u ati o ns  a n d/ or 
p ost  tr e at m e nt  f oll o w -u p   ass ess m e nt s.   D uri n g  t h at   e v al u ati o n   p eri o d,   us u all y   o nl y  t u m or  
m e as ur e m e nts ( a n d/ or r es p o ns e st at us)  a n d s ur vi v al  d at a  ar e  c oll e ct e d. I n s o m e  pr ot o c ols, t h e 
s u bs e q u e nt  a nti -c a n c er t h er a pi es  m a y  als o  b e  r e c or d e d. 
 
1 4. 1. 3 1   St u d y  e v al u ati o n  c o m pl eti o n  
At t h e  e n d  of t h e st u d y  e v al u ati o n  p eri o d, t h e  st u d y  e v al u ati o n  c o m pl eti o n  p a g e  is fill e d  o ut 
wit h t h e f oll o wi n g  o pti o ns:  
•   S u bj e ct  wit h dr e w   c o ns e nt 
•   L ost t o  f oll o w- u p 
•   A d mi nistr ati v e  pr o bl e ms  
•   D e at h  
•   N e w  c a n c er  t h er a p y 
•   Dis e as e   pr o gr essi o n 
T h er e aft er,   p ati e nts   w ill   b e  f oll o w e d  f or  s ur vi v al   usi n g  t h e  s ur vi v al  f oll o w-u p   p a g es.   If 
i nf or m ati o n  o n  d e at h  b e c o m es  a v ail a bl e f or  p ati e nts  w h o  w er e l ost t o f oll o w-u p  or  wit h dr e w 
c o ns e nt, t his  m a y  als o  b e  e nt er e d i n t h e  d at a b as e.  T h e r e as o n f or  d e at h  m ust  b e  d o c u m e nt e d 
( a n d   will  b e  c o d e d  usi n g    M e d D R A);  it    m ust  b e  als o  st at e d  if  d e at h    w as  d u e  t o  ‘ St u d y 
i n di c ati o n’  or ‘ Ot h er’ r e as o n. 
I n  c o m p ar ati v e st u di es  wit h l o n g f oll o w-u p  p eri o d  a n d t h er ef or e  e xt e n d e d  visit  s c h e d ul e, it 
m a y   b e   us ef ul  t o   c oll e ct  t h e  s ur vi v al  st at us   at   a   pr e -sp e cifi e d   c ut -off   wit hi n   a  li mit e d  
ti m efr a m e f or  all  p ati e nts  wit h  n o  d o c u m e nt e d  d e at h. I n t his  c as e, t his r e q uir es  a  c o nt a ct t o  b e 
m a d e  wit h t h e  p ati e nt  or  wit h  a n y r eli a bl e s o ur c e  of i nf or m ati o n  o n t h e  p ati e nt’s st at us,  b ut  
n ot r e q uiri n g  a s p e cifi c  visit  t o  b e s c h e d ul e d 
U ntil t h e s p e cifi e d  c ut -off  p oi nt  h as  b e e n r e a c h e d,  t h e  g o al is t o  c oll e ct t u m or   ass ess m e nts  
u ntil  dis e as e  pr o gr essi o n f or  all  p ati e nts r e g ar dl ess  of  w h et h er t h e  p ati e nts  ar e still r e c ei vi n g 
st u d y  tr e at m e nt.  If   p ati e nts   ar e   n ot  f oll o w e d  f or   pr o gr essi o n,   e. g.  i n   a   P h as e  I   or  II  st u d y  
m ai nl y  e v al u ati n g s af et y, t h e  e v al u ati o n is  c o m pl et e d  w h e n st u d y tr e at m e nt is  c o m pl et e d (i n 
t his  c as e  o nl y t h e first  c o m pl eti o n  p a g e is  us e d). 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 3 3
0  Pr ot o c ol  N o. 
 
 
 
1 4. 1. 3 2   M e di c al  v ali d ati o n  of  pr o gr a m m e d  o v er all l e si o n  r e s p o n s e 
As  R E CI S T is  v er y stri ct r e g ar di n g  m e as ur e m e nt  m et h o ds (i. e.  a n y  ass ess m e nt  wit h  m or e  or 
l ess s e n siti v e  m et h o d t h a n t h e  o n e  us e d t o  ass e ss t h e l esi o n  at  b as eli n e is  c o nsi d er e d  U N K) 
a n d   n ot   a v ail a bl e   e v al u at i o ns  (i. e.  if   a n y  t ar g et   or   n o n-t ar g et  l esi o n   w as   n ot   e v al u at e d  t h e  
w h ol e  o v er all l esi o n r es p o ns e is  U N K  u nl ess r e m ai ni n g l esi o ns  q u alifi e d f or  P D), t h es e  U N K 
ass e ss m e nt s   m a y   b e  r e -e v al u at e d   b y   cli ni ci a ns   at   N o v artis   or   e xt er n al   e x p erts.  I n   a d diti o n,  
d at a  r e vi e w  r e p orts   will   b e   a v ail a bl e  t o  i d e ntif y   ass ess m e nts  f or   w hi c h  t h e  i n v esti g at ors’  
o pi ni o n  d o es  n ot  m at c h t h e  pr o gr a m m e d  c al c ul at e d r es p o ns e  b as e d  o n  R E CI S T  crit eri a.  T his 
m a y  b e  q u eri e d f or  cl arifi c ati o n.  H o w e v er, t h e i n v esti g at or r es p o ns e  ass e ss m e nt  w ill  n e v er  b e 
o v err ul e d. 
If   N o v artis   el e ct  t o  i n v ali d at e   a n   e v al u ati o n   of   o v er all  l esi o n  r es p o ns e   u p o n  i nt er n al     or  
e xt er n al r e vi e w  of t h e  d at a, t h e  c al c ul at e d  o v er all l esi o n r es p o ns e  at t h at s p e cifi c  ass ess m e nt is 
t o   b e   k e pt  i n   a   d at as et.   T his   m ust   b e   cl e arl y   d o c u m e nt e d  i n  t h e   R A P   d o c u m e nt ati o n   a n d   
a gr e e d  b ef or e  d at a b as e l o c k.  T his  d at as et s h o ul d  b e  cr e at e d  a n d st or e d  as  p art  of t h e ‘r a w’  d at a.  
A n y  dis c o nti n u ati o n  d u e t o ‘ Dis e as e  pr o gr essi o n’   wit h o ut  d o c u m e nt ati o n  of  pr o gr essi o n  b y 
R E CI S T  crit eri a s h o ul d  b e  c ar ef ull y r e vi e w e d.  O nl y  p ati e nts  wit h  d o c u m e nt e d  d et eri or ati o n  of 
s y m pt o ms i n di c ati v e  of  pr o gr essi o n  of  dis e as e s h o ul d  h a v e t his r e as o n f or  dis c o nti n u ati o n  of 
tr e at m e nt  or st u d y  e v al u ati o n. 
 
1 4. 1. 3 3   Pr o gr a m mi n g r ul e s  
T h e f oll o wi n g s h o ul d  b e  us e d f or  pr o gr a m mi n g  of  effi c a c y r es ults:  
 
1 4. 1. 3 4   C al c ul ati o n  of ‘ti m e t o  e v e nt’  v ari a bl e s  
Ti m e t o  e v e nt  =  e n d  d at e  - st art  d at e  +  1 (i n  d a ys) 
W h e n   n o   p ost -b a s eli n e  t u m or   ass e ss m e nt s   ar e   a v ail a bl e,  t h e   d at e   of  r a n d o mi z ati o n/st art   of  
tr e at m e nt  will  b e  us e d  as  e n d  d at e ( d ur ati o n  =  1  da y)  w h e n ti m e is t o  b e  c e ns or e d  at l ast t u m or 
ass e ss m e nt, i. e. ti m e t o  e v e nt  v ari a bl es  c a n  n e v er  b e  n e g ati v e.  
 
1 4. 1. 3 5   I n c o m pl et e  a s s e s s m e nt d at e s  
All i n v esti g ati o n  d at es ( e. g.  X -r a y,  C T s c a n)  m ust  b e  c o m pl et e d  wit h  d a y,  m o nt h  a n d  y e ar. 
If  o n e  or  m or e i n v esti g ati o n  d at es  ar e i n c o m pl et e  b ut  ot h er i n v esti g ati o n  d at es  ar e  a v ail a bl e, 
t his/t h es e i n c o m pl et e  d at e(s)   ar e  n ot  c o nsi d er e d  f or   c al c ul ati o n  of t h e  ass ess m e nt   d at e ( a n d 
ass e ss m e nt  d at e is  c al c ul at e d  as  o utli n e d i n  S e cti o n  1 4. 1. 2 5 ). If  all  m e as ur e m e nt  d at es  h a v e  n o 
d a y r e c or d e d, t h e  1 st of t h e  m o nt h is  us e d.  
If t h e  m o nt h is  n ot  c o m pl et e d, f or  a n y  of t h e i n v esti g ati o ns, t h e r es p e cti v e  ass e ss m e nt  will  b e 
c o nsi d er e d t o  b e  at t h e  d at e  w hi c h is  e x a ctl y  b et w e e n  pr e vi o us  a n d f oll o wi n g  ass ess m e nt. If  a 
pr e vi o us  a n d f oll o wi n g  ass ess m e nt is  n ot  a v ail a bl e, t his  ass e ss m e nt  will  n ot  b e  us e d f or  a n y 
c al c ul ati o n.  
 
1 4. 1. 3 6   I n c o m pl et e  d at e s f or l a st  c o nt a ct  or d e at h  
All  d at es  m ust  b e  c o m pl et e d  wit h  d a y,  m o nt h  a n d  y e ar. If t h e  d a y is  missi n g, t h e  1 5 t h of t h e 
m o nt h  will  b e  us e d f or i n c o m pl et e  d e at h  d at es  or  d at es  of l ast  c o nt a ct.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 3 4
0  Pr ot o c ol  N o. 
 
 
 
1 4. 1. 3 7   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-t ar g et l esi o ns  ar e i d e ntifi e d  at  b as eli n e ( a n d t h er ef or e  n ot f oll o w e d t hr o u g h o ut t h e 
st u d y), t h e  n o n-t arg et l esi o n r es p o ns e  at  e a c h  ass ess m e nt  will  b e  c o nsi d er e d ‘ n ot  a p pli c a bl e 
( N A)’. 
 
1 4. 1. 3 8   St u d y/ pr oj e ct  s p e cifi c  pr o gr a m mi n g  
T h e st a n d ar d  a n al ysis  pr o gr a ms  n e e d t o  b e  a d a pt e d f or  e a c h st u d y/ pr oj e ct.  
 
1 4. 1. 3 9   C e n s ori n g r e a s o n  
I n   or d er  t o  s u m m ari z e  t h e   v ari o us  r e as o ns  f or   c e ns ori n g,  t h e  f oll o wi n g   c at e g ori es   will   b e  
c al c ul at e d f or  e a c h ti m e t o  e v e nt  v ari a bl e  b as e d  o n t h e tr e at m e nt  c o m pl eti o n  p a g e, t h e st u d y 
e v al u ati o n  c o m pl eti o n  p a g e  a n d t h e s ur vi v al  p a g e.  
F or s ur vi v al t h e f oll o wi n g  c e ns ori n g r e as o ns  ar e  p ossi bl e:  
•   Ali v e  
•   L ost t o  f oll o w- u p 
F or  P F S  a n d  T T P ( a n d t h er ef or e  d ur ati o n  of r es p o ns es) t h e f oll o wi n g  c e ns ori n g r e as o ns  ar e 
p ossi bl e: 
•   O n g oi n g  wit h o ut  e v e nt  
•   L ost t o  f oll o w- u p 
•   Wit h dr e w   c o ns e nt 
•   A d e q u at e  ass e ss m e nt  n o l o n g er  a v ail a bl e *  
•   E v e nt  d o c u m e nt e d  aft er t w o  or  m or e  missi n g t u m or  ass ess m e nt s ( o pti o n al,  s e e 
T a bl e   1 4- 5) 
•   D e at h  d u e t o r e as o n  ot h er t h a n  u n d erl yi n g  c a n c er  
•   N e w  c a n c er t h er a p y  a d d e d  
*  A d e q u at e  ass ess m e nt is  d efi n e d i n  S e cti o n  1 4. 1. 2 5  T his r e as o n is  a p pli c a bl e  w h e n  a d e q u at e 
e v al u ati o ns   ar e   missi n g  f or   a  s p e cifi e d   p eri o d   pri or  t o   d at a   c ut -off  ( or   pri or  t o   a n y   ot h er  
c e ns ori n g  r e as o n)   c orr es p o n di n g  t o  t h e   u n a v ail a bilit y   of  t w o   or   m or e   pl a n n e d  t u m or  
ass e ss m e nt s   pri or  t o  t h e   c ut -off   d at e.   T h e  f oll o wi n g   cl arifi c ati o ns   c o n c er ni n g  t his  r e as o n  
s h o ul d  als o  b e  n ot e d: - 
•   T his  m a y  b e  w h e n t h er e  h as  b e e n  a  d efi nit e  d e cisi o n t o st o p  e v al u ati o n ( e. g. 
r e as o n =’ A d mi nistr ati v e  pr o bl e ms’  o n st u d y  e v al u ati o n  c o m pl eti o n  p a g e),  w h e n  p ati e nts 
ar e  n ot f oll o w e d f or  pr o gr essi o n  aft er tr e at m e nt  c o m pl eti o n  or  w h e n  o nl y  U N K 
ass e ss m e nt s  ar e  a v ail a bl e j ust  pri or t o  d at a  c ut -off).  
•   T h e r e as o n  " A d e q u at e  ass ess m e nt  n o l o n g er  a v ail a bl e "  als o  pr e v ails i n sit u ati o ns  w h e n 
a n ot h er  c e ns ori n g r e as o n ( e. g.  wit h dr a w al  of  c o ns e nt, l oss t o f oll o w -u p  or  alt er n ati v e  a nti - 
c a n c er t h er a p y)  h as  o c c urr e d  m or e t h a n  t h e s p e cifi e d  p eri o d f oll o wi n g t h e l ast  a d e q u at e 
ass e ss m e nt.  
•   T his r e as o n  will  als o  b e  us e d f or  c e ns or i n  c as e  of  n o  b as eli n e  ass ess m e nt.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 3 5
0  Pr ot o c ol  N o. 
 
 
 
1 4. 1. 4 0   R ef er e n c e ( a v ail a bl e  u p o n  r e q u e st) 
D e nt  S,  Z e e ( 2 0 0 1)  a p pli c ati o n  of  a  n e w  m ulti n o mi al  p h as e II st o p pi n g r ul e  usi n g r es p o ns e 
a n d  e arl y  pr o gr essi o n, J  Cli n  O n c ol;  1 9:  7 8 5 - 7 9 1 
Eis e n h a u er  E,  et  al ( 2 0 0 9)  N e w r es p o ns e  e v al u ati o n  crit eri a i n s oli d t u m ors: r e vis e d  R E CI S T 
g ui d eli n e ( v ersi o n  1. 1).  E ur o p e a n J o ur n al  of  C a n c er,  V ol. 4 5:  2 2 8 - 4 7 
Ellis  S,  et  al ( 2 0 0 8)  A n al ysis  of  d ur ati o n  of r es p o ns e i n  o n c ol o g y tri als.  C o nt e m p  Cli n  Tri als 
2 0 0 8;  2 9:  4 5 6 - 4 6 5 
F D A  G ui d eli n es ( 2 0 0 5)  Cli ni c al  Tri al  E n d p oi nts f or t h e  A p pr o v al  of  C a n c er  Dr u gs  a n d 
Bi ol o gi cs,  A pril  2 0 0 5  
F D A  G ui d eli n es ( 2 0 0 7)  Cli ni c al  Tri al  E n d p oi nts f or t h e  A p pr o v al  of  C a n c er  Dr u gs  a n d 
Bi ol o gi cs,  M a y  2 0 0 7  
M or g a n  T M ( 1 9 8 8)  A n al ysis  of  d ur ati o n  of r es p o ns e:  a  pr o bl e m  of  o n c ol o g y tri als.  C o nt  Cli n 
Tri als;  9:  1 1 - 1 8 
T h er ass e  P,  Ar b u c k  S,  Eis e n h a u er  E,  et  al ( 2 0 0 0)  N e w  G ui d eli n es t o  E v al u at e t h e  R es p o ns e t o 
Tr e at m e nt i n  S oli d  T u m ors, J o ur n al  of  N ati o n al  C a n c er I n stit ut e,  V ol.  9 2;  2 0 5- 1 6 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 3 6
0  Pr ot o c ol  N o. 
 
 
 
 
1 4. 2  
R e vi e w  of  crit eri a f or i nt err u pti o n  a n d r e-i niti ati o n  of  st u d y 
tr e at m e nt 
T a bl e  1 4 - 6  
Crit eri a f or i nt err u pti o n  a n d r e -i niti ati o n  of B Y L 7 1 9  
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  B Y L 7 1 9  
W or st t o xi cit y 
C T C A E  gr a d e ( v al u e)  
D uri n g  a  c y cl e  of t h er a p y  
N o t o xi cit y  
M ai nt ai n  d o s e l e v el  
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)  
M ai nt ai n  d o s e l e v el  
Gr a d e  2 ( A N C  <  1 5 0 0  - 1 0 0 0/ m m 3 )  
M ai nt ai n  d o s e l e v el  
Gr a d e  3 ( A N C  <  1 0 0 0  - 5 0 0/ m m 3 ) 
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  ↓  1  d o s e l e v el 
Gr a d e  4 ( A N C  <  5 0 0/ m m 3) 
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 s u m e  at  ↓  1  d o s e l e v el  
F e bril e  n e utr o p e ni a  
( A N C  <  1. 0  x  1 09/ L,  wit h  a  si n gl e 
t e m p er at ur e  of  ≥  3 8. 3  ° C  or  a 
s u st ai n e d t e m p er at ur e  of  ≥  3 8  ° C f or  
m or e t h a n  o n e  h o ur )  
O mit  d o s e  u ntil r e s ol v e d, t h e n    1  d o s e l e v el  
T hr o m b o c yt o p e ni a  
Gr a d e  1 ( P L T  <  L L N  - 7 5, 0 0 0/ m m 3 )  
M ai nt ai n  d o s e l e v el  
Gr a d e  2 ( P L T  <  7 5, 0 0 0  - 5 0, 0 0 0/ m m 3 )  
M ai nt ai n  d o s e l e v el  
Gr a d e  3 ( P L T  <  5 0, 0 0 0  - 2 5, 0 0 0/ m m 3 ) 
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  ↓  1  d o s e l e v el 
Gr a d e  4 ( P L T  <  2 5, 0 0 0/ m m 3 ) 
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  ↓  1  d o s e l e v el  
Bl e e di n g  
A n y  bl e e di n g, r el at e d t o  B Y L 7 1 9  u s e, 
r e s ulti n g i n  pl at el et tr a n sf u si o n 
O mit  d o s e  u ntil  n o f urt h er  bl e e di n g  h a s  b e e n  o b s er v e d.  M o dif y  d o s e 
a c c or di n g t o t h e t hr o m b o c yt o p e ni a r e c o m m e n d e d  d o s e  m o difi c ati o n s.  
R e s pir at or y  di s or d er s  
P n e u m o niti s  
A n y  Gr a d e  
O mit  B Y L 7 1 9 f or  a n y  c a s e  of  s u s p e ct e d  p n e u m o niti s.  
O bt ai n  a p pr o pri at e i m a gi n g ( hi g h r e s ol uti o n  C T  s c a n)  a n d  c o n si d er 
br o n c h o al v e ol ar l a v a g e  a n d  bi o p s y  o n  cli ni c al j u d g e m e nt.  S e e  S e cti o n  
1 4. 3. 1  f or  d et ail s  of  m a n a g e m e nt  of  p n e u m o niti s. Tr e at m e nt f or 
p n e u m o niti s  s h o ul d  b e i niti at e d  b a s e d  o n i n stit uti o n  g ui d eli n e s 
a n d  g e n er all y i n cl u d e s  hi g h  d o s e c orti c o st er oi d;  a nti bi oti c t h er a p y 
s h o ul d  b e  a d mi ni st er e d  c o n c urr e ntl y if i nf e cti o u s  c a u s e s  h a v e  n ot 
b e e n r ul e d  o ut.  
B Y L 7 1 9  s h o ul d  b e  p er m a n e ntl y  di s c o nti n u e d i n  all  p ati e nt s  wit h 
c o nfir m e d  p n e u m o niti s.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 3 7
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  B Y L 7 1 9  
W or st t o xi cit y 
C T C A E  gr a d e ( v al u e)  
D uri n g  a  c y cl e  of t h er a p y  
I n v e sti g ati o n s ( R e n al) 
S er u m  cr e ati ni n e  
<  2  x  U L N  
M ai nt ai n  d o s e l e v el  
2  - 3  x  U L 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  ↓  1  d o s e l e v el 
Gr a d e  ≥  3 ( >  3. 0  b a s eli n e;  >  3. 0  x  U L 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  st u d y tr e at m e nt  
I n v e sti g ati o n s ( H e p ati c) 
I s ol at e d t ot al  Bilir u bi n  el e v ati o n 
 
(*f or  p ati e nt s  wit h  Gil b ert  S y n dr o m e t h e s e  d o s e  m o difi c ati o n s  a p pl y t o  c h a n g e s i n  dir e ct  bilir u bi n  o nl y)  
Gr a d e  1 ( >  U L N  - 1. 5  x  U L N)  
M ai nt ai n  d o s e l e v el  wit h  L F T s*  m o nit or e d  a s  p er  pr ot o c ol  
Gr a d e  2 ( >  1. 5  - 3. 0  x  U L N)  
O mit  d o s e.  M o nit or  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 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  ≤  1 4  d a y s, t h e n  m ai nt ai n  d o s e l e v el 
●   If r e s ol ve d i n  >  1 4  d a y s,  ↓  1  d o s e  l e v el. 
Gr a d e  3 ( >  3. 0  - 1 0. 0  x  U L N)*  
O mit  d o s e.  M o nit or  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 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  ≤  1 4  d a y s,  ↓  d o s e  1  d o s e l e v el. 
●   If r e s ol v e d i n >  1 4  d a y s  di s c o nti n u e  p ati e nt fr o m  st u d y tr e at m e nt 
T h e  p ati e nt  s h o ul d  b e  m o nit or e d  w e e kl y (i n cl u di n g  L F T s a ), or  m or e 
fr e q u e ntl y if  cli ni c all y i n di c at e d,  u ntil t ot al  bilir u bi n  h a v e r e s ol v e d t o 
b a s eli n e  or  st a bili z ati o n  o v er  4  w e e k s  
Gr a d e  4 ( >  1 0. 0  x  U L N)*  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  B Y L 7 1 9  
T h e  p ati e nt  s h o ul d  b e  m o nit or e d  w e e kl y (i n cl u di n g  L F T s a ),  or  m or e 
fr e q u e ntl y if  cli ni c all y i n di c at e d,  u ntil t ot al  bilir u bi n  h a v e r e s ol v e d t o 
b a s eli n e  or  st a bili z ati o n  o v er  4  w e e k s.  
I s ol at e d  A S T  or  A L T  El e v ati o n 
C o nf o u n di n g f a ct or s  a n d/ or  alt er n ati v e  c a u s e s f or i n cr e a s e d tr a n s a mi n a s e s li k e  c o n c o mit a nt  m e di c ati o n s, 
i nf e cti o n,  h e p at o-bili ar y  di s or d er s,  o b str u cti o n, li v er  m et a st a si s,  et c.  s h o ul d  b e  e x cl u d e d  b ef or e  d o s e 
i nt err u pti o n/r e d u cti o n 
Gr a d e  1 ( >  U L N  - 3. 0  x  U L N)  
M ai nt ai n  d o s e l e v el  wit h  L F T s
a m o nit or e d  p er  pr ot o c ol  
Gr a d e  2 ( >  3. 0  - 5. 0  x  U L N)  
•   
F or  p ati e nt s  wit h  b a s eli n e  v al u e  ≤  
3. 0  x  U L N  
 
 
 
•   
F or  p ati e nt s  wit h  b a s eli n e  v al u e   > 
3. 0  -5. 0  x  U L N  
•   
M ai nt ai n  d o s e l e v el.  R e p e at  L F T s
a a s  s o o n  a s  p o s si bl e,  pr ef er a bl y 
wit hi n  4 8 -7 2  h o ur s fr o m  a w ar e n e s s  of t h e  a b n or m al r e s ult s; if 
a b n or m al l a b  v al u e s  ar e  c o nfir m e d  u p o n t h e r e p e at t e st, t h e n 
m o nit or  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 
r e s ol v e d t o  ≤  3. 0  x U L N  
 
•   
M ai nt ai n  d o s e l e v el  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 3 8
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  B Y L 7 1 9  
W or st t o xi cit y 
C T C A E  gr a d e ( v al u e)  
D uri n g  a  c y cl e  of t h er a p y  
Gr a d e  3 ( >  5. 0  - 2 0. 0  x  U L N)  
>  5. 0  - 1 0. 0  x  U L N  
•   
F or  p ati e nt s  wit h  b a s eli n e  v al u e  ≤  
3. 0  x  U L N  
 
 
 
•   
F or  p ati e nt s  wit h  b a s eli n e  v al u e   > 
3. 0  -5. 0  x  U L N  
 
 
 
 
 
 
>  1 0. 0  x  U L N  
 
 
•   
O mit  d o s e.  R e p e at  L F T s a a s  s o o n  a s  p o s si bl e,  pr ef er a bl y  wit hi n 
4 8 -7 2  h o ur s fr o m  a w ar e n e s s  of t h e  a b n or m al r e s ult s;  m o nit or 
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 
r e s ol v e d t o  ≤  3. 0  x  U L N T h e n  
If r e s ol v e d i n  ≤  1 4  d a y s,  m ai nt ai n  d o s e l e v el 
If r e s ol v e d i n  >  1 4  d a y s,   1  d o s e l e v el  
•   
M ai nt ai n  d o s e l e v el.  R e p e at  L F T s
a a s  s o o n  a s  p o s si bl e,  pr ef er a bl y 
wit hi n  4 8 -7 2  h o ur s fr o m  a w ar e n e s s  of t h e  a b n or m al r e s ult s; if 
a b n or m al l a b  v al u e s  ar e  c o nfir m e d  u p o n t h e r e p e at t e st, t h e n 
m o nit or  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 r e s ol v e d t o  ≤  5. 0  x  U L N  
If r e s ol v e d i n  ≤  2 1  d a y s,  m ai nt ai n  d o s e l e v el 
If r e s ol v e d i n  >  2 1  d a y s  a n d  c o nf o u n di n g f a ct or s  h a v e  b e e n 
e x cl u d e d,    1  d o s e l e v el  
 
O mit  d o s e.  R e p e at  L F T s a a s  s o o n  a s  p o s si bl e,  pr ef er a bl y  wit hi n  4 8 -7 2 
h o ur s fr o m  a w ar e n e s s  of t h e  a b n or m al r e s ult s;  m o nit or  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 r e s ol v e d t o  ≤  b a s eli n e.  
T h e n    1  d o s e l e v el.  
Gr a d e  4 ( >  2 0. 0  x  U L N)  
•   
F or  p ati e nt s  d eri vi n g  cl i ni c al 
b e n efit  u p o n i n v e sti g at or’ s 
j u d g e m e nt 
 
 
 
 
•   
F or  all  ot h er  p ati e nt s  
 
•   
O mit  d o s e.  R e p e at  L F T s a  a s  s o o n  a s  p o s si bl e,  pr ef er a bl y  wit hi n 
4 8 -7 2  h o ur s fr o m  a w ar e n e s s  of t h e  a b n or m al r e s ult s;  m o nit or 
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 
r e s ol v e d t o  ≤  3  x  U L N ( or  ≤  5  x  U L N f or  p ati e nt s  wit h  b a s eli n e 
v al u e  >  3. 0  -5. 0  x  U L N), t h e n r e s u m e tr e at m e nt  at    1  d o s e l e v el. 
O nl y  1  d o s e r e d u cti o n i s  all o w e d; if r e o c c ur s  at  >  5  x  U L N, 
di s c o nti n u e  p ati e nt fr o m  B Y L 7 1 9.  
 
 
•   
Di s c o nti n u e  p ati e nt fr o m  B Y L 7 1 9. R e p e at  L F T s a  a s  s o o n  a s 
p o s si bl e,  pr ef er a bl y  wit hi n  4 8 -7 2  h o ur s fr o m  a w ar e n e s s  of t h e 
a b n or m al r e s ult s;  m o nit or  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 r e s ol v e d t o  b a s eli n e  or  st a bili z ati o n  o v er  4 
w e e k s  
C o m bi n e d b el e v ati o n s  of  A S T  or  A L T  a n d t ot al  Bilir u bi n  
•   
F or  p ati e nt s  wit h  n or m al  b a s eli n e 
A L T  a n d  A S T  a n d t ot al  bilir u bi n 
v al u e:  
A S T  or  A L T  >  3. 0  x  U L N  a n d  c o m bi n e d 
wit h t ot al  bilir u bi n  >  2. 0  x  U L N  
 
•   
F or  p ati e nt s  wit h  el e v at e d  b a s eli n e 
A S T  or  A L T  or t ot al  bilir u bi n   val u e  
[ A S T  or  A L T > 2 x  b a s eli n e  A N D  >  3. 0 
x U L N]  O R [ A S T  or  A L T  >  8. 0  x U L N],  
c o m bi n e d  wit h [t ot al  bilir u bi n  > 2 x 
b a s eli n e  A N D  > 2. 0  x U L N  
•   
P er m a n e ntl y  di s c o nti n u e  B Y L 7 1 9  
 
 
 
•   
R e p e at  a s  s o o n  a s  p o s si bl e,  pr ef er a bl y  wit hi n  4 8  h o ur s fr o m 
a w ar e n e s s  of t h e  a b n or m al r e s ult s, t h e n  wit h  w e e kl y  m o nit ori n g  of 
L F T s a ,  or  m or e fr e q u e ntl y if  cli ni c all y i n di c at e d,  u ntil  A S T,  A L T,  or 
bilir u bi n  h a v e r e s ol v e d t o  b a s eli n e  or  st a bili z ati o n  o v er  4  w e e k s. 
R ef er t o  S e cti o n 1 4. 3. 1  f or  a d diti o n al f oll o w-u p  e v al u ati o n s  a s 
a p pli c a bl e  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 3 9
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  B Y L 7 1 9  
W or st t o xi cit y 
C T C A E  gr a d e ( v al u e)  
D uri n g  a  c y cl e  of t h er a p y  
a C or e  L F T s i n cl u d e  al b u mi n,  A L T,  A S T, t ot al  bilir u bi n (fr a cti o n at e d [ dir e ct  a n d i n dir e ct], if t ot al  bilir u bi n  >  2. 0  x 
U L N),  al k ali n e  p h o s p h at a s e (fr a cti o n at e d [ q u a ntifi c ati o n  of i s of or m s], if  al k ali n e  p h o s p h at a s e i s  > gr a d e  2)  a n d 
G G T.  F or  p ati e nt s  wit h  Gil b ert  S y n dr o m e: t ot al  a n d  dir e ct  bilir u bi n  m u st  b e  m o nit or e d, i nt e n sifi e d  m o nit ori n g 
a p pli e s t o  c h a n g e s i n  dir e ct  bilir u bi n  o nl y; t h e  m o nit ori n g i n cl u d e s t h e f oll o wi n g  L F T s:  al b u mi n,  A L T,  A S T, t ot al 
bilir u bi n (fr a cti o n at e d [ dir e ct  a n d i n dir e ct] if t ot al  bilir u bi n  >  2. 0  x  U L N),  al k ali n e  p h o s p h at a s e (fr a cti o n at e d 
[ q u a ntifi c ati o n  of i s of or m s] if  al k ali n e  p h o s p h at a s e i s  >  gr a d e  2)  a n d  G G T). 
b “ C o m bi n e d”  d efi n e d  a s t ot al  bilir u bi n i n cr e a s e t o t h e  d efi n e d t hr e s h ol d  c o n c urr e ntl y  wit h  A L T/ A S T i n cr e a s e t o t h e 
d efi n e d  t hr e s h ol d 
If  c o m bi n e d  el e v ati o n s  of  A S T  or  A L T  a n d t ot al  bilir u bi n  d o  n ot  m e et t h e  d efi n e d t hr e s h ol d s,  pl e a s e f oll o w t h e 
i n str u cti o n s f or i s ol at e d  el e v ati o n  of t ot al  bilir u bi n  a n d i s ol at e d  el e v ati o n  of  A S T/ A L T,  a n d t a k e  a  c o n s er v ati v e 
a cti o n  b a s e d  o n t h e  d e gr e e  of t h e  el e v ati o n s ( e. g.  di s c o nti n u e tr e at m e nt  at t h e  sit u ati o n  w h e n  o mit  d o s e i s 
n e e d e d f or  o n e  p ar a m et er  a n d  di s c o nti n u e tr e at m e nt i s r e q uir e d f or  a n ot h er  p ar a m et er).  Aft er  all  el e v ati o n s 
r e s ol v e t o t h e  d efi n e d t hr e s h ol d s t h at  all o w tr e at m e nt r e-i niti ati o n, r e-st art t h e tr e at m e nt  eit h er  at t h e  s a m e  d o s e  or 
at  o n e  d o s e l o w er if  m e eti n g  a  crit eri o n f or  d o s e  r e d u cti o n 
*  N ot e: If t ot al  bilir u bi n  >  3. 0  x  U L N i s  d u e t o t h e i n dir e ct ( n o n-c o nj u g at e d)  c o m p o n e nt  o nl y,  a n d  h e m ol y si s  a s t h e 
eti ol o g y  h a s  b e e n r ul e d  o ut  a s  p er i n stit uti o n al  g ui d eli n e s ( e. g., r e vi e w  of  p eri p h er al  bl o o d  s m e ar  a n d  h a pt o gl o bi n  
d et er mi n ati o n), t h e n    1  d o s e l e v el  a n d  c o nti n u e tr e at m e nt  at t h e  di s cr eti o n  of t h e i n v e sti g at or.  
I n v e sti g ati o n s ( m et a b oli c) 
A s y m pt o m ati c  A m yl a s e  a n d/ or  Li p a s e  el e v ati o n(  s e e  al s o  S e cti o n  1 4. 3. 1 ) 
Gr a d e  1 ( >  U L N  - 1. 5  x  U L N)  
M ai nt ai n  d o s e l e v el  
Gr a d e  2 ( >  1. 5  - 2. 0  x  U L N)  
M ai nt ai n  d o s e l e v el  
Gr a d e  ≥ 3 ( >  2. 0)  
O mit  d o s e  u ntil r e s ol v e d t o  b a s eli n e, t h e n:  
●   If r e s ol v e d i n  ≤  1 4  d a y s,  m ai nt ai n  d o s e l e v el 
●   If r e s ol v e d i n >  1 4  d a y s,  ↓  b y  1  d o s e l e v el 
N ot e:  
I n  c a s e s  of i s ol at e d  a m yl a s e  el e v ati o n s  o nl y,  d o si n g  m a y  b e  m ai nt ai n e d 
pr o vi d e d  a m yl a s e fr a cti o n ati o n  d e m o n str at e s t h at  p a n cr e ati c  a m yl a s e i s  
≤  Gr a d e  1.  M o nit or t ot al  a m yl a s e ( a n d  c o nti n u e t o  a s s e s s fr a cti o n at e d  
a m yl a s e)  a s  s p e cifi e d i n  S e cti o n  1 4. 3. 1 . 
N ot e:  Wit h h ol d  st u d y tr e at m e nt f or  a c ut e  o n s et  of  n e w  or  pr o gr e s si v e  u n e x pl ai n e d  a b d o mi n al  s y m pt o m s,  s u c h  a s 
s e v er e  p ai n  or  v o miti n g;  a n d  p erf or m  di a g n o sti c  pr o c e d ur e s ( e. g.,  a b d o mi n al  C T  s c a n  or  ultr a s o u n d) t o  e x cl u d e  
p a n cr e ati c  p at h ol o g y.  
H y p er gl y c e mi a  ( s e e  al s o S e cti o n  1 4. 3 ) 
Al w a y s  c o n si d er  c o n s ult ati o n  wit h  a  di a b et ol o gi st  a n d r e c o m m e n d/r ei nf or c e  o n lif e st yl e  c h a n g e s  a s  p er  A D A, i. e. 
e x er ci s e  a n d  di et ar y  a d vi c e ( e. g.  s m all fr e q u e nt  m e al s, l o w  c ar b,  hi g h fi b er,  b al a n ci n g  c ar b s  o v er t h e  c o ur s e  of t h e 
d a y.  T hr e e  s m all  m e al s  a n d  2  s m all  s n a c k s r at h er t h a n  o n e l ar g e  m e al).  
Gr a d e  1 ( >  U L N  - 1 6 0  m g/ d L) [ >  U L N  - 
8. 9  m m ol/ L]  
F or  p ati e nt s  wit h  b a s eli n e  v al u e s 
b et w e e n  > U L N  –  1 4 0  m g/ d L ( U L N  – 
7. 7  m m ol/ L) t hi s  a p pl y  o nl y f or  v al u e s  >  
1 4 0  m g/ d L ( 7. 7  m m ol/ L)  
 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 4 0
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  B Y L 7 1 9  
W or st t o xi cit y 
C T C A E  gr a d e ( v al u e)  
D uri n g  a  c y cl e  of t h er a p y  
Gr a d e  2 ( > 1 6 0  - 2 5 0  m g/ d L) [ >  8. 9  - 
1 3. 9  m m ol/ L]  
M ai nt ai n  d o s e l e v el  a n d r e mi n d  p ati e nt  o n lif e st yl e  c h a n g e s*,  e x cl u d e 
c o nf o u n di n g  f a ct or s  li k e   e. g.   uri n ar y  tr a ct  i nf e cti o n,   c o n si d er  
c o n s ult ati o n   wit h   a  di a b et ol o gi st   a n d   st art   or al -a nti di a b eti c   tr e at m e nt, 
e. g.   m etf or mi n   5 0 0   m g   bi d   wit h   br e a kf a st   a n d   di n n er.  If   n o   GI  
i nt ol er a n c e, i n cr e a s e t o  5 0 0  m g  wit h  br e a kf a st,  1 0 0 0  m g  wit h  di n n er. If 
t ol er at e d,   1 0 0 0   m g   bi d   wit h   br e a kf a st   a n d   di n n er.  If   n ot  t ol er at e d,  
r e d u c e t o  pri or t ol er at e d  d o s e.  Titr at e t o t h e  m a xi m u m  t ol er at e d  d o s e 
o v er  a  p eri o d  of  3  w e e k s.  
 
If   F P G  i s   still  ri si n g   o n   m a xi m u m  t ol er at e d   d o s e   of   m etf or mi n   or  
p er si st e ntl y   > 1 6 0 m g/ dl  ( > 8. 9   m m ol/ L),   a d d   a n  i n s uli n -s e n siti z er,   e. g.  
pi o glit a z o n e  3 0  m g ( m a x.  d o s e).  
M o nit or   F P G   a s   cli ni c all y  i n di c at e d   a n d   at  l e a st   w e e kl y   u ntil   F P G  
r e s ol v e s t o  ≤  Gr a d e  1 
•    If  F P G  d o e s  n ot r e s ol v e t o  ≤  Gr a d e  1  wit hi n  2 1  d a y s  aft er i n stit uti o n 
of   a p pr o pri at e   a nti -di a b eti c  tr e at m e nt,  r e d u c e   B Y L 7 1 9   b y   1   d o s e  
l e v el 
•   
C o nti n u e   wit h   a nti -di a b eti c  tr e at m e nt   a n d   c h e c k   F P G   at  l e a st  
w e e kl y f or  8  w e e k s, t h e n  c o nti n u e  c h e c ki n g  at l e a st  e v er y  2  w e e k s,  
al ert tr e ati n g  p h y si ci a n if  F P G > 2 5 0 m g/ dl  
Gr a d e  3 ( >  2 5 0  - 5 0 0  m g/ d L) [ >  1 3. 9  - 
2 7. 8  m m ol/ L]  
O mit   B Y L 7 1 9   a n d   c o nfir m  f a sti n g   st at u s   of  t h e   a s s e s s m e nt.  If   n o n - 
f a sti n g, r e-c h e c k  wit hi n  2 4  h o ur s.  
E x cl u d e   c o nf o u n di n g  f a ct or s  li k e   e. g.   uri n ar y  tr a ct  i nf e cti o n   a n d  
c o n si d er  c o n s ult ati o n  wit h  a  di a b et ol o gi st.  
 
A d mi ni st er 
 i ntr a v e n o u s 
  h y dr ati o n 
  a n d 
 i nt er v e nti o n 
 f or 
 
el e ctr ol yt e/ k et o a ci d o si s/ h y p er o s m ol ar 
  di st ur b a n c e s 
  a s 
  cli ni c all y 
 
a p pr o pri at e.   St art   m etf or mi n   a n d  titr at e   a s   o utli n e d  f or   Gr a d e   2,   a d d  
pi o glit a z o n e  a s  o utli n e d f or  Gr a d e  2. I n s uli n  m a y  b e  u s e d f or  1 -2  d a y s 
u ntil  h y p er gl y c e mi a r e s ol v e s,  h o w e v er t hi s  m a y  n ot  b e  n e c e s s ar y i n t h e 
m aj orit y   of   B Y L 7 1 9 -i n d u c e d   h y p er gl y c e mi a   gi v e n  t h e   s h ort   h alf-lif e   of  
B Y L 7 1 9.  
 
M o nit or  F P G  a s  cli ni c all y i n di c at e d  a n d  at l e a st t wi c e  w e e kl y  u ntil  F P G 
r e s ol v e s t o  ≤  Gr a d e  1. 
 
•   
If  F P G r e s ol v e s t o  ≤  Gr a d e 1  wit hi n  3-5  d a y s,  w hil e  off  st u d y 
tr e at m e nt  a n d  o n  m etf or mi n, r e-st art  B Y L 7 1 9  a n d r e d u c e  1  d o s e 
l e v el,  c o nti n u e  wit h  a nti-di a b eti c tr e at m e nt  a n d  c h e c k  F P G  at l e a st 
w e e kl y f or  8  w e e k s, t h e n  c o nti n u e  c h e c ki n g  at l e a st  e v er y  2  w e e k s , 
al ert tr e ati n g  p h y si ci a n if  F P G > 2 5 0 m g/ dl  
•   
If  F P G  d o e s  n ot r e s ol v e t o  Gr a d e 1  wit hi n  3-5  d a y s  w hil e  off  st u d y 
tr e at m e nt  a n d  o n  m etf or mi n,  c o n s ult  a  di a b et ol o gi st f or 
m a n a g e m e nt  of  di a b et e s i s  str o n gl y r e c o m m e n d e d. If  F P G  d o e s 
n ot r e s ol v e t o  ≤  Gr a d e  1  wit hi n  2 1  d a y s  aft er i n stit uti o n  of 
a p pr o pri at e  a nti -di a b eti c tr e at m e nt i n  c o o p er ati o n  wit h  di a b et ol o gi st 
a n d  e x cl u si o n  of  c o nf o u n di n g f a ct or s  e. g.  uri n ar y tr a ct i nf e cti o n, 
p er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  B Y L 7 1 9  tr e at m e nt 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 4 1
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  B Y L 7 1 9  
W or st t o xi cit y 
C T C A E  gr a d e ( v al u e)  
D uri n g  a  c y cl e  of t h er a p y  
Gr a d e  4 ( >  5 0 0  m g/ d L) [ ≥  2 7. 8  m m ol/ L]   
O mit  B Y L 7 1 9 ,  c o nfir m f a sti n g  st at u s  of t h e  a s s e s s m e nt. If  n o n-f a sti n g, 
r e-c h e c k  wit hi n  2 4  h o ur s.  
E x cl u d e  c o nf o u n di n g f a ct or s li k e  e. g.  uri n ar y tr a ct i nf e cti o n.  
C o n si d er  c o o p er ati o n  wit h  di a b et ol o gi st, i niti at e  or i nt e n sif y  m e di c ati o n 
wit h  a p pr o pri at e  a nti -di a b eti c tr e at m e nt ( s e e  Gr a d e  3), r e -c h e c k  wit hi n 
2 4  h o ur s.  
•   
If  gr a d e i m pr o v e s t h e n f oll o w  s p e cifi c  gr a d e r e c o m m e n d ati o n s 
•   
If  F P G i s  c o nfir m e d  at  Gr a d e  4  a n d  c o nf o u n di n g f a ct or s  c o ul d  b e 
e x cl u d e d,  p er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  B Y L 7 1 9  
A  di a b et ol o gi st  c o n s ult ati o n  s h o ul d  al w a y s  b e  c o n si d er e d.  
F or  all  gr a d e s : i n str u ct  p ati e nt t o f oll o w  di et ar y  g ui d eli n e s  a c c or di n g t o l o c al  a n d/ or i n stit uti o n al  st a n d ar d s f or 
m a n a g e m e nt  of  di a b et e s  m ellit u s ( s u c h  a s t h o s e  pr o vi d e d  b y t h e  A m eri c a n  Di a b et e s  A s s o ci ati o n)  d uri n g t h e 
st u d y,  e. g. . s m all fr e q u e nt  m e al s, l o w  c ar b o h y dr at e  c o nt e nt,  hi g h fi b er,  b al a n ci n g  c ar b o h y dr at e s  o v er t h e  c o ur s e 
of t h e  d a y; t hr e e  s m all  m e al s  a n d  2  s m all  s n a c k s r at h er t h a n  o n e l ar g e  m e al  
*s p e cifi c r e c o m m e n d ati o n s  pl e a s e  s e e  S e cti o n  1 4. 3. 1 . 
C ar di a c  
C ar di a c  - pr ol o n g e d  Q T c F i nt er v al  
 
Q T c F  ≥  5 0 1  m s e c ( ≥  Gr a d e  3 )  or  >  6 0 
m s e c  c h a n g e fr o m  b a s eli n e  o n  at l e a st 
t w o  s e p ar at e  E C G s 
Fir st  O c c urr e n c e:  
1.   A s s e s s t h e  q u alit y  of t h e  E C G r e c or di n g  a n d t h e  Q T  v al u e  a n d 
r e p e at if  n e e d e d 
2.   I nt err u pt  st u d y tr e at m e nt 
3.   D et er mi n e t h e  s er u m  el e ctr ol yt e l e v el s (i n  p arti c ul ar  h y p o k al e mi a, 
h y p o m a g n e s e mi a). If  a b n or m al,  c orr e ct  a b n or m aliti e s  b ef or e 
r e s u mi n g  st u d y  dr u g tr e at m e nt. 
4.   R e vi e w  c o n c o mit a nt  m e di c ati o n  u s e f or  ot h er  c a u s e s f or  Q T 
pr ol o n g ati o n (r ef er t o  cr e di bl e m e d s. or g f or  k n o w n  Q T  pr ol o n gi n g 
dr u g s),  a n d  f or dr u g s  wit h  t h e p ot e nti al  t o i n cr e a s e t h e ri s k of  dr u g 
e x p o s ur e r el at e d  Q T  pr ol o n g ati o n  
5.   C h e c k  st u d y  dr u g  d o si n g  s c h e d ul e  a n d tr e at m e nt  c o m pli a n c e  
6.   C o n si d er  c oll e cti n g  a ti m e -m at c h e d  P K  s a m pl e  a n d r e c or d  ti m e 
a n d  d at e  of  l a st  st u d y  dr u g i nt a k e. 
Aft er  c o nfir mi n g  E C G r e a di n g  at  sit e, if  Q T c F  >  5 0 0  m s  or  >  6 0  m s 
c h a n g e fr o m  b a s eli n e  
•   
I nt err u pt  st u d y tr e at m e nt 
•   
R e p e at  E C G  a n d  c o nfir m  E C G  di a g n o si s  b y  a  c ar di ol o gi st  
 
If  Q T c F  c o nfir m e d  >  5 0 0  m s  or  >  6 0  m s  c h a n g e fr o m  b a s eli n e 
•   
C orr e ct  el e ctr ol yt e s,  eli mi n at e  c ul prit  c o n c o mit a nt tr e at m e nt s,  a n d 
i d e ntif y  cli ni c al  c o n diti o n s t h at  c o ul d  p ot e nti all y  pr ol o n g t h e Q T  
•   
C o n s ult  wit h  a  c ar di ol o gi st ( or  q u alifi e d  s p e ci ali st)  
•   
I n cr e a s e  c ar di a c  m o nit ori n g  a s i n di c at e d,  u ntil t h e  Q T c F r et ur n s t o 
≤  4 8 0  m s  or  <  6 0 m s  c h a n g e fr o m  b a s eli n e.  
•   
Aft er r e s ol uti o n t o  ≤  4 8 0  m s / 6 0  m s  c h a n g e fr o m  b a s eli n e,  c o n si d er 
r e-i ntr o d u ci n g tr e at m e nt  at r e d u c e d  d o s e,  a n d i n cr e a s e  E C G 
m o nit ori n g  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 4 2
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  B Y L 7 1 9  
W or st t o xi cit y 
C T C A E  gr a d e ( v al u e)  
D uri n g  a  c y cl e  of t h er a p y  
 
•   
If  Q T c F r e m ai n s  ≤  5 0 0  m s/ 6 0  m s  c h a n g e fr o m  b a s eli n e  aft er  d o s e 
r e d u cti o n,  c o nti n u e  pl a n n e d  E C G  m o nit ori n g  d uri n g  s u b s e q u e nt 
tr e at m e nt 
If  Q T c F r e c ur s  >  5 0 0  m s/ 6 0  m s  c h a n g e fr o m  b a s eli n e  aft er  d o s e 
r e d u cti o n,  di s c o nti n u e  p ati e nt fr o m  B Y L 7 1 9. 
C ar di a c  - L eft  V e ntri c ul ar  S y st oli c  D y sf u n cti o n  
A s y m pt o m ati c,  
r e sti n g  ej e cti o n fr a cti o n  4 0-5 0 %; 
or  1 0 -2 0 %  dr o p fr o m  b a s eli n e  
•   
M ai nt ai n  d o s e l e v el,  a n d  c o nti n u e  B Y L 7 1 9  wit h  c a uti o n  
•   
R e p e at  L V E F  wit hi n  4  w e e k s  or  a s  cli ni c all y  a p pr o pri at e  
S y m pt o m ati c,  
r e s p o n si v e t o i nt er v e nti o n, 
ej e cti o n fr a cti o n  2 0 -3 9 %  
or  >  2 0 %  dr o p fr o m  b a s eli n e  
•   
O mit  B Y L 7 1 9  u ntil r e s ol v e d* ( a s  d efi n e d  b el o w), t h e n    1  d o s e 
l e v el 
•   
L V E F  m e a s ur e m e nt t o  b e r e p e at e d, if  n ot r e s ol v e d*  wit hi n  2 8  d a y s 
p er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  B Y L 7 1 9  tr e at m e nt 
R efr a ct or y  or  p o orl y  c o ntr oll e d, 
ej e cti o n fr a cti o n  <  2 0 %  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  B Y L 7 1 9  
*t h e  e v e nt i s  c o n si d er e d r e s ol v e d  w h e n t h e  p ati e nt i s  a s y m pt o m ati c,  h a s  a r e sti n g  ej e cti o n fr a cti o n  ≥  4 0 %  a n d  
≤ 2 0 %  d e cr e a s e fr o m  b a s eli n e.  
C ar di a c  g e n er al  
Gr a d e  1  or  2  
M ai nt ai n  d o s e l e v el  
Gr a d e  3  
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  ↓  1  d o s e l e v el  
Gr a d e  4  
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  
N er v o u s  s y st e m  di s or d er s  
≥  1  C T C A E  gr a d e l e v el i n cr e a s e  of 
n e ur ot o xi cit y  
O mit  d o s e  u ntil r e s ol v e d t o  ≤  gr a d e  2, t h e n  ↓  1  d o s e l e v el  
≥  Gr a d e  3  n e ur ot o xi cit 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  
G a str oi nt e sti n al  
P a n cr e atiti s  
Gr a d e  2 ( e n z y m e  el e v ati o n  or 
r a di ol o gi c fi n di n g  o nl y) 
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 s u m e tr e at m e nt  at  ↓  1 
d o s e l e v el. If t o xi cit y r e c ur s,  p er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m 
B Y L 7 1 9  
Gr a d e  ≥  3  
•   F or  p ati e nt s  d eri vi n g  cli ni c al  b e n efit 
u p o n i n v e sti g at or’ s  j u d g e m e nt: 
 
•   F or  ot h er  p ati e nt s:  
•   
O mit  d o s e  u ntil  c o m pl et e r e s ol uti o n  of  s y m pt o m s  a n d li p a s e 
r e s ol v e d t o  Gr a d e  ≤  1, t h e n r e s u m e tr e at m e nt  at ↓  1  d o s e l e v el. 
O nl y  1  d o s e r e d u cti o n i s  all o w e d.  
•   
If r e c o v er y t o  ≤  Gr a d e  1 i s  gr e at er t h a n  2 8  d a y s, t h e  p ati e nt 
m u st  b e  di s c o nti n u e d fr o m t h e  st u d y.  
•   
If t o xi cit y r e o c c ur s,  p er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m 
B Y L 7 1 9  
 
•   
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  B Y L 7 1 9  
Di arr h e a ( s e e  al s o S e cti o n  1 4. 3. 1 ) 
Gr a d e  1  
M ai nt ai n  d o s e l e v el  
Gr a d e  2  
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 -st art  at t h e  c urr e nt  d o s e.  
Gr a d e  ≥  3  
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  ↓  1  d o s e l e v el  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 4 3
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  B Y L 7 1 9  
W or st t o xi cit y 
C T C A E  gr a d e ( v al u e)  
D uri n g  a  c y cl e  of t h er a p y  
Vi s u al  s y m pt o m s  or  si g n s  
≥  Gr a d e  3  o c ul ar/ vi si o n  s y m pt o m s 
i nt erf eri n g  wit h  A D L ( A cti viti e s  of  d ail y 
li vi n g)  or r e q uiri n g  m e di c al i nt er v e nti 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  st u d y  
St o m atiti s/ Or al  m u c o siti s  ( s e e  al s o S e cti o n  1 4. 3. 1 ) 
Gr a d e  1/ T ol er a bl e  Gr a d e  2  
M ai nt ai n  d o s e l e v el.  
N o n -al c o h oli c  or  s alt  w at er  m o ut h  w a s h.  
I nt ol er a bl e  Gr a d e  2  or  Gr a d e  3  
Fir st  o c c urr e n c e:  h ol d  u ntil  ≤  Gr a d e  1  a n d    1  d o s e l e v el (if  st o m atiti s 
i s r e a dil y  m a n a g e a bl e  wit h  o pti m al  m a n a g e m e nt, r e-i ntr o d u cti o n  at t h e 
s a m e l e v el  mi g ht  b e  c o n si d er e d  at t h e  di s cr eti o n  of t h e i n v e sti g at or).  
S e c o n d  o c c urr e n c e:  h ol d  u ntil  ≤  Gr a d e  1  a n d    1  d o s e l e v el.  
Gr a d e  4  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  B Y L 7 1 9.  
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  
C o n s ult ati o n  wit h  a  d er m at ol o gi st i s  hi g hl y r e c o m m e n d e d f or  b ett er  a s s e s s m e nt  a n d  m a n a g e m e nt  of  B Y L 7 1 9 - 
i n d u c e d  s ki n t o xi cit y. ( s e e  al s o S e cti o n 1 4. 3. 1 ) 
P h ot o s e n siti vit y  
Gr a d e  1 ( < 1 0 %  B S A  wit h  a cti v e  s ki n 
t o xi cit y*) 
M ai nt ai n  d o s e l e v el  
•   
I niti at e t o pi c al  c orti c o st er oi d s  3-4  x  d ail y,  pr ef err e d  c o m p o u n d s t o 
u s e  ar e  Tri a m ci n ol o n e,  B et a m et h a s o n e  a s l o n g  a s  s ki n t o xi cit y i s 
a cti v e,  d uri n g  m a xi m u m  2 8  d a y s  
 
F or  p ati e nt s  wit h  s y m pt o m s li k e  b ur ni n g  a n d/ or  pr urit u s  a d d  n o n - 
s e d ati n g  a nti -hi st a mi n e,  c o n si d er  a d di n g  a  s e d ati n g  a nti -hi st a mi n e  at 
ni g ht  
If  a cti v e r a s h i s  n ot r e s ol v e d  wit hi n  2 8  d a y s  of  a p pr o pri at e tr e at m e nt, 
c o n si d er  a d di n g l o w  d o s e  s y st e mi c  c orti c o st er oi d ( 2 0 -4 0  m g/ d)  
Gr a d e  2 ( 1 0 -3 0 %  B S A  wit h  a cti v e  s ki n 
t o xi cit y*) 
M ai nt ai n  d o s e l e v el . 
•   
I niti at e t o pi c al  c orti c o st er oi d s  3-4 x  d ail y,  pr ef err e d  c o m p o u n d s t o 
u s e  ar e  Tri a m ci n ol o n e  or  B et a m et h a s o n e  a s l o n g  a s  s ki n t o xi cit y  i s 
a cti v e,  d uri n g  m a x.  2 8  d a y s  
•   
C o n si d er  a d di n g  s y st e mi c  c orti c o st er oi d s  2 0 -4 0 m g/ d  
If r a s h r e s ol v e s t o  ≤ G 1  wit hi n  1 0  d a y s  s y st e mi c  c orti c o st er oi d  m a y 
b e  di s c o nti n u e d  
 
F or  p ati e nt s  wit h  s y m pt o m s li k e  b ur ni n g,  sti n gi n g  a n d/ or  pr urit u s  a d d 
n o n -s e d ati n g  a nti -hi st a mi n e,  c o n si d er  a d di n g  a  s e d ati n g  a nti -hi st a mi n e 
at  ni g ht  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 4 4
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  B Y L 7 1 9  
W or st t o xi cit y 
C T C A E  gr a d e ( v al u e)  
D uri n g  a  c y cl e  of t h er a p y  
Gr a d e  ≥  3 (  >  3 0 %  B S A  wit h  a cti v e  s ki n 
t o xi cit y*) 
O mit  B Y L 7 1 9  d o s e  u ntil r a s h / s ki n t o xi cit y i s  n o l o n g er  a cti v e  b ut f a di n g 
( G 1), 
 
•   
I niti at e t o pi c al  c orti c o st er oi d s  3-4 x  d ail y,  pr ef err e d  c o m p o u n d s 
t o  u s e  ar e  Tri a m ci n ol o n e  or  B et a m et h a s o n e f or  at l e a st  2 8 
d a y s  
•   
A d d  s y st e mi c  c orti c o st er oi d s   2 0 -4 0 m g/ d  
If r a s h r e s ol v e s t o  ≤  G 1  wit hi n  1 0  d a y s  s y st e mi c  c orti c o st er oi d  m a y 
b e  di s c o nti n u e d  
F or  p ati e nt s  wit h  s y m pt o m s li k e  b ur ni n g,  sti n gi n g  a n d/ or  pr urit u s  a d d 
n o n -s e d ati n g  a nti -hi st a mi n e  d uri n g  d a y ti m e,  c o n si d er  a d di n g  a 
s e d ati n g  a nti -hi st a mi n e  at  ni g ht  
R e -st art  B Y L 7 1 9  d o s e  o n c e r a s h / s ki n t o xi cit y i s  n o l o n g er  a cti v e  b ut 
f a di n g ( G 1): 
•   
at  s a m e  d o s e i n  c a s e  of fir st  o c c urr e n c e,  at r e d u c e d  d o s e l e v el i n 
c a s e  of  s e c o n d  o c c urr e n c e  
•   
If r a s h/ s ki n t o xi cit y  still  a cti v e i n  u p t o  1 0 %  B S A  aft er  m or e t h a n 
1 4  d a y s,  c o nti n u e  or al  c orti c o st er oi d f or  at l e a st  4 8  h o ur s  u p o n r e - 
c h all e n g e  wit h  B Y L 7 1 9; if r a s h  a n d/ or  pr urit u s  d o  n ot r e o c c ur 
wit hi n  4 8  h o ur s  aft er r e -c h all e n g e  wit h  B Y L 7 1 9,  s y st e mi c 
c orti c o st er oi d  m a y  b e  di s c o nti n u e d  
F or  p ati e nt s  wit h  s y m pt o m s li k e  b ur ni n g,  sti n gi n g  a n d/ or  pr urit u s 
a nti hi st a mi n e r e gi m e n  s h o ul d  b e  c o nti n u e d f or  a  mi ni m u m  of  2 8  d a y s 
af t er r e-c h all e n g e  wit h  B Y L 7 1 9.  
Gr a d e  4  
( a n y  %  B S A  a s s o ci at e d  wit h  e xt e n si v e 
s u p eri nf e cti o n,  wit h I V  a nti bi oti c s 
i n di c at e d; lif e-t hr e at e ni n g 
c o n s e q u e n c e s)  
•   
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  B Y L 7 1 9  a n d  c o n si d er  a 
d er m at ol o g y  c o n s ult.  
•   
Tr e at m e nt  of r a s h  s h o ul d f oll o w  g ui d eli n e s f or  Gr a d e  3  a b o v e  wit h 
t h e  e x c e pti o n  of r e c h all e n g e  a n d  wit h  a n y  a d diti o n al  m e a s ur e s 
n e e d e d.  
 
*“ A cti v e”  s ki n t o xi citi e s: If t h er e  ar e  n o  n e w l e si o n s  or  n e w  ar e a s  of i n v ol v e m e nt  d e v el o pi n g,  a n d if l e si o n 
a p p e ar a n c e i s  c h a n gi n g  c ol or fr o m r e d t o  p al e  or li g ht  br o w n, it i s li k el y t h e  s ki n t o xi cit y  h a s  b e g u n t o f a d e  a n d i s 
n ot t o  b e  c o n si d er e d “ a cti v e”  a n y l o n g er.  Tr e at m e nt r e d u cti o n  c a n  b e  c o n si d er e d f or t h e s e  ar e a s.  T h e  a p p e ar a n c e 
of  s ki n t o xi cit y  m a y f a d e  sl o wl y,  o v er  1 0  d a y s  or  m or e  b ut  n ot r e q uiri n g  o n g oi n g t h er a p y.  
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  
M ai nt ai n  d o s e l e v el  
Gr a d e  3  
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,  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,  ↓  1  d o s e  l e v el 
Ot h er  a d v er s e  e v e nt s  
Gr a d e  1  or  2  
M ai nt ai n  d o s e l e v el  
Gr a d e  3  
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  ↓  1  d o s e l e v el  
Gr a d e  4  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  B Y L 7 1 9  
O mit  d o s e f or  ≥  gr a d e  3  v o miti n g  or  gr a d e  3  n a u s e a  o nl y if t h e  v o miti n g 
or  n a u s e a  c a n n ot  b e  c o ntr oll e d  wit h  o pti m al  a nti e m eti c ( a s  p er l o c al  
pr a cti c e)  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 4 5
0  Pr ot o c ol  N o. 
 
 
 
 
T a bl e  1 4 - 7  
Crit eri a f or i nt err u pti o n  a n d r e -i niti ati o n  of I N C 2 8 0 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or I N C 2 8 0  
W or st t o xi cit y 
C T C A E  Gr a d e  ( v al u e) 
D uri n g  a  c y cl e  of t h er a p y  
N o t o xi cit y  
M ai nt ai n  d o s e l e v el  
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 (  L L N  - 1 5 0 0/ m m 3 or  L L N  - 1. 5 
x 1 0 9 / L) 
M ai nt ai n  d o s e l e v el  
Gr a d e  2 ( <  1 5 0 0  - 1 0 0 0/ m m 3 or  < 1. 5  - 
1. 0  x 1 0 9/ L) 
M ai nt ai n  d o s e l e v el  
Gr a d e  3 ( <  1 0 0 0  - 5 0 0/ m m 3 or  <  1. 0  - 
0. 5  x 1 0 9/ L) 
Di s c o nti n u e I N C 2 8 0:  
●   If  el e v ati o n l a st s f or  ≤  7  d a y s:  R e s u m e tr e at m e nt  1  s a m e  d o s e l e v el 
●   If  el e v ati o n l a st s f or  > 7  d a y s:  R e s u m e tr e at m e nt  at   1  d o s e  l e v el 
Gr a d e  4 ( <  5 0 0/ m m 3 or  <  0. 5  x 1 0 9/ L)  
Di s c o nti n u e I N C 2 8 0  
F e bril e  n e utr o p e ni a ( A N C  <  1. 0  x  1 0 9/ L 
or  1 0 0 0/ m m 3 a n d  a  si n gl e t e m p er at ur e 
of  > 3 8. 3° C ( 1 0 1 ° F)  or  a  s u st ai n e d 
t e m p er at ur e  of  ≥ 3 8  ° C ( 1 0 0. 4  °  F) f or 
m or e t h a n  o n e  h o ur.)  
Di s c o nti n u e I N C 2 8 0:  
●   If  ≤  7  d a y s i n  d ur ati o n:  R e s u m e tr e at m e nt  at   1  d o s e  l e v el 
●   If  >  7  d a y s i n  d ur ati o n:  Di s c o nti n u e I N C 2 8 0 
T hr o m b o c yt o p e ni a  
Gr a d e  1  or  2 ( <  L L N  –  5 0  x 1 0 9/ L) 
Gr a d e  3 ( < 5 0  –  2 5  x 1 0 9 / L) 
 
 
Gr a d e  4 ( <  2 5  x 1 0 9 / L) 
M ai nt ai n  d o s e l e v el  
Di s c o nti n u e I N C 2 8 0  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  ≤ 7  d a y s i n  d ur ati o n:  R e s u m e tr e at m e nt  at  s a m e  d o s e l e v el 
●   If  >  7  d a y s i n  d ur ati o n:  R e s u m e tr e at m e nt  at   1  d o s e l e v el 
Di s c o nti n u e  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    1 
d o s e l e v el  
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)  
M ai nt ai n  d o s e l e v el  
Gr a d e  2 ( >  1. 5  - 3  x  U L N)  
Di s c o nti n u e I N C 2 8 0  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 
r e s u m e tr e at m e nt  at t h e  s a m e  d o s e l e v el.  P ati e nt s  will  b e i n str u ct e d t o 
i n cr e a s e t h eir fl ui d i nt a k e  u ntil r e s ol uti o n t o  ≤  Gr a d e  1  or  b a s eli n e. 
Gr a d e  3  or  4 ( ≥  3  x  U L N)  
Di s c o nti n u e I N C 2 8 0  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 
r e s u m e tr e at m e nt  at   1  d o s e l e v el.  P ati e nt s  will  b e i n str u ct e d t o 
i n cr e a s e t h eir fl ui d i nt a k e  u ntil r e s ol uti o n t o  ≤  Gr a d e  1  or  b a s eli n e. 
If  Gr a d e  4  e v e nt r e c ur s  at  a n y  p oi nt  d uri n g  p arti ci p ati o n,  di s c o nti n u e 
I N C 2 8 0. 
I n v e sti g ati o n s ( H e p ati c) 
I s ol at e d  T ot al  Bilir u bi na  
Gr a d e  1 ( >  U L N  - 1. 5  x  U L N)  
M ai nt ai n  d o s e l e v el  of I N C 2 8 0  wit h  L F T s*  m o nit or e d  
Gr a d e  2 ( >  1. 5  - 3  x  U L N)  
O mit/ d el a y  d o s e  of I N C 2 8 0  wit h  w e e kl y  m o nit ori n g  of  L F T s*,  or  m or e 
fr e q u e ntl y if  cli ni c al i n di c at e d,  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,  m ai nt ai n  d o s e l e v el  of I N C 2 8 0 
●   If r e s ol v e d i n  >  7  d a y s,  ↓  1  d o s e l e v el  of I N C 2 8 0 
Gr a d e  3 ( >  3  - 1 0  x  U L N)  
O mit/  d el a y  d o s e  of I N C 2 8 0  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,  ↓  1  d o s e l e v el  of I N C 2 8 0 
●   If r e s ol v e d i n  >  7  d a y s,  di s c o nti n u e  p ati e nt fr o m  st u d y  dr u g 
tr e at m e nt.  T h e  p ati e nt  s h o ul d  b e  m o nit or e d  w e e kl y (i n cl u din g  L F T s*) , 
or  m or e fr e q u e ntl y if  cli ni c all y i n di c at e d,  u ntil t ot al  bilir u bi n  h a v e  
r e s ol v e d t o  b a s eli n e  or  st a bili z ati o n  o v er  4  w e e k s. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 4 6
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or I N C 2 8 0  
W or st t o xi cit y 
C T C A E  Gr a d e  ( v al u e) 
D uri n g  a  c y cl e  of t h er a p y  
Gr a d e  4 ( >  1 0  x  U L N)  
Di s c o nti n u e  p ati e nt fr o m  st u d y  dr u g tr e at m e nt.  T h e  p ati e nt  s h o ul d  b e 
m o nit or e d  w e e kl y (i n cl u di n g  L F T s*),  or  m or e fr e q u e ntl y if  cli ni c all y 
i n di c at e d,  u ntil t ot al  bilir u bi n  h a v e r e s ol v e d t o  b a s eli n e  or  st a bili z ati o n 
o v er  4  w e e k s.  
I s ol at e d  A S T  or  A L T 
Gr a d e  1  or  2 ( >  U L N  - 5  x  U L N)   
M ai nt ai n  d o s e l e v el  of I N C 2 8 0  wit h  L F T s*  m o nit or e d  
Gr a d e  3 ( >  5  - 2 0  x  U L N)  
O mit/ d el a y  d o s e  of I N C 2 8 0  u ntil r e s ol v e d t o  ≤  gr a d e  1  or  ≤  gr a d e  2 if 
gr a d e  2  el e v ati o n  at  b a s eli n e, t h e n:  
●   If  el e v ati o n i n  ≤  7  d a y s:  R e s u m e tr e at m e nt  s a m e  d o s e l e v el 
●   If  el e v ati o n s i n  > 7  d a y s:  R e s u m e tr e at m e nt  at   1  d o s e  l e v el 
Gr a d e  4 ( > 2 0  x  U L 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.  
C o m bi n e d c el e v ati o n s  of  A S T  or  A L T  a n d t ot al  bilir u bi n  
F or  p ati e nt s  wit h  n or m al  b a s eli n e  A L T 
a n d  A S T  a n d t ot al  bilir u bi n  v al u e:  
A S T  or  A L T  > 3. 0 x U L N  c o m bi n e d  wit h 
t ot al  bilir u bi n  > 2. 0  x  U L N  wit h o ut 
e vi d e n c e  of  c h ol e st a si s d  
O R  
F or  p ati e nt s  wit h  el e v at e d  b a s eli n e  A S T 
or  A L T  or t ot al  bilir u bi n  v al u e  
[ A S T  or  A L T > 2 x  b a s eli n e  A N D  >  3. 0 
x U L N]  O R [ A S T  or  A L T  >  8. 0  x U L N],  
c o m bi n e d  wit h [t ot al  bilir u bi n  > 2 x  
b a s eli n e  A N D  > 2. 0  x U L N  
Di s c o nti n u e  st u d y tr e at m e nt  p er m a n e ntl y  
R e p e at  L F T s  a s  s o o n  a s  p o s si bl e,  pr ef er a bl y  wit hi n  4 8  h o ur s fr o m 
a w ar e n e s s  of t h e  a b n or m al  r e s ult s, t h e n  wit h  w e e kl y  m o nit ori n g  of 
L F T s*,  or  m or e fr e q u e ntl y if  cli ni c all y i n di c at e d,  u ntil  A S T,  A L T,  or 
bilir u bi n  h a v e r e s ol v e d t o  b a s eli n e  or  st a bili z ati o n  o v er  4  w e e k s.  
* L F T s i n cl u d e  al b u mi n,  A L T,  A S T,  G G T, t ot al  bilir u bi n (fr a cti o n at e d [ dir e ct  a n d i n dir e ct] if t ot al  bilir u bi n  >  2. 0  x 
U L N)  a n d  A L P (fr a cti o n at e d [ q u a ntifi c ati o n  of i s of or m s], if  al k ali n e  p h o s p h at a s e  >  2. 0  x  U L N.  
I n v e sti g ati o n( m et a b oli c) 
A m yl a s e  or  Li p a s e I n cr e a s e d b  
A s y m pt o m ati c  Gr a d e  1  or  2 ( > U L N  -2. 0 
x  U L N)  
M ai nt ai n  d o s e l e v el  of I N C 2 8 0  
A s y m pt o m ati c  Gr a d e  3 ( >  2. 0  - 5. 0  x 
U L N)  
O mit  d o s e  u ntil r e s ol v e d t o  Gr a d e  ≤  2, 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 ↓  1  d o s e l e v el 
A s y m pt o m ati c  Gr a d e  4 ( > 5. 0  x  U L 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  
S y m pt o m ati c  el e v ati o n s  of  a n y  gr a d e   
Di s c o nti n u e  p ati e nt fr o m  st u d y  dr u g tr e at m e nt  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 4 7
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or I N C 2 8 0  
W or st t o xi cit y 
C T C A E  Gr a d e  ( v al u e) 
D uri n g  a  c y cl e  of t h er a p y  
a If t ot al  bilir u bi n  >  3. 0  x  U L N i s  d u e t o t h e i n dir e ct ( n o n-c o nj u g at e d)  c o m p o n e nt  o nl y,  a n d  h e m ol y si s  a s t h e 
eti ol o g y  h a s  b e e n r ul e d  o ut  a s  p er i n stit uti o n al  g ui d eli n e s ( e. g. r e vi e w  of  p eri p h er al  bl o o d  s m e ar  a n d  h a pt o gl o bi n 
d et er mi n ati o n), t h e n  ↓  1  d o s e l e v el  of I N C 2 8 0,  a n d  c o nti n u e tr e at m e nt  at t h e  di s cr eti o n  of t h e I n v e sti g at or  
b A  C T  s c a n  or  ot h er i m a gi n g  st u d y t o  a s s e s s t h e  p a n cr e a s, li v er,  a n d  g all bl a d d er  m u st  b e  p erf or m e d  wit hi n  1 
w e e k  of t h e fir st  o c c urr e n c e  of  a n y  ≥  Gr a d e  3  of  a m yl a s e  or li p a s e.  
c “ C o m bi n e d”  d efi n e d  a s: t ot al  bilir u bi n i n cr e a s e t o t h e  d efi n e d t hr e s h ol d  c o n c urr e ntl y  wit h  A L T/ A S T i n cr e a s e t o 
t h e  d efi n e d t hr e s h ol d 
If  c o m bi n e d  el e v ati o n s  of  A S T  or  A L T  a n d t ot al  bilir u bi n  d o  n ot  m e et t h e  d efi n e d t hr e s h ol d s,  pl e a s e f oll o w t h e 
i n str u cti o n s f or i s ol at e d  el e v ati o n  of t ot al  bilir u bi n  a n d i s ol at e d  el e v ati o n  of  A S T/ A L T,  a n d t a k e  a  c o n s er v ati v e 
a cti o n  b a s e d  o n t h e  d e gr e e  of t h e  el e v ati o n s ( e. g.  di s c o nti n u e tr e at m e nt  at t h e  sit u ati o n  w h e n  o mit  d o s e i s 
n e e d e d f or  o n e  p ar a m et er  a n d  di s c o nti n u e tr e at m e nt i s r e q uir e d f or  a n ot h er  p ar a m et er).  Aft er  all  el e v ati o n s 
r e s ol v e t o t h e  d efi n e d t hr e s h ol d s t h at  all o w tr e at m e nt r e-i niti ati o n, r e-st art t h e tr e at m e nt  eit h er  at t h e  s a m e  d o s e  or 
at  o n e  d o s e l o w er if  m e eti n g  a  crit eri o n f or  d o s e  r e d u cti o n 
d “ C h ol e st a si s”  d efi n e d  a s:  A L P  el e v ati o n ( > 2 x U L N  a n d  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  
N ot e :  T h e  R  v al u e i s  c al c ul at e d  b y  di vi di n g t h e  A L T  b y t h e  A L P,  u si n g  m ulti pl e s  of t h e  U L N f or  b ot h  v al u e s. It 
d e n ot e s  w h et h er t h e r el ati v e  p att er n  of  A L T  a n d/ or  A L P  el e v ati o n  i s  d u e t o  c h ol e st ati c ( R ≤ 2),  h e p at o c ell ul ar ( R ≥ 5), 
or  mi x e d ( R > 2  a n d  < 5) li v er i nj ur y  
N e ur ol o gi c  
A n y  N e ur ol o gi c al  T o xi cit y  
Gr a d e  2 ( >  1. 5  - 3  x  U L N)  
Di s c o nti n u e I N C 2 8 0.  
N e ur ol o gi c al  a s s e s s m e nt s  m u st  b e r e p e at e d  at l e a st t wi c e  a  w e e k  u ntil 
r e s ol uti o n t o  <  gr a d e  1.  U n s c h e d ul e d  M RI  a n d  g a d oli ni u m  e n h a n c e d 
T 1 i m a gi n g  m a y  al s o  b e  c o n d u ct e d t o  e v al u at e  p ati e nt s f or 
i ntr a m y eli ni c  e d e m a li k e l e si o n s,  br ai n  m et a st a s e s  a n d  ot h er 
u n a nti ci p at e d  C N S  o c c urr e n c e s.  A n  E E G  m a y  b e  p erf or m e d t o  m o nit or  
f or  p h y si ol o gi c al  c h a n g e s i n  br ai n  a cti vit y. 
C ar di a c  
C ar di a c  g e n er al  
Gr a d e  1  or  2  
M ai nt ai n  d o s e l e v el  
Gr a d e  3  
Di s c o nti n u e I N C 2 8 0  u ntil r e s ol v e d t o  ≤  Gr a d e  1, t h e n    1  d o s e l e v el  
Gr a d e  4  
Di s c o nti n u e I N C 2 8 0  
Ot h er  a d v er s e  e v e nt s  
Gr a d e  1  or  2  
M ai nt ai n  d o s e l e v el  
Gr a d e  3  
Di s c o nti n u e I N C 2 8 0  u ntil r e s ol v e d t o  ≤  Gr a d e  1, t h e n    1  d o s e l e v el  
Gr a d e  4  
Di s c o nti n u e I N C 2 8 0  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 4 8
0  Pr ot o c ol  N o. 
 
 
 
 
T a bl e  1 4 - 8  
Crit eri a f or i nt err u pti o n  a n d r e -i niti ati o n  of L D K 3 7 8  
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  L D K 3 7 8  
W or st t o xi cit y 
C T C A E  Gr a d e  ( v al u e) 
D uri n g  a  c y cl e  of t h er a p y  
N o t o xi cit y  
M ai nt ai n  d o s e l e v el  
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  x  1 0 9/ L) 
Gr a d e  2 ( A N C  <  1. 5  a n d  ≥  1. 0  x  1 0 9 / L) 
Gr a d e  3 ( A N C  <  1. 0  a n d  ≥  0. 5  x  1 0 9 / L) 
M ai nt ai n  d o s e l e v el  
 
Gr a d e  4 ( A N C  <  0. 5  x  1 0 9/ L) 
O mit  d o s e  u ntil r e s ol v e d t o  ≤  Gr a d e  2, 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   1  d o s e  l e v el 
F e bril e  n e utr o p e ni a  
( A N C  <  1. 0  x  1 09/ L,  wit h  a  si n gl e 
t e m p er at ur e  of  ≥  3 8. 3  ° C  or  a  s u st ai n e d 
t e m p er at ur e  of  ≥  3 8  ° C f or  m or e t h a n  o n e 
h o ur )  
O mit  d o s e  u ntil  cli ni c all y r e s ol v e d  a n d  n e utr o p e ni a  ≤  Gr a d e  2, 
t h e n   1  d o s e l e v el  
T hr o m b o c yt o p e ni a  
Gr a d e  1 ( P L T  <  L L N  - 7 5  x  1 0 9/ L) 
Gr a d e  2 ( P L T  <  7 5  a n d  ≥  5 0  x  1 0 9/ L) 
M ai nt ai n  d o s e l e v el  
Gr a d e  3 ( P L T  <  5 0  a n d  ≥  2 5  x  1 0 9/ L) 
O mit  d o s e  u ntil r e s ol v e d t o  ≤  Gr a d e  2, 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   1  d o s e  l e v el 
Gr a d e  4 ( P L T  <  2 5  x  1 0 9/ L) 
O mit  d o s e  u ntil r e s ol v e d t o  ≤  Gr a d e  2, t h e n    1  d o s e l e v el  
I n v e sti g ati o n s ( H e p ati c) 
Al k ali n e  p h o s p h at a s e  a n d/ or  G G T  
I s ol at e d  el e v ati o n s  of  a n y  gr a d e 
M ai nt ai n  d o s e l e v el  
T ot al  Bilir u bi n*  
(f or  p ati e nt s  wit h  Gil b ert  S y n dr o m e t h e s e  d o s e  m o difi c ati o n s  a p pl y t o  c h a n g e s i n  dir e ct [ c o nj u g at e d]  bilir u bi n  o nl y) 
Gr a d e  1 ( >  U L N  a n d  ≤  1. 5  x  U L N)  
M ai nt ai n  d o s e l e v el  wit h  L F T s**  m o nit or e d  a s  p er  pr ot o c ol  
Gr a d e  2 ( >  1. 5  a n d  ≤  3. 0  x  U L N)  wit h  A L T  or 
A S T  ≤  3. 0  x  U L 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   1  d o s e  l e v el 
Gr a d e  3 ( >  3. 0  a n d  ≤  1 0. 0  x  U L N)  wit h  A L T 
or  A S T  ≤  3. 0  x  U L 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,   1  d o s e l e v el  
●   If r e s ol v e d i n >  7  d a y s, t h e n  di s c o nti n u e  p ati e nt fr o m  L D K 3 7 8. 
T h e  p ati e nt  s h o ul d  b e  m o nit or e d  L F T s ** p er  pr ot o c ol  s e cti o n 
1 4. 3. 3,  or  m or e fr e q u e ntl y if  cli ni c all y i n di c at e d,  u ntil t ot al  bilir u bi n 
h a v e r e s ol v e d t o  b a s eli n e  or  st a bili z ati o n  o v er  4  w e e k s.  
Gr a d e  4 ( >  1 0. 0  x  U L N)  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  L D K 3 7 8.  
T h e  p ati e nt  s h o ul d  b e  m o nit or e d  L F T s ** p er  pr ot o c ol  
S e cti o n  1 4. 3. 3 ,  or  m or e fr e q u e ntl y if  cli ni c all y i n di c at e d,  u ntil t ot al 
bilir u bi n  h a v e r e s ol v e d t o  b a s eli n e  or  st a bili z ati o n  o v er  4  w e e k s.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 4 9
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  L D K 3 7 8  
W or st t o xi cit y 
C T C A E  Gr a d e  ( v al u e) 
D uri n g  a  c y cl e  of t h er a p y  
A S T  or  A L T  
Gr a d e  1 ( >  U L N  a n d  ≤  3. 0  x  U L N)  
M ai nt ai n  d o s e l e v el  wit h  L F T s**  m o nit or e d  p er  pr ot o c ol  
Gr a d e  2 ( >  3. 0  a n d  ≤  5. 0  x  U L N)  wit h o ut 
t ot al  bilir u bi n  el e v ati o n t o  >  2. 0  x  U L N 
M ai nt ai n  d o s e l e v el  wit h  L F T s**  m o nit or e d  p er  pr ot o c ol 
S e cti o n  1 4. 3. 3  
 
or  m or e fr e q u e ntl y if  cli ni c all y i n di c at e d,  u ntil r e s ol v e d t o  ≤  3. 0  x 
U L N  
Gr a d e  3 ( >  5. 0  a n d  ≤  2 0. 0  x  U L N)  wit h o ut 
t ot al  bilir u bi n  el e v ati o n t o  >  2. 0  x  U L 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    1  d o s e l e v el  
Gr a d e  4 ( >  2 0. 0  x  U L N)  wit h o ut  bilir u bi n 
el e v ati o n t o  >  2. 0  x  U L 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    1  d o s e l e v el 
M o nit ori n g  L F T s
** p er  pr ot o c ol  S e cti o n  1 4. 3. 3 ,  or  m or e fr e q u e ntl y if 
cli ni c all y i n di c at e d,  u ntil r e s ol v e d t o  b a s eli n e  or  st a bili z ati o n  o v er  4  
w e e k s.  
A S T  or  A L T  a n d  c o n c urr e nt  Bilir u bi n  
A S T  or  A L T  >  3. 0  x  U L N  a n d t ot al  bilir u bi n  >  
2. 0  x  U L N  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  L D K 3 7 8  
P A N C R E A TI C  
A m yl a s e  a n d/ or li p a s e  el e v ati o n s (i n t h e  a b s e n c e  of  cli ni c al  s y m pt o m s)  
Gr a d e  1 ( >  U L N  a n d  ≤ 1. 5  x  U L N)  
M ai nt ai n  d o s e l e v el  
Gr a d e  2 ( > 1. 5  - 2. 0  x  U L N)  
M ai nt ai n  d o s e l e v el  
Gr a d e  3 ( >  2. 0  –  5. 0  x  U L N)  
O mit  d o s e  u ntil r e s ol v e d t o  ≤  Gr a d e  2, t h e n 
If r e s ol v e d i n  ≤  7  d a y s,  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,   1  d o s e l e v el  
Gr a d e  4 ( >  5. 0  x  U L N)  
O mit  d o s e  a n d t h e n  di s c o nti n u e fr o m  st u d y  dr u g tr e at m e nt  
I n v e sti g ati o n s ( R e n al) 
S er u m  cr e ati ni n e  
Gr a d e  1 ( > 1  a n d  ≤ 1. 5  x  b a s eli n e;  > U L N  a n d  
<  1. 5  x  U L N)  
M ai nt ai n  d o s e l e v el  
Gr a d e  2 ( > 1. 5  a n d  ≤ 3. 0  x  b a s eli n e;  ≥  1. 5 
a n d  ≤  3  x  U L 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   1  d o s e  l e v el 
Gr a d e  3 ( > 3. 0  x  b a s eli n e;  >  3. 0  a n d  ≤  6. 0  x 
U L 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    1  d o s e l e v el  
Gr a d e  4 ( >  6. 0  x  U L N)  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  L D K 3 7 8  
G a str oi nt e sti n al  
Di arr h e a  
Gr a d e  1 ( d e s pit e  m a xi m al  a nti -di arr h e al 
m e di c ati o n)  
M ai nt ai n  d o s e l e v el  b ut  a dj u st  a nti -di arr h e a tr e at m e nt  
Gr a d e  2 ( d e s pit e  m a xi m al  a nti -di arr h e al 
m e di c 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  s u s p e n d  d o s e  u ntil r e s ol v e d 
t o  ≤  Gr a d e  1, t h e n  ↓  1  d o s e l e v el 
Gr a d e  3 ( d e s pit e  m a xi m al  a nti -di arr h e al 
m e di c 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  ↓  1  d o s e l e v el  
Gr a d e  4 ( d e s pit e  m a xi m al  a nti -di arr h e al 
m e di c 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  ↓  1  d o s e l e v el  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 5 0
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  L D K 3 7 8  
W or st t o xi cit y 
C T C A E  Gr a d e  ( v al u e) 
D uri n g  a  c y cl e  of t h er a p y  
N a u s e a  
Gr a d e  1  or  2 ( d e s pit e  st a n d ar d  a nti -e m eti c s)   
M ai nt ai n  d o s e l e v el  b ut  a dj u st  a nti -e m eti c tr e at m e nt  
Gr a d e  3 ( d e s pit e  st a n d ar d  a nti -e m eti c s)   
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  ↓  1  d o s e l e v el  
V o miti n g  
Gr a d e  1 ( d e s pit e  st a n d ar d  a nti -e m eti c s)   
M ai nt ai n  d o s e l e v el  b ut  a dj u st  a nti -e m eti c tr e at m e nt  
Gr a d e  2 ( d e s pit e  st a n d ar d  a nti -e m eti c s)  
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  v o miti n g r et ur n s  a s  ≥  Gr a d e  2, t h e n  s u s p e n d  d o s e  u ntil r e s ol v e d 
t o  ≤  Gr a d e  1, t h e n  ↓  1  d o s e l e v el. 
Gr a d e  3 ( d e s pit e  st a n d ar d  a nti -e m eti c s)   
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  ↓  1  d o s e l e v el  
Gr a d e  4 ( d e s pit e  st a n d ar d  a nti -e m eti c s)   
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  ↓  1  d o s e l e v el  
M E T A B O LI C  
A n y  Gr a d e  h y p o p h o s p h at e mi a  
Tr e at m e nt  wit h  p h o s p h at e  s u p pl e m e nt s  a s  cli ni c all y 
i n di c at e d  a n d  m ai nt ai n  d o s e l e v el 
P er si st e nt  h y p er gl y c e mi a ( gl u c o s e  > 2 5 0 
m g/ d L)  d e s pit e  o pti m al  a nti - h y p er gl y c e mi c 
t h er a p y 
O mit  d o s e  u ntil  h y p er gl y c e mi a i s  a d e q u at el y  c o ntr oll e d, t h e n 
r e s u m e  L D K 3 7 8  at  ↓  1  d o s e l e v el 
If  a d e q u at e  h y p er gl y c e mi c  c o ntr ol  c a n n ot  b e  a c hi e v e d  wit h 
o pti m al  m e di c al  m a n a g e m e nt,  p er m a n e ntl y  di s c o nti n u e  p ati e nt 
fr o m  L D K 3 7 8 
F ati g u e/ a st h e ni a  
Gr a d e  1  or  2  
M ai nt ai n  d o s e l e v el  
Gr a d e  3  
●   If  gr a d e  3 f ati g u e r e s ol v e s i n  ≤  7  d a y s,  m ai nt ai n  d o s e l e v el 
●   If  gr a d e  3 f ati g u e l a st s  >  7  d a y s,  o mit  d o s e  u ntil r e s ol v e d t o ≤  
Gr a d e  2  a n d t h e n    d o s e l e v el  
P U L M O N A R Y  
N ot e s:  
●   Wit h h ol d  L D K 3 7 8 f or  a c ut e  o n s et  of  n e w  or  pr o gr e s si v e  u n e x pl ai n e d  p ul m o n ar y  s y m pt o m s,  s u c h  a s  d y s p n e a, 
c o u g h  a n d f e v er  a n d  d uri n g  di a g n o sti c  w or k u p f or  p n e u m o niti s/I L D.  
●   D uri n g  e v al u ati o n  of  p ot e nti al  gr a d e  2,  3,  a n d   4 p n e u m o niti s,  if a n  i nf e cti o u s eti ol o g y  i s c o nfir m e d  (i. e., 
p n e u m o ni a)  a n d  p n e u m o niti s  i s e x cl u d e d,  t h e n c o n si d er  r e s u mi n g L D K 3 7 8  at  c urr e nt  d o s e  l e v el aft er  t h e 
p n e u m o ni a r e s ol v e s.  
P N E U M O NI TI S  
Gr a d e  1  
A s y m pt o m ati c;  cli ni c al  or  di a g n o sti c 
o b s er v ati o n s  o nl y; i nt er v e nti o n  n ot i n di c at e d  
E x cl u d e i nf e cti o u s  eti ol o g y.  O mit  L D K 3 7 8  d o s e  d uri n g  di a g n o sti c 
w or k u p f or  p n e u m o niti s/I L D.  
O mit  L D K 3 7 8  d o s e  u ntil r e s ol v e d, t h e n  ↓  1  d o s e l e v el. 
Di s c o nti n u e  L D K 3 7 8 if  d o e s  n ot r e s ol v e  wit hi n  6  w e e k s.  
If  gr a d e  1  p n e u m o niti s r e c ur s  aft er  d o s e r e d u cti o n,  o mit  L D K 3 7 8 
d o s e  u ntil r e s ol v e d, t h e n  ↓  1  d o s e l e v el (i. e.,  4 5 0  m g  Q D).  
Di s c o nti n u e  L D K 3 7 8 if  d o e s  n ot r e s ol v e  wit hi n  6  w e e k s.  
If  gr a d e  1  p n e u m o niti s r e c ur s  aft er  2 n d  d o s e r e d u cti o n (i. e.,  4 5 0 
m g  Q D), t h e  p ati e nt  m u st  b e  di s c o nti n u e d.  
Gr a d e  2  
S y m pt o m ati c;  m e di c al i nt er v e nti o n i n di c at e d; 
li miti n g i n str u m e nt al  A D L 
E x cl u d e i nf e cti o u s  eti ol o g y.  O mit  L D K 3 7 8  d o s e  d uri n g  di a g n o sti c 
w or k u p f or  p n e u m o niti s/I L D.  
A d mi ni st er  s y m pt o m ati c t h er a p y.  C o n si d er tr e at m e nt  wit h 
c orti c o st er oi d s  a n d/ or  a nti bi oti c s.  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  L D K 3 7 8.  
Gr a d e  3  
S e v er e  s y m pt o m s; l i miti n g  s elf-c ar e  A D L; 
o x y g e n i n di c at e d  
E x cl u d e i nf e cti o u s  eti ol o g y.  O mit  L D K 3 7 8  d o s e  d uri n g  di a g n o sti c 
w or k u p f or  p n e u m o niti s/I L D.  
A d mi ni st er  s y m pt o m ati c t h er a p y.  C o n si d er tr e at m e nt  wit h 
c orti c o st er oi d s  a n d/ or  a nti bi oti c s.  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  L D K 3 7 8.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 5 1
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  L D K 3 7 8  
W or st t o xi cit y 
C T C A E  Gr a d e  ( v al u e) 
D uri n g  a  c y cl e  of t h er a p y  
Gr a d e  4  
Lif e -t hr e at e ni n g r e s pir at or y  c o m pr o mi s e; 
ur g e nt i nt er v e nti o n  
i n di c at e d ( e. g., tr a c h e ot o m y  or i nt u b ati o n) 
E x cl u d e i nf e cti o u s  eti ol o g y.  O mit  L D K 3 7 8  d o s e  d uri n g  di a g n o sti c 
w or k u p f or  p n e u m o niti s/I L D.  
A d mi ni st er  s y m pt o m ati c t h er a p y.  C o n si d er tr e at m e nt  wit h 
c orti c o st er oi d s  a n d/ or  a nti bi oti c s.  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  L D K 3 7 8.  
C A R DI A C  
El e ctr o c ar di o gr a m  Q T  c orr e ct e d ( Q T c) i nt er v al  pr ol o n g e d  
Gr a d e  1 ( Q T c F  4 5 0 -4 8 0   m s) 
Gr a d e  2 ( Q T c F  4 8 1 -5 0 0  m s)  
M ai nt ai n  d o s e l e v el  
Gr a d e  3 ( Q T c F  ≥ 5 0 1  m s  o n  at l e a st t w o 
s e p ar at e  E C G s)  
O mit  d o s e  u ntil  Q T c F i s l e s s t h a n  <  4 8 1 m s, t h e n  ↓  1  d o s e l e v el  
●   A s s e s s t h e  q u alit y  of t h e  E C G r e c or di n g  a n d t h e  Q T  v al u e  a n d 
r e p e at if  n e e d e d 
R e p e at  E C G i n  2 4  h o ur s,  or l e s s,  a s  cli ni c all y i n di c at e d;  c o nti n u e 
m o nit ori n g  a s  cli ni c all y i n di c at e d  u ntil  Q T c F  <  4 8 1  m s  
I n  a d diti o n:-D et er mi n e t h e  s er u m  el e ctr ol yt e l e v el s (i n  p arti c ul ar 
h y p o k al e mi a,  h y p o m a g n e s e mi a). If  a b n or m al,  c orr e ct 
a b n or m aliti e s  b ef or e r e s u mi n g  st u d y  dr u g tr e at m e nt  
●   R e vi e w  c o n c o mit a nt  m e di c ati o n  u s e f or  dr u g s  wit h t h e 
p ot e nti al t o i n cr e a s e t h e ri s k  of  dr u g  e x p o s ur e r el at e d t o  Q T 
pr ol o n g ati o n  
●   C o n si d er  c oll e cti n g  a ti m e -m at c h e d  P K  s a m pl e  a n d r e c or d 
ti m e  a n d  d at e  of l a st  st u d y  dr u g i nt a k e 
Aft er r e s u m pti o n  of  d o si n g:  
●   R e p e at  E C G s  7  d a y s  aft er  d o s e r e s u m pti o n f or  all  p ati e nt s  
w h o  h a d t h er a p y i nt err u pt e d  d u e t o  Q T c F  ≥  5 0 1  m s.  
Gr a d e  4 ( Q T c F  ≥ 5 0 1  or  > 6 0  m s  c h a n g e fr o m 
b a s eli n e  a n d  T or s a d e s  d e  p oi nt e s  or 
p ol y m or p hi c  v e ntri c ul ar t a c h y c ar di a  or  
si g n s/ s y m pt o m s  of  s eri o u s  arr h yt h mi a)  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  L D K 3 7 8  
Br a d y c ar di a  
Gr a d e  1  or  2  
O mit  d o s e  u ntil r e c o v er y t o  a s y m pt o m ati c  br a d y c ar di a  or t o  a 
h e art r at e  ≥ 6 0  b p m  
E v al u at e  c o n c o mit a nt  m e di c ati o n s  k n o w n t o  c a u s e  br a d y c ar di a, 
a n d  a dj u st t h e  d o s e  of  L D K 3 7 8.  
Gr a d e  3  
Gr a d e  4 (i n  p ati e nt s t a ki n g  a  c o n c o mit a nt 
m e di c ati o n  al s o  k n o w n t o  c a u s e  br a d y c ar di a 
or  a  m e di c ati o n  k n o w n t o  c a u s e  
h y p ot e n si o n)  
O mit  d o s e  u ntil r e c o v er y t o  a s y m pt o m ati c  br a d y c ar di a  or t o  a 
h e art r at e  ≥ 6 0  b p m  
If t h e  c o n c o mit a nt  m e di c ati o n  c a n  b e  a dj u st e d  or  di s c o nti n u e d, 
r e s u m e  c eriti ni b  at  ↓  1  d o s e l e v el  wit h fr e q u e nt  m o nit ori n g 
Gr a d e  4 (i n  p ati e nt s  w h o  ar e  n ot t a ki n g  a 
c o n c o mit a nt  m e di c ati o n  al s o  k n o w n t o 
c a u s e  br a d y c ar di a  or  k n o w n t o  c a u s e  
h y p ot e n si o n)  
P er m a n e ntl y  di s c o nti n u e  L D K 3 7 8.  
* If  Gr a d e  3  or  4  h y p er bilir u bi n e mi a i s  d u e t o t h e i n dir e ct ( n o n -c o nj u g at e d)  c o m p o n e nt  o nl y,  a n d  h e m ol y si s  a s t h e 
eti ol o g y  h a s  b e e n r ul e d  o ut  a s  p er i n stit uti o n al  g ui d eli n e s ( e. g., r e vi e w  of  p eri p h er al  bl o o d  s m e ar  a n d  h a pt o gl o bi n 
d et er mi n ati o n), t h e n  ↓  1  d o s e l e v el  a n d  c o nti n u e tr e at m e nt  at t h e  di s cr eti o n  of t h e i n v e sti g at or.  
** L F T s i n cl u d e  al b u mi n,  A L T,  A S T, t ot al  bilir u bi n (fr a cti o n at e d if t ot al  bilir u bi n  >  2. 0  x  U L N),  al k ali n e  p h o s p h at a s e 
a n d  G G T.  
Ot h er  a d v er s e  e v e nt s  
Gr a d e  1  or t ol er a bl e 
Gr a d e  2  
P ati e nt s  ar e  e n c o ur a g e d t o  c o nti n u e  at t h e  c urr e nt  d o s e  of  st u d y tr e at m e nt.  
I nt ol er a bl e  Gr a d e  2  
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  ↓  1  d o s e l e v el  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 5 2
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  L D K 3 7 8  
W or st t o xi cit y 
C T C A E  Gr a d e  ( v al u e) 
D uri n g  a  c y cl e  of t h er a p y  
Gr a d e  ≥  3  
 
•   F or  p ati e nt s 
d eri vi n g  cli ni c al 
b e n efit  a n d  A E i s 
n ot lif e t hr e at e ni n g 
u p o n i n v e sti g at or’ s 
j u d g e m e nt: 
If it i s  n ot  c o n si d er e d  b y t h e i n v e sti g at or t o  b e lif e-t hr e at e ni n g,  st u d y tr e at m e nt  s h o ul d 
b e i nt err u pt e d  u ntil r e s ol uti o n t o  ≤  Gr a d e  1, t h e n  st u d y tr e at m e nt  m a y  c o nti n u e 
f oll o wi n g  a  d o s e r e d u cti o n t o t h e  n e xt  d o s e l e v el. 
•   F or  ot h er  p ati e nt s:  
P er m a n e ntl y  di s c o nti n u e  st u d y tr e at m e nt  
 
T a bl e  1 4 - 9  
Crit eri a f or i nt err u pti o n  a n d r e -i niti ati o n  of M E K 1 6 2  
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  M E K 1 6 2  
W or st t o xi cit y 
C T C A E  Gr a d e  ( v al u e) 
D uri n g  a  c y cl e  of t h er a p y  
N o t o xi cit y  
M ai nt ai n  d o s e l e v el  
E y e  di s or d er  - R eti n al  e v e nt:  T h e  c urr e nt  g ui d a n c e i s  b a s e d  o n  gr a di n g  b y  T a bl e  1 4 -1 0 f or  R eti n al 
D et a c h m e nt.  A n y  di a g n o si s  of r eti n al  e v e nt s  m u st  b e  s u p p ort e d  b y  pr e s e n c e  or  a b s e n c e  of  s y m pt o m s,  or 
vi s u al  a c uit y i m p air m e nt  a n d fi n di n g s i n  O c ul ar  C o h er e n c e  T o m o gr a p h y ( O C T)  
N ot e:  R e s ult s  a n d i m a g e s  of  O c ul ar  C o h er e n c e  T o m o gr a p h y ( O C T)  m u st  b e  m a d e  a v ail a bl e  u p o n r e q u e st.  
Gr a d e  1**  
M ai nt ai n  d o s e l e v el  of  M E K 1 6 2  a n d r e p e at  o p ht h al mi c  m o nit ori n g* i n cl u di n g  vi s u al 
a c uit y  a s s e s s m e nt  a n d  O C T  wit hi n  1 0  d a y s  
●   If  p ati e nt r e m ai n s  a s y m pt o m ati c ( Gr a d e  1)  m ai nt ai n  d o s e l e v el  of  M E K 1 6 2  a n d 
c o nti n u e t h e  s c h e d ul e  of  vi s u al  a s s e s s m e nt s  e st a bli s h e d  p er  pr ot o c ol i n cl u di n g  vi s u al 
a c uit y  a s s e s s m e nt  a n d  O C T  at  e a c h  vi sit. I n  c a s e  O C T fi n di n g s  d e n ot e  d efi niti v e 
w or s e ni n g, tr e at m e nt  s h o ul d  b e i nt err u pt e d  a n d t h e  c a s e  s h o ul d  b e  di s c u s s e d  wit h t h e 
i n v e sti g at or, i n cl u di n g  o p ht h al m ol o gi st  a n d t h e  S p o n s or  pri or to r e s u mi n g  tr e at m e nt. 
●   If  p ati e nt  b e c o m e s  s y m pt o m ati c ( bl urr e d  vi si o n,  p h ot o p si a,  et c)  or  vi s u al  a c uit y 
a s s e s s m e nt  s h o w s  gr a d e  2, f oll o w  Gr a d e  2  d o s e  g ui d eli n e s  b el o w  
Gr a d e  2**  
I nt err u pt  d o s e  of  M E K 1 6 2  a n d r e p e at  o p ht h al mi c  m o nit ori n g* i n cl u di n g  vi s u al  a c uit y 
a s s e s s m e nt  a n d  O C T  wit hi n  1 0  d a y s  
●   If r e s ol v e d t o  b a s eli n e  or  Gr a d e  ≤  1 , r e s u m e  d o s e  of  M E K 1 6 2  at t h e  s a m e  d o s e 
l e v el  a n d  c o nti n u e t h e  s c h e d ul e  of  vi s u al  a s s e s s m e nt s  e st a bli s h e d  p er  pr ot o c ol 
i n cl u di n g  vi s u al  a c uit y  a s s e s s m e nt  a n d  O C T i n  e a c h vi sit.  
●   If  n ot r e s ol v e d t o  b a s eli n e  or  Gr a d e  ≤  1, r e s u m e  d o si n g  of  M E K 1 6 2  at  a r e d u c e d 
d o s e l e v el  a n d  c o nti n u e t h e  s c h e d ul e  of  vi s u al  a s s e s s m e nt s  e st a bli s h e d  p er  pr ot o c ol 
i n cl u di n g  vi s u al  a c uit y  a s s e s s m e nt  a n d  O C T i n  e a c h  vi sit. I n  c a s e  O C T fi n di n g s  d e n ot e 
d efi niti v e  w or s e ni n g, tr e at m e nt  s h o ul d r e m ai n i nt err u pt e d  a n d t h e  c a s e  s h o ul d  b e 
di s c u s s e d  wit h t h e i n v e sti g at or , i n cl u di n g  o p ht h al m ol o gi st  a n d t h e  S p o n s or  pri or t o 
r e s u mi n g tr e at m e nt.  C o nti n u e t h e  s c h e d ul e  of  vi s u al  a s s e s s m e nt s  e st a bli s h e d  p er 
pr ot o c ol i n cl u di n g  vi s u al  a c uit y  a s s e s s m e nt  a n d  O C T i n  e a c h  vi sit.  
Gr a d e  3**  
I nt err u pt  M E K 1 6 2  a n d r e p e at  o p ht h al mi c  m o nit ori n g* i n cl u di n g  vi s u al  a c uit y 
a s s e s s m e nt  a n d  O C T  wit hi n  1 0  d a y s:  
●   If r e s ol v e d t o  b a s eli n e  or  Gr a d e  ≤  2, r e s u m e  M E K 1 6 2  at  a r e d u c e d  d o s e l e v el  a n d 
c o nti n u e t h e  s c h e d ul e  of  vi s u al  a s s e s s m e nt s  e st a bli s h e d  p er  pr ot o c ol i n cl u di n g  vi s u al 
a c uit y  a s s e s s m e nt  a n d  O C T  at  e a c h  vi sit. I n  c a s e  O C T fi n di n g s  d e n ot e  d efi niti v e 
w or s e ni n g, tr e at m e nt  s h o ul d  b e i nt err u pt e d  a n d t h e  c a s e  s h o ul d  b e  di s c u s s e d  wit h t h e 
i n v e sti g at or, i n cl u di n g  o p ht h al m ol o gi st  a n d t h e  S p on s or  pri or t o r e s u mi n g  tr e at m e nt. 
●   If  n ot r e s ol v e d t o  b a s eli n e  or  Gr a d e  ≤  2,  c o nti n u e t h e i nt err u pti o n  a n d r e p e at t h e 
o p ht h al mi c  a s s e s s m e nt  i n cl u di n g vi s u al  a c uit y  a s s e s s m e nt  a n d  O C T  i n 1 0  d a y s.  
 
●   If r e m ai n s  Gr a d e  3,  p er m a n e ntl y  di s c o nti n u e M E K 1 6 2  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 5 3
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  M E K 1 6 2  
W or st t o xi cit y 
C T C A E  Gr a d e  ( v al u e) 
D uri n g  a  c y cl e  of t h er a p y  
Gr a d e  4  
P er m a n e ntl y  di s c o nti n u e  M E K 1 6 2  a n d i m m e di at el y f oll o w  u p  wit h  o p ht h al mi c 
m o nit ori n g*  
N O T E:  A n y  vi s u al  a c uit y i m p air m e nt  at  s cr e e ni n g  s h o ul d  b e  d o c u m e nt e d  a n d  s h o ul d  b e  c o n si d er e d  a s 
b a s eli n e  
N O T E: I n  c a s e t h at t h e  p ati e nt i m pr o v e s  or r e m ai n s  st a bl e i n t er m s  of  s y m pt o m s  a n d  vi s u al  a c uit y 
a s s e s s m e nt  b ut t h e  O C T  d e n ot e s  d efi niti v e  si g n s  of  w or s e ni n g, t h e tr e at m e nt  m u st  b e i nt err u pt e d.  R e - 
i niti ati o n  of tr e at m e nt  will  b e  di s c u s s e d  b et w e e n t h e i n v e sti g at or (i n cl u di n g  o p ht h al m ol o gi st)  a n d t h e 
s p o n s or.  
Ot h er  e y e  di s or d er s  
Gr a d e  1  -  2 
M ai nt ai n  d o s e l e v el  of  M E K 1 6 2  a n d i n cr e a s e fr e q u e n c y  of  o p ht h al mi c  m o nit ori n g* t o  at 
l e a st  e v er y  1 4  d a y s. 
Gr a d e  3  
O mit  d o s e  of  M E K 1 6 2  a n d r ef er  p ati e nt t o  o p ht h al m ol o gi st  wit hi n  o n e  w e e k:  
●   If r e s ol v e d t o  Gr a d e  ≤  1 i n  ≤  2 1  d a y s, t h e n  ↓  1  d o s e l e v el  of M E K 1 6 2  
●   If  n ot r e s ol v e d t o  Gr a d e  ≤  1 i n  ≤  2 1  d a y s, t h e n  di s c o nti n u e  p ati e nt fr o m  st u d y 
tr e at m e nt  a n d r ef er t h e  p ati e nt t o o p ht h al m ol o gi st f or  o p ht h al mi c  m o nit ori n g*
a . 
Gr a d e  4  
O mit  d o s e  of  M E K 1 6 2  a n d  di s c o nti n u e  p ati e nt fr o m  st u d y tr e at m e nt  a n d r ef er t h e 
p ati e nt t o  o p ht h al m ol o gi st f or  o p ht h al mi c  m o nit ori n g* a . 
E y e  di s or d er  –  R V O  
N ot e:  R e s ult s  of  o p ht h al mi c  e x a mi n ati o n s  m u st  b e  m a d e  a v ail a bl e  u p o n r e q u e st.  T hi s i n cl u d e s  
s c a n s/i m a g e s  of fl u or e s c ei n  a n gi o gr a p h y  s h o ul d  a  p ati e nt  b e  a s s e s s e d  u si n g t hi s t e c h ni q u e  
R V O  of  a n y  gr a d e   
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  M E K 1 6 2.  
I n v e sti g ati o n s ( H e p ati c) 
A S T  or  A L T  
Gr a d e  1 ( >  U L N  - 3  x 
U L N)  
M ai nt ai n  d o s e l e v el  
Gr a d e  2 
A S T  or  A L T  
( >  3 - 5. 0  x  U L N  or  3  X  
b a s eli n e  v al u e****) 
wit h o ut  bilir u bi n 
el e v ati o n  >  2. 0  x  U L N  
 
A S T  or  A L T  >  3. 0  - 5. 0  
x  U L N  a n d  bl o o d 
bilir u bi n a  >  2. 0  x  U L N  
O mit  d o s e  u ntil r e s ol v e d t o  Gr a d e  ≤  1 ( or  Gr a d e  ≤  2 i n  c a s e  of li v er  m et a st a si s), t h e n:  
●   If r e s ol v e d i n  ≤  1 4  d a y s, t h e n  m ai nt ai n  d o s e l e v el. 
●   If r e s ol v e d i n  >  1 4  d a y s, t h e n  ↓  1  d o s e l e v el. 
 
 
 
I nt err u pt  d o s e  of  M E K 1 6 2  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, r e d u c e  d o s e l e v el**  of M E K 1 6 2.  
●  If r e s ol v e d i n  >  7  d a y s,  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  3  
A S T  or  A L T  ( > 
5. 0  - 8. 0  x  U L N) 
wit h o ut   bilir u bi n  
el e v ati o n  >  2. 0  x 
U L N  
A S T  or  A L T  ( > 8. 0 
x   U L N)   wit h o ut  
bilir u bi n  el e v ati o n  
>  2. 0  x  U L N  
 
O mit  d o s e  u ntil r e s ol v e d t o  Gr a d e  ≤  1 ( or  Gr a d e  ≤  2 i n  c a s e  of li v er  m et a st a si s), t h e n:  
●   If r e s ol v e d i n  ≤  1 4  d a y s, t h e n  m ai nt ai n  d o s e l e v el . 
●   If r e s ol v e d i n  >  1 4  d a y s, t h e n  ↓  1  d o s e l e v el. 
 
 
P er m a n e ntl y  di s c o nti n u e  M E K 1 6 2  
Gr a d e  4 ( >  2 0. 0  x 
U L N)  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  M E K 1 6 2.  
A S T  or  A L T  a n d  Bilir u bi n  
A S T  or  A L T  >  3. 0  - 5. 0  
x  U L N  a n d  bl o o d  
bilir u bi n  >  2. 0  x  U L 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  ↓  1  d o s e l e v el 
●   If r e s ol v e d i n  >  7  d a y s, t h e n  di s c o nti n u e  p ati e nt fr o m  st u d y tr e at m e nt. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 5 4
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  M E K 1 6 2  
W or st t o xi cit y 
C T C A E  Gr a d e  ( v al u e) 
D uri n g  a  c y cl e  of t h er a p y  
A S T  or  A L T  ≥  5. 0  x 
U L N  a n d  bl o o d  
bilir u bi n  ≥  2. 0  x  U L N  
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  M E K 1 6 2.  
C ar di a c  di s or d er s  
L eft  v e ntri c ul ar  s y st oli c  d y sf u n cti o n  
A s y m pt o m ati c  a b s ol ut e 
d e cr e a s e  of  > 1 0 % i n 
L V E F  c o m p ar e d t o 
b a s eli n e  a n d t h e 
ej e cti o n fr a cti o n i s 
b el o w t h e i n stit uti o n’ s 
l o w er li mit  of  n or m al** 
(i. e.  a  d e cr e a s e  of  6 0 % 
t o  4 8 % i s  a n  a b s ol ut e 
d e cr e a s e  of  1 2 %)  
O mit  d o s e  a n d r e p e at  e v al u ati o n  of  L V E F  wit hi n  2  w e e k s  
If t h e  L V E F r e c o v er s ( d efi n e d  a s  L V E F  ≥ 5 0 %  or  ≥  L L N  a n d  a b s ol ut e  d e cr e a s e  ≤  1 0 % 
c o m p ar e d t o  b a s eli n e)  wit hi n  ≤  3  w e e k s, t h e n r e d u c e  1  d o s e l e v el .  M o nit or  L V E F  2 
w e e k s  aft er r e st arti n g  o n  M E K 1 6 2, t h e n  e v er y  3  w e e k s f or  1 2  w e e k s  a n d t h e n  p er 
pr ot o c ol . 
If t h e  L V E F r e c o v er s  ≥  3  w e e k s, t h e n  di s c o nti n u e  p ati e nt fr o m  st u d y tr e at m e nt.  Cl o s e 
f oll o w-u p  of  L V E F f or  1 6  w e e k s  or  u ntil r e s ol uti o n.  
Gr a d e  3  -  4 
P er m a n e ntl y  di s c o nti n u e  p ati e nt fr o m  st u d y tr e at m e nt.  Cl o s e f oll o w -u p  of  L V E F f or  1 6 
w e e k s  or  u ntil r e s ol uti o n  
N ot e:  C o pi e s  of  E C H O  a n d/ or  M U G A  s c a n s  c o ul d  b e r e q u e st e d f or  p ati e nt s  wit h 
a b s ol ut e  d e cr e a s e  of  > 1 0 % i n  L V E F  c o m p ar e d t o  b a s eli n e  a n d  L V E F  <  L L N  
C K  el e v ati o n  
Gr a d e  1 - 2 
C o nti n u e tr e at m e nt  o n  s a m e  d o s e l e v el.  E n s ur e  p ati e nt i s  a d e q u at el y  h y dr at e d  a n d 
m o nit or  C K  a n d  cr e ati ni n e ( S e cti o n  7. 2. 2. 6. 3 ) 
(If t ot al  C K  ≥  3  X  U L N,  m e a s ur e i s o e n z y m e s,  s er u m  cr e ati ni n e  a n d  m y o gl o bi n i n  bl o o d 
or  uri n e  
Gr a d e  3  
( >  5. 0 - 1 0. 0  x  U L N)  
wit h o ut  r e n al 
i m p air m e nt (i. e.  s er u m 
cr e ati ni n e  <  1. 5  X  U L N 
or  <  1. 5  X  b a s eli n e)  
If  a s y m pt o m ati c,  m ai nt ai n  d o s e  of  M E K 1 6 2.  E n s ur e  p ati e nt i s  a d e q u at el y  h y dr at e d. 
M o nit or  cl o s el y  a n d  m e a s ur e i s o e n z y m e s,  s er u m  cr e ati ni n e  a n d  m y o gl o bi n i n  bl o o d  or 
uri n e ( S e cti o n  7. 2. 2. 6. 3 ) 
 
If  s y m pt o m ati c ( m u s cl e  p ai n/ s p a s m s), i nt err u pt  d o s e  of  M E K 1 6 2  u ntil r e s ol v e d t o 
C T C A E  Gr a d e  ≤  1  a n d  m o nit or  cl o s el y ( S e cti o n  7. 2. 2. 6. 3 ), t h e n: 
- If r e s ol v e d i n  ≤  2 1  d a y s, r e d u c e  1  d o s e l e v el  of M E K 1 6 2  
- If r e s ol v e d i n  >  2 1  d a y s,  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  wit h o ut  r e n al 
i m p air m e nt (i. e.  s er u m 
cr e ati ni n e  <  1. 5  X  U L N 
or  <  1. 5  X  b a s eli n e)  
 
Gr a d e  3  or  4  wit h 
r e n al i m p air m e nt (i. e. 
s er u m  cr e ati ni n e  ≥  1. 5 
X  U L N  or  ≥  1. 5  X  
b a s eli n e  
If  a s y m pt o m ati c, i nt err u pt  d o s e  of  M E K 1 6 2.  E n s ur e  p ati e nt i s  a d e q u at el y  h y dr at e d  a n d 
m o nit or  cl o s el y  a n d  m e a s ur e i s o e n z y m e s,  s er u m  cr e ati ni n e  a n d  m y o gl o bi n i n  bl o o d  or 
uri n e ( S e cti o n  7. 2. 2. 6. 3 ) 
- If r e s ol v e d i n  ≤  2 1  d ay s, r e d u c e  1  d o s e l e v el  of  M E K 1 6 2  
- If r e s ol v e d i n  >  2 1  d a y s,  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 
If  s y m pt o m ati c,  p er m a n e ntl y  di s c o nti n u e  st u d y  dr u g tr e at m e nt 
Q T c  Pr ol o n g ati o n  
Q T c F  >  5 0 0  m s e c 
( Gr a d e  3) 
( c o nfir m e d  b y tri pli c at e 
E C G s  5  mi n ut e s  a p art)  
1 st o c c urr e n c e:  Tr e at m e nt  wit h  M E K 1 6 2  s h o ul d  b e t e m p or aril y  s u s p e n d e d.  El e ctr ol yt e 
a b n or m aliti e s, if  a n y,  s h o ul d  b e  c orr e ct e d  a n d  a n y  c o n c o mit a nt  m e di c ati o n t h at  m a y 
p ot e nti all y  pr ol o n g  Q T  s h o ul d  b e  di s c o nti n u e d.  P ati e nt  m o nit ori n g  u ntil r e s ol uti o n  of t h e 
a d v er s e  e v e nt  s h o ul d  b e i m pl e m e nt e d i n t h e  h o s pit al i n cl u di n g  a  c o n s ult ati o n  wit h  a 
c ar di ol o gi st.  O n c e t h e  Q T c F  pr ol o n g ati o n  h a s r e s ol v e d (r et ur n e d t o  b a s eli n e  v al u e  or 
C T C  Gr a d e  <  1),  M E K 1 6 2  m a y  b e r e st art e d  at  a r e d u c e d  d o s e ( 3 0  m g  BI D).  
2 n d o c c urr e n c e: If  a  s e c o n d  e pi s o d e  o c c ur s t h at i s  attri b ut e d t o  M E K 1 6 2,  st u d y  dr u g 
m u st  b e  p er m a n e ntl y  di s c o nti n u e d.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 5 5
0  Pr ot o c ol  N o. 
 
 
 
R e c o m m e n d e d  d o s e  m o difi c ati o n s f or  M E K 1 6 2  
W or st t o xi cit y 
C T C A E  Gr a d e  ( v al u e) 
D uri n g  a  c y cl e  of t h er a p y  
R a s h  
Gr a d e  1  
Tr e at m e nt  wit h  M E K 1 6 2  s h o ul d  b e  m ai nt ai n e d  at t h e  c urr e nt  d o s e  
I niti at e  pr o p h yl a cti c r e gi m e n if it  w a s  n ot  alr e a d y  st art e d  a n d  m o nit or  cl o s el y 
Gr a d e  2  
1 st o c c urr e n c e:  Tr e at m e nt  wit h  M E K 1 6 2  s h o ul d  b e  m ai nt ai n e d  at t h e  c urr e nt  d o s e  a n d 
r a s h  s h o ul d  b e  cl o s el y  m o nit or e d. I niti at e  pr o p h yl a cti c r e gi m e n if it  w a s  n ot  alr e a dy 
st art e d  
R e a s s e s s  wit hi n  a  m a xi m u m  of t w o  w e e k s. If r a s h  w or s e n s  or  d o e s  n ot i m pr o v e, 
i nt err u pt  d o si n g  u ntil i m pr o v e m e nt t o  Gr a d e  ≤  1.  R e s u m e tr e at m e nt  at t h e  s a m e  d o s e 
l e v el. 
2 n d o c c urr e n c e:  R e a s s e s s  wit hi n  a  m a xi m u m  of  2  w e e k s. If r a s h  w or s e n s  or  d o e s  n ot 
i m pr o v e, i nt err u pt  d o si n g  u ntil i m pr o v e m e nt t o  Gr a d e  ≤  1.  R e s u m e tr e at m e nt  at  a 
r e d u c e d  d o s e l e v el. 
O nl y  o n e  d o s e r e d u cti o n i s  p er mitt e d.  
Gr a d e  3  
1 st o c c urr e n c e:  Tr e at m e nt  wit h  M E K 1 6 2  s h o ul d  b e i nt err u pt e d.  R e a s s e s s t h e  p ati e nt 
w e e kl y.  C o n si d er r ef err al t o  d er m at ol o gi st  a n d  m a n a g e r a s h  p er  d er m at ol o gi st’ s 
r e c o m m e n d ati o n. 
-I nt err u pt tr e at m e nt  u ntil i m pr o v e m e nt t o  Gr a d e  ≤  1.  R e s u m e tr e at m e nt  wit h  M E K 1 6 2  at 
t h e  s a m e  d o s e l e v el. 
2 n d o c c urr e n c e: I nt err u pt tr e at m e nt  u ntil i m pr o v e m e nt t o  Gr a d e  ≤  1.  R e s u m e tr e at m e nt 
wit h  M E K 1 6 2  at  a r e d u c e d  d o s e l e v el.  
C o n si d er r ef err al t o  d er m at ol o gi st  a n d  m a n a g e r a s h  p er  d er m at ol o gi st’ s  
r e c o m m e n d ati o n 
Gr a d e  4  
P er m a n e ntl y  di s c o nti n u e  M E K 1 6 2  
Ot h er  a d v er s e  e v e nt s  
Gr a d e  1 - 2 
I n t h e  e v e nt  of  a  p er si st e nt  Gr a d e  2  ot h er  A E t h at i s  n ot r e s p o n si v e t o  s u p pl e m e nt al 
t h er a p y  or t h at  pr e v e nt s t h e  p ati e nt fr o m r e c ei vi n g tr e at m e nt  at f ull  d o s e, t h e n  st u d y 
tr e at m e nt  s h o ul d  b e r e d u c e d. 
Gr a d e  3  
F or  ot h er  A E s, i nt err u pt  st u d y tr e at m e nt  u ntil r e s ol uti o n t o  Gr a d e  ≤ 1  or t o  w or st  pr e - 
tr e at m e nt/  B a s eli n e l e v el,  w hi c h e v er i s  m or e  a b n or m al. If t h e  e v e nt r e s ol v e s  wit hi n  2 1 
d a y s t h e n  st u d y tr e at m e nt  m a y  b e r e st art e d  at  a l o w er  d o s e ( o n e l e v el  b el o w t h at  
p r e vi o u sl y r e c ei v e d)  b a s e d  u p o n t h e I n v e sti g at or’ s  di s cr eti o n. 
Gr a d e  4  
P er m a n e ntl y  di s c o nti n u e  st u d y tr e at m e nt***  
*  O p ht h al mi c  m o nit ori n g r e c o m m e n d e d: f urt h er  e v al u ati o n  wit h  s p e ci ali z e d r eti n al i m a gi n g ( e. g.  O c ul ar  c o h er e n c e 
t o m o gr a p h y,  a n gi o gr a p h y) 
*a O p ht h al mi c  m o nit ori n g  m a n d at e d f or r eti n al  e v e nt s,  p o st eri or  u v eiti s,  R V O: f urt h er  e v al u ati o n  wit h  s p e ci ali z e d 
r eti n al i m a gi n g ( e. g.  o c ul ar  c o h er e n c e t o m o gr a p h y,  a n gi o gr a p h y) 
** N ot  a c c or di n g t o  C T C A E,  F or r eti n al  d et a c h m e nt,  pl e a s e f oll o w t h e  T a bl e  1 4 -1 0,  gr a di n g f or r eti n al  d et a c h m e nt.  
*** A  p ati e nt  wit h  a  Gr a d e  4  A E  m a y r e s u m e tr e at m e nt  at t h e l o w er  d o s e l e v el if t h e  A E r e c o v er s t o  Gr a d e  ≤ 1 
wit hi n  2 1  d a y s  of  di s c o nti n ui n g  dr u g  a n d, if i n t h e  o pi ni o n  of t h e I n v e sti g at or  a n d  N o v arti s  M e di c al  M o nit or, t h e 
e v e nt i s  n ot lif e -t hr e at e ni n g,  a n d t h e  p ati e nt  c a n  b e  m a n a g e d  a n d  m o nit or e d f or r e c urr e n c e  of  A E. 
**** F or  p ati e nt s  e nr oll e d  wit h li v er  m et a st a s e s  a n d  b a s eli n e  L F T  el e v ati o n s.  
 
T a bl e  1 4 -1 0   
Gr a di n g f or r eti n al  d et a c h m e nt  
Gr a d e   D e s cri pti o n  
 
1  
A s y m pt o m ati c (  B ut  wit h fi n di n g s  of r eti n al  d et a c h m e nt i n  O C T, f u n d o s c o p y  or  bi o mi cr o s c o p y)  
2  
S y m pt o m ati c  wit h  m o d er at e  d e cr e a s e i n  vi s u al  a c uit y ( 2 0/ 4 0  or  b ett er); li miti n g i n str u m e nt al  a cti vit i e s  of 
d ail y li vi n g  
3  
S y m pt o m ati c  wit h  m ar k e d  d e cr e a s e i n  vi s u al  a c uit y ( w or s e t h a n  2 0/ 4 0); li miti n g  s elf -c ar e  a cti viti e s  of 
d ail y li vi n g  
4  
Bli n d n e s s ( 2 0/ 2 0 0  or  w or s e) i n t h e  aff e ct e d  e y e  
 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 5 6
0  Pr ot o c ol  N o. 
 
 
 
1 4. 3  
A nti ci p at e d ri s k s  a n d  n otifi c ati o n t o i n v e sti g at or s 
It is i n t h e i n v esti g at ors’ j u d g m e nt  o n  h o w t o tr e at st u d y tr e at m e nt i n d u c e d  a d v ers e  e v e nts. 
B el o w  ar e r e c o m m e n d ati o ns  of tr e at m e nt  g ui d eli n e.  
 
1 4. 3. 1   
B Y L 7 1 9 
 
G ui d eli n e f or t h e tr e at m e nt  of  st u d y tr e at m e nt i n d u c e d  h y p er gl y c e mi a  
B Y L 7 1 9,  li k e  ot h er   PI 3 K i n hi bit ors,   m a y  aff e ct   gl u c os e  h o m e ost a sis  w hi c h  c o ul d r es ult  i n  
i n cr e as es   of   pl as m a   gl u c os e   a n d  i ns uli n  r esist a n c e  (B us ai d y   2 0 1 2 ).   B Y L 7 1 9  i n d u c e d  
h y p er gl y c e mi a  is   g e n er all y   m a n a g e a bl e   wit h   a d e q u at e   a nti di a b eti c  tr e at m e nt.   B Y L 7 1 9  
i n d u c e d  h y p er gl y c e mi a t y pi c all y  o c c urs  wit hi n t h e first  m o nt h  of tr e at m e nt.  P ati e nts  wit h  pr e- 
di a b et es  (  i. e.   F P G   1 0 0   –  1 2 5    m g/ dl;   5. 6  -  6. 9   m m ol/ L)   a n d  t h os e   wit h   a n   est a blis h e d  
di a g n osis  of t y p e  2  di a b et es  m ellit us  s h o ul d  b e  m o nit or e d  c ar ef ull y, t h us  all o wi n g  a n  e arl y 
d et e cti o n  a n d  pr o m pt  m a n a g e m e nt  of i n cr e as es i n  F P G  w hil e  o n  B Y L 7 1 9 tr e at m e nt.  H o w e v er 
all  p ati e nts,   e v e n t h os e  wit h  F P G  wit hi n  n or m al li mi ts  at s cr e e ni n g,   m a y  d e v el o p  B Y L 7 1 9 
i n d u c e d   h y p er gl y c e mi a.   P ati e nts  s h o ul d   al w a ys   b e  i nstr u ct e d  t o  f oll o w   di et ar y   g ui d eli n es  
pr o vi d e d  b y t h e  A m eri c a n  Di a b et es  Ass o ci ati o n,  e. g. s m all fr e q u e nt  m e als, l o w  c ar b o h y dr at e 
c o nt e nt,  hi g h fi b er,  b al a n ci n g  c ar b o h y dr at es  o v er t h e  c o urs e  of t h e  d a y; t hr e e  s m all  m e als  a n d 
2 s m all s n a c ks r at h er t h a n  o n e l ar g e  m e al  a n d  e x er cis e,  as   a p pr o pri at e. 
D et ail e d  g ui d eli n es f or  m a n a g e m e nt  of  B Y L 7 1 9 i n d u c e d  h y p er gl y c e mi a is  pr o vi d e d i n  T a bl e  
1 4- 6   f oll o wi n g   dis c ussi o n   wit h   a n   a d vis or y   b o ar d.   T his  i n cl u d es   e arl y   a d mi nistr ati o n   of  
m etf or mi n.  M etf or mi n  m a y  b e titr at e d t o  a  d ail y  d os e  of  1 0 0 0  m g  BI D.  L o c al  pr ot o c ols  p er 
st a n d ar d  cli ni c al  pr a cti c e  m a y  b e f oll o w e d.  F asti n g  pl as m a  gl u c os e  m a y  b e  p erf or m e d l o c all y 
f or r a pi d  a v ail a bilit y f or s af et y  e v al u ati o n  a n d  m a n a g e m e nt  g ui d a n c e.  S p e ci al  att e nti o n s h o ul d 
b e   p ai d  t o  t h e  ris k   of   h y p o gl y c e mi a  i n   p ati e nts  i nt err u pti n g   B Y L 7 1 9  tr e at m e nt   a n d  
c o n c o mit a ntl y r e c ei vi n g i ns uli n  a n d/ or s ulf o n yl ur e as.  
C o ns ult ati o n   wit h   a   di a b et ol o gist  is   hi g hl y  r e c o m m e n d e d  f or   b ett er   ass ess m e nt   a n d  
m a n a g e m e nt  of  B Y L 7 1 9 -i n d u c e d  h y p er gl y c e mi a. 
 
G ui d eli n e s f or t h e tr e at m e nt  of  st u d y  dr u g i n d u c e d  s ki n t o xi cit y  
S ki n t o xi cit y is  a  cl ass -eff e ct  a d v ers e  e v e nt  o bs er v e d  wit h  PI 3 K i/ m T O Ri  a g e nts.  
Cl os e  m o nit ori n g  of  p ot e nti al s ki n r e a cti o ns  will  b e  p erf or m e d  at  e a c h  pl a n n e d  visit  a n d  will 
b e  r e p ort e d   as   a d v ers e   e v e nt.   T h e   m ost  fr e q u e nt  s ki n   a d v ers e   e v e nts  r e p ort e d   ar e:  
m a c ul o p a p ul ar r as h ( o nl y  a  mi n orit y  pr es e nt  a c n eif or m r as h);  pr urit us  a n d  dr y  s ki n.  T h e  o ns et 
is  t y pi c all y   wit hi n  t h e  first   2   m o nt hs   of  tr e at m e nt  st art   a n d  is  r e v ersi bl e   wit h   a d e q u at e  
c o m e di c ati o n  a n d tr e at m e nt i nt err u pti o n if  n e e d e d.  S ki n r e a cti o ns  m a y f a d e sl o wl y  o v er  1 0 
d a ys  or  m or e  a n d  m a y  n ot r e q uir e  o n g oi n g  c o n c o mit a nt t h er a p y. If t h er e  ar e  n o  n e w l esi o ns  or 
n e w  ar e as  of i n v ol v e m e nt  d e v el o pi n g,  a n d if t h e  a p p e ar a n c e is  c h a n gi n g  c ol or fr o m r e d t o  p al e 
or li g ht  br o w n, it is li k el y t h e  er u pti o n  h as  b e g u n t o f a d e, i. e.  n ot  c o nsi d er e d  a cti v e  a n y l o n g er. 
C o ns ult ati o n   wit h   a   d er m at ol o gist  is   hi g hl y  r e c o m m e n d e d  f or   b ett er   ass ess m e nt   a n d  
m a n a g e m e nt  of  B Y L 7 1 9 -i n d u c e d s ki n t o xi cit y.  P h ot o gr a p hs  of s ki n r as h es  e v e nts  a s  w ell  as 
s ki n  bi o ps y, if  p ossi bl e,  ar e r e c o m m e n d e d.  A c c or di n g t o t h e i n v esti g at or  dis cr eti o n,  a  p air e d 
s ki n  bi o ps y  c o ul d  b e  o bt ai n e d  (fr o m  b ot h  aff e ct e d   a n d   a n   u n aff e ct e d   s ki n  ar e a)   f or  l o c al 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 5 7
0  Pr ot o c ol  N o. 
 
 
 
hist o p at h ol o g y  ass ess m e nt t o f urt h er  ass ess r as h if  cli ni c all y  a p pr o pri at e. I n  c as e  of  Gr a d e  3/ 4 
s ki n t o xi cit y,  N o v artis r e q u ests t h at  a s ki n  bi o ps y is  p erf or m e d  a n d s e nt t o  N o v artis  C e ntr al 
l a b or at or y f or  f urt h er  r es e ar c h  p ur p os e  o n t h e  p at h ol o g y  a n d  m e c h a nis m   of   PI 3 K i n hi bit or 
tr e at m e nt i n d u c e d s ki n t o xi cit y.  At t h e I n v esti g at or’s  dis cr eti o n,  n o n-s e d ati n g  a nti hist a mi n es 
( e. g.  c etiri zi n e ( Z yrt e c© )  o n c e  d ail y)  m a y  b e  us e d  as  pr o p h yl a cti c tr e at m e nt t o r e d u c e s e v erit y 
of  r as h,   es p e ci all y  f or   p ati e nts   wit h   a   h ist or y   of   h y p ers e nsiti vit y  r e a cti o ns  li k e  s e as o n al  
all er gi es,  h a y f e v er,  all er gi c  ast h m a  or  dr u g i n d u c e d  e x a nt h e m a.  
C o ns ult ati o n  wit h  a  d er m at ol o gist is  hi g hl y r e c o m m e n d e d f or  b ett er  ass ess m e nt  a n d 
m a n a g e m e nt  of  B Y L 7 1 9 -i n d u c e d s ki n t o xi cit y. 
R e c o m m e n d e d t h er a pi es f or s ki n t o xi cit y  e v e nts i n cl u d e:  
•   T o pi c al st er oi ds  Tri a m ci n ol o n e  or  B et a m et h as o n e  3 -4 x  d ail y f or  at l e ast  2 8  d a ys.  C o nsi d er 
s pr a y  pr e p ar ati o n f or  e as e  of  a p pli c ati o n  o n tr u n k.  F or s c al p i n v ol v e m e nt,  c o nsi d er  a f o a m 
pr e p ar ati o n  
•   I n   c as e   of   b ur ni n g,  sti n gi n g,   pr urit us:   or al   a nti hist a mi n es  (s e d ati n g,   e v e ni n g):  
di p h e n h y dr a mi n e  2 5 -5 0 m g t.i. d.;  h y dr o xi zi n e  2 5 m g t.i. d.  or  q.i. d  
•   Or al   a nti hist a mi n es  ( n o n -s e d ati n g,   d a y  ti m e):  f e x of e n a di n e   1 8 0 m g   q. d.   or   6 0 m g   TI D  
( m o nit or t h e  us e  of t his  cl ass  of  dr u gs si n c e s ki n t o xi cit y  h as  als o  b e e n r e p ort e d) 
•   L o w  d os e  or al  c orti c ost er oi ds,  e. g.  2 0 -4 0 m g  q. d.  pr e d nis o n e  or  e q ui v al e nt  u p t o  1 0  d a ys  of 
tr e at m e nt.  If  l esi o ns   ar e  still  n ot  c o ntr oll e d  wit h  all   of  t h e   a b o v e,   c o nsi d er ati o n   c a n  b e  
gi v e n t o t h e  us e  of:  
•   T o pi c al   a nti bi oti cs:   cli n d a m y ci n   1   -  2 %;   er yt hr o m y ci n   1 %  -2 %  ( g el   or   s ol uti o n 
f or m ul ati o n   c a n   b e   us e d,   oi nt m e nts   c a n n ot   b e   us e d);    m etr o ni d a z ol e   1 %;   sil v er 
s ul p h a di a zi n e 
•   Or al  a nti bi oti cs:  d o x y c y cli n e  1 0 0 m g  b.i. d.;  mi n o c y cli n e  1 0 0 m g  b.i. d.;  o x yt etr a c y cli n e 
5 0 0 m g  b.i. d  
•   T o pi c al  a nti pr uriti cs ( pr a m o xi n e  1 %,  d o x e pi n  5 %  cr e a m)  a p pli e d t wi c e  d ail y  
•   G A B A   A g o nists:   G a b a p e nti n   3 0 0 m g   e v er y   8   h o urs,   Pr e g a b ali n   5 0 -7 5   m g   e v er y   8  
h o urs  (t o   a dj ust   of  r e n al  i m p air m e nt).   D e p e n di n g   o n   p ati e nt’s   cli ni c al   c o n diti o n   b e  
a w ar e  of  p o t e nti al  a n d  c o m m o n si d e  eff e cts  o bs er v e d  wit h  G A B A  a g o nists s u c h  as:  
s o m n ol e n c e,  di z zi n ess ( b ot h  dr u gs)  a n d  p eri p h er al  e d e m a ( G a b a p e nti n)  a m o n g  ot h ers 
a d v ers e  e v e nts.  
Dr y  s ki n   h as   b e e n  r e p ort e d.   It  is  r e c o m m e n d e d  t h at   p ati e nts   wit h   dr y  s ki n   us e   mil d  a n d 
fra gr a n c e  fr e e s o a ps   a n d   d et er g e nts.   A c c or di n g t o  t h e s e v erit y  a n d   B S A  e xt e nsi o n   p ati e nts 
m a y  a p pl y  mil d  m oist uri z ers,  e. g.  a m m o ni u m l a ct at e  cr e a m  1 2 %.  
It is r e c o m m e n d e d t o  c a uti o n  p ati e nts t o  a v oi d s u n  e x p os ur e  d uri n g tr e at m e nt  wit h  B Y L 7 1 9, 
es p e ci all y  w h e n  t h e y  alr e a d y  h a v e  e x p eri e n c e d r a s h  or  ot h er s ki n t o xi citi es  as t h e i n cr e as e d 
bl o o d  fl o w   of  t h e  s ki n   m a y   w ors e n  s ki n  s y m pt o ms.   P ati e nts  s h o ul d   b e   a d vis e d  t o  t a k e  
m e as ur es  t o   pr ot e ct  t h e ms el v e s  fr o m   dir e ct   e x p os ur e  t o  s u nli g ht,  i n cl u di n g  t h e   w e ari n g   of  
s u n glass es   as   w ell   as  t h e  r e g ul ar   us e   of  s u ns cr e e n,   h ats,  l o n g -sl e e v e  s hirts   a n d  l o n g   p a nts  
w h e n   o ut d o ors. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 5 8
0  Pr ot o c ol  N o. 
 
 
 
M a n a g e m e nt  of  p n e u m o niti s  
All  p ati e nts  will  b e r o uti n el y  as k e d  a b o ut  a n d  o bs er v e d f or t h e  o c c urr e n c e  of  a d v ers e  e v e nts 
i n cl u di n g  n e w  or  c h a n g e d  p ul m o n ar y s y m pt o ms ( c o nsist e nt  wit h l u n g  a b n or m aliti es).  P ati e nts 
w h o   ar e  s us p e ct e d  t o   h a v e   d e v el o p e d   p n e u m o nitis  s h o ul d  st o p  st u d y  tr e at m e nt   B Y L 7 1 9  
i m m e di at el y  a n d  u n d er g o  a p pr o pri at e i m a gi n g ( hi g h r es ol uti o n  C T s c a n)  a n d  br o n c h o al v e ol ar 
l a v a g e  f or   bi o ps y  s h o ul d   b e   c o nsi d er e d  if   cli ni c all y   a p pr o pri at e.  I nf e cti o us   c a us es   of  
i nt erstiti al l u n g  dis e as e s h o ul d  b e r ul e d  o ut. I n v esti g at ors s h o ul d f oll o w i nstit uti o n al  pr a cti c e 
f or   m a n a g e m e nt   of   p n e u m o nitis   w hi c h  s h o ul d  i n cl u d e  tr e at m e nt   wit h   hi g h   d os e  
c orti c ost er oi ds;  a nti bi oti c  t h er a p y  s h o ul d  b e  a d mi nist er e d  c o n c urr e ntl y  if  i nf e cti o us  c a us es 
h a v e  n ot  b e e n r ul e d  o ut.  C o ns ult ati o n  wit h  a  p ul m o n ol o gist is  hi g hl y r e c o m m e n d e d f or  a n y 
p n e u m o nitis   c as e   d uri n g  t h e  st u d y  tr e at m e nt.  If   p n e u m o nitis  is   c o nfir m e d,  t h e n   B Y L 7 1 9  
s h o ul d  b e  p er m a n e ntl y   dis c o nti n u e d. 
 
F oll o w -u p  o n  a m yl a s e  or li p a s e  el e v ati o n ( ≥  C T C A E  Gr a d e  3)  
P ati e nt   wit h  a m yl as e  or  li p as e  el e v ati o n  ≥   C T C A E   Gr a d e  3   m ust  b e  t est e d   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  ≤   Gr a d e  1  ( or  b as eli n e).   Aft er  r es u m pti o n  of  d osi n g, 
c o nti n u e  t o  t est    w e e kl y  f or  o n e  a d diti o n al  c y cl e.  If  n o  r e o c c urr e n c e  of  ≥   Gr a d e   2   e v e nt,  
c o nti n u e  m o nit ori n g  e v er y  c y cl e.  
A n   e x c e pti o n  t o  t h es e  f oll o w -u p   g ui d eli n es   will   b e   m a d e  f or   c as es   of  is ol at e d   a m yl as e  
el e v ati o ns i n  w hi c h  a m yl as e  fr a cti o n ati o n  d e m o nstr at es t h at  p a n cr e ati c  a m yl as e is  ≤  Gr a d e  1. 
I n s u c h  c as es, t ot al  a m yl as e a n d fr a cti o n at e d  a m yl as e s h o ul d  b e  m o nit or e d  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)  f or  4    w e e ks.  If  p a n cr e ati c  a m yl as e  r e m ai ns   ≤    Gr a d e  1, 
s u bs e q u e nt   m o nit ori n g   m ust   b e   p erf or m e d   at  l e ast   e v er y   4   w e e ks  ( or   m or e  fr e q u e ntl y  if  
cli ni c all y i n di c at e d).  
P ati e nts  w h o  dis c o nti n u e st u d y tr e at m e nt  d u e t o  p a n cr e ati c t o xi cit y  m ust  b e  m o nit or e d  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 t h e  e v e nt r es ol v es t o  ≤  gr a d e  1  or  st a bili z ati o n 
o c c urs ( n o  C T C A E  gr a d e  c h a n g e  o v er  4  w e e ks).  
If   a m yl as e   a nd/ or  li p as e   el e v ati o ns   ar e   a c c o m p a ni e d   b y   n e w   or   pr o gr essi v e   u n e x pl ai n e d  
a b d o mi n al s y m pt o ms s u c h  as s e v er e  p ai n  or  v o miti n g,  wit h h ol d st u d y tr e at m e nt, t h e n  p erf or m 
di a g n osti c   pr o c e d ur es  ( e. g.,   a b d o mi n al   C T  s c a n   or   ultr as o u n d)  t o   e x cl u d e   p a n cr e ati c  
p at h ol o g y. 
S e e  als o  d os e  m o difi c ati o n  g ui d eli n es  d es cri b e d i n  T a bl e  1 4 - 6. 
 
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 
R ef er t o  S e cti o n  1 4. 3. 2  ( 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 as es) 
 
G ui d eli n e s f or t h e tr e at m e nt  of  st u d y tr e at m e nt i n d u c e d  di arr h e a  
I n t h e  e v e nt  di arr h e a is  o bs er v e d i n  p ati e nts t h e  b el o w  m a n a g e m e nt  pl a n s h o ul d  b e f oll o w e d. 
T his  tr e at m e nt   al g orit h m  is   b as e d   o n   p u bli c ati o ns   o n   h o w  t o   m a n a g e   di arr h e a   c a us e d   b y  
c yt ot o xi c r e gi m e ns ( W a dl er  1 9 9 8 , K or n bl a u  2 0 0 0 ). 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 5 9
0  Pr ot o c ol  N o. 
 
 
 
•   Fi rst  r e p o rt  of  di a r r h e a  
Pl e as e   o bt ai n   a   hist or y   of   o ns et   a n d   d ur ati o n   of  t h e   di arr h e a.   T his  s h o ul d  i n cl u d e  t h e  
d es cri pti o n  of  n u m b er  of st o ols fr o m  p ati e nt  a n d st o ol  c o m p ositi o n ( e. g.  w at er y,  pr es e n c e  of 
o c c ult  bl o o d  or  m u c us i n st o ol  et c.)  P ati e nts f e v er s h o ul d  b e  ass e ss e d  a n d  d et ails  s h o ul d  b e 
o bt ai n e d  w h et h er   p ati e nt  is  als o  e x p eri e n ci n g  a b d o mi n al   p ai n,   cr a m ps,   bl o ati n g,   dist e nsi o n, 
n a us e a,   v o miti n g,   di z zi n ess   a n d   w e a k n ess  i n   or d er  t o  r ul e   o ut  t h e  ris k   of  s e psis,   b o w el  
o bstr u cti o n   or   d e h y dr ati o n.   Pl e as e  r e vi e w   p ati e nt’s   m e di c ati o n   pr ofil e   a n d  i d e ntif y   a n y  
di arr h e a g e ni c  a g e nts.  Pl e as e  als o  as k  a b o ut  p ati e nt’s  di et ar y  pr ofil e t o i d e ntif y  a n y  di arr h e a 
c a usi n g f o o ds.  P ati e nts s h o ul d  b e  c h e c k e d  aft er st arti n g st u d y tr e at m e nt t o  pr o a cti v el y l o o k f or 
st art   of   di arr h e a  s o  t h at   a nti -di ar r h e al  tr e at m e nt   c a n   b e  st art e d   as  s o o n   as   p ossi bl e  t o  li mit 
s e v erit y  of t h e  di arr h e al t o xi cit y.  C all  p ati e nts  at  h o m e, if  n e c ess ar y,  e arl y  d uri n g t h e first  8 
w e e ks  of tr e at m e nt st art. I nstr u ct t h e  p ati e nt t o  c all  at t h e first si g n  of  di arr h e a.  
•   M a n a g e m e nt  of  di a r r h e a  
G e n er al r e c o m m e n d ati o ns:  
•   St o p  all l a ct os e -c o nt ai ni n g  pr o d u cts,   al c o h ol 
•   St o p l a x ati v es,  b ul k fi b er ( e. g.  M et a m u cil ® )  a n d st o ol s oft e n ers ( e. g.  d o c us at e s o di u m, 
C ol a c e ® ) 
•   St o p  hi g h -os m ol ar f o o d s u p pl e m e nts s u c h  as  E ns ur e  Pl us ®  a n d J e vit y  Pl us ®  ( wit h fi b er) 
•   Dri n k  8 t o  1 0 l ar g e  gl ass es  of  cl e ar li q ui ds  p er  d a y ( e. g.  w at er,  P e di al yt e ® ,  G at or a d e® , 
br ot h)  
•   E at fr e q u e nt s m all  m e als ( e. g.  b a n a n as, ri c e,  a p pl e s a u c e,  t o ast) 
It is r ec o m m e n d e d t h at  p ati e nts  ar e  pr o vi d e d  wit h l o p er a mi d e t a bl ets  at t h e st art  of  e a c h  c y cl e. 
P ati e nts s h o ul d  b e i nstr u ct e d  o n t h e  us e  of l o p er a mi d e  at  C y cl e  1 i n  or d er t o  m a n a g e si g ns  or 
s y m pt o ms  of  di arr h e a  at  h o m e.  P ati e nts s h o ul d  b e i nstr u ct e d t o st art  or al  l o p er a mi d e (i niti al 
a d mi nistr ati o n  of  4  m g, t h e n  2  m g  e v er y  4  hrs ( m a xi m u m  of  1 6  m g/ d a y)  at t h e first si g n  of 
l o os e st o ol   or  s y m pt o ms  of  a b d o mi n al   p ai n.   T h es e i nstr u cti o ns s h o ul d  b e  pr o vi d e d  at   e a c h 
c y cl e  a n d t h e sit e s h o ul d  e ns ur e t h at t h e  p ati e nt  u n d erst a n ds t h e i nstr u cti o n.  At t h e  b e gi n ni n g 
of   e a c h   c y cl e,   e a c h   p ati e nt  s h o ul d   b e  s p e cifi c all y   q u esti o n e d  r e g ar di n g   a n y   e x p eri e n c e   of  
di arr h e a  or  di arr h e a r el at e d s y m pt o ms. If s y m pt o ms  w er e  e x p eri e n c e d, t h e n t h e sit e s h o ul d 
q u esti o n t h e  p ati e nt r e g ar di n g t h e  a cti o ns t a k e n f or t h es e s y m pt o ms.  
I nt e nsi v e  m a n a g e m e nt  of  di arr h e a  m ust  b e i nstit ut e d  at t h e first si g n  of  a b d o mi n al  cr a m pi n g, 
l o os e  st o ols   or   o v ert   di arr h e a.   N ot e  t h at   all   c o n c o mit a nt  t h er a pi es   us e d  f or  tr e at m e nt   of  
di arr h e a  m ust  b e r e c or d e d  o n t h e  C o n c o mi t a nt  M e di c ati o ns/ N o n-dr u g  T h er a pi es  e C R F.  
•   L o p er a mi d e is t h e first -li n e tr e at m e nt  of  di arr h e a ( a n y  Gr a d e) i n t his r e c o m m e n d e d 
al g orit h m.  P ersist e nt s y m pt o ms  m a y r e q uir e t h e  a d mi nistr ati o n  of  hi g h  d os e l o p er a mi d e 
f oll o w e d  b y tr e at m e nt  wit h s e c o n d-li n e  a g e nts s u c h  as  o pi u m ti n ct ur e  a n d  o ctr e oti d e 
a c e t at e,  b as e d  o n s e v erit y  a n d  d ur ati o n  of  di arr h e a  a n d r el at e d si g ns/s y m pt o ms.  A n ot h er 
first-li n e tr e at m e nt f or  di arr h e a is  di p h e n o x yl at e  h y dr o c hl ori d e/ atr o pi n e s ulf at e.  T his 
m e di c ati o n  m a y  b e  us e d i n  pl a c e  of l o p er a mi d e  h o w e v er it is i m p ort a nt t o  n ot e t h at 
l o p er a mi d e  a n d  di p h e n o x yl at e  h y dr o c hl ori d e/ atr o pi n e s ulf at e  m ust  n ot  b e  us e d i n 
c o nj u n cti o n  wit h  o n e  a n ot h er  d u e t o t h e ris k  of  d e v el o pi n g  p ar al yti c il e us.  U p o n tr e at m e nt 
wit h  a n y  a nti di arr h e al  a g e nts, t h e  p ati e nt’s r es p o ns e t o tr e at m e nt s h o ul d  b e  o bs er v e d  a n d  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 6 0
0  Pr ot o c ol  N o. 
 
 
 
a p pr o pri at el y  d o c u m e nt e d i n t h e s o ur c e  d o c u m e nt  a n d  e C R F T r e at m e nt  of  g r a d e  1  a n d 
g r a d e  2  di a r r h e a  
Gr a d e  1  or  gr a d e  2  di arr h e a  will  b e tr e at e d  wit h  st a n d ar d l o p er a mi d e r e gi m e n 
(i niti al  a d mi ni str ati o n  of  4  m g, t h e n  2  m g  e v er y  4  h o ur s ( m a xi m u m  of  1 6  m g/ d a y) 
or  aft er  e a c h  u nf or m e d  st o ol).  Di arr h e a r e s ol v e d  
•   C o nti n u e i nstr u cti o ns f or  di et ar y  m o difi c ati o n  
•   Gr a d u all y  a d d s oli d f o o ds t o  di et  
•   Dis c o nti n u e l o p er a mi d e  aft er  1 2  hrs  di arr h e a -fr e e i nt er v al 
Di arr h e a  u nr e s ol v e d  
P ersisti n g   di arr h e a  C T C A E   gr a d e  1  or   2  will   b e tr e at e d  wit h  a d diti o n  of   o pi u m  ti n ct ur e  or  
di h y dr o c o d ei n e  t artr at e  t a bl ets/i nj e cti o ns   wit h   m o nit ori n g   of   p ati e nts   c o n diti o n  t o  r ul e   o ut  
d e h y dr ati o n,  s e psis,  il e us)   m e di c al   c h e c k   a n d   s el e ct e d   w or k u p  if   p ati e nt   d o es   n ot   n e e d  
h os pit ali z ati o n (s e e s e cti o n  Di arr h e a  w or k u p  a n d  a d diti o n al t est i n t h e  p arti c ul ar tri al  pr ot o c ol). 
O bs er v e  p ati e nt f or r es p o ns e t o  a nti di arr h e al tr e at m e nt.  
P ersisti n g   di arr h e a   C T C A E   gr a d e   3   or   4   m a y   b e  tr e at e d   wit h   h os pit ali z ati o n,   hi g h   d os e  
l o p er a mi d e (i niti al  4  mg, t h e n  2  m g  e v er y  2  hrs)   a n d  a d diti o n  of  o pi u m ti n ct ur e ( D T O)   or 
di h y dr o c o d ei n e  t artr at e  t a bl ets/i nj e cti o ns,  st art   of  I V  fl ui ds   a n d   a nti bi oti cs   as   n e e d e d   wit h  
m o nit ori n g   of   p ati e nts   c o n diti o n  (t o  r ul e   o ut   d e h y dr ati o n,  s e psis,  il e us)   m e di c al   c h e c k   a n d 
w or k u p ( p erf or m  a p pr o pri at e  a d diti o n al t esti n g).  O bs er v e  p ati e nt f or r es p o ns e.  
 
Aft er  a g ai n  1 2 -2 4  hr s:  
 
Di arr h e a r e s ol v e d  
•   C o nti n u e i nstr u cti o ns f or  di et ar y  m o difi c ati o n  
•   Gr a d u all y  a d d s oli d f o o ds t o  di et  
•   Dis c o nti n u e l o p er a mi d e  a n d/ or  ot h er tr e at m e nt  aft er  1 2  hrs  di arr h e a -fr e e i nt er v al 
Di arr h e a  u nr e s ol v e d  
•   If  di arr h e a still  p ersisti n g ( C T C A E  gr a d es  1  a n d  2),  aft er  2 x  2 4  hrs  wit h  hi g h  d os e 
l o p er a mi d e  a n d  o pi at es t h e n  a d mit t o  h os pit al  a n d  e m pl o y  m e as ur es  as for  C T C A E  gr a d e 
3  a n d  4  u ntil  di arr h e a r es ol v e d.  
•   If  di arr h e a still  p ersisti n g  a n d  pr o gr ess e d t o  C T C A E  gr a d es  3  a n d  4,  e m pl o y  m e as ur es 
d es cri b e d   b el o w. 
•   T r e at m e nt  of  g r a d e  3  a n d  g r a d e  4  di a r r h e a  
P ati e nts  e x p eri e n ci n g  gr a d e  3  a n d  gr a d e  4  di arr h e a  m ust  b e  h os pit ali z e d.  U p o n  h os pit ali z ati o n 
p ati e nt s h o ul d  b e tr e at e d  wit h  hi g h  d os e l o p er a mi d e (i niti al  4  m g, t h e n  2  m g  e v er y  2  h o urs 
wit h  a d diti o n  of  o pi u m ti n ct ur at e  or  di h y dr o c o d ei n e t artr at e t a bl ets/i nj e cti o ns).  P ati e nt s h o ul d 
r e c ei v e  i. v.  fl ui ds   a n d   a nti b oiti cs  if  i n di c at e d   a n d  s h o ul d   b e   m o nit or e d  t o  r ul e   o ut  s e psis,  
d e h y dr ati o n   or  il e us.   P ati e nt  s h o ul d   b e  f oll o w e d   p er   di arr h e a   w or k u p   pl a n.   C o nti n u e  t o  
o bs er v e  p ati e nt f or r es p o ns e t o  a nti -di arr h e al  tr e at m e nt. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 6 1
0  Pr ot o c ol  N o. 
 
 
 
Aft er  1 2 -2 4  hr s:  
•   If  di arr h e a  p ersisti n g  a d mi nist er s. c.  S a n d ost ati n/ o ctr e oti d e ( 1 0 0-5 0 0  µ g  ti d) 
•   C o nti n u e  I V fl ui ds  a n d  a nti bi oti cs  as n e e d e d  
•   If  di arr h e a  C T C A E  gr a d e  3  or  4 still  p ersists  p ati e nts s h o ul d r e c ei v e  o pi u m ti n ct ur e  or 
di h y dr o c o d ei n e t artr at e i nj e cti o ns s. c.  or  i. m. 
•   If  di arr h e a  C T C A E  gr a d e  3  or  4 is still  p ersisti n g s. c.  S a n d ost ati n/ o ctr e oti d e ( 5 0 0-1 0 0 0  µ g 
TI D) s h o ul d  b e  a d mi nist er e d.  
•   T o  c o ntr ol  a n d/ or r es ol v e  di arr h e a,  n e xt  c y cl e  of tr e at m e nt s h o ul d  b e  d el a y e d  b y  1  or  2 
w e e ks.  Tr e at m e nt s h o ul d  b e  c o nti n u e d  o nl y  w h e n  di arr h e a  r es ol v e d. 
•   Di a r r h e a  w o r k u p  
T h e f oll o wi n g  a p pr o pri at e t ests  ar e  b as e d  o n t h e f oll o wi n g  p u bli c ati o n ( A G A  T e c h ni c al 
R e vi e w  o n t h e  E v al u ati o n  a n d  M a n a g e m e nt  of  C hr o ni c  Di arr h e a  1 9 9 9).  
•   S p ot st o ol  a n al ysis  
C oll e ct st o ol  a n d s e p ar at e it fr o m  uri n e,  us e s p e ci al  c o nt ai n ers  a n d  a n al y z e i m m e di at el y. If 
a n al ysis  c a n n ot  b e  d o n e i m m e di at el y, fr e e z e s a m pl es f or l at er  a n al ysis.  E x a mi n e t h e  c oll e ct e d 
st o ol f or  o c c ult  bl o o d  a n d  u n d er t h e  mi cr os c o p e  e x a mi n e f or f e c al l e u c o c yt es  utili zi n g  Wri g ht 
st ai ni n g.   T h e  st o ol  s h o ul d   als o   b e   e x a mi n e d  f or   C. diffi cil e  t o xi n.   L astl y,   e x a mi n e  f e c al  
c ult ur es  f or   p at h o g e ns  s u c h   as   S hi g ell a   a n d   p at h o g e ni c   E.   c oli.  If  it  is  s us p e ct e d  t h at  t h e  
p ati e nt   mi g ht   h a v e   b e e n  i n   c o nt a ct   wit h   c o nt a mi n at e d   w at er,   e x a mi n e  f e c al   c ult ur es  f or  
A er o m o n as  a n d  Pl eisi o m a n as.  
•   E n d os c o pi c  e x a mi n ati o ns  
E n d os c o pi c  e x a mi n ati o ns s h o ul d  b e  o nl y  c o nsi d er e d if  a bs ol ut el y  n e c ess ar y.  P ati e nt’s  b o w el 
is li k el y t o  b e fr a gil e  wit h  e vi d e n c e  of  c olitis  a n d  gr e at  c ar e  a n d  c a uti o n m ust  b e  e x er cis e d i n 
u n d ert a ki n g s u c h  a n i n v asi v e  pr o c e d ur e. If  e n d os c o p y is  u n d ert a k e n  c o nsi d er  g astr os c o p y t o 
o bt ai n j ej u n al fl ui d f or  ass ess m e nt  of  b a ct eri al  o v er gr o wt h f or  c ult ur es  a n d  bi o ps y  of  pr o xi m al 
j ej u n u m  t o   ass ess   e xt e nt   of  i nfl a m m at or y  j ej u nitis.   Als o,   c o nsi d er  si g m oi d os c o p y  f or  
r e ass e ss m e nt  of  c olitis. 
 
1 4. 3. 2   
I N C 2 8 0 
 
G ui d eli n e s f or t h e f oll o w -u p  of l a b or at or y li v er  a b n or m aliti e s  
I n  p ati e nts  wit h  a n y  cli ni c all y r el e v a nt l a b or at or y li v er  a b n or m alit y,  as  d efi n e d  b el o w,  h e p ati c 
t o xi cit y  m o nit ori n g  m ust i n cl u d e  A L L  of t h e f oll o wi n g li v er f u n cti o n t ests ( L F Ts):  al b u mi n, 
A S T,  A L T, t ot al  bilir u bi n (fr a cti o n at e d if t ot al  bilir u bi n  > 2. 0  x  U L N),  al k ali n e  p h os p h at as e 
a n d  G G T.  
I n  c as e  of is ol at e d  el e v ati o ns i n t ot al  bilir u bi n,  A S T  or  A L T,  a d diti o n al f oll o w-u p  e v a l u ati o ns 
ar e r e c o m m e n d e d  as  o utli n e d i n  T a bl e  1 4 - 1 2. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 6 2
0  Pr ot o c ol  N o. 
 
 
 
 
T a bl e  1 4 -1 1   
F oll o w -u p  e v al u ati o n s f or  s el e ct e d  t o xi citi e s* 
 
T O XI CI T Y  
F O L L O W -U P  E V A L U A TI O N  
H E P A TI C  
I s ol at e d t ot al  bilir u bi n  el e v ati o n 
C T C A E  Gr a d e  1  
M o nit or  L F T s  p er  pr ot o c ol  or  m or e fr e q u e ntl y if  cli ni c all y i n di c at e d  
C T C A E  Gr a d e  2  
W e e kl y  m o nit ori n g  of  L F T s,  or  m or e fr e q u e ntl y if  cli ni c all y i n di c at e d,  u ntil 
r e s ol v e d t o  ≤  1. 5  x  U L N 
C T C A E  Gr a d e  3  
W e e kl y  m o nit ori n g  of  L F T s,  or  m or e fr e q u e ntl y if  cli ni c all y i n di c at e d,  u ntil 
r e s ol v e d t o  ≤  1. 5  x  U L N. If r e s ol v e d i n  >  7  d a y s,  aft er  di s c o nti n ui n g t h e 
p ati e nt fr o m I N C 2 8 0  p er m a n e ntl y, t h e  p ati e nt  s h o ul d  b e  m o nit or e d  w e e kl y 
(i n cl u di n g  L F T s),  or  m or e fr e q u e ntl y if  cli ni c all y i n di c at e d,  u ntil t ot al  bilir u bi n 
h a v e r e s ol v e d t o  b a s eli n e  or  st a bili z ati o n  o v er  4  w e e k s  
C T C A E  Gr a d e  4  
Aft er  di s c o nti n ui n g t h e  p ati e nt fr o m I N C 2 8 0  p er m a n e ntl y, t h e  p ati e nt 
s h o ul d  b e  m o nit or e d  w e e kl y (i n cl u di n g  L F T s),  or  m or e fr e q u e ntl y if  cli ni c all y 
i n di c at e d,  u ntil t ot al  bilir u bi n  h a v e r e s ol v e d t o  b a s eli n e  or  st a bili z ati o n o v er  
4  w e e k  
I s ol at e d  A S T/ A L T  el e v ati o n 
C T C A E  Gr a d e  2  
F or  p ati e nt s  wit h  b a s eli n e  v al u e  ≤  
3. 0  x  U L N  
 
R e p e at  L F T s  a s  s o o n  a s  p o s si bl e,  pr ef er a bl y  wit hi n  4 8 -7 2  h o ur s fr o m 
a w ar e n e s s  of t h e  a b n or m al r e s ult s; if  a b n or m al l a b  v al u e s  ar e  c o nfir m e d 
u p o n t h e r e p e at t e st, t h e n  m o nit or  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 r e s ol v e d t o  ≤  3. 0  x  U L N  
F or  p ati e nt s  wit h  b a s eli n e  v al u e  >  
3. 0  - 5. 0  x  U L N  
M o nit or  L F T s  p er  pr ot o c ol  or  m or e fr e q u e ntl y if  cli ni c all y i n di c at e d  
C T C A E  Gr a d e  3  -F or  el e v ati o n  > 
5. 0  - 1 0. 0  x  U L N:  
F or  p ati e nt s  wit h  b a s eli n e  v al u e  ≤  
3. 0  x  U L N  
F or  p ati e nt s  wit h  b a s eli n e  v al u e  >  
3. 0  - 5. 0  x  U L N:  
 
R e p e at  L F T s  a s  s o o n  a s  p o s si bl e,  pr ef er a bl y  wit hi n  4 8 -7 2  h o ur s fr o m 
a w ar e n e s s  of t h e  a b n or m al r e s ult s;  m o nit or  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 r e s ol v e d t o  ≤  3. 0  x  U L N 
R e p e at  L F T s  a s  s o o n  a s  p o s si bl e,  pr ef er a bl y  wit hi n  4 8 -7 2  h o ur s fr o m 
a w ar e n e s s  of t h e  a b n or m al r e s ult s; if  a b n or m al l a b  v al u e s  ar e  c o nfir m e d 
u p o n t h e r e p e at t e st, t h e n  m o nit or  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 r e s ol v e d t o  ≤  5. 0  x  U L N  
C T C A E  Gr a d e  3  
F or  A S T/ A L T  el e v ati o n  >  1 0. 0  - 
2 0. 0  x  U L N:  
R e p e at  L F T s  a s  s o o n  a s  p o s si bl e,  pr ef er a bl y  wit hi n  4 8 -7 2  h o ur s fr o m 
a w ar e n e s s  of t h e  a b n or m al r e s ult s;  m o nit or  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 r e s ol v e d t o  ≤  b a seli n e  
C T C A E  Gr a d e  4  
R e p e at  L F T s  a s  s o o n  a s  p o s si bl e,  pr ef er a bl y  wit hi n  4 8 -7 2  h o ur s fr o m 
a w ar e n e s s  of t h e  a b n or m al r e s ult s;  m o nit or  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 r e s ol v e d t o  b a s eli n e  or  st a bili z ati o n 
o v er  4  w e e k s.  
* N ot e: t hi s t a bl e r ef er s  o nl y t o t h e  e v al u ati o n  s c h e d ul e t o  m o nit or  s el e ct e d t o xi citi e s.  R ef er t o  T a bl e 1 4 -7  f or  d o s e 
m o difi c ati o n s r e q uir e d f or  a p pli c a bl e t o xi citi e s  
 
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 
P ati e nts   wit h  tr a ns a mi n as e  i n cr e as e   c o m bi n e d   wit h  t ot al   bilir u bi n  ( T BI L)  i n cr e as e   m a y   b e  
i n di c ati v e   of   p ot e nti al   DI LI  ( Dr u g  I n d u c e d   Li v er  I nj ur y),   a n d  s h o ul d   b e   c o nsi d er e d   as  
cli ni c all y i m p ort a n t  e v e nts. 
T h e t hr es h ol d f or  p ot e nti al  DI LI  m a y  d e p e n d  o n t h e  p ati e nt ’ s  b as eli n e  A S T/ A L T  a n d  T BI L 
v al u e;  p ati e nts  m e eti n g  a n y  of t h e f oll o wi n g  crit eri a  will r e q uir e f urt h er f oll o w -u p  as  o utli n e d 
b el o w: 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 6 3
0  Pr ot o c ol  N o. 
 
 
 
•   F or  p ati e nts  wit h  n or m al  A L T  a n d  A S T  a n d  T BI L  v al u e  at  b as eli n e:  A S T  or  A L T  >  3. 0  x 
U L N  c o m bi n e d  wit h  T BI L  >  2. 0  x  U L N  
•   F or  p ati e nts  wit h  el e v at e d  A S T  or  A L T  or  T BI L  v al u e  at  b as eli n e: [ A S T  or  A L T  >  2  x 
b as eli n e  A N D  >  3. 0  x  U L N]  O R [ A S T  or  A L T  >  8. 0  x  U L N],  c o m bi n e d  wit h [ T BI L  >  2  x 
b as eli n e  A N D  >  2. 0  x  U L N]  
M e di c al r e vi e w  n e e ds t o  e ns ur e t h at li v er t est  el e v ati o ns  ar e  n ot  c a us e d  b y  c h ol est asis,  d efi n e d 
as:   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 nts   wit h o ut   b o n e   m et ast asis,   or  
el e v ati o n  of  A L P li v er fr a cti o n i n  p ati e nts  wit h  b o n e  m et ast asis.  
N ot e: ( T h e  R  v al u e is  c al c ul at e d  b y  di vi di n g t h e  A L T  b y t h e  A L P,  usi n g  m ulti pl es  of t h e  U L N 
f or   b ot h   v al u es.  It   d e n ot es  t h e  r el ati v e   p att er n   of   A L T   a n d/ or   A L P   el e v ati o n  is   d u e  t o  
c h ol est ati c ( R  ≤  2),  h e p at o c ell ul ar ( R  ≥  5),  or  mi x e d ( R  >  2  a n d  <  5) li v er i nj ur y)  
I n t h e  a bs e n c e  of  c h ol est asis, t h es e  p ati e nts s h o ul d  b e i m m e di at el y  dis c o nti n u e d fr o m st u d y 
dr u g tr e at m e nt,  a n d r e p e at  L F T t esti n g  as s o o n  as  p ossi bl e,  pr ef er a bl y  wit hi n  4 8  h o urs fr o m 
t h e  a w ar e n ess  of t h e  a b n or m al r es ults.  T h e  e v al u ati o n s h o ul d i n cl u d e l a b or at or y t ests,  d et ail e d 
hist or y,   p h ysi c al   ass ess m e nt   a n d  t h e   p oss i bilit y   of  li v er   m et ast asis   or   n e w  li v er  l esi o ns,  
o bstr u cti o ns/ c o m pr essi o ns,  et c.  
•   L a b or at or y t ests s h o ul d i n cl u d e  A L T,  A S T,  al b u mi n,  cr e ati n e  ki n as e, t ot al  bilir u bi n,  dir e ct 
a n d i n dir e ct  bilir u bi n,  G G T,  pr ot hr o m bi n ti m e ( P T)/I N R  a n d  al k ali n e   p h os p h at as e. 
•   A  d et ail e d  hist or y, i n cl u di n g r el e v a nt i nf or m ati o n, s u c h  as r e vi e w  of  et h a n ol,  c o n c o mit a nt 
m e di c ati o ns,  h er b al r e m e di es, s u p pl e m e nt  c o ns u m pti o n,  hist or y  of  a n y  pr e -e xisti n g li v er 
c o n diti o ns  or ris k f a ct ors, s h o ul d  b e  c oll e ct e d.  
•   F urt h er t esti n g f or  a c ut e  h e p atitis  A,  B,  C  or  E i nf e cti o n  a n d li v er i m a gi n g ( e g,  bili ar y tr a ct) 
m a y  b e  w arr a nt e d.  
•   O bt ai n  P K s a m pl e,  as  cl os e  as  p ossi bl e t o l ast  d os e  of st u d y  dr u g, if  P K  a n al ysis is 
p erf or m e d i n t h e  st u d y. 
•   A d diti o n al t esti n g f or  ot h er  h e p at otr o pi c  vir al i nf e cti o n ( C M V,  E B V  or  H S V), 
a ut oi m m u n e  h e p atitis  or li v er  bi o ps y  m a y  b e  c o nsi d er e d  as  cli ni c all y i n di c at e d  or  aft er 
c o ns ult ati o n  wit h  s p e ci alist/ h e p at ol o gist.  
All  c as es  c o nfir m e d  o n r e p e at t esti n g  m e eti n g t h e l a b or at or y  crit eri a  d efi n e d  a b o v e,  wit h  n o 
ot h er  alt er n ati v e  c a us e f or  L F T  a b n or m aliti es i d e ntifi e d s h o ul d  b e  c o nsi d er e d  as  “ m e di c all y 
si g nifi c a nt ”, t h us,  m et t h e  d efi niti o n  of  S A E ( S e cti o n  8. 2. 1 )  a n d r e p ort e d  as  S A E  usi n g t h e 
t er m  “ p ot e nti al  dr u g-i n d u c e d li v er i nj ur y ”.  All  e v e nts s h o ul d  b e f oll o w e d  u p  wit h t h e  o ut c o m e 
cl e arl y  d o c u m e nt e d.  
 
1 4. 3. 3   
L D K 3 7 8  
 
G ui d eli n e s f or t h e f oll o w -u p  of l a b or at or y  h e m at ol o gi c  a b n or m aliti e s  
I n  c as e  of  a n y  o c c urr e n c e  of f e bril e  n e utr o p e ni a,  n e utr o p e ni a  ≥  gr a d e  3,  or t hr o m b o c yt o p e ni a 
≥  gr a d e  3, t ests  m ust  b e  p erf or m e d  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 t h e 
e v e nt r es ol v es t o  ≤  gr a d e  2.  S u bs e q u e nt  m o nit ori n g  m ust  b e  p erf or m e d  e v er y  4  w e e ks.  Pl e as e 
als o r ef er t o  T a bl e  1 4 - 1 2. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 6 4
0  Pr ot o c ol  N o. 
 
 
 
G ui d eli n e s f or t h e f oll o w -u p  of l a b or at or y li v er  a b n or m aliti e s  
I n  p ati e nts  wit h  a n y  cli ni c all y r el e v a nt l a b or at or y li v er  a b n or m alit y,  as  d efi n e d  b el o w,  h ep ati c 
t o xi cit y  m o nit ori n g  m ust i n cl u d e  A L L  of t h e f oll o wi n g li v er f u n cti o n t ests ( L F Ts):  al b u mi n, 
A S T,  A L T, t ot al  bilir u bi n (fr a cti o n at e d if t ot al  bilir u bi n  > 2. 0  x  U L N),  al k ali n e  p h os p h at as e 
a n d   G G T).   N ot e:  f or   p ati e nts   wit h   Gil b ert   S y n dr o m e,  t ot al   a n d   dir e ct   bilir u bi n   m ust   b e  
m o nit or e d,  b ut i nt e nsifi e d  m o nit ori n g  a p pli es t o  c h a n g es i n  dir e ct  bilir u bi n  o nl y.  
I n  c as e  of  a n y  o c c urr e n c e  of  A S T/ A L T/t ot al  bilir u bi n i n cr e as e t o  gr a d e  2, t h e  L F Ts  m ust  b e 
m o nit or e d   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  t h e  e v e nt  r es ol v es  t o  ≤ 
gr a d e   1.   T h er e aft er   m o nit ori n g   m ust   b e   c o nti n u e d   e v er y   ot h er   w e e k  ( or   m or e  fr e q u e ntl y  if  
cli ni c all y i n di c at e d) f or t w o  a d diti o n al  c y cl es ( e. g.  8  w e e ks). If t h er e is  n o r e c urr e n c e  of  gr a d e 
2   A S T/ A L T/t ot al   bilir u bi n   el e v ati o ns   d uri n g  t his   p eri o d,  s u bs e q u e nt   m o nit ori n g   m ust   b e  
p erf or m e d  e v er y  4  w e e ks.  F or  p ati e nts  wit h li v er  m et ast asis  a n d  gr a d e  2  A S T/ A L T  at  b as eli n e, 
i n cr e as e d   m o nit ori n g  is  r e q uir e d  f or  gr a d e  3/ 4   A S T/ A L T;  f oll o w  g ui d eli n es  f or  gr a d e  3  or  4 
A S T/ A L T.  
I n  c as e  of  an y  o c c urr e n c e  of  A S T/ A L T/t ot al  bilir u bi n i n cr e as e t o  gr a d e  3  or  4,  L F Ts  m ust  b e 
m o nit or e d    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  t h e  e v e nt  r es ol v es  t o  ≤ 
gr a d e  1 ( or t o  b as eli n e).  T h er e aft er  m o nit ori n g  m ust  b e  c o nti n u e d  e v er y  ot h er  w e e k ( or  m or e 
fr e q u e ntl y  if   cli ni c all y  i n di c at e d)  f or  f o ur   a d diti o n al   c y cl es  ( e. g.   1 6   w e e ks).  If  t h er e  is   n o  
r e c urr e n c e  of  ≥  gr a d e  2    A S T/ A L T/t ot al  bilir u bi n  el e v ati o ns  d uri n g  t his  p eri o d,  s u bs e q u e nt 
m o nit ori n g  m ust  b e  p erf or m e d  e v er y  4  w e e ks.  
P ati e nts  w h o  dis c o nti n u e st u d y tr e at m e nt  d u e t o li v er t o xi cit y  m ust  b e  m o nit or e d  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  t h e  e v e nt  r es ol v es  t o  ≤  gr a d e  1  or  st a bili z ati o n 
o c c urs ( n o  C T C A E  gr a d e  c h a n g e  o v er  4  w e e ks).  R ef er t o  T a bl e  1 4 - 8. 
P ati e nts   wit h  tr a ns a mi n as e  i n cr e as e   c o m bi n e d   wit h  t ot al   bilir u bi n  ( T BI L)  i n cr e as e   m a y   b e  
i n di c ati v e  of  p ot e nti al  DI LI,  a n d s h o ul d  b e  c o nsi d er e d  as  cli ni c all y i m p ort a nt  e v e nts. 
R ef er t o  S e cti o n  1 4. 3. 2  ( 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 as es) 
 
G ui d eli n e s f or t h e f oll o w -u p  of l a b or at or y r e n al  a b n or m aliti e s  
I n  c as e  of  a n y  o c c urr e n c e  of s er u m  cr e ati ni n e  gr a d e  2, t ests  m ust  b e  p erf or m e d  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  t h e   e v e nt  r es ol v es  t o   ≤  gr a d e  1.   S u bs e q u e nt 
m o nit ori n g  m ust  b e  p erf or m e d  e v er y  4  w e e ks.  
I n  c as e  of  a n y  o c c urr e n c e  of s er u m  cr e ati ni n e  ≥  gr a d e  3, t ests  m ust  b e  p erf or m e d t wi c e  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  t h e  e v e nt  r es ol v es  t o  ≤  gr a d e  1.  S u bs e qu e nt 
m o nit ori n g  m ust  b e  p erf or m e d  e v er y  4  w e e ks.  R ef er t o  T a bl e  1 4 - 8. 
 
G ui d eli n e s f or  m o nit ori n g  p n e u m o niti s  
M o nit or   p ati e nts f or   p ul m o n ar y s y m pt o ms i n di c ati v e  of   p n e u m o nitis.  I n  a d diti o n,   wit h h ol d 
c eriti ni b  f or   a c ut e   o ns et   o f   n e w   or   pr o gr essi v e   u n e x pl ai n e d   p ul m o n ar y  s y m pt o ms,  s u c h   as  
d ys p n e a,  c o u g h  a n d f e v er  a n d  d uri n g  di a g n osti c  w or k u p f or  p n e u m o nitis/I L D.  
S e e  als o  d os e  m o difi c ati o n  g ui d eli n es  d es cri b e d i n  T a bl e  1 4 - 8. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 6 5
0  Pr ot o c ol  N o. 
 
 
 
G ui d eli n e s f or t h e tr e at m e nt  of  st u d y tr e at m e nt i n d u c e d  di arr h e a  
R ef er t o  S e cti o n  1 4. 3. 1  ( G ui d eli n e f or tr e at m e nt  of st u d y i n d u c e d  di arr h e a f or  B Y L 7 1 9) 
 
G ui d eli n e s f or t h e tr e at m e nt  of  st u d y tr e at m e nt i n d u c e d  n a u s e a  a n d  v o miti n g  
N a us e a  a n d  v o miti n g  ar e  a m o n g t h e  m ost fr e q u e ntl y r e p ort e d  A Es f oll o wi n g tr e at m e nt  wit h 
L D K 3 7 8  a n d  p ati e nts  m ust t h er ef or e  b e  cl os el y  m o nit or e d f or t h e  a p p e ar a n c e  of t h es e  A Es. 
T h e  i n v esti g at or  s h o ul d   c o nsi d er/i n v esti g at e   p ot e nti al   c o n c o mit a nt   m e di c ati o n,  f o o d   or  
c o m or bi dit y  dri v e n  c a us es  of  n a us e a  a n d/ or  v o miti n g  a n d r e m e d y t h es e  c a us e s if  p ossi bl e ( e. g. 
dis c o nti n u ati o n  of  c o n c o mit a nt  m e di c ati o n,  di et ar y  m o difi c ati o n, tr e at m e nt  of  c o m or bi dit y). 
I n di vi d u ali z e d s u p p orti v e  a n d  a nti-e m eti c tr e at m e nt s h o ul d  b e i niti at e d,  as  a p pr o pri at e,  at t h e 
first  si g ns  a n d/ or  s y m pt o ms  of  t h es e  A Es.  I n  p ati e nts  wit h  v o miti n g,  t h e  p ati e nt  s h o ul d  b e 
m o nit or e d  f or  si g ns   of   d e h y dr ati o n   a n d  i nstr u ct e d  t o  t a k e   pr e v e nti v e   m e as ur es   a g ai nst  
d e h y dr ati o n. 
C o n c o mit a nt   m e di c ati o n  f or  t h e  tr e at m e nt   of   n a us e a   a n d/ or   v o miti n g  s h o ul d  f oll o w  l o c al  
pr a cti c e   a n d  t h e  i n v esti g at or’s   b est  j u d g m e nt.   F or   m o d er at e   e m et o g e ni c   dr u gs,  s u c h   as  
L D K 3 7 8, I nt er n ati o n al  G ui d eli n es f or  a nti -e m eti c tr e at m e nt r e c o m m e n d  e arl y tr e at m e n t  wit h 
5- H T 3 -r e c e pt or  a nt a g o nists ( 5-H T 3 R As).  
D os e  a d a pt ati o n  of  c eriti ni b i n  c as e  of tr e at m e nt r el at e d  n a us e a  a n d/ or  v o miti n g  m ust f oll o w 
t h e  g ui d eli n es  pr es e nt e d  a b o v e i n T a bl e  1 4 - 1 2. 
 
G ui d eli n e s f or tr e at m e nt  of  h y p o p h o s p h at e mi a  
I n  t h e  p h as e  I  st u d y  [ C L D K 3 7 8 X 2 1 0 1],   as   of   3 1-O ct -2 0 1 3,  t h er e   w er e   9   c as es   of   gr a d e   3  
h y p o p h os p h at e mi a i n  all  d os e  gr o u ps,  o n e  of  w hi c h  w as  a  D L T t h at  c o ntri b ut e d t o t h e  M T D 
d et er mi n ati o n  –  t his  p ati e nt  w as  a bl e t o  c o nti n u e  L D K 3 7 8  at t h e s a m e  d os e.  O n e  p ati e nt i n t h e 
7 5 0   m g   gr o u p   h a d   gr a d e   3   h y p o p h os p h at e mi a  t h at  r es ol v e d   aft er   d os e   a dj ust m e nt   or  
i nt err u pti o n;  i n  t h e  r e m ai ni n g  8  c as es,  p ati e nts    w er e  a bl e  t o  c o nti n u e  t h er a p y    wit h o ut  d os e 
m o difi c ati o n.    H y p o p h os p h at e mi a    w as   a   c o m m o nl y   r e p ort e d    A E   ( 6. 3 %) ,  r e g ar dl ess   of  
r el ati o ns hi p  t o  L D K 3 7 8  tr e at m e nt.   T h er ef or e,   p h os p h at e  l e v els   will   b e  c h e c k e d   at   b as eli n e  
a n d   d uri n g  tr e at m e nt.  I n   c as es   of   h y p o p h os p h at e mi a   at   b as eli n e,   p h os p h at e  s u p pl e m e nt s  
s h o ul d  b e st art e d  b ef or e tr e at m e nt  wit h  L D K 3 7 8.  F or  a n y  gr a d e  of  h y p o p h os p h at e mi a  d uri n g 
t h e st u d y, tr e at m e nt  wit h  p h os p h at e s u p pl e m e nts s h o ul d  b e  gi v e n  as  cli ni c all y i n di c at e d,  a n d 
t h e  L D K 3 7 8  d os e  c a n  b e  m ai nt ai n e d. 
 
G ui d eli n e s f or t h e f oll o w -u p  of l a b or at or y  p a n cr e ati c  a b n or m aliti e s  
I n   c as e   of   a n y   o c c urr e n c e   of  li p as e   or   a m yl as e  i n cr e as e  t o   gr a d e   3   or   4,   b ot h  li p as e   a n d  
a m yl as e  m ust  b e  m o nit or e d  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 t h e  e v e nt 
r es ol v es t o  ≤  gr a d e  1 ( or t o  b as eli n e). 
Aft er  r es u m pti o n   of   d osi n g,   m o nit ori n g   m ust   b e   c o nti n u e d   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) f or  o n e  a d diti o n al  c y cl e (i. e.  4  w e e ks). If t h er e is  n o r e c urr e n c e  of  ≥  gr a d e 
2  a m yl as e  or li p as e  el e v ati o ns  d uri n g t his  p eri o d, s u bs e q u e nt  m o nit ori n g  m ust  b e  p erf or m e d 
e v er y  4  w e e ks.  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 6 6
0  Pr ot o c ol  N o. 
 
 
 
P ati e nts  w h o  dis c o nti n u e st u d y tr e at m e nt  d u e t o  p a n cr e ati c t o xi cit y  m ust  b e  m o nit or e d  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 t h e  e v e nt r es ol v es t o  ≤  gr a d e  1  or  st a bili z ati o n 
o c c urs ( n o  C T C A E  gr a d e  c h a n g e  o v er  4  w e e ks).  R ef er t o  T a bl e  1 4 - 8. 
If   a m yl as e   a n d/ or  li p as e   el e v ati o ns   ar e   a c c o m p a ni e d   b y   n e w   or   pr o gr essi v e   u n e x pl ai n e d  
a b d o mi n al  s y m pt o ms  s u c h   as  s e v er e   p ai n   or   v o miti n g,   wit h h ol d   L D K 3 7 8,  t h e n   p erf or m  
di a g n osti c   pr o c e d ur es  ( e. g.,   a b d o mi n al   C T  s c a n   or   ultr as o u n d)  t o   e x cl u d e   p a n cr e ati c  
p at h ol o g y. 
S e e  als o f oll o w -u p  e v al u ati o n  d es cri b e d i n  T a bl e  1 4 - 1 2. 
 
T a bl e  1 4 -1 2  F oll o w -u p  e v al u ati o n s f or  s el e ct e d t o xi citi e s  
T o xi cit y   
F oll o w -u p  e v al u ati o n*  
I n v e sti g ati o n s 
( h e m at ol o gi c) 
 
I n v e sti g ati o n s 
( h e p ati c) 
 
 
 
 
 
 
 
 
 
I n v e sti g ati o n s 
(r e n al) 
 
 
 
 
I n v e sti g ati o n s 
( p a n cr e ati c) 
F e bril e  n e utr o p e ni a,  n e utr o p e ni a  or t hr o m b o c yt o p e ni a  ≥  C T C A E  Gr a d e  3  
T e st  w e e kl y ( or  m or e fr e q u e nt)  u ntil  ≤  Gr a d e  2  
S u b s e q u e nt  m o nit ori n g  m u st  b e  p erf or m e d  e v er y  c y cl e ( 4  w e e k s)  
T ot al  bilir u bi n/ A S T/ A L T  Gr a d e  2:  ( p ati e nt s  wit h li v er  m et a st a si s  a n d  gr a d e  2  AS T/ A L T  at 
b a s eli n e, i n cr e a s e d  m o nit ori n g r e q uir e d f or  gr a d e  3  A L T/ A S T.  F oll o w  g ui d eli n e s f or  gr a d e  3  or 
4  A S T/ A L T  
T e st  w e e kl y ( or  m or e fr e q u e ntl y)  u ntil  ≤  Gr a d e  1  
T h er e aft er,  c o nti n u e t o t e st  e v er y  2  w e e k s ( or  m or e fr e q u e ntl y) f or  2  c y cl e s ( 8  w e e k s) 
If  n o r e c urr e n c e  of  ≥  Gr a d e  2  e v e nt,  c o nti n u e  m o nit ori n g  e v er y  c y cl e ( 4  w e e k s) 
T ot al  bilir u bi n/ A L T/ A S T  ≥  Gr a d e  3:  
T e st  w e e kl y ( or  m or e fr e q u e nt)  u ntil  ≤  Gr a d e  1  
T h er e aft er,  c o nti n u e t o t e st  e v er y  2  w e e k s ( or  m or e fr e q u e ntl y) f or  4  c y cl e s ( 1 6  w e e k s) 
If  n o r e c urr en c e  of  ≥  gr a d e  2  e v e nt,  c o nti n u e  m o nit ori n g  e v er y  c y cl e ( 4  w e e k s) 
Di s c o nti n u ati o n  d u e t o li v er t o xi cit y:  
T e st  w e e kl y ( or  m or e fr e q u e nt)  u ntil  ≤  Gr a d e  1  or  st a bili z ati o n  
S er u m  cr e ati ni n e  Gr a d e  2:  
T e st  w e e kl y ( or  m or e fr e q u e nt)  u ntil  Gr a d e  1 
T h er e aft er, t e st  e v er y  c y cl e ( 4  w e e k s) 
S er u m  cr e ati ni n e  ≥  Gr a d e  3:  
T e st t wi c e  w e e kl y ( or  m or e fr e q u e nt)  u ntil  ≤  Gr a d e  1 
T h er e aft er, t e st  e v er y  c y cl e ( 4  w e e k s)  
A m yl a s e/li p a s e  ≥  Gr a d e  3:  
T e st  w e e kl y ( or  m or e fr e q u e ntl y)  u ntil  ≤  Gr a d e  1.  Aft er r e s u m pti o n  of  d o si n g,  c o nti n u e t o t e st 
w e e kl y f or  o n e  a d diti o n al  c y cl e ( 4  w e e k s). If  n o r e o c c urr e n c e  of  ≥  Gr a d e  2  e v e nt,  c o nti n u e 
m o nit ori n g  e v er y  c y cl e ( 4  w e e k s) . 
 
 
* N ot e: t hi s t a bl e r ef er s t o t h e  e v al u ati o n  s c h e d ul e  o nl y.  R ef er t o  T a bl e  1 4 -8  f or  d o s e  m o difi c ati o n s r e q uir e d f or 
a p pli c a bl e t o xi citi e s  
 
 
1 4. 3. 4   
M E K 1 6 2  
 
G ui d eli n e s f or t h e  m a n a g e m e nt  of  st u d y tr e at m e nt i n d u c e d  di arr h e a  
R ef er t o  S e cti o n  1 4. 3. 1  ( G ui d eli n e f or tr e at m e nt  of st u d y i n d u c e d  di arr h e a f or  B Y L 7 1 9) 
 
G ui d eli n e s f or t h e  m a n a g e m e nt  of  st u d y tr e at m e nt i n d u c e d  s ki n t o xi cit y  
Cli ni c al j u d g m e nt  a n d  e x p eri e n c e  of t h e tr e ati n g  p h ysi ci a n s h o ul d  g ui d e t h e  m a n a g e m e nt  pl a n 
of  e a c h  p ati e nt. I n  g e n er al, t h e f oll o wi n g i nt er v e nti o ns  ar e i n  a d diti o n t o t h e  d os e r e d u cti o n: 
•   Pr o p h yl a xis  of s ki n t o xi cit y t o  b e i niti at e d  2 4  h o urs  pri or t o t h e first tr e at m e nt  wit h 
M E K 1 6 2  or l at er  as  n e e d e d  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 6 7
0  Pr ot o c ol  N o. 
 
 
 
•   A p pli c ati o n  of t o pi c al  a g e nts t o t h e  m ost  c o m m o nl y  aff e ct e d s ki n  ar e as s u c h  as f a c e, s c al p, 
n e c k,  u p p er  c h est  a n d  u p p er  b a c k  
T o pi c al  a g e nts i n cl u d e  n o n -oil y s u ns cr e e n ( P A B A fr e e,  S P F  ≥  3 0,  U V A/ U V B  pr ot e cti o n), 
t o pi c al st er oi ds ( pr ef er a bl y  m o m et as o n e  cr e a m i. e.  El o c o n®  a n d t o pi c al  er yt hr o m y ci n 
e v e ni n g i. e.  Er y a k n e n ®  or t o pi c al  pi m o cr oli m us  
N ot e:  T o pi c al  a g e nts s h o ul d  b e  a p pli e d  o n  a  d ail y  b asis st arti n g  o n  D a y  1  of st u d y 
tr e at m e nt  or  2 4  h o urs  pri or t o t h e first  d os e,  a n d  m or e  oft e n  as  n e e d e d. 
•   P ossi bl y  or al  d o x y c y cli n e ( 1 0 0  m g  d ail y) f or t h e first  2 -3  w e e ks  of st u d y tr e at m e nt 
a d mi nistr ati o n.  
Ot h er  eff e cti v e  m e di c ati o ns  ar e  a nti hist a mi n es,  ot h er t o pi c al  c orti c ost er oi ds,  ot h er t o pi c al 
a nti bi oti cs  a n d l o w -d os e s yst e mi c  c orti c ost er oi ds.  
T h e tr e at m e nt  al g orit h m  b as e d  o n  C T C A E  gr a d e is  as f oll o ws:  
 
Mil d r a s h ( gr a d e  1)  
•   C o nsi d er  pr o p h yl a cti c r as h tr e at m e nt if  n ot  alr e a d y  st art e d 
•   T o pi c al  or  ot h er t o pi c al  c orti c ost er oi d (i. e.  m o m et as o n e  cr e a m)  a n d/ or t o pi c al  a nti bi oti c 
(i. e.  er yt hr o m y ci n  2 %)  ar e r e c o m m e n d e d. 
•   T h e  p ati e nt s h o ul d  b e r e ass ess e d  wit hi n  a  m a xi m u m  of  2  w e e ks  or  as  p er i n v esti g at or 
o pi ni o n.  
 
M o d er at e r a s h ( gr a d e  2)  
•   Us e   of  t o pi c al   er yt hr o m y ci n   or   cli n d a m y ci n   ( 1 %)   pl us   t o pi c al    m o m et as o n e   or 
pi m e cr oli m us   cr e a m  ( 1 %)   pl us   or al   a nti bi oti cs   s u c h   as:,  l y m e c y cli n e  ( 4 0 8    m g   q d), 
d o x y c y cli n e ( 1 0 0  m g  bi d)  or  mi n o c y cli n e ( 5 0 t o  1 0 0  m g   q d). 
•   Alt h o u g h t h er e  h as  b e e n  n o  e vi d e n c e  of  p h ot ot o xi cit y  or  p h ot os e nsiti vit y  i n p ati e nts  b ei n g 
tr e at e d  wit h  M E K 1 6 2,  d o x y c y cli n e ( or  mi n o c y cli n e  as s e c o n d-li n e) s h o ul d  b e  us e d  wit h 
t h or o u g h  U V  pr ot e cti o n (i. e.,  a v oi d a n c e  of  dir e ct  e x p os ur e t o s u nli g ht,  us e  of s u ns cr e e n 
a n d s u n gl ass e s,  et c.).  
•   Us e  of  a citr eti n  is  n ot r e c o m m e n d e d 
S e v er e r a s h ( gr a d e  3 -4)  
Gr a d e  3  
•   I n   a d diti o n  t o  t h e  i nt er v e nti o ns  r e c o m m e n d e d  f or   m o d er at e  r as h,   c o nsi d er   or al  
pr e d nis ol o n e   at   a   d os e   of   0. 5   m g/ k g.   U p o n  i m pr o v e m e nt,  t a p er  t h e   d os e  i n   a  st e p wis e  
m a n n er ( 2 5  m g f or  7  d a ys, s u bs e q u e ntl y  d e cr e asi n g t h e  d os e  b y  5  m g/ d a y  e v er y   d a y). 
•   Alt er n ati v e l y, i n  a d diti o n t o t h e i nt er v e nti o ns r e c o m m e n d e d f or  m o d er at e r as h,  c o nsi d er 
or al is otr eti n oi n (l o w  d os es, i. e.  0. 3 t o  0. 5  m g/ k g) ( L a c o ut ur e  et  al   2 0 1 1) 
•   Us e  of  a citr eti n is  n ot  r e c o m m e n d e d 
Gr a d e  4  
•   I m m e di at el y  dis c o nti n u e t h e  p ati e nt fr o m st u d y tr e at m e nt  a n d tr e at t h e  p ati e nt  wit h  or al 
a n d t o pi c al  m e di c ati o ns (s e e r e c o m m e n d ati o n  gr a d e   3). 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 6 8
0  Pr ot o c ol  N o. 
 
 
 
S y m pt o m ati c tr e at m e nt:  
It is str o n gl y r e c o m m e n d e d t h at  p ati e nts  w h o  d e v el o p r as h/s ki n t o xi cities r e c ei v e s y m pt o m ati c 
tr e at m e nt: 
•   F or  pr uriti c l esi o ns,  us e  c o ol  c o m pr ess es  a n d  or al  a nti hist a mi ni c  a g e nts  
•   F or fiss uri n g,  us e  M o ns el’s s ol uti o n, sil v er  nitr at e,  or  zi n c  o xi d e  cr e a m. If  n ot s uffi ci e nt 
us e  mil d st er oi d  oi nt m e nts  or  c o m bi n ati o ns  of st er oi ds  a n d  a nti bi oti cs s u c h  as  F u ci c ort ®  
•   F or  d es q u a m ati o n,  us e  e m olli e nts  wit h  mil d  p H  5/ n e utr al ( b est  c o nt ai ni n g  ur e a  1 0 %)  
•   F or  p ar o n y c hi a,  a ntis e pti c  b at h  a n d l o c al  p ot e nt  c orti c ost er oi ds,  us e  or al  a nti bi oti cs  a n d if 
n o i m pr o v e m e nt is s e e n, r ef er t o  a  d er m at ol o gist  or  s ur gi o n 
•   F or i nf e ct e d l esi o ns,  o bt ai n  b a ct eri al  a n d f u n g al  c ult ur es  a n d tr e at  wit h t o pi c al  or s yst e mi c 
a nti bi ot i cs  b as e d  o n s e nsiti vit y  of  c ult ur e 
1 4. 3. 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)  
B us ai d y  N L,  F ar o o ki  A,  D o wl ati  A,  et  al. ( 2 0 1 2).  M a n a g e m e nt  of  m et a b oli c  eff e cts  ass o ci at e d 
wit h  a nti c a n c er  a g e nts t ar g eti n g t h e  PI 3 K  -A kt -m T O R  p at h w a y. J  Cli n  O n c ol. 1 0; 3 0( 2 3): 2 9 1 9 - 
2 8. 
L a c o ut ur e  M E,  A n a d k at  MJ,  B e ns a d o u n  RJ,  Br y c e J,  et  al ( 2 0 1 1)  Cli ni c al  pr a cti c e  g ui d eli n es 
f or t h e  pr e v e nti o n  a n d tr e at m e nt  of  E G F R i n hi bit or-ass o ci at e d  d er m at ol o gi c t o xi citi es.  
S u p p ort  C ar e  C a n c er;  1 9:  1 0 7 9 – 9 5.  
K or n bl a u  S,  B e ns e n  A B,  C at al a n o  R,  et  al ( 2 0 0 0)  M a n a g e m e nt  of  c a n c er tr e at m e nt -r el at e d 
di arr h e a: Iss u es  a n d t h er a p e uti c str at e gi es. J o ur n al  of  P ai n  a n d  S y m pt o m  M a n a g e m e nt; 
1 9: 1 1 8- 1 2 9. 
W a dl er  S,  B e ns o n  A B,  E n g el ki n g  C,  et  al ( 1 9 9 8)  R e c o m m e n d e d  g ui d eli n es f or t h e tr e at m e nt 
of  c h e m ot h er a p y -i n d u c e d  diarr h e a. J  Cli n  O n c ol;  1 6: 3 1 6 9 - 7 8. 


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 6 9
9  Pr ot o c ol  N o. 
 
 
 
 
 
1 4. 4  
C o n c o mit a nt  M e di c ati o n s  Pr o hi bit e d  or  P er mitt e d  wit h  C a uti o n 
If  a  m e di c ati o n is list e d i n  b ot h T a bl e  1 4 - 1 3 a n d  T a bl e  1 4 - 1 4 f or  a  c ert ai n tr e at m e nt  ar m,  m or e 
stri n g e nt  pr a cti c e s h all  b e  a p pli e d (t h at is, t h e  m e di c ati o n s h all  b e  pr o hi bit e d  as i n  T a bl e  1 4 - 
1 4 ). 
 
T a bl e  1 4 -1 3  P er mitt e d  c o n c o mit a nt  m e di c ati o n s r e q uiri n g  c a uti o n  
M e c h a ni s m  of I nt er a cti o n   
Dr u g  N a m e  
 
M o d er at e  C Y P 3 A 4 i n hi bit or   
a m pr e n a vir,  a pr e pit a nt,  at a z a n a vir,  c a s o pit a nt,  ci m eti di n e,  ci pr of l o x a ci n, 
cri z oti ni b,  c y cl o s p ori n,  d ar u n a vir/rit o n a vir,  dilti a z e m,  dr o n e d ar o n e, 
er yt hr o m y ci n, fl u c o n a z ol e, f o s a m pr e n a vir, i m ati ni b, l o mit a pi d e,  n et u pit a nt, 
nil oti ni b,  s c hi s a n dr a  s p h e n a nt h er a( W u  W ei  Zi), t ofi s o p a m,  v er a p a mil  
 
M o d er at e  C Y P 3 A 4 i n d u c er   
b o s e nt a n,  ef a vir e n z,  etr a viri n e,  g e ni st ei n, l er si viri n e, l o pi n a vir,  m o d afi nil,  
n af cilli n, rit o n a vir,  s e m a g a c e st at, t al vir ali n e, t hi ori d a zi n e,  
 
S e n siti v e  C Y P 1 A 2  s u b str at e   
al o s etr o n,  c aff ei n e,  d ul o x eti n e,  m el at o ni n, r a m elt e o n,  s el e gili n e,  t a cri n e, 
ti z a ni di n e 
 
S e n siti v e  C Y P 2 C 9  s u b str at e   
C el e c o xi b, ( S) -W arf ari n 
C Y P 2 C 9  s u b str at e  wit h  N TI  
( S)-W arf ari n,  P h e n yt oi n  
 
S e n siti v e  C Y P 2 C 1 9  s u b str at e   
cl o b a z a m,  d e xl a n s o pr a z ol e,  di a z e p a m,  gli cl a zi d e, l a n s o pr a z ol e,  ( R)- 
m e p h o b ar bit al,  o m e pr a z ol e,  p a nt o pr a z ol e, ( +)  p a nt o pr a z ol e, r a b e pr a z ol e, 
tili di n e 
 
S e n siti v e  C Y P 2 C 8  s u b str at e   
R e p a gli ni d e 
C Y P 2 C 8  s u b str at e  wit h  N TI   
p a clit a x el  
S e n siti v e  C Y P 3 A 4  s u b str at e   
dr o n e d ar o n e,  e b a sti n e,  br oti z ol a m,  mi d a z ol a m, tri a z ol a m,  f el o di pi n e, 
ni s ol di pi n e,  br e c a n a vir,  c a pr a viri n e,  d ar u n a vir,  at or v a st ati n, l o v a st ati n, 
si m v a st ati n,  e v er oli m u s, l ur a si d o n e,  p er o s pir o n e,  q u eti a pi n e, l e v o m et h a d yl, 
b u d e s o ni d e, fl uti c a s o n e,  sil d e n afil,  v ar d e n afil,  a pr e pit a nt,  c a s o pit a nt,  al p h a - 
di h y dr o er g o cr y pti n e,  a pl a vir o c,  b u s pir o n e,  d arif e n a ci n,  el etri pt a n,  e pl er e n o n e, 
l u m ef a ntri n e,  m ar a vir o c, ri d af or oli m u s, ti c a gr el or, t ol v a pt a n,  vi cri vir o c, 
alf e nt a nil,  al m or e x a nt,  at a z a n a vir,  a v a n afil,  b o s uti ni b,  c o ni v a pt a n,  d a n o pr e vir, 
d a s ati ni b,  el vit e gr a vir, i br uti ni b, i n di n a vir, i v a c aft or, l o mit a pi d e, l o pi n a vir, 
mi d o st a uri n,  n er ati ni b,  s a q ui n a vir,  si m e pr e vir, ti c a gr el or, t erf e n a di n e, tili di n e, 
ti pr a n a vir,  v o cl o s p ori n 
 
P- g p  i n hi bit or 
al o gli pti n,  a mi o d ar o n e,  a zit hr o m y ci n,  c a n a glif o zi n,  c a pt o pril,  c ar v e dil ol, 
cl ar it hr o m y ci n,  c o ni v a pt a n,  cr e m o p h or  R H 4 0,  c ur c u mi n,  dilti a z e m, 
dr o n e d ar o n e,  el a cri d ar,  er yt hr o m y ci n, f el o di pi n e, fl u v o x a mi n e,  gi n k o, i n di n a vir, 
i n di n a vir/rit o n a vir, itr a c o n a z ol e,  k et o c o n a z ol e, l a p ati ni b, l o pi n a vir/rit o n a vir, 
mi b efr a dil,  mil k t hi sl e,  mir a b e gr o n,  n elfi n a vir,  nif e di pi n e,  nitr e di pi n e, 
p ar o x eti n e,  pr o p af e n o n e,  q u er c eti n,  q ui ni di n e, r a n ol a zi n e, rif a m pi n, rit o n a vir, 
s e q ui n a vir/rit o n a vir,  s c hi s a n dr a  c hi n e si s  e xtr a ct,  si m e pr a vir,  St.  J o h n’ s  w ort 
e xtr a ct, t ali n ol ol, t el a pr e vir, t el mi s art a n, ti c a gr el or,  ti pr a n a vir/rit o n a vir, 
t ol v a pt a n,  v al s p o d ar,  v a n d et a ni b,  v er a p a mil, v o cl o s p ori n  
 
P- g p  i n d u c er 
a v a si mi b e,  c ar b a m a z e pi n e,  ef a vir e n z,  g e ni st ei n,  p h e n yt oi n,  q u er c eti n, 
rif a m pi n,  St.  J o h n’ s  W ort e xtr a ct  
 
P- g p  s u b str at e  wit h  N TI   
c y cl o s p ori n e,  di g o xi n, f e nt a n yl,  p a clit a x el,  p h e n yt oi n,  q ui ni di n e,  sir oli m u s,  
t a cr oli m u s 
 
H 2 r e c e pt or  a nt a g o ni st  
Ci m eti di n e, r a niti d i n e, f a m oti di n e,  ni z ati di n e. 
T a k e  m e di c ati o n  a s i n str u ct e d i n  S e cti o n  6. 3. 2 . 
 
U G T 1 A 1  i n hi bit or s 
at a z a n a vir,  erl oti ni b,  fl u nitr a z e p a m, g e mfi br o zil,  i n di n a vir, k et o c o n a z ol e,  
nil oti ni b,  p a z o p a ni b,  pr o p of ol, r e g or af e ni b,  s or af e ni b,  sil y b u m  m ari a n u m  
( h er b al  al s o  k n o w n  a s  mil k t hi stl e), v al eri a n a  offi c i n ali s ( h er b al), 
U G T 1 A 1 i n d u c er s  
c ar b a m a z e pi n e, rif a m pi ci n, t e st o st er o n e  pr o pi at e,  ci g ar ett e  s m o k e  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 7 0
9  Pr ot o c ol  N o. 
 
 
 
 
 
M e c h a ni s m  of I nt er a cti o n   
Dr u g  N a m e  
B C R P i n hi bit or s  
a b a c a vir,  a m pr e n a vir,  at a z a n a vir,  at or v a st ati n,  c eri v a st ati n,  c y cl o s p ori n e,  
d a u n o m y ci n,  d el a vir di n e,  ef a vir e n z,  el a cri d ar,  eltr o m b o p a g,  erl oti ni b, 
fl u v a st ati n, f u mitr e m or gi n,  g efiti ni b, l o pi n a vir,  n elfi n a vir,  nil oti ni b,  pit a v a st ati n, 
r o s u v a st ati n,  s a q ui n a vir,  si m v a st ati n,  s ulf a s al a zi n e,  S N-3 8 (iri n ot e c a n), 
p a nt o pr a z ol e 4  
 
B C R P  s u b str at e  
at or v a st ati n  d a u n or u bi ci n,  d o x or u bi ci n,  
h e m at o p or p h yri n, i m ati ni b,  m et h otr e x at e,  mit o x a ntr o n e,  pit a v a st ati n, 
r o s u v a st ati n,  S N-3 8 (iri n ot e c a n),  et hi n yl e str a di ol,  si m v a st ati n,  s ulf a s al a zi n e, 
s of o s b u vir, t o p ot e c a n,  s ulf a s al a zi n e  
 
M A T E  s u b str at e  
m etf or mi n, t e nf o vir  
 
O A T P  s u b str at e s  
ali s kir e n,  a m bri s e nt a n,  a n a c etr a pi b,  at e n ol ol, 
atr a s e nt a n,  at or v a st ati n,  b o s e nt a n,  br o m o ci pti n e, 
c a s p of u n gi n,  c eri v a st ati n,  c eli pr ol ol,  d a n o pr e vir,  
e m p a n glifl o zi n,  e z eti mi b e, fi m a s art a n, f e x of e n a di n e, fl u v a st ati n,  gl y b uri d e, 
m ar a vir o c,  S N -3 8, r o s u v a st ati n,  si m v a st ati n  a ci d,  pit a v a st ati n,  pr a v a st ati n, 
r e p a gli ni d e, rif a m pi n,  v al s art a n,  ol m e s art a n, t el mi s art a n, 
m o nt el u k a st, ti cl o pi di n e  
 
Pr ot o n  p u m p  i n hi bit or s 
O m e pr a z ol e,  p a nt o pr a z ol e, l a n s o pr a z ol e,  e s o m e pr a z ol e,  r a b e pr a z ol e, 
d e xl a n s o pr a z ol e  
 
S o ur c e:  A d a pt e d fr o m  O n c ol o g y  Cli ni c al  P h ar m a c ol o g y  Dr u g -Dr u g I nt er a cti o n  D at a b a s e (r el e a s e  d at e:  A pr  2 0 1 5) 
w hi c h  w a s  c o m pil e d fr o m t h e I n di a n a  U ni v er sit y  S c h o ol  of  M e di ci n e’ s “ Cli ni c all y  R el e v a nt”  T a bl e  a n d 
s u p pl e m e nt e d  wit h t h e  F D A  Dr aft  G ui d a n c e f or I n d u str y,  Dr u g I nt er a cti o n  St u di e s  –  St u d y  D e si g n,  D at a  A n al y si s, 
a n d I m pli c ati o n s f or  D o si n g  a n d  L a b eli n g ( F e br u ar y  2 0 1 2),  a n d t h e  U ni v er sit y  of  W a s hi n gt o n’ s  Dr u g I nt er a cti o n 
D at a b a s e  
T h e li st s  pr o vi d e d  m a y  n ot  b e  e x h a u sti v e 
S e n siti v e  s u b str at e s:  Dr u g s t h at  e x hi bit  a n  A U C r ati o ( A U Ci/ A U C)  of  5 -f ol d  or  m or e  w h e n  c o-a d mi ni st er e d  wit h  a 
k n o w n  p ot e nt i n hi bit or.  
 
 
T a bl e  1 4 -1 4   
Pr o hi bit e d  c o n c o mit a nt  m e di c ati o n s  
M e c h a ni s m  of I nt er a cti o n   
Dr u g  N a m e  
Str o n g  C Y P 3 A 4 i n hi bit or 
( B Y L 7 1 9, I N C 2 8 0, L D K 3 7 8)  
 
 
 
Str o n g  C Y P 3 A 4 i n d u c er 
( B Y L 7 1 9, I N C 2 8 0, L D K 3 7 8)  
C Y P 1 A 2  s u b str at e  wit h  N TI 
(I N C 2 8 0) 
C Y P 3 A 4  s u b str at e  wit h  N TI 
(I N C 2 8 0,  L D K 3 7 8) 
 
C Y P 2 C 9  s u b str at e  wit h  N TI 
( L D K 3 7 8) 
Pr ot o n  p u m p i n hi bit or s 
( M E K 1 6 2) 
E n z y m e- i n d u ci n g  a nti-e pil e pti c 
dr u g s  
( L D K 3 7 8) 
b o c e pr e vir,  cl arit hr o m y ci n,  c o bi ci st at,  c o ni v a pt a n,  gr a p efr uit j ui c e, 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,  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, t el a pr e vir, t elit hr o m y ci n,  v ori c o n a z ol e, 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, i n di n a vir/rit o n a vir, l o pi n a vir/rit o n a vir, 
s a q ui n a vir/rit o n a vir, ti pr a n o a vir/rit o n a vir,  J o pi n a vir  
a v a si mi b e,  c ar b a m a z e pi n e,  e n z al ut a mi d e,  mit ot a n e,  p h e n o b ar bit al,  p h e n yt oi n, 
rif a b uti n, rif a m pi n,  St.  J o h n’ s  w ort, 
t h e o p h ylli n e, ti z a ni di n e, 
 
alf e nt a nil,  a st e mi z ol e,  ci s a pri d e,  c y cl o s p ori n e,  di er g ot a mi n e, 
di h y dr o er g ot a mi n e,  er g ot a mi n e, f e nt a n yl,  pi m o zi d e,  q ui ni di n e,  sir oli m u s, 
t a cr oli m u s, t erf a n a di n e, t hi ori d a zi n e, 
w arf ari n,  p h e n yt oi n  
 
O m e pr a z ol e,  p a nt o pr a z ol e, l a n s o pr a z ol e,  e s o m e pr a z ol e, r a b e pr a z ol e, 
d e xl a n s o pr a z ol e  
C ar b a m a z e pi n e,  et h ot oi n, f el b a m at e, f o s p h e n yt oi n,  p h e n o b ar bit al,  p h e n yt oi n, 
pri mi d o n e, t o pir a m at e  
 
S o ur c e:  A d a pt e d fr o m  O n c ol o g y  Cli ni c al  P h ar m a c ol o g y  Dr u g -Dr u g I nt er a cti o n  D at a b a s e (r el e a s e  d at e:  A pr  2 0 1 5) 
w hi c h  w a s  c o m pil e d fr o m t h e I n di a n a  U ni v er sit y  S c h o ol  of  M e di ci n e’ s “ Cli ni c all y  R el e v a nt”  T a bl e  a n d 
s u p pl e m e nt e d  wit h t h e  F D A  Dr aft  G ui d a n c e f or I n d u str y,  Dr u g I nt er a cti o n  St u di e s  –  St u d y  D e si g n,  D at a  A n al y si s, 
a n d I m pli c ati o n s f or  D o si n g  a n d  L a b eli n g ( F e br u ar y  2 0 1 2),  a n d t h e  U ni v er sit y  of  W a s hi n gt o n’ s  Dr u g I nt er a cti o n  


N o v arti s  
A m e n d e d  Pr ot o c ol  V er si o n  0 7 ( Cl e a n)  
C o nfi d e nti al  
P a g e  1 7 1
1  Pr ot o c ol  N o. 
 
 
 
 
M e c h a ni s m  of I nt er a cti o n   
Dr u g  N a m e 
D at a b a s e.  T hi s li st s  pr o vi d e d  m a y  n ot  b e  e x h a u sti v e. 
N TI:  n arr o w t h er a p e uti c i n d e x  
 
 
T a bl e  1 4 -1 5   
M e di c ati o n s  wit h ri s k  o f T d P/ Q T  
 
M e di c ati o n s 
wit h  a  k n o w n 
ri s k t o  pr ol o n g 
t h e  Q T i nt er v al 
a n d/ or  k n o w n  t o 
c a u s e  T or s a d e s 
d e  P oi nt e  
a mi o d ar o n e,  a n a gr eli d e,  ar s e ni c tri o xi d e,  a st e mi z ol e ( off  U S  m kt),  a zit hr o m y ci n,  b e pri dil ( off 
U S  m kt),  c hl or o q ui n e,  c hl or pr o m a zi n e,  ci s a pri d e ( off  U S  m kt),  cit al o pr a m,  cl arit hr o m y ci n, 
c o c ai n e,  di s o p yr a mi d e,  d of etili d e,  d o m p eri d o n e ( n ot  o n  U S  m kt),  dr o n e d ar o n e,  dr o p eri d ol, 
er yt hr o m y ci n,  e s cit al o pr a m, fl e c ai ni d e,  gr e p afl o x a ci n ( off  m ar k et  w orl d wi d e),  h al of a ntri n e, 
h al o p eri d ol, i b utili d e, l e v ofl o x a ci n, l e v o m et h a d yl ( off  U S  m kt),  m e s ori d a zi n e ( off  U S  m kt), 
m et h a d o n e,  m o xifl o x a ci n,  o n d a n s etr o n,  p e nt a mi di n e,  pi m o zi d e,  pr o b u c ol ( off  U S  m kt), 
pr o c ai n a mi d e ( or al  off  U S  m kt),  q ui ni di n e,  s e v ofl ur a n e,  s ot al ol,  s p arfl o x a ci n ( off  U S  m kt), 
s ul piri d e ( n ot  o n  U S  m kt), t erf e n a di n e ( off  U S  m kt), t hi ori d a zi n e,  v a n d et a ni b  
F or  a  c o m pr e h e n si v e li st  of  dr u g s , r ef er t o  w w w. qt dr u g s. or g 
P o s si bl e ri s k  of 
T d P/ Q T 
pr ol o n g ati o n  
g atifl o x a ci n,  g e mifl o x a ci n,  ofl o x a ci n, t elit hr o m y ci n,  cl o z a pi n e, il o p eri d o n e,  p ali p eri d o n e, 
q u eti a pi n e, ri s p eri d o n e,  s erti n d ol e,  zi pr a si d o n e,  d ol a s etr o n,  gr a ni s ertr o n,  v e n l af a xi n e, 
r a n ol a zi n e,  v ori c o n a z ol e,  a m a nt a di n e, f o s c ar n et, i sr a di pi n e,  m o e xi pril,  ni c ar di pi n e, fi n g oli m o d, 
t a cr oli m u s,  at a z a n a vir, f el b a m at e, f a m oti di n e, f o s p h e n yt oi n,  alf u z o si n,  c hl or al  h y dr at e, 
i n d a p a mi d e, lit hi u m,  o ct e ori d e,  p a sir e oti d e,  o x yt o ci n, r a n ola zi n e, ti z a ni di n e,  v ar d e n afil  
S o ur c e:  A d a pt e d fr o m  O n c ol o g y  Cli ni c al  P h ar m a c ol o g y  Dr u g -Dr u g I nt er a cti o n  D at a b a s e (r el e a s e  d at e:  A pril  2 0 1 5) 
w hi c h  w a s  c o m pil e d fr o m t h e I n di a n a  U ni v er sit y  S c h o ol  of  M e di ci n e’ s “ Cli ni c all y  R el e v a nt”  T a bl e  a n d 
s u p pl e m e nt e d  wit h t h e  F D A  Dr aft  G ui d a n c e f or I n d u str y,  Dr u g I nt er a cti o n  St u di e s  –  St u d y  D e si g n,  D at a  A n al y si s, 
a n d I m pli c ati o n s f or  D o si n g  a n d  L a b eli n g ( F e br u ar y  2 0 1 2),  a n d t h e  U ni v er sit y  of  W a s hi n gt o n’ s  Dr u g I nt er a cti o n  
D at a b a s e.  T h e li st s  pr o vi d e d  m a y  n ot  b e  e x h a u sti v e.  
 

SAP_001.pdf: 
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Clinical Development
INC280
Protocol CINC280X2205 / NCT02276027
A Phase II, open label, multiple arm study of single agent 
AUY922, BYL719, INC280, LDK378 and MEK162 in Chinese 
patients with advanced non-small cell lung cancer (NSCLC)
RAP Module 3 – Detailed Statistical Methodology
Author:
Document type:
RAP Documentation
Document status:
Final Version
Release date:
Number of pages:
28
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Table of contents
Amendment 1 .............................................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Objectives and endpoints.........................................................................................7
2
Data Analysis.......................................................................................................................8
3
Analysis sets ........................................................................................................................8
3.1
Analysis sets ............................................................................................................8
3.1.1
Full Analysis Set .....................................................................................8
3.1.2
Safety Set ................................................................................................8
3.1.3
Per-Protocol Set ......................................................................................9
3.1.4
Pharmacokinetic analysis set...................................................................9
3.2
Additional criteria..................................................................................................10
4
Patient demographics and other baseline characteristics...................................................10
4.1
Basic demographic and background data ..............................................................10
4.2
Medical History .....................................................................................................10
4.3
Prior antineoplastic therapy...................................................................................11
4.4
Diagnosis and extent of cancer..............................................................................11
5
Patient disposition .............................................................................................................11
6
Protocol deviations ............................................................................................................12
7
Treatments (study treatment, rescue medication, other concomitant therapies, 
compliance) .......................................................................................................................12
7.1
Study treatment exposure ......................................................................................13
Cumulative dose ....................................................................................................14
Dose intensity and relative dose intensity .............................................................14
Dose reduction.......................................................................................................15
7.2
Concomitant therapies ...........................................................................................15
7.3
Compliance............................................................................................................15
8
Analysis of the primary variable(s) ...................................................................................15
8.1
Definitions .............................................................................................................16
8.2
Statistical model, analysis and output....................................................................17
Supportive analyses for ORR ................................................................................18
8.2.1
Handling of missing values/censoring/discontinuations.......................18
9
Analysis of the secondary variable(s)................................................................................18


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9.1
Efficacy evaluation................................................................................................18
9.2
Safety evaluation ...................................................................................................19
9.2.1
Adverse event........................................................................................19
9.2.2
Laboratory data .....................................................................................21
9.2.3
Vital signs, weight and physical examinations .....................................21
9.2.4
ECOG status..........................................................................................22
9.2.5
Electrocardiograms ...............................................................................22
9.2.6
Tolerability............................................................................................23
9.2.7
Other safety analyses.............................................................................23
9.3
Pharmacokinetic data.............................................................................................23
9.3.1
Descriptive statistics..............................................................................24
24
24
10 Interim analyses.................................................................................................................25
11 Definitions and general methodology ...............................................................................25
11.1
General definitions.................................................................................................25
11.1.1
Subgroup analyses.................................................................................25
11.1.2
Assessment windows, baseline and post baseline definitions, 
missing data handling............................................................................25
11.1.3
Handling of missing and partial dates and imputation rules.................26
12 References .........................................................................................................................28


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Amendment 1
Amendment rationale
To align the statistical analysis description with the latest protocol amendment 7 (dated on 22nd 
of May 2019).
Changes to the RAP M3:
Changes to specific sections of the RAP Module 3 are shown in the track changes version of 
the RAP M3 using strike through font for deletions and underlined for insertions.
The following main changes were made:

Section 3.1.3 – Update the definition of Per-Protocol Set as per protocol amendment.

Section 3.1.4 – Update the table 3-1 for patient classification into analysis sets.

Section 8.1 – Update the definition of BOR as per protocol amendment.

Section 8.2 – Update the description of statistical analysis as per protocol amendment.

Section 9.2.1.1 – Update the adverse events of special interest


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1
Introduction
This document provides detailed statistical methodology for the analysis of data from study 
INC280X2205 that will be presented in the Clinical Study Report (CSR). The output shells (in-
text and post-text) accompanying this document can be found in RAP module 7. RAP module 
8 provides the programming specifications for derived variables, datasets and outputs.
All changes to the planned analysis described in RAP modules 3, 7 and 8 required before or 
after database lock will be made through an amendment or addendum, respectively. Note that 
obvious corrections will be made at the time of analysis to address minor formatting or spelling 
mistakes present in RAP module 7 without the need to amend these modules.
RAP modules 3, 7 and 8 may also serve as a reference for the creation of any outputs required 
outside of the CSR, e.g., IB updates, abstracts, posters, presentations, manuscripts, management 
updates.
RAP modules 3, 7 and 8 are created based on final protocol version 03 released on 22-May-
2019.
1.1
Study design
This is a Phase II, multiple arm, open-label study of single agent BYL719, INC280, LDK378 
and MEK162. This study will enroll approximately 20-25 advanced NSCLC patients to each 
treatment arm according to their molecular alterations (Figure 1-1). Each treatment arm is 
independent from one another and will be analyzed separately. Despite the title of this study, 
AUY922 was decided not to be included for investigation as detailed in protocol Amendment 
3.
Figure 1-1
Study Design
The multiple arm design was chosen, with objective response rate (ORR) as primary endpoint, 
to evaluate the efficacy of single agent BYL719, INC280, LDK378 and MEK162 in advanced 


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NSCLC patients. In addition, safety, tolerability, PK and gene alterations that may be related 
with resistance will also be evaluated for each agent.
For each treatment arm the sample size was calculated based on a Bayesian approach using 
either a minimally informative prior (BYL719, INC280 and MEK162) or an informative prior 
using relevant historical data ( LDK378). The proposed sample size will allow detecting with 
high likelihood statistically and clinically relevant anti-tumor activity.
1.2
Objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
To investigate the anti-tumor activity of single 
agent BYL719, INC280, LDK378 and MEK162
ORR per RECIST v1.1
Secondary
To further assess the clinical activity of single 
agent BYL719, INC280, LDK378 and MEK162
OS, PFS, DCR, duration of overall response per 
RECIST v1.1
To characterize the safety and tolerability of 
single agent BYL719, INC280, LDK378 and 
MEK162
Frequency/severity of AEs and SAEs; laboratory 
abnormalities
Dose interruptions and dose reductions
To characterize the pharmacokinetic profiles of 
single agent BYL719, INC280, LDK378 and 
MEK162
PK parameters including but not limited to 
AUC0-t, Cmax, Tmax, T1/2, CL/F and Vz/F


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2
Data Analysis 
The data will be analyzed by Novartis personnel and/or designated CRO(s) using SAS version 
9.4. PK parameters will be calculated using non-compartmental methods available in Phoenix 
WinNonlin version 6.2 or above.
The study data will be analyzed and reported based on all patients’ data up to the time when all 
patients have potentially completed at least six cycles of treatment or discontinued the study. 
The CSR will include all outputs planned within RAP module 7. 
Data from participating centers in this study protocol will be combined, so that an adequate 
number of patients will be available for analysis. No center effect will be assessed. The data 
will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and all relevant 
pharmacokinetic (PK) and pharmacodynamics (PD) measurements using descriptive statistics 
(n, mean, standard deviation, median, minimum, and maximum) for quantitative data and 
contingency tables (frequencies and percentages) for qualitative data.
3
Analysis sets 
The patients who are screen failure will not be included in any of these sets. They will be listed 
with the reason for screening failure. 
3.1
Analysis sets
3.1.1
Full Analysis Set
For each treatment arm the Full Analysis Set (FAS) comprises all patients who received at least 
one dose of the respective study treatment. The FAS will be used for all listings of raw data. 
Unless otherwise specified the FAS will be the default analysis set used for all analyses.
3.1.2
Safety Set
For each treatment arm the Safety Set includes all patients who received at least one dose of the 
respective study medication and had at least one valid post-baseline safety assessment. Please 
note: A “no” to indicate that the patient had no AEs (on the AE eCRF) constitutes a valid safety 
assessment.
Patients will be classified according to treatment received, where treatment received is defined 
as:

The treatment assigned if it was received at least once, or

If the assigned treatment was never received, then the first treatment received when starting 
therapy with study treatment will be used for classification
The safety set will be used for all the safety summary of the study.


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3.1.3
Per-Protocol Set
For each treatment arm the Per-Protocol Set (PPS) consists of a subset of the patients in the 
respective FAS who are compliant with requirements of the clinical study protocol (CSP).
Protocol deviations potentially leading to exclusion from the PPS are:

type of indication different from those required in protocol Section 5 (e.g., incorrect 
histology/cytology, incorrect molecular alteration etc.)

prior therapy does not match with requirements in protocol Section 5 in terms of number 
and types of previous therapy regimens

missing or incomplete documentation of stage of disease

ECOG>2

another anti-neoplastic therapy administered after start of study treatment and prior to first 
tumor assessment

study treatment received different from treatment assigned

patient without measurable lesions
Any other protocol deviations leading to exclusion from the PPS will be described in the RAP 
prior to clinical database lock.
Patients will be classified according to treatment as assigned.
The PPS will define the patients used in the sensitivity analysis of the primary endpoint. If the 
PPS and the FAS are identical, then analyses described using the PPS below will not be 
performed.
3.1.4
Pharmacokinetic analysis set
For each treatment arm the PK analysis set (PAS) consists of all patients who have at least one 
blood sample providing evaluable PK concentration. The PAS will be used for summaries of 
PK concentration (Tables and Figures). For a concentration to be evaluable, subjects are 
required to:

Take a dose of the treatment prior to sampling (expect pre-dose samples);

For post-dose samples, do not vomit with the specified hours after the treatment;

For steady state trough concentrations, take the same dose of the treatment for at least 
the required consecutive days prior to sampling.
The PAS for PK parameter calculations includes all subjects who provide an evaluable PK 
profile.  The PAS will be used for summaries as well as listings of derived PK parameters. A 
profile is considered evaluable if all of the following conditions are satisfied:

Subject receives one of the planned treatments;

Subject provides at least one primary PK parameter;

Subject follows the specified meal instructions for the treatment;

Subject does not vomit within the specified period of the treatment.


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Note: patients may be removed from the estimation of certain PK parameters on an individual 
basis depending on the PK profiles. These patients will be identified at the time of the analyses
along with the reason for their removal.
3.2
Additional criteria
Table 3-1 gives additional details to those included in Section 3.
Patients are excluded from the analysis populations based on the protocol deviations entered in 
the database and/or on specific patient classification rules as shown in Table 3-1 below. 
Table 3-1: Patient classification into analysis sets
Analysis Population
Additional patient classification rules leading to exclusion
Full Analysis Set
Patient who did not receive at least one dose of study treatment 
component
Safety Set
Patient who did not receive at least one dose of study treatment 
component
Per Protocol Set
Protocol deviations that will lead to removal of patients from Per 
Protocol Set (defined in Section 3.1.3)
Pharmacokinetic 
Analysis Set
Patients who do not have at least one evaluable PK sample as defined in 
Section 3.1.4
4
Patient demographics and other baseline characteristics
Unless noted otherwise, summaries described in this section will be based on the FAS. 
Summaries will be produced by treatment arm and overall. Data will be listed individually by 
patient based on the FAS. 
4.1
Basic demographic and background data
Demographic data, including age, sex, height, baseline weight, body mass index, medical 
condition, and disease characteristics will be listed and summarized.
4.2
Medical History
Medical history and current (ongoing) medical conditions, including cancer-related conditions
and symptoms will be summarized and listed. Separate summaries will be presented for current 
and historical medical conditions by primary system organ class and preferred term. Medical 
history and current medical conditions are coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) terminology. Lastest MedDRA version available at time of reporting will 
be used.


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4.3
Prior antineoplastic therapy
Prior anti-neoplastic therapy will be summarized for three distinct subtypes (medication, 
radiotherapy and surgery).
The number (%) of patients who received, separately, any prior anti-neoplastic medication, 
radiotherapy or surgery will be summarized.
The summary of prior anti-neoplastic medications will include the total number of regimens 
(note: there can be more than one medication per regimen), setting at last medication, time (in 
days) between end of last medication to start of study treatment, best response at last medication 
(defined to be the best response during the last treatment regimens recorded), duration (in 
months) of last best response (last best response is the best response at last medication), reason 
for discontinuation at last medication and time (in months) from start of last medication to 
progression. The last medication is defined based on the last end date of all prior regimen 
components. Prior antineoplastic medications will also be summarized by Anatomical 
Therapeutic Chemical (ATC) class, and preferred term. 
The summary of prior anti-neoplastic radiotherapy will include a summary of radiotherapy 
locations, including all locations recorded for each subjects. Setting at last radiotherapy, and 
method also be summarized. The time between the last radiotherapy to start of treatment will 
be summarized in category (< 1 month, 1 - <6 months, 6 - <12 months, and >=12 month). Last 
radiotherapy is based on end date. 
The summary of prior anti-neoplastic surgeries will include the time between the last surgery 
to start of treatment and procedure applied in last surgery. Last surgery (non-biopsy procedure) 
is based on the date of surgery. The time between the last surgery to start of treatment will be 
summarized in category (< 1 month, 1 - <6 months, 6 - <12 months, and >=12 month).
4.4
Diagnosis and extent of cancer
The summary of diagnosis and extent of cancer will include details of primary site of cancer, 
tumor histology/cytology, histological grade, stage at initial diagnosis, time (in months) from 
initial diagnosis of primary site to start of study treatment, time (in months) since most recent 
recurrence/relapse or progression to start of study treatment, time (in months) from initial 
diagnosis of primary site to first recurrence/relapse or progression, current stage of cancer, 
current extent of disease (metastatic sites), types of lesions (target and non-target lesions) at 
baseline, and disease burden at baseline for target lesion.
5
Patient disposition
The FAS will be used for the patient disposition summary tables and listings. The following
will be tabulated:

Number (%) of patients who discontinued treatment (based on completion of the ‘End of 
Treatment Disposition’ page with discontinuation date and reason entered),

Primary reasons for study treatment discontinuation (based on discontinuation reason 
entered in the ‘End of Treatment Disposition’ page),


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
Number (%) of patients no longer being followed for study evaluation (based on completion 
of the ‘End of Post Treatment Phase Disposition’ page with discontinuation date and reason 
entered), 

Number (%) of patients continued to be followed for study evaluation(based on non-
completion of the ‘End of Post Treatment Phase Disposition’ page with discontinuation date 
and reason entered)

Primary reasons for study evaluation completion (based on discontinuation reason entered 
in the ‘End of Post Treatment Phase Disposition’ page).
A listing of study completion by treatment group will be produced separately using the FAS. 
Patients are considered to be ongoing if they have not discontinued due to any reason (e.g., 
disease progression, AE, withdrawn consent).
6
Protocol deviations
The number and percentage of patients with any protocol or non-protocol deviation will be 
tabulated by the deviation category (entry criteria not satisfied; wrong treatment or incorrect 
dose; developed withdrawal criteria, but not withdrawn; took an excluded concomitant 
medication; others). The full list of protocol deviations are documented in the SSD. Major 
protocol deviations will be tabulated separately by treatment.
All protocol deviations will be listed by treatment.
7
Treatments (study treatment, rescue medication, other 
concomitant therapies, compliance)
Unless otherwise noted, the Safety set will be used for all medication data summaries.
Study drug and study treatment
Study drug and study treatment both refer to the following four investigational drugs in this 
study:
A: BYL719
B: INC280 
C: LDK378
D: MEK162
To maintain consistency, we will only use the term “study treatment” throughout the remaining 
document.
Date of first/last administration of study treatment
The date of first (last) administration of study treatment is derived as the first (last) date when 
a non-zero dose of study treatment was administered and recorded on the Dosage 
Administration Record (DAR) eCRF. For the sake of simplicity, the date of first (last) 
administration of study treatment will also be referred as start (last) date of study treatment.


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Last date of exposure to study treatment
Last date of exposure to study treatment is the last date of study treatment.
Study day
The study day for all assessments/events will be calculated using the start date of study 
treatment as reference. For assessments/events occurring on or after the start date of study 
treatment, study day will be calculated as:
Study day (days) = Event date – Start date of study treatment + 1.
Therefore, the first day of study treatment is study day 1.
For all assessment/events occurring prior to the start of the study treatment, study day will be 
negative and will be calculated as:
Study day (days) = Event date – Start date of study treatment.
On-treatment assessment/event
An on-treatment assessment/event is defined as any assessment/event obtained in the time 
interval from the start date of study treatment until the last date of study treatment + 30 days 
inclusive.
Definition of end of the study
The end of study is defined as the earliest occurrence of one of the following:

All patients have completed 30-day safety follow up and a minimum of 12 months has 
elapsed since last patient first treatment, or patients have been transferred to another 
Novartis study that they can continue to receive study drug

Study is terminated early
7.1
Study treatment exposure
Duration of exposure to study treatment will be summarized by treatment arm. 
The duration of exposure to study treatment (including categories: <10, 10-<20, 20-<30,  ≥30 
weeks) will be summarized. In addition, the cumulative dose, average daily dose, DI, and RDI
(including categories: <0.5, 0.5-<0.75, 0.75- <0.9, 0.9-<1.1, ≥1.1) will be summarized by
treatment arm. Frequency counts and percentages of patients who have dose reductions or 
delays, percentage of actual days dosed, and the corresponding reasons, will be provided. 
All doses of the study treatment along with reasons for any dose change will be listed.
The number of dose delays will be summarized by treatment arm. 
Duration of study drug/treatment exposure
The following algorithm will be used to calculate the duration of study treatment exposure (in 
days) for patients who take at least 1 dose of the study treatment:


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Duration of exposure of any study treatment (days) = last date of exposure to the study treatment
– date of first administration of the study treatment + 1
In case patient has died, discontinued the treatment, or there is a data cut-off date, use the 
following definition for the duration of exposure for both the study treatments for all arms
Duration of exposure in days = date of death/date of discontinuation(from EOT disposition 
page)/data cut-off date − first date of dose administration of the study treatment + 1 
For patients who did not take any drug, the duration of drug exposure is by definition equal to 
zero.
Duration of dose delays or interruption (days): Sum of the duration (in days) of all dose 
delays/interruptions
between the first and last non-zero dose. Definition of dose 
delay/interruption is given below.
Dose delay/interruption: For any of the treatments arms, when the actual total dose received 
of the corresponding study treatment is zero, it will be considered as dose delay. The algorithms 
for dose delay can be defined as follows.
The number of dose delays will be counted as the number of periods in the eCRF DAR page 
with actual total daily dose administered = 0 mg. For example, 2 dose delays correspond to two 
different records in which the actual total daily dose administered = 0 mg. Those records may 
involve more than 1 day. This will be identified using the start and end date of dosing on the 
corresponding eCRF DAR page. The last zero dose of each treatment arms followed by 
permanent discontinuation are not considered as dose interruption.
Cumulative dose
The actual cumulative dose for each study treatment is defined as the total dose for the 
corresponding study treatment given during the study treatment exposure and is expressed in 
mg. For patients who did not take any dose of this drug, the actual cumulative dose is by 
definition equal to zero. 
The planned cumulative dose is defined as the total dose planned to be given during the study 
treatment exposure and is expressed in mg.
For all the arms, it is obtained by multiplication of the treatment exposure in appropriate unit 
(days) by the first planned total daily dose (e.g., treatment duration = 10 days => planned 
cumulative dose = 10 × daily dosing).
Number of dosing days is defined as the duration of exposure minus the number of zero dose 
days.
Dose intensity and relative dose intensity
Dose intensity 
For each of the study treatments, the dose intensity (DI), expressed as mg/day, for patients with 
non-zero duration of exposure is defined as follows: 
Actual dose intensity (DI) (dosing unit/unit of time) = actual cumulative dose (mg) / duration 
of study treatment exposure (days).


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Planned dose intensity (PDI) (dosing unit/unit of time) = planned cumulative dose (mg) / 
duration of study treatment exposure (days).
Relative dose intensity (RDI) is the actual dose intensity (DI) divided by the planned dose 
intensity (PDI).
For patients who do not take any drug, the actual DI is by definition equal to zero. 
Dose reduction
For each treatment arm, the corresponding eCRF allows the recording of dose changes including 
dose increase, dose reduction and dose delay. A dose change is defined as a change in dosing 
from one level to the next, however a dose interruption will not be counted as a dose change. 
At time points at which the dose change flag is checked and the actual total daily dose received 
is non-zero, if the actual dose is lower than the previous last non-zero actual total daily dose
then the dose change is identified as a dose reduction.
7.2
Concomitant therapies
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and 
blood transfusions) administered in the study and are recorded in the Concomitant 
Medications/significant non-drug therapies eCRF. These therapies will be coded using the 
WHO Drug Reference Listing (WHO DRL) dictionary that employs the WHO Anatomical 
Therapeutic Chemical (WHO ATC) classification system.
Concomitant therapies will be summarized by ATC class and preferred term. These summaries 
will include 1) medications starting on or after the start of study treatment but starting no later 
than 30 days after last dose of study treatment and 2) medications starting prior to the start of 
study treatment and continuing after the start of study treatment.
All therapies will be listed. Any therapies starting and ending prior to the start of study treatment
or starting more than 30 days after the last date of study treatment will be flagged in the listing. 
Anti-neoplastic therapies since discontinuation of study treatment will be listed and tabulated 
by ATC class and preferred term.
7.3
Compliance 
Compliance to each of the study treatments will be assessed by the number of dose reductions 
and dose interruptions as mentioned in Section 7.1.
8
Analysis of the primary variable(s)
Evaluation of anti-tumor activity will be based on investigator assessment of overall lesion 
response according to RECIST v1.1 (see Protocol Appendix 14.4). 


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8.1
Definitions 
Best overall response (BOR) is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking the nadir of the sum of the diameter recorded since the 
treatment started as reference for PD assessment). The best overall response will be determined 
from response assessments undertaken while on treatment. However, any assessments taken 
more than 28 days after the last dose of study therapy will not be included in the best overall 
response derivation. Moreover, if any alternative cancer therapy is taken while on study, any 
subsequent assessments will be excluded from the best overall response determination.
The study requires that for a response PR or CR changes in tumor measurements must be 
confirmed by repeat assessments performed not less than 4 weeks after the criteria for the 
response are first met.
The best overall response for each patient is determined from the sequence of overall (lesion)
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation is required or one determination of CR prior to progression where 
confirmation is not required.

PR = at least two determinations of PR or better at least 4 weeks apart before 
progression (and not qualifying for a CR) where confirmation is required or one 
determination of PR prior to progression where confirmation is not required.

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of study
treatment (and not qualifying for CR or PR).

PD = progression ≤12 weeks after randomization/ start of study treatment (and not 
qualifying for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after
more than 6 weeks or early progression within the first 12 weeks)
Overall response rate (ORR): For each treatment arm, individual lesion measurements and 
overall response at each assessment will be listed by patient, from which the best overall 
response (BOR) will be derived for all patients. The ORR is the proportion of patients with 
BOR of either CR or PR among all patients in the respective FAS.
Patients with symptoms of rapidly progressing disease without radiologic evidence will be 
classified as progression only when clear evidence of clinical deterioration is documented 
and/or patient discontinued due to ‘Disease progression’ or death due to study indication.
A patient with documented PD as per RECIST will not be considered for clinical progression 
and their date of PD will always be the date of disease progression as per RECIST.
Clinical progression: Clinical progression will be considered for BOR. 
If documented progression is present, then that data will always be used. If there is no 
documented progression but if the reason for end of treatment is disease progression or the 
reason for death is due to study indication, then that will also be considered as disease 
progression.


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8.2
Statistical model, analysis and output
A Bayesian approach will be used to estimate ORR and to provide inferential statements in each 
arm.
Based on prior clinical assumption, the prior median of ORR of each treatment arm is obtained. 
For INC280, BYL719 and MEK162, a minimally informative unimodal Beta prior distribution 
for each arm i with parameters ai and bi (Neuenschwander et al. 2010) that reflects the degree 
of uncertainty around ORR before starting the current trial was elicited. Based on prior clinical 
assumption, the prior median of ORR of each treatment arm is obtained. If the prior median 
ORR is smaller than 50%, bi =1 and ai=ln(0.5)/ln(mediani); otherwise ai =1 and bi =ln(0.5)/ln(1-
mediani). The values of prior mediani, ai and bi for the three treatment arms are listed in Table 
8-1.
For BYL719 arm, based on the assumption that similar response is expected in adenocarcinoma 
and squamous cell carcinoma patients, primary analyses will be done using the pooled data 
from these two subgroups of patients.    
For LDK378 arm, a mixture prior was considered. Table 8-1 gives the priors for all the treatment 
arms. Details of these priors are described in Section 10.4.2 of the Clinical study protocol (CSP). 
At time of analysis, for each treatment arm, the posterior distribution will be derived using the 
prior and with all available data collected on study. Once the posterior distribution is derived, 
the posterior probabilities that the true ORR lies in the following efficacy intervals will be 
provided for each treatment arm:

[0, Li) unacceptable efficacy

[Li, Mi) limited efficacy

[Mi, 100%] clinically relevant efficacy
The values of thresholds Li and Mi for the five treatment arms are listed in Table 8-1. 
If (i) the posterior mean ORR in arm i is equal to or greater than Mi and (ii) the posterior 
probability of being in the unacceptable efficacy category is lower than 5%, then the 
corresponding study treatment is declared efficacious for the patient population in that arm.
For each treatment arm, the estimated ORR will be the median value of the respective posterior 
distribution.
Table 8-1
Parameters of prior distributions and thresholds for posterior 
distributions of ORR
Arm
Prior distribution
Threshold
i
Component
a
b
Median
90% Credible interval
Li
Mi
1. LDK378
1**
(80%)
2 
(20%)
Mixture
6.9374
1
5.2562
0.7565
57%
60%
58%
(34%, 
79%)
(7%,
98%)
(26%, 87%)
40%
55%
2. INC280
1
0.3654
1
15%
(0.03%, 87%)
7.5%
17.5%
3. MEK162
1
0.3654
1
15%
(0.03%, 87%)
7.5%
17.5%
4. BYL719
1
0.3654
1
15%
(0.03%, 87%)
7.5%
17.5%


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Arm
Prior distribution
Threshold
i
Component
a
b
Median
90% Credible interval
Li
Mi
** Component derived from MAP approach. Based on [CLDK378X1101] data with 2 responders in 5 patients at 
750 mg QD, with cut-off date of 29-Apr-2013, and [CLDK378X2101] data with 47 responders in 78 patients at 
750 mg QD, with cut-off date of 28-Feb-2013. This component received 80% weight and will be updated with 
additional data prior to the final analysis.
For each treatment arm the mean, median, and two-sided 90% credible interval for ORR from 
the posterior distribution will be presented. Individual tumor lesion assessments will be listed 
along with the overall response by assessment.
Supportive analyses for ORR

For each treatment arm the Bayesian posterior estimate of median and two-sided 90% 
credible interval of ORR will be presented using PPS, if PPS is different from FAS.

For each treatment arm, individual tumor lesion assessments will be listed along with the 
overall response by assessment. BOR will be listed by patient and summarized with 
frequency and percentage, together with the observed ORR and frequentist exact two-sided 
90% confidence interval (CI) (Clopper and Pearson 1934) provided by treatment.

For BYL719 arm, BOR summaries may be provided by subtypes of cancer (e.g. lung 
adenocarcinoma and lung squamous cell carcinoma)
8.2.1
Handling of missing values/censoring/discontinuations
Missing data will simply be noted as missing on appropriate tables/listings. Patients with 
missing best overall response will be considered as non- responders for the primary ORR 
analysis.
9
Analysis of the secondary variable(s) 
9.1
Efficacy evaluation
For disease progression, beside documented radiological progression, clinical progression will 
also be used.  When there is a documented progression, the radiological scan date will we used 
as date of progression. When there is no documented progression, and 
(i) the patient discontinued for ‘Disease progression’ due to documented clinical 
deterioration of disease, the date of discontinuation is used as date of progression
(ii) the patient died with reason for death is due to study indication, then death date will be 
used as date of progression 
The secondary efficacy objective of this study is to further estimate clinical activity of single 
agent BYL719, INC280, LDK378 and MEK162 in Chinese patients with advanced NSCLC 
carrying specific molecular alterations. Tumor response will be evaluated based on RECIST 
v1.1. Disease control rate (DCR), duration of response, PFS and OS will be assessed and 
analyzed as follows:

DCR is defined as the proportion of patients with a BOR of CR, PR or SD at any time on 
study. For each treatment arm the observed DCR with exact two-sided 90% confidence 
interval will be presented.


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
Duration of overall response is defined as the time from the first documented CR or PR 
(confirmed by the subsequent assessment) to the date of the first documented progression 
or death due to underlying cancer. If a patient has not experienced a documented progression 
or death due to underlying cancer, duration of overall response is censored at the date of the 
last adequate tumor assessment. If a patient discontinued trial treatment and received a new 
anti-neoplastic therapy prior to disease progression, duration of overall response is censored 
at the start date of the new therapy. The Kaplan-Meier curve, median and quartile will be 
presented if a sufficient number of responses is observed. For each treatment arm the subset 
of patients with documented CR or PR in FAS will be used.

PFS is defined as the time from start of study treatment to the date of the first documented 
progression or death due to any cause. If a patient has not experienced a documented 
progression or death, PFS is censored at the date of the last adequate tumor assessment. If 
a patient discontinued trial treatment and received a new anti-neoplastic therapy prior to 
disease progression, PFS is censored at the start date of the new therapy. The Kaplan-Meier 
estimate of PFS distribution function will be presented graphically using FAS. The resulting 
median and quartile estimates will be provided along with two-sided 90% confidence 
intervals. 

OS is defined as the time from start of study treatment to date of death due to any cause. If 
a patient is not known to have died, OS will be censored at the date of the last contact. The 
Kaplan-Meier estimate of OS distribution function will be presented graphically using FAS. 
The resulting median and quartile estimates will be provided along with two-sided 90% 
confidence intervals.
For BYL719 arm, based on the assumption that similar response is expected in adenocarcinoma 
and squamous cell carcinoma patients, analyses for the secondary endpoints will be done using 
the pooled data from these two subgroups of patients.
9.2
Safety evaluation
The assessment of safety is based on the type and frequency of Adverse Events (AEs) as well 
as on the number of laboratory values that fall outside of pre-determined ranges (Common 
Toxicity Criteria for AEs [CTCAE] version 4.03 grading limits or normal ranges as appropriate). 
Other safety data includes electrocardiogram, vital signs and ECOG performance status. 
The Safety set will be used for summaries and listings of safety data in Section 14 of the CSR. 
All listings and tables will be presented for each treatment arm separately. Unless otherwise, 
specified, data from all arms will not be pooled and “All patients” column will not be presented 
in any safety summary.
The safety summary tables will only include assessments collected no later than 30 days after 
study treatment discontinuation. All safety assessments will be listed, and those collected later 
than 30 days after study treatment discontinuation will be flagged.
9.2.1
Adverse event
AEs will be coded using the latest version of MedDRA available prior to clinical database lock 
and will be graded using Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03. If CTCAE grading does not exist for an AE, grades 1, 2, 3, or 4 corresponding to the 
severity of mild, moderate, severe, and life-threatening, respectively, will be used. CTCAE 


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grade 5 (death) will not be used in this study. Death information will be collected on the “End 
of Treatment” or “Survival Information” eCRF pages.
All AE summaries will be summarized (frequency counts and percentages) by system organ 
class and/or preferred term, and maximum severity grades, except where otherwise noted.
The following AE summaries will be produced:

AEs regardless of study drug relationship (including CTC grade 3/4)

AEs suspected to be study drug related (including CTC grade 3/4)

AEs leading to discontinuation of study drug regardless of study drug relationship.

AEs leading to discontinuation of study drug suspected to be study drug related.

AEs requiring dose adjustment and/or study drug interruption regardless of study drug 
relationship

AEs requiring dose adjustment and/or study drug interruption suspected to be study drug 
related 

SAEs regardless of study drug relationship

SAEs suspected to be study drug related

All deaths and on-treatment deaths, with cause of death by preferred term
A patient with multiple CTC grades for an AE will be summarized under the maximum CTC 
grade recorded for the event. A subject with multiple occurrences of an AE is counted only once 
in the AE category (system organ class, preferred term etc.).
Reporting of death: As mentioned above, summary tables will be produced separately for “All 
deaths” (post-text) and “on-treatment deaths” (in-text). All deaths will be listed with a flag to 
identify on-treatment deaths and with reasons of death.
9.2.1.1
Adverse events of special interest
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound INC280 and LDK378. These groupings are defined 
using MedDRA terms, SMQs (standardized MedDRA queries), HLGTs (high level group 
terms), HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis 
MedDRA queries, NMQ) may also be used. A NMQ is a customized group of search terms 
which defines a medical concept for which there is no official SMQ available or the available 
SMQ does not completely fit the need. It may include a combination of single terms and/or an 
existing SMQ, narrow or broad.
All AESI definitions or AE grouping are specified in the electronic Case Retrieval Strategy 
(eCRS), in which they are identified by the flag “SP”. Additional AESI may be reported if there 
are any updates to the eCRS at the time of the analyses.
Adverse events of special interest (AESIs) INC280 are:

Hepatotoxicity

Pneumonitis/Interstitial lung disease

Central nervous system toxicity

Renal dysfunction

Pancreatitis

Teratogenicity


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
Photosensitivity

Drug-drug interactions with strong CYP3A4 inducers

QTc interval prolongation
Adverse events of special interest (AESIs) LDK378 are:

Hepatotoxicity

Interstitial lung disease/pneumonitis

QTc prolongation

Hyperglycemia

Bradycardia

GI toxicity (nausea, diarrhea, vomiting)

Pancreatitis
9.2.2
Laboratory data
Laboratory data will be converted into SI units and classified (by Novartis Oncology statistical 
programming) into CTC grades according to the NCI CTCAE v4.03 as applicable. Grade 5 will 
not be used. For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-
missing values not graded as 1 or higher.
For cases when the CTC grade definition includes change from baseline criteria (e.g., Creatinine, 
Ejection fraction, Fibrinogen, Hemoglobin, INR): When a lab value is of grade X based on 
threshold/ranges, but grade X+1 when considering change from baseline, the final Grade is set 
to X+1. For other cases, a Grade 0 CTC grade will be set when laboratory value is:
Within LLN and ULN and grading in both direction,
Below ULN and grading in hyper direction,
Above LLN and grading in hypo direction.
Laboratory data for which a CTC grading does not exist will be classified into low, normal, or 
high based on local laboratory normal ranges as applicable.
The following listings will be produced:

Listing of patients with laboratory abnormalities of CTC grade 3 and 4,

Listing of all laboratory data with values flagged to show corresponding CTC grades and
the classifications relative to the laboratory reference ranges (i.e., High (H) or Low (L))
9.2.3
Vital signs, weight and physical examinations
Vital sign parameters collected are systolic and diastolic blood pressure (mmHg), pulse rate 
(beats per minute), respiratory rate (breaths per minute), body temperature (°C), and weight 
(kg). Vital sign values considered notably abnormal are defined in Table 7-3.
Table 9-1
Criteria for notable vital sign values
Vital sign
Criteria for clinically notable vital sign values


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Systolic 
blood 
pressure 
[mmHg]
≥180 mmHg/≤90 mmHg with increase/decrease from baseline of ≥20 
mmHg
Diastolic 
blood 
pressure 
[mmHg]
≥105 mmHg/≤50 mmHg with increase/decrease from baseline of ≥15 
mmHg
Pulse rate [bpm]
≥120 bpm/≤50 bpm with increase/decrease from baseline of ≥15 bpm
Respiratory rate
≥30 breaths per minute; ≤10 breaths per minute
Body temperature [°C]
39; ≤ 35
Weight [kg]
≥10% decrease/increase from baseline
Vital signs will be listed by subject, and visit/time. Clinically notable vital sign values will be 
flagged in the listings.
9.2.4
ECOG status
Shift tables of ECOG performance status at baseline to worst post-baseline ECOG status will 
be provided by cohort using safety set.
9.2.5
Electrocardiograms
9.2.5.1
ECG data descriptive statistics
Baseline for ECG analysis is defined as the average of all available ECG measurements
associated with the baseline assessment. Scheduled study day 1 pre-dose ECGs will be
considered to have been obtained prior to study treatment administration if dosing time is 
missing. If a scheduled pre-dose measurement actually occurred post-dose, then the 
corresponding measurement will be treated and analyzed similar to an unscheduled post-dose 
measurement.
If a patient has more than one post-baseline measurement at a specific time point, the median
of all available measurements associated with the nominal time point will be used for the 
analyses. The summaries will include all ECG assessments performed no later than 30 days 
after the last date of study drug. All ECG assessments will be listed, and those collected later 
than 30 days after study drug discontinuation will be flagged in the listing. All ECG data will 
be reported based on the local reading of the ECG.
The following summaries will be provided for each applicable ECG parameter:

Frequency counts and percentages of patients having notable ECG values according to 
Table 9-4.
Table 9-2
Criteria for notable ECG values
ECG parameter
Criteria for ECG notable values
QT, QTcF
Increase from baseline >30 ms to 60ms, >60 ms
HR (bpm)
Increase from baseline >25% and value >100 bpm
Decrease from baseline >25% and value <50 bpm
PR (ms)
Increase from baseline >25% and value >200 ms
QRS (ms)
Increase from baseline >25% and value >120 ms
Notable ECG values (including notable QT interval values) will be flagged in the listings.


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9.2.6
Tolerability
Tolerability of study treatment will be assessed by summarizing the number of dose 
interruptions and dose reductions by treatment group. Reasons for dose interruption and dose 
reductions will be listed by patient and treatment group and summarized by treatment group. 
Cumulative dose, dose intensity and relative dose intensity of study treatment will be listed 
separately by patient and treatment group and summarized separately by treatment group. 
Categories for relative dose intensity of study treatment will be specified as < 0.5, ≥ 0.5 - < 0.75, 
≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The number and proportion of patients within each 
category will be presented by treatment group.
9.2.7
Other safety analyses
9.2.7.1
Cardiac Imaging
LVEF data will be listed for BYL719 and MEK162 treatment arm.
9.2.7.2
Cardiac enzymes
For BYL719, MEK162 and LDK378 arms, troponin-I or troponin-T will be listed. For MEK162 
treatment arm, CK will be listed.
9.2.7.3
Ophthalmology assessments (MEK162)
Full ophthalmic examination including slit lamp examination, visual acuity testing, visual field 
testing, intraocular pressure (IOP) and indirect fundoscopy with attention to retinal 
abnormalities, especially central serous retinopathy and RVO will be performed at the following 
time points:

Screening/baseline

Day 15, Cycle 1 

Day 1 of all subsequent Cycles

End of Treatment 
For patients with clinical suspicion of central serous retinopathy or RVO, additional 
assessments of fluorescein angiography and/or optical coherence tomography and 
Electroretinogram (ERG) may be done.
For Fundoscopy, slit lamp, visual field testing and color vision test the incidence of 
abnormalities at baseline along with the incidence of new abnormalities reported at the 
timepoints given above will be summarized by type of abnormality for both eyes.
For the visual acuity, Landolt score values are captured in CRF for both eyes. 
Ophthalmology examination data will be listed.
9.3
Pharmacokinetic data
All PK analyses will be performed based on the PAS unless otherwise specified. Listings will 
be generated using the FAS.


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Concentration values below the lower limit of quantitation (LLOQ) will be displayed in listings 
as zero with a flag and handled as zero in the calculations for mean, CV for mean, standard 
deviation, minimum, median, maximum, but handled as missing for the calculation of the 
geometric means and their CV.
9.3.1
Descriptive statistics
For each study treatment, concentration data will be listed and summarized by time point, 
patient and treatment group. Descriptive statistics will include arithmetic and geometric mean, 
median, standard deviation, coefficient of variation (CV), geometric CV, minimum and 
maximum.
PK parameters will be calculated using noncompartmental methods for serial intensive PK 
sampling and summarized as described in Table 9-8. The PK parameters considered primary 
are AUClast, AUCtau, Cmax, and Tmax. Other PK parameters (CL/F, Vz/F, and T1/2) are 
considered as secondary. All PK parameters will be listed.  
The geometric mean and arithmetic mean (SD) and individual concentration versus time 
profiles will be displayed by treatment arms separately graphically for the patients in PAS.
Table 9-8
PK parameters – descriptive statistics
Parameters
Descriptive statistics
AUC(1) , Cmax, CL/F, Vz/F, T1/2
Mean standard deviation, CV% mean, geometric 
mean, CV% geo-mean, median, minimum, and 
maximum.
Tmax
Median, minimum, and maximum.
(1) Includes AUClast and AUCtau
CV% = coefficient of variation (%) = sd/mean*100
CV% geo-mean = sqrt (exp (variance for log transformed data)-1)*100
9.4.1
Analyses of next Generation Sequencing data: 
If Next generation sequencing data is available, then they will be listed.


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10
Interim analyses 
NA
11
Definitions and general methodology
11.1
General definitions
11.1.1
Subgroup analyses
NA
11.1.2
Assessment windows, baseline and post baseline definitions, missing 
data handling
11.1.2.1 Baseline
Baseline is the last available and valid assessment performed or value measured within 28 days 
before the first administration of study treatment, unless otherwise stated under the related 
assessment section. Baseline can be the day before first treatment administration or the same 
day as first treatment administration if a pre-dose assessment/value is available (e.g., ECG, PK 
samples, 
).
If time is recorded for the first treatment dose and for a specific assessment performed the day 
of first dose, this assessment will be considered as baseline only if it is actually performed 
before the first dose, as checked using both times.
If time is not recorded, a specific assessment performed the day of first dose administration will 
be considered as baseline if, according to protocol, it should be performed before the first dose.
Patients with no data on a particular parameter before the first treatment administration will 
have a missing baseline for this parameter.
11.1.2.2 Scheduled study visit and window for the analysis
Unless otherwise specified, when more than one assessment is available for a visit, all 
assessments will be listed under the visit while only the assessment closest to the planned day 
for the visit will used for summaries and analyses.  
Construction of waterfall graphs
Waterfall graphs will be used to depict anti-tumor activity. These plots will display the best 
percentage change from baseline in the sum of diameters of target lesions for each patient.
Note: Patients without any valid assessments to calculate a percentage change from baseline 
value will be excluded from the graphs. Assessments with an unknown overall response will be 
included as long as the sum of diameters of target lesions is correctly computed on the same 
lesions assessed at baseline.
Patients will be ordered in the graph from left (worst change) to right (best change).
1. Bars above the horizontal axis (0%) representing tumor growth,


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2. Bars under the horizontal axis (0%) representing tumor shrinkage.
A special symbol (e.g. ∗) will be added below the bottom of respective bars for confirmed 
RECIST response (CR or PR), with corresponding specifications in footnote. The total number 
of patients displayed in the graph (n) over the total number of patients in the FAS (N) will be 
shown. The best overall response (BOR) will be shown above each of the displayed bars in the 
graph. A horizontal threshold line at -30% will be shown.
11.1.3
Handling of missing and partial dates and imputation rules
For patients not known to have died prior to the cut-off date used for reporting:
All events (e.g. AEs and concomitant medications) that started before or on the cut-off date, 
and with end date missing or after the cut-off date will be reported as continuing at the cut-off 
date. For these events, the end date will not be imputed.
For patients known to have died prior to or on the cut-off date used for reporting:
All events (e.g. AEs and concomitant medications) that started before or on the cut-off date, 
and with end date missing or after the cut-off date will have the end date imputed to the date of 
death. For these events, the imputed end date will not appear in the listings.
If imputation of an end date is required for a specific analysis (e.g. a dose administration record 
with missing end date, or last date of study treatment is after the cut-off date), the end date will 
be imputed to the cut-off date in order to calculate e.g., the duration of exposure to study 
treatment. The imputed date will be displayed and flagged in the listings.
11.1.3.1 Imputation Rules for AE
A missing AE start date will be imputed using the following logic matrix described in Table 
11-2.
Table 11-2
Imputation rules for a partially missing AE start date
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
No imputation
No imputation
No imputation
No imputation
AEY < TRTY
(D)
(C)
(C)
(C)
AEY = TRTY
(B)
(C)
(B)
(A)
AEY > TRTY
(E)
(A)
(A)
(A)
AEM: Month AE started; AEY: Year AE started
TRTM: Month treatment started; TRTY: Year treatment started
Table 11-3 is the legend to the logic matrix shown in Table 11-2 and details the relationship of 
AE start date to study treatment start date.


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Table 11-3
Imputation legend and AE/treatment start date relationship
AE start date relationship
Imputation
(A)
After treatment start or Uncertain
MAX( 01MONYYYY, TRTSTD+1 )
(B)
Uncertain
TRTSTD+1
(C)
Before treatment start
15MONYYYY
(D)
Before treatment start
01JULYYYY
(E)
After treatment start
01JANYYYY
Before treatment start: Partial date indicates AE start date is prior to treatment start date.
After treatment start: Partial date indicates AE start date is after treatment start date.
Uncertain: Partial date insufficient to determine relationship of AE start date to treatment start date.
No imputation will be performed for AE end dates.
11.1.3.2
Concomitant medication date imputation
The imputation of the start date of concomitant medication will follow the same conventions as 
for AE date. Partial concomitant medication end dates will not be imputed.
11.1.3.3 Incomplete date of initial diagnosis of cancer and date of most recent 
recurrence
For incomplete date of initial diagnosis of cancer and date of most recent recurrence, missing 
day is defaulted to the 15th of the month and missing month and day is defaulted to 01-Jan. If 
because of this imputation the chronology of the events is altered then the imputation should be 
made to the minimum value up to where chronology remains unchanged. E.g. if due to 
imputation the date of most recent recurrence becomes prior to the initial diagnosis date then it 
should be set to initial diagnosis date.
11.1.3.4 Incomplete date for anti-neoplastic therapies
Prior therapies
Start date: 
The same rule which is applied to the imputation of AE/concomitant medication start 
date will be used with the exception that for scenario (B) will be replaced to be 
‘randomization date −1’.
End date:
Imputed date = min (study start date, last day of the month), if day is missing;
Imputed date = min (randomization date, 31DEC), if month and day are missing.
If the end date is not missing and the imputed start date is after the end date, use the end 
date as the imputed start date.
If both the start date and the end date are imputed and if the imputed start date is after 
the imputed end date, use the imputed end date as the imputation for the start date.
Post therapies
Start date:
Imputed date = max (last date of study treatment + 1, first day of the month), if day is 
missing;


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Imputed date = max (last date of study treatment + 1, 01JAN), if day and month are 
missing.
End date: No imputation.
11.1.3.5
Incomplete date for death or last contact
All dates must be completed with day, month and year.
If the day or month is missing, death will be imputed to the maximum of the full (non-imputed) 
last contact date (excluding the date of death) and the following:
•
Missing day:
15th day of the month and year of death
•
Missing day and month:
July 1st of the year of death
If the day is missing from the date of last contact it will be imputed to 15th day of the month 
and year of last contact only if derived from the ‘Survival Information’ page.
12
References
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time, 
Biometrics 38, 29 - 41. 
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika; 26, 404-413.