BRF117277: A Phase II, Open-Label, Multicentre Study of Dabrafenib Plus Trametinib in Subjects With BRAF Mutation-Positive Melanoma That Has Metastasized to the Brain
Phase: PHASE2
Conditions: Melanoma and Brain Metastases
Sponsor: Novartis Pharmaceuticals

Cli ni c al D e v el o p m e nt 
G S K 2 1 1 8 4 3 6 + G S K 1 1 2 0 2 1 2 
Pr ot o c ol B R F 1 1 7 2 7 7  / N C T 0 2 0 3 9 9 4 7
A P h a s e II, O p e n- L a b el, M ulti c e ntr e St u d y of D a br af e ni b 
pl u s Tr a m eti ni b i n S u bje ct s w it h B R A F M u t ati o n- P o siti v e 
M el a n o m a t h at h a s M et a st a si z e d t o t he Br ai n
A ut h or s  
 
 
 
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 ( cl e a n ) 
E U D R A C T n u m b er  
2 0 1 3 -0 0 3 4 5 2 -2 1  
V er si o n n u m b er  
9 . 0 
D e v el o p m e nt 
p h a s e  
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 1 -J U N -2 0 1 7
N o v arti s i nt er n al 
r ef er e n c e n u m b er 
C D R B 4 3 6 B 2 2 0 4  
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 
C o nfi d e nti al 
P a g e 2 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
A m e n d m e nt 7 
A m e n d m e nt r ati o n al e  
T he mai n p ur p ose of t his pr ot oc ol a me n d me nt, is t o e xte n d t he st u d y l e n gt h, as t he c urre nt 
pr ot oc ol (a me n d me nt 5) ma n dates t he st u d y t o cl ose w he n 7 0 % of all e nr olle d patie nts ha ve 
die d or are l ost t o f oll o w u p. ( T his has n o w bee n met a n d 9 patie nts are still o n treat me nt.) 
T he e xte nsi o n is re q uire d d ue t o i m mat urit y of c o h ort A data, t he pri mar y efficac y p o p ulati o n, 
w hic h is a res ult of sl o w recr uit me nt i n t his c o h ort.   
Pr ot oc ol a me n d me nt 7 defi nes st u d y cl ose w h e n 7 0 % of all c o h ort A p atie nts ha ve die d o r 
bee n l ost t o f oll o w u p, or w he n all c o h ort A p atie nts ha ve bee n o n st u d y f or t hree years, 
w hic he ver is earlier. T his will all o w f or a de q u ate ti me f or all c o h ort A p atie nts t o be f oll o we d 
u p, as t he last patie nt recr uite d has o nl y be o n st u d y f or 2 1 m o nt h s. 
It is e x pecte d t hat 7 0 % of c o h ort A patie nts ( a f urt her 3 patie nts) will be c o m plete wit hi n 3- 6 
m o nt hs, as hist oric data s h o ws c o m pleti o n rate at o ne patie nt per m o nt h.  T h us, u p o n 
i m ple me ntati o n of pr ot oc ol a me n d me nt 6, t he ne w L P L V f or t his st u d y will be ar o u n d 
Oct o ber 2 0 1 7. 
I n a d diti o n t o t he a b o ve c ha n ge t w o n ot e t o files a p plica ble t o pr ot oc ol a me n d me nts 4 a n d 5, 
a n d mi n or t y p o gra p hical err ors h a ve bee n u p date d.   
Re visi o n C hr o n ol o g y  
Gl a x o S mit h Kli ne D oc u me nt 
N u m ber  
D ate  
Versi o n  
2 0 1 3 N 1 6 8 4 3 7 _ 0 0  
2 0 1 3 -O C T -0 4  
Ori gi nal  
2 0 1 3 N 1 6 8 4 3 7 _ 0 1  
2 0 1 4 -A P R -2 7  
A me n d me nt N o. 1  
2 0 1 3 N 1 6 8 4 3 7 _ 0 2  
2 0 1 4 -A U G -2 0  
A me n d me nt N o. 2  
2 0 1 3 N 1 6 8 4 3 7 _ 0 3  
2 0 1 4 -S E P -0 4  
A me n d me nt N o. 2  
2 0 1 3 N 1 6 8 4 3 7 _ 0 4  
2 0 1 5 -M A R -1 6  
A me n d me nt N o. 3  
2 0 1 3 N 1 6 8 4 3 7 _ 0 5  
2 0 1 5 -D E C -0 6  
A me n d me nt N o. 4  
2 0 1 3 N 1 6 8 4 3 7 _ 0 6  
2 0 1 5 -D E C -1 4  
A me n d me nt N o. 4  
2 0 1 3 N 1 6 8 4 3 7 _ 0 7  
2 0 1 6 -J U L-1 3  
A me n d me nt N o. 5  
2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
1 6 -M A Y -2 0 1 7  
A me n d me nt N o. 6  
2 0 1 3 N 1 6 8 4 3 7 _ 0 9  
2 1 -J U N-2 0 1 7  
A me n d me n t N o. 7 

N o v arti s 
C o nfi d e nti al 
P a g e 3 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
1)  Mi n or a d mi nistrati ve c ha n ges a n d c orrecti o n t o ty p o gra p hical err ors t hr o u g h o ut t he 
d oc u me nt.  
2)  S ur vi val f oll o w -u p peri o d has bee n e xte n de d i n or der t o c ollect a d diti o nal l o n g -ter m 
o verall s ur vi val data.  
3)  A d diti o n of sec o n dar y  o bjecti ve  of  l o ng -ter m ( p artic ularl y 5 -y ear) O S.  
4)  A d diti o nal i nf or mati o n a vaila ble: Da brafe ni b, a n ot her s mall m olec ule B R A F - i nhi bit or 
recei v e d F DA -a p pr o val  i n Ma y  2 0 1 3 a n d E M A a p pr o val i n A u g ust 2 0 1 3.  
5)  Refere n ce t o a bst ai ni n g t o a n y  f o o d or dri n k c o nt ai ni n g gra p efr uit a n d gra p efr uit j uice, 
Se ville ora n ges, or p o m mel os was re m o ve d.  
6)  A d diti o nal i nf or mati o n a vaila ble: I n J a n 2 0 1 4 t he c o m bi nati o n of da brafe ni b a n d 
tra meti ni b recei v e d F D A a p pr o val, a n d i n Fe br u ar y 2 0 1 4 t he c o m bi nati o n recei ve d 
a p pr o val i n A ustralia.  
7)  S u bje cts w h o are recei vi n g c o n c o mita nt c ortic ost er oi ds m ust be o n a sta bl e or 
decreasi n g d ose f or at least (c ha n ge d fr o m 3 wee ks) 1 m o nt h pri or t o first d ose of 
st u dy  tr eat me nt. 
8)  T y p o gra p hical c orrecti o n of ne ur ol o gist t o ne ur ora di ol o gist a n d t he a d diti o n of 
ap pr o priate ly q ualifie d ra di ol o gist / ne ur os ur ge o n b ase d u p o n c o u ntr y re q uir e me nts.  
9)  Re vise d Defi niti o ns f or A de q uate Bas eli ne Or ga n F u ncti o n - Al b u mi n re m o ve d, 
P T/ IN Ra a n d P T T was u p date d fr o m  1. 5  x  U L N  to   1. 3 x U L N t o ali g n wit h t he 
u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d tra meti ni b c o m bi nati o n. 
1 0)  Re vise d i ncl usi o n criteria f or W o me n of c hil d beari n g p ote ntial t o i ncl u de ha vi n g t o 
use effecti ve c o ntrace pti o n 1 4 da y s pri or t o e nr oll me nt, a n d f or 4 m o nt hs after t he last 
d ose of st u d y  treat me nt. 
1 1)  R evise d e x cl usi o n criteri a:  
 
Pri or treat me nt wit h a B R A F i n hi bit or or a M E K i n hi bit or.  
 
K n o w n oc ular or pri mar y m uc osal mela n o ma . 
 
Pri or  sy ste mic a nti-ca n cer treat me nt . 
 
Hist or y  of  mali g na n c y  wit h c o nfir me d acti vati n g R A S m utati o n at a n y  ti me. 
 
A hist or y  or c u rre nt e vi d e nce of reti nal vei n occl usi o n ( R V O). 
1 2)  Re m o val of e x cl usi o n criteria:  
 
Ac ute i nfecti o n re q uiri n g i ntra ve n o us a nti bi otics.  
1 3)  Clarificati o n t hat 5 y ears f oll o w u p is fr o m t he dat e of first d ose of st u d y  tr eat me nt. 
 

N o v arti s 
C o nfi d e nti al 
P a g e 4 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
1 4)  U p date d t he f oll o wi n g  secti o ns t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or 
t he da brafe ni b a n d tra meti ni b c o m bi nati o n. 
 
Secti o n 5. 2. 1 Da brafe ni b a n d Tra meti ni b C o m bi nati o n t o ali g n wit h t he u p date d  
asset sta n dar d la n g u a ge f or t he da brafe ni b a n d tra meti ni b c o m bi nati o n . 
 
Secti o n 5. 8. 4. 3 G ui deli nes f or c u S C C a n d treat me nt e mer ge nt mela n o mas . 
 
Secti o n 6. 1 Per mitte d Me dicati o ns a n d N o n -dr u g T hera pies . 
 
Secti o n 6. 4 Treat me nt of St u d y  Treat me nt O ver d ose u p date d.  
 
Ta bl e  2 4 Cli nical C he mistr y  a n d He mat ol o g y  Para meters . 
 
Secti o n 7. 4. 2. 2 Defi niti o n of a S A E . 
 
Secti o n 7. 4. 5 O p ht hal mic E xa mi nati o n . 
1 5)  U p date Ta ble 3 t o c orrectl y  reflect cate g ories of d ose m o dificati o n g ui d eli nes. 
1 6)  U p date d Ta ble 1 8 M e dic ati o ns t o be use d wit h Ca uti o n . 
1 7)  Re vise d D ose M o dificati o n G ui deli nes f or:  
E ve nts C o nsi dere d Relat e d t o St u d y  Treat me nt ( Da brafe ni b a n d Tra meti ni b  
C o m bi nati o n Treat me nt)  
 
L V E F  
 
Q T c-Pr ol o n gati o n  
 
P y re xia 
 
Vis ual C ha n ges a n d/ or O p ht hal mic E x a mi nati o n Fi n di n gs  
 
Reti nal pi g me nt e pit helial detac h me nts ( R P E D) U p date d g ui deli nes f or c u S C C  
a n d ne w cases of s ec o n d ar y  mela n o mas  
 
P ne u m o n itis 
1 8)  C ha n ges t o t he Ti me a n d E ve nts Ta bles i ncl u di n g m o dificati o n t o fre q ue n c y  of 
E C H O i n t he ta ble t o matc h t he f o ot n ote refere nce, u p date t o i nstr ucti o n f or 
scree ni n g, o p ht hal m ol o g y e x a m, dis pe ns ati o n  of  st u d y treat me nt, f oll ow -u p c o ntact, 
a n d wee k 1 c ha n ge d  t o D a y  1.  
1 9)  A d diti o n of A p pe n di x 9:  C o u ntr y  S pecific Re q uire me nts f or Fra n ce a n d Ger ma n y . 
 
T he f oll o wi n g s u bjects are e x cl u de d fr o m t he st u d y ; s u bjects wit h HI V, u n der 
g uar dia ns hi p / u n der s u p er visi o n or de pri ve d of li berty , prese nt wit h 
electr ol y te a b n or malities, a n d ta ki n g m e dicati o ns k n o w n t o i n d uce Q T 
pr ol o n gati o n.  
G ui deli nes a d de d; Val v ul ar T o xicit y  a n d N o n-c uta ne o us sec o n dar y/rec urre nt mali g na nc y 
2 0 1 3 N 1 6 8 4 3 7 _ 0 2  
2 0 1 4 -A U G -2 0  
A me n d me nt N o. 2  
1)  A  c o u ntr y -s pecific a me n d me nt as re q ueste d b y t h e Fre nc h re g ul at ory  a ge n c y . 
 
Re m o ve d f o ot n otes u n der t he p ne u m o nitis g ui deli nes as t he y  di d n ot 
pertai n t o p ne u m o nitis g ui deli nes.  
 
U p date d Ta ble 8 Wit h h ol di n g a n d St o p pi n g Criteria f or Q Tc B -Pr ol o n gati o n . 
 
U p date d A p pe n di x 6 –  re m o val of P hase III t o I V al g orit h m a n d place me nt of 
p hase  II al g orit h m. 

N o v arti s 
C o nfi d e nti al 
P a g e 5 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
2 0 1 3 N 1 6 8 4 3 7 _ 0 3  
2 0 1 4 -S E P -0 4  
A me n d me nt N o. 2  
Re p u blis hi n g ( Ta ble n u m ber was wr o n g)  
2 0 1 3 N 1 6 8 4 3 7 _ 0 4  
2 0 1 5 -M A R -1 6  
A me n d me nt N o. 3  
1)  Re vise d list of a ut h ors . 
2)  Clarificati o n Pr ot oc ol A me n d me nt 2 is a c o u ntr y -s pecific a m e n d me nt as re q ueste d b y 
t he Fre n c h re g ulat or y a ge n c y . 
3)  Mi n or a d mi nistrati ve c ha n ges a n d c orrecti o n t o ty p o gra p hical err ors t hr o u g h o ut t he 
d oc u me nt.  
4)  Ta ble of C o nte nts U p dat e d wit h Secti o n 1. 3, A p pe n di x 1 1 a n d 1 2 refere nces.  
5)  Secti o n 1. 3 hea der a d de d f or clari ty  bet w ee n  st ud y a n d d os e rati o nal e.  
6)  St u d y  d esi g n re vise d f or clarit y  ar o u n d tr eat me nt disc o nti n uati o n a n d f oll o w u p of 
s u bjects. 
7)  E x cl usi o n  H IV re m o ve d per Marc h 2 0 1 4 u p dates t o In c/ E x c (c o m bi nati o n). 
8)  Per ma ne nt disc o nti n uati o n fr o m st u d y  tr eat me nt re vise d f or clarit y ar o u n d tr eat me nt 
disc o nti n uati o n a n d f oll o w u p of s u bjects.  
9)  D osa ge a n d a d mi nistrati o n secti o n re vise d bas e d o n c o m bi nati o n d osa ge a n d 
a d mi nistrati o n Marc h 2 0 1 4.  
1 0)  Ta ble 3 a d de d  f o ot n otes f or c o nsiste nc y acr oss M E K/ B R A F pr ot oc ols.  
1 1)  D ose Le vel Re d u cti o n G ui deli n es re vise d f or c o nsiste nc y acr oss M E K/ B R A F 
pr ot oc ols.  
1 2)  Ta ble 6 s u pers cri pt b a n d c a d de d t o sy m pt o matic L V E F f or c o nsiste nc y  acr oss 
M E K/ B R A F  pr ot oc ols.  
1 3)  Ta ble 7 well c o ntr olle d B P re vise d f or c o nsiste n c y acr oss M E K/ B R A F pr ot oc ols.  
1 4)  Secti o n 5. 8. 4 a d de d ‘ ker a t oaca nt h o ma f or c o nsiste nc y acr oss M E K/ B R A F pr ot oc ols.  
1 5)  Secti o n 5. 8. 4. 3 a d de d ‘ kerat oaca nt h o ma f or c o nsiste nc y  acr oss M E K/ B R A F 
pr ot oc ols.  
1 6)  Ta ble 1 1 re vise d d a brafe ni b d ose re d ucti o n f or c o nsiste nc y  acr oss M E K/ B R A F 
pr ot oc ols.  
1 7)  S ecti o n 5. 8. 5. 4 a d de d refere n ce S ecti o n 7. 5. 5.  
1 8)  Ta ble 1 4 a d de d f o ot n ote f or P K refere nce.  
1 9)  Ta ble 1 6 a d de d f o ot n otes f or c o nsiste nc y  acr oss M E K/ B R A F pr ot oc ols.  
2 0)  Secti o n 6. 1 re vise d f or cl arit y  t o ti me req uire me nts f or c o nc o mita nt me dicati o ns.  
2 1)  Ta ble 1 7 hea d er re vise d f or clari ty  o n  pr o hi bite d me dicati o ns.  
2 2)  Ta ble 1 9 re vise d f or cl arit y  o n re q uire d ass ess me nts.  
2 3)  Secti o n 7. 3. 2. 1 re vise d f or c o nsiste nc y  bet w ee n u p date d I ma ge Ac q uisiti o n 
G ui deli nes f or Brai n M RI.  
 

N o v arti s 
C o nfi d e nti al 
P a g e 6 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
2 4)  Secti o n 7. 3. 2. 2 re vise d f or clari ty ar o u n d treat me nt disc o nti n uati o n a n d f oll o w u p  of  
s u bjects. 
2 5)  Secti o n 7. 5. 3. 1 re vise d seri u m pre g na nc y  t est t o 7  da y s pri or t o e nr ol me nt i n 
acc or d a nce wit h Oct 2 0 1 4 safe ty  g ui da nce.  
2 6)  Secti o n 7. 5. 5 re vise d wit h ne w o p ht hal mic criteria fr o m J ul y  2 0 1 4 tra meti ni b safe ty 
g ui da n ce.  
2 7)  Secti o n 9. 2. 1 re vise d wit h descri pti o n o n h o w sa m ple siz e of 7 5 was calc ulate d.  
2 8)  Secti o n 9. 3. 3 Treat me nt c o m paris o n clarifie d as N A f or t his st u d y . 
2 9)  Ta ble 2 5 re vise d f or cl arit y  bet wee n r o w 1 a n d  r o w 2 i n a s u peri ority bi n o mial trial.  
3 0)  Secti o n 9. 3. 5. 1. 1 Sec o n dar y  A na ly ses a d de d li ne f or clarificati o n t o i nter pretati o n. 
3 1)  A p pe n di x 1 1 a d de d t o reflect a me n d me nt 0 2 c h a n ges.  
3 2)  A p pe n di x 1 2 a d de d t o reflect a me n d me nt 0 3 c h a n ges  
 2 0 1 3 N 1 6 8 4 3 7 _ 0 5  
2 0 1 5 -D E C -0 6  
A me n d me nt N o. 4  
1)  U p dati n g c o ntact det ails of Me dical M o nit or  
2)  Ta ble 1 St u d y  O bjecti ves –  1. Pri mar y  e n d p oi nt a me n de d t o all o w f or l ocall y 
c o nfir me d B R A F V 6 0 0 E (f oll o we d b y ce ntral c o nfir mati o n as wit h all ot her c o h orts) 
a n d 2 s ec o n dary  e n d p oi nt n u m ber 9 O S c ha n ge d fr o m 5 t o 3  y ear.  
3)  Secti o n 3 St u d y  d esi g n –  c o h ort A patie nt p o p ulati o n u p date d  t o all o w f or l ocall y 
c o nfir me d B R A F V 6 0 0 E (f oll o we d b y ce ntral c o nfir mati o n as wit h all ot her c o h orts). 
A n d defi niti o n of st u d y  cl os ure u p date d fr o m “ w here all s u bjects still i n f oll o w u p 
ha ve ha d at least 5 y ears f oll o w u p …” t o “ w here all s u bjects still i n f oll o w u p ha ve 
ha d at least 3 y ears f oll o w u p …”  
4)  Secti o n 3. 1 Disc ussi o n of Desi g n –  pri m ar y  efficac y o bjecti ve e n d p oi nt a me n de d  t o 
all o w f or l ocal ly c o nfir m e d B R A F V 6 0 0 E (f oll o we d b y ce ntr al c o nfir mati o n as wit h 
all ot her c o h orts) . 
5)  Secti o n 4. 1. 2 In cl usi o n Criteria 4 u p date d t o all o w f or l ocal ly  c o nfir me d B R A F 
V 6 0 0 E (f oll o we d b y  ce ntral c o nfir mati o n as wit h all ot her c o h orts) a n d I ncl usi o n 
criteria 1 0 - peri o d f or c o ntrace pti o n a me n de d fr o m 1 4 da y s pri or t o b aseli ne t o 7 
da y s t o be c o nsiste nt wit h all ot her secti o ns of pr ot oc ol a n d c urre nt I B 7 safet y 
u p date.  
6)  Secti o n 4. 2. 1 refere nce t o 5 y ear s ur vi val c ha n ge d t o 3.  
7)  Secti o n 4. 2. 2 re fere nce t o 5 y ear s ur vi val c ha n ge d t o 3.  
8)  Secti o n 5. 2, 1 D u plicate d se nte nce d elete d.  
9)  Secti o n 5. 8. 1 A me n de d fr o m d ose re d u cti o ns b el o w 5 0 t o d ose re d ucti o ns bel o w 7 5 
m g BI D . 
1 0)  Ta ble 5 “ or great er  occ urre nc e” d elete d.  
1 1)  Ta ble 1 9 Ti me a n d E v e nts Ta ble  –  f o ot n otes 2 a n d 3 a me n de d t o all o w f or l ocall y 
c o nfir me d B R A F V 6 0 0 E (f oll o we d b y ce ntral c o nfir mati o n as wit h all ot her c o h orts) . 
 

N o v arti s 
C o nfi d e nti al 
P a g e 7 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
1 2)  Secti o n 7. 2. 1. 1 sec o n dar y e n d p oi nt refere nce t o 5 y ear s ur vi val c ha n ge d t o 3 . 
1 3)  7. 4. 3. 1 Pre g n a nc y  T esti n g a n d Pre ve nti o n –  secti o n u p date d peri o d f or c o ntrace pti o n 
a me n de d fr o m 1 4 da y s pri or t o baseli ne t o 7 day s t o be c o nsiste nt wit h all ot her 
secti o ns of pr ot oc ol a n d c urre nt I B 7 s afety  u p date.  
1 4)  7. 6. 2 B R A F m utati o n ass a y  s ecti o n a me n de d t o all o w f or l ocally c o nfir me d B R A F 
V 6 0 0 E (f oll o we d b y  ce ntral c o nfir mati o n as wit h all ot her c o h orts).  
1 5)  Secti o n 9. 3. 5. 1. 1 Pri mar y A nal y sis refere n ce t o 5 y ear s ur vi val c ha n ge d t o 3 . 
1 6)  Secti o n  1 0. 5  St u d y  a n d Site Cl os ure refere n ce t o 5 y ear s ur vi val c ha n ge d t o 3 . 
1 7)  A p pe n di x 1 3 a d de d t o reflect a me n d me nt 0 4 c ha n ges . 
 
2 0 1 3 N 1 6 8 4 3 7 _ 0 6  
2 0 1 5 -D E C -1 4  
A me n d me nt N o. 4  
1 Mi n or a d mi nistrati ve  c ha n ges f o u n d d uri n g p O P R C re vie w:  
1)  Secti o n 4. 1. 2 In cl usi o n Crit eria 4 ty p o gra p hical d u plicati o n err or re m o ve d “c o h orts”  
2)  Secti o n O bjecti ves/ pri mar y  o bjecti ve T y p o  u p d ate d  i n sce nte nce be gi n ni n g “ T he 
pri mar y  effi cac y  e n d p oi nts will be accesse d c ha n ge d t o assesse d.  
3)  Secti o n 1 0. 5 St u d y  a n d Site Cl os ure n u m ber 3 a d d e d t o sce nte nce starti n g:” T he 
st u dy  will be c o nsi dere d . 
 2 0 1 3 N 1 6 8 4 3 7 _ 0 7  
2 0 1 6 -J U L-1 3  
A me n d me nt N o.  5  
1)  Delete or re pla ce refere n ces t o G S K or its staff wit h t hat of N o vartis/ N o vartis a n d      
it’s a ut h orize d a ge nts. 
2)  Ma ke a d mi nistrati ve c h a n ges t o ali g n wit h N o vartis pr ocesses a n d pr oce d ures  
 
2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
1 6 -M A Y -2 0 1 7  
A me n d me nt N o. 6  
 
A me n d me nt 6 di d n ot i nc or p or ate a me n d me nt 5, as it w as o nl y f or 
s u b missi o n i n c o u ntries t h at h ad n ot s u b mitte d G S K t o N o v artis s p o ns os hi p 
c h a n ge 
1.  St u d y d esi g n secti o n ( pa ge 2 2 a n d 3 6) a me n de d t o defi ne st u d y cl ose as w he n 
7 0 % of c o h ort A p atie nts are l ost t o f oll o w u p or c o m plete d or w he n all 
c o h ort A patie nts ha v e bee n f oll o we d u p f or 3 years, w hic he ver is earlier.  
 
2.  Secti o n 1 0. 5 ( pa ge 1 1 4) –  St u d y cl os ure d efi niti o n a me n de d fr o m 7 0 % of all 
e nr olle d st u d y p o p ul ati o n t o 7 0 % of pri mar y efficac y p o p ul ati o n (c o h ort A) 
a n d a d diti o n of at least t hree years f oll o w u p f or all c o h ort A patie nts.  
Esti mati o n of st u d y l e n gt h a me n de d t o a p pr o xi matel y 5 years fr o m st u d y 
start. 
 
3.  A d mi nistrati ve err ors fr o m pr ot oc ol a me n d me nt 4:  
 Ta ble of ass ess me nt  tra nscri pti o n err or rect ificati o n  
 Discre pa n c y wit h wi n d o w fr o m pre g n a nc y testi n g pri or t o s cree ni n g i n 
secti o n 7. 4. 3. 1  
4.  Secti o n 3. 1 pa ge 3 7 & 1 0 6 Statistical p o wer a me n de d fr o m 8 4 % t o 8 2 % t o 
ali g n wit h fi nal statistical a nal ysis pla n.  
 

N o v arti s 
C o nfi d e nti al 
P a g e 8 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
2 0 1 3 N 1 6 8 4 3 7 _ 0 9  
2 1 -J U N-2 0 1 7  
A me n d me nt N o. 7  
A me n d me nt 7  di d i nc or p or ate a me n d me nt 5, as it w as f or s u b missi o n i n 
c o u ntries t h at h ad alre a d y s u b mitte d G S K t o N o v artis s p o ns os hi p c h a n ge 
 
1.  St u d y d esi g n secti o n ( pa ge 2 2 a n d 3 4 ) a me n de d t o defi ne st u d y cl ose as w he n 7 0 % of 
c o h ort A patie nts are l ost t o f oll o w u p or c o m plete d or w he n all c o h ort A patie nts 
ha ve bee n f oll o we d u p f or 3 years, w hic he v er is earlier.  
 
2.  Secti o n 1 0. 5 ( pa ge 1 0 8 ) –  St u d y cl os ure d efi niti o n a me n de d fr o m 7 0 % of all e nr olle d 
st u d y p o p ulati o n t o 7 0 % of pri mar y efficac y p o p ulati o n (c o h ort A) a n d a d diti o n of at 
least t hree years f oll o w u p f or all c o h ort A p atie nts.  Esti mati o n of st u d y le n gt h 
a me n de d t o a p pr o xi matel y 5 years fr o m st u d y start.  
3.  A d mi nistrati ve err ors fr o m pr ot oc ol a me n d me nt 4:  
o  Ta ble of ass ess me nt  tra nscri pti o n err or rectificati o n  
o  Discre pa n c y wit h wi n d o w fr o m pre g n a nc y testi n g pri or t o s cree ni n g 
i n secti o n 7. 4. 3. 1  
4.  Secti o n 3. 1 pa ge 3 5  & 1 0 0  Statistical p o wer a me n de d fr o m 8 4 % t o 8 2 % t o ali g n wit h 
fi nal statistical a nal ysis pla n. 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 9 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
S p o ns or Si g n at or y:  
Si g n at ure:  D ate:  
 
 
 
 
 
N o vartis P har mace uticals C or p orati o n . 
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 1 0  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
S P O N S O R I N F O R M A TI O N P A G E  
Cli nic al St u d y I de ntifier:  
B R F 1 1 7 2 7 7 
S p o ns or C o nt act I nf or m ati o n 
N o vartis P har mace uticals C or p orati o n 
I n s o me c o u ntries, t he cli nical trial s p o ns or ma y b e t he l ocal N o v artis a n d its a ut h orize d 
a ge nts. W here a p plica ble, t he details of t he S p o ns or a n d c o ntact pers o n will be pr o vi de d t o 
t he rele v a nt re g ul at or y a ut h orit y as part of t he cli ni cal trial s u b missi o n. 
S p o ns or Seri o us A d verse E ve nts ( S A E) C o nt act I nf or m ati o n: 
Please refer t o t he st u d y pr oce d ures ma n ual. 
F or st u d y c o n d uct q u esti o ns n ot relate d t o patie nt safet y t hat nee d t o be a d dresse d t o t he 
s p o ns or, t he first li ne of c o ntact s h o ul d be wit h t he desi g nat e d l ocal c o u ntr y c o m pa n y c o ntact.  
I n t he e ve nt t hat t he d esi g nat e d c o m pa n y c o ntact is n ot a vaila ble, please c o ntact t he Me dical 
Lea d. 
Me dic al Le a d C o nt act I nf or m ati o n 
N o vartis P har mace uticals C or p orati o n 
O ne Healt h Plaza, 3 3 7/ A 1 1. 6 F 
East Ha n o ver, NJ 0 7 9 3 6- 1 0 8 0 
U S A 
Tele p h o ne N u m ber:
E mail:
 
N o vartis P ha r ma A G 
P ostfac h 
C H - 4 0 0 2 Bas el 
S WI T Z E R L A N D 
 
Cli nic al Tri al He a d C o nt act I nf or m ati o n  
Tele p h o ne N u m be r: 
E mail: 
If y o u ha ve a n y q uesti o ns re gar di n g t he pr ot oc ol, please c o ntact y o ur l ocal N o vartis office. 
Re g ul at or y A ge nc y I de ntif yi n g N u m ber(s):  
I nv esti g atio n al N e w Dr u g (I N D) Nu m b er 
1 1 3 5 5 7  
E ur o p e a n Dr u g R e gul at ory A ut h oriti es Cli nic al Tri als ( E u dr a C T) Nu m b er  
2 0 1 3 -0 0 3 4 5 2 -2 1  

N o v arti s 
C o nfi d e nti al 
P a g e 1 1  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
I N V E S TI G AT O R A G R E E M E N T P A G E  
F or pr ot oc ol B R F 1 1 7 2 7 7 a me n d me nt n u m ber 0 5 . 
I c o nfir m a gree me nt t o c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol, as a me n de d b y 
t his pr ot oc ol a me n d me nt. 
I ac k n o wle d ge t h at I a m res p o nsi ble f or o v erall st u d y c o n d u ct. I a gree t o p ers o nall y 
c o n d uct or s u per vise t he descri be d st u d y.  
I a gree t o e ns ure t hat all ass ociates, c ollea g ues a n d e m p l oyees assisti n g i n t he c o n d uct of 
t he st u d y are i nf or me d a b o ut t heir o bli gati o ns. Mec ha nis ms are i n place t o e ns ure t hat site 
staff recei ves t he a p pr o priate i nf or mati o n t hr o u g h o ut t he st u d y. 
I n v esti gat or Na me: 
 
I n v esti gat or A d dress: 
 
I n v esti gat or P h o ne N u m ber:  
 
I n v esti gat or Si g nat ure 
Da te 

N o v arti s 
C o nfi d e nti al 
P a g e 1 2  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
T A B L E O F  C O N T E N T S 
P A G E 
 
A m e n d m e nt 5 .................................................................................................................... 2 
I N V E S TI G AT O R A G R E E M E N T P A G E  ............................................................................ 1 1  
A B B R E VI A TI O N S ............................................................................................................ 1 6  
P R O T O C O L S U M M A R Y  .................................................................................................. 1 9  
O bj e cti v e s ................................................................................................................. 2 0  
Pri m ar y O bj e cti v e ........................................................................................... 2 0  
S e c o n d ar y O bj e cti v e ....................................................................................... 2 0  
St u d y D e si g n .................................................................................................. 2 1  
St u d y A s s e s s m e nt s ........................................................................................ 2 2  
1.  
I N T R O D U C TI O N ...................................................................................................... 2 2  
1. 1. 
B a c k gr o u n d .................................................................................................... 2 2  
1. 1. 1.  
T h e B R A F I n hi bit or D a br af e ni b a s M o n ot h er a p y ............................. 2 3  
1. 1. 2.  
T h e M E K I n hi bit or Tr a m eti ni b a s M o n ot h er a p y ............................... 2 4  
1. 1. 3. 
B R A F a n d M E K I n hi bit or s a s C o m bi n ati o n T h er a p y ........................ 2 5  
 
 2 5  
1. 1. 3. 2.  
D a br af e ni b a n d Tr a m eti ni b C o m bi n ati o n ...................... 2 5  
1. 2. 
St u d y R ati o n al e .............................................................................................. 2 7  
 
 2 8  
2.  
O B J E C TI V E A N D E N D P OI N T S ................................................................................ 2 9  
3.  
S T U D Y D E SI G N ....................................................................................................... 3 1  
3. 1. 
Di s c u s si o n of  D e si g n ...................................................................................... 3 4  
4.  
S U B J E C T S E L E C TI O N A N D DI S C O N TI N U A TI O N/ C O M P L E TI O N C RI T E RI A ....... 3 5  
4. 1. 
S u bj e ct S el e cti o n Crit eri a ................................................................................ 3 5  
4. 1. 1.  
N u m b er of S u bj e ct s ........................................................................ 3 5  
4. 1. 2.  
I n cl u si o n Crit eri a ............................................................................. 3 5  
4. 1. 3.  
E x cl u si o n Crit eri a ............................................................................ 3 7  
4. 2. 
P er m a n e nt Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt a n d S u bj e ct C o m pl eti o n 
Crit eri a ............................................................................................................ 3 9  
4. 2. 1.  
P er m a n e nt Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt .......................... 3 9  
4. 2. 2.  
S u bj e ct C o m pl eti o n a n d Wit h dr a w al ............................................... 4 0  
5.  
S T U D Y T R E A T M E N T S ............................................................................................ 4 0  
5. 1. 
I n v e sti g ati o n al Pr o d u ct .................................................................................... 4 0  
5. 1. 1.  
D a br af e ni b ...................................................................................... 4 0  
5. 1. 2.  
Tr a m eti ni b ...................................................................................... 4 0  
5. 2. 
D o s a g e a n d A d mi ni str ati o n ............................................................................. 4 1  
5. 2. 1.  
D a br af e ni b a n d Tr a m eti ni b C o m bi n ati o n ......................................... 4 1  
5. 3. 
H a n dli n g a n d St or a g e of St u d y Tr e at m e nt ...................................................... 4 1  
5. 4. 
Tr e at m e nt A s si g n m e nt .................................................................................... 4 1  
5. 5. 
Bli n di n g .......................................................................................................... 4 2  
5. 6. 
Pr o d u ct A c c o u nt a bilit y .................................................................................... 4 2  
5. 7. 
Tr e at m e nt C o m pli a n c e .................................................................................... 4 2  
5. 8. 
D o s e M o difi c ati o n G ui d eli n e s .......................................................................... 4 2  
5. 8. 1.  
D o s e L e v el s of d a br af e ni b a n d tr a m eti ni b ....................................... 4 3  
5. 8. 2.  
G e n er al G ui d eli n e s f or Cli ni c all y Si g nifi c a nt T o xi citi e s o n t h e    
d a br af e ni b a n d tr a m eti ni b c o m bi n ati o n tr e at m e nt ar m .................... 4 4  
5. 8. 3.  
G ui d eli n e s f or C ar di o v a s c ul ar A d v er s e E v e nt s o n t h e d a br af e ni b a n d 
tr a m eti ni b c o m bi n ati o n tr e at m e nt ar m ............................................. 4 5  
5. 8. 3. 1.  
L eft V e ntri c ul ar Ej e cti o n Fr a cti o n ( L V E F) ..................... 4 5  
5. 8. 3. 2.  
H y p ert e n si o n ................................................................ 4 6  
5. 8. 3. 2. 1.  M o nit ori n g of H y p ert e n si o n  ......................... 4 7  

N o v arti s 
C o nfi d e nti al 
P a g e 1 3  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
5. 8. 3. 2. 2. 
M a n a g e m e nt of H y p ert e n si o n ..................... 4 7  
5. 8. 3. 3.  
G ui d eli n e s f or Pr ol o n g e d Q T c ...................................... 4 9  
5. 8. 4.  
G ui d eli n e s f or S ki n-r el at e d A d v er s e E v e nt s o n t h e d a br af e ni b a n d 
tr a m eti ni b c o m bi n ati o n tr e at m e nt ar m ............................................. 4 9  
5. 8. 4. 1.  
R a s h ............................................................................ 4 9  
5. 8. 4. 2.  
G ui d eli n e s f or H a n d-f o ot S ki n R e a cti o n s ( H F S R) ......... 5 1  
5. 8. 4. 3.  
G ui d eli n e s f or c u S C C a n d tr e at m e nt e m er g e nt 
m el a n o m a s .................................................................. 5 2  
5. 8. 5.  
G ui d eli n e s f or Ot h er A d v er s e E v e nt s of S p e ci al I nt er e st o n t h e 
d a br af e ni b a n d tr a m eti ni b c o m bi n ati o n tr e at m e nt ar m .................... 5 2  
5. 8. 5. 1.  
G ui d eli n e s f or P yr e xi a .................................................. 5 2  
5. 8. 5. 2.  
G ui d eli n e s f or Di arr h e a ................................................ 5 4  
5. 8. 5. 3.  
G ui d eli n e s f or R e n al I n s uffi ci e n c y ................................ 5 5  
5. 8. 5. 4.  
G ui d eli n e s f or Vi s u al C h a n g e s ..................................... 5 6  
5. 8. 5. 5.  
G ui d eli n e s f or P n e u m o niti s .......................................... 5 8  
5. 9. 
M o nit ori n g, I nt err u pti o n, a n d  St o p pi n g Crit eri a f or H e p at o bili ar y E v e nt s .......... 6 0  
5. 9. 1.  
Li v er C h e mi str y St o p pi n g Crit eri a ................................................... 6 0  
5. 9. 1. 1.  
Li v er E v e nt F oll o w- u p A s s e s s m e nt s ............................. 6 1  
5. 9. 1. 2.  
Li v er C h e mi str y M o nit ori n g Crit eri a .............................. 6 3  
5. 9. 1. 3.  
Dr u g R e st art/ R e c h all e n g e F oll o wi n g Li v er E v e nt s t h at ar e 
P o s si bl y R el at e d t o St u d y Tr e at m e nt A p p e n di x 7 ......... 6 3  
5. 9. 1. 4.  
Dr u g R e st art F oll o wi n g Tr a n si e nt R e s ol vi n g Li v er E v e nt s 
N ot R el at e d t o St u d y Tr e at m e nt ................................... 6 3  
6.  
C O N C O MI TA N T M E DI C A T I O NS A N D  N O N- D R U G T H E R A PI E S ............................ 6 4  
6. 1. 
P er mitt e d M e di c ati o n s a n d N o n- dr u g T h er a pi e s ............................................. 6 4  
6. 2. 
Pr o hi bit e d M e di c ati o n s a n d N o n- dr u g T h er a pi e s ............................................. 6 5  
6. 3. 
M e di c ati o n s t o b e  u s e d wit h C a uti o n ............................................................... 6 6  
6. 4. 
Tr e at m e nt of St u d y Tr e at m e nt O v er d o s e ........................................................ 6 8  
7.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S ........................................................ 6 9  
7. 1. 
Criti c al B a s eli n e A s s e s s m e nt s ........................................................................ 7 5  
7. 1. 1.  
B a s eli n e D o c u m e nt ati o n of I ntr a cr a ni al T ar g et a n d N o n- T ar g et 
L e si o n s ........................................................................................... 7 5  
7. 1. 2.  
 B a s eli n e D o c u m e nt ati o n of E xtr a cr a ni al T ar g et a n d N o n- T ar g et 
L e si o n s ........................................................................................... 7 5  
7. 2. 
Effi c a c y ........................................................................................................... 7 6  
7. 2. 1.  
Effi c a c y E n d p oi nt s .......................................................................... 7 6  
7. 2. 1. 1.  
S e c o n d ar y E n d p oi nt s ................................................... 7 6  
 
 7 7  
7. 2. 2.  
Effi c a c y A s s e s s m e nt ...................................................................... 7 7  
7. 2. 2. 1. 
A s s e s s m e nt G ui d eli n e s .................................................................. 7 8  
7. 2. 2. 2.  
F oll o w- U p A s s e s s m e nt s f or S u bj e ct s P er m a n e ntl y 
Di s c o nti n u e d fr o m St u d y Tr e at m e nt ............................. 7 9  
7. 2. 2. 3.  
A s s e s s m e nt of S u bj e ct C o m pl eti o n .............................. 7 9  
7. 3. 
G ui d eli n e s f or E v al u ati o n of  Di s e a s e ............................................................... 7 9  
7. 3. 1.  
M e a s ur a bl e a n d N o n- M e a s ur a bl e D efi niti o n s f or I ntr a cr a ni al Di s e a s e
 ....................................................................................................... 7 9  
7. 3. 1. 1.  
M e a s ur a bl e a n d N o n- M e a s ur a bl e D efi niti o n s f or 
E xtr a cr a ni al Di s e a s e .................................................... 8 0  
7. 3. 2.  
R e s p o n s e Crit eri a ........................................................................... 8 0  
7. 3. 2. 1.  
I ntr a cr a ni al R e s p o n s e (I R) - E v al u ati o n of  I ntr a cr a ni al 
T ar g et L e si o n s ............................................................. 8 0  
7. 3. 2. 2.  
I ntr a cr a ni al R e s p o n s e (I R) - E v al u ati o n of  I ntr a cr a ni al 
N o n- T ar g et L e si o n s ...................................................... 8 1  
7. 3. 2. 3.  
E xtr a cr a ni al R e s p o n s e ( E R) - E v al u ati o n of E xtr a cr a ni al 

N o v arti s 
C o nfi d e nti al 
P a g e 1 4  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
T ar g et L e si o n s ............................................................. 8 1  
7. 3. 2. 4.  
E xtr a cr a ni al R e s p o n s e ( E R) - E v al u ati o n of E xtr a cr a ni al 
N o n- T ar g et L e si o n s ..................................................... 8 2  
7. 3. 2. 5.  
O v er all R e s p o n s e - E v al u ati o n of  T ar g et L e si o n s ......... 8 2  
7. 3. 2. 6.  
O v er all R e s p o n s e - E v al u ati o n of  N o n- T ar g et L e si o n s . 8 3  
7. 3. 2. 7. 
N e w L e si o n s ................................................................ 8 4  
7. 3. 2. 8.  
E v al u ati o n of I ntr a cr a ni al R e s p o n s e ............................. 8 4  
7. 3. 2. 9.  
E v al u ati o n of E xtr a cr a ni al R e s p o n s e ............................ 8 5  
7. 3. 2. 1 0.  
E v al u ati o n of O v er all R e s p o n s e ................................... 8 5  
7. 3. 2. 1 1.  
E v al u ati o n of B e st I ntr a cr a ni al, E xtr a cr a ni al a n d O v er all 
R e s p o n s e .................................................................... 8 6  
7. 4. 
S af et y ............................................................................................................. 8 7  
7. 4. 1.  
S af et y E n d p oi nt s ............................................................................ 8 7  
7. 4. 2.  
A d v er s e E v e nt s .............................................................................. 8 7  
7. 4. 2. 1.  
D efi niti o n of a n A E ....................................................... 8 7  
7. 4. 2. 2.  
D efi niti o n of a S A E ....................................................... 8 8  
7. 4. 2. 3.  
L a b or at or y a n d Ot h er S af et y A s s e s s m e nt A b n or m aliti e s 
R e p ort e d a s A E s a n d S A E s  ......................................... 8 9  
7. 4. 2. 4.  
Di s e a s e- R el at e d E v e nt s a n d/ or Di s e a s e- R el at e d 
O ut c o m e s N ot Q u alif yi n g a s  S AE s  ............................... 9 0  
7. 4. 2. 5.  
Ti m e P eri o d a n d Fr e q u e n c y f or D et e cti n g A E s  a n d  S AE s
 .................................................................................... 9 0  
7. 4. 2. 6.  
Pr o m pt R e p orti n g of S eri o u s A d v er s e E v e nt s a n d Ot h er 
E v e nt s t o N o v arti s ........................................................ 9 0  
7. 4. 2. 7.  
R e g ul at or y r e p orti n g r e q uir e m e nt s f or S A E s  ................ 9 2  
7. 4. 3.  
Pr e g n a n c y ...................................................................................... 9 2 
7. 4. 3. 1.  
Pr e g n a n c y T e sti n g a n d Pr e v e nti o n .............................. 9 2  
7. 4. 3. 2.  
Pr e g n a n c y R e p orti n g ................................................... 9 3  
7. 4. 4.  
L a b or at or y A s s e s s m e nt s ................................................................ 9 3  
7. 4. 5.  
O p ht h al mi c E x a mi n ati o n ................................................................. 9 5  
7. 4. 6.  
Vit al Si g n s ...................................................................................... 9 5  
7. 4. 7. 
P h y si c al E x a mi n ati o n s .................................................................... 9 5  
7. 4. 8.  
El e ctr o c ar di o gr a m s ( E C G) .............................................................. 9 6  
7. 4. 9.  
E c h o c ar di o gr a m s ( E C H O) .............................................................. 9 6  
 
 9 6  
 
 9 6  
 
 9 7  
 
 9 7  
 
 9 8  
8.
D A T A M A N A G E M E N T .............................................................................................. 9 8  
9.
D A T A A N A L Y SI S A N D S T A TI S TI C A L C O N SI D E R A TI O N S ..................................... 9 8  
9. 1. 
H y p ot h e s e s  .................................................................................................... 9 8  
9. 2. 
St u d y D e si g n C o n si d er ati o n s .......................................................................... 9 9  
9. 2. 1.  
S a m pl e Si z e A s s u m pti o n s .............................................................. 9 9  
9. 2. 2.  
S a m pl e Si z e R e- e sti m ati o n ........................................................... 1 0 0  
9. 3. 
D at a A n al y s i s C o n si d er ati o n s ....................................................................... 1 0 0  
9. 3. 1.  
A n al y si s P o p ul ati o n s ..................................................................... 1 0 0  
9. 3. 2.  
A n al y si s D at a S et s ........................................................................ 1 0 0  
9. 3. 3.  
Tr e at m e nt C o m p ari s o n s ............................................................... 1 0 1  
9. 3. 4.  
I nt eri m A n al y si s ............................................................................ 1 0 1  
9. 3. 5. 
K e y El e m e nt s of  An al y si s  Pl a n ..................................................... 1 0 1  
9. 3. 5. 1.  
Effi c a c y A n al y s e s ....................................................... 1 0 2  
9. 3. 5. 1. 1.  Pri m ar y A n al y si s  ....................................... 1 0 2  
9. 3. 5. 2.  
S af et y A n al y s e s ......................................................... 1 0 3  

N o v arti s 
C o nfi d e nti al 
P a g e 1 5  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
9. 3. 5. 2. 1.  E xt e nt of E x p o s ur e  ................................... 1 0 3  
9. 3. 5. 2. 2.  A d v er s e E v e nt s  ........................................ 1 0 3  
9. 3. 5. 2. 3.  Cli ni c al L a b or at or y E v al u ati o n s  ................. 1 0 4  
9. 3. 5. 2. 4.  Ot h er S af et y M e a s ur e s  ............................. 1 0 4  
 
 
 
 
 
 1 0 4  
 
 
 
 1 0 4  
 
 1 0 5  
 
 1 0 5  
1 0.  S T U D Y C O N D U C T C O N SI D E R A TI O N S ................................................................ 1 0 5  
1 0. 1. P o sti n g of  I nf or m ati o n o n  P u bli cl y A v ail a bl e Cli ni c al Tri al R e gi st er s .............. 1 0 5  
1 0. 2. R e g ul at or y a n d  Et hi c al C o n si d er ati o n s, I n cl u di n g t h e I nf or m e d C o n s e nt Pr o c e s s 
  
 ..................................................................................................................... 1 0 5  
1 0. 3. 
Q u alit y C o ntr ol ( St u d y M o nit ori n g) ................................................................ 1 0 6  
1 0. 4. 
Q u alit y A s s ur a n c e ........................................................................................ 1 0 7  
1 0. 5. St u d y a n d  Sit e Cl o s ur e ................................................................................. 1 0 7  
1 0. 6. R e c or d s R et e nti o n ........................................................................................ 1 0 8  
1 0. 7. Pr o vi si o n of St u d y R e s ult s t o I n v e sti g at or s, P o sti n g of I nf or m ati o n o n P u bli cl y 
A v ail a bl e Cli ni c al Tri al s R e gi st er s a n d P u bli c ati o n ........................................ 1 0 8  
1 0. 8. 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 (I D M C) .......................................... 1 0 9  
1 1.  
R E F E R E N C E S ....................................................................................................... 1 0 9  
1 2.  A P P E N DI C E S ........................................................................................................ 1 1 5  
1 2 .1 . A p p e n di x  1 : M el a n o m a  of  t h e S ki n  St a gi n g  .................................................. 1 1 5  
1 2. 2. A p p e n di x 2: E a st er n C o o p er ati v e O n c ol o g y Gr o u p ( E C O G) P erf or m a n c e 
St at u s ........................................................................................................... 1 1 6  
1 2. 3. A p p e n di x 3: C o c k cr oft- G a ult F or m ul a .......................................................... 1 1 7  
1 2. 4. A p p e n di x 4: Q T i nt er v al o n el e ctr o c ar di o gr a m c orr e ct e d u si n g t h e B a z ett’ s 
f or m ul a ( Q T c B) ............................................................................................. 1 1 8  
1 2. 5. A p p e n di x 5: N e w Y or k H e art A s s o ci ati o n ( N Y H A) G ui d eli n e s ...................... 1 1 9  
1 2. 6. A p p e n di x 6: Li v er C h e mi str y M o nit ori n g, I nt err u pti o n St o p pi n g a n d  F oll o w-u p  
Crit eri a .......................................................................................................... 1 2 0  
1 2. 7. A p p e n di x 7: Li v er S af et y Dr u g R e st art or  R e c h all e n g e G ui d eli n e s ............... 1 2 1  
 1 2 7  
1 2. 9. A p p e n di x 9: C o u ntr y S p e cifi c R e q uir e m e nt s ( Fr a n c e/ G er m a n y ). ................. 1 3 2  
1 2. 1 0. A p p e n di x 1 0:  Pr ot o c ol C h a n g e s f or A m e n d m e nt 0 1  ...................................... 1 3 4  
1 2. 1 1. A p p e n di x 1 1 : Pr ot o c ol C h a n g e s f or A m e n d m e nt 0 2  ...................................... 1 8 5  
1 2. 1 2. A p p e n di x 1 2 : Pr ot o c ol C h a n g e s f or A m e n d m e nt 0 3  ...................................... 1 9 1  
1 2. 1 3. A p p e n di x 1 3 : Pr ot o c ol C h a n g e s f or A m e n d m e nt 0 4  ...................................... 1 9 3  
1 2. 1 4. A p p e n di x 1 3 : Pr ot o c ol C h a n g e s f or A m e n d m e nt 0 5 ( d at e d D D- M m m- 2 0 1 6) fr o m 
A m e n d m e nt 0 4 ( d at e d 0 4 F e b 2 0 1 6) ............................................................ 1 9 4  

N o v arti s 
C o nfi d e nti al 
P a g e 1 6  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
A B B R E VI A TI O N S  
A D L  
Acti vities of dail y  li vi n g 
A E  
A d verse e ve nt(s)  
A L T  
Ala ni ne tra nsa mi nase ( S G P T)  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A S P C R  
Allel e-s pecific p olym erase c hai n reacti o n 
A S T  
As partate a mi n otra n sferase ( S G O T) 
A T P  
A de n osi ne tri p h os p hate  
A U C  
Area u n d er t he c o nce ntr ati o n -ti me c ur ve 
A U C( 0 -) 
Area u n d er t he c o nce ntr ati o n -ti me c ur ve o ver t he d osi n g i nter val 
B A L  
Br o nc h o al ve olar l a va ge  
B C C  
Basal cell carci n o ma  
B C R P  
Breast ca n cer resista nce pr otei n  
BI D  
T wice dai ly  
BI R C  
Bli n de d I n de p e n de nt Re vie w C o m mittee  
B P  
Bl o o d press ur e  
B R A T  
Ba na n a, ric e, a p ples, t oast  
B U N  
Bl o o d urea nitr o ge n  
C A F  
C y t o ki nes a n d a n gi o ge ni c fact ors 
 
 
CI  
C o nfi de nce i nter val  
C L / F 
A p pare nt cl eara nce f oll o wi n g  oral d osi n g  
C ma x  
Ma xi m u m o bser ve d c o nce ntrati o n  
C N S  
Ce ntral ner v o us sy ste m 
C P K  
Creati ni ne p h os p h o ki nase  
C R  
C o m plete res p o nse  
C R O  
Cli nical Researc h Or ga ni zati o n  
Cr Cl  
Creati ni ne cleara n ce  
C S R  
Ce ntral ser o us r eti n o pat h y  
C T  
C o m p ute d t o m o gra p h y  
C T C A E  
C o m m o n Ter mi n ol o g y  Criteria f or A d ve rse E ve nts  
C T L A  
C y t ot o xic T -ly m p h oc y t e a nti ge n 
c u S C C 
C uta ne o us S q ua m o us Cell Carci n o ma  
C V %  
C oefficie nt of v ariati o n  
C Y P  
C y t oc hr o me P 4 5 0 
D B P  
Diast olic bl o o d press ure  
D M S O  
Di met h y l s ulf o xi de 
D N A  
De o x yri b o n uclei c  aci d  
D E R  
D urati o n of E xtracra ni al Res p o nse  
D IR  
D urati o n of I ntr acra nial Res p o nse  
D O R  
D urati o n of O verall Res p o nse  
D T IC  
Dacar bazi ne  
E  
Gl uta mate  
E C  
E xtracra nial Diseas e  
E C G  
Electr ocar di o gra m  

N o v arti s 
C o nfi d e nti al 
P a g e 1 7  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
E C H O  
Ec h ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y  Gr o u p  
e C R F 
Electr o nic case re p ort f or m  
E D T A  
Et h y le n e dia mi netetraacetic aci d 
E R R  
E xtracra nial Res p o nse R ate  
E u dra C T  
E ur o pea n Dr u g Re g ulat or y  A ut h orities Cli nical Trials  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F D G -P E T  
Fl u or o de o x y gl uc os e p ositr o n e missi o n t o m o gra p h y  
F S H  
F ollicl e-sti m ulati n g h or m o ne 
F T IH  
First ti me i n h u ma ns  
G C P  
G o o d Cli nical Practice  
G C S P  
Gl o bal Cli nical Safet y  a n d P har mac o vi gila nce  
G C P H  
Gl o bal Cli nical Pr o gra m Hea d  
G C L  
Gl o bal Cli nical Lea d  
G L P  
G o o d La b orat or y  Practice  
G S K  
Gla x o S mit h Kli ne  
G 6 P D  
Gl uc os e-6 -p h os p hate de h y dr o ge nase  
H B V  
He patitis B vir us  
H C G  
H u ma n c h ori o nic g o na d otr o pi n  
H C V  
He patitis C vir us  
H F S R  
Ha n d -f o ot s ki n reacti o n 
H g  
Merc ur y  
H IV  
H u ma n i m m u n o deficie nc y vir us  
H M G -C o A  
3 -h y dr o x y -3 -m et h y lg l utaryl-c oe nz ym e A  
H P M C  
H y dr o x y pr o p y l m et h yl cell ul os e 
H R  
Hazar d rati o  
H R Q O L  
Healt h -relate d q uality  of  life 
H R T  
H or m o n e-re place ment t hera p y  
I B 
I n v esti gat or’s Br oc h ure 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I D C 
I ntr acra nial Disease C o ntr ol  
ID E  
I n v esti gati o nal De vice E x e m pti o ns 
I D M C 
I n d e pe n de nt Data M o nit ori n g C o m mittee 
I E C 
I n d e pe n de nt Et hics C o m mittee 
I g M 
I m m u n o gl o b uli n M 
IN D  
I n v esti gati o nal Ne w Dr u g 
I N R 
I nter nati o nal n or malize d rati o 
IU O  
I n v esti gati o nal Use O nly  
I C 
I ntr acra nial Disease 
I R 
I ntr acra nial Res p o nse Rate 
IR B  
I nstit uti o nal Re vie w B oar d 
I T T 
I nte nt-to -treat 
I V R S 
I nteracti ve v oice res p o ns e sy ste m 
K  
L y sine  
L D H  
Lactate d e h y dr o ge nase  
L L N  
L o w er li mit of n or mal  
L S L V  
Last s u bje ct’s last visit  

N o v arti s 
C o nfi d e nti al 
P a g e 1 8  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
L S M  
Least s q uare mea ns 
L V E F  
Left ve ntric ular ejecti o n fracti o n  
M A P K  
Mit o ge n -acti vate d pr otei n ki nase  
Me d D R A  
Me dical Dicti o nar y  f or R e g ul at or y  Acti vities  
m m  
Milli m eter(s) 
M RI  
Ma g n etic res o n a nce i ma gi n g  
M S D S  
Material Safe ty Data S heet  
N A  
N ot a p plica ble  
N CI  
Nati o nal Ca ncer I nstit ute  
N E  
N ot e val ua ble  
N E D  
N o e vi de nce of diseas e  
N S AI D S  
N o n -ster oi dal a nti-i nfla m mat or y dr u gs  
N Y H A  
Ne w Y or k Heart Ass ociati o n  
O D C  
O v erall Disease C o ntr ol 
O R R  
O verall res p o nse rate  
O S  
O verall s ur vi val  
P D  
Pr o gressi ve disease  
P F S  
Pr o gressi o n -free s ur vi val 
P g p  
P -g lyc o pr otei n  
 
 
P K  
P har mac o ki netics  
P R  
Partial res p o nse  
P T  
Pr ot hr o m bi n ti me  
P T T  
Partial t hr o m b o plasti n ti me  
Q Tc  
C orrecte d Q T i nter val o n electr ocar di o gra m  
Q Tc B  
Q T i nter val o n electr ocar di o gra m c orrecte d usi n g t he Bazett’s f or m ula  
R A P  
Re p orti n g a n d a na ly sis pla n 
R E C IS T  
Res p o nse E val uati o n Criteria I n S oli d T u m o urs  
R N A  
Ri b o n ucleic aci d  
R P E D  
Reti nal pi g me nt e pit helial detac h me nt  
R V O  
Reti nal vei n occl usi o n  
S A E  
Seri o us a d verse e ve nt(s)  
S B P  
S y st olic bl o o d press ure 
S C C  
S q ua m o us cell carci n o ma  
S D  
Sta ble disease  
S G O T  
Ser u m gl uta mic o x al oacetic tra nsa mi n ase ( A S T) 
S G P T  
Ser u m gl uta mic p yr u vi c tra nsa mi nase ( A L T)  
S O P  
Sta n dar d O perati n g Pr oce d ure(s)  
S P F  
S ki n pr otecti o n fact or  
S P M  
St u d y  Pr oce d ures  Ma n ual  
U L N  
U p per li mit of n or mal  
U P  
U p per Pr o vi de nce  
U S/ U S A  
U nite d States  
V  
Vali ne  
V A S  
Vis ual a nal o g ue scale  
V/ F  
V ol u me of distri b uti o n  
W B C  
W hite bl o o d cell  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 9  
 
P R O T O C O L S U M M A R Y  
R ati o n al e  
O ne of t he m ost c o m m o n a n d seri o us c o m plicati o ns of c uta ne o us mela n o m a is t he 
de vel o p me nt of metastati c sites i n t he ce ntral n er v o us s yste m ( C N S).  U p t o 2 0 % of 
patie nts are dia g n os e d wit h brai n metastases at t he ti me of i nitial dia g n osis, a n d u p t o 
7 5 % of patie nts are f o u n d t o ha ve brai n metast ases t hr o u g h o ut t he c o urse of t heir 
disease [ Da vies , 2 0 1 1].  Cli nical o utc o mes are us uall y q uite p o or, wit h me dia n o verall 
s ur vi val esti mate d t o be bet wee n 3. 8 a n d 4. 7 m o nt hs [Sa m ps o n , 1 9 9 8] [Fife , 2 0 0 4] 
[Da vies , 2 0 1 1].  Treat me nt selecti o n is dri ve n b y cli nical a n d disease criteri a, 
i ncl u di n g n u m ber of cere bral metastases, p erf or m a nce stat us, a n d e xte nt of 
e xtracra nial diseas e [ H o n g , 2 0 1 2]. S ur gi cal i nter ve nti o n a n d ra diati o n ha ve 
de m o nstrate d i m pr o ve d l ocal c o ntr ol, b ut hist oricall y s yst e mic treat me nts h a ve bee n 
ge n erall y i neffecti ve, wit h res p o nse rates of less t ha n 1 0 % a n d disease sta bilizati o n 
rates of ar o u n d 2 0- 3 0 % [A gar wala , 2 0 0 4] [ Mar g oli n , 2 0 1 2]. 
A p pr o xi matel y 4 0 t o 6 0 % of c uta n e o us mela n o m as carr y m utati o ns i n B R A F t hat lea d t o 
c o nstit uti ve acti vati o n of d o w nstrea m si g nalli n g t hr o u g h t he M A P K pat h wa y. 
A p pr o xi matel y 9 0 % of t h ese m utati o ns res ult i n t he s u bstit uti o n of gl uta mic aci d f or v ali ne 
at c o d o n 6 0 0 ( B R A F V 6 0 0 E), alt h o u g h ot h er acti vati n g m utati o ns are k n o w n (e. g., B R A F 
V 6 0 0 K a n d B R A F V 6 0 0 R) [ Da vies , 2 0 0 2].  Da brafe ni b is a n orall y a vaila ble, re versi ble, 
A T P-c o m petiti ve i n hi bit or t hat selecti vel yi n hi bits B R A F V 6 0 0 E ki nase wit h a 
c o nce ntr ati o n re q uire d f or 5 0 % i n hi biti o n of t he ki nase acti vit y (I C 5 0) fi ve ti mes l o wer 
t ha n t he I C 5 0 f or wil d-t y pe B R A F or C R A F.  A rece nt st u d y of da brafe ni b m o n ot hera py 
( B R E A K- M B) i n 1 7 2 patie nts wit h B R A F V 6 0 0 E/ K- m utati o n p ositi ve mela n o ma t hat has 
metastasiz e d t o t he brai n i n re p orte d e nc o ura gi n g res ults.  A n o verall i ntracra nial res p o nse 
rate of 3 9 % a n d o verall disease c o ntr ol rate of 8 0 % was re p orte d i n patie nts wit h V 6 0 0 E-
m utati o n p ositi ve t u m o urs w h o ha d n ot recei ve d pri or l ocal ( brai n) treat me nt.  Si milar 
res ults ( o verall i ntracra ni al res p o nse rate = 3 1 %; o verall disease c o ntr ol rat e = 8 3 %) were 
o bser ve d i n patie nts wit h V 6 0 0 E- m utati o n p ositi ve t u m o urs w h ose diseas e ha d pr o gress e d 
after pre vi o us i nter ve nti o n wit h s ur ger y,  w h ol e- brai n ra diati o n, or stere otactic 
ra di os ur ger y.  I n patie nts wit h V 6 0 0 K- m utati o n p ositi ve t u m o urs, o verall disease c o ntr ol 
rates of 4 7 % a n d 5 0 % w ere re p orte d i n t he l ocal- treat me nt nai ve a n d pre vi o us-l ocal 
treat me nt c o h orts, r es pecti vel y[L o n g , 2 0 1 2]. 
I n a rece nt st u d y of da brafe ni b i n c o m bi nati o n wit h tra meti ni b, a n orall y a v aila ble, s mall 
m olec ule, selecti ve i n hi bit or of M E K 1 a n d M E K 2, a c o nfir me d O R R of 7 6 % was re p orte d 
i n patie nts wit h B R A F V 6 0 0 E/ K m utati o n p ositi ve metastatic mela n o ma wit h o ut e vi de nce 
of C N S metastases w h o were tr eate d at f ull d ose l e vels of b ot h a ge nts.  I n t his sa me 
c o h ort, n o patie nt ha d a b est o verall res p o ns e of P D, a n d efficac y o utc o mes were 
si g nifica ntl y i m pr o ve d w he n c o m pare d wit h da brafe ni b m o n ot hera p y ( O R R: 7 6 % vs 5 4 %; 
p = 0. 0 2 6; me dia n P F S = 9. 4 vs 5. 8 m o, H R 0. 3 9; 9 5 % CI ( 0. 2 5, 0. 6 2), p < 0. 0 0 1). 
w w w. gs k.c o m/c o nte nt/ da m/ gs k/ gl o bals/ d oc u m e nts/ p df/I n vest ors/ pres e ntati o ns/ 2 0 1 2/ E S M
O-a nal yst- prese nt ati o n- 1 - oct- 2 0 1 2. p df.

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
2 0  
 
 
W hile t he B R E A K- M B trial de m o nstrate d acti vit y i n patie nts wit h acti ve br ai n metastases, 
all of t he patie nts i n t hat trial were as y m pt o matic fr o m C N S disease. Ve m ur afe ni b, a n ot her 
electi ve i n hi bit or of o nc o ge ni c B R A F ki nase t hat s pecificall y tar gets ca ncer cells 
har b o uri n g m utate d B R A F V 6 0 0, was rece ntl y st u die d i n a c o h ort of 2 4 p atie nts wit h 
sy m pt o matic brai n metastases.  Me dia n P F S i n t he brai n was 4. 3 m o nt hs a n d f or ot her sites 
was 4. 6 m o nt hs.  I n a d diti o n, a n i m pr o ve me nt i n perf or ma nce stat us ( d ecrease fr o m 
baseli ne of at least 1 p oi nt of E C O G sc ore) was see n i n 8 3. 3 % of patie nts, a n d 6 6. 7 % 
re p orte d a re d u cti o n of ≥3 0 % (c o m pare d wit h bas eli ne d ose) or c o m plete disc o nti n uati o n of 
cortic oster oi ds. D u m m er , 2 0 1 3]. 
T his c urre nt trial is e x pecte d t o b uil d u p o n t he c urre nt b o d y of e vi d e nce of t ar get e d 
t hera p y i n m ela n o ma brai n metastases t hr o u g h a n e val uati o n of t he c o m bi nati o n of 
da brafe ni b a n d tr a meti ni b i n patie nts wit h V 6 0 0- m utati o n p ositi ve mela n o ma brai n 
metastases. 
O bj e cti v e s  
Pri m ar y O bj e cti v e  
T he pri mar y o bje cti ve of t he st u d y is t o assess t he i ntracra ni al res p o nse (I R) of s u bjects 
wit h l ocall y c o nfir me d B R A F V 6 0 0 E c uta ne o us mela n o ma wit h metastas es t o t he brai n 
c o nfir me d b y M RI,  asy m pt o m ati c , wit h o ut pri or l ocal t hera p y a n d E C O G s c ore of 0- 1 
( C o h ort A).  I R is defi ne d as t he pr o p orti o n of s u bjects wit h a c o nfir me d i ntracra nial 
c o m plete res p o nse ( C R) or partial res p o ns e ( P R) b y i n vesti gat or ass ess me nt usi n g 
m o difie d R E CI S T 1. 1 g ui deli nes [ Eise n ha uer , 2 0 0 9]. 
T he pri mar y effi cac y e n d p oi nts will be i n vesti gat or assesse d via l o cal M RI sca ns. 
Ra di ol o gical sc a ns will be c ollecte d via A G Me d net, st ore d via Ves ali us a n d ma y be 
ce ntrall y re vie we d t o s u p p ort i n de pe n de nt assess m e nt of effi cac y if nee d e d. 
T he st u d y is desi g ne d t o pr o vi de e vi de nce t o s u p p ort t he n ull h y p ot h esis, H 0: I R ≤ 3 5 % or 
t o reject it i n fa v or of t he alter nati ve h y p ot hesis, HA : I R ≥ 5 0 % f or B R A F V 6 0 0 E 
m utati o n- p ositi ve s u bjects i n C o h ort A. 
S e c o n d ar y O bj e cti v e  
Safet y e n d p oi nts will be e val uate d i n all c o h orts a n d efficac y e n d p oi nts will be e val uate d 
i n 3 a d diti o nal c o h orts. 
T he f oll o wi n g e n d p oi nts will be assesse d as sec o n dar y e n d p oi nts i n all c o h orts ( u nless 
state d ot her wise) 
1.  I R i n C o h ort B, C a n d D 
2.  I ntr acra nial diseas e c o ntr ol (I D C) 
3.  E xtracra nial res p o ns e rat e ( E R R) 
4.  O verall res p o nse rate ( O R R) 
5.  D urati o n of i ntracra nial, e xtracra nial a n d o v erall res p o nse ( DI R, D E R a n d D O R 
res pecti vely)  
6.  Pr o gressi o n-free s ur vi val ( P F S) 
7.  O verall s ur vi val ( O S) a n d l o n g-ter m ( p artic ularl y 3- year) O S 
8.  Safet y of da brafe ni b a n d tra meti ni b c o m bi nati o n t hera p y 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
2 1  
 
L o n g- t er m s ur vi val, i n partic ular 3 year s ur vi v al, is of i nterest f or t he p o p ul ati o n of 
V 6 0 0 E a n d V 6 0 0 K B R A F m utati o n- p ositi ve metastatic mela n o ma patie nts treate d wit h 
da brafe ni b a n d tra m eti ni b c o m bi nati o n t hera p y. 
St u d y D e si g n  
T his is a m ulti-c o h ort, o pe n la bel, P hase II st u d y wit h da brafe ni b ( G S K 2 1 1 8 4 3 6) a n d 
tra meti ni b ( G S K 1 1 2 0 2 1 2) c o m bi nati o n t hera p y i n s u bjects wit h B R A F M ut ati o n- P ositi ve 
Mela n o ma t hat has metastasize d t o t he Brai n. T his st u d y will e val uate t h e safet y a n d 
effic ac y of 4 c o h orts. L o cal t hera p y i s defi ne d as t hera p y t o t he brai n w herever it is 
m e nti o ne d t hr o u g h o ut t his pr ot oc ol e ve n if n ot i de ntifie d as s uc h. 

C o h ort A: Se ve nt y-fi ve s u bjects wit h l ocall y c o nfir me d B R A F V 6 0 0 E c uta ne o us
mela n o ma wit h metastas es t o t he brai n c o nfir me d b y M RI, as y m pt o matic,
wit h o ut pri or l oc al ( br ai n) t her a p y a n d E C O G s c ore of 0- 1.

C o h ort B: Fiftee n s u bj ects wit h l ocall y c o nfir m e d B R A F V 6 0 0 E c uta ne o us
mela n o ma wit h metastas es t o t he brai n c o nfir me d b y M RI, as y m pt o matic, wit h
pri or l oc al ( br ai n) t her a p y a n d E C O G sc ore of 0- 1.

C o h ort C:  U p t o fift ee n s u bjects wit h l ocall y c o nfir me d B R A F V 6 0 0 D/ K/ R
c uta ne o us mela n o ma wit h metastases t o t he brai n c o nfir me d b y M RI,
as y m pt o matic, wit h or wit h o ut pri or l ocal ( brai n) t hera p y a n d E C O G sc ore of 0- 1.

C o h ort D: Fiftee n s u bjects wit h l ocall y c o nfir me d B R A F V 6 0 0 D/ E/ K/ R
c uta ne o us mela n o ma wit h metastases t o t he brai n c o nfir me d b y M RI,
s y m pt o m atic, wit h or wit h o ut pri or l ocal ( brai n) t hera p y a n d E C O G sc ore of 0-
2.
S u bjects will recei ve d a brafe ni b ca ps ules 1 5 0 m g t wice dail y a n d  tra meti ni b ta blets 2 m g 
o nce dail y u ntil e vi de nce of disease pr o gressi o n, d eat h, or u nacce pt a ble t o xicit y. 
S u bjects will be re q uire d t o meet all eli gi bilit y criteria a n d ret ur n t o cli nic o n a m o nt hl y 
basis f or cli nical a n d l a b orat or y assess me nts.  I ntr acra ni al a n d e xtracra nial disease will be 
assesse d at bas eli ne, Wee k 4, Wee k 8, a n d e ver y 8 wee ks t hereaft er.  Aft er Wee k 4 0, 
disease assess me nts ma y be perf or me d e v er y 1 2 wee ks.  Res p o nse t o tre at me nt will be 
e val uate d usi n g m o difie d Res p o nse E val uati o n Criteria i n S oli d T u m o urs ( R E CI S T) 
versi o n 1. 1 [ Eise n ha uer , 2 0 0 9]. 
All s u bjects w h o per ma n e ntl y disc o nti n ue st u d y tr eat me nt will ha ve m o nt hl y s ki n 
assess me nts, s ur vi val f oll o w u p a n d ne w a nti-ca ncer t hera p y (i ncl u di n g ra di ot h era p y a n d 
s ur ger y f oll o w u p) t hr o u g h m o nt h 6 after treat me nt disc o nti n uati o n. If t he y start ne w a nti- 
ca ncer t hera p y or at t he e n d of t he 6 m o nt h f oll o w u p visit, t he y will be f oll o we d e ver y 1 2 
wee ks f or s ur vi val f oll o w u p a n d ne w a nti-ca n cer t hera p y (i ncl u di n g ra di ot hera p y a n d 
s ur ger y) u ntil deat h, ha v e wit h dra w n c o nse nt or are l ost t o f oll o w- u p, or st u d y cl os ur e.  
St u d y cl os ure is defi ne d b y  w h ere all c o h ort A s u bjects still i n f oll o w u p ha ve ha d t he 
o p p ort u nit y f or at least 3 years f oll o w- u p fr o m t he date of first d ose of st u d y treat me nt or 
7 0 % of c o h ort A p atie nts ha ve die d or are l ost t o f oll o w u p,  w hic he ver is earlier. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
2 2  
Eit her d ose of t he st u d y treat me nts ma y be m o difi e d a n d/ or i nterr u pt e d f or ma na ge me nt of 
ass ociate d t o xicities ( Secti o n 5. 8 ). 
St u d y A s s e s s m e nt s  
T he pri mar y e n d p oi nt is I R. I ntr acr a nial res p o ns e (I R), e xtracra nial res p o ns e ( E R), o verall 
res p o nse ( O R), dis ease c o ntr ol (i ntracra nial, e xtracra nial, a n d o v erall), P F S, O S a n d d urati o n 
of all res p o nse e n d p oi nts will be deter mi ne d bas e d o n t he i n vesti gat or’s ass ess me nt of tar get- 
a n d n o n-tar get lesi o ns as e val uate d b y t he m o difie d Res p o nse E val uati o n Criteria i n S oli d 
T u m o urs ( R E CI S T), versi o n 1. 1.  Safet y will be e val uate d b y cli nical assess me nts i ncl u di n g 
m o nt hl y s ki n ass ess me nts, vital si g ns a n d p h ysical e x a mi nati o ns, ne ur ol o gi cal e xa ms, 1 2-lea d 
electr ocar di o gra ms ( E C G), ec h o car di o gra ms ( E C H O), c he mistr y a n d  hae mat ol o g y la b orat or y 
val ues, a n d a d v erse e ve nts ( A Es). T he s u bjects will be f oll o we d f or s ur vi val. 
1.
I N T R O D U C TI O N
1. 1.  
B a c k gr o u n d 
C uta ne o us mela n o ma is t he m ost a g gressi ve f or m of all s ki n ca ncers.  W orl d wi de, it is 
e x pecte d t hat o ver 1 3 2, 0 0 0 pe o ple will be dia g n ose d wit h mela n o ma eac h year a n d m ore t ha n 
3 7, 0 0 0 pe o ple are e x pect e d t o die of t his t u m o ur disease a n n u all y. I n t he U S A a n d m ost 
c o u ntries of t he Wester n W orl d i ncl u di n g A ustralia, t he i nci de nce of mel a n o ma c o nti n ues t o 
rise faster t h a n a n y ot her t y pe of ca n cer i n me n a n d t he a n n ual i ncrease i n t he i nci de nce of 
mela n o ma i n w o me n is sec o n d o nl y t o l u n g ca ncer [ Li n os , 2 0 0 9] [Ries , 2 0 0 8]. 
I n t he p ast 4 0 years, t he me dia n s ur vi val ti me f or patie nts wit h u nresecta bl e mela n o ma has 
re mai ne d s h ort wit h a p pr o xi matel y o nl y 6 t o 9 m o nt hs fr o m t he ti me of dia g n osis a n d wit h 
o nl y 1 0 - 1 5 % of s u bjects ali ve after 3- years  Alt h o u g h, c o m bi nati o n t hera pi es of 
c he m ot hera p e utic a ge nts a n d c yt o ki n es s uc h as i nt erfer o n-al p ha a n d i nterle u ki n- 2 ha ve res ulte d 
i n a n i ncreas e of res p o ns e rates, t he o v erall s ur vi v al ( O S) of patie nts wit h u nresect a ble 
mela n o ma ha d s o f ar n ot bee n i m pr o ve d[ H o di , 2 0 1 0]. 
H o we ver, m uc h has c ha n ge d i n t he tr eat me nt la n dsca pe of m ela n o ma si nce 2 0 1 1 wit h t he 
re g ulat or y a p pr o val of t w o ne w a ge nts w hi c h de m o nstrate d a si g nifica nt s ur vi val be nefit i n 
well-c o ntr olle d P hase III trials. I pili m u ma b, a m o n ocl o nal a nti b o d y t hat bl o c ks c yt ot o xic T-
l y m p h o c yte a nti ge n or C T L A- 4, was a p pr o ve d b y  t he U S- F o o d a n d Dr u g A d mi nistrati o n 
( F D A) 2 5- Marc h- 2 0 1 1 a n d E ur o pea n M e dici nes A ge nc y ( E M A) 1 3-J ul- 2 0 1 1 f or 
u nresect a ble or metast atic mela n o ma bas e d o n a si g nifica nt ( p = 0. 0 0 3) pr ol o n gati o n of O S 
( H R 0. 6 8)  c o m pare d t o g p 1 0 0 t u m o ur vacci ne [H o di , 2 0 1 0].  I n a d diti o n, i pili m u ma b i n 
c o m bi nati o n wit h sta n dar d dacar bazi ne ( D TI C) c h e m ot hera p y si g nifica ntl y ( p < 0. 0 0 1) 
i m pr o ve d t he O S of pre vi o usl y u ntreate d metastati c mela n o ma patie nts as c o m pare d t o D TIC 
al o ne ( H R 0. 7 2). [ R o bert , 2 0 1 1].  W hile i pili m u ma b was a p pr o ve d f or t he cli nical use i n 
u nselecte d patie nts, t he s electi ve s mall m olec ule B R A F- i n hi bit or ve m urafe ni b recei ve d F D A-
a p pr o val i n A u g ust of 2 0 1 1 a n d E M A-a p pr o val Fe br uar y 2 0 1 2 as t he first m olec ular-tar gete d 
a ge nt f or u nresecta ble or metastatic mela n o ma har b o uri n g B R A F V 6 0 0 E m utati o ns. 
O nc o ge nic m utati o ns of t he B R A F seri n e-t hre o ni n e occ ur i n a p pr o xi matel y 5 0 % of t u m o urs 
i n mela n o ma a n d res ult i n a c o nstit uti ve acti vati o n of t he M A P- ki nase pat h wa y t hr o u g h 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
2 3  
d o w nstrea m p h os p h or yl ati o n a n d acti vati o n of t he M E K 1 a n d M E K 2 ki nas es. I n t he pi v otal 
P hase III st u d y B RI M- 3 treat me nt wit h ve m u rafe ni b res ulte d i n a si g nifi ca nt ( p < 0. 0 0 1) 
i m pr o ve me nt of pr o gressi o n-free s ur vi val ( H R 0. 2 6) a n d o verall s ur vi val ( H R 0. 3 7) i n t he 
i nteri m data a nal ysis c o m pare d t o D TI C c he m ot hera p y [C ha p ma n , 2 0 1 1].  Da brafe ni b, 
a n ot her s mall m olec ule B R A F-i n hi bit or recei ve d F D A - a p pr o val i n Ma y 2 0 1 3 a n d E M A 
a p pr o val i n A u g ust 2 0 1 3. 
Des pite t his maj or i nitial pr o gress i n t he cli nical m a na ge me nt of u nresecta bl e mela n o ma, 
i m m u ne- me diate d t o xicities a n d t he lac k of a vali d ate d bi o mar ker f or p atie nt selecti o n ma y 
restrict t he use of i pili m u ma b [S o n da k , 2 0 1 1]. As has bee n t he patter n wit h ot her hi g hly 
selecti ve s mall m olec ule ki nase i n hi bit ors (e. g. i mati ni b i n bcr-a bl c hr o nic m yel oi d le u kae mia 
( C M L); erl oti ni b a n d gefiti n ui b i n E G F R- m uta nt n o n-s mall cell l u n g ca n cer ( N S C L C) t he 
ra pi d o nset of dr u g resista nce restricts t he efficac y of ve m urafe ni b a n d li mits t he me dia n 
d urati o n of res p o ns e t o o nl y 6. 7 m o nt hs [ C ha p ma n , 2 0 1 1] . It is wi del y belie ve d, t hat 
c o m bi nati o n t hera pies of tar gete d a ge nts ca n f urt h er i m pr o ve t he s ur vi v al c urre ntl y ac hie ve d 
wit h i pili m u ma b- a n d ve m urafe ni b- si n gle a ge nt-t hera pies [E g ger m o nt , 2 0 1 1].  . In J a n 2 0 1 4 
t he c o m bi nati o n of da brafe ni b a n d tra m eti ni b recei ve d F D A a p pr o val, a n d i n Fe br u ar y 2 0 1 4 
t he c o m bi nati o n recei ve d a p pr o val i n A ustralia. 
F or mela n o ma p atie nts w h ose t u m o ur har b o ur a B R A F-acti vati n g m utati o n, a c o m bi nati o n of 
a selecti ve a n d p ote nt B R A F- a n d a M E K-i n hi bit or is fa v o ure d t o a d dress s pecific m olec ul ar 
mec ha nis ms of i ntri nsic a n d ac q uir e d resista nce t o a B R A F-i n hi bit or m o n ot hera p y [ Nissa n , 
2 0 1 1].  U n dersta n di n g t h ese s pecifi c mec h a nis ms of resista nce t o B R A F-i n hi bit ors is critical 
f or t he de v el o p me nt of m ore effecti ve str ate gies i n B R A F- m uta nt mela n o m a. Rece ntl y, 
se veral disti nct mec h a nis ms of resista nce t o B R A F- i n hi biti o n ha ve bee n pr o p ose d base d o n 
data o btai ne d i n e x peri me ntal mela n o ma cell m o dels a n d s mall series of t u m o ur sa m ples. I n a 
maj orit y of cell m o dels a n d mela n o ma sa m ples, ac q uire d a n d p ote ntiall y pri mar y resista nce t o 
B R A F-i n hi bit ors was ass ociate d wit h a reacti vati o n of t he M A P K- pat h wa y i n dicati n g t hat t he 
‘a d dicti o n’ t o t his pat h wa y i n B R A F- m uta nt mela n o ma re mai ns u nc h a n ge d. I n t hes e resista nt 
B R A F- m uta nt mela n o mas t he M A P K- pat h wa y ca n be reacti vate d t hr o u g h sec o n dar y 
acti vati n g m utati o ns of t he u pstrea m N R A S- or t h e d o w nstrea m M E K 1- ki n ase or a n o v er 
e x pressi o n of t he R A F 1- a n d C O T- ki nase. Alt h o u g h t he fre q u e nc y of s p ecific resista nce 
mec ha nis ms is c urre ntl y n ot k n o w n, alterati o ns t hat rest ore M A P ki nas e pat h wa y acti vit y 
d o w nstrea m of B R A F (e. g. M A P ki nase p at h wa y de pe n de nt mec ha nis ms) ma y re n der 
mela n o ma cells s usce pti ble t o a c o m bi ne d B R A F- a n d M E K-i n hi biti o n. 
Data fr o m t he o n g oi n g P hase I/II st u d y B R F 1 1 3 2 2 0 s u g gest t hat t he s mall- m olec ule 
B R A F-i n hi bit or da brafe ni b ca n be safel y c o m bi ne d wit h t he s mall m olec ule M E K- 
i n hi bitor tra meti ni b. In a d diti o n, t he a nti-t u m o ur acti vit y of t he c o m bi nati o n of b ot h 
a ge nts gi v e n c o nti n u o usl y a n d at f ull-si n gle-a ge nt d ose a p pears t o be s u peri or as 
c o m pare d t o si n gle- a ge nt da brafe ni b. 
1. 1. 1. 
T h e B R A F I n hi bit or D a br af e ni b a s M o n ot h er a p y  
Da brafe ni b, a sel ecti ve B R A F i n hi bit or, has s h o w n acti vit y wit h a ma n a gea ble safet y pr ofile 
i n p hase 1 a n d 2 st u dies i n patie nts wit h B R A F V 6 0 0 E/ K- m utati o n p ositi ve metastatic 
mela n o ma. T he B R E A K- 3 ( B R F 1 1 3 6 8 3) gl o bal p hase III tri al was c o n d uct e d i n patie nts wit h 
B R A F V 6 0 0 E m utati o n- p ositi ve a d va nce d or met astatic mela n o ma ra n d o mize d ( 3: 1) t o 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
2 4  
 
 
recei v e treat me nt wit h eit her da brafe ni b [ 1 5 0 m g , t wice dail y ( BI D)] or dacar bazi ne ( D TIC) . 
S u bjects were ra n d o mize d b y diseas e sta ge ( u nres ecta ble Sta ge III, I V M 1a a n d I V M 1 b vers us 
I V M 1 c).  S u bjects r a n d o mize d t o t he D TI C ar m were all o we d t o cr oss o v er t o recei ve 
da brafe ni b after c o nfir mati o n of pr o gressi ve diseas e ( P D). T he pri mar y e n d p oi nt was 
pr o gressi o n free s ur vi val ( P F S) base d o n i n vesti gat or assess me nt i n t he i nte nt-t o -treat (I T T) 
p o p ulati o n c o m prise d of all ra n d o mize d s u bjects, re gar dless of w het her or n ot treat me nt was 
a d mi nistere d.  Sec o n dar y e n d p oi nts were o v erall s ur vi val ( O S), o verall res p o nse rate ( O R R) i n 
b ot h gr o u ps a n d after cr oss o ver, P F S f or s u bjects r a n d o mize d t o t he D TI C treat me nt gr o u ps 
after cr oss o ver, d urati o n of res p o nse, safet y/t olera bilit y a n d B R A F m utati o n assa y vali dati o n. 
T w o h u n dre d a n d fift y s u bjects were e nr olle d; i ncl u di n g 1 8 7 t hat were ra n d o mize d t o 
da brafe ni b a n d 6 3 t o D TI C. At t he ti me of data c ut- off f or t he pri mar y a n al ysis, 1 4 1 s u bjects 
were o n st u d y treat me nt ( da brafe ni b n = 1 2 7; D TI C n = 1 4) i ncl u di n g 2 1/ 2 8 D TI C s u bjects t hat 
cr osse d o ver t o da brafe ni b. Me dia n a ge was 5 2 ye ars; 3 1 % ha d a n Easter n C o o perati ve 
O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us 1, 6 6 % were M 1c, a n d 3 3 % lactate 
de h y dr o ge nase ( L D H) greater t ha n t h e u p per li mit of n or mal ( > U L N) [ Ha usc hil d , 2 0 1 2]. 
At t he ti me of t he pri mar y a n al ysis, t here were 1 1 8 e ve nts ( 7 7 da brafe ni b a n d 4 1 D TI C). 
T he hazar d rati o ( H R) f or P F S was 0. 3 0 ( 9 5 % CI: 0. 1 8- 0. 5 3; p < 0. 0 0 0 1). Me dia n P F S 
was 5. 1 m o nt hs f or da brafe ni b a n d 2. 7 m o nt hs f or D TI C b y i n v esti gat or ass ess me nt. O S 
data were i m mat ure.  C o nfir me d res p o ns e rate ( R R) was 5 3 % f or d a brafe ni b a n d 1 9 % f or 
D T I C. Be n efits i n P F S a n d R R were o bser ve d i n all s u b gr o u ps e val u ate d. T he m ost 
fre q ue nt a d vers e e ve nts (2 0 %) i n t he da brafe ni b ar m were h y per kerat osis ( 3 9 %), 
hea dac he ( 3 5 %), art hral gia ( 3 5 %), p yre xia ( 3 2 %), al o pecia ( 2 9 %),  na us ea ( 2 8 %),  s ki n 
pa pill o mas ( 2 5 %), fati g u e ( 2 3 %) p al mar- pla ntar er yt hr o d ys aest hesia s y n dr o me ( 2 0 %),  
ast he nia ( 2 0 %). 
Seri o us a d verse e ve nts ( S A Es) ( > 1 %) o n t h e da brafe ni b ar m i ncl u de d s q ua m o us cell 
carci n o mas ( 1 0 %), p yr e xia ( 5 %),  Bas al cell Carci n o ma ( 2 %) atrial fi brillati o n ( 2 %), 
c hills  ( 2 %), eje cti o n fracti o n decreas e d ( 2 %) , mali g na nt m ela n o ma ( 2 %). 
F urt her e vi de nce f or t h e safet y a n d efficac y of da brafe ni b h as bee n esta blis he d i n a lar ge 
( N = 1 7 2) st u d y of patie nts B R F 1 1 3 9 2 9 ( B R E A K- M B) w here s u bjects were assesse d f or 
metastatic mela n o ma t o t he brai n.  S u bjects wit h V 6 0 0 E wit h o ut pre vi o us l ocal t hera p y 
( C o h ort A) de m o nstrate d 3 9. 2 % o verall i ntracra ni al res p o nse rate a n d 8 1. 1 % i ntracra nial 
disease c o ntr ol (I D C); patie nts wit h V 6 0 0 E wit h pre vi o us l ocal t hera p y ( C o h ort B) 
de m o nstrate d 3 0. 8 % o verall i ntracra nial res p o ns e rate a n d 8 9. 2 % i ntracra ni al disease c o ntr ol 
(I D C) wit h a c o h ort me dia n s ur vi val of 3 3. 1 a n d 3 1. 4 wee ks, res pecti vel y. T his st u d y 
de m o nstrates t hat da brafe ni b has acti vit y a n d  acce pta ble ma na gea ble s afet y pr ofile i n patie nts 
wit h mela n o ma metastas es t o t he brai n. [ L o n g , 2 0 1 2]. 
1. 1. 2. 
T h e M E K I n hi bit or Tr a m eti ni b a s M o n ot h er a p y 
Tra meti ni b is a re v ersi ble, hi g hl y sel ecti ve all osteric i n hi bit or of M E K 1/ 2 acti vati o n a n d 
ki nase acti vit y. A P hase 3 trial, M E T RI C ( M E K 1 1 4 2 6 7), was c o n d u cte d i n patie nts wit h 
B R A F V 6 0 0 E/ K m utati o n p ositi ve a d va nce d or metastatic mela n o ma.  S u bjects were 
ra n d o mize d 2: 1 t o tra meti ni b ( 2 m g o nce d ail y) or c he m ot hera p y ( D TI C or paclita xel). 
S u bjects were str atifie d b y b aseli ne L D H le vel a n d pri or c he m ot hera p y; s u bjects i n t he 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
2 5  
 
 
c he m ot hera p y ar m were all o we d t o cr oss o ver t o recei ve tra meti ni b after c o nfir mati o n of P D.  
T he pri mar y e n d p oi nt w as P F S i n s u bjects wit h B R A F V 6 0 0 E m utati o n - p ositi ve metastatic 
mela n o ma a n d n o pri or brai n metastases; P F S was als o e val uate d i n t he I T T p o p ulati o n.  
Sec o n dar y e n d p oi nts w ere O S, O R R i n t he pri mar y a n d I T T p o p ulati o n a n d safet y i n t he 
safet y p o p ul ati o n. 
T hree h u n dre d a n d t w e nt y-t w o s u bjects were ra n d o mize d t o tra meti ni b ( n = 2 1 4) or 
c he m ot hera p y ( n = 1 0 8); 2 7 3 s u bjects were B R A F V 6 0 0 E m utati o n - p ositi ve wit h n o pri or brai n 
metastases. Me dia n a ge was 5 4 years; all ha d a n E C O G perf or ma nce stat us of 0 ( 6 4 %) or 1 
( 3 6 %), a n d 6 5 % were M 1c [Fla hert y , 2 0 1 2]. 
T he H R f or t he pri mar y effic ac y p o p ulati o n f or P F S b y i n vesti gat or was 0. 4 4 ( 9 5 % CI 
0. 3 1 – 0. 6 4; p < 0. 0 0 0 1) i n fa v or of tra meti ni b wit h a me dia n P F S of 4. 8 m o nt hs vs. 1. 4 
m o nt hs wit h c he m ot hera p y. T he c o nfir me d O R R was 2 4 % wit h tra meti ni b a n d 7 % wit h 
c he m ot hera p y. H R f or i nteri m O S was 0. 5 3 ( 9 5 % CI 0. 3 0 – 0. 9 4; p = 0. 0 1 8 1), i n fa v or of 
tra meti nib.  
T he m ost fre q ue nt A Es ( 2 0 %) wit h tra meti ni b were s ki n ras h ( 5 7 %), di arr hea ( 4 3 %), 
fati g u e ( 2 6 %), a n d e d e m a ( 2 6 %).  K n o w n M E K i n hi bit or class effects were o bser ve d i n t his 
st u d y i ncl u di n g c h ori oreti n o pat h y ( < 1 %) a n d decrease d ej ecti o n fracti o n ( 7 %). 
1. 1. 3. B R A F a n d M E K I n hi bit or s a s C o m bi n ati o n T h er a p y  
1. 1. 3. 2.  
D a br af e ni b a n d Tr a m eti ni b C o m bi n ati o n 
T he c o m bi nati o n of da brafe ni b a n d tra meti ni b is i n de vel o p me nt f or t he treat me nt of B R A F 
m uta nt a d va nce d a n d metastatic mela n o ma. As of 8 A pril 2 0 1 3, t he c o m bi nati o n of 
da brafe ni b a n d tra m eti ni b has bee n u n d er e v al uati o n i n 6 cli nical trials a n d 2 c o m plete d 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
2 6  
 
 
si n gle- patie nt c o m passi o nate care pr ot o c ols ( B R F 1 1 5 0 1 5, B R F 1 1 5 2 6 2), a n d o ne m ulti- patie nt 
c o m passi o nate pr o gra m ( M E K 1 1 7 3 4 1) is o n g oi n g. 
A 4- part P hase I/II st u d y ( B R F 1 1 3 2 2 0; Fi g ur e 1 ) i n vesti gati n g t he da brafe ni b/tra meti ni b 
c o m bi nati o n f or metastatic mela n o ma is disc usse d bel o w. 
Fi g ur e  1  
B R F 1 1 3 2 2 0 St u d y D e si g n 
  
 
I n Part B, s u bjects were treate d o n 4 escal ati n g d ose le vels of da brafe ni b/tra meti ni b ( m g 
BI D/ m g o nce dail y): 7 5/ 1, 1 5 0/ 1, 1 5 0/ 1. 5, 1 5 0/ 2. De m o gra p hic a n d efficac y dat a f or t he 
mela n o ma s u bjects a n d s afet y data f or all 1 2 5 Part B s u bjects w ere re p orte d [ We ber , 2 0 1 2]. 
A m o n g 7 7 tr eat me nt- naï ve s u bjects wit h B R A F V 6 0 0 m utati o n- p ositi ve mela n o ma a n d 
meas ura ble disease acc or di n g t o Res p o nse E val u ati o n Criteria i n S oli d T u m o urs versi o n 
1. 1( R E CI S T 1. 1), me dia n a ge was 5 2 years, 6 1 % male, 5 7 % E C O G perf or ma nce stat us of 0, 
9 1 % V 6 0 0 E, 6 5 % M 1c sta ge, 2 6 % pri or brai n metastases, a n d 5 2 % L D H > U L N. C o nfir me d 
O R R was 5 6 % ( 9 5 % CI: 4 4. 1 %- 6 7. 2 %) wit h 4 c o m plete res p o nse ( C R), 3 9 partial res p o nse 
( P R), 2 9 sta ble disease ( S D) a n d, 3 P D. C o nfir me d res p o nse rates f or eac h d ose le vel teste d i n 
Part B were 6 7 % ( n = 6), 6 4 % ( n = 2 2), 4 4 % ( n = 2 5), a n d 6 3 % ( n = 2 4), res p ecti vel y. Me dia n P F S 
was 7. 4 m o nt hs o verall ( 9 5 % CI: 5. 5 - 9. 2), a n d 1 0. 8 m o nt hs ( 9 5 % CI: 5. 3, N R) i n t he c o h ort 
treate d wit h 1 5 0/ 2.  Me di a n d urati o n of res p o nse f or t he e ntire c o h ort was 1 1. 3 m o nt hs ( 9 5 % CI: 
9. 2, n ot reac he d) wit h a me dia n d urati o n o n treat me nt of 1 0. 7 m o nt hs (i ncl u di n g 3 8 % of 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
2 7  
 
 
s u bjects o n g oi n g at t he ti me of t he a nal ysis).  T he m ost c o m m o n a d verse e v e nts ( A E) were 
p yre xia ( 5 2 %), ras h ( 4 5 %), c hills ( 3 8 %), fati g u e ( 3 7 %), a n d n a usea ( 3 4 %).  T here were t w o 
gra d e 5 a d verse e v e nts ( A Es), p ne u m o nia a n d h y p o natre mia. T he m ost c o m m o n Gra de 3/ 4 A Es 
were p yre xia ( n = 6, 5 %), fati g u e ( n = 6, 5 %) a n d d e h y drati o n ( n = 6, 5 %). S ki n t o xicit y ≥ Gra d e 2 
occ urre d i n 1 7 ( 1 4 %) s u bjects. C uta ne o us s q ua m o us cell carci n o ma occ urre d i n 3 ( 2 %) s u bjects 
a n d acti nic kerat oses i n 2 ( 2 %).  T he m ost c o m m o n treat me nt relat e d A Es ( 2 0 %, all gra des) 
a m o n g s u bjects i n Part B recei vi n g 1 5 0 m g BI D da brafe ni b a n d 2 m g o nce dail y tra m eti ni b 
( n = 7 9) were p yre xia ( 5 8 %), s ki n t o xicities i ncl u di n g ras h ( 4 2 %), c hills ( 3 7 %), fati g ue ( 3 8 %) 
a n d na usea ( 3 4 %). 
1. 2.  
St u d y R ati o n al e  
 
Cli nical data fr o m P hase I, II a nd  III st u dies f or da brafe ni b a n d tra meti ni b 
m o n ot hera pies ha v e de m o nstrate d si n gl e-a ge nt cli nical acti vit y i n s u bjects wit h 
B R A F- V 6 0 0 E- or B R A F- V 6 0 0 K- m uta nt mela n o ma. 
 St u d y B R F 1 1 3 9 2 9 ( B R E A K- M B): Res ults of i n vesti gat or ass esse d metastatic 
mela n o ma t o t he brai n de m o nstrate d t hat patie nts wit h o ut pre vi o us l ocal t hera p y ( C o h ort 
A) de m o nstrate d 3 9. 2 % o verall i ntracra nial res p o nse rate a n d 8 1. 1 % i ntracra nial disease 
c o ntr ol (I D C); patie nts wit h pre vi o us l ocal t hera p y ( C o h ort B) de m o nstrate d 3 0. 8 % 
o verall i ntracra nial res p o nse rate a n d 8 9. 2 % i ntracra nial disease c o ntr ol (I D C) wit h a 
c o h ort me dia n s ur vi val of 3 3. 1 a n d 3 1. 4 wee ks, res pecti vel y.  T his st u d y de m o nstrates 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
2 8  
 
 
t hat da brafe ni b has acti vit y a n d ma na ga ble safet y pr ofile i n patie nts wit h mela n o ma 
metastases t o t he brai n. [ L o n g , 2 0 1 2] 
 
Precli nical st u dies a n d cli nical data i n dicate t hat pri mar y- a n d ac q uire d resista nce t o a 
B R A F-i n hi bit or si n gle- a ge nt t hera p y m a y be a d dresse d a n d p ote ntiall y o verc o me b y a 
c o m bi nati o n of a B R A F- a n d M E K-i n hi bit or 
 
Cli nical data fr o m t he P hase I/II st u d y B R F 1 1 3 2 2 0 t hat e val uate d t he c o m bi nati o n of 
da brafe ni b a n d tra m eti ni b de m o nstrate d g o o d cli nical acti vit y a n d a ma na gea ble cli nical 
safet y pr ofile. 
 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
2 9  
 
2.  
O B J E C TI V E A N D E N D P OI N T S  
Ta ble 1  lists t he st u d y o bjecti ves a n d c orres p o n di n g e n d p oi nts. 
T a bl e 1  
St u d y O bj e cti v e s a n d E n d p oi nt s 
O bj e cti ve s  
E n d p oi nt s  
 
To  assess t he i ntracra nial res p o nse (I R) of  s u bj ects 
wit h  l ocall y c o nfirme d  B R A F  V 6 0 0 E -m u tati o n 
p ositi ve  mela n o ma  t hat has  metastasize d  t o t he brai n  
w it h o ut s y m pt o ms a n d  ha ve  n ot  u n der g o ne pri or  
l ocal t hera p y f or brai n  metastases,  E C O G sc ore  of  0 -
1  ( C o h ort A).  
 
 is defi ne d  as t he pr o p orti o n  of  s u bj ects wit h a 
c o nfir me d  i ntracra nial  c o m plete res p o nse  ( C R) or  
partial  res p o nse ( P R) as per i n vesti gat or  
assess me nt  usi n g  m o difie d R E CI S T  1. 1  g ui deli nes  
[Eise n ha ue r, 2 0 0 9].  
S e c o n d ary  
1.  T o  assess  c o h ort  B f or  I R of  s u bj ects w it h l ocall y 
c o nfir me d B R A F  V 6 0 0 E  c uta ne o us  mela n o ma wit h  
metastases  t o t he brai n  c o nfir me d  b y  M RI, 
as y m pt o matic  wit h  pri or  l ocal t hera p y f or brai n 
metastases;  E C O G  sc ore of  0 -1.  
2.  T o  assess c o h ort  C f or  I R of  s u bj ects w it h l ocall y 
c o nfir me d  B R A F  V 6 0 0  D/ K/ R  c uta ne o us mela n o m a 
wit h  metastases  t o t he brai n  c o nfir me d b y M RI,  
as y m pt o matic,  wit h  or  wit h o ut  pri or l ocal  t hera p y; 
E C O G  sc ore of  0 -1.  
3.  T o  assess c o h ort  D f or  I R of  s u bj ects w it h l ocall y 
c o nfir me d  B R A F  V 6 0 0  D/ E/ K/ R  c uta ne o us 
mela n o ma  wit h  metastases  t o t he brai n  c o nfir me d b y 
M RI,  s y m pt o matic; wit h  or  w it h o ut pri or  l ocal 
t hera p y; E C O G  sc ore of  0 -2.  
4.  T o assess C o h orts A, B, C a n d D f or Disease 
C o ntr ol f or i ntracra nial, e xtracra nial a n d o verall 
res p o nse (I D C, E D C a n d O D C res pecti vel y) 
5.  T o  assess C o h orts  A,  B,  C  a n d  D  fo r e xtracra nial 
res p o nse rate ( E R) 
 
 
 
6.  T o  assess C o h orts  A,  B,  C  a n d  D  f or o verall 
res p o nse rate ( O R) 
 
 
7.  T o  assess C o h orts  A,  B,  C  a n d  D  f or o verall 
res p o nse rate ( O R) 
 
 
 
I R is defi ne d  as t he perce nta ge  of  s u bj ects wit h a 
c o nfir me d  i ntracra nial c o m plete res p o nse  ( C R) or  
partial  res p o nse ( P R) as per i n vesti gat or  
assess me nt  usi n g  m o difie d R E CI S T  1. 1  g ui deli nes  
[Eise n ha ue r, 2 0 0 9].  
 
 
 
 
 
 
 
 
 
 
 
 
 
I ntracra nial  Disease  C o ntr ol  (I D C)  is defi ne d  
as C R + P R + S D f or  i ntracra nial, e xtracra nial, a n d  
o verall  disease  c o ntr ol.  

 
E xtracra nial  res p o nse ( E R), defi ne d  as t he  
perce nta ge  of  s u bj ects w it h a best e xtracra nial  
res p o nse of  a c o nfir m e d  C R or  P R  b y  i n vesti gat or 
assess me nt  usi n g m o difie d  R E CI S T  1. 1  
 
 
O verall  res p o nse ( O R), defi ne d  as t he perce nta ge 
of  s u bj ects wit h  a best  o verall c o nfir me d  res p o nse 
of  C R  or  P R  b y i n vesti gat or  assess me nt.  
 
 
D urati o n  of  i ntracra nial, e xtra cra nial  a n d o verall  
res p o nse ( DI R, D E R  a n d  D O R), defi ne d  as t he 
ti me fr o m first d oc u me nte d e vi de nce  of  C R  or  P R  
u ntil ti me  of  first d oc u me nte d  i ntracra nial, 
e xtracra nial  a n d  o verall  diseas e pr o gressi o n.  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
3 0  
 
 
O bj e cti ve s  
E n d p oi nt s  
8.  T o  assess C o h orts  A,  B,  C a n d  D f or  pr o gressi o n - 
free s ur vi val ( P F S). 
 
9.  T o  assess C  C o h orts  A,  B,  C  a n d  D  f or o verall 
s ur vi val ( O S) a n d  l o ng -ter m ( partic ularl y 3 -year) 
O S.  
1 0.  T o  assess C o h orts  A,  B,  C  a n d  D  t o c haracterize t he  
safet y of  da brafe ni b  a n d  tra meti ni b co m b i nati o n 
t hera p y 
 
P F S,  defi ne d  as t he i nter val bet w ee n first d ose a n d  
t he earliest  date  of  disease pr o gressi o n  or  deat h  d ue  
t o a n y ca use  
 
O verall  s ur vi val ( O S), defi ne d  as t he ti me fr o m 
first d ose  u ntil  deat h  d ue  t o a n y ca use . 
 
Assess me nt  of  safet y of  da brafe ni b  a n d tr am eti ni b  
meas ure d  b y  t he fre q ue nc y a n d se verit y  o f 
a d verse  e ve nts,  s ki n assess me nts, la b orat or y  
a b n or malities,  vital  si g ns, a n d assess me nt  data  ( 12 -
lea d electr ocar di o gra ms ( E C G),  ec h ocar di o gra ms,  
a n d  cli nical m o nit ori n g/ o bser vati o n  i ncl u di n g 
ne ur ol o gical e xa mi nati o n)  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
3 1  
 
 
3.   
S T U D Y D E SI G N 
Pr ot oc ol wai vers or e x e m pti o ns are n ot all o we d wit h t he e x ce pti o n of i m me diate safet y 
c o ncer ns. T h eref ore, a d h ere nce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d 
i n t he Ti me a n d E ve nts (Ta ble 1 9 ) are ess e ntial a n d re q uire d f or st u d y c o n d uct. 
T his is a m ulti-c o h ort, o pe n la bel, P hase II st u d y wit h da brafe ni b ( G S K 2 1 1 8 4 3 6) a n d 
tra meti ni b ( G S K 1 1 2 0 2 1 2) c o m bi nati o n t hera p y i n s u bjects wit h B R A F M ut ati o n- P ositi ve 
Mela n o ma t hat has metastasize d t o t he brai n. T his st u d y will e val uate t h e safet y a n d efficac y 
of 4 c o h orts. C o h ort A: Se ve nt y-fi ve s u bjects wit h l ocall y c o nfir me d B R A F V 6 0 0 E 
c uta ne o us mela n o ma wit h metastases t o t he brai n c o nfir me d b y M R I, as y m pt o matic, wit h o ut 
pri or l ocal ( brai n) t hera p y a n d E C O G sc ore of 0- 1.  C o h ort B: Fiftee n s u bjects wit h l ocall y 
c o nfir me d B R A F V 6 0 0 E c uta ne o us mela n o ma wit h metastases t o t he brai n c o nfir me d b y 
M RI, as y m pt o matic, wit h pri or l ocal ( brai n) t hera p y a n d E C O G s c ore of 0- 1.  C o h ort C: U p 
t o fiftee n s u bjects wit h l o call y c o nfir me d B R A F V 6 0 0 D/ K/ R c uta ne o us mel a n o ma wit h 
metastases t o t he brai n c o nfir me d b y M RI, as y m pt o matic, wit h or wit h o ut pri or l ocal ( brai n) 
t hera p y a n d E C O G s c ore of 0- 1. C o h ort D: Fiftee n s u bjects wit h l ocall y c o nfir me d B R A F 
V 6 0 0 D/ E/ K or R c uta ne o us mela n o ma wit h m etastases t o t he brai n c o nfir m e d b y M RI, 
s y m pt o matic, wit h or wit h o ut pri or l ocal ( brai n) t hera p y a n d E C O G sc ore of 0- 2. 
Mel a n o m a Met ast atic B r ai n  
D a br afe ni b a n d Tr a m ati ni b  
C o h ort A ( 7 5):  
C o h ort B ( 1 5):  
C o h ort C ( u p t o 1 5):  
C o h ort C ( 1 5):  
L ocall y  C o nfri me d  
L ocall y  C o nfri me d  
L ocall y  C o nfri me d  
L ocall y  C o nfri me d  
V 6 0 0 E  
V 6 0 0 E  
V 6 0 0 D/ K/ R  
V 6 0 0 D E// K/ R  
As y m pt o matic  
As y m pt o matic  
As y m pt o matic  
S ym pt o matic  
Wit h o ut Pri or L ocal 
t herap y  
Wit h Pri or L ocal 
t herap y  
Wit h or Wit h o ut  
Pri or  L o ca l t h era p y 
Wit h or Wit h o ut  
Pri or  L o ca l t h era p y 
E C O G 0 -1  
E C O G 0 -1  
E C O G 0 -1  
E C O G 0 -2  
 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
3 2  
 
 
C ortic oster oi d/ A nti-e pile ptic Use a n d Pri or L oc al T her a p y i n C o h orts 
C o h ort A:  
 
S u bjects w h o are recei vi n g c o n c o mita nt c ortic ost er oi ds m ust be o n a sta bl e or 
decreasi n g d ose f or at least 1  m o nt h pri or t o first d ose of st u d y tr eat me nt.  ( Refer t o 
Secti o n 6. 3  Ca uti o nar y Me dicati o ns). 
 
N o pr o p h yl actic or pre v e nti ve a nti-e pile ptic t hera p y.  E xce pti o n: a nti-e pil e ptic 
t hera p y i n dicate d i n or der t o pre ve nt ne ur ol o gi c s y m pt o ms ca us e d b y  a pr e- e xisti n g 
c o n diti o n a n d n ot relate d t o brai n metastasis is all o we d. 
C o h ort B:  
 
M ust ha ve recei ve d at least o ne l ocal t hera p y f or brai n metastases i ncl u di n g b ut n ot 
restricte d t o br ai n s ur ger y, W h ole Brai n Ra di ot hera p y ( W B R T) or Stere otactic 
Ra di os ur ger y ( S R S e. g. ga m ma k nife, li near-accel erate d- bas e d ra di os ur ger y, c h ar ge d 
particles, a n d C y ber K nif e). M ulti ple l ocal ( brai n) t hera pies or c o m bi nati o ns of l ocal 
t hera pies are all o w e d. F or s u bjects recei vi n g l ocal t hera p y t o all brai n lesi o ns 
(i ncl u di n g W B R T), pr o gressi o n of pre-e xisti n g lesi o ns base d on  R E CI S T 1. 1 ( > 2 0 % 
i ncreas e i n l o n gest dia meter o n baseli ne sca n) or ne w meas ura ble lesi o ns are re q uir e d. 
F or s u bjects r ecei vi n g l o cal ( brai n) t hera p y f or s o me b ut n ot all lesi o ns, disease 
pr o gressi o n base d o n R E CI S T 1. 1 is n ot re q uire d as l o n g as t h ere are re mai ni n g brai n 
lesi o ns t hat are meas ura ble a n d n ot pre vi o usl y treate d. 
 
S u bjects w h o are recei vi n g c o n c o mita nt c ortic ost er oi ds m ust be o n a sta bl e or 
decreasi n g d ose f or at least 1  m o nt h pri or t o first d ose of st u d y tr eat me nt.  ( Refer t o 
Secti o n 6. 3  Ca uti o nar y Me dicati o ns). 
 
N o pr o p h yl actic or pre v e nti ve a nti-e pile ptic t hera p y.  E xce pti o n: a nti-e pil e ptic 
t hera p y i n dicate d i n or der t o pre ve nt ne ur ol o gic s y m pt o ms ca us e d b y  a pr e- e xisti n g 
c o n diti o n a n d n ot relate d t o brai n metastasis is all o we d. 
C o h ort C:  
 
N ot re q uire d t o ha v e pri or l ocal t hera p y b ut if s u bj ect has ha d pri or l ocal t h era p y f or 
brai n metastases c o ul d i ncl u de b ut n ot restricte d t o brai n s u r ger y, W h ole Brai n 
Ra di ot hera p y ( W B R T) or Stere otactic Ra di os ur ger y ( S R S e. g. ga m ma k nif e, li near-
accelerat e d- base d ra di os ur ger y, c h ar ge d p articles, a n d C y ber K nife). M ulti ple l ocal 
( brai n) t hera pies or c o m bi nati o ns of l ocal t hera pies are all o we d. F or s u bj ects recei vi n g 
l ocal t hera p y t o all brai n lesi o ns (i ncl u di n g W B R T), pr o gressi o n of pr e-e xisti n g 
lesi o ns base d o n R E CI S T 1. 1 ( > 2 0 % i ncreas e i n l o n gest dia meter o n baseli ne sca n) or 
ne w meas ur a ble lesi o ns are re q uir e d. F or s u bjects recei vi n g l ocal ( brai n) t h era p y f or 
s o me b ut n ot all lesi o ns, disease pr o gressi o n base d o n R E CI S T 1. 1 is n ot re q uire d as 
l o n g as t here are re mai ni n g brai n lesi o ns t hat are meas ura ble a n d n ot pre vi o usl y 
treate d. 
 
S u bjects w h o are recei vi n g c o n c o mita nt c ortic ost er oi ds m ust be o n a st a bl e or 
decreasi n g d ose f or at least 1  m o nt h pri or t o first d ose of st u d y tr eat me nt.  ( Refer t o 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
3 3  
 
 
Secti o n 6. 3  Ca uti o nar y Me dicati o ns). 
 
N o pr o p h yl actic or pre v e nti ve a nti-e pile ptic t hera p y.  E xce pti o n: a nti-e pil e ptic 
t hera p y i n dicate d i n or der t o pre ve nt ne ur ol o gic s y m pt o ms ca us e d b y  a pr e- e xisti n g 
c o n diti o n a n d n ot relate d t o brai n metastasis is all o we d 
C o h ort D:  
 
N ot re q uire d t o ha v e pri or l ocal t hera p y b ut if s u bj ect has ha d pri or l ocal t h era p y f or 
brai n metastases c o ul d i ncl u de b ut n ot restricte d t o brai n s ur ger y, W h ole Brai n 
Ra di ot hera p y ( W B R T) or Stere otactic Ra di os ur ger y ( S R S e. g. ga m ma k nif e, li near-
accelerat e d- base d ra di os ur ger y, c h ar ge d p articles, a n d C y ber K nife). M ulti ple l ocal 
( brai n) t hera pies or c o m bi nati o ns of l ocal t hera pies are all o we d. F or s u bjects recei vi n g 
l ocal t hera p y t o all brai n lesi o ns (i ncl u di n g W B R T), pr o gressi o n of pr e-e xisti n g 
lesi o ns base d o n R E CI S T 1. 1 ( > 2 0 % i ncreas e i n l o n gest dia meter o n baseli ne sca n) or 
ne w meas ur a ble lesi o ns are re q uire d. F or s u bjects recei vi n g l ocal ( brai n) t h era p y f or 
s o me b ut n ot all lesi o ns, disease pr o gressi o n base d o n R E CI S T 1. 1 is n ot re q uire d as 
l o n g as t here are re mai ni n g brai n lesi o ns t hat are meas ura ble a n d n ot pre vi o usl y 
treate d. 
 
C o nc o mita nt c ortic oster oi ds:  per missi ble a n d sta bilit y of d osi n g n ot r e q uire d. 
 
Pr o p h yla ctic or pre v e nti ve a nti-e pile ptic t hera p y is all o we d ( Refer t o Secti o n 6. 3  
 
Ca uti o nar y M e dicati o ns). 
S u bjects will recei ve d a brafe ni b 1 5 0 m g t wice dail y a n d tr a meti ni b 2 m g o nce dail y u ntil 
e vi de nce of disease pr o gressi o n, deat h, or u nacce pta ble t o xicit y.  S u bjects will be re q uire d t o 
meet all eli gi bilit y criteri a a n d ret ur n t o cli nic o n a m o nt hl y b asis f or cli nical, s ki n a n d 
la b orat or y assess me nts.  I ntr acra nial a n d e xtracra nial disease will be assesse d at baseli ne, 
Wee k 4, Wee k 8, a n d e v er y 8 wee ks t hereafter.  After Wee k 4 0, disease assess me nts ma y b e 
perf or me d e ver y 1 2 wee ks.  Res p o nse t o treat me nt will be e val uate d usi n g m o difie d 
Res p o nse E val uati o n Criteria i n S oli d T u m o urs ( R E CI S T) versi o n 1. 1 [ Eise n ha uer , 2 0 0 9]. 
A n I n de pe n d e nt Data M o nit ori n g C o m mittee (I D M C) will be use d i n t his st u d y. 
Pr ot oc ol-s pecifie d g ui deli nes f or d ose a dj ust me nts, i nterr u pti o ns a n d disc o nti n uati o n d ue t o 
a d verse e ve nts are pr o vi d e d bel o w. All s u bjects w h o per ma ne ntl y disc o nti n ue st u d y 
treat me nt will ha ve m o nt hl y s ki n assess me nts, s ur vi val f oll o w u p a n d ne w a nti-ca ncer t hera py 
(i ncl u di n g ra di ot hera p y a n d s ur ger y f oll o w u p) t hr o u g h m o nt h 6 after treat me nt 
disc o nti n uati o n. If t h e y st art ne w a nti- ca ncer t hera p y or at t he e n d of t he 6 m o nt h f oll o w u p 
visit, t he y will be f oll o we d e ver y 1 2 wee ks f or s ur vi val f oll o w u p a n d ne w a nti-ca ncer t hera p y 
(i ncl u di n g ra di ot hera p y a n d s ur ger y) u ntil deat h, h a ve wit h dra w n c o nse nt or are l ost t o 
f oll o w- u p, or st u d y cl os ure. St u d y cl os ur e is d efi n e d b y  w here all c o h ort A s u bjects still i n 
f oll o w u p ha ve ha d t he o p p ort u nit y f or at least 3 years f oll o w- u p fr o m t he d ate of first d ose of 
st u d y treat me nt or 7 0 % of c o h ort A patie nts ha v e die d or are l ost t o f oll o w u p, w hic he ver is 
earlier 
. 
S u p ple me ntar y st u d y c o n d uct i nf or mati o n n ot ma n date d t o be pres e nt i n t his pr ot oc ol is 
pr o vi de d i n t he acc o m pa n y i ng St u d y Pr oce d ures Ma n ual ( S P M).  T he S P M will pr o vi de t he site 

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pers o n nel wit h a d mi nistrati ve a n d detaile d tec h nical i nf or mati o n t hat d oes n ot i m pact s u bject 
safety.  
3. 1.  
Di s c u s si o n of  D e si g n 
T he effic ac y of t he c o m bi nati o n of da brafe ni b 1 5 0 m g t wice dail y a n d tra meti ni b 2 m g 
o nce dail y i n patie nts wit h metastatic mela n o ma has bee n d escri b e d a b o ve, b ut has n ot 
bee n c h aracteriz e d f ull y i n patie nts wit h mela n o ma t hat has metastasiz e d t o t he brai n. 
T he pri mar y effi cac y o bj ecti ve of t his st u d y is t o assess t he i n vesti gat or-re p orte d i ntracra nial 
res p o nse (I R) i n l ocall y- c o nfir me d B R A F V 6 0 0 E m utati o n- p ositi ve mela n o ma s u bjects w h o 
ha ve n ot pre vi o usl y recei ve d l ocal treat me nt f or brai n metastases ( C o h ort A) usi n g m o difie d 
R E CI S T 1. 1 g ui d eli nes. 
T he st u d y is desi g ne d t o pr o vi de e vi de nce t o s u p p ort t he n ull h y p ot hesis, H 0: I R R ≤ 3 5 % or 
t o reject it i n fa v or of t he alter nati ve h y p ot hesis, HA : I R R ≥ 5 0 % f or B R A F V 6 0 0 E m ut ati o n-
p ositi ve s u bjects i n C o h ort A. 
T he n ull h y p ot hesis is base d o n res ults of B R F 1 1 3 9 2 9, a st u d y of da brafe ni b i n t w o c o h orts of 
patie nts wit h hist ol o gicall y c o nfir m e d metastatic mela n o ma t o t he brai n [ L o n g , 2 0 1 2]. T he I R 
i n patie nts wit h n o pri or l ocal treat me nt f or brai n metastases was 3 9 %; i n patie nts wit h pri or 
l ocal treat me nt, t he I R w as 3 1 %.  T he alter nati ve h y p ot hesis was selecte d as t he I R t h at w o ul d 
be cli nicall y rele v a nt f or t his c o m bi nati o n t hera p y.  T he st u d y is desi g ne d t o ha ve 8 2 % 
statistical p o wer t o detect a n I R of 5 0 % i n V 6 0 0 E m utati o n- p ositi ve s u bjects w h o recei ve 
da brafe ni b i n c o m bi nati o n wit h tra meti ni b i n C o h ort A.  T his h y p ot hesis will be teste d usi n g a 
o n e-si de d test f or s u peri orit y wit h α = 0. 0 5. T here will be n o ot her testi n g; t heref ore, t here will 
be n o a dj ust me nt of t he T y p e I err or f or m ulti ple testi n g. 
W hile t he B R E A K- M B trial de m o nstrate d acti vit y i n patie nts wit h acti ve brai n metastases, 
all of t he patie nts i n t hat trial were as y m pt o matic fr o m C N S disease. Ve m ur afe ni b, a n ot her 
selecti ve i n hi bit or of o nc o ge ni c B R A F ki nase t hat s pecificall y tar gets ca ncer cells 
har b o uri n g m utate d B R A F V 6 0 0, was rece ntl y st u die d i n a c o h ort of 2 4 p atie nts wit h 
s y m pt o matic brai n metastases.  Me dia n P F S i n t he brai n was 4. 3 m o nt hs a n d f or ot her sites 
was 4. 6 m o nt hs.  I n a d diti o n, a n i m pr o ve me nt i n perf or ma nce stat us ( d ecrease fr o m bas eli ne 
of at least 1 p oi nt of E C O G sc ore) was s ee n i n 8 3. 3 % of patie nts, a n d 6 6. 7 % re p orte d a 
re d ucti o n of ≥3 0 % (c o m pare d wit h bas eli ne d ose) or c o m plete disc o nti n uati o n of 
c ortic oster oi ds. [ D u m mer , 2 0 1 3]. 
T he c urre nt trial is e x pecte d t o b uil d u p o n t he c urre nt b o d y of e vi de nce of t ar gete d t hera p y i n 
mela n o ma brai n metastas es t hr o u g h a n e v al uati o n of t he c o m bi nati o n of da brafe ni b a n d 
tra meti ni b i n patie nts wit h V 6 0 0- m utati o n p ositi ve mela n o ma brai n metastases. 

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4.   
S U B J E C T S E L E C TI O N A N D DI S C O N TI N U A TI O N/ C O M P L E TI O N 
C RI T E RI A  
4. 1.  
S u bj e ct  S el e cti o n Crit eri a 
4. 1. 1. N u m b er of S u bj e ct s 
A p pr o xi matel y 1 2 0 s u bjects will be e nr olle d i n t his st u d y:  C o h ort A ( n = 7 5); C o h ort B 
( n = 1 5); C o h ort C ( n = u p t o 1 5); a n d C o h ort D ( n = 1 5).  See Secti o n 9. 2. 1  f or sa m ple siz e 
ass u m pti o ns. C o h orts will be cl ose d t o e nr oll me nt as t he y are fille d. 
4. 1. 2. I n cl u si o n Crit eri a 
S pecific i nf or mati o n r e gar di n g w ar ni n gs, preca uti o ns, c o ntrai n dicati o ns, A Es, a n d ot her 
perti ne nt i nf or mati o n o n t he i n vesti gati o nal pr o d u cts t h at m a y i m pact s u bject eli gi bilit y is 
pr o vi de d i n t he tra meti ni b ( G S K 1 1 2 0 2 1 2), da brafe ni b ( G S K 2 1 1 8 4 3 6), a n d da brafe ni b a n d 
tra meti ni b c o m bi nati o n I Bs. 
De viati o ns fr o m i ncl usi o n criteria are n ot all o w e d beca use t h e y ca n p ote nti all y je o par dize t he 
scie ntific i nte grit y o f t he st u d y, re g ulat or y acce pta bilit y or s u bject safet y. T heref ore, 
a d here n ce t o t he criteria as s pecifie d i n t he pr ot oc ol is esse ntial. 
S u bjects eli gi ble f or e nr ol me nt i n t he st u d y m ust meet all of t he f oll o wi n g criteria: 
1. Is 1 8  years of a ge. 
2. 
Has si g n e d writte n i nf or me d c o nse nt. 
3. 
A n Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce Stat us of 0- 1 f or 
C o h orts A, B a n d C a n d E C O G sc ore of 0 - 2 f or C o h ort D. See A p pe n di x 4  [O ke n , 1 9 8 2] 
( See A p pe n di x 3 ). 
4. 
Hist ol o gicall y c o nfir me d c uta ne o us mela n o ma t h at is Sta ge I V ( metastatic t o t he 
brai n), a n d d eter mi ne d t o be B R A F V 6 0 0 E/ K/ D/ R m utati o n- p ositi ve  
 
 
  T he ass a y will be c o n d ucte d b y a ce ntral refere nce l a b orat or y. S u bjects 
wit h oc ular or m uc osal m ela n o ma are n ot eli gi ble. S u bjects i n A L L c o h orts are 
eli gi ble t o e nr oll bas e d o n l ocal test res ults. Certifie d l ocal test res ults will be s u bjecte d 
t o retr os pecti ve ce ntral c o nfir mati o n b y a d esi g nat e d assa y. 
5. Ma y b e s yste mic n aï ve or recei ve d u p t o t w o pre vi o us s yst e mic treat me nt re gi me ns 
f or metastatic mela n o m a i ncl u di n g c h e m o-, c yt o ki ne-, i m m u ne-, bi ol o gical- a n d 
vacci ne t hera p y. Pri or te m oz ol o mi de f or brai n metastases a n d a dj u va nt i nterfer o n 
are acce pta ble a n d d o es n ot c o u nt t o war d t he t w o pre vi o us s yst e mic treat m e nt 
re gi me ns. 
6. 
M ust be a ble t o u n der g o M RI a n d h a ve at least o ne meas ura ble i ntracra nial lesi o n f or 
w hic h all of t he f oll o wi n g criteria h a ve t o be met: 
a.  
Pre vi o usl y u ntreate d or pr o gressi ve acc or di n g t o R E CI S T 1. 1 ( >/ = 2 0 % 
i ncreas e i n l o n gest dia meter o n baseli ne sca n) after pre vi o us l ocal t hera p y. 

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b.   
Lar gest dia meter of >/ = 0. 5c m dia meter b ut </ = 4c m as deter mi ne d b y c o ntrast- 
e n ha nce d M RI. 
c.  
F or tar get lesi o ns wit h dia meter of > 0. 5c m b ut  1 c m d oc u me nte d meas ure me nt 
b y a ne ur ora di ol o gist/a p pr o priatel y q ualifie d ra di ol o gist / ne ur os ur ge o n is 
re q uire d. 
d.   
F or all lesi o ns wit h a dia meter of  3c m b ut  4 c m d oc u me nte d meas ure me nt b y  
a ne ur ora di ol o gist / a p pr o priatel y q u alifie d ra di ol o gist / ne ur os ur ge o n is 
re q uire d. 
7. 
All pri or a nti-ca ncer treat me nt-relate d t o xicities (e x ce pt al o pecia a n d la b orat or y val u es 
as liste d o n Ta ble 1 ) m ust be  Gra de 1 acc or di n g t o t he C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts versi o n 4 ( C T C A E versi o n 4. 0; Nati o nal Ca ncer I nstit ute (N C I, 
2 0 0 9)  at t he ti me of e ntr y. 
8. 
A ble t o s wall o w a n d retai n oral me dicati o n a n d m ust n ot h a ve a n y cli nicall y si g nifica nt 
gastr oi ntesti nal a b n or malities t hat ma y alter a bs or pti o n s uc h as mala bs or pti o n 
s y n dr o me or maj or resecti o n of t he st o mac h or b o wels. 
9. 
M ust ha ve a de q u ate or ga n f u ncti o n as defi ne d i n Ta ble 2  
T a bl e 2  
D efi niti o n s f or A d e q u at e B a s eli n e Or g a n F u n cti o n  
S y st e m  
L a b orat ory V al u e s  
He m at ol o gi c  
A N C  
 1. 2 ×  1 0 9/ L 
He m o gl o bi n  
 9 g/dL 
Pl at el et c o u nt  
 1 00  x 1 0 9/ L 
P T/I N R a a n d P T T  
 1. 3 x U L N 
He p ati c  
T ot al bilir u bi n  
 1. 5 x U L N c 
A S T a n d A L T  
 2. 5 x UL N  
Re n al  
S er u m cr e ati nin e b 
 1. 5 m g/ dL  
Car di a c  
L eft V e ntric ul ar Ej ecti o n fr acti on ( L V E F) d 
≥ L L N by E C H O  
A b br evi ati o ns: A L T = al a ni n e tr a ns a mi n as e; A N C = a bs ol ut e n e utr o p hil c o u nt; A S T  = as p art at e a mi n otr a nsf er as e; 
I N R = i nt er n ati o n al n or m aliz e d r ati o; L L N  = l o w er li mit of  n or m al; P T  = pr ot hr o m bi n ti m e; P T T = p arti al 
t hr o m b o pl asti n ti m e; U L N = u p p er  li mit of  n or m al. 
a)   
S u bj ects r ec eivi n g a ntic o a g ul ati o n tr e at m e nt m ay b e  all o w e d t o p artici p at e wit h I N R est a blis h e d wit hi n t h e 
t h er a p e utic r a n g e pri or t o e nr oll me nt. 
b)  
If s er u m cr e ati ni n e is > 1. 5  m g/ d L, c alc ul at e cr e ati ni n e cl e ar a nc e usi n g st a n d ar d C ockcr oft- G a ult 
f or m ul a (A p p e n dix 4 ). Cr e ati ni n e cl e ar a nc e m ust b e   5 0  m L/ mi n t o b e  eli gi bl e. 
c) 
Exc e pt s u bj ects wit h k n o w n Gil b ert’s  sy n dr o m e. 
d)  
E C H O sc a ns m ust b e  us e d t hr o u g h o ut t h e st u dy 
 
1 0. 
W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g n a nc y t est 
wit hi n 1 4 da ys pri or t o e nr oll me nt a n d a gree t o use effecti ve c o ntrace pti o n, as 
d efi ne d i n Secti o n 7. 4. 3. 1  fr o m 7 d a ys pri or t o e nr oll me nt, t hr o u g h o ut t he 
treat me nt peri o d, a n d f or 4 m o nt hs after t he last d ose of st u d y treat me nt. 

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1 1. 
4. 1. 3. 
E x cl u si o n Crit eri a 
De viati o ns fr o m e x cl usi o n criteria are n ot all o w e d beca use t h e y ca n p ote nti all y je o par dize 
t he scie ntific i nte grit y of t he st u d y, re g ulat or y acce pta bilit y or s u bject s afet y. T heref ore, 
a d here n ce t o t he criteria as s pecifie d i n t he pr ot oc ol is esse ntial. 
S u bjects meeti n g a n y of t he f oll o wi n g criteria m ust n ot be e nr olle d i n t he st u d y: 
1. 
Ne ur ol o gical s y m pt o ms r elate d t o brai n metastasis e x ce pt f or C o h ort D w here 
s u bjects ca n be s y m pt o m atic. 
2. Pri or treat me nt wit h a B R A F i n hi bit or or a M E K i n hi bit or. 
3. 
K n o w n oc ular or pri mar y m uc osal mela n o ma 
4. Pri or s yste mic a nti- ca n cer treat me nt ( c he m ot hera p y, i m m u n ot hera p y, bi ol o gic 
t hera p y,  vacci ne t herap y, wit hi n t he last 3 wee ks, or c he m ot hera p y wit h o ut del a ye d  
t o xicit y wit hi n t he last 2 wee ks prece di n g t he first d ose of t he c o m bi nati o n.  Pri or 
s yste mic treat me nt i n t he a dj u va nt setti n g is all o we d (sa me ti meli nes as a b o ve). 
( N ote: I pili m u ma b treat me nt m ust e n d at least 8 wee ks pri or t o e nr oll me nt.) 
5. 
Treat me nt wit h stere otactic ra di os ur ger y wit hi n 1 4 da ys pri or t o start of st u d y 
treat me nt, or treat me nt wit h w h ole- brai n ra diati o n wit hi n 2 8 da ys pri or t o st u d y 
treat me nt. 
6. A n y prese nce of le pt o me ni n geal disease or a n y pare nc h y m al brai n metastasis > 4. 0 c m 
i n dia meter. 
7. 
Ta ke n a n i n vesti gati o nal dr u g wit hi n 2 8 da ys or 5 half-li ves ( mi ni m u m 1 4 da ys), 
w hic he ver is l o n ger, pri or t o d osi n g 
8. 
C urre nt or e x pecte d use of a pr o hi bite d me dicati o n as descri be d i n Secti o n 6. 2  
9. 
Hist or y of  mali g na n c y wit h c o nfir me d acti vati n g R A S m utati o n at a n y ti me. N ote : 
Pr os pecti ve R A S testi n g is n ot re q uire d. H o we ver, if t he res ults of pre vi o us R A S 
testi n g are k n o w n, t he y m ust be use d i n assessi n g eli gi bilit y. 
1 0. Hist or y of  mali g na n c y ot her t ha n diseas e u n der st u d y wit hi n 3 years, of st u d y 
e nr ol me nt wit h e x ce pti o ns bel o w.  
E xce pti o n : S u bjects wit h a hist or y of c o m pletel y resecte d n o n- mela n o ma s ki n 
ca ncer, or s u bjects wit h i n d ole nt sec o n d mali g n a n ci es are eli gi ble. 
1 1. A n y seri o us or u nsta ble pre-e xisti n g me dical c o n diti o ns (asi de fr o m mali g n a nc y 
ex ce pti o ns s pecifie d a b o ve), ps yc hiatric dis or d ers, or ot her c o n diti o ns t hat, i n t he 
o pi ni o n of t he i n vesti gat or, c o ul d i nterfere wit h t he s u bject’s safet y,  o btai ni n g 
i nf or me d c o nse nt, or c o m plia nce wit h st u d y pr o ce d ures. 
1 2. A hist or y of), He patitis B Vir us ( H B V), or He patitis C Vir us ( H C V) i nfecti o n 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
3 8  
 
 
  
(s u bjects wit h la b orat or y e vi de nce of cleare d H B V a n d/ or H C V will be per mitte d. 
1 3. A hist or y or e vi de nce of car di o vas c ular ris k i ncl u di n g a n y of t he f oll o wi n g: 
a)  
C urre nt L V E F < L L N 
b)  
A Q T i nter val c orrecte d f or heart rate usi n g t he Bazett’s f or m ula ( Q Tc B; 4 8 0 
msec; See A p pe n di x 4 ) 
c)  
 A hist or y or e vi de nce of c urre nt cli nicall y si g nifica nt u nc o ntr olle d 
arr h yt h mias; 
Cl arific ati o n: S u bjects wit h atrial fi brillati o n c o ntr olle d f or > 3 0 da ys pri or t o 
d osi n g are eli gi ble 
d) 
A hist or y of ac ut e c or o n ar y s y n dr o mes (i ncl u di n g m y ocar dial i nfarcti o n or 
u nsta ble a n gi na), c or o nar y a n gi o plast y, or ste nti n g wit hi n 6 m o nt hs pri or t o 
e nr oll me nt. 
e) 
A hist or y or e vi de nce of c urre nt Class II c o n gesti ve heart fail ure as d efi ne d b y 
t he Ne w Y or k Heart Ass ociati o n ( N Y H A) g ui deli nes.  See A p pe n di x 5  
f) 
Treat me nt r efract or y h y p erte nsi o n defi ne d as a bl o o d press ure of s yst olic 
> 1 4 0 m m H g a n d/ or diast olic > 9 0 m m H g w hi c h ca n n ot be c o ntr olle d b y a nti- 
h y pert e nsi ve  t hera p y 
g) Patie nts wit h i ntra-car diac defi brillat ors 
h) 
A b n or mal car diac v al ve m or p h ol o g y ( ≥gra de 2) d oc u me nte d b y 
ec h ocar di o gra m (s u bj ects wit h gra d e 1 a b n or malities [i.e., mil d 
re g ur gitati o n/ste n osis] ca n be e ntere d o n st u d y).  S u bjects wit h m o derate 
val v ular t hic ke ni n g s h o ul d n ot be e ntere d o n st u d y.  
1 4. A hist or y or c urre nt e vi de nce of reti nal vei n occl usi o n ( R V O) 
1 5. K n o w n i m me diate or del a ye d  h y perse nsiti vit y reacti o n or i di os y ncras y t o dr u gs 
c he micall y rel ate d t o t he st u d y treat me nts, t heir e x ci pie nts, a n d/ or di met h yl 
s ulf o xi de ( D M S O). 
1 6. Pre g n a nt or n ursi n g fe m ales. 
1 7. Hist or y of i nterstitial l u n g diseas e or p ne u m o nitis 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
3 9  
 
 
1 8.  S u bjects re gistere d i n Fr a nce a n d Ger m a n y: Fre nc h/ Ger m a n S u bjects please refer t o 
A p pe n di x 9  f or c o u ntr y s pecific g ui da nce. 
4. 2.  
P er m a n e nt Di s c o nti n u ati o n fr o m St u dy Tr e at m e nt a n d  S u bj e ct 
C o m pl eti o n  Crit eri a 
4. 2. 1. 
P er m a n e nt Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt  
S u bjects will recei ve st u d y treat me nt u ntil disease pr o gressi o n, deat h, or u nacce pta ble A E, 
i ncl u di n g he mat ol o gic or ot her n o n- he mat ol o gic t o xicit y, a n d/ or meeti n g st o p pi n g criteria 
f or li ver c h e mistr y d efi ne d i n Secti o n 5. 9. 1  a n d A p pe n di x 6.  N ote: c o nti n uati o n of eit her t he 
c o m bi nati o n or eit her of t he si n gle a ge nt st u d y tre at me nts be y o n d r a di o gr a p hic dise ase 
pr o gressi o n (as defi ne d b y R E CIS T  1. 1) ma y be p ossi ble if t he i n vesti gat or deter mi nes t hat 
s u bject has cle ar e vi de n ce of cli nical be nefit fr o m st u d y treat me nt, c o nti n ui n g st u d y dr u g(s) 
ma y be i n t he b est i nterest f or t he s u bject a n d t he s u bject is willi n g t o c o nti n ue o n st u d y 
dr u g(s). I n t his cas e, c o ns ultati o n bet wee n t he i n vesti gat or a n d t h e N o vartis Gl o bal Cli nical 
Lea d is ma n dat or y a n d t he patie nt m ust si g n a se parate i nf or me d c o ns e nt f or m. If c o nti n ui n g 
t he s u bject o n st u d y treat me nt is a gree d t he n all st u d y pr o ce d ures, i ncl u di n g t u m o ur 
assess me nts, m ust be f oll o we d as sc he d ule d ( Ta bl e 1 9 ). I n a d diti o n, after eac h t u m o ur 
assess me nt, t he i n vesti gat ors m ust c o nfir m wit h t he N o vartis Gl o bal Cli nical Lea d  t hat t he 
s u bject is still be nefitti n g fr o m st u d y tr eat me nt a n d t heref ore ca n c o nti n ue recei vi n g st u d y 
treat me nt. 
I n a d diti o n, st u d y tr eat m e nt ma y b e per m a ne ntl y disc o nti n ue d f or a n y of t he f oll o wi n g 
reas o ns: 
 
De viati o n(s) fr o m t he pr ot oc ol 
 
Re q uest of t he s u bject or  his/ her pr o x y 
 
I n v esti gat or’s discreti o n 
 
S u bject is l ost t o f oll o w- u p 
 
St u d y is cl ose d or ter mi n ate d. 
T he pri mar y reas o n st u d y treat me nt was per ma ne ntl y dis c o nti n ue d m ust be d oc u me nte d i n 
t he s u bject’s me dical rec or ds a n d electr o nic case re p ort f or m (e C R F). O nce a s u bject has 
per ma ne ntl y disc o nti n ue d fr o m st u d y treat me nt, t he s u bject will n ot be all o we d t o be 
retreate d. 
If t he s u bject disc o nti n ues treat me nt d ue t o t o xicit y, ‘a d verse e ve nt’ will be rec or d e d as t he 
pri mar y reas o n f or p er ma ne nt disc o nti n uati o n i n t he e C R F. 
N ote:  If o ne st u d y treat me nt is wit h hel d or disc o nti n ue d t he ot her treat me nt ma y c o nti n ue t o 
be a d mi nistere d if a p pr o priate.  S u bjects w h o disc o nti n ue o ne t hera p y b ut re mai n o n t he ot her 
will be c o nsi dere d t o be o n st u d y treat me nt a n d s h o ul d be assesse d as i n di cate d i n t he Ti me 
a n d E ve nts (Ta ble 1 9 ).  Per ma ne nt disc o nti n uati o n bel o w refere n ces re q uires disc o nti n uati o n 
of b ot h st u d y treat me nts. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
4 0  
 
 
All s u bjects w h o per ma n e ntl y disc o nti n ue all st u d y tr eat me nt wit h o ut disease pr o gressi o n will 
be f oll o we d f or pr o gressi o n acc or di n g t o t he Ti me a n d E ve nts ( Ta ble 1 9 ). 
All s u bjects w h o per ma n e ntl y disc o nti n ue st u d y tr eat me nt will ha ve m o nt hl y s ki n 
assess me nts, s ur vi val f oll o w u p a n d ne w a nti-ca ncer t hera p y (i ncl u di n g ra di ot hera p y a n d 
s ur ger y f oll o w u p) t hr o u g h m o nt h 6 after treat me nt disc o nti n uati o n. If t he y start ne w a nti- 
ca ncer t hera p y or at t he e n d of t he 6 m o nt h f oll o w u p visit, t he y will be f oll o we d e ver y 1 2 
wee ks f or s ur vi val f oll o w u p a n d ne w a nti-ca n cer t hera p y (i ncl u di n g ra di ot hera p y a n d s ur ger y ) 
u ntil deat h, ha ve wit h dra w n c o nse nt or are l ost t o f oll o w- u p, or st u d y cl os ure. St u d y cl os ur e is 
defi ne d b y  w h ere all s u bjects still i n f oll o w u p ha ve ha d at least 3  years f oll o w- u p fr o m t he 
date of first d ose of st u d y treat me nt, w hic he ver is earlier. Refer t o s p ecific g ui deli nes i n t he 
Ti me a n d E ve nts Ta ble ( Ta ble 1 9 ). 
4. 2. 2. S u bj e ct C o m pl eti o n a n d Wit h dr a w al  
A s u bject will be c o nsi dere d t o ha ve c o m plete d t h e st u d y if t he s u bject dies d uri n g t he st u d y 
treat me nt or f oll o w- u p p eri o d or has h a d at least 3 years f oll o w- u p fr o m t he date of first d ose 
of st u d y treat me nt at t he e n d of t he trial. T he ca us e of deat h will be d oc u me nte d i n t he e C R F.  
A s u bject will be c o nsi dere d t o ha ve wit h dr a w n fr o m t he st u d y if t he s u bject has n ot die d a n d 
is l ost t o f oll o w- u p, has wit h dra w n c o nse nt, is n o l o n ger bei n g f oll o we d at t he i n vesti gat or’s 
discreti o n, or if t he st u d y is cl ose d or ter mi nate d. 
5.   
S T U D Y T R E A T M E N T S 
5. 1.  
I n v e sti g ati o n al Pr o d u ct 
I n v esti gati o nal pr o d uct m ust be st ore d i n a sec ure area u n der t he a p pr o pri ate p h ysical 
c o n diti o ns f or t he pr o d uct.  Access t o a n d a d mi nistrati o n of t he i n vesti gati o nal pr o d uct will 
be li mite d t o t he i n vesti gat or a n d a ut h orize d site staff.  I n vesti gati o nal pr o d uct m ust be 
dis pe nse d or a d mi nistere d o nl y t o s u bjects e nr olle d i n t he st u d y a n d i n acc or da nce wit h t he 
pr ot oc ol. 
N o s pecial pre parati o n of st u d y me dicati o n is re q uire d.  U n der n or mal c o n diti o ns of 
ha n dli n g a n d a d mi nistrati o n, i n vesti gati o nal pr o d uct is n ot e x pecte d t o p ose si g nifica nt 
safet y ris ks t o site staff.  Material Safet y Data S heets ( M S D S) descri bi n g t he occ u p ati o nal 
hazar ds a n d rec o m me n de d ha n dli n g preca uti o ns will be pr o vi de d t o site staff if re q uir e d b y 
l ocal la ws or will ot her wise be a vaila bl e fr o m N o vartis u p o n re q uest. 
5. 1. 1. D a br af e ni b 
Da brafe ni b st u d y me dicati o n will be pr o vi de d as 5 0 m g a n d 7 5 m g ca ps ules.  Eac h 
ca ps ule will c o ntai n 5 0 m g or 7 5 m g of free base 
Da brafe ni b will be pr o vi de d t o sites b y N o vartis. T he c o nte nts of t he la bel will be i n 
acc or d a nce wit h all a p plica ble re g ulat or y re q uire me nts. 
5. 1. 2. Tr a m eti ni b  
Tra meti ni b st u d y me dicati o n will be pr o vi de d as 0. 5 m g a n d 2. 0 m g ta blets.  Eac h ta blet will 
c o ntai n 0. 5 m g or 2. 0 m g of tra meti ni b pare nt

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
4 1  
 
 
Tra meti ni b will be pr o vi de d t o sites b y N o vartis. T he c o nte nts of t he la bel will be i n 
acc or d a nce wit h all a p plica ble re g ulat or y re q uire me nts.  
5. 2.  
D o s a g e a n d A d mi ni str ati o n  
5. 2. 1. D a br af e ni b a n d Tr a m eti ni b C o m bi n ati o n  
 
Da brafe ni b, 1 5 0 m g, BI D; 
 
Tra meti ni b, 2. 0 m g, o n ce dail y. 
W he n a d mi nistere d i n c o m bi nati o n wit h tra meti ni b, ta ke t he o nce- dail y d ose of tra meti ni b at 
a p pr o xi matel y t he sa me ti me eac h da y wit h eit her t he m or ni n g d ose or t he e ve ni n g d ose of  
da brafe ni b.  T he sec o n d d ose of da brafe ni b ( 1 5 0 m g) s h o ul d be a d mi nistere d a p pr o xi matel y 
1 2 h o urs after t h e m or ni n g d ose.  St u d y me dicati o n s h o ul d be ta ke n orall y wit h 
a p pr o xi matel y 2 0 0  m L of water u n der fasti n g c o n diti o ns, eit her 1 h o ur bef ore or 2 h o urs after 
a meal. 
If a s u bject v o mits after t a ki n g st u d y me dicati o n, t he s u bject s h o ul d be i nstr ucte d n ot t o 
reta ke t he d os e a n d s h o ul d ta ke t he ne xt d ose as ori gi nall y sc he d ule d. 
If a d mi nistrati o n of tra m eti ni b is i nterr u pte d or per ma n e ntl y disc o nti n ue d, a d mi nistrati o n of 
da brafe ni b m a y b e c o nti n ue d.  If a d mi nistrati o n of da brafe ni b is i nterr u pte d or per ma n e ntl y 
disc o nti n ue d, a d mi nistrati o n of tra meti ni b ma y c o nti n ue. 
If a s u bject misses a d os e of da brafe ni b, t he s u bject ma y ta ke t h e d ose i m me diatel y if t he ne xt 
d ose is sc he d ule d f or at least 6 h o urs later.  If t he ne xt sc he d ule d d ose of da brafe ni b is d ue i n 
less t ha n 6 h o urs, t he s u bject s h o ul d s ki p t he d ose a n d res u me d a brafe ni b d osi n g at t he ne xt 
sc he d ule d d ose. If a s u bj ect misses a d ose of tra m eti ni b, t he s u bject ma y ta ke t he d ose 
i m me diatel y if t he ne xt d ose is sc he d ule d f or at least 1 2 h o urs later. 
1.  See Secti o n 5. 8  f or d ose m o dificati o n g ui deli nes o n da brafe ni b a n d tra m eti ni b. 
5. 3.  
H a n dli n g a n d St or a g e of St u d y Tr e at m e nt  
Da brafe ni b a n d tra meti ni b m ust be dis pe nse d a n d a d mi nistere d i n acc or da n ce wit h t he 
pr ot oc ol, a n d o nl y t o s u bj ects e nr olle d i n t he st u d y .  Da brafe ni b a n d tra meti ni b m ust be 
st ore d i n a sec ure area u n der t he a p pr o priate p h ysi cal c o n diti o ns f or t he pr o d uct.  St u d y 
me dicati o n is t o be st ore d at t he te m perat ure s pecifie d o n t he la bel.  Mai nt e na nce of a 
te m perat ur e l o g ( ma n ual or a ut o mate d) is r e q uire d. Access t o a n d a d mi nistrati o n of 
da brafe ni b a n d tra m eti ni b will be li mite d t o t he i n vesti gat or a n d a ut h orize d site staff. 
Pr oce d ures f or fi nal dis p ositi o n of u n use d st u d y tr eat me nts will be pr o vi de d i n t he St u d y 
Pr oce d ures M a n ual ( S P M). 
5. 4.  
Tr e at m e nt A s si g n m e nt 
S u bjects will be e ntere d i nt o t he a p pr o priate c o h ort base d o n t he m utati o n a n d disease stat us.  
S u bjects will be i de ntifie d b y a u ni q ue s u bject n u m ber t hat will re mai n c o nsiste nt f or t he 
d urati o n of t he st u d y.  E ac h site will be gi ve n a s u bject n u m ber ra n ge. T his ca n be o btai n e d 
fr o m y o ur site m o nit or. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
4 2  
 
 
U p o n o btai ni n g c o ns e nt fr o m t he s u bject f or t he st u d y t h e s u bject will be re gistere d i nt o 
i nteracti ve v oic e res p o ns e s yste m (I V R S), b y t he i n vesti gat or or a ut h orize d site staff t o 
re gister a n d rec or d s u bject acti vit y. St u d y-s pecific i nstr ucti o nal w or ks heets will be pr o vi de d 
f or t he use of I V R S. 
O nce t he tar get n u m ber of eac h c o h ort has b ee n e nr olle d, t hat c o h ort will be cl ose d t o 
f urt her e nr ol me nt a n d I V R S will n o l o n ger all o w a s u bject t o be e ntere d. 
5. 5.  
Bli n di n g  
T his is a n o pe n -la bele d st u d y. 
5. 6.  
Pr o d u ct A c c o u nt a bilit y 
I n acc or da n ce wit h l ocal re g ulat or y re q uire me nts, t he i n vesti gat or, d esi g n at e d site staff, or 
hea d of t he me di cal i nstit uti o n ( w here a p plica ble) m ust d oc u me nt t he a m o u nt of 
i n vesti gati o nal pr o d u ct dis pe nse d a n d/ or a d mi nistere d t o st u d y s u bj ects, t he a m o u nt ret ur ne d 
b y st u d y s u bjects, a n d t h e a m o u nt recei ve d fr o m a n d ret ur ne d t o N o vartis, w he n a p plica bl e.  
Pr o d uct acc o u nta bilit y rec or ds m ust be mai ntai ne d t hr o u g h o ut t he c o urse of t he st u d y.  Refer 
t o t he S P M f or f urt her detaile d i nstr ucti o ns o n pr o d uct acc o u nt a bility. 
5. 7.  
Tr e at m e nt C o m pli a n c e 
S u bjects will be i nstr ucte d t o ret ur n treat me nt b ottles at eac h visit.  C o m plia nce wit h st u d y 
treat me nt will be assesse d b y q u er yi n g t h e s u bject a n d t hr o u g h pill c o u nt at eac h visit.  
C o m plia nce will be d oc u me nte d i n t he s o urce d oc u me nts a n d t he e C R F. 
A rec or d of t he n u m ber of da brafe ni b ca ps ules a n d tra meti ni b ta blets dis pe nse d t o a n d 
ta ke n b y eac h s u bject m ust be mai ntai ne d a n d rec o ncile d wit h st u d y treat me nt a n d 
c o m plia nce rec or ds.  Treat me nt start a n d st o p dates, i ncl u di n g d ates of d ose m o dificati o ns 
a n d/ or i nterr u pti o ns will als o be rec or de d i n t he e C R F. T he i n vesti gat or will ma ke e ver y 
eff ort t o bri n g n o n- c o m plia nt s u bjects i nt o c o m plia nce. 
5. 8.  
D o s e  M o difi c ati o n G ui d eli n e s  
T he se verit y of A Es will be gra de d usi n g t he C T C A E, versi o n 4. 0 
w w w.e ort c. be/ser vi ces/ d oc/ctc/ C T C A E _ 4. 0 3 _ 2 0 1 0- 0 6-
1 4 _ Q uic k Refere nce _ 5 x 7. p df. T he secti o n i ncl u des: 
 
Ge neral g ui d eli nes f or cli nicall y si g nifica nt t o xicities relate d t o st u d y treat me nts a n d 
 
S pecific g ui deli nes f or a d verse e v e nts of s pecial i nterest, w hic h are e v e nts t hat 
ha ve bee n o bser ve d wit h hi g her fre q u e nc y or s e verit y i n s u bjects recei vi n g 
da brafe ni b, tra meti ni b, or a c o m bi nati o n of b ot h t hera pies. 
Wit h t he e xce pti o ns of p yre xi a a n d ne w pri m a r y R A S- m ut ati o n p ositi ve n o n- c ut a ne o us 
m ali g n a ncies(li kel y rel ate d t o d a br afe ni b); a n d decre ase d L V E F, R V O (reti n al vei n 
occl usi o n), R P E D, a n d p ne u m o nitis (li kel y rel ate d t o tr a meti ni b), t he g ui d a nce s u g gests 
t h at b ot h t her a pies be re d uce d, i nterr u pte d or disc o nti n ue d si m ult a ne o usl y i n res p o nse 
t o t o xicities t h at a re c o nsi dere d b y t he i n vesti g at or t o be tre at me nt rel ate d. 
T a bl e 3  
C at e g ori e s  of D o s e M o difi c ati o n G ui d eli n e s 
A d v er s e E v e nt  
D a br af e ni b  
Tr a m eti ni b  
S e cti o n  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
4 3  
 
 
G e n er al G ui d eli n es 
f or Cli nic ally Si g nific a nt 
T oxiciti es  
X  
X  
5. 8. 2 
G ui d eli n es f or S p e cifi c A d ver s e E v e nt s C ar di o v a s c ul ar  A d v er s e E v e nt s a  
L V E F  
 
X  
5. 8. 3. 1  
Hy p ert e nsi o n  
X  
X  
5. 8. 3. 2  
Pr ol o n g e d Q Tc  
X  
X  
5. 8. 3. 3  
S ki n – R el at e d  A dv er s e  E ve nt s  ( E x c e pt c u S C C) b  or n e w pri m ar y m el a n o m as  
Ras h  
X  
X  
5. 8. 4. 1  
Ha n d -F o ot Ski n R e acti o n  
X  
X  
5. 8. 4. 2  
c u S C C 
X  
X  
5. 8. 4. 3  
Ot h er A d v er s e E v e nts  
Pyr exi a  
X  
 
5. 8. 5. 1  
Di arr h e a  
X  
X  
5. 8. 5. 2  
R e n al I ns uffici ency  
X  
X  
5. 8. 5. 3  
Vis u al Ch an g es  
 
X  
5. 8. 5. 4  
P n e u m o nitis  
 
X  
5. 8. 5. 5  
Liv er Ch e mistry 
St o p pi n g Criteri a  
X  
X  
5. 9. 1 
a.   
F or s u bj ects e nr oll e d i n Fr a nc e pl e as e s e e Ap p e n dix 9  a n d Ap p e n dix 1 1  f or a d diti o n al d os e 
m o dific ati o n g ui d eli n es 
b.   
R ef er t o S ecti o n 5. 8. 4. 3  f or m a n a g e m e nt of c u S C C 
5. 8. 1. D o s e L e v el s of d a br af e ni b a n d tr a m eti ni b  
T he d ose le vels f or t his st u d y are pr o vi de d i n T a ble 4 . 
T a b l e 4  
D o s e L e v el R e d u cti o n G ui d eli n e s 
D o s e L e v el  
D a br af e ni b D o s e/ S c h e d ul e  
Tr a m eti ni b D o s e/ S c h e d ul e  
St arti n g D ose  
1 5 0 m g BI D 
2 m g o nc e d aily  
-1 ( 1 st Dos e r e d uctio n)  
1 0 0 m g BI D 
1. 5 m g onc e d aily  
-2 ( 2 nd Dos e r e d ucti o n)  
7 5 m g BI D 
1. 0 m g onc e d aily  
A b br evi ati o n: BI D = t wic e d aily  
If a n A E res ol ves t o gra d e 1 or baseli ne at t he re d uce d d ose le vel, a n d n o a d diti o nal 
t o xicities are see n after 4 wee ks of st u d y treat me nt at t he re d uce d d ose, t he d ose ma y be 
i ncreas e d t o t he pre vi o us d ose le vel. 
If t he s u bject re q uir es b ot h a d ose re d u cti o n bel o w 7 5 m g BI D f or da brafe ni b a n d a d ose 
re d ucti o n bel o w 1 m g o n ce dail y f or tra meti ni b, t he s u bject m ust disc o nti n ue t he 
c o m bi nati o n st u d y treat m e nt. 
If a d ose re d ucti o n bel o w 7 5 m g BI D f or da brafe ni b is re q uire d, da brafe ni b will be 
per ma ne ntl y disc o nti n ue d b ut t hese s u bjects will be all o we d t o c o nti n ue tra meti ni b.  If a d ose 
re d ucti o n bel o w 1. 0 m g o nce dail y f or tr a meti ni b is re q uire d, t he n tr a meti ni b will be 
per ma ne ntl y disc o nti n ue d, b ut t hese s u bjects will be all o we d t o c o nti n ue d a brafe ni b. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
4 4  
 
 
N ote: A p pr o v al f r o m t h e N o v artis  Gl o b al Cli nic al Le a d is re q uire d t o rest art 
st u d y tre at me nt after ≥2 1 d a ys of i nterr u pti o n. 
5. 8. 2.   
G e n er al G ui d eli n e s f or Cli ni c all y Si g nifi c a nt T o xi citi e s o n t h e    
d a br af e ni b a n d tr a m eti ni b c o m bi n ati o n tr e at m e nt ar m  
Ge neral g ui d eli nes re gar di n g ma na ge me nt a n d d ose re d ucti o n f or a d verse e ve nts t hat are 
c o nsi dere d b y t he i n v esti gat or t o b e rel ate d t o st u d y treat me nt a n d w hic h d o n ot ha ve st u d y 
s pecific d ose m o dificati o n g ui deli nes as i n Ta bl e 3  are pr o vi d e d i n Ta ble 5   bel o w. T hese 
g ui deli nes are i nte n d e d pri maril y f or t o xicities n ot easil y ma na ge d wit h r o uti ne s u p p orti ve 
care.  F or e x a m ple, al o pe cia is n ot a n i n dicati o n f or d ose m o dificati o n, n or is gra de 2 n a usea 
a n d v o miti n g t hat ca n b e easil y ma n a ge d wit h a nti-e metics. 
T hese are ge n eral g ui deli nes a n d i n vesti gat ors s h o ul d al wa ys us e cli nical j u d g me nt i n 
deter mi ni n g d os e a dj ust me nts f or a n y i n di vi d ual patie nt.  S o me t o xicities ma y re q uire 
h os pitaliz ati o n f or sta bilizati o n, a d diti o nal w or k- u p, a n d c o ns ultati o n wit h a s pecialist 
bef ore tr eat me nt c a n be restarte d.  S pecifi c a d verse e ve nts a n d rec o m me n d e d ma na ge m e nt 
i ncl u de: 
 P a ncre atitis –  I n t he e ve nt of a b d o mi nal pai n or s us pecte d pa n creatitis, a m yl ase a n d 
li pase la b orat or y sa m ples s h o ul d be c ollecte d f or c o nfir mati o n of t he dia g n osis. 
Patie nts s h o ul d be cl osel y m o nit ore d w he n r e-starti n g da brafe ni b after a n e pis o de of 
pa ncreatitis. 
 U veitis: Treat me nt wit h da brafe ni b has bee n ass ociate d wit h t he de vel o p me nt of 
u veitis, i ncl u di n g iritis. M o nit or patie nts f or vis ual si g ns a n d s y m pt o ms (s uc h as, 
c ha n ge i n visi o n, p h ot o p h o bia a n d e ye p ai n) d uri n g t hera p y. 
 H y per gl yce mi a : H y p er gl yce mia re q uiri n g a n i ncrease i n t he d ose of, or i nitiati o n of 
i ns uli n or oral t hera p y ca n  occ ur wit h da brafe ni b. M o nit or ser u m gl uc os e le vels as 
cli nicall y a p pr o priate d uri n g treat me nt wit h da brafe ni b i n s u bjects wit h pre- e xisti n g 
dia betes or h y per gl yce mi a. A d vise patie nts t o re p ort s y m pt o ms of se vere 
h y p er gl yce mia s uc h as e x cessi ve t hirst or a n y i n crease i n t he v ol u me or fre q ue nc y of 
uri nati o n.

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
4 5  
 
 
T a bl e 5  
D o s e M o difi c ati o n G ui d eli n e s f or E v e nt s C o n si d er e d R el at e d t o St u d y 
Tr e at m e nt ( D a br af e ni b a n d Tr a m eti ni b C o m bi n ati o n Tr e at m e nt) 
 
C T C A E  Gr a d e  
A cti o n a n d D o s e M o difi c ati o n a, b  
Gr a d e 1 or Gr a d e 
2 t ol er a bl e  
C o nti n u e st u d y tr e at m e nt at s a me d o s e l ev el ( n o d os e 
m o difi c ati o n) a n d m o nit or a s cli ni cally i n di cat e d . 
Gr a d e 2 (I nt ol er a ble) or Gra d e 3  
1 st, 2 nd 
I nt err u pt st u dy tr e at me nt u ntil toxicity r es olv es to ≤ gr ad e 1 th e n r estart at n ext 
l o w er d os e l evel 
3r d  
Disc o nti n u e tre at m ent.  
Gr a de 4  
1 st occ urr e nc e  
I nt err u pt st u dy tr e at me nt u ntil toxicity r es olv es to ≤ gr ad e 1 or b as eli n e  t he n r est art 
at n ext l o w er d os e l ev el or disc o nti nu e at discr eti o n of i nv esti g at or  
2 nd occ urr e nce  
I nt err u pt st u dy tr e at me nt u ntil toxicity r es olv es to ≤ gr ad e 1 or b as eli n e t he n 
r est art at t w o d ose l ev els l o w er t h a n t h e st artin g d os e or disco nti n u e at discr eti o n 
of i nv esti gat or a nd aft er disc ussi o n with t h e G L o b al Cli nic al Le a d . 
3 rd  occ urrenc e  
Disc o nti n u e tre at m ent  
a.  
Tr e at m e nt s h o ul d b e  disc o nti n u e d if m or e t h a n 2 d os e r e d ucti o ns ar e r e q uir e d 
b.  
A p pr ov al fr o m t h e N ov artis Global Clinical L e a d  is r e q uir e d t o r est art st u dy tr e at m e nt aft er  ≥2 1  d ays 
W h e n a n i ndivi d u al’s a dv erse r e acti ons ar e u nd er eff ectiv e m a n ag e m ent, d os e r e- esc al ati o n 
f oll o wi n g th e sa m e d osi n g st e ps as d e- escal ati o n m ay b e c o nsid er e d. T h e d abr afe nib d ose 
s h o ul d n ot exc ee d 1 50 m g t wic e d aily a nd th e tr a metinib s h o ul d n ot exc ee d 2 m g o nc e d aily. 
5. 8. 3.   
G ui d eli n e s f or C ar di o v a s c ul ar A d v er s e E v e nt s o n t h e d a br af e ni b 
a n d tr a m eti ni b c o m bi n ati o n tr e at m e nt ar m  
Car di o vasc ular a d vers e e ve nts ha ve bee n see n i n s u bjects recei vi n g eit her da brafe ni b, 
tra meti ni b or b ot h i n c o m bi nati o n (see t he tra m eti ni b, da brafe ni b a n d c o m bi nati o n I Bs f or 
a d diti o nal i nf or mati o n); [ Gla x o S mit h Kli ne D oc u me nt N u m ber H M 2 0 0 9/ 0 0 1 5 1/ 0 2  2 0 1 1; 
Gla x o S mit h Kli ne D oc u me nt N u m ber C M 2 0 1 0/ 0 0 0 1 0/ 0 2  2 0 1 1 a n d Gla x o S mit h Kli ne 
D oc u me nt N u m ber 2 0 1 1 N 1 2 6 8 1 1 _ 0 0 . 2 0 1 2] 
5. 8. 3. 1.  
L eft V e ntri c ul ar Ej e cti o n Fr a cti o n ( L V E F) 
Decreases of t he left- ve ntric ular-ejecti o n-fracti o n ( L V E F) ha ve b ee n o bs er ve d i n s u bjects 
recei vi n g tr a meti ni b m o n ot hera p y a n d i n c o m bi nati o n wit h da brafe ni b. T h eref ore, E C H Os 
m ust  be perf or me d t o ass ess car diac ejecti o n fracti o n i n re g ular i nter vals as o utli ne d i n t he 
Ti me a n d E ve nts ( Ta ble 1 9) . All E C H Os will be c ollecte d; i nstr ucti o ns are pr o vi de d i n 
A g M e d Net I m a gi n g Ac q uisiti o n G ui deli nes. D ose m o dificati o n g ui da nce a n d st o p pi n g 
criteria f or L V E F decrease are pr o vi de d i n Ta ble 6  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
4 6  
 
 
T a bl e 6  
D o s e M o difi c ati o n G ui d eli n e s a n d St o p pi n g Crit eri a f or L V E F D e cr e a s e 
D ose M o dificati o n G ui deli nes a n d St o p pi n g Criteria f or L V E F.  
Cli ni c  
L V E F -dr o p ( %) or  C T C A E  
gr a d e  
A cti o n a n d D o s e M o difi c ati o n  
Asy m pto m atic  
A bs ol ut e d ecr eas e of > 1 0 % 
i n L V E F c o m p ar e d t o 
b as eli n e  an d ej ecti on 
fr acti o n b el o w th e 
i nstituti o n’s  LL N 
 
I nt err u pt tr a m etini b an d r e p eat E C H O wit hi n 2 w e ek s a, b 
 
If t h e L V E F re c o vers wit hi n 4 w e eks ( d efi n e d as L V E F 
≥L L N a n d  a bs ol ute d ecr e as e ≤1 0 % c o m par e d t o 
b as eli n e)  
o  C o ns ult with t h e N ov artis  Glo bal C li nic al L e a d  
a n d r e q u est a ppr ov al f or r est art . 
o  If a p pr ove d, r est art tr e at m e nt wit h tr a m eti ni b 
r e d uc e d by on e d os e l ev el. 
o  R e p e at E C H O at 2 , 4, 8 a nd  12 w e eks 
aft er r e -st art; c onti n ue i n int ervals of  1 2 
w e eks t her e aft er . 
 
If L V E F d o e s n ot r ec o v er  withi n 4 w e eks  
o  C o ns ult with c ar di ol ogist . 
o  P er m a n e ntl y di s c o nti n u e tra m eti ni b . 
o  R e p ort a s S A E . 
o  R e p e at E C H O aft er 2, 4, 8, 1 2, a n d 1 6 w e eks or 
u ntil r es ol ut ion. 
Sy m pt o mati c b,c 
Gr a d e 3: r esti n g L V E F 3 9 -2 0 %  
or  > 2 0 % a bs ol ut e r e d ucti on 
fr o m b as elin e 
 
P er m a n e ntl y di s c o nti n u e tra m eti ni b . 
 
I nt err u pt d a br af e ni b.d  
 
R e p ort  a s  S A E . 
 
C o n s ult wit h c ar di ol o gi st  
 
R e p e at E C H O aft er 2, 4, 8, 1 2, a n d 1 6 w e eks or u ntil 
r es ol uti o nb,d 
Gr a d e 4: r esti n g L V E F < 20 %  
A b br evi ati o ns: C T C A E = C o m m o n T er mi n ol o gy Crit eri a f or Adv ers e Ev e nts; E C H O = ec h oc ar di o gr a m; L L N  = l o w er li mit of  
n or m al; L V E F = l eft v e ntric ul ar ej ecti o n fr acti o n; 
a.  
If E C H O d o es  n ot  s h o w L V E F r ec ov ery aft er  2 w e eks, r e p e at E C H O 2 w e eks l at er. 
b.  
If r ec urr e nt e pis o d es of  L V E F r e d ucti o n occ ur i n s u bj ects r ec eivi n g d a br af e ni b m o n ot h er a py, c o ns ult Gl o b al 
Cli nic al L e a d . 
c. 
Sy m pt o ms m ay i ncl u d e: dys p n e a, ort h o p e n e a, a n d  ot h er  si g ns a n d  sy m pt o ms of  p ul m o n ary c o n g esti o n a n d 
e d e m a. 
d.  
O nc e L V E F r ec ov ers, i ncl u di n g r es ol uti o n of  sy m pt o ms, r est art of  d a br af e ni b m o n ot h er a py o nly c a n be 
c o nsi d er e d i n c o ns ult ati o n wit h N ov artis Gl o b al Cli nic al L e a d . 
5. 8. 3. 2.  
H y p ert e n si o n 
I n creas es i n bl o o d press ure ha ve b ee n o bs er ve d i n s u bjects recei vi n g tr a meti ni b. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
4 7  
 
 
Rec o m me n dati o ns f or bl o o d press ure m o nit ori n g a n d ma na ge m e nt are pr o vi de d i n 
Secti o n 5. 8. 3. 2. 1  a n d Secti o n 5. 8. 3. 2. 2 . 
5. 8. 3. 2. 1.  
M o nit ori n g of H y p ert e n si o n  
All bl o o d press ure assess me nts s h o ul d be perf or m e d u n der t he f oll o wi n g o pti mal 
c o n diti o ns: 
 
T he s u bject has bee n seate d wit h bac k s u p p ort, e ns uri n g t hat le gs are u n cr osse d a n d flat 
o n t he fl o or. 
 
T he s u bject is rela x e d c o mf orta bl y f or at least 5 mi n utes. 
 
Restricti ve cl ot hi n g has b ee n re m o v e d fr o m  t he c uff area a n d t h e ri g ht c uff size has 
bee n selecte d. 
 
T he s u bject’s ar m is s u p p orte d s o t hat t he mi d dle of t he c uff is at heart le vel. 
 
T he s u bject re m ai ns q uiet d uri n g t he meas ure me nt. 
I n s u bjects wit h a n i nitial bl o o d press ure rea di n g wit hi n t he h y perte nsi ve ra n ge, a sec o n d 
rea di n g s h o ul d be ta k e n at least 1 mi n ute later, wit h t he 2 rea di n gs a vera ge d t o o btai n a fi nal 
bl o o d press ure me as ure m e nt. T he a vera ge d val ue s h o ul d be rec or de d i n t he e C R F. 
Persiste nt h y perte nsi o n is defi ne d as a n i ncreas e of s yst olic bl o o d press ur e ( S B P) > 1 4 0 m m 
H g a n d/ or diast olic bl o o d press ure ( D B P) > 9 0 m m H g i n t hree c o nsec uti ve visits wit h 
bl o o d press ure ass ess me nts fr o m t w o rea di n gs c ollecte d as descri be d a b o ve. Visits t o 
m o nit or i ncrease d bl o o d press ure ca n be s c he d ule d i n de pe n de ntl y fr o m t he per- pr ot oc ol 
visits o utli ne d i n t he Ti me a n d E ve nts ( Ta ble 1 9 ).  I d eall y, s u bse q ue nt bl o o d press ure 
assess me nts s h o ul d be perf or me d wit hi n o ne wee k. 
As y m pt o m atic h y pert e nsi o n is defi ne d as a n i ncrease of S B P > 1 4 0 m m H g a n d/ or D B P > 9 0 
m m H g i n t he a bse nce of hea dac he, li g ht- hea de d n ess, verti g o, ti n nit us, e pis o des of fai nti n g or 
ot her s y m pt o ms i n dicati v e of h y perte nsi o n. 
5. 8. 3. 2. 2.  
M a n a g e m e nt of H y p ert e n si o n 
F or s u bjects e x perie nci n g a n i ncreas e i n s yst olic a n d/ or diast olic bl o o d press ure t hat is 
persiste nt a n d ma y be ass ociate d wit h t he st u d y tr eat me nt, rec o m me n d ati o ns f or t he cli nical  
ma na ge me nt of h y p e rte nsi o n are descri be d bel o w i n Ta ble 7:  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
4 8  
 
 
T a bl e 7  
M a n a g e m e nt a n d D o s e M o difi c ati o n G ui d eli n e s f or H y p ert e n si o n 
Hy p ert e n si o n  
A cti o n a n d D o s e M o difi c ati o n  
( Sc e n ari o A) 
 Asy m pto m atic a nd p ersist ent a S B P of > 1 4 0 a n d 
< 1 6 0  m m Hg,  or D B P ≥9 0 a n d < 1 0 0 m m H g,  
or  
 Cli nic ally si gnific a nt i ncr eas e in D B P of 2 0 
m m H g ( b ut still b el o w 1 0 0 m m H g).  
 C o nti n u e st u dy tr e at m e nt at t he c urr e nt 
d os e 
 A dj ust c urr e nt or i niti at e ne w 
a nti hyp ert e nsiv e m e dic ati o n  
 Titr at e a nti hyp ert e nsi ve m e dic ati o n(s)  
d uri n g t he n ext 2 w e eks as i n dic at e d t o 
ac hi ev e w el l-co ntr oll e d b B P  
 If B P is n ot w ell c o ntr oll e d withi n 2 
w e eks, c o nsi d er r eferr al t o a sp eci alist  
a n d g o t o sce n ari o ( B).  
( Sc e n ari o B) 
 
Asy m pto m atic S B P ≥1 6 0  m m H g,  or  D B P  ≥1 0 0  
m m H g,  
or  
 F ai lur e t o ac hiev e w el l-c o ntrolle d B P wit hi n 2 
we eks in Sc e n ari o A  
 I nt err u pt st u dy tr e at me nt if cli nic ally 
i n dicat e d. 
 A dj ust c urr e nt or i niti at e ne w 
a nti hyp ert e nsiv e m e dic ati o n(s) . 
 Titr at e a nti hyp ert e nsiv e m e dic ati o n(s)  
d uri n g t he n ext 2 w e eks as i n d ic at e d t o 
a chi ev e  w el l-co ntr oll e d B P 
 O nc e B P is w ell c o ntr oll ed b, r est art stu dy 
tr e at m e nt r e d u c e d b y o n e d os e l e v el 
 Sy m pt o mati c c hy pert e nsi o n  
or  
 P ersist ent S B P ≥16 0  m m H g,  or  D B P  ≥1 00  m m H g, 
d es pite a ntihy p erte nsiv e  m e dic ati o n a n d dos e 
r e d uctio n of st u dy tr e at m e nt 
 I nt err u pt st u dy tr e at me nt 
 A dj ust c urr e nt or i niti at e ne w 
a nti hyp ert e nsiv e m e dic ati o n(s)  
 Titr at e a nti hyp ert e nsiv e m e dic ati o n 
d uri n g t he n ext 2 w e eks as i n dic at e d t o 
ac hi ev e w el l-co ntr oll e d B P 
 R ef err al t o a s p eci alist for f urth er 
ev al u ati o n a n d f oll o w -up is 
r ec o m m e n d e d 
 O nc e B P is w ell c o ntr oll ed, r est art st u dy 
tr e at m e nt r e d u c e d b y o n e d os e l e v el 
Refr act ory hy p erte nsio n u nresp o nsiv e t o a b ove 
i nt erv enti o ns or hy p ert ensiv e crisis. 
 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 
 C o nti n u e f oll o w -u p  p er  prot oc ol.  
B P  = bl o o d pr ess ur e; D B P = di ast olic bl o o d pr ess ur e; m m H g = milli m etr es m erc ury; S B P = syst olic bl o o d pr ess ur e; 
a.  
Hy p ert e nsi o n d et ect e d i n t w o s e p ar at e r e a di n gs d uri n g u p  t o t hr e e c o ns ec utiv e visits 
b.  
W ell-c o ntr oll e d bl o o d pr ess ur e d efi n e d as  S B P ≤1 4 0  m m  H g  a n d  D B P ≤9 0  m m  H g  i n t w o s e p ar at e r e a di n gs 
d uri n g u p  t o t hr e e c o ns ec utiv e visits. 
c.  
Sy m pt o m atic hy p ert e nsi o n d efi n e d as  hy p ert e nsi o n a g g r av at e d by  sy m pt o ms ( e. g., h e a d ac h e, li g ht- h e a d e d n ess, 
v erti g o, ti n nit us, e pis o d es of  f ai nti n g) t h at r es olv e aft er  t h e bl o o d pr ess ur e is c o ntr oll e d wit hi n t h e n or m al r a n g e 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
4 9  
 
 
5. 8. 3. 3. G ui d eli n e s f or Pr ol o n g e d Q T c 
G ui deli nes f or d ose m o dificati o n a n d st o p pi n g crit eria d ue t o Q T c- pr ol o n gati o n are 
pr o vi de d i n Ta ble 8  
T a bl e 8 Wit h h ol di n g a n d St o p pi n g Crit eri a f or Q T c B- Pr ol o n g ati o n  
Q T c -Pr ol o n g ati o n a A cti o n a n d D o s e M o difi c ati o n  
 
Q Tc B  ≥5 0 1 
ms ec  
 
I nt err u pt all stu dy tre at m ents until Q Tc B pr ol o n g ati o n r es olv es t o gr a de 1 or 
b as eli n e  
 
T est s eru m p ot assi u m, c alci u m, p h os p h or us a n d m a g nesi u m. If a b nor m al 
c orr ect p er r o uti n e cli nic al pr actic e t o wit hi n n or m al li mits. 
 
R evi e w c o nc o mit a nt m e dic ation  us ag e f or a g e nts t h at pr ol o ng Q Tc.  
 
If ev e nt res olv es, r estart st udy tr e at m e nt at l o w er d os e  l evel or c urr e nt d os e l eve lb 
 
If ev e nt d o es n ot r es olv e, p er m a n e ntly disco nti n ue st udy tr eat m e nts. C o nsi d er 
ev al u ati o n with c ardi olo gist.  
 
If ev ent r ecurs, p er ma ne ntly disc o nti nu e st u dy tr e at me nts. C o nsi der 
ev al u ati o n wit h c ar di ol ogist.  
A b br evi ati o ns: ms ec = millis ec o n ds; Q Tc B = Q T  i nt erv al o n  el ectr oc ar di o gr a m c orr ect e d usi n g t h e B az ett’s  f or m ul a. 
a)  
B as e d o n  av er a g e Q Tc v al u e of  tri plic at e E C Gs. F or ex a m pl e, if a n  E C G d e m o nstr at es a pr ol o n g e d 
Q T  i nt erv al, o bt ai n t w o or  m or e E C Gs ov er a bri ef p eri o d, a n d  t h e n us e t h e av er a g e d Q Tc v al u es of  
t h e t hr e e E C Gs t o d et er mi n e if st u dy tr e at m e nts s h o ul d b e  i nt err u pt e d or disc o nti n u e d. 
b)  If t h e Q Tc pr ol o n g ati o n r es olv es t o gr a d e 1 or  b as eli n e, t h e s u bj ect m ay r es u m e st u dy tr e at m e nt if t h e 
i nv esti g at or a n d  N ov artis Gl o b al Cli nic al Le a d  a gr e e t h at t h e s u bj ect will  b e n efit fr o m f urt h er 
tr e at m e nt. 
Fre n c h O nl y Se e A p pe n di x 9 , f or Val v ular T o xicit y criteri a 
5. 8. 4.  
G ui d eli n e s f or S ki n-r el at e d A d v er s e E v e nt s o n t h e d a br af e ni b a n d 
tr a m eti ni b c o m bi n ati o n tr e at m e nt ar m 
C uta ne o us a d vers e e ve nts ha ve bee n o bser v e d i n s u bjects recei vi n g d a brafe ni b, 
tra meti ni b or b ot h t hera pies i n c o m bi nati o n (see t he I n vesti gat or Br oc h ures f or m ore 
i nf or mati o n); [ Gla x o S mit h Kli ne D oc u me nt N u m b er H M 2 0 0 9/ 0 0 1 5 1/ 0 2  2 0 1 1; 
Gla x o S mit h Kli ne D oc u me nt N u m ber C M 2 0 1 0/ 0 0 0 1 0/ 0 2  2 0 1 1 a n d Gla x o S mit h Kli ne 
D oc u me nt N u m ber 2 0 1 1 N 1 2 6 8 1 1 _ 0 0 . 2 0 1 2]. Rec o m me n dati o ns f or s u p p orti ve care a n d 
g ui deli nes f or d ose m o dificati o ns are pr o vi de d ( S ecti o n 5. 8. 4. 1 , Secti o n 5. 8. 4. 2  a n d 
Secti o n 5. 8. 4. 3 ). T he i nstit uti o nal sta n dar ds f or t he ma na ge m e nt of s ki n-relate d A Es ca n 
differ fr o m t hese g ui deli nes. I n t his case, b est cli nical j u d g me nt s h o ul d be a p plie d a n d a 
c o ns ultati o n wit h t he N o vartis Gl o bal Cli nical Lea d ma y b e re q uire d. I n a d diti o n, t he 
S p o ns or ma y re q uire bi o psies of a n y ne w s ki n lesi o ns es peciall y t h ose s us pici o us of 
c u S C C a n d kerat oaca nt h o mas ( K A) f or f urt h er st u d y.  
5. 8. 4. 1.  
R a s h 
Ras h is a fre q u e nt A E o bser ve d i n s u bjects recei vi n g tra m eti ni b, da brafe ni b, or t he 
c o m bi nati o n of b ot h t hera pies. G ui deli nes f or ras h ma na ge me nt are bas e d o n e x perie nce 
wit h ot her M E K i n hi bit ors a n d E G F R i n hi bit ors [ Bala g ula , 2 0 1 0; Lac o ut ur e , 2 0 1 1]. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
5 0  
 
 
T a bl e 9  
G ui d eli n e s f or S u p p orti v e C ar e of R a s h  
T y p e of Car e  
A cti o n  
Pr ev e nti on/ Pr o p hyl axis  St art 
fr o m D ay 1a 
 
Av oi d u nn ec ess ary exp os ure to s u nli g ht  
 
A p ply br oa d -s pectr u m s u nscr ee n (c o ntai nin g tit ani u m dioxi de or 
zi nc oxi de) wit h a ski n pr otectio n f act or ( S P F) ≥1 5 at l east t wic e 
d aily. 
 
Us e t hick, alc o h o l-fre e e molli ent cr e a m ( e. g., glyc eri ne a n d 
c et o m acr o g ol cr ea m) o n dry ar e as of th e b o dy at l e ast t wic e 
d aily. 
Pr ev e nti on/ Pr o p hyl axis  
St art fr o m D ay  2 9  a n d 
i m pl e m e nt for a t otal of 6 
we eks  
 
T o pic al st eroi ds a n d anti bi otics s h o ul d b e a p pli e d at l e ast t wic e 
d aily st arti n g o n D ay 2 9 of st udy tr e at m e nt, to b o dy ar e as s uc h 
as f ace,  c hest, an d u p per b ack. 
o  Us e mild -str e ngt h t o pic al st eroi d  ( hy droc ortis o ne 1%  
cr e a m) 
or  
o  T o pic al a nti bi otic ( e.g., cli n d a mycin) or or al a nti bi otics 
( e. g., d oxycycli n e 10 0 m g BI D, mi n ocycli n e 1 0 0 mg BI D) 
Sy m pt o matic C ar e  
 
Pr uritic l esio ns: c o ol c o m pr esses a n d or al anti hist a mi n e   
t h er a pi es 
 
Fiss uri n g lesio ns: M o ns el’s s oluti o n, silv er nitr at e, or zinc 
oxi d e cr e a m  
 
D es q u a m ati o n: t hick e m olli e nts a n d mil d s o a p  
 
P ar o nyc hi a: a ntis eptic b at h, l oc al p ote nt corticost er oi ds i n 
a d diti on t o oral a nti bi otics; if no i m pr ov e m ent, co ns ult 
d er m at ol o gist or  sur g e o n 
 
I nf ect e d l esi o ns: a p pr opri at e b a ct eri al/fu n g al c ult ur e-driv e n 
syst e mic or t o pic al a ntibi otics 
BI D = t wic e d aily; S P F  = ski n pr ot ecti o n f act or 
a.  
S u bj ects w h o d ev el o p r as h/ski n t oxiciti es s h o ul d b e  s e e n by  a q u alifi e d p hysici a n a n d  s h o ul d r ec eiv e ev al u ati o n f or 
sy m pt o m atic/s u p p ortiv e c ar e m a n a g e m e nt

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
5 1  
 
 
G ui deli nes f or ma na ge m e nt a n d d ose a dj ust me nt f or ras h c o nsi dere d t o be relate d t o 
st u d y tr eat me nt are pr o vi de d i n Ta ble 1 0  
T a bl e 1 0  
M a n a g e m e nt a n d D o s e M o difi c ati o n G ui d eli n e s f or R a s h  
C T C A E  
Gr a d e  
A d v er s e E v e nt M a na g e m e nt  
A cti o n a n d D o s e M o difi c ati o n  
Gr a d e 1  
 
I niti at e pr o p hyl actic a n d 
sy m pto m atic tr eat m e nt m e as ur es
 
Us e m o d erat e stre n gt h to pic al 
st er oi d a 
 
R e ass ess after 2 we eks  
 
C o nti n u e st u dy tr e at m e nt 
 
If r as h do es not r ecov er t o b aseli n e 
wit hi n 2 w e eks  des pit e b est 
s u p p ortiv e c ar e, r e d u ce st u dy 
tr e at m e nt b y o n e d o s e l ev elb  
Gr a d e 2  
 
I niti at e pr o p hyl actic a n d 
sy m pto m atic tr eat m e nt m e as ur es 
 
Us e m o d erat e stre n gt h to pic al 
st er oi d a 
 
R e ass ess after 2 w e eks  
 
R e d u c e st u d y tr e at me nt b y o n e 
d o s e l e v el  
o  If r as h r ec ov ers t o ≤gr ad e 1 
wit hi n 2  w e eks, i ncr eas e dos e t o 
pr evi o us d os e lev el  
o  If n o r ec ov ery t o ≤gr ad e 1 
wit hi n 2  w e eks, i nt err u pt st udy 
tr e at m e nt u ntil r ec ov ery t o ≤gra d e  
1  
 
R e st art st u d y tr e at m e nt at r e d u c e d 
d o s e l e v el b  
Gr a d e  ≥3 
 
Us e m o d erat e stre n gt h  t o pic al 
st er oi ds a P L U S or al m et hy l- 
pr e d nisol o ne d ose p ack  
 
C o ns ult der m at ol o gist  
 
I nt err u pt st u dy tr e at me nt u ntil r as h 
r ec ov ers t o gra d e ≤1  
 
R e st art b  wit h st u d y tr e at m e nt 
r e d u c e d b y o n e d o s e l ev el c 
 
If n o r ecov ery t o gr ad e ≤2 wit hi n 4 
w e ek 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  
C T C A E = C o m m o n T er mi n ol o gy Crit eri a f or A dv ers e Ev e nts 
a.  
M o d er at e-str e n gt h t o pic al st er oi ds: hy dr oc ortis o n e 2. 5 % cr e a m or  fl utic as o n e pri o pri o n at e 0. 5 % cr e a m. 
b.  
A p pr ov al of  N ov artis Gl o b al Cli nic al Le a d  is r e q uir e d t o r est art st u dy tr e at m e nt aft er  > 2 1 d ays of  
i nt err u pti o n. 
c. 
Esc al ati o n of  st u dy tr e at m e nt t o pr evi o us d os e l ev el m ay b e  c o nsi d er e d if n o  r as h is evi d e nt 4 w e eks aft er r est arti n g 
st u dy tr e at m e nt 
5. 8. 4. 2.  
G ui d eli n e s f or H a n d-f o ot S ki n R e a cti o n s ( H F S R) 
E pis o des of Ha n d-f o ot S ki n Reacti o n ( H F S R) ha v e bee n o bser ve d i n s u bjects recei vi n g 
da brafe ni b a n d ot her c o m bi nati o n st u dies of da brafe ni b a n d tra meti ni b. G ui deli nes f or 
ma na ge me nt of H F S R are base d o n e x perie n ce wit h ot her ki nase i n hi bit ors [ Lac o ut ure , 
2 0 0 8; Mc Lella n , 2 0 1 1]. 
Meas ures f or P P E S s h o ul d i ncl u de: 
 
Lif est yle m o dificati o n:  a v oi da nce of h ot wat er, tra u matic acti vit y, c o nstricti ve 
f o ot wear, or e x cessi ve fricti o n o n t he s ki n a n d t he use of t hic k c ott o n s oc ks a n d 
gl o ves, a n d s h oes wit h p a d de d i ns oles 
 
S y m pt o matic treat me nts:  a p pl y m oist urizi n g crea ms fre q ue ntl y, t o pical kerat ol ytics 
(e. g. urea 2 0- 4 0 % crea m, salic ylic aci d 6 %, tazar ote ne 0. 1 % crea m, fl u or o uracil 5 % 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
5 2  
 
 
crea m), cl o betas ol pr o pi o nate 0. 0 5 % oi n t me nt f or er yt h e mat o us areas, t o pical 
li d ocai ne 2 %, a n d / or s yste mic pai n me dicati o n s uc h as n o nster oi dal a nti-
i nfla m mat or y dr u gs, c o dei ne, a n d pre ga bali n f or pai n. 
 
D ose m o dificati o n ma y als o be re q uire d. 
5. 8. 4. 3.  
G ui d eli n e s f or c u S C C a n d tr e at m e nt e m er g e nt m el a n o m a s 
C ut a ne o us s q u a m o us cell c arci n o m as a n d kerat oaca nt h o mas ( K A) ha ve bee n o bser ve d i n 
s u bjects treate d wit h da brafe ni b a n d t he c o m bi nati o n of da brafe ni b a n d tra meti ni b (see 
da brafe ni b a n d tra m eti ni b c o m bi nati o n I B); [ Gla x o S mit h Kli ne D oc u me nt N u m ber  
2 0 1 1 N 1 2 6 8 1 1 _ 0 0 . 2 0 1 2]. T hese treat me nt-relate d c u S C C s h o ul d be s ur gicall y re m o ve d 
acc or di n g t o i nstit uti o nal practice.  D ose m o dificati o ns or i nterr u pti o ns of t he st u d y tr eat me nt 
are n ot r e q uire d f or c u S C C.  Occ urre nce o f c u S C C m ust be re p orte d as a n S A E. Pat h ol o g y 
re p ort s h o ul d be place d i n s u bject c hart. 
Ne w Pri m a r y Mel a n o m a : Ne w pri mar y mela n o mas ha ve bee n re p orte d i n patie nts treate d 
wit h da brafe ni b. T hese w ere i de ntifie d pri maril y wit hi n t he first 5 m o nt hs of t hera p y a n d 
di d n ot re q uire treat me nt m o dificati o n ot her t ha n e x cisi o n. M o nit ori n g f or s ki n lesi o ns 
s h o ul d occ ur as d escri be d f or c u S C C. 
Ne w pri mar y ca ncers a n d treat me nt-e mer ge nt mali g na n cies, wit h t he e x ce pti o n of basal cell 
carci n o ma ( B C C) s h o ul d be re p ort e d as a S A E.  B C C s h o ul d be re p orte d as a n A E or S A E 
base d o n t he discreti o n of t he i n vesti gat or. A bi o ps y of t he ne w m ali g n a nc y s h o ul d be ta ke n, 
w here p ossi ble, a n d res ults s u b mitte d t o N o vartis f or f urt her a nal ys es.  Testi n g of t hes e 
bi o psies ma y i n cl u de R A S m ut ati o n testi n g a n d a n al ysis of pr ot ei ns relate d t o t he acti o n of 
da brafe ni b.  Ge n o mic alterati o ns, w hic h i ncl u de b ut n ot li mite d t o D N A, R N A a n d pr otei n 
a nal ysis of t hese bi o ps y s peci me ns ma y be p erf or me d, a n d w o ul d be restricte d t o t he a nal ysis 
of  pat h wa y m utati o ns k n o w n t o be ass ociate d wit h, a n d rele va nt t o, B R A F- m uta nt t u m ors or 
pat h wa y acti vati o n. 
E val uate f or s y m pt o ms or cli nical si g ns of n o n-c ut a ne o us, ne w pri mar y/rec urre nt 
mali g na n cies bef ore i nitiati o n of treat m e nt, peri o dicall y d uri n g tr eat me nt, or as cli nicall y 
i n dicate d. F oll o wi n g disc o nti n uati o n of st u d y treat me nt, m o nit ori n g f or n o n-c uta ne o us 
sec o n dar y/r ec urre nt mali g na n cies s h o ul d c o nti n ue f or u p t o 6 m o nt hs or u ntil i nitiati o n 
of a n ot her a nti- ne o plastic t hera p y. A b n or mal fi n di n gs s h o ul d be ma n a ge d acc or di n g t o 
cli nical practices. 
5. 8. 5. G ui d eli n e s f or Ot h er A d v er s e E v e nt s of S p e ci al I nt er e st o n t h e d a br af e ni b 
a n d tr a m eti ni b c o m bi n ati o n tr e at m e nt ar m  
5. 8. 5. 1.  
G ui d eli n e s f or P yr e xi a 
E pis o des of p yre xia ha ve bee n o bser ve d i n s u bjects recei vi n g da brafe ni b m o n ot hera p y, a n d is 
i ncreas e d i n i nci de nce a n d se verit y i n s u bjects recei vi n g da brafe ni b i n c o m bi nati o n wit h 
tra meti ni b (see da brafe ni b a n d da brafe ni b a n d tra meti ni b c o m bi nati o n I Bs); 
[ Gla x o S mit h Kli ne D oc u me nt N u m ber C M 2 0 1 0/ 0 0 0 1 0/ 0 2  2 0 1 1 a n d Gla x o S mit h Kli ne 
D oc u me nt N u m ber 2 0 1 1 N 1 2 6 8 1 1 _ 0 0 . 2 0 1 2]. I n a mi n orit y of cases t he p yr e xia was 
acc o m pa ni e d b y s y m pt o ms s uc h as se vere c hills, de h y drati o n,  h y p ote nsi o n, dizzi ness or 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
5 3  
 
 
wea k ness. 
S u bjects s h o ul d be i nstr ucte d o n t he i m p orta nce of i m me diatel y re p orti n g fe brile e pis o des.  
I n t he e ve nt of a fe v er, t h e s u bject s h o ul d be i nstr ucte d t o ta ke a nti- p yretics (e. g. i b u pr ofe n 
or acet a mi n o p he n/ paraceta m ol) as a p pr o priate t o c o ntr ol fe ver.  T h e use of oral 
c ortic oster oi ds s h o ul d be c o nsi dere d i n t h ose i nsta nces i n w hic h a nti- p yreti cs are 
i ns ufficie nt.  M o nit or ser u m creati ni ne a n d ot h er e vi de nce of re nal f u n cti o n d uri n g a n d 
f oll o wi n g se vere e ve nts of p yre xia (see Secti o n 5. 8. 5. 3 ). 
G ui deli nes re gar di n g m a na ge me nt a n d d ose m o dificati o ns f or p yre xia c o nsi dere d t o be 
relate d t o st u d y tr eat me nt are pr o vi d e d i n Ta ble 1 1  
T a bl e 1 1  
M a n a g e m e nt a n d D o s e M o difi c ati o n G ui d eli n e s f or P yr e xi a a, b  
A d v er s e  
E v e nt  
A d v er s e E ve nt M a n a g e me nt  
A cti o n a n d D o s e M o difi c ati o n  
Pyr exi a a 
All  Ev e nt s b: 
 
Cli nic al eval u ati o n f or i nf ecti on 
a n d hy pers e nsitivit y c 
 
L a b or at ory w or k-u p c 
 
Hy dr ati o n as r e quir e d d 
1 st Ev e nt b: 
 
A d mi nist er a nt i-pyr etic tre at m ent as 
cli nic ally in dic at e d a n d initi at e 
pr o p hylactic tr e at m e nt if ass oci at e d 
wit h ri g ors, r e n al f ail ur e, d ehydr ati o n 
or hy p ote nsio n e 
 
 
 
 
2 nd Ev e nt f 
 
Wit hi n 3 d ays of ons et of pyr exi a  
o  O pti miz e a nt i-pyretic  t h era py 
o  C o nsi d er oral corticost er o ids  (i. e., 
pr e d niso n e 10 m g) for at l east 5 
d ays or as cli nic ally i n dic at e d f 
 
 
 
 
 
 
1 st Ev e nt:  
 
I nt err u pt d a br af e ni b 
 
C o nti n u e tr a m etini b  
 
O nc e pyr exi a r es olv es to b aseli n e, r est art 
d a br af e ni b at t he s a m e d os e lev el  
o  If f ev er was ass oci at e d wit h ri g ors, 
r e n al f ail ur e, d e hydr ati on or 
hy p ot e nsi on, r e d u c e da br af e ni b b y 
o n e d o s e l ev el g  
2 n d Ev e nt:  
 
I nt err u pt d a br af e ni b 
 
C o nti n u e tr a m etini b  
 
O nc e pyr exi a r es olv es to b aseli n e, r est art 
d a br af e ni b at t he s a m e d os e lev el  
o  If f ev er was ass oci at e d wit h ri g ors, 
r e n al f ail ur e, d e hydr ati on or 
hy p ot e nsi on, r e d u c e da br af e ni b b y 
o n e d o s e l ev el g 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
5 4  
 
 
A d v er s e  
E v e nt  
A d v er s e E ve nt M a n a g e me nt  
A cti o n a n d D o s e M o difi c ati o n  
 
S u bs e q u ent  Ev e nt s: 
 
Wit hi n 3 d ays of ons et of pyr exi a:  
o  O pti miz e or al  c ortic ost eroid 
d os e as cli nic ally i ndicat e d f or 
r ec alcitr a nt pyr exi af 
o  
If c ortic ost er oi ds h av e be en 
t a p er e d a n d pyr exi a r ec urs, 
r est art st er oi ds 
o  If c ortic oster oi ds c a nn ot be 
t a p er e d c o nsult Gl o b al 
Cli nic al L e ad 
S u bs e q u ent  Ev e nts:  
 
I nt err u pt d a br af e ni b 
 
C o nti n u e tr a m etini b  
 
O nc e pyr exi a r es olv es to b aseli n e, r est art 
d a br af e ni b  r e d u c e d b y o n e d o s e l e v elg  
 
If d a br af eni b must be r e d uc e d t o < 7 5m g 
BI D, p er m a n e ntly  dis c o nti n ue   
d a br af e ni b. Tra m eti ni b m a y b e 
c o nti n u e d . 
a.  
Pyr exi a is d efi n e d as  a b o dy  t e m p er at ur e e q u al  t o or  a b ov e 3 8. 5  C elsi us or  1 0 1. 3º F a hr e n h eit. 
b.  
F or s u bj ects ex p eri e nci n g pyr exi a c o m plic at e d by  ri g ors, s ev er e c hills, etc., a cli nic al ev al u ati o n a n d l a b or at ory 
w ork- u p  is m a n d at ory f or e ac h ev e nt; a nti - pyr etic tr e at m e nt s h o ul d b e  st art e d i m m e di at ely at  t h e first occ urr e nc e 
a n d  pr o p hyl actic a nt i- pyr etic tr e at m e nt is r ec o m m e n d e d 
c. 
T h or o u g h cli nic al ex a mi n ati o n f or si g ns a n d  sy m pt o ms of  i nf ecti o n or  hy p ers e nsitivity is r e q uir e d; l a b or at ory w ork-u p  
s h o ul d i ncl u d e f ull- bl o o d-c o u nt, el ectr olyt es, cr e ati ni n e, bl o o d ur e a nitr o g e n ( B U N), C-r e activ e pr ot ei n ( C R P), liv er-
f u ncti o n t ests, bl o o d c ult ur e, a n d  uri n e c ult ur e. 
d.  
Or al hy dr ati o n s h o ul d b e  e nc o ur a g e d i n s u bj ects wit h o ut evi d e nc e of  d e hy dr ati o n. I ntr av e n o us hy dr ati o n is 
r ec o m m e n d e d i n s u bj ects ex p eri e nci n g pyr exi a c o m plic at e d by  d e hy dr ati o n/ hy p ot e nsi o n. 
e.  
A nti- pyr etic tr e at m e nt m ay i ncl u d e ac et a mi n o p h e n, i b u pr of e n, or  s uit a bl e a nt i- pyr etic m e dic ati o n acc or di n g t o 
i nstit uti o n al st a n d ar ds. Pr o p hyl actic a nti - pyr etic tr e at m e nt m ay b e  disc o nti n u e d aft er  t hr e e d ays i n t h e a bs e nc e of  
pyr exi a. 
f. 
I n s u bj ect ex p eri e nci n g pyr exi a c o m plic at e d by  ri g ors, s ev er e c hills, etc., w hic h c a n n ot b e  c o ntr oll e d wit h a nt i- pyr etic 
m e dic ati o n, or al c ortic ost er oi ds s h o ul d b e  st art e d at  t h e 2 n d  ev e nt a n d  d os es s h o ul d b e  gr a d u ally i ncr e as e d f or 
s u bs e q u e nt ev e nts. 
g.  
D a br af e ni b s h o ul d b e  r e d uc e d by  o n e  d os e l ev el aft er  t hr e e e pis o d es of  pyr exi a c o m plic at e d by  ri g ors, s ev er e c hills, etc., 
w hic h c a n n ot b e  m a n a g e d by  b est s u p p ortiv e c ar e a n d  i ncr e asi n g d os es of  or al st er oi ds. Esc al ati o n of  d a br af e ni b is 
all o w e d if n o  e pis o d e of  pyr exi a is o bs erv e d i n t h e 4 w e eks s u bs e q u e nt t o d os e r e d ucti o n. 
5. 8. 5. 2.  
G ui d eli n e s f or Di arr h e a 
E pis o des of diarr h ea ha v e occ urre d i n s u bjects r ecei vi n g da brafe ni b, tra meti ni b, or b ot h 
t hera pies i n c o m bi nati o n. Ot her, fre q ue nt ca uses f or diarr hea i ncl u di n g c o n c o mita nt 
me dicati o ns (e. g., st o ol s ofte ners, la x ati ves, a ntaci ds, etc.), i nfecti o ns b y C.  difficile or ot her 
pat h o ge ns, partial b o wel o bstr ucti o n, etc., s h o ul d be cli nicall y e x cl u de d. 
G ui deli nes re gar di n g m a na ge me nt a n d d ose re d u cti o n f or diarr hea c o nsi dere d t o be 
relate d t o st u d y tr eat me nt b y t he i n vesti gat or are pr o vi de d i n Ta ble 1 2 . 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
5 5  
 
 
T a bl e 1 2  
M a n a g e m e nt a n d D o s e M o difi c ati o n G ui d eli n e s f or Di arr h e a  
C T C A E  Gra d e  
A d v ers e  E v e nt  M a n a g e m e nt  
A cti o n  a n d  D o s e  M o difi c ati o n  
U nc o m plic at e d  
Di arr h e a a  
Gr a d e  1 or 2  
 
Di et:  st o p all  l act os e c o nt ai ni n g pr o d ucts; e at  s m all 
m e als,  B R A T -di et  ( b a n a n a, ric e, a p pl es,  t o ast) 
r ec o m m e n d e d. 
 
Hy dr ati o n:  8 -1 0  l ar g e gl ass es  of  cl e ar li q ui ds p er  d ay  
( e. g., G at or a d e  or br ot h) . 
 
L o p er a mi d e c: i niti ally 4  m g,  f oll o w e d by 2  m g  ev ery  
f o ur h o urs  or  aft er ev ery  u nf or m ed  st o ol; m axi m u m  1 6 
m g/ d ay.  C o nti n u e  u ntil  di arr h e a  fr e e f or 1 2  h o urs . 
 
Di arr h e a   2 4 h:  l o p er a mi d e 2 m g ev ery  t w o h o urs;  
m axi m u m  1 6 m g/ d ay.  C o nsi d er  a d di n g  or al 
a nti bi otics . 
 
Di arr h e a   4 8 h:  l o p er a mi d e 2  m g ev ery  t w o h o urs;  
m axi m u m  1 6 m g/ d ay.  A d d  b u d es o ni d e  or  ot h er 
s ec o nd -li n e t h er a pi es ( otr e oti d e, or ti nct ur e  of  o pi u m)  
a n d  or al  a nti bi otics . 
 
C o nti n u e  st u dy tr e at m e nt. 
 
If di arr h e a  is gr a d e  2  for  4 8 h,  
i nt err u pt st u dy tr e at m e nt 
u ntil  di arr h e a  r es olv es t o 
gr a d e  ≤1 . 
 
R est art  st u dy tr e at m e nt at  
t h e s a m e d os e  l ev el 
U nc o m plic at e d  
Di arr h e a a  
Gr a d e  3 or 4  A ny  
C o m plic at e d  
Di arr h e a b  
 
Cli nic al  ev al u ati o n  m a n d at ory . 
 
L o p er a mi d e c: i niti ally 4  m g,  f oll o w e d by 2  m g  ev ery  
f o ur h o urs  or  aft er  ev ery  u nf or m ed  st o ol; m axi m u m  
1 6  m g/ d ay.  C o nti n u e  u ntil  di arr h e a  fr e e f or 1 2  h o urs  
 
Or al  a nti bi otics  a n d  s ec o nd -li n e t h er a pi es if cli nic ally 
i n dic at e d. 
 
Hy dr ati o n:  i ntr av e n o us fl ui ds if cli nic ally i n dic at e d. 
 
A nti bi otics  ( or al or  i ntr av e n o us) if cli nic ally i n dic at e d. 
 
I nt erv e nti o n s h o ul d b e  c o nti n u e d u ntil t h e  s u bj ect is 
di arr h e a  fr e e f or ≥ 2 4  h o urs . 
 
I nt erv e nti o n m ay  r e q uir e h os pit aliz ati o n  f or s u bj ects 
at  risk of lif e -t hr e at e ni n g c o m plic ati o ns 
 
I nt err u pt st u dy tr e at m e nt 
u ntil di arr h e a  r es olv es t o 
gr a d e  ≤1 . 
 
R est art  wit h  st u dy 
tr e at m e nt r e d uc e d by  
o n e  d os e  l ev eld . 
 
If 3  d os e  r e d ucti o ns of  st u dy 
tr e at m e nt ar e  cli nic ally 
i n dic at e d, p er m a n e ntl y  
di s c o nti n u e  st u d y  
tre at m e nt. 
C T C A E = C o m m o n T er mi n ol o gy Crit eri a f or Adv ers e Ev e nts 
a.  
U n c o m pli c at e d di arr h e a d efi n e d by  t h e a bs e nc e of  sy m pt o ms s uc h as, cr a m pi n g, n a us e a/v o miti n g ≥gr a d e  2, 
d ecr e as e d p erf or m a nc e st at us, pyr exi a, s e psis, n e utr o p e ni a gr a d e ≥3,  fr a nk bl e e di n g, a n d/ or  d e hy dr ati o n r e q uiri n g 
i ntr av e n o us fl ui d s u bstit uti o n 
b.  
C o m pli c at e d di arr h e a d efi n e d by  t h e pr es e nc e of  sy m pt o ms s uc h as, cr a m pi n g, n a us e a/v o miti n g ≥gr a d e 2,  d ecr e as e d  
p erf or m a nc e st at us, pyr exi a, s e psis, n e utr o p e ni a gr a d e ≥3,  fr a nk bl e e di n g, a n d/ or  d e hy dr ati o n r e q uiri n g i ntr av e n o us fl ui d 
s u bstit uti o n 
c. 
L o p er a mi d e s h o ul d b e  m a d e av ail a bl e pri or t o st art of  st u dy tr e at m e nt s o l o p er a mi d e a d mi nistr ati o n c a n b e gi n at t h e  
first si g ns of  di arr h e a 
d.  
Esc al ati o n of  st u dy tr e at m e nt t o pr evi o us d os e l ev el is all o w e d aft er  c o ns ult ati o n wit h t h e Gl o b al Cli nic al Le a d  a n d  i n t h e 
a bs e nc e of  a n ot h er  e pis o d e of  c o m plic at e d or  s ev er e di arr h e a i n t h e 4 w e eks s u bs e q u e nt t o d os e r e d ucti o n 
5. 8. 5. 3.  
G ui d eli n e s f or R e n al I n s uffi ci e n c y 
Cases of re n al i ns ufficie n c y h a ve occ urre d i n s u bjects recei vi n g d a brafe ni b a n d t he 
c o m bi nati o n of da brafe ni b a n d tra meti ni b. Pri or t o start of st u d y tr eat me nt, c o nc o mita nt 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
5 6  
 
 
me dicati o ns s h o ul d be re vie we d f or t h e p ote ntial ris k of i n d uci n g ne p hr ot o xicit y a n d 
c o nc o mita nt me dicati o ns s h o ul d be m o difie d if cli nicall y p ossi ble. 
G ui deli nes re gar di n g m a na ge me nt a n d d ose re d u cti o n f or re nal i ns uffi cie nc y c o nsi dere d 
t o be relate d t o st u d y treat me nt b y  t he i n vesti gat or are pr o vi d e d i n Ta ble 1 3.  
T a bl e 1 3  
M a n a g e m e nt a n d D o s e M o difi c ati o n G ui d eli n e s f or R e n al  I n s uffi ci e n c y 
S er u m 
Cr e ati ni n e L e v el  
A d v er s e E v e nt M a na g e m e nt  
A cti o n a n d D o s e 
M o difi c ati o n  
S er u m cr e ati nin e 
i ncr e as e > 0.2 
m g/ d L  ( 1 8 u m ol/ L) 
b ut 0. 5 mg/ d L 
( 4 4 u m ol/ L) a b ov e 
b as eli n e  
 
R ec h eck s er u m cr eati ni n e withi n  1 w e ek 
 
S er u m cr e ati nin e i ncr e ase > 1 w e ek: c ont act 
N ov artis  Gl ob al Cli nic al L ea d .  If el evati o n p ersists 
b ey o n d 4 w e eks, r ec o m m e n d ev al u ati o n (c o nsi d er 
r e n al bio psy) f or eti ol ogy; c o nsi d er n e phr ol o gy 
c o ns ult atio n.
 
If pyr exi a is pr es e nt, tre at pyr exi a as p er gui d eli n es a. 
 
C o nti n u e st u dy 
tr e at m e nt at t h e 
s a m e dos e l ev el. 
S er u m cr e ati nin e 
i ncr e as e > 0.5 
m g/ d L ( 44 u m ol/ L) 
a b ov e bas eli n e or  
s er u m cr e atini n e 
> 2 m g/ d L ( > 1 7 7 
u m ol/ L) 
 
M o nit or s er u m cr e ati nin e ≥ 2 - ti m es p er w e ek. 
 
H os pit aliz ati o n m ay be n ec essary  if s eru m 
cr e ati ni n e c a n n ot b e mo nit or ed fr e q u e ntly. 
 
If pyr exi a is pr es e nt, tre at pyr exi a p er g ui deli nes a. 
 
C o ns ult ne p hr olo gist if cli nic ally i n dic at ed . 
 
P erf or m r e n al bi opsy if cli nic ally i n dic at ed, f or 
ex a m pl e:  
o  
R e n al i ns uffici e ncy persists d es pit e v ol u m e 
r e pl eti on. 
o  S u bj ect h as ne w r as h or si gns of 
hy p erse nsitivity (s uc h as el ev at e d e osi n o p hil 
c o u nt) 
 
I nt err u pt st u dy 
tr e at m e nt u ntil 
s er u m cr e atini n e 
r ec ov ers t o 
b as eli n e . 
 
R est art wit h 
st u dy 
tr e at m e ntb  
N S AI D S = n o n-st er oi d al a nti -i nfl a m m at ory dr u gs 
a.  N S AI Ds c a n i n d uc e r e n al i ns uffici e ncy, es p eci ally i n s u bj ects wit h d e hy dr ati o n; e nc o ur a g e or al fl ui ds or 
c o nsi d er i ntr av e n o us fl ui ds as  cli nic ally i n dic at e d. Se e g ui d eli n es f or pyr exi a Secti o n 5. 8. 5. 1.  
b.  I nv esti g at or m ay r est art at  eit h er th e s a m e or  a r e d uc e d d os e l ev el. Esc al ati o n of  st u dy tr e at m e nt t o pr evi o us d os e 
l ev el is all o w e d if a n ot h er  e pis o d e of  r e n al i ns uffici e ncy d o es  n ot occ ur aft er  4 w e eks of  d os e r e d ucti o n. 
C o ns ult ati o n wit h N ov artis Global Clinical L e a d  is r e q uir e d b ef or e r est arti n g st u dy tr e at m e nt if t h er e is evi d e nc e of  
t hr o m b otic micr o a n gi o p at hy. 
5. 8. 5. 4.  
G ui d eli n e s f or Vi s u al C h a n g e s 
E pis o des of vis ual c ha n ges ha ve bee n o bser ve d i n s u bjects recei vi n g tr a meti ni b, da brafe ni b, 
a n d c o m bi nati o n t hera p y.  A n o p ht hal m ol o gist s h o ul d be c o ns ulte d if c ha n ges i n visi o n 
de vel o p [ Refer t o Secti o n 7. 4. 5 ].  H o we ver, if t he vis ual c ha n ges are cl earl y u nrelate d t o st u dy 
treat me nt (e. g., aller gic c o nj u ncti vitis), t he n m o nit or cl osel y as it ma y be reas o na ble t o defer 
o p ht hal mic e x a mi nati o n. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
5 7  
 
 
Treat me nt wit h da brafe ni b has bee n ass o ciate d wit h t he de vel o p me nt of u veitis, i ncl u di n g 
iritis. M o nit or patie nts f or vis ual si g ns a n d s y m pt o ms (s uc h as, c ha n ge i n visi o n, p h ot o p h o bia 
a n d e ye pai n) d uri n g t hera p y. S peci al atte nti o n s h o ul d be gi ve n t o reti nal fi n di n gs [ e. g., reti nal 
pi g me nt e pit helial deta c h me nt ( R P E D) or reti n o vasc ular a b n or m alities (i.e., bra nc h or ce ntr al 
reti nal vei n occl usi o ns ( R V O)].  F or e ve nts of vis ual c ha n ges (re gar dless of se verit y) f or 
w hic h a n o p ht hal mic e x a mi nati o n is c o n d ucte d, a bl o o d sa m ple f or P K a nal ysis m ust be 
dra w n as cl ose as p ossi bl e t o t he ti me of t he e ve nt. 
G ui deli nes re gar di n g m a na ge me nt a n d d ose re d u cti o n f or vis ual c ha n ges a n d/ or o p ht hal mic 
e x a mi nati o n fi n di n gs c o nsi dere d t o be relate d t o st u d y tr eat me nt are pr o vi d e d i n Ta ble 1 4.  
T a bl e 1 4  
M a n a g e m e nt a n d D o s e M o difi c ati o n G ui d eli n e s f or Vi s u al C h a n g e s a n d/ or 
O p ht h al mi c E x a mi n ati o n Fi n di n g s  
C T C A E  
Gr a d e a  
A d v ers e  E v e nt  M a n a g e m e nt  
A cti o n  a n d  D o s e  M o difi c ati o n  
Gr a d e  1 b c  
C o ns ult  o p ht h al m ol o gist  wit hi n  
7  d ays  of o ns et  
 
If dil at e d  f u n d us ex a mi n ati o n  c a n n ot b e  p erf or m e d  wit hi n  7  d ays  of  
o ns et,  i nt err u pt tr a m eti ni b u ntil  R P E D  a n d  R V O  c a n b e  excl u d e d  by  
r eti n a s p eci alist/o p ht h al m ol o gist. If s u bj ect is r ec eivi n g 
tr a m eti ni b/ d a br af e ni b c o m bi n ati o n t h er a py d a br af e ni b  m ay  b e  
c o nti n u e d. 
 
If R P E D  a n d  R V O  excl u d e d,  c o nti n u e ( or r est art) tr a m eti ni b at  s a me 
d os e  l ev el. 
 
If R P E D  s us p ect e d or  di a g n os e d:  s e e R P E D  
d os e  m o dific ati o n  T a bl e 1 5  b el o w;  re p ort a s S A E  if di a g n o s e d.  
 
If R V O  di a g n os e d : Per m a n e ntl y  di s c o nti n u e tra m eti ni b  a n d  re p ort a s  
S A E.  
Gr a d e  2 c 
a n d  
Gr a d e  3 c 
 
C o ns ult  
o p ht h al m ol o gist  
i m m e di at ely
 
I nt err u pt tr a m eti ni b. If s u bj ect is 
r ec eivi n g tr a m eti ni b/ d a br af e ni b 
c o m bi n ati o n t h er a py d a br af e ni b 
m ay  b e  c o nti n u e d. 
 
If R P E D  a n d  R V O  excl u d e d,  r est art tr a m eti ni b at  s a m e d os e  l ev el. 
 
If R P E D  di a g n os e d , s e e R P E D  d os e m o dific ati o n  T a bl e 1 5  b el o w;  r e p ort 
a s S A E.  
 
If R V O  di a g n os e d:  P er m a n e ntl y di s c o nti n u e  tra m eti ni b a n d  re p ort a s  
S A E . 
Gr a d e  4 c 
 
C o ns ult  o p ht h al m ol o gist  
i m m e di at ely
 
I nt err u pt tr a m eti ni b. If s u bj ect is 
r ec eivi n g tr a m eti ni b/ d a br af e ni b 
c o m bi n ati o n t h er a py d a br af e ni b 
m ay  b e  c o nti n u e d. 
 
If R P E D  a n d  R V O  excl u d e d,  m ay  c o nsi d er r est arti n g tr a m eti ni b at  s a m e 
or  r e d uc e d d os e aft er  disc ussi o n  wit h  st u dy m e dic al  m o nit or 
 
If R V O or  R P E D  di a g n o s e d,  p er m a n e ntl y di s c o nti n u e  tra m eti ni b a n d  
re p ort a s  S A E.  
A b br evi ati o ns: R P E D = r eti n al pi g m e nt e pit h eli al d et ac h m e nt; C T C A E = C o m m o n T er mi n ol o gy Crit eri a f or Adv ers e Ev e nts; 
R V O = r eti n al v ei n occl usi o n; S A E = s eri o us a dv ers e ev e nt 
a)  
R ef ers t o C T C A E V ersi o n 4. 0  ‘ Ey e dis or d ers –  Ot h er, s p ecify’ 
b)  If vis u al c h a n g es ar e cl e arly u nr el at e d t o st u dy tr e at m e nt ( e. g., all er gic c o nj u nctivitis), m o nit or cl os ely b ut 
o p ht h al mic ex a mi n ati o n is n ot  r e q uir e d. 
c)  
Bl o o d s a m pl e f or P K  a n alysis s h o ul d b e  dr a w n as  cl os e as  p ossi bl e t o t h e ti m e of  t h e ev e nt. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
5 8  
 
 
T a bl e 1 5  
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 tr a m eti ni b f or r eti n al pi g m e nt 
e pit h eli al d et a c h m e nt s ( R P E D) a  
C T C A E Gr a d e  
Acti o n a n d D ose M o dific ati o n  
Gr a d e  1 R P E D ( Asy m pt o matic; 
cli nic al or  di a g n ostic o bs ervati o ns 
o nly)  
 C o nti n ue tr eat m e nt wit h r etin al eval u ati on m ont hly until 
r es ol uti o n. If R P E D w ors e ns f oll o w i nstr uctio ns b el o w 
Gr a d e  2 -3 R P E D ( Sy m pt o matic wit h  
mil d t o m o d erat e d ecr eas e in vis u al 
ac ui ty; li miti n g i nstr u m ent al A D L) 
 I nt erru pt tr a m eti nib 
 R eti n al eval u atio n m ont hly  
 If i m pr ov e d t o ≤ Gr ad e 1, r est art tr a m eti nib at l o w er dose 
(re d uc e d by 0. 5 m g) or disco nti nu e i n p atie nts t aki ng 
tr a m eti ni b 1 m g d aily 
a)  
R ef ers t o C T C A E V ersi o n 4. 0  ‘ R eti n o p at hy’ 
5. 8. 5. 5.  
G ui d eli n e s f or P n e u m o niti s 
P ne u m o nitis has bee n o bser ve d i n s u bjects r ecei vi n g tra meti ni b, da brafe ni b, a n d i n 
da brafe ni b i n c o m bi nati o n wit h tra meti ni b. T o re d uce t he ris k of p n e u m o nitis, s u bjects will 
be m o nit ore d cl osel y f or s y m pt o ms, e v al uate d wit h i ma gi n g a n d f u n cti o nal tests. D ose 
m o dificati o n a n d s u p p orti ve care g ui deli nes f or p n e u m o nitis are descri be d i n Ta ble 1 6 .

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
5 9  
 
 
T a bl e 1 6  
M a n a g e m e nt a n d D o s e M o difi c ati o n G ui d eli n e s f or P n e u m o niti s  
C T C A E  
Gr a d e  
A d v ers e  E v e nt  M a n a g e m e nt  
A cti o n  a n d  D o s e  M o difi c ati o n  
Gr a d e  1  
 
C T  s c a n  ( hi g h- re s ol uti o n wit h  l u n g 
wi n d o w s ) re c o m m e n d e d 
 
Cli ni c al  e v al u ati o n  a n d l a b orat ory  
w or k -u p  f or i nf e cti o n 
 
M o nit ori n g  of o x y g e n ati o n  vi a  p ul s e - 
o xi m etr y  r e c o m m e n d e d 
 
C o n s ult ati o n  of  p ul m o n ol o gi st 
re c o m m e n d e d 
 
C o nti n u e  tra m eti ni b at c urre nt  d o s e  
Gr a d e  2  
 
C T  s c a n  ( hi g h- re s ol uti o n wit h  l u n g 
wi n d o w s)  
 
Cli ni c al  e v al u ati o n  a n d l a b orat ory  
w or k -u p  f or i nf e cti o n 
 
C o n s ult  p ul m o n ol o gi st  
 
P ul m o n ar y  f u n cti o n t e sts  – if < 
n or m al, r e p e at  e v er y  8  w e e k s u nti l ≥ 
n or m al  
 
Br o n c h o s c o p y  wit h bi o p s y  a n d/ or  
B A L r e c o m m e n d e d 
 
S y m pt o m ati c  t h er a p y i n cl u di n g 
c orti c o st er oi d s  if cli ni c all y i n di c at e d 
 
I nt err u pt tra m eti ni b u ntil  re c o ver y t o 
gra d e  ≤1  
 
R e st art  wit h  tra m eti ni b b e  re d u c e d b y 
o n e  d o s e  l e v el 
 
Es c al ati o n  t o pre vi o u s  d o s e  l e vel aft er  4 
w e e k s  a n d  c o n s ult ati o n  wit h  me di c al  
m o nit o r p o s si bl e  
 
If n o  re c o v ery t o gra d e  ≤1  wit hi n  4 
w e e k s,  p er m a n e ntl y  di s c o nti n ue 
tra m eti ni b 
Gr a d e  3  
 
C T  s c a n  ( hi g h- re s ol uti o n wit h  l u n g 
wi n d o w s)  
 
Cli ni c al  e v al u ati o n  a n d l a b orat ory  
w or k -u p  f or i nf e cti o n 
 
C o n s ult  p ul m o n ol o gi st  
 
P ul m o n ar y  f u n cti o n t e sts -if <  n or m al,  
re p e at e v er y  8  w e e k s  u ntil  ≥ n or m al  
 
Br o n c h o s c o p y  wit h bi o p s y  a n d/ or  
B A L  if p o s si bl e  
 
S y m pt o m ati c  t h er a p y i n cl u di n g 
c orti c o st er oi d s  a s cli ni c all y  i n di c at e d 
 
I nt err u pt tra m eti ni b u ntil  re c o ver y t o 
gra d e  ≤1  
 
Aft er  c o n s ult ati o n  wit h  m e di c al  m o nit or, 
tra m eti ni b m a y  b e  re st art e d re d u c e d b y  
o n e  d o s e  l e v el 
 
If n o  re c o v ery t o gra d e  ≤1  wit hi n  4 
w e e k s,  p er m a n e ntl y  di s c o nti n ue 
tra m eti ni b tre at m e nt 
Gr a d e  4  
 
S a m e  a s  gra d e  3  
 
Per m a n e ntl y  di s c o nti n u e  tra m eti ni b 
B A L = br o nci o alv e ol ar l av a g e; C T  = c o m p ut e d t o m o gr a p hy; C T C A E = C o m m o n T er mi n ol o gy Crit eri a f or Adv ers e Ev e nts 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
6 0  
 
 
5. 9.  
M o nit ori n g, I nt err u pti o n, a n d  St o p pi n g Crit eri a  f or H e p at o bili ar y 
E v e nt s 
5. 9. 1. Li v er C h e mi str y St o p pi n g Crit eri a  
T hese li ver c h e mistr y st o p pi n g a n d f oll o w- u p criteria ha ve b ee n desi g n e d t o ass ure s u bject 
safet y a n d e val uate li ver e ve nt eti ol o g y i n ali g n me nt wit h t he F D A G ui d a nce f or I n d ustr y –  
Dr u g-I n d u ce d Li ver I nj ur y: Pre mar keti n g Cli nical E val uati o n (J ul y 2 0 0 9, w w w.f da. g o v).  
Li ver c he mistr y st o p pi n g criteri a 1- 5 are defi ne d as:  
1. 
A L T 3 x U L N a n d bilir u bi n 2 x U L N ( > 3 5 % direct bilir u bi n) ( or A L T 3 x U L N a n d 
I N R > 1. 5, if I N R meas ure d) 
N O T E: If ser u m bilir u bi n fracti o nati o n is n ot i m me diatel y a vaila bl e, st u d y 
treat me nt s h o ul d be disc o nti n ue d if A LT  3 x U L N a n d bilir u bi n  2 x U L N. 
Ser u m bilir u bi n fracti o nati o n s h o ul d be perf or me d if testi n g is a vaila ble.  If 
testi n g is u na vaila ble, rec or d prese n ce of detect a ble uri nar y bilir u bi n o n 
di pstic k, i n dicati n g direct bilir u bi n ele vati o ns a n d s u g gesti n g li ver i nj ur y. 
2. 
A L T  8 x U L N 
3. 
A L T  5 x U L N b ut < 8 x U L N persists f or 2  wee ks 
4. 
A L T  3 x U L N if ass ociate d wit h t he a p peara nce or w orse ni n g of s y m pt o ms of 
he patitis or h y perse nsiti vit y s u c h as fati g u e, na usea, v o miti n g, ri g ht u p per q ua dra nt 
pai n or te n der ness, p yre xia, ras h or e osi n o p hilia. 
5. 
A L T  5 x U L N b ut < 8 x U L N a n d ca n n ot be m o nit ore d wee kl y f or > 2 wee ks. 
W he n a n y of t he li ver c he mist r y st o p pi n g criteri a 1 –  5 is met, d o t he f oll o wi n g:  
 
I m me di atel y disc o nti n ue s u bject fr o m st u d y treat me nt 
 
Re p ort t he e ve nt t o N o vartis wit hi n 2 4 h o urs of lear ni n g its occ urre n ce 
 
C o m plete t he li ver e ve nt C R F a n d S A E data c ollecti o n t o ol if t he e ve nt als o meets t he 
criteria f or a n S A E 
 
All e ve nts of A L T  3 x U L N a n d bilir u bi n  2 x U L N ( > 3 5 % dir ect bilir u bi n) ( or 
A L T 3 x U L N a n d I N R > 1. 5, if I N R meas ure d; I N R meas ure me nt is n ot re q uire d a n d 
t he t hres h ol d val ue state d will n ot a p pl y t o s u bjects recei vi n g a ntic o a g ula nts), 
ter me d ‘ H y’s La w’, m ust be re p orte d as a n S A E.  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
6 1  
 
 
 
N O T E: if ser u m bilir u bi n fracti o nati o n is n ot i m me diatel y a vaila ble, st u dy 
treat me nt s h o ul d be disc o nti n ue d if A LT  3 x U L N a n d bilir u bi n  2 x U L N. Ser u m 
bilir u bi n fracti o nati o n s h o ul d be perf or m e d if testi n g is a vaila bl e. If t esti n g is 
u na vaila ble, rec or d pres e nce of detect a ble uri n a r y bilir u bi n o n di pstic k , 
i n dicati n g direct bilir u bi n ele vati o ns a n d s u g gesti n g li ver i nj ur y. 
 
C o m plete t he li ver i ma gi n g a n d/ or li ver bi o ps y C R Fs if t hese tests are perf or me d. 
 
Perf or m li ver e v e nt f oll o w u p assess me nts, a n d m o nit or t he s u bject u ntil li ver 
c he mistries res ol ve, sta bilize, or ret ur n t o baseli ne val ues as descri be d bel o w 
 
F oll o w u p f or o verall s ur vi val is re q uire d f oll o wi n g disc o nti n uati o n fr o m st u d y 
treat me nt. 
 
D o  n ot rec halle n ge wit h st u d y treat me nt. 
I n a d diti o n, f or s u bjects meeti n g li ver st o p pi n g criteri o n 1: 
 
Ma ke e v er y reas o na bl e atte m pt t o ha ve s u bjects ret ur n t o cli nic wit hi n 2 4 h o urs f or 
re peat li ver c he mistries, li ver e ve nt f oll o w u p assess me nts (refer t o Secti o n 5. 9. 1. 1 ), a n d 
cl ose m o nit ori n g 
 
A s pecialist or he pat ol o g y c o ns ultati o n is rec o m me n de d 
 
M o nit or s u bjects t wice w ee kl y u ntil li ver c he mistries ( A L T, A S T, al kali ne 
p h os p hatase, bilir u bi n) res ol ve, sta bilize or ret ur n t o wit hi n baseli ne val ues. 
F or s u bjects meeti n g a n y of t he li ver st o p pi n g crit eria 2 –  5: 
 
Ma ke e ver y reas o n a ble atte m pt t o ha ve s u bjects ret ur n t o cli nic wit hi n 2 4- 7 2 hrs f or 
re peat li ver c he mistries a n d li ver e ve nt f oll o w u p assess me nts (refer t o Secti o n 5. 9. 1. 1 ) 
 
M o nit or s u bjects wee kl y u ntil li ver c he mistries ( A L T, A S T, al kali ne p h os p hatase, 
bilir u bi n) res ol ve, sta bilize or ret ur n t o wit hi n bas eli ne val ues; 
 
S u bjects meeti n g criteri o n 5 s h o ul d be m o nit ore d as fre q u e ntl y as p ossi ble. 
5. 9. 1. 1.  
Li v er E v e nt F oll o w- u p A s s e s s m e nt s 
F or s u bjects meeti n g a n y of t he li ver c he mistr y st o p pi n g criteria 1 – 5, ma ke e v er y 
atte m pt t o carr y o ut t he li ver e v e nt f oll o w u p assess me nts descri be d bel o w: 
 
Viral he patitis ser ol o g y i ncl u di n g: 
 
He patitis A I g M a nti b o d y 
 
He patitis B s urface a nti ge n a n d He p atitis B C ore A nti b o d y (I g M) 
 
He patitis C R N A 
 
C yt o me gal o vir us I g M a nti b o d y 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
6 2  
 
 
 
E pstei n- Barr viral c a psi d a nti ge n I g M a nti b o d y ( or if u na vaila ble, o bt ai n 
heter o p hile a nti b o d y or m o n os p ot testi n g) 
 
He patitis E I g M a nti b o d y. 
 
Bl o o d sa m ple f or p h ar mac o ki netic ( P K) a n al ysis, o btai ne d wit hi n 1 0 da ys of last 
d ose.  Rec or d t he d ate/ti me of t he P K bl o o d sa m ple dra w a n d t h e date/ti me of t he 
last d ose of st u d y tr eat me nt pri or t o bl o o d sa m ple dra w o n t he C R F.  If t he date or 
ti me of t he last d ose is u nclear, pr o vi de t he s u bject’s best a p pr o xi mati o n.  If t he 
date/ti me of t he last d ose ca n n ot be a p pr o xi m ate d O R a P K sa m ple ca n n ot be 
c ollecte d i n t he ti me peri o d i n dicate d a b o ve, d o n ot o btai n a P K sa m ple.  I nstr ucti o ns 
f or sa m ple ha n dli n g a n d s hi p pi n g are i n t he S P M. 
 
Ser u m creati ne p h os p h o ki nase ( C P K) a n d lactat e d e h y dr o ge nas e ( L D H). 
 
Fracti o nate bilir u bi n, if t otal bilir u bi n 2 x U L N.  
 
O btai n c o m plete bl o o d c o u nt wit h differe ntial t o assess e osi n o p hilia. 
 
Rec or d t he a p p eara nce or w orse ni n g of cli nical s y m pt o ms of he patitis, or 
h y pers e nsiti vit y, s uc h as fati g ue, n a usea, v o miti n g, ri g ht u p per q ua dra nt pai n or 
te n der ness, p yr e xia, ras h or e osi n o p hilia as rele va nt o n t he A E f or m. Pleas e n ote t hat 
treat me nt wit h tra meti ni b ofte n ass ociates wit h ras h w hic h is us uall y ac neif or m a n d 
affects t he scal p, f ace, nec k, c hest, a n d u p per bac k. Disc uss wit h N o vartis Gl o bal Cli nical 
Lea d as n ee de d. 
 
Rec or d use of c o nc o mita nt me dicati o ns s uc h as aceta mi n o p he n, h er bal re me dies, 
ot her o ver t he c o u nter me dicati o ns, or p utati ve he pat ot o xi ns, o n t he c o nc o mita nt 
me dicati o ns f or m. 
 
Rec or d alc o h ol use o n t h e li ver e ve nt alc o h ol i nta ke f or m. 
T he f oll o wi n g assess me nts are re q uire d f or s u bjects wit h A L T 3 x U L N a n d bilir u bi n 2 x U L N 
( > 3 5 % dir ect) b ut are o pti o nal f or ot her a b n or mal li ver c he mistries: 
 
A nti- n uclear a nti b o d y, a nti-s m o ot h m uscle a nti b o d y, a n d T y p e 1 a nti-li ver ki d ne y 
micr os o mal a nti b o dies a n d q ua ntitati ve t otal i m m u n o gl o b uli n G (I g G or ga m ma 
gl o b uli ns). 
 
Li ver i ma gi n g ( ultras o u n d, ma g n etic res o n a nce, or c o m p uterize d t o m o gra p h y) t o 
e val uate li ver disease. 
 
Ser u m aceta mi n o p he n a d d uct assa y ( qu a ntifies p ot e ntial aceta mi n o p he n c o ntri b uti o n t o 
li ver i nj ur y, det ecta ble b y H P L C assa y m ore t h a n 1 wee k f oll o wi n g aceta mi n o p he n use). 
 
O nl y i n t h ose wit h u n derl yi ng c hr o nic he patitis B at st u d y e ntr y (i de ntifie d b y p ositi ve 
he patitis B s urface a nti ge n):  q ua ntitati ve he patitis B D N A a n d he p atitis delta a nti b o d y.  
N O T E :  if he patitis delta a nti b o d y ass a y ca n n ot b e perf or me d, it ca n b e re place d wit h a 
P C R of he patitis D R N A vir us ( w here nee d e d) –  as o utli ne d i n: 
w w w. nc bi. nl m. ni h. g o v/ p mc/articles/ P M C 1 1 5 3 7 9 3/. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
6 3  
 
 
5. 9. 1. 2.  
Li v er C h e mi str y M o nit ori n g Crit eri a 
F or s u bjects wit h A L T 3 x U L N b ut < 8 x U L N w hic h e x hi bit a decreas e t o A L T 3 x U L N, b ut 
< 5 x U L N a n d bilir u bi n < 2 x U L N, wit h o ut he p atitis s y m pt o ms or ras h, a n d w h o ca n be 
m o nit ore d wee kl y f or 4 wee ks, t he f oll o wi n g acti o n s s h o ul d be ta ke n: 
 
N otif y t he N o v artis Gl o b al Cli nical Lea d wit hi n 2 4 h o urs of lear ni n g of t he a b n or malit y 
t o disc uss s u bject safet y 
 
C o nti n ue st u d y treat me nt 
 
Ret ur n wee kl y f or re p eat li ver c he mistries ( A L T, A S T, al kali ne p h os p hatase, 
bilir u bi n) u ntil t he y res ol ve, sta bilize or ret ur n t o wit hi n baseli ne val ues 
 
If at a n y ti me t he s u bject meets a n y of t he li ver c h e mistr y st o p pi n g criteri a 1 –  5, 
pr ocee d as descri be d a b o ve 
 
If, after 4 wee ks of m o nit ori n g, A L T < 3 x U L N a n d bilir u bi n < 2 x U L N, m o nit or s u bjects 
t wice m o nt hl y u ntil li ver c he mistries n or malize or ret ur n t o wit hi n baseli ne val ues. 
 
Refer t o A p pe n di x 6  f or a n al g orit h m of li ver c h e mistr y m o nit ori n g, st o p pi n g, a n d 
f oll o w- u p criteria. 
5. 9. 1. 3.  
Dr u g R e st art/ R e c h all e n g e F oll o wi n g Li v er E v e nt s t h at ar e P o s si bl y  
  
  
R el at e d t o St u d y Tr e at m e nt A p p e n di x 7 
A p pr o val b y N o vartis f or st u d y treat me nt restart ca n be c o nsi dere d w here: 
T he s u bject is recei vi n g c o m pelli n g be nefit, be nefit of dr u g restart e x cee ds ris k, a n d n o 
effecti ve alter nati ve t hera p y is a vaila ble.  Et hics C o m mittee or I nstit uti o nal Re vie w B o ar d 
a p pr o val of st u d y treat me nt restart/rec halle n ge m ust be o btai ne d, as re q uire d. 
If t he rest art/rec halle n ge is a p pr o ve d by N o vartis i n writi n g, t he s u bject m ust be pr o vi de d 
wit h a clear descri pti o n of t he p ossi ble be nefits a n d ris ks of dr u g a d mi nistrati o n, i ncl u di n g 
t he p ossi bilit y of rec urre nt, m ore se vere li ver i nj ur y or deat h. 
T he s u bject m ust als o pr o vi de si g ne d i nf or me d c o nse nt s pecificall y f or t he st u d y treat me nt 
restart/rec halle n ge. D oc u me ntati o n of i nf or me d c o nse nt m ust be rec or d e d i n t he st u d y 
c hart. 
St u d y tr eat me nt m ust be a d mi nistere d at t he d ose s pecifie d b y N o vartis.  
S u bjects a p pr o ve d b y N o vartis f or rest art/rec halle n ge of st u d y tr eat me nt m ust ret ur n t o t he 
cli nic t wice a w ee k f or li ver c he mistr y tests u ntil sta ble, li ver c he mistries h a ve bee n 
de m o nstrate d a n d t he n l a b orat or y m o nit ori n g ma y res u me as per pr ot oc ol. 
5. 9. 1. 4.  
Dr u g R e st art F oll o wi n g Tr a n si e nt R e s ol vi n g Li v er E v e nt s N ot R el at e d t o 
St u d y Tr e at m e nt 
A p pr o val b y N o vartis f or dr u g restart ca n be c o nsi dere d w here: 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
6 4  
 
 
 
Li ver c he mistries ha v e a clear u n derl yi n g ca use (e. g., biliar y o bstr ucti o n, 
h y p ote nsi o n a n d li ver c h e mistries ha ve i m pr o ve d t o n or mal or are wit hi n 1. 5 x 
baseli ne a n d A L T < 3 x U L N).  Et hics C o m mittee or I nstit uti o nal Re vie w B oar d 
a p pr o val of st u d y treat me nt restart/rec halle n ge m ust be o btai ne d, as re q uire d. 
 
If restart of st u d y treat me nt is a p pr o ve d by N o vartis i n writi n g, t he s u bject m ust be 
pr o vi de d wit h a cle ar des cri pti o n of t he p ossi ble be nefits a n d ris ks of dr u g 
a d mi nistrati o n, i ncl u di n g t he p ossi bilit y of rec urre nt, m ore se vere li ver i nj ur y or 
deat h. 
 
T he s u bject m ust als o pr o vi de si g ne d i nf or me d c o nse nt s pecificall y f or t he restart. 
  
D oc u me ntati o n of i nf or m e d c o nse nt m ust be rec or de d i n t he st u d y c h art. 
 
St u d y tr eat me nt m ust be a d mi nistere d at t he d ose s pecifie d b y N o vartis. 
 
S u bjects a p pr o ve d b y N o vartis f or rest arti n g st u d y treat me nt m ust ret ur n t o t he cli nic 
o nce a w ee k f or li ver c h e mistr y tests u ntil sta ble li ver c he mistries h a ve bee n 
de m o nstrate d, a n d t he n l a b orat or y m o nit ori n g ma y res u me as per pr ot oc ol. If pr ot oc ol 
defi ne d st o p pi n g criteri a f or li ver c h e mistr y ele vati o ns are met, st u d y treat me nt m ust 
be st o p pe d. 
6.   
C O N C O MI TA N T M E DI C A TI O N S A N D  N O N- D R U G T H E R A PI E S  
6. 1.  
P er mitt e d M e di c ati o n s a n d  N o n- dr u g T h er a pi e s  
T he i n vesti gat or m ust be i nf or me d as s o o n as p ossi ble a b o ut a n y me di cati o n ta ke n fr o m t he 
ti me of scree ni n g u ntil 3 0 da ys after t h e last d ose of st u d y treat me nt wit h t he e x ce pti o n of 
ne w a nti-ca n cer t hera p y, if ta ke n aft er st u d y treat me nt disc o nti n uati o n; t hese will be 
d oc u me nte d u ntil st u d y c o m pleti o n/ wit h dra wal or deat h.  A n y c o n c o mita nt me dicati o n(s), 
i ncl u di n g dietar y s u p ple me nts, ta ke n d uri n g t he st u d y will be rec or de d i n t he e C R F.  T he 
mi ni m u m re q uire me nt is t hat dr u g n a me, d ose, a n d t he dates of a d mi nistrati o n are t o be 
rec or d e d.  A d diti o nall y, a c o m plete list of all pri or s ur gical pr oce d ures will be rec or de d i n 
t he e C R F. 
S u bjects s h o ul d recei ve f ull s u p p orti ve care d uri n g t he st u d y, i ncl u di n g tr a nsf usi o ns of 
bl o o d a n d bl o o d pr o d ucts, a n d treat me nt wit h a nti bi otics, a nti-e metics, a nti- diarr heals, a n d 
a nal gesics, a n d ot h er care as dee m e d a p pr o priate, a n d i n acc or da nce wit h t heir i nstit uti o nal 
g ui deli nes.  Us e of a ntic o a g ul a nts s uc h as w arfari n is per mitte d h o we ver, ca uti o n s h o ul d be 
e x ercise d a n d a d diti o nal I nter nati o nal N or m alize d Rati o (I N R) m o nit ori n g is rec o m me n de d 
w he n da brafe ni b is use d c o nc o mita ntl y wit h warfari n. 
W hile patie nts are o n st u d y treat me nt, p alli ati ve ra diati o n t hera p y is per mitte d f or n o n- 
tar get lesi o ns t hat are eit her ne w or pres e nt at bas eli ne. 
Ra diati o n s ki n i nj ur y has bee n re p orte d wit h c o nc urre nt use of d a brafe ni b a n d ra diati o n. It is 
rec o m me n de d t h at da brafe ni b be hel d f or s e ve n da ys bef ore a n d t w o da ys after X R T i n 
s u bjects recei vi n g d a brafe ni b m o n ot hera p y or i n c o m bi nati o n wit h tra meti ni b. T hese 
rec o m me n dati o ns ca n be m o difie d base d o n t he p h ysicia n’s assess me nt of t he ris k of 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
6 5  
 
 
ra diati o n s ki n i nj ur y. 
6. 2.  
Pr o hi bit e d M e di c ati o n s a n d  N o n-dr u g T h er a pi e s  
T he use of certai n me di cati o ns a n d illicit dr u gs wit hi n 2 8 da ys or 5 half li v es, w hic he ver is 
s h orter, pri or t o d osi n g a n d f or t he d urati o n of t he st u d y will n ot be all o we d. T he N o vartis 
Gl o bal Cli nical Lea d ca n a p pr o ve t he us e of a pr o hi bite d me dicati o n if it is re q uire d f or a 
si n gle use (s uc h as f or a pr oce d ure) w hile tr eat me nt wit h st u d y dr u g is i nterr u pte d. 
T he f oll o wi n g m e dicati o ns or n o n- dr u g t hera pies are als o pr o hi bite d w hile o n treat me nt i n 
t his st u d y: 
 Ot her a nti-ca n cer t h era pi es; 
 Ot her i n vesti gati o nal dr u gs; 
 A ntiretr o viral dr u gs ( N ote: Patie nts wit h k n o w n HI V are i neli gi ble f or st u d y 
partici pati o n);  
 
Her bal r e me dies ( e. g., St. J o h n’s w ort); 
 
Da brafe ni b is meta b olize d pri maril y b y C yt oc hr o me P 4 5 0 ( C Y P) 2 C 8 a n d C Y P 3 A 4.  
C o -a d mi nistrati o n of da brafe ni b wit h ket o c o naz ole, a C Y P 3 A 4 i n hi biti o n, or wit h 
ge mfi br ozil, a C Y P 2 C 8 i n hi bit or, res ulte d i n i ncreases i n da brafe ni b A U C of 7 1 % 
a n d 4 7 %, res p ecti vel y.  Dr u gs t hat are str o n g i n hi bit ors or i n d ucers of C Y P 3 A a n d 
C Y P 2 C 8 (see list i n Ta ble 1 ) m a y o nl y be us e d u n der s peci al circ u msta n ces (e. g. as a 
si n gle use f or a pr oce d ure) w hile treat me nt wit h st u d y dr u g is i nterr u pt e d as t he y m a y 
alter da brafe ni b c o nce ntr ati o ns; c o nsi der t hera p e utic s u bstit uti o ns f or t hese 
me dicati o ns.  A p pr o val of t he N o vartis Gl o bal Cli nical L ea d is r e q uire d i n t hese 
sit uati o ns. T he list ma y b e m o difie d base d o n e mer gi n g dat a. Refer t o t he S P M f or 
t he m ost c urre nt list.

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6 6  
N o v arti s 
C o nfi d e nti al 
P a g e 6 6  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
T a bl e 1 7  
Pr o hi bit e d M e di c ati o n s: Dr u g s t h at ar e Str o n g I n hi bit or s or  I n d u c er s 
of C Y P 3 A a n d C Y P 2 C 8  
P R O HI BI T E D –  str o n g i n d u cer s of C Y P 3 A or C Y P 2 C 8, si n c e c o n c e ntr ati o n s of d a br af e ni b m a y b e 
d e cr e a s e d  
Cl a s s/ T h e ra p e uti c  Are a  
Dr u g s/ A g e nt s  
A nti bi otics  
Rif a myci n  cl ass a g e nts  ( e. g., rif a m pi n, rif a b uti n, rif a p e nti n e), 
A ntic o nv uls a nt  
C ar b a m az e pi n e,  oxc ar b az e pi n e  p h e n o b ar bit al,  p h e nyt oi n,  s-m e p h e nyt oi n  
Misc ell a n e o us  
b os e nt a n,  St -J o h n’s w ort  
P R O HI BI T E D –  Str o n g i n hi bit ors of C Y P 3 A, or C Y P 2 C 8 si n c e c o n c e ntr ati o n s of  da br af e ni b m a y  b e 
i n cr e a s e d 
Cl a s s/ T h er a p e uti c  Are a  
Dr u g s/ A g e nt s  
A nti bi otics  
Cl arit hr o myci n,  t elit hr o myci n, tr ol e a n d o myci n 
A nti d e pr ess a nt  
N ef az o d o n e  
A ntif u n g als  
Itr ac o n az ol e, k et oc o n az ol e, p os ac o n az ol e , v oric o n az ol e 
Hy p erli pi d e mi a  
G e mfi br ozil  
A ntir etr ovir al  
rit o n avir, s a q ui n avir, at az a n avir  
Misc ell a n e o us  
C o niv a pt a n  
 
6. 3.  
M e di c ati o n s t o b e  u s e d wit h C a uti o n  
T he f oll o wi n g m e dicati o ns s h o ul d be use d wit h ca uti o n as t heir c o nce ntrati o ns ma y b e 
altere d b y da brafe ni b or tra meti ni b or t he y ma y alter da brafe ni b or tra meti ni b 
c o nce ntr ati o ns: 
 
Dr u gs t hat are mil d/ m o derate i n hi bit ors or i n d ucers of C Y P 3 A a n d C Y P 2 C 8 as 
t he y m a y alter c o n ce ntrati o ns of da brafe ni b. 
 
Da brafe ni b has bee n s h o w n t o i n d uce C Y P 3 A 4 a n d C Y P 2 C 9 i n vi v o usi n g 
mi daz ola m ( C Y P 3 A 4 s u bstrate) a n d S- warfari n ( C Y P 2 C 9 s u bstrate). Da brafe ni b is 
a n i n vitr o i n d ucer of C Y P 2 B 6 a n d ot her e nz y mes s uc h as C Y P 2 C 8, C Y P 2 C 1 9, 
U D P- gl uc ur o n yl tr a nsferases, a n d tra ns p orters ma y als o be affecte d.  C o-
a d mi nistrati o n of da brafe ni b a n d me dicati o ns w hic h are affecte d b y t he i n d ucti o n 
of t hese e nz y m es (i ncl u di n g warfari n) a n d tra ns p orters ma y res ult i n l oss of 
effic ac y.  If c o- a d mi nistrati o n of t hese me dicati o ns is necessar y, i n vesti gat ors 
s h o ul d m o nit or s u bjects f or l oss of efficac y or c o nsi der s u bstit uti o ns of t hese 
me dicati o ns A partial list of t hese me dicati o ns is pr o vi de d i n Ta ble 1 8 . T he list 
ma y b e m o difie d base d o n e mer gi n g data. Refer t o t he S P M f or t he m ost c urre nt 
list. 
  
T hera pe utic le v el d osi n g of warfari n ca n be use d wit h a p pr o val b y t he N o vartis 
Gl o bal Cli nical Lea d a n d cl ose m o nit ori n g of P T/I N R b y t he site. Warfari n e x p os ure 
has bee n s h o w n t o decrease ( 3 7 % decrease) d ue t o da brafe ni b- me diate d e nz y m e 
i n d ucti o n. C o n versel y, if da brafe ni b d osi n g is re d u ce d, i nterr u pt e d, or disc o nti n ue d, 

I n v esti gat ors ma y  b e re q ueste d t o perf or m a d diti o nal safe ty tests d uri n g t he c o urse of t he  
6 7  
N o v arti s 
C o nfi d e nti al 
P a g e 6 7  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
warfari n e x p os ure ma y b e i ncrease d. T h us, warfari n d osi n g ma y nee d t o b e a dj uste d 
base d o n P T/I N R d uri n g a n d after treat me nt wit h da brafe ni b. Pr o p h yl actic l o w d ose 
warfari n ma y be gi ve n t o mai ntai n ce ntral cat heter pate nc y. 
  
Da brafe ni b s ol u bilit y is p H- de pe n de nt wit h decrease d s ol u bilit y at hi g h er p H. Dr u gs 
s uc h as pr ot o n p u m p i n hi bit ors t hat i n hi bit gastric aci d secreti o n t o ele vate gastri c 
p H ma y d ecrease t h e s ol u bilit y of d a brafe ni b a n d re d uce its bi oa vaila bilit y. N o 
cli nical st u d y has b ee n c o n d ucte d t o e val uat e t he effect of p H o n da brafe ni b 
p har mac o ki netics. I n a n a d- h oc a n al ysis, n o differe nces i n C ma x a n d A U C were 
n ote d bet wee n s u bjects w h o re p orte d t a ki n g p H-ele vati n g pr o d ucts r elati ve t o ot her 
s u bjects. D ue t o t he t he oretical ris k t hat p H-ele vati n g a ge nts ma y decrease oral 
bi oa vaila bilit y a n d e x p os ure t o da brafe ni b, t hes e me dici nal pr o d ucts t hat i ncreas e 
gastri c p H s h o ul d be use d wit h ca uti o n w he n a d mi nistere d wit h da brafe ni b. 
  
Pr o p h yla ctic tam o xife n ma y be us e d wit h t he a p pr o val of t he N o vartis Gl o bal 
Cli nical L ea d.  Ta m o xife n is a s u bstrate f or C Y P 2 C 9 a n d C Y P 3 A 4.  C o- 
a d mi nistrati o n of da brafe ni b wit h ta m o xife n ma y res ult i n l oss of efficac y of 
ta m o xife n. 
T a bl e 1 8  
M e di c ati o n s t o b e u s e d wit h C a uti o n  
U S E WI T H C A U TI O N: C o n c e ntr ati o n s of t h e s e dr u gs m ay b e i n cr e a se d or d e cr e a se d b y d a br af e ni b  
Cl a s s/ T h er a p e uti c Ar ea  
Mil d/ M o d er ate C Y P 3 A a n d C Y P 2 C 8  
A nti arr hyt h mics  
Dilti aze m, v er a p a mil  
A nti bi otic  
Eryt hr o myci n  
A ntif u n g al  
Fl uc o naz ole  
Mi scell an eous 
A pr e pit a nt  
U S E  WI T H  C A U TI O N:  C o -a d mi ni strati o n of t h e se dr u g s wit h st u d y tr e at m e nt m ay r es ult i n l o s s of 
effi c a c y.  M o nit or s u bje ct s f or l o s s of effi c ac y or s u b stit ut e wit h a n ot her m e di c ati o n.  
Cl a s s/ T h er a p e uti c Ar ea  
C Y P 3 A 4,  C Y P 2 B 6,  C Y P 2 C 8,  C Y P 2 C 9, or C Y P 2 C 1 9 S u b strat e s t h at 
M a y b e Aff e ct e d b y I n d ucti o n  
A n al g esics  
Alf e nt a nil, b upr e n or p hi n e,  c el ec oxi b, c o dei n e, f e nt a nyl, m et ha d o n e, 
oxyco d o n e  
A nti arr hyt h mics  
Dis o pyr a mi d e, dr o n ed ar o n e,  m exil eti ne, pr o p af e n o ne, q uinidi n e  
A nti bi otics  
C hl or a m p he n ic ol, d oxycycli n e, eryt hr o myci n, moxifl ox aci n  
A ntic o a gul a nts/ A ntipl at el ets  
Cil ost az ol e, w arf ari n  
A ntic o nv uls a nts  
Div al pr o ex, la m otri gi n e, v alpr oat e, z o nis a mi d e  
A nti d e pr ess a nts a nd  
A nti psyc h otics  
Ari pi pr azol e, bu pr o pi o n, b us piro n e, d esi pr a mi n e,  hal o per idol, mirt az a pi n e, 
pi m ozi d e, q u etia pi n e, tr az od on e, a mitri ptyli ne, clo mi pra min e, i mi pra mi ne  
A nti di a betics  
Gly buri d e, s axa glipti n, tol b uta mi d e, nat e gli ni de, pi oglitaz o ne, r e p a gli ni d e, 
r osi glit azo n e 
A ntif u n g als  
C as p of u n gi n, fluc o naz ol e, t er bi n afi n e  
A nti hi sta mi nes 
Ast e miz ol e, c hlor p h e nir a min e, e b astin e  

I n v esti gat ors ma y  b e re q ueste d t o perf or m a d diti o nal safe ty tests d uri n g t he c o urse of t he  
6 8  
N o v arti s 
C o nfi d e nti al 
P a g e 6 8  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Cl a s s/ T h er a p e uti c Ar ea  
C Y P 3 A 4,  C Y P 2 B 6,  C Y P 2 C 8,  C Y P 2 C 9, or C Y P 2 C 1 9 S u b strat e s t h at Ma y 
b e Aff e ct e d b y I n d ucti o n  
A nti hy p ert e nsiv es  
A ml o di pi n e, dilti az e m, f elo di pin e, nif edi pin e, nilv adi pi ne, nisol di pin e, 
v er a p a mil 
A nti mi gr ai n e A ge nts  
Di er g ot a mi n e, el etri pta n, er gota mi n e  
Cortic oster oi ds  
D ex a m et has o ne, m ethyl pre d nis ol o n e,  or al  bu d eso ni d e  
Er ectil e Dysf u ncti on  A g e nts  
Sil d e n afil, t ad al afil, v ar d e nafil  
H M G -C o A R e d uct ase  
I n hi bitors 
At orv ast ati n, lov ast atin, si mv ast ati n, r os uv ast ati n, pr av ast ati n  
Hy p n otics a nd  S e d ativ es  
Al pr az ol a m, brotizol a m, di az ep a m, est az ol a m, mi daz ola m, tri az ola m, 
z ol pid e m, z o picl on e 
I m m u n os u p pressa nts 
Ev er oli m us, sir oli m us, t acr oli mus  
Miscell an e o us  
A pr e pit a nt, cis a pri de, d arif e n aci n, di g oxi n, dis opyr a mi d e, l eflun o mi d e, 
m et h o h exit al, or al c o ntr ac eptives, q uini n e, r a niti di n e, s olif e naci n, 
s ulf as al azi n e, tr a m ad ol, tolv apt a n, c hl or o q ui n e, z o picl o ne  
S el ectiv e Al dost er on e  Bl ock ers  E pl er e n o n e  
U S E WI T H C A U TI O N: C o -a d mi nistr ati o n of dr u gs t h at i ncr e as e g astric p H s h o ul d b e us e d wit h 
c a uti o n w he n a d mi nist er e d wit h d a br af e ni b a s e x p o s ur e t o d a br af e ni b m ay b e d e cr ea s e d  
 
p H  alt eri n g  a g e nts  
d exl a ns o pr az ol e.  es o m e pr az ol e,  f a m oti di n e, il a pr az ol e, l a ns o pr az ol e, o m e pr az ol e, 
p a nt o pr az ol e,  r a b e pr az ol e, r a niti di n e 
 A b br evi ati o ns: C Y P = cyt oc hr o m e P 4 5 0; H M G- C o A = 3- hy dr oxy- 3- m ethyl gl ut aryl-c o e nzy m e A.  
Q uesti o ns re gar di n g c o nc o mita nt me dicati o ns s h o ul d be directe d t o t he N o vartis Gl o bal 
Cli nical Lea d  f or clarificati o n. 
6. 4.  
Tr e at m e nt of St u d y Tr e at m e nt O v er d o s e 
I n t he e ve nt of a da brafe ni b o ver d ose, defi ne d as a d mi nistrati o n of m ore t ha n 3 0 0 m g as a 
si n gle d ose or 6 0 0 m g p er da y (t he hi g hest d ose t este d i n cli nical st u dies t o date), a n d/ or a 
tra meti ni b o ver d ose, defi ne d as a d mi nistrati o n of m ore t ha n 3. 0 m g o n ce d ail y (t he m a xi m u m 
t olerate d d ose d efi ne d i n t he M E K 1 1 1 0 5 4 St u d y), t he I n v esti gat or s h o ul d c o ntact t he N o vartis 
Gl o bal Cli nical Lea d i m me diatel y a n d cl osel y m o nit or t he s u bject f or A Es/ S A Es a n d 
la b orat or y a b n or malities.  N o vartis d oes n ot rec o m me n d s pecific treat me nt. T he i n vesti gat or 
will use cli nical j u d g me nt t o treat a n y o ver d ose. Hae m o dial ysis is n ot e x pecte d t o e n ha nce t he 
eli mi nati o n of eit her da brafe ni b or tra meti ni b as b ot h are hi g hl y b o u n d t o plas ma pr otei ns.  
Decisi o ns re gar di n g d ose m o dificati o ns or i nterr u pti o ns s h o ul d be ma de b y t he 
i n vesti gat or i n c o ns ultati o n wit h t he N o vartis Gl o bal Cli nical Lea d base d o n t he 
cli nical e val uati o n of t he s u bj ect. 
A plas ma sa m ple f or P K a nal ysis m a y be re q u este d b y  t h e N o vartis Gl o bal Cli nical Lea d  
o n a case- b y- case basis.  T his plas ma sa m ple s h o ul d be c ollecte d as s o o n as p ossi ble, b ut 
wit hi n 1 0 da ys fr o m t he date of t he last d ose of o n-st u d y d osi n g. 

I n v esti gat ors ma y  b e re q ueste d t o perf or m a d diti o nal safe ty tests d uri n g t he c o urse of t he  
6 9  
N o v arti s 
C o nfi d e nti al 
P a g e 6 9  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
I nf or mati o n re gar di n g t h e q ua ntit y of t h e e x cess d ose as well as t he d urati o n of t he 
o ver d osi n g s h o ul d b e d o c u me nte d i n t he e C R F. 
7.   
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S 
A si g ne d, writte n i nf or m e d c o nse nt f or m m ust be o btai ne d fr o m t he s u bject pri or t o a n y 
st u d y-s pecific pr oce d ures or assess me nts. 
Pr oce d ures c o n d ucte d as part of t he s u bject’s r o uti ne cli nical ma na ge me nt (e. g., i ma gi n g) a n d 
o btai ne d pri or t o si g ni n g of i nf or me d c o ns e nt ma y be use d f or s cree ni n g or baseli ne p ur p oses 
pr o vi de d t he pr oce d ure meets t he pr ot oc ol- defi ne d criteria a n d has be e n perf or me d wit hi n t he 
ti mefra me s pecifie d i n t he pr ot oc ol. Ce ntral la b orat or y res ults f or B R A F testi n g, c oa g ul ati o n, 
he mat ol o g y, cli nic al c he mistr y, a n d ser u m pre g na nc y are re q uir e d f or eli gi bilit y. 
Refer t o t he Ti me a n d E v e nts ( Ta ble 1 9 ) f or t he ti mi n g of all assess me nts.  Assess me nts 
m ust be perf or me d o n a cale n dar s c he d ule; dela ys i n treat me nt a d mi nistrati o n will n ot del a y 
perf or ma n ce of assess me nts.  Details o n efficac y a n d safet y assess me nts are prese nte d i n 
Secti o n 7. 2  a n d Secti o n 7. 4 , res pecti vel y. 
 
 
st u d y b ase d o n ne wl y a v aila ble data t o e ns ure a p pr o priate safet y m o nit ori n g. 
A p pr o priate l ocal re g ulat or y a n d et hical a p pr o vals s h o ul d be o btai ne d bef ore a n y a d diti o nal 
testi n g is perf or me d.(T a ble 1 9 ) o utli nes st u d y assess me nts a n d t heir ti mi n g.

N o v arti s 
 
C o nfi d e nti al 
  
  
 
                      P a g e 7 0  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
  
  
 
        Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
 
 
St u d y A s s e s s m e nt s 1 
Scr e e n -2 
D a y 1  
W e e k 4  
W e e k 8  
W e e k 1 2  
W e e k 1 6  
W e e k 2 0  
W e e k 2 4  
W e e k 2 8  
W e e k 3 2  
W e e k 3 6  
W e e k 4 0 t h e n 
m o nt hl y U ntil 
Tre at m e nt 
Di s c  
1. 1.  
Tre at m e nt  
Di s c 2 6 
F oll o w u p 9   2 7 
C o n cl u si o n  
I nf or m e d c o ns e nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T u m o ur tiss u e s a m pl e f or B R A F V 6 0 0 m ut ati o n 3  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ntr acr a ni al t ar g et a n d n o n – t ar g et l esi o n ass ess m e nt a n d r es p o ns e2 1   2 7  
X  
 
X  
X  
 
X  
 
X  
 
X  
 
X  
X  
 
 
Extr acr a ni al t ar g et a n d n o n -t ar g et l esi o n ass ess m e nt a n d r es p o ns e2 2     2 7  
X  
 
X  
X  
 
X  
 
X  
 
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C o a g ul ati o n  
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Physic al ex a mi n ati o n  
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H ei g ht 7  
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W ei g ht, T e m p, B P, R es p a n d H R 8 
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Pri or a nti -c a nc er t h er a py, r a di ot h er a py a n d s ur gic al pr oc e d ur es  
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Past a n d c urr e nt m e dic al c o n diti o ns, f a mily hist ory  
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        Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
St u d y A s s e s s m e nt s 1 
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D er m at ol o gic ski n ass ess m e nt 1 5 
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Dis p e ns e or al st u dy tr e at m e nt a n d ass ess tr e at m e nt c o m pli a nc e 1 6 
 
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E C H O 1 8 
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F oll o w -u p m o nt hly d er m at ol o gic ski n ass ess m e nt c o nt act, a nti -c a nc er t h er a py 2 0 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Surviv al F oll o w -u p, a nti -c a nc er t h er a py 2 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
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; M RI = m a g n etic r es o n a nc e i m a gi n g; E C O G = East er n C o o p er ativ e O nc ol o gy Gr o u p; E C G = el ectr oc ar di o gr a m; E C H O = ec h oc ar di o gr a m; U ns hc = 
u nsc h e d ul e d; Disc = disc o nti n u ati o n; F w p = f oll o w- u p;  C o nc = c o ncl usi o n 
1. 
F or W e ek 1 visit a n d  t h er e aft er, all visits will  h av e a wi n d o w of   3 d ays a n d  sc a ns will h av e  7 d ays f or fl exi bl e sc h e d uli n g. All ass ess m e nts m a n d at e d t hr o u g h o ut t h e st u dy m ust 
b e  p erf or me d  o n  a c al e n d ar sc h e d ul e; d el ays i n tr e at m e nt a d mi nistr ati o n will  n ot  d el ay p erf or m a nc e of  ass ess m e nts. 
2. 
Scr e e ni n g pr oc e d ur es m ay b e  p erf or m e d 1 4  d ays pri or t o first d os e of  st u dy dr u g, exc e pt f or t u m o ur ass ess m e nts w hic h m ay b e  p erf or m e d 2 8  d ays pri or t o first d os e of  st u dy 

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                      P a g e 7 2  
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        Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
dr u g, a n d  ec h oc ar di o gr a ms a n d  E C Gs w hic h m ay b e  p erf or m e d 3 5  d ays pri or t o t h e first d os e of  st u dy dr u g. Alls Su bj ects w h o h av e u n d er g o n e l oc al B R A F t esti n g a n d  w h o ar e 
B R A F V 6 0 0 D/ E/ K/ R m ut ati o n p ositiv e, m ay b e gi n scr e e ni n g pr oc e d ur e s.F o r AL L c o h orts, sit es still n e e d t o s e n d i n tiss u e s a m pl e t o t h e c e ntr al l a b or at ory f or r etr os p ectiv e 
t esti n g. Be gi n ni n g wit h D ay 1 visit, all visits h av e a  3 d ay  visit wi n d o w a n d  sc a ns will h av e  7 d ays f or fl exi bl e sc h e d uli n g. 
3. 
B R A F t u m o ur tiss u e at  scr e e ni n g will  b e  c e ntr ally t est e d all s u bj ects r e g ar dl ess of  c o h ort vi a C e ntr al L a b or at ory. Su bj ects w h o q u alify e nr oll m e nt , m ust s e n d t u m o ur tiss u e 
s a m pl e t o t h e c e ntr al l a b or at ory f or r etr os p ectiv e c o nfir m ati o n a n d  a d diti o n al bi o m ark er t esti n g wit hi n 2 1  d ays of  visit. Arc hiv al tiss u e s a m pl es ar e s uffici e nt f or m ol ec ul ar t esti n g, 
b ut  fr es h t u m o ur bi o psi es ar e als o acc e pt a bl e. 
4. 
O nly s u bj ects w h o m e et all i ncl usi o n a n d  excl usi o n crit eri a will  b e  eli gi bl e t o e nt er  i nt o t h e st u dy. N o  w aiv ers c a n b e  gr a nte d.  
5. 
C h e mistry a n d  h a e m at ol o gy ev al u ati o ns ar e p erf or m e d by  t h e c e ntr al l a b or at ory. Su bj ects will b e  d os e d b as e d o n  t h e c e ntr al l a b or at ory r es ults. Scr e e ni n g l a b or at ory 
ass ess m e nts p erf or m e d wit hi n 1 4  d ays of  first d os e of  st u dy dr u g d o  n ot  n e e d  t o b e  r e p e at e d. 
6. 
A n e g ativ e s er u m pr e g n a ncy t est will  b e  r e q uir e d wit hi n t h e 1 4  d ays pri or t o t h e first d os e of  st u dy tr eat m e nt. Su bs e q u e nt t ests m ay b e  uri n e t ests, a n d  s h o ul d b e  p erf or m e d as 
cli nic ally i n dic at e d. 
7. 
H ei g ht M e as ur e m e nts s h o ul d b e  i n m etric sc al e a n d  r e q uire d  o nly at  scr e e ni n g. 
8. 
W ei g ht, b o dy  t e m p er at ur e, bl o o d pr ess ur e, h e art r at e, a n d  r es pir atio ns ar e t o b e  r ec or d e d at  e ac h visit. 
9. 
Dis e as e c h ar act eristics: R ec or d d at a i n e C R F o n  i niti al di a g n osis: T u m o ur Cl assific ati o n (c ut a n e o us, etc), d at e  of  i ntr acr a nial  a n d  d at e of  extr acr a ni al i niti al di a g n osis, st a g e at  
i niti al di a g n osis, T N M st a gi n g at  i niti al di a g n osis, hist ol o gy at  i niti al di a g n osis; R ec or d d at a  o n  L ast R ec urr e nc e: d at e  of  l ast r ec urr e nc e of  i ntr acr a ni al a n d  extr acr a ni al dis e as e; 
R ec or d d at a  at  Scr e e ni n g: D at e of  St a g e at  Scr e e ni n g, St a g e at  Scr e e ni n g, T N M st a gi n g at  Scr e e ni n g. 
1 0 . 
 A ny tiss u e r e m ai ni n g af t er 
t h e scr e e ni n g B R A F t u m o ur t esti n g f or t h e c e ntr al a n d  r etr os p ectiv e c o nfir m ati o n ( C o h orts A,  B,  C,  D)  will  b e  us e d f or bi o m ark er t esti n g. 
1 1 . 
1 2  Cyt oki n es: A bl o o d s a m pl e f or p ot e nti al a n alysis of  cyt oki n es is m a n d at ory at  Scr e e ni n g a n d  at  w e ek 4.  Su bs e q u e nt cyt oki n e s a m pl es s h o ul d als o b e  c oll ect e d if i n dic at e d. ( S e e 
 
S ecti o n 5. 8. 5. 1  M a na g e me nt of G ui deli n es  f or Pyrexi a). 
1 3 . N e ur ol o gic al ass ess m e nts will r e m ai n at  ev ery 1 2  w e eks st arti n g at  W e ek 4 0  ev e n t h o u g h t h e s u bj ects ar e r e q uir e d t o h av e m o nt hly visits. 
1 4 . O p ht h al m ol o gy Ex a m: A n  o p ht h al mic ex a mi n ati o n will b e  p erf or m e d pri or t o first d os e ( b as eli n e) a n d  w e ek 4,  w e ek 2 4  a n d  a n n u ally t h er e aft er u nl ess cli nic ally i n dic at e d 
s o o n er. A d diti o n al o p ht h al mic ex a mi n ati o ns will  b e  p erf or m e d o nly as  sy m pt o m atic ally w arr a nt e d. R ef er t o Secti o n 7. 4. 5  f or d et ails 
1 5 . D er m at ol o gic ski n ass ess m e nts s h o ul d b e  p erf or m e d by  t h e s a m e I nv esti g at or or  d er m at ol o gist at  e ac h visit t o e ns ur e c o nsist e ncy of  ass ess m e nts; Us e of  a d er m at ol o gist is 

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pr ef err e d b ut  n ot  m a n d at ory. D er m at ol o gic ski ns ass ess m e nts ar e r e q uir e d m o nt hly w hil e o n  st u dy tr e at m e nt a n d  m o nt hly f or a 6- m o nt h ti m e fr a m e aft er  disc o nti n u ati o n of  st u dy 
tr e at m e nt as  p er  t h e E ur o p e a n l a b el. As  p art of  t h e ski n ass ess m e nts, F ull-b o dy  p h ot o gr a p hy of  s u bj ects at  scr e e ni n g is r ec o m m e n d e d wit h p h ot o gr a p hs of  a ny  n e w  or  c h a n gi n g 
l esi o ns r ec o m m e n d e d at  s u bs e q u e nt visits. 
1 6 . Dis p e ns ati o n of  St u dy Tr e at m e nt: Dis p e ns e a 4- 6 w e ek s u p ply of  t h e st u dy m e dic ati o n wit h i nstr ucti o ns. R ec or d d os e r e d ucti o ns, d os e i nt err u pti o ns/ d el ays a n d/ or  d os e 
esc al ati o ns. 
1 7 . E C G ass ess m e nts m ust b e  p erf or m e d wit hi n 3 5  d ays pri or t o first d os e. T h er e aft er, E C G ass ess m e nts will  b e  c o n d uct e d at  w e eks 4,  8 a n d  1 2  a n d  t h e n ev ery 1 2  w e eks u p  t o 
a n d i ncl u di n g disc o nti n u ati o n visit. 1 2-l e ad E C G will be  p erf or m e d by  qu alifi e d p ers o n n el at th e sit e aft er at  l e ast a five- mi nut e r est wit h t h e su bj ect i n a s e mi-
r ec u m be nt or s u pi n e positi o n. M e as ure m e nts a n d  c alc ul ati o ns t h at m ust b e  c oll ect ed ar e as f oll o ws: D ate a nd ti m e of  E C G, h e art r at e, P R  I nt erv al, Q R S d ur ati o n, 
Q R S Axis, U nc orr ect e d Q T  i nterv al, C orr ect e d Q T  i nterv al ( Q Tc), M et h od of Q Tc c alc ul ati on (i. e. B az ett) 
1 8 . 
Ec h oc ar di o gr a m scr e e ni n g ass ess m e nts ( m ovi n g vi d e o gr a p hy) m ust b e  p erf or m e d wit hi n 3 5  d ays pri or t o first d os e a n d  at  w e eks 4, 1 2 a n d  t h e n ev ery 1 2  w e eks u p to 
a n d i ncl u di n g disc o nti n u ati o n visit. A n  ec h oc ar di o gr a m will n e e d  t o b e  p erf or m e d at  st u dy disc o nti n u ati o n u nl ess o n e  h as  b e e n  p erf or m e d wit hi n t h e l ast 8 w e eks. Pl e as e s e e 
S ecti o n 7. 4. 9  f or L V E F g ui d eli n es f or st u dy dr u g m a n a g e m e nt a n d  r e q uir e m e nts f or E C H O Sc a ns. 
1 9 . A dv ers e ev e nts a n d S eri o us A dv ers e Ev e nts will b e  r ec or d e d f or m t h e ti m e of  first d os e of  st u dy tr e at m e nt is a d mi nist er e d u ntil 3 0  d ays aft er  disc o nti n u ati o n of  st u dy tr e at m e nt.  
All S A Es ass ess e d as r el at e d t o st u dy p artici p ati o n ( e. g. r el at e d t o st u dy pr oc e d ur es) s h o ul d b e c oll ect e d fr o m ti m e of i nf or m e d c o ns e nt. Pl e as e r ef er t o s ecti o n 7. 4. 2. 6 f or 
r e p orti n g ti m eli n es.  
2 0 . S ki n E x a m F oll o w- u p  c o nt a ct: Ev ery m o nt h u p  t o a n d i ncl u di n g m o nt h 6 f oll o wi n g st u dy tr e at m e nt disc o nti n u ati o n ( or u ntil n e w  a nt i-c a nc er t h er a py i niti at e d),, all s u bj ects w h o 
p er m a n e ntly disc o nti n u e st u dy tr e at m e nt will  b e  f oll o w e d f or s urviv al, d er m at ol o gic ski n ass ess m e nts a n d  n e w  a nti -c a nc er t h er a pi es (i ncl u di n g r a di ot h er a py a n d  s ur g ery). T h e 
d at e  of  t h e visit m ust b e  r ec or d e d. 
2 1 .  I ntr acr a ni al T u m o ur ass ess m e nt is c o n d uct e d wit h c o ntr ast- e n h a nc e d M RI a n d  a p pli e d usi n g m o difi e d R E CI S T 1. 1 crit eri a. T ar g et a n d  n o n-t ar g et l esi o ns m ust b e  i d e ntifi e d at  
ti m e of scr e e ni n g sc a n a n d  t h e s a m e l esi o ns m ust b e  r e- ass ess e d at  e ac h r est a gi n g sc a n. Br ai n sc a ns s h o ul d occ ur at  4 w e eks, 8 w e eks, a n d  t h e n ev ery 8 w e eks t h er e aft er 
u ntil w e ek 4 0.  At  w e ek 4 0,  sc a ns m ay occ ur ev ery 1 2  w e eks, u nl ess r es p o ns e c o nfir m ati o n is i n dict e d. C o m pl et e r es p o ns e/ p arti al r es p o ns e c o nfir m ati o n ass ess m e nts m ust 
t ak e pl ac e at  l e ast 4 w e eks aft er  t h e i niti al r es p o ns e. If t h e l ast r a di o gr a p hic ass ess m e nt f or i ntr acr a ni al dis e as e w as m or e t h a n 8 w e eks pri or t o disc o nti n u ati o n fr o m st u dy a n d  
pr o gr essiv e dis e as e h as  n ot  b e e n  d oc u m e nt e d, dis e as e ass ess m e nt s h o ul d b e  o bt ai n e d at  t h e ti m e of  st u dy disc o nti n u ati o n. 
2 2 . Extr acr a ni al t u m o ur ass ess m e nt is c o n d uct e d usi n g R E CI S T 1. 1  crit eri a. T ar g et a n d  n o n-t ar g et l esi o ns m ust b e  i d e ntifi e d at  ti m e of  scr e e ni n g sc a n a n d  t h e s a m e l esi o ns m ust b e 
r e- ass ess e d at  e ac h r est a gi n g sc a n. Sc a ns s h o ul d occ ur at  4 w e eks, 8 w e eks a n d  t h e n ev ery 8 w e eks t h er e aft er u ntil w e ek 4 0.  At  w e ek 4 0,  sc a ns m ay occ ur ev ery 1 2  w e eks, 
u nl ess r es p o ns e c o nfir m ati o n is i n dic at e d. C o m pl et e r es p o ns e / p arti al r es p o ns e c o nfir m ati o n ass ess m e nts m ust t ak e pl ac e at  l e ast 4 w e eks aft er  t h e i niti al r es p o ns e. If t h e l ast 
r a di o gr a p hic ass ess m e nt f or extr acr a ni al dis e as e w as m or e t h a n 8 w e eks pri or t o disc o nti n u ati o n fr o m st u dy a n d  pr o gr essiv e dis e as e h as  n ot  b e e n  d oc u m e nt e d, dis e as e 
ass ess m e nt s h o ul d b e  o bt ai n e d at  t h e ti m e of  st u dy disc o nti n u ati o n. 
2 3 . 
 
2 4 . S urvi v al F oll o w- u p c o nt a ct : All s u bj ects w h o p er m a n e ntly disc o nti n u e st u dy tr e at m e nt will  b e  f oll o w e d f or s urviv al f oll o w u p a n d n e w a nt i-c a nc er t h er a py, ev ery 1 2  w e eks (7 

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d ays) u ntil d e at h, s u bj ect wit h dr a w al or  st u dy cl os ur e. F oll o w u p  c o nt act m ay i ncl u d e cli nic visits, t el e p h o n e c o nt acts or  e m ail c o m m u nic ati o ns. T h e d at e  of  c o nt act m ust b e  
r ec or d e d. 
2 5.  D oc u m e nt all m e dic ati o ns t ak e n fr o m t h e ti m e of  scr e e ni n g u ntil 3 0  d ays aft er  t h e l ast d os e of  st u dy tr e at m e nt wit h t h e exc e pti o n of  n e w  a nti -c a nc er t h er a py, if t ak e n aft er st u dy 
tr e at m e nt disc o nti n u ati o n; t h es e will  b e  d oc u m e nt e d u ntil st u dy c o m pl eti o n/ wit h dr a w al or  d e at h.  Any c o nc o mit a nt m e dic ati o n(s), i ncl u di n g di et ary s u p pl e m e nts, t ak e n d uri n g 
t h est u dy will b e  r ecor d e d i n t h e e C R F 
2 6.  T h e tre at m e nt di s c o nti n u ati o n vi sit  s h o ul d b e  p erf or m e d wit hi n 3 0  d ays of  t h e s u bj ect’s l ast d os e. If a s u bj ect disc o nti n u es st u dy tr e at m e nt at  a sc h e d ul e d visit, t h e 
ass ess m e nts p erf or m e d at  t h at visit c a n b e  us e d t o f ulfill t h e tr e at m e nt disc o nti n u ati o n visit r e q uir e m e nts. L a b or at ory ass ess m e nts a n d  ot h er  r e q uir e d ass ess m e nts d o  n ot  n e e d  t o 
b e  r e p e at e d at t h e  disc o nti n u ati o n visit if t h ey w er e p erf or m e d wit hi n 1 4  a n d  3 0  d ays, r es p ectiv ely, of  t h e disc o nti n u ati o n visit. If t h e l ast dis e as e ass ess m e nt w as > 8  w e eks pri or 
t o st u dy with dr a w al a n d  dis e as e pr o gr essi o n h a d  n ot  b e e n  d oc u m e nt e d, a dis e as e ass ess m e nt s h o ul d b e  o bt ai n e d. 
2 7.  Pr o gre s si v e Di s e a s e F oll o w U p  (if a p pli c a bl e): F or t h os e s u bj ects w h o p er m a n e ntly disc o nti n u e st u dy tr e at m e nt wit h o ut pr o gr essiv e dis e as e will h av e r a di o gr a p hic dis e as e 
ass ess m e nts p erf or m e d o n  t h e s a m e ass ess m e nt sc h e d ul e n ot e d  i n t h e Ti m e a n d  Ev e nts (T a bl e 1 9)  ev ery 8 w e eks u ntil W e ek 4 0  a n d  t h e n ev ery 1 2  w e eks t h er e aft er u ntil 
dis e as e pr o gr essi o n, st art of  n e w  a nt i-c a nc er t h era py  or  d e at h.  T h e d at e  of  t h e visit m ust b e  r ec or d e d. 
*** S p e ci al N ot e*** D o s e M o difi c ati o n G ui d eli n e s m a y re q uire bl o o d s a m pl e s t h at ar e n ot  i n dic at e d i n t hi s ti m e a n d e v e nt s e c ti o n T a bl e 1 9 . If a p ati e nt h a s a d os e 
m o difi c ati o n, ref er t o t h e s p e cifi c D o s e M o difi c ati o n G ui d eli n e s e cti o n of  t h e pr ot o c ol f or f urt her re c o m m e n d ati o n s a n d re q uire m e nt s of  bl o o d s a m pl e s. 

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7. 1.  
Criti c al  B a s eli n e A s s e s s m e nt s 
Efficac y assess me nts c o n d ucte d at baseli ne are des cri be d i n Secti o n 7. 2. 2 , t u m o ur 
bi o mar ker a n al ysis are d escri be d i n Secti o n 7. 6 .  Safet y assess me nts c o n d ucte d at 
baseli ne a n d d uri n g tr eat me nt are des cri be d i n Secti o n 7. 4 .  Car di o vasc ular me dical 
hist or y/ris k fact ors will be assesse d at baseli ne. 
7. 1. 1. B a s eli n e D o c u m e nt ati o n of I ntr a cr a ni al T ar g et a n d N o n- T ar g et  L e si o n s 
 
All baseli ne lesi o n assess me nts m ust be perf or me d 2 8 da ys pri or t o t he first d ose 
of st u d y tr eat me nt. 
 
Meas ura ble a n d n o n- meas ura ble i ntracra nial (i. e. brai n pare nc h y ma) l esi o ns (refer 
t o Secti o n 7. 3. 1  f or st u d y defi niti o n of meas ura ble i ntracra ni al lesi o ns) u p t o a 
ma xi m u m of 5 lesi o ns s h o ul d be i de ntifie d as tar get lesi o ns, a n d rec or de d a n d 
meas ure d at baseli ne. T h ese lesi o ns s h o ul d be selecte d o n t he basis of t heir siz e 
(lesi o ns wit h t he l o n gest dia meter) a n d t heir s uita bilit y f or acc urate re peat e d 
meas ure me nts ( b y i ma gi n g tec h ni q ues). 
N ote: C ystic lesi o ns t h o u g ht t o re prese nt c ystic m etastases s h o ul d n ot be 
selecte d as t ar get lesi o ns w he n ot her s uita ble tar get lesi o ns are a vaila bl e. 
N ote : Meas ur a ble i ntracra nial lesi o ns t hat ha ve bee n pre vi o usl y irra diate d a n d 
ha ve n ot bee n s h o w n t o be p r o gressi n g f oll o wi n g irra diati o n s h o ul d n ot be 
c o nsi dere d as tar get lesi o ns. 
 
All ot her i ntracra nial lesi o ns s h o ul d be i de ntifie d as n o n-tar get a n d s h o ul d 
als o be rec or de d at baseli ne. Meas ure me nts of n o n-tar get lesi o ns are n ot 
re q uire d, b ut t he prese n ce or  a bse nce of eac h s h o ul d be n ote d t hr o u g h o ut 
f oll o w- u p. 
7. 1. 2.   
B a s eli n e D o c u m e nt ati o n of E xtr a cr a ni al T ar g et a n d N o n- T ar g et 
  
  
L e si o n s 
 
All baseli ne lesi o n assess me nts m ust be perf or me d 2 8 da ys pri or t o t he first d ose 
of st u d y tr eat me nt. 
 L y m p h n o des t hat ha ve a s h ort a xis of < 1 0 m m are c o nsi dere d n o n- pat h ol o gical 
a n d s h o ul d n ot be rec or de d or f oll o we d. 
 
Pat h ol o gical l y m p h n o des wit h < 1 5 m m a n d 1 0 m m s h ort a xis are c o nsi dere d n o n 
meas ura ble. 
 
Pat h ol o gical l y m p h n o des wit h 1 5 m m s h ort a xis are c o nsi dere d meas ura ble a n d 
can be sele cte d as tar get lesi o ns, h o we ver l y m p h n o des s h o ul d n ot be selecte d as 
tar get lesi o ns w he n ot her s uita ble tar get lesi o ns are a vaila ble. 
 
Meas ura ble l esi o ns u p t o a ma xi m u m of 2 lesi o ns per or ga n a n d 5 lesi o ns i n t otal, 
re pres e ntati ve of all i n v ol ve d e xtracra nial or ga ns, s h o ul d be i de ntifie d as tar get 
lesi o ns, a n d rec or de d a n d meas ure d at baseli ne. T h ese lesi o ns s h o ul d be selecte d 
o n t he basis of t heir siz e (lesi o ns wit h t he l o n gest dia meter) a n d t heir s uita bilit y f or 

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acc urate re peate d meas ur e me nts (eit her b y i ma gi n g tec h ni q ues or cli nicall y). 
N ote: C ystic lesi o ns t h o u g ht t o re prese nt c ystic m etastases s h o ul d n ot be selecte d 
as tar get lesi o ns w he n ot her s uita ble tar get lesi o ns are a v aila ble. 
N ote : Meas ur a ble e xtracra nial lesi o ns t hat ha ve bee n pre vi o usl y irra di ate d a n d 
ha ve n ot bee n s h o w n t o be pr o gressi n g f oll o wi n g irra diati o n s h o ul d n ot be 
c o nsi dere d as tar get lesi o ns. 
 L y ti c b o ne lesi o ns or mi x e d l ytic- blastic lesi o ns, wit h i de ntifia ble s oft tiss ue 
c o m p o ne nts, t hat ca n be e val uate d b y C T or M RI ca n be c o nsi dere d m eas ura ble. 
B o ne sca ns, F D G- P E T sca ns or X- r ays are n ot c o nsi dere d a d e q uate i ma gi n g 
tec h ni q ues t o meas ur e b o ne lesi o ns. 
 
All ot her lesi o ns ( or sites of disease, e x cl u di n g t h e brai n) s h o ul d be i de ntifi e d as 
n o n -tar get a n d s h o ul d als o be rec or d e d at bas eli ne. N o n-tar get lesi o ns will be 
gr o u pe d b y or ga n. Meas ure me nts of t hese l esi o ns are n ot r e q uire d, b ut t he 
prese nce or a bs e nce of ea c h s h o ul d be n ote d t hr o u g h o ut f oll o w- u p.  
7. 2.  
Effi c a c y 
F or t his st u d y,  effi cac y c o m prises i ntracra ni al, e xtracra nial a n d o v erall res p o nse a n d 
disease c o ntr ol, d ur ati o n of all res p o nses, P F S, a n d O S.  I ntr acra nial, e xtracra nial a n d 
o verall res p o ns e assess m e nts c o n d ucte d at b aseli n e a n d d uri n g t he st u d y are descri b e d i n 
Secti o n 7. 2.   I ntracra nial, e xtracra nial, a n d o v erall res p o nse will be ass esse d b y R E CIS T  
1. 1 wit h m o dificati o ns. 
7. 2. 1. Effi c a c y E n d p oi nt s  
T he pri mar y effi cac y e n d p oi nt of t his st u d y is t he i ntracra nial res p o nse rate (I R) i n B R A F 
V 6 0 0 E m utati o n p ositi ve s u bjects ( C o h ort A).  T h e I R is defi ne d as t he p erce nta ge of 
s u bjects w h ose i ntracra ni al res p o nse is a c o nfir me d C o m plete Res p o nse ( C R) or Partial 
res p o nse ( P R) assess e d b y i n v esti gat or usi n g m o difie d R E CI S T 1. 1 criteria. 
7. 2. 1. 1.  
S e c o n d ar y E n d p oi nt s 
T he f oll o wi n g e n d p oi nts will be assesse d as sec o n dar y e n d p oi nts i n all c o h orts ( u nless 
state d ot her wise) 
 
I R i n C o h ort B, C a n d D 
 
I ntr acra nial diseas e c o ntr ol (I D C) 
 
e xtracra nial res p o nse rate ( E R R) 
 
o verall res p o ns e rate ( O R R) 
 
d urati o n of i ntracra nial, e xtracra nial a n d o verall res p o nse ( DI R, D E R a n d D O R 
  
res pecti vely)  
 
pr o gressi o n-free s ur vi val ( P F S) 

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 
o verall s ur vi val ( O S) a n d l o n g-ter m ( p artic ularl y 3- year) O S 
 
Safet y of da brafe ni b a n d tra meti ni b c o m bi nati o n t hera p y 
7. 2. 2. Effi c a c y A s s e s s m e nt  
Disease pr o gressi o n a n d res p o nse e v al uati o ns f or i ntr acr a ni al a n d e xtr acr a ni al disease 
will be deter mi ne d acc or di n g t o t he defi niti o ns est a blis he d i n t he Res p o nse E val uati o n 
Criteria i n S oli d T u m o urs ( R E CI S T 1. 1) [ Eise n ha uer , 2 0 0 9]; Mi n or m o dificati o ns will be 
a p plie d t o t he assess me nt of i ntracra nial lesi o ns: 
 
Ge ner al : tar get lesi o ns s h o ul d be re prese ntati ve of t he s u bject’s bas eli ne t u m o ur 
b ur de n a n d s h o ul d be s electe d bas e d o n t heir siz e (i.e. lesi o ns wit h t he l o n gest 
dia meter) a n d t heir s uita bilit y f or acc urate re peat assess me nt. 
 
I ntr acr a ni al lesi o ns: (t he m o dificati o ns t o R E CI S T 1. 1. i m pact t he n u m ber a n d 
t he mi ni mal size of t he tar get lesi o ns selecte d at baseli ne) u p t o fi ve lesi o ns 
s h o ul d be selecte d as tar get lesi o ns; all brai n l esi o ns i n e xcess of t hese fi ve t ar get 
lesi o ns ha ve t o be re gar de d as n o n-tar get lesi o ns.  Meas ura ble l esi o ns are d efi ne d 
as t h ose t hat ca n b e acc uratel y meas ure d i n at least o ne di me nsi o n wit h t he 
l o n gest dia meter  5 m m w he n e val u ate d wit h c o ntrast-e n ha nce d M RI.  
C o ntr ast-e n h a nce d M RI is t he o nl y i m a gi n g m o d alit y acce pte d f or t he 
assess me nt of i ntr acr a ni al lesi o ns.  
 
E xtr acr a ni al lesi o ns : u p t o t w o lesi o ns per or ga n re prese nt ati ve of all i n v ol ve d 
or ga ns s h o ul d be selecte d as tar get lesi o ns; t he t otal n u m ber of tar get lesi o ns 
s h o ul d n ot e x cee d fi ve a n d all lesi o ns i n e x cess of t hese fi ve tar get lesi o ns ha ve 
t o be re gar de d as n o n-tar get lesi o ns. 
See t he Ti me a n d E v e nts ( Ta ble 1 9 ) f or t h e sc he d ule of i ntracra nial a n d o v erall efficac y 
assess me nts.  Assess me nts m ust be perf or me d o n a cale n dar sc h e d ule a n d s h o ul d n ot be 
affecte d b y d ose i nterr u pti o ns.  F or p ost baseli ne assess me nts, a wi n d o w of 3  da ys is 
per mitte d t o all o w f or fle xi ble sc he d uli n g. 
T he f oll o wi n g assess me nts are re q uire d at b aseli ne: 
 
C o ntrast e n ha nce d brai n M RI 
 
C T f or c hest/a b d o me n/ pel vis or M RI f or a b d o me n/ pel vis 
 
Cli nical assess me nt f or p al pa ble a n d/ or c uta ne o us lesi o ns usi n g calli pers or 
p h ot o gra p h y.  
As o utli ne d i n ( Ta ble 1 9 ) at s pecific p ost bas eli ne assess me nt ti me p oi nts, re peat 

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e val uati o ns of t he tar get- a n d n o n -tar get lesi o ns i d e ntifie d b y t he b aseli ne M RI / C T sca ns 
a n d cli nical assess me nts (calli per, p h ot o gra p h y)  are re q uire d. 
C o nfir m ati o n of i ntr acr a ni al, e xtr acr a ni al a n d o ver all C R a n d P R is re q uire d per 
pr ot oc ol.  C o nfir mati o n assess me nts m ust be perf or me d n o less t ha n 4 wee ks after t he 
criteria f or res p o ns e ha ve i nitiall y b ee n met a n d m a y b e perf or me d at t he ne xt pr ot oc ol 
sche d ule d ass ess me nt.  If a c o nfir mati o n assess me nt is perf or me d pri or t o t he ne xt 
pr ot oc ol sc he d ule assess me nt, t he ne xt pr ot oc ol sc he d ule d e v al uati o n is still re q uire d 
(i.e., re g ularl y sc he d ul e d st u d y visit e val uati o ns m ust occ ur at eac h pr ot o c ol sc he d ule d 
ti me p oi nt re gar dless of u nsc he d ule d assess me nts). If t he criteria f or a C R or P R are n ot 
c o nfir me d, t he n sta ble disease ( S D) ca n b e c o nsi d ere d t he best res p o nse if it has bee n 
de m o nstrate d f or a mi ni m u m of 8 wee ks. 
7. 2. 2. 1.  
A s s e s s m e nt G ui d eli n e s  
F or i ntr acr a ni al lesi o n assess me nts:  
 
C o ntrast-e n ha nce d M RI m ust be use d t hr o u g h o ut t he st u d y. C o ntrast-e n ha n ce d 
M R I is t he o nl y i ma gi n g m o dalit y acce pte d f or t he assess me nt of i ntracra ni al 
lesi o ns. 
 
T he tec h nic al s pecificati o n of t he M RI sca n ni n g s e q ue nces s h o ul d be o pti mise d 
f or t he e v al uati o n of brai n lesi o ns w hic h m ust be meas ure d i n t he sa m e a n at o mic 
pla ne b y use of t he s a me i ma gi n g e x a mi nati o ns. W he ne ver p ossi ble t he sa me 
sca n ner s h o ul d b e use d. [Eise n ha uer , 2 0 0 9]. 
 
 As a m o dificati o n t o R E CI S T 1. 1, tar get lesi o ns as s mall as 5 m m ma y be 
selecte d, h o we ver t h e sca n ni n g s h o ul d be i n acc or da nce wit h R E CI S T 1. 1: 
c o nti g u o us slices of m a xi m u m t hic k ness c orres p o n di n g t o half t he size of t h e 
lesi o n. [Eise n ha uer , 2 0 0 9] All meas ure me nts m ust be ta ke n a n d rec or de d i n 
milli metres ( m m), usi n g a r uler or calli pers. 
 
Refer t o I ma ge Ac q uisiti o n G ui deli nes ( Brai n M RI) f or slice t hic k ness 
re q uire me nts t hat s h o ul d be perf or me d i n acc or d a nce wit h R E CI S T 1. 1 crit eria. 
F or e xtr acr a ni al lesi o n assess me nts:  
 
C o ntrast-e n ha nce d C T ( preferre d) or M RI is rec o m me n de d. 5 m m c o nti g u o us 
slices are rec o m me n d e d. T he mi ni m u m size of a meas ura ble e xtracra nial 
baseli ne lesi o n s h o ul d be t wice t he slice t hic k ness, wit h a mi ni m u m lesi o n size 
of 1 0 m m. w he n t he slice t hic k ness is 5 m m. M RI is acce pta bl e, b ut w he n use d, 
t he tec h nical s pe cificati o n of t he sca n ni n g se q ue n ces s h o ul d be o pti mise d f or t he 
e val uati o n of t he t y pe a n d site of disease a n d l esi o ns m ust be meas ure d i n t he 
sa me a nat o mic pla n e b y use of t he sa me i ma gi n g e x a mi nati o ns.  W he ne ver 
p ossi ble t he sa me sca n n er s h o ul d be use d. [ Eise n ha uer , 2 0 0 9]. 
 
Cli nical e x a mi nati o n: S ki n n o d ules or pal pa ble lesi o ns will o nl y be c o nsi dere d 
meas ura ble w he n t he y are s u perfici al. I n t he case of s ki n lesi o ns, d oc u me ntati o n 
b y c ol o ur p h ot o gra p h y ( ca meras will be pr o vi d e d b y t he s p o ns or fr o m ce ntral 
ve n d or) is necessar y. F or b ot h s ki n n o d ules a n d pal pa ble lesi o ns, size 
meas ure me nts usi n g a r uler/calli per are re q uir e d. [ Eise n ha uer , 2 0 0 9]. 

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 
X-r ay s h o ul d n ot be us e d f or tar get lesi o n meas ure me nts o wi n g t o p o or lesi o n 
defi niti o n. 
 
Ultras o u n d is n ot a s uita ble m o dalit y of diseas e ass ess me nt.  If ne w l esi o ns are 
i de ntifie d b y ultras o u n d, c o nfir mati o n b y C T o r M R I is r e q uire d. 
 
Fl u or o de ox y gl uc os e ( F D G)- P E T is ge nerall y n ot s uita ble f or o n g oi n g 
assess me nts of disease.  H o we ver F D G- P E T ca n be usef ul i n c o nfir mi n g n e w 
sites of disease w h ere a p ositi ve F D G- P E T sca ns c orrelates wit h t he ne w site of 
disease pres e nt o n  C T/ M RI or w he n a b aseli ne F D G- P E T was pre vi o usl y 
ne gati ve f or t h e site of t h e ne w lesi o n. F D G- P E T ma y als o be us e d i n lie u of a 
sta n dar d b o ne s ca n pr o vi di n g c o v era ge all o ws i nterr o gati o n of all li kel y sites of 
b o ne disease a n d F D G- P E T is perf or me d at all assess me nts. 
 
If P E T/ C T is perf or me d t he n t he C T c o m p o ne nt ca n o nl y be use d f or sta n d ar d 
res p o nse ass ess me nts if perf or me d t o dia g n ostic q ualit y, w hic h i ncl u des t h e 
re q uire d a nat o mical c o v era ge a n d prescri be d use of c o ntrast.  T he m et h o d of 
assess me nt s h o ul d be n ote d as C T o n t he C R F. 
7. 2. 2. 2.  
F oll o w- U p A s s e s s m e nt s f or S u bj e ct s P er m a n e ntl y Di s c o nti n u e d fr o m 
  
  
St u d y Tr e at m e nt 
All s u bjects w h o per ma n e ntl y disc o nti n ue st u d y tr eat me nt will ha ve m o nt hl y s ki n 
assess me nts, s ur vi val f oll o w u p a n d ne w a nti-ca ncer t hera p y (i ncl u di n g ra di ot hera p y a n d 
s ur ger y f oll o w u p) t hr o u g h m o nt h 6 after treat me nt disc o nti n uati o n. If t he y start ne w a nti- 
ca ncer t hera p y or at t he e n d of t he 6 m o nt h f oll o w u p visit, t he y will be f oll o we d e ver y 1 2 
wee ks f or s ur vi val f oll o w u p a n d ne w a nti-ca n cer t hera p y (i ncl u di n g ra di ot hera p y a n d 
s ur ger y) u ntil deat h or st u d y c o m pleti o n. I n a d diti o n, t h ose s u bjects w h o p er ma ne ntl y 
disc o nti n ue st u d y tr eat m e nt wit h o ut pr o gressi ve disease will ha ve ra di o gra p hic disease 
assess me nts perf or me d o n t he sa me assess me nt sc he d ule n ote d i n t he Ti me a n d E ve nts 
(Ta ble 1 9 ) e v er y 8 w ee ks u ntil W ee k 4 0 a n d t he n e ver y 1 2 wee ks t hereafter u ntil disease 
pr o gressi o n, start of n e w a nti-ca ncer t hera p y or deat h. 
7. 2. 2. 3.  
A s s e s s m e nt of S u bj e ct C o m pl eti o n 
If t he last ra di o gra p hic assess me nt f or i ntracra nial disease, e xtracra nial disease or b ot h 
was m ore t ha n 8 wee ks pri or t o disc o nti n uati o n fr o m st u d y a n d pr o gressi ve disease has 
n ot bee n d oc u me nte d, t h e a p pr o pri ate diseas e ass ess me nt s h o ul d be o bt ai ne d at t he ti me 
of st u d y disc o nti n uati o n. 
7. 3.  
G ui d eli n e s  f or E v al u ati o n of  Di s e a s e 
7. 3. 1. M e a s ur a bl e a n d N o n- M e a s ur a bl e D efi niti o n s f or I ntr a cr a ni al Di s e a s e  
Me as ur a ble i ntr acr a ni al lesi o n: A lesi o n t hat ca n be acc uratel y meas ure d i n at least o ne 
di me nsi o n wit h t he l o n gest dia meter  5 m m w he n e val uate d wit h c o ntrast- e n ha nce d M R I. 
N o n- me as ur a ble i ntr acr a ni al lesi o n: All ot her lesi o ns i ncl u di n g lesi o ns t o o s mall t o be 
c o nsi dere d me as ura bl e (l o n gest dia met er < 5 m m). 
Me as ur a ble i ntr acr a ni al dise as e : T he prese nce of at least o ne meas ura bl e lesi o n. 

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N o n- Me as ur a ble o nl y i ntr acr a ni al dise as e : T he prese nce of o nl y n o n- meas ura ble 
lesi o ns w hic h w o ul d e x cl u de t he s u bject fr o m p artici pati o n i n t his st u d y. 
7. 3. 1. 1.  
M e a s ur a bl e a n d N o n- M e a s ur a bl e D efi niti o n s f or E xtr a cr a ni al Di s e a s e 
Me as ur a ble e xtr acr a ni al lesi o n: A n o n n o dal lesi o n t hat ca n be acc uratel y meas ure d i n 
at least o ne di me nsi o n (l o n gest di me nsi o n) of 
 
 1 0 m m wit h M RI or C T wit h a rec o m me n de d c o nti g u o us slice t hic k ness of 5 m m. 
i.e. mi ni m u m size of meas ura ble baseli ne l esi o n s h o ul d be t wice t he slice t hic k ness 
 
 1 0 m m calli per/r uler m eas ure m e nt or me dical p h ot o gra p h y.  
A d diti o nall y l y m p h n o des ca n be c o nsi d ere d p at h ol o gicall y e nlar ge d a n d meas ura ble if: 
 
1 5 m m i n t he s h ort a xis w he n assesse d b y C T  or M RI (slice t hic k n ess 
rec o m me n de d t o b e n o m ore t ha n 5 m m).  At baseli ne a n d f oll o w- u p, o nl y t he 
s h ort a xis will be meas ure d [Eise n ha uer , 2 0 0 9]. 
N o n- me as ur a ble e xtr acr a ni al lesi o n: All ot her lesi o ns i ncl u di n g lesi o ns t o o s mall t o be 
c o nsi dere d me as ura ble (l o n gest dia met er < 1 0 m m or pat h ol o gical l y m p h n o des wit h ≥ 1 0 
m m a n d < 1 5 m m s h ort a xis) as well as tr ul y n o n - meas ura ble l esi o ns, w hic h i ncl u de: 
ascites, ple ural or pericar dial eff usi o ns, i nfla m mat or y breast disease, l y m p h a n gitic 
i n v ol ve me nt of t he s ki n or l u n g, a b d o mi nal masses/a b d o mi nal or ga n o me gal y i d e ntifie d b y 
p h ysical e x a m t hat is n ot meas ura ble b y re pr o d u ci ble i ma gi n g tec h ni q ues [ Eise n ha uer , 
2 0 0 9]. 
Me as ur a ble e xtr acr a ni al dise as e : T he prese nce of at least o ne meas ura bl e lesi o n. 
Pal pa ble lesi o ns t hat are n ot meas ura ble b y ra di ol o gic or p h ot o gra p hic e val uati o ns ma y 
n ot be utilise d as t he o nl y meas ura ble lesi o n. 
N o n- Me as ur a ble o nl y e xtr acr a ni al dise as e : T he prese nce of o nl y n on - meas ura ble 
lesi o ns. 
7. 3. 2. R e s p o n s e Crit eri a  
7. 3. 2. 1.  
I ntr a cr a ni al R e s p o n s e (I R) - E v al u ati o n of  I ntr a cr a ni al T ar g et L e si o n s 
Defi niti o ns f or assess me nt of res p o nse f or i ntr acr a ni al t ar get lesi o n(s) are as f oll o ws: 
 
C o m plete Res p o nse ( C R): Disa p peara nce of all tar get lesi o ns. 
 
Partial Res p o nse ( P R):  At least a 3 0 % decrease i n t he s u m of t he dia meters of t ar get 
lesi o ns, ta ki n g as a refere nce, t he baseli ne s u m of t he dia meters (e. g. perce nt c ha n ge 
fr o m baseli ne). 
 
Sta ble Disease ( S D): N eit her s ufficie nt s hri n k a ge t o q ualif y f or P R n or s ufficie nt 
i ncreas e t o q ualif y f or pr o gressi ve diseas e. 
 
Pr o gressi ve Diseas e ( P D): At least a 2 0 % i ncrease i n t he s u m of t he dia meters of 
tar get lesi o ns, ta ki n g as a refere nce, t he s mallest s u m of dia meters rec or d e d si nce t he 
treat me nt starte d (e. g. perce nt c ha n ge fr o m na dir, w here n a dir is defi ne d as t he 
s mallest s u m of dia meters rec or d e d si nce tr eat me nt start). I n a d diti o n, t he s u m m ust 

8 1  
N o v arti s 
C o nfi d e nti al 
P a g e 8 1  
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
ha ve a n a bs ol ute i ncrease fr o m na dir of 5 m m. 
 
N ot E val ua ble ( N E): Ca n n ot be classifie d b y o ne of t he f o ur prece di n g d efi niti o ns. 
N ote:  
 
If a n i ntracra ni al tar get lesi o n disa p p ears a n d rea p pears at a s u bse q ue nt ti m e p oi nt it 
s h o ul d c o nti n ue t o be meas ure d.  T he res p o nse at t he ti me w he n t he lesi o n r ea p pears 
will de pe n d u p o n t he stat us of t he ot her lesi o ns.  F or e x a m ple, if t he disease ha d 
reac h e d a C R stat us t he n P D w o ul d be d oc u me nte d at t he ti me of rea p peara nce. 
H o we ver, if t he res p o ns e stat us was P R or S D, t he dia meter of t he rea p p eari n g lesi o n 
s h o ul d be a d de d t o t he re mai ni n g dia meters a n d res p o nse deter mi ne d bas e d o n perce nt 
c ha n ge fr o m baseli ne a n d perce nt c ha n ge fr o m na dir.  
7. 3. 2. 2.  
I ntr a cr a ni al R e s p o n s e (I R) - E v al u ati o n of  I ntr a cr a ni al N o n- T ar g et  
  
  
L e si o n s 
Defi niti o ns f or assess me nt of res p o nse f or i ntracra nial n o n-tar get lesi o ns are as f oll o ws: 
 
C o m plete Res p o nse ( C R):  T he disa p peara nce of all n o n-tar get lesi o ns. 
 
N o n- C R/ N o n- P D:  T he persiste nce of 1 or m ore n o n-tar get lesi o n(s) i de ntifie d as a 
site of disease. 
 
Pr o gressi ve Diseas e ( P D): U ne q ui v ocal pr o gressi o n of e xisti n g n o n-tar get l esi o ns. 
 
N ot A p plica ble ( N A): N o i ntracra ni al n o n-tar get l esi o ns at baseli ne. 
 
N ot E val ua ble ( N E): Ca n n ot be classifie d b y o n e of t he f o ur prece di n g d efi niti o ns. 
N ote:  
 
I ntr acra nial n o n-tar get lesi o ns, w hic h are n ot ass esse d at a partic ul ar ti me p oi nt base d 
o n t he assess me nt sc he d ule, s h o ul d be e x cl u de d fr o m t he res p o nse deter mi nati o n (e. g. 
n o n -tar get res p o nse d o es n ot ha ve t o be " N ot E val ua ble"). 
7. 3. 2. 3.  
E xtr a cr a ni al R e s p o n s e ( E R) - E v al u ati o n of E xtr a cr a ni al T ar g et L e si o n s 
Defi niti o ns f or assess me nt of res p o nse f or e xtr acr a ni al t ar get lesi o n(s) are as f oll o ws: 
 
C o m plete Res p o nse ( C R): Disa p peara nce of all tar get lesi o ns. 
 
Partial Res p o nse ( P R):  At least a 3 0 % decrease i n t he s u m of t he dia met ers of tar get 
lesi o ns, ta ki n g as a refere nce, t he baseli ne s u m of t he dia meters (e. g. perce nt c ha n ge 
fr o m baseli ne). 
 
St a ble Disease ( S D): N eit her s ufficie nt s hri n k a ge t o q ualif y f or P R n or s ufficie nt 
i ncreas e t o q ualif y f or pr o gressi ve diseas e. 
 
Pr o gressi ve Diseas e ( P D): At least a 2 0 % i ncrease i n t he s u m of t he dia meters of 
tar get lesi o ns, ta ki n g as a refere nce, t he s mallest s u m of dia meters rec or d e d si nce t he 
treat me nt starte d (e. g. perce nt c ha n ge fr o m na dir, w here n a dir is defi ne d as t he 
s mallest s u m of dia meters rec or d e d si nce tr eat me nt start). I n a d diti o n, t he s u m m ust 

8 2  
N o v arti s 
C o nfi d e nti al 
P a g e 8 2  
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
ha ve a n a bs ol ute i ncrease fr o m na dir of 5 m m. 
  
N ot E val ua ble ( N E):  Ca n n ot be classifie d b y o ne of t he f o ur prece di n g d efi niti o ns. 
N ote:  
 
If a n e xtracra nial tar get lesi o n disa p pears a n d rea p pears at a s u bse q ue nt ti me p oi nt it 
s h o ul d c o nti n ue t o be meas ure d.  T he res p o nse at t he ti me w he n t he lesi o n r ea p pears 
will de pe n d u p o n t he stat us of t he ot her lesi o ns.  F or e x a m ple, if t he disease ha d 
reac h e d a C R stat us t he n P D w o ul d be d oc u me nte d at t he ti me of rea p peara nce. 
H o we ver, if t he res p o ns e stat us was P R or S D, t he dia meter of t he rea p p eari n g lesi o n 
s h o ul d be a d de d t o t he re mai ni n g dia meters a n d res p o nse deter mi ne d bas e d o n perce nt 
c ha n ge fr o m b aseli ne a n d perce nt c ha n ge fr o m na dir. 
7. 3. 2. 4.  
E xtr a cr a ni al R e s p o n s e ( E R) - E v al u ati o n of E xtr a cr a ni al N o n- T ar g et 
L e si o n s 
Defi niti o ns f or assess me nt of res p o nse f or e xtracra nial n o n -tar get lesi o ns are as f oll o ws: 
 
C o m plete Res p o nse ( C R):  T he disa p peara nce of all n o n -tar get lesi o ns. 
 
N o n- C R/ N o n- P D:  T he persiste nce of 1 or m ore n o n-tar get lesi o n(s) i de ntifie d as a 
site of disease. 
 
Pr o gressi ve Diseas e ( P D): U ne q ui v ocal pr o gressi o n of e xisti n g n o n-tar get l esi o ns. 
 
N ot A p plica ble ( N A): N o e xtracra nial n o n-tar get lesi o ns at baseli ne. 
 
N ot E val ua ble ( N E): Ca n n ot be classifie d b y o ne of t he f o ur prece di n g d efi niti o ns. 
N ote:  
 
E xtracra nial n o n-tar get lesi o ns w hic h are n ot ass esse d at a partic ular ti me p oi nt base d 
o n t he assess me nt sc he d ule s h o ul d be e x cl u de d fr o m t he res p o n se deter mi n ati o n (t hat 
is., t he n o n-tar get res p o nse d oes n ot ha ve t o be " N ot E val ua ble" if t he n o n-tar get 
lesi o ns were n ot sc h e d ule d f or ass ess me nt at a partic ular ti me p oi nt). 
7. 3. 2. 5.  
O v er all R e s p o n s e - E v al u ati o n of  T ar g et L e si o n s 
O verall tar get lesi o n res p o nse is base d o n all (t hat is, i ntracra nial a n d e xtracra nial) tar get 
lesi o ns, u p t o 1 0 t otal.  T he s u m of l o n gest dia meters of all tar get lesi o ns will be use d t o 
deter mi ne o verall res p o nse.  Defi niti o ns f or ass ess me nt of res p o nse f or tar get lesi o n(s) 
base d o n m o difie d R E CI S T 1. 1 are as f oll o ws: 
 
C o m plete Res p o nse ( C R): Disa p peara nce of all tar get lesi o ns.  A n y p at h ol o gical 
l y m p h n o des m ust be < 1 0 m m i n t he s h ort a xis. 
 
Partial Res p o nse ( P R):  At least a 3 0 % decrease i n t he s u m of t he dia meters of tar get 
lesi o ns, ta ki n g as a refere nce, t he baseli ne s u m of t he dia meters (e. g. perce nt c ha n ge 
fr o m baseli ne). 
 
Sta ble Disease ( S D): N eit her s ufficie nt s hri n k a ge t o q ualif y f or P R n or s ufficie nt 
i ncreas e t o q ualif y f or pr o gressi ve diseas e. 

8 3  
N o v arti s 
C o nfi d e nti al 
P a g e 8 3  
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
  
Pr o gressi ve Diseas e ( P D): At least a 2 0 % i ncrease i n t he s u m of t he dia meters of 
tar get lesi o ns, ta ki n g as a refere nce, t he s mallest s u m of dia meters rec or d e d si nce 
t he treat me nt starte d (e. g. perce nt c ha n ge fr o m na dir, w here n a dir is defi ne d as 
t hes mallest s u m of dia meters rec or de d si nce tr eat me nt start).  I n a d diti o n, t he s u m 
m ust ha ve a n a bs ol ute i n creas e fr o m n a dir of 5 m m. 
  
N ot A p plica ble ( N A): N o e xtracra nial tar get lesi o ns at baseli ne. 
 
N ot E val ua ble ( N E): Ca n n ot be classifie d b y o ne of t he fi ve prece di n g d efi niti o ns. 
N ote:  
 
If l y m p h n o des are d oc u me nte d as tar get lesi o ns t he s h ort a xis is a d de d i nt o t he s u m 
of t he dia meters (e. g. s u m of dia meters is t he s u m of t he l o n gest dia m eters f or n o n- 
n o dal lesi o ns a n d t he s h ort a xis f or n o dal lesi o ns).  W he n l y m p h n o des d ecrease t o 
n o n - pat h ol o gical size (s h ort a xis < 1 0 m m) t he y s h o ul d still ha ve a meas ure me nt 
re p orte d i n or d er n ot t o o verstate pr o gressi o n. 
 
If at a gi ve n assess me nt ti me p oi nt all tar get lesi o ns i de ntifie d at baseli ne are n ot 
assesse d, s u m of t he dia meters ca n n ot b e calc ul ate d f or p ur p oses of assessi n g C R, 
P R, or S D, or f or use as t he na dir f or f ut ure assess me nts.  H o we ver, t h e s u m of t he 
dia meters of t he assesse d lesi o ns a n d t he perce nt c ha n ge fr o m n a dir s h o ul d be 
calc ulate d t o e ns ure t hat pr o gressi o n has n ot bee n d oc u me nte d.  If a n assess me nt of 
P D ca n n ot be ma de, t h e res p o nse assess me nt s h o ul d be N E. 
 
All tar get lesi o ns ( n o dal a n d n o n- n o dal) s h o ul d ha ve t heir meas ure me nts rec or de d 
e ve n w he n v er y s mall (e. g. 2 m m).  If lesi o ns are prese nt b ut t o o s mall t o meas ure, 5 
m m s h o ul d be rec or de d a n d s h o ul d c o ntri b ute t o t he s u m of t he dia meters, u nless it is 
li k el y t hat t he lesi o n has disa p peare d i n w hic h case 0 m m s h o ul d be re p orte d. 
 
If a tar get lesi o n disa p pears a n d rea p pears at a s u bse q ue nt ti me p oi nt it s h o ul d 
c o nti n ue t o be meas ure d.  T he res p o nse at t he ti m e w he n t he lesi o n r ea p p ears will 
de pe n d u p o n t he stat us of t he ot her lesi o ns.  F or e x a m ple, if t he disease h a d reac h e d a 
C R stat us t he n P D w o ul d be d oc u me nte d at t he ti me of rea p peara nce.  H o we ver, if 
t he res p o nse stat us w as P R or S D, t he dia meter of t he rea p p eari n g lesi o n s h o ul d be 
a d de d t o t he re m ai ni n g di a meters a n d res p o nse deter mi ne d base d o n p erce nt c ha n ge 
fr o m baseli ne a n d p erce nt c ha n ge fr o m na dir. 
7. 3. 2. 6.  
O v er all R e s p o n s e - E v al u ati o n of  N o n- T ar g et L e si o n s 
O verall n o n-tar get lesi o n res p o nse is base d o n all (t hat is, i ntracra nial a n d e xtracra nial) 
n o n-tar get lesi o ns.  Defi niti o ns f or assess me nt of res p o nse f or n o n-tar get lesi o ns are as 
f oll o ws: 
 
C o m plete Res p o nse ( C R):  T he disa p peara n ce of all n o n-tar get lesi o ns. All l y m p h 
n o des i de ntifie d as a site of disease at baseli ne m ust be n o n- pat h ol o gical (e. g. < 1 0 
m m s h ort a xis). 
 
N o n- C R/ N o n- P D:  T he persiste nce of 1 or m ore n o n-tar get lesi o n(s) or l y m p h n o des 
i de ntifie d as a site of dise ase at bas eli ne ≥ 1 0 m m s h ort a xis. 
 
Pr o gressi ve Diseas e ( P D): U ne q ui v ocal pr o gressi o n of e xisti n g n o n-tar get lesi o ns. 

8 4  
N o v arti s 
C o nfi d e nti al 
P a g e 8 4  
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
 
N ot A p plica ble ( N A): N o i ntr acr a ni al or e xtr acr a ni al n o n-t ar get lesi o ns at 
baseli ne. 
 
N ot E val ua ble ( N E): Ca n n ot be classifie d b y o ne of t he fi ve prece di n g d efi niti o ns. 
N ote:  
 
I n t he prese n ce of meas ura ble disease, pr o gressi o n o n t he basis of s olel y n o n -tar get 
disease re q uires s u bsta ntial w orse ni n g s uc h t hat e v e n i n t he prese n ce of S D or P R i n 
tar get disease, t h e o verall t u m o ur b ur de n has i ncrease d s uffici e ntl y t o merit 
disc o nti n uati o n of t hera p y. 
 
I n t he prese nce of n o n- m eas ura bl e o nl y disease c o nsi derati o ns s h o ul d be gi ve n t o 
w het her or n ot t he i n crease i n o verall diseas e b ur de n is c o m para bl e i n ma g nit u de t o 
t he i ncreas e t hat w o ul d b e re q uir e d t o declare P D f or meas ura ble diseas e. 
 
Sites of n o n-tar get lesi o ns w hic h are n ot assesse d at a partic ular ti me p oi nt base d o n 
t he assess me nt sc he d ule s h o ul d be e x cl u de d fr o m t he res p o nse deter mi nati o n (i.e., 
n o n -tar get res p o nse d o es n ot ha ve t o be " N ot E val ua ble"). 
7. 3. 2. 7. 
N e w L e si o n s 
Ne w i ntracra nial or e xtracra nial mali g na n ci es de n oti n g disease pr o gressi o n m ust be 
u ne q ui v ocal.  Lesi o ns i de ntifie d i n f oll o w- u p i n a n a nat o mical l ocati o n n ot sca n ne d at 
baseli ne are c o nsi dere d n e w lesi o ns. 
A n y e q ui v o cal ne w l esi o ns s h o ul d c o nti n ue t o be f oll o we d.  Treat me nt ca n c o nti n ue at 
t he discreti o n of t he i n vesti gat or u ntil t he ne xt sc he d ule d assess me nt.  If at t he ne xt 
assess me nt t he ne w lesi o n is c o nsi dere d t o be u ne q ui v ocal, pr o gressi o n s h o ul d be 
d oc u me nte d. 
7. 3. 2. 8.  
E v al u ati o n of I ntr a cr a ni al R e s p o n s e 
Ta ble 2 0  pres e nts t he i ntracra ni al res p o nse at a n i n di vi d ual ti me p oi nt f or all p ossi ble 
c o m bi nati o ns of t u m o ur res p o nses i n tar get a n d n o n -tar get i ntracra ni al lesi o ns wit h or 
wit h o ut t he a p peara nce of ne w i ntracra nial lesi o ns f or s u bjects wit h meas ura ble (as 
defi ne d i n Secti o n 7. 3. 1 ) i ntracra ni al disease at b aseli ne. 
T a bl e 2 0  
E v al u ati o n of I ntr a cr a ni al R e s p o n s e  
T ar g et  L e si o n s  
N o n -T ar g et L esi o n s  
N e w L e si o n s  
I ntra cr a ni al R e s p o n se  
C R  
C
R
 
o
r
 
N
A  
N o  
C R  
C R  
N o n -C R/ No n -P D  or 
N E  
N o  
P R  
P R  
N o n -P D  or  N A  or 
N E  
N o  
P R  
S D  
N o n -P D  or  N A  or 
N E  
N o  
S D  
N E  
N o n -P D  or  N A  or 
N E  
N o  
N E  
P D  
A
n
y 
Y es or N o  
P D  
A ny  
P
D  
Y es or N o  
P D  
A ny  
A
n
y 
Y es  
P D  
C R =c o m pl et e r es p o ns e, P R  = p arti al r es p o ns e, S D =st a bl e dis e as e, P D = pr o gr essiv e dis e as e, N A = N ot a p plic a bl e, 
a n d  N E = N ot Ev al u a bl e 

8 5  
N o v arti s 
C o nfi d e nti al 
P a g e 8 5  
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
N ote:  
  
S u bjects wit h a gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n 
of treat me nt wit h o ut o bjecti ve e vi de nce of diseas e pr o gressi o n at t hat ti me 
s h o ul d be classifie d as ha vi n g "s y m pt o matic deteri orati o n." O bj ecti ve 
res p o nse stat us is deter mi ne d b y e v al uati o ns of disease b ur de n. E ver y eff ort 
s h o ul d be ma de t o d oc u me nt t he o bjecti ve pr o gressi o n e ve n aft er 
disc o nti n uati o n of treat me nt. 
  
I n s o me circ u msta n ces, it ma y be diffic ult t o disti n g uis h resi d u al disease 
fr o m n or mal tiss ue. W he n t he e val uati o n of C R de pe n ds o n t his 
deter mi nati o n, it is rec o m me n de d t hat t he resi d u al lesi o n be i n vesti gate d 
(fine nee dle as pir ate/ bi o ps y) t o c o nfir m t he C R. 
7. 3. 2. 9.  
E v al u ati o n of E xtr a cr a ni al R e s p o n s e 
Ta ble 2 1  pres e nts t he e xtracra nial res p o ns e at a n i n di vi d ual ti me p oi nt f or all p ossi ble 
c o m bi nati o ns of t u m o ur res p o nses i n tar get a n d n o n -tar get e xtracra nial lesi o ns wit h or 
wit h o ut t he a p peara nce of ne w e xtracra nial lesi o ns f or s u bjects wit h meas ura ble (as 
defi ne d i n Secti o n 7. 3. 1 ) e xtracra nial diseas e at baseli ne. 
T a bl e 2 1  
E v al u ati o n of E xtr a cr a ni al R e s p o n s e  
T ar g et  L e si o n s  
N o n -T ar g et L esi o n s  
N e w L e si o n s  
E xt ra cr a ni al  R e s p o ns e  
C R  
C
R
 
o
r
 
N
A  
N
o 
C R  
C R  
N o n -C R/ No n -P D  or 
N E  
N
o 
P R  
P R  
N o n -P D  or  N A  or 
N E  
N
o 
P R  
S D  
N o n -P D  or  N A  or 
N E  
N
o 
S D  
N E  
N o n -P D  or  N A  or 
N E  
N
o 
N E  
P D  
A
n
y 
Y es or N o  
P D  
A ny  
P
D  
Y es or N o  
P D  
A ny  
A
n
y 
Y e
s 
P D  
C R =c o m pl et e r es p o ns e, P R  = p arti al r es p o ns e, S D =st a bl e dis e as e, P D = pr o gr essiv e dis e as e, N A = N ot a p plic a bl e, 
a n d  N E = N ot Ev al u a bl e 
N ote:  
 
S u bjects wit h a gl o bal deteri orati o n of healt h stat us t hat ma y re q uir e 
disc o nti n uati o n of st u d y treat me nt wit h o ut o bjecti ve e vi de nce of disease 
pr o gressi o n at t hat ti me s h o ul d be classifie d as h a vi n g "s y m pt o matic 
deteri orati o n." O bjecti ve res p o nse stat us is deter mi ne d b y e val uati o ns of disease 
b ur de n. E ver y eff ort s h o ul d be ma de t o d oc u me nt t he o bjecti ve pr o gressi o n e ve n 
if st u d y tr eat me nt is disc o nti n ue d. 
 
I n s ome circ u msta nces, it ma y be diffic ult t o disti n g uis h resi d u al disease fr o m 
n or mal tiss ue. W he n t he e val uati o n of C R de pe n ds o n t his deter mi nati o n, it is 
rec o m me n de d t h at t he resi d ual lesi o n be i n vesti gate d (fi ne nee dle 
as pirate/ bi o ps y) t o c o nfir m t he C R. 
7. 3. 2. 1 0.  
E v al u ati o n of O v er all R e s p o n s e 
Ta ble 2 2  pres e nts t he o verall res p o nse at a n i n di vi d ual ti me p oi nt f or all p ossi ble 

8 6  
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P a g e 8 6  
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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
c o m bi nati o ns of t u m o ur res p o nses i n all i ntracra nial a n d e xtracra nial tar get a n d n o n- 
tar get lesi o ns wit h or wit h o ut t he a p peara nce of ne w lesi o ns. 
T a bl e 2 2  
E v al u ati o n of O v er all R e s p o n s e  
T ar g et  L e si o n s  
N o n -T ar g et L esi o n s  
N e w L e si o n s  
O v er all Re s p o ns e  
C R  
C
R
 
o
r
 
N
A  
N o  
C R  
C R  
N o n -C R/ No n -P D  or 
N E  
N o  
P R  
P R  
N o n -P D  or  N A  or 
N E  
N o  
P R  
S D  
N o n -P D  or  N A  or  
N E  
N o  
S D  
N E  
N o n -P D  or  N A  or 
N E  
N o  
N E  
P D  
A
n
y 
Y es or N o  
P D  
A ny  
P
D  
Y es or N o  
P D  
A ny  
A
n
y 
Y es  
P D  
C R =c o m pl et e r es p o ns e, P R  = p arti al r es p o ns e, S D =st a bl e dis e as e, P D = pr o gr essiv e dis e as e, N A = N ot a p plic a bl e, 
a n d  N E = N ot Ev al u a bl e 
N ote:  
 
S u bjects wit h a gl o bal deteri orati o n of healt h stat us t hat ma y re q uire 
disc o nti n uati o n of st u d y treat me nt wit h o ut o bjecti ve e vi de nce of disease 
pr o gressi o n at t hat ti me s h o ul d be classifie d as h a vi n g "s y m pt o matic 
deteri orati o n". O bjecti ve res p o nse stat us is deter mi ne d b y e val uati o ns of disease 
b ur de n. E ver y eff ort s h o ul d be ma de t o d oc u me nt t he o bjecti ve pr o gressi o n e ve n 
if st u d y tr eat me nt is disc o nti n ue d. 
 
I n s o me circ u msta n ces, it ma y be diffic ult t o disti n g uis h resi d u al disease fr o m 
n or mal tiss ue. W he n t he e val uati o n of C R de pe n ds o n t his deter mi nati o n, it is 
rec o m me n de d t h at t he resi d ual lesi o n be i n vesti gate d (fi ne nee dle as pir ate/ bi o ps y) 
t o c o nfir m t he C R. 
7. 3. 2. 1 1.  
E v al u ati o n of B e st I ntr a cr a ni al, E xtr a cr a ni al a n d O v er all R e s p o n s e 
T he best i ntracra nial, e xtracra nial, a n d o verall res p o nse is t he best res p o ns e rec or de d fr o m 
t he start of t he treat me nt u ntil i ntracra nial, e xtracra nial, a n d o verall disease pr o gressi o n 
a n d will be deter mi ne d pr o gra m maticall y b y N o vartis base d o n t he i n vesti gat ors 
assess me nt of i ntracra nial, e xtracra nial, a n d o verall res p o nse at eac h ti me p oi nt. 
 
T o be assi g ne d a stat us of i ntracra nial, e xtracra nial, o verall sta ble diseas e ( S D) 
f oll o w- u p disease assess me nt m ust ha ve met t he S D criteria at least o nce after 
first d ose of st u d y tr eat m e nt at a mi ni m u m i nter val of 8 wee ks. 
 
If t he mi ni m u m ti me f or S D is n ot met, best res p o nse will de pe n d o n t he 
s u bse q ue nt assess me nts.  F or e x a m ple if a n assess me nt of P D f oll o ws t he 
assess me nt of S D a n d S D d oes n ot meet t he mi ni m u m ti me re q uire me nt t he best 
res p o nse will be P D.  Alt er nati vel y s u bjects l ost t o f oll o w- u p after a n S D 
assess me nt n ot meeti n g t he mi ni m u m ti me criteria will be c o nsi dere d n ot 
e val ua ble. 
C o nfir m ati o n Crite ri a:  
 
T o be assi g ne d a stat us of i ntracra nial, e xtracra nial, or o verall P R or C R, a 
c o nfir mat o r y diseas e ass ess me nt s h o ul d be perf or me d n ot less t ha n 4 wee ks after t he 

8 7  
N o v arti s 
C o nfi d e nti al 
P a g e 8 7  
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
criteria f or res p o ns e are first met. 
7. 4.  
S af e t y 
7. 4. 1. S af et y E n d p oi nt s  
T he sec o n d ar y o bjecti ves of t he st u d y i ncl u de c haracterizi n g t he s afet y of da brafe ni b a n d 
tra meti ni b c o m bi nati o n t hera p y. As a c o nse q u e nce, cli nical assess me nts i n cl u di n g vital 
si g ns a n d p h ysic al e x a mi nati o ns, 1 2-lea d E C G, E C H O, c he mistr y a n d hae mat ol o g y 
la b orat or y val ues, a n d A Es will be m o nit ore d a n d e val uate d. 
7. 4. 2. A d v er s e E v e nt s  
T he i n vesti gat or or site st aff will be res p o nsi ble f or detecti n g, d oc u me nti n g a n d re p orti n g 
e ve nts t hat meet t he defi niti o n of a n A E or S A E as o utli ne d i n Secti o n 7. 4. 2. 1   a n d Secti o n 
7. 4. 2. 2  res pecti vel y. 
7. 4. 2. 1.  
D efi niti o n of a n A E 
A n y u nt o war d me dical o cc urre nce i n a patie nt or cli nical i n vesti gati o n s u bject, 
te m p orall y ass ociate d wit h t he use of a me di ci nal pr o d uct, w het her or n ot c o nsi dere d 
relate d t o t he me dici n al pr o d uct. 
N ote: A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i n cl u di n g a n 
a b n or mal la b orat or y fi n di n g), s y m pt o m, or diseas e ( ne w or e x acer bate d) t e m p orall y 
ass ociate d wit h t he use of a me dici nal pr o d u ct.  F or mar kete d m e dici nal pr o d ucts, t his als o 
i ncl u des fail ure t o pr o d u ce e x pecte d be nefits (i. e., lac k of efficac y), a b us e or mis use. 
E ve nts meeti n g t h e defi niti o n of a n A E i ncl u de: 
 
A n y n e w pri mar y ca ncer m ust be re p orte d as a n S A E.  
 
E x acer bati o n of a c hr o ni c or i nter mitte nt pre- e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncreas e i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n 
 
Ne w c o n diti o ns detect e d or dia g n os e d after st u d y treat me nt a d mi nistrati o n e ve n 
t h o u g h it ma y h a ve b ee n prese nt pri or t o t he start of t he st u d y. 
 
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d i nteracti o n. 
 
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y 
treat me nt or a c o nc o mita nt me dicati o n ( o ver d ose per se will n ot be re p orte d as a n 
A E/ S A E) u nless t his is a n i nte nti o nal o ver d ose ta ke n wit h p ossi ble s uici dal/self- 
har mi n g i nte nt.  T his s h o ul d be re p orte d re gar dless of se q uela e.

8 8  
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P a g e 8 8  
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
 “ Lac k of efficac y” or “fail ure of e x pecte d p har mac ol o gical acti o n” p er se will n ot be 
re p orte d as a n A E or S A E. H o we ver, a n y si g ns a n d s y m pt o ms a nd/ or cli nical se q uelae  
res ulti n g fr o m lac k of efficac y will be re p orte d as a n A E or S A E if t he y f ulfill t he 
defi niti o n of a n A E or S A E. 
E ve nts t hat d o  n ot meet t he defi niti o n of a n A E i n cl u de: 
 
Me dical or s ur gic al pr oce d ure (e. g., e n d os c o py,  a p pe n dect o m y); t he c o n diti o n t hat 
lea ds t o t he pr oce d ure is a n A E 
 
Sit uati o ns w here a n u nt o war d me dical occ urre n ce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital) 
 
A ntici pate d da y-t o-d a y fl uct uati o ns of pre-e xisti n g disease(s) or c o n diti o n(s) prese nt 
or detecte d at t he start of t he st u d y t hat d o n ot w orse n 
 
T he disease/ dis or der bei n g st u die d, or e x pecte d pr o gressi o n, si g ns, or s y m pt o ms of t he 
disease/ dis or der bei n g st u die d, u nless m ore se vere t ha n e x pecte d f or t he s u bject’s 
c o n diti o n 
7. 4. 2. 2.  
D efi niti o n of a S A E 
A seri o us a d verse e v e nt is a n y u nt o war d m e dical occ urre nce t hat, at a n y d ose: 
 
Res ults i n deat h 
 
Is life-t hr eate ni n g 
N O T E:  T he ter m ‘life-t hreate ni n g’ i n t he defi niti o n of ‘seri o us’ refers t o a n e ve nt i n 
w hic h t he s u bject was at ris k of d eat h at t he ti me of t he e ve nt.  It d oes n ot refer t o a n 
e ve nt, w hic h h y p ot heticall y mi g ht ha ve ca us e d deat h, if it were m or e se vere. 
 
Re q uires h os pitaliz ati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
N O T E:  I n ge n eral, h os pitaliz ati o n si g nifies t hat t he s u bject has bee n detai n e d ( us uall y 
i n v ol vi n g at least a n o v er ni g ht sta y) at t he h os pital or e mer ge n c y war d f or o bser vati o n 
a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h ysicia n’s office or o ut-
patie nt setti n g.  C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are A Es. If a 
c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her s eri o us criteria, t h e e ve nt is 
seri o us.  W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was necessar y, t he 
A E s h o ul d be c o nsi dere d seri o us. 
 
H os pitalizati o n f or electi ve treat me nt of a pre-e xisti n g c o n diti o n t hat di d n ot 
w orse n fr o m b aseli ne is n ot c o nsi dere d a n A E. 
 
Res ults i n disa bilit y/i nca pacit y, or 
N O T E:  T he ter m disa bilit y m ea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o 
c o n d uct n or mal life f u n cti o ns.  T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces 
of relati vel y mi n or me dic al si g nifica nce s u c h as u n c o m plicate d hea d ac h e, n a usea, 
v o miti n g, diarr hea, i nfl ue nza, a n d acci d e ntal tra u m a (e. g. s prai ne d a n kle) w hic h ma y 
i nterfere or pre ve nt e v er y da y life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial 
disr u pti o n. 

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P a g e 8 9  
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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
 
Is a c o n ge nital a n o mal y/ birt h defect. 
 
Me dical or scie ntifi c j u d ge m e nt s h o ul d be e x ercis e d i n deci di n g w het her re p orti n g is 
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be 
i m me diatel y life-t hr eate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he 
s u bject or ma y re q uir e m e dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t h e ot her 
o utc o mes liste d i n t he a b o ve defi niti o n. T hese s h o ul d als o be c o nsi dere d s eri o us.  
E x a m ples of s uc h e ve nts are i n vasi ve or mali g n a nt ca ncers, i nte nsi ve treat me nt i n a n 
e mer ge n c y r o o m or at h o me f or aller gi c br o nc h os pas m, bl o o d d ys crasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g d e pe n de nc y or 
dr u g a b use. 
 
Pr ot oc ol-s pecific S A Es: 
O  
All e ve nts of p ossi ble dr u g-i n d uce d li ver i nj ur y wit h  h y per bilir u bi nae defi n e d as 
A L T  3 x U L N a n d bilir u bi n  2 x U L N ( > 3 5 % dir ect) ( or A L T  3 x U L N a n d 
I N R > 1. 5, if I N R meas ure d) ter me d ‘ H y’s La w’ e v e nts (I N R meas ure me nt is n ot 
re q uire d a n d t he t hres h ol d val ue state d will n ot a p pl y t o patie nts recei vi n g 
a ntic oa g ula nts). 
o  
N ote: bilir u bi n fracti o nati o n is perf or me d if testi n g is a v aila ble. If testi n g is 
u na vaila ble, rec or d prese nce of detecta ble uri nar y bilir u bi n o n di pstic k i n dicati n g 
direct bilir u bi n ele vati o ns a n d s u g gesti n g li ver i nj ur y. If testi n g is u na vaila ble a n d 
a s u bject meets t he criteri o n of t otal bilir u bi n  2 x U L N, t he n t he e ve nt is still 
re p orte d as a n S A E. If I N R is o btai ne d, i ncl u de val ues o n t he S A E f or m. I N R 
ele vati o ns > 1. 5 s u g gest s e vere li ver i nj ur y. 
o  
A n y n e w pri mar y ca ncers a n d treat me nt e mer ge nt mali g na n cies (i ncl u di n g 
s q ua m o us cell carci n o ma a n d ne w pri mar y mela n o ma) wit h t he e x ce pti o n of basal 
cell carci n o ma ( B C C).  B C C s h o ul d be re p orte d as a n A E or S A E bas e d o n t he 
discreti o n of t he i n vesti gat or. 
o  
S y m pt o matic L V E F decrease t hat meets st o p pi n g criteria or as y m pt o matic L V E F 
decrease t hat d o es n ot rec o ver, as o utli ne d as L V E F g ui da nce ( Secti o n 5. 8. 3. 1 ). 
o  
Reti nal pi g me nt e pit helial detac h me nt ( R P E D) or reti nal vei n occl usi o n ( R V O) 
7. 4. 2. 3.  
L a b or at or y a n d Ot h er S af et y A s s e s s m e nt A b n or m aliti e s R e p ort e d a s 
  
  
A E s a n d S A E s  
A n y a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y,  or uri nal ysis) or 
ot her safet y ass ess me nts (e. g., E C Gs, ra di ol o gical sca ns, vital si g ns meas ure me nts), 
i ncl u di n g t h ose t hat w ors e n fr o m baseli ne, a n d felt t o be cli nicall y si g nifica nt i n t he 
me dical a n d scie ntific j u d ge m e nt of t he i n vesti gat or are t o b e rec or de d as A Es or S A Es, 
i n acc or d a nce wit h t he defi niti o ns pr o vi de d. 
H o we ver, a n y cli nicall y si g nifica nt s afet y assess m e nts t hat are ass ociate d wit h t he 
u n derl yi n g dise ase, u nless j u d ge d b y t he i n vesti gat or t o be m ore se vere t h a n e x pecte d f or 
t he s u bject’s c o n diti o n, are n ot t o be re p ort e d as A Es or S A Es. 

9 0  
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P a g e 9 0  
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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
7. 4. 2. 4.  
Di s e a s e- R el at e d E v e nt s a n d/ or Di s e a s e- R el at e d O ut c o m e s N ot  
  
  
Q u alif yi n g a s  S AE s  
A n e ve nt w hic h is part of t he nat ural c o urse of t he disease u n der st u d y (i.e., disease 
pr o gressi o n or h os pitaliz ati o n d ue t o disease pr o gressi o n) d oes n ot nee d t o be re p ort e d as 
a n S A E.  Deat h d u e t o disease u n der st u d y is t o be rec or d e d o n t he Deat h e C R F f or m.  If 
h o we ver, t he u n derl yi n g disease (i.e., pr o gressi o n) is greater t ha n t h at w hic h w o ul d 
n or mall y be e x pecte d f or t he s u bject, or if t he i n vesti gat or c o nsi ders t hat t here was a 
ca usal relati o ns hi p bet wee n treat me nt wit h st u d y me dicati o n(s) or pr ot o c ol 
desi g n/ pr o ce d ures a n d disease pr o gressi o n, t he n t his m ust be re p orte d as a n S A E. 
7. 4. 2. 5.  
Ti m e P eri o d a n d Fr e q u e n c y f or D et e cti n g A E s  a n d  S AE s  
T he i n vesti gat or or site st aff is res p o nsi ble f or detecti n g, d oc u m e nti n g, a n d re p orti n g 
e ve nts t hat meet t he d efi niti o n of a n A E or S A E. 
All S A Es a n d a d verse e v e nts ( A Es) will be c ollecte d fr o m t he ti me t he first d ose of st u d y 
treat me nt is a d mi nistere d u ntil 3 0 da ys aft er disc o nti n uati o n of st u d y treat me nt re gar dl ess 
of i nitiati o n of a ne w a nti-ca ncer t hera p y or tra nsfer t o h os pice. 
Fr o m t he ti me a s u bject c o nse nts t o partici pate i n a n d c o m pletes t he st u d y ( See 
Secti o n 4. 2 ), all S A Es assesse d as rel ate d t o st u d y partici pati o n (e. g., pr ot oc ol- ma n date d 
pr oce d ures, i n vasi ve tests, or c ha n ge i n e xisti n g t hera p y) , will be re p ort e d pr o m ptl y t o 
N o vartis as i n dicate d i n Ta ble 2 3. 
After st u d y treat me nt disc o nti n uati o n, t he i n vesti gat or will m o nit or all A Es/ S A Es t hat are 
o n g oi n g u ntil res ol uti o n or sta bilizati o n of t he e ve nt or u ntil t he s u bject is l ost t o f oll o w- 
u p.  At a n y ti me after 3 0 da ys fr o m t he last d ose of st u d y treat me nt, t he i n v esti gat or m a y 
re p ort a n y A E t hat h e/s he belie ves is p ossi bl y rel ate d t o st u d y treat me nt. 
7. 4. 2. 6.  
Pr o m pt R e p orti n g of S eri o u s A d v er s e E v e nt s a n d Ot h er E v e nt s t o 
N o v arti s 
Seri o us a d verse e ve nts ( S A Es), pre g na n cies, a n d li ver f u ncti o n a b n or malities meeti n g pr e-
defi ne d criteria will be re p orte d pr o m ptl y b y t he i n vesti gat or t o N o vartis as descri be d i n 
Ta ble 2 3  o nce t h e i n vesti gat or d eter mi nes t hat t he e ve nt meets t he pr ot o c ol- defi niti o n f or 
t hat e ve nt.

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P a g e 9 1  
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T a bl e 2 3  
Ti m e Fr a m e s f or R e p orti n g S A E s a n d Ot h er E v e nt s  
  
I niti al R e p ort s  
F oll o w -u p  I nf or m ati o n o n  a  Pr e vi o u s  
R e p ort  
T y p e  of  E v e nt  
Ti m e  Fra m e  
D o c u m e nt s  
Ti m e  Fra m e  
D o c u m e nt s  
All  S A Es  
2 4  h o urs  
S A E  d at a  
c oll ecti o n t o ol 
2 4  h o urs  
U p d at e d  S A E  
d at a  c oll ecti o n 
to ol 
Pr e g n a ncy  
2 4 h o urs  
Pr e g n a ncy  
n otific ati o
n f or m  
2  w e eks  
Pr e g n a ncy  f oll o w-
u p f or m  
C ar di ov asc ul ar 
or  d e at h ev e nt  
I niti al a n d foll o w 
u p r e p orts to b e 
c o m pl et ed wit hi n 
o n e we ek of 
w h e n t h e 
c ar di ov asc ular 
ev e nt or d e at h is 
r e p ort ed 
“ C V ev e nts” 
a n d/or  
“d e at h” d at a 
c oll ecti o n 
t o ol(s) if 
a p plic abl e  
I niti al a n d foll o w 
u p r e p orts to b e 
c o m pl et ed 
wit hi n o ne w eek 
of w h e n th e 
c ar di ov asc ular 
ev e nt or de ath 
is r e p ort ed 
U p d ate d 
“ C V 
ev e nts” 
a n d/or 
“d e at h” 
d at a 
c oll ecti o n 
to ol(s) if 
a p plic abl e  
Li v er  C h e mi stry  A b n or m aliti e s:  
A L T   3  x U L N P L U S 
t ot al bilir u bi n   2  x 
U L N (> 3 5 %  dir ect)  
or A L T   3  x U L N  
a n d  I N R >  1. 5,  if I N R 
m e as ur e d a  
2 4  h o urs b 
S A E  d at a  
c oll ecti o n t o ol, 
liv er ev e nt  
e C R F  f or m, a n d  
liv er i m a gi n g 
a n d/ or  bi o psy 
e C R Fs,  if 
a p plic a bl e c 
2 4  h o urs  
U p d at e d  S A E  
d at a c oll ecti o n 
t o ol a n d  u p d at e d  
liv er ev e nt e C R F  
form c 
A L T   8  x U L N;  A L T   
3 x U L N  wit h  h e p atitis  
or r as h or  3  x U L N  
b ut  <  5  x U L N  t h at 
p ersists   4  w e eks  
2 4  h o urs b 
Liv er  ev e nt  
e C R F  f orm c 
2 4  h o urs  
U p d at e d  liv er 
ev e nt e C R F  
f orm c 
A L T   5  x U L N 
P L U S  t ot al bilir u bi n  <  
2  x U L N  
2 4  h o urs b 
Liv er  ev e nt  
e C R F  f or m 
d o es  n ot  n e e d 
c o m pl eti n g 
u nl ess 
el ev ati o ns  
p ersist  f or 2  
w e eks  or  
s u bj ect c a n n ot 
b e  m o nitor e d 
w e ekly  f or 2  
w e ek s c 
2 4  h o urs  
 
A L T   5  x U L N 
P L U S  t ot al bilir u bi n  < 
2  x U L N  t h at p ersists  
 2  w e eks  
2 4  h o urs b 
Liv er  ev e nt  
e C R F  f orm c 
2 4  h o urs  
U p d at e d  liv er ev e nt  
e C R F  form c 
A L T   3  x U L N  b ut  <  5  
x U L N  P L U S  t ot al 
bilir u bi n  < 2  x U L N  
2 4  h o urs b 
Liv er  ev e nt  e C R F  
f or m d o es  n ot  
n e e d c o m pl eti n g 
u nl ess el ev ati o ns  
p ersist  f or 4  
w e eks  or  s u bj ect 
c a n n ot b e  
m o nit or e d w e ekly  
f or 4  w e ek s c 
 
 
A b br evi ati o ns: A L T = al a ni n e tr a ns a mi n as e; A S T  = as p art at e a mi n otr a nsf er as e; e C R F = el ectr o nic c as e r e p ort 
f or m; I N R = i nt er n ati o n al n or m aliz e d r ati o; S A E = s eri o us a dv ers e ev e nt; U L N = u p p er  li mit of  n or m al. 
a.  I N R m e as ur e m e nt is n ot  r e q uir e d; if m e as ur e d, t h e t hr es h ol d v al u e st at e d will  n ot  a p ply t o s u bj ects r ec eivi n g 
a ntic o a g ul a nts. 
b.  
N ov artis t o b e  n otifi e d at  o ns et of  liv er c h e mistry el ev ati o ns t o disc uss s u bj ect s af ety. 
c. 
Liv er Ev e nt D oc u m e nts (i. e., “Liv er Ev e nt C R F”  a n d  “Liv er I m a gi n g C R F”  a n d/ or “Liv er Bi o psy C R F”,  as 
a p plic a bl e) s h o ul d b e  c o m pl et e d as  s o o n as  p ossi bl e. 
I n t h e ev e nt of  a b d o mi n al p ai n or  s us p ect e d p a ncr e atitis, a myl as e a n d li p as e l a b or at ory s a m pl es s h o ul d b e  
c oll ect e d. 

9 2  
N o v arti s 
C o nfi d e nti al 
P a g e 9 2  
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Li ver c he mistr y st o p pi n g, f oll o w- u p, a n d m o nit ori n g criteria are pr o vi de d i n A p pe n di x 7.  
Met h o ds f or dete cti n g, rec or di n g, e val uati n g, a n d f oll o wi n g- u p o n A Es a n d S A Es a n d 
pr oce d ures f or c o m pleti n g a n d tr a ns mitti n g S A E re p orts t o N o vartis are pr o vi de d i n t he 
S P M. 
7. 4. 2. 7.  
R e g ul at or y r e p orti n g r e q uir e m e nt s f or S A E s  
Pr o m pt n otificati o n of S A Es b y  t he i n v esti gat or t o N o vartis is esse ntial s o t hat 
le gal o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of s u bjects are 
met. 
N o vartis has a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal re g ul at or y a ut h ori t y a n d ot her 
re g ulat or y a ge ncies a b o ut t he safet y of a pr o d uct u n der cli nical i n vesti gati o n.  N o vartis will 
c o m pl y wit h c o u ntr y-s p ecific re g ulat or y re q uire m e nts relati n g t o safet y re p orti n g t o 
re g ulat or y a ut h orities, I nstit uti o nal Re vie w B oar ds (I R B)/I n de p e n de nt Et hics C o m mittees 
(I E C) a n d i n vesti gat ors. 
I n v esti gat or safet y re p orts will be pre pare d f or s us pecte d u ne x pecte d s eri o us a d verse 
reacti o ns acc or di n g t o l o cal re g ulat or y re q uir e me nts a n d N o vartis p olic y a n d will be 
f or war de d t o i n vesti gat ors as necess ar y. 
A n i n vesti gat or w h o recei ves a n i n vesti gat or s afet y re p ort des cri bi n g a n S A E(s) or ot her 
s pecific safet y i nf or mati o n (e. g., s u m mar y or listi n g of S A Es) fr o m N o vartis will file it 
wit h t he I B a n d w ill n otif y t he I R B/I E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts. 
7. 4. 3. Pr e g n a n c y  
7. 4. 3. 1.  
Pr e g n a n c y T e sti n g a n d Pr e v e nti o n 
T he nee d f or a s cree ni n g pre g na nc y t est de pe n ds o n w het her a fe mal e s u bject is of 
c hil d beari n g p ote ntial or n o n-c hil d beari n g p ote ntial. 
A fe m ale of n o n-c hil d be ari n g p ote nti al (i.e., p h ysi ol o gicall y i nca p a ble of bec o mi n g 
pre g na nt) is defi ne d as a n y fe male w h o has ha d a h ysterect o m y, bilateral o o p h orect o m y 
( o variect o m y) or bilateral t u bal li gati o n or t u bal o ccl usi o n, or is p ost- me n o pa usal. 
A practical defi niti o n acce pts me n o pa use after 1 year wit h o ut me nses wit h a n a p pr o pri ate 
cli nical pr ofile, e. g., a ge a p pr o priate, > 4 5 years i n t he a bse nce of h or m o n e-re place me nt 
t hera p y ( H R T).  I n q uesti o na ble cas es, t he s u bject m ust ha ve a f ollicl e-sti m ulati n g h or m o ne 
( F S H) val u e > 4 0 mI U/ m L a n d a n estr a di ol val ue < 4 0 p g/ m L ( < 1 4 0 p m ol/ L). 
A fe m ale of c hil d- be ari n g p ote nti al is defi ne d as a n y fe male w h o d oes n ot meet t he 
criteria of n o n- c hil d beari n g p ote ntial as d escri be d i n t he pre vi o us para gra p h. 
W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g n a nc y test wit hi n 1 4  
da ys pri or t o e nr oll me nt a n d a gree t o use effecti ve c o ntrace pti o n, S u bjects wit h a p ositi ve 
pre g na nc y t est res ult m ust be e x cl u de d fr o m t he st u d y.  S u bjects wit h a ne gati ve pre g na n c y 
t est res ult m ust a gree t o use a n effecti ve c o ntrace pti o n met h o d as descri be d bel o w 
t hr o u g h o ut t he tr eat me nt peri o d a n d u ntil 4 m o nt hs after t he last d ose of st u d y treat me nt. 
N o vartis acce pta ble c o ntr ace pti ve met h o ds, w h e n use d c o nsiste ntl y a n d i n acc or d a nce 
wit h b ot h t he pr o d uct la bel a n d t he i nstr ucti o ns of t he p h ysicia n , are as f oll o ws: 

9 3  
N o v arti s 
C o nfi d e nti al 
P a g e 9 3  
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
 
A n i ntra uteri ne d e vice wit h a d oc u me nte d fail ure rate of less t ha n 1 % p er year. 
 
Male part ner steriliz ati o n pri or t o t he fe male s u bj ect’s e ntr y, a n d t his male is t he s ole 
se x ual part ner f or t hat fe male. 
 
C o m plete a bsti ne nce fr o m se x ual i nterc o urse f or 7 da ys pri or t o e nr oll me nt, 
t hr o u g h o ut t he tr eat me nt peri o d, a n d f or at least 4 m o nt hs after t he last d ose of st u d y 
treat me nt. A bsti ne nce is o nl y acce pta bl e w he n i n li ne wit h t he preferre d a n d us ual 
lifest yle of t h e s u bject. Peri o dic a bsti ne nce (e. g. cale n dar, o v ulati o n, s y m pt ot her mal, 
p ost- o v ulati o n met h o ds, etc) a n d wit h dr a wal are n ot acce pt a ble met h o ds of 
c o ntrace pti o n. 
 
D o u ble- barrier c o ntrace pti o n: c o n d o m a n d occl usi ve ca p ( di a p hra g m or 
cer vical/ va ult ca ps) wit h a va gi nal s per mici d al a ge nt (f oa m/ gel/crea m/s u p p osit or y ). 
N ote: H or m o nal - base d met h o ds (e. g., oral c o ntrace pti ves) are n ot per mitte d d ue t o 
p ote ntial dr u g- dr u g i nteracti o ns wit h da brafe ni b. 
Fe male s u bjects w h o are lactati n g m ust disc o nti n ue pri or t o first d ose of st u d y treat me nt 
a n d m ust refrai n fr o m n ursi n g t hr o u g h o ut t he tr eat me nt peri o d a n d f or 4 m o nt hs 
f oll o wi n g t he last d ose of st u d y tr eat me nt. 
If a s u bject b ec o mes pre g na nt d uri n g t he treat me nt peri o d of t he st u d y, t he st u d y 
treat me nts s h o ul d be st o p pe d i m me diatel y. 
N ote: Fre nc h/ Ger ma n s u bjects: n o c o ntrace pti o n f or me n is re q uire d 
7. 4. 3. 2.  
Pr e g n a n c y R e p orti n g 
A n y pre g n a n c y t hat occ urs d uri n g st u d y partici p ati o n m ust be re p orte d usi n g a cli nical 
trial pre g na n c y f or m.  T o e ns ure s u bject s afet y, eac h pre g na n c y m ust be re p orte d t o 
N o vartis wit hi n 2 4 h o urs of lear ni n g of its occ urre nce.  T he pre g na n c y m ust be f oll o we d-
u p t o deter mi ne o utc o me (i ncl u di n g pre mat ure t er mi nati o n) a n d stat us of m ot her a n d 
c hil d. Pre g n a nc y c o m plic ati o ns a n d electi ve ter mi nati o ns f or me dical r eas o ns m ust be 
re p orte d as a n A E or S A E.  S p o nta ne o us a b orti o ns m ust be re p orte d as a n S A E. 
A n y S A E occ urri n g i n ass ociati o n wit h a pre g na n c y br o u g ht t o t he i n vesti gat or’s 
atte nti o n after t he s u bject has c o m plete d t he st u d y a n d c o nsi dere d b y t he i n vesti gat or as 
p ossi bl y rel ate d t o st u d y treat me nt, m ust be pr o m ptl y re p ort e d t o N o vartis. 
I n a d diti o n, t he i n vesti gat or m ust atte m pt t o c ollect pre g na nc y i nf or mati o n o n  a n y fe m ale 
part ners of m ale st u d y s u bjects w h o bec o me pre g n a nt w hile t he s u bject is e nr olle d i n t he 
st u d y.  Pre g na n c y i nf or m ati o n m ust be re p orte d t o N o vartis as descri be d a b o ve. 
7. 4. 4. L a b or at or y A s s e s s m e nt s  
All pr ot oc ol-re q uire d la b orat or y assess me nts m ust be c o n d ucte d i n acc or da nce wit h t he 
Ce ntral La b orat or y Ma n ual a n d Pr ot oc ol Ti me a n d E ve nts Sc he d ule ( Ta ble 1 9 ). If a ny 
l ocal la b orat or y assess me nts are u n dert a ke n d uri n g t he c o urse of t h e trial a n d t he y res ult 
i n a c ha n ge i n p atie nt ma na ge me nt (f or e x a m ple S A E or A E or d os e m o dificati o n) t he 
assess me nt data m ust be rec or d e d i n t he patie nts C R F. 

9 4  
N o v arti s 
C o nfi d e nti al 
P a g e 9 4  
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
La b orat or y re q uisiti o n f or ms m ust be c o m plete d a n d sa m ples m ust be clearl y la belle d 
wit h t he s u bject n u m ber, pr ot oc ol n u m ber, site/ce ntre n u m ber, a n d visit date.  Det ails f or 
t he pre parati o n a n d s hi p me nt of sa m ples a n d a list of refere n ce ra n ges f or all safety 
para meters will be pr o vi de d b y t he ce ntral la b orat or y i n a s e parate i nstr ucti o n ma n ual. 
La b orat or y assess me nts m ust be pr ocess e d t hr o u g h  
 Ce ntr al La b orat ories.  If a n 
i n vesti gat or feels t hat t hat safet y of t he patie nt is j e o par dize d b y waiti n g f or ce ntr al la bs t o 
ret ur n, l ocal la bs ma y b e dra w n i n a d diti o n t o t he ce ntral la b f or treat me nt p ur p oses. If a n y 
a d diti o nal la b orat or y ass ess me nts are perf or me d at t he i nstit uti o n’s l ocal la b orat or y, refer 
t o t he S P M f or a p pr o priate pr ocessi n g a n d ha n dli n g of sa m ples t o a v oi d d u plicati o n a n d/ or 
a d diti o nal bl o o d dra ws. 
If l ocal la b orat or y assess me nts d oc u me nt a nee d f or d ose m o dificati o n/i nterr u pti o n, a n 
A E or a n S A E, t hese assess me nts s h o ul d be e ntere d i nt o t he e C R F per t he e C R F 
c o m pleti o n g ui deli nes. 
Cli nical c he mistr y a n d hae mat ol o g y para met ers t o be teste d are liste d i n Ta ble 2 4.  
Fe male s u bjects will ha v e a ser u m pre g na n c y test at Scree ni n g; uri ne pre g n a n c y testi n g 
ma y be d o n e d uri n g st u d y tr eat me nt, if necessar y.
T a bl e 2 4  
Cli ni c al C h e mi str y a n d H e m at ol o g y P ar a m et er s  
Cli ni c al  C h e mi stry  P ara m et er s  
Al b u mi n  
Alk ali n e  P h os p h at as e  
Al a ni n e  Tr a ns a mi n as e  ( A L T) or  S er u m  Gl ut a mic  Pyr u vic Tr a ns a mi n as e  ( S G P T) 
As p art at e  A mi n otr a nsf er as e  ( A S T) or  S er u m  Gl ut a mic  Ox al o ac etic  Tr a ns a mi n as e  ( S G O T)  
G a m m a -Gl ut a myl  Tr a ns p e pti d as e  ( G G T) 
Bl o o d  Ur e a  Nitr o g e n  ( B U N) or  ur e a  
C alci u m Cr e ati ni n e c  
Gl uc os e  (r a n d o m) 
L act at e  D e hy dr o g e n as e  ( L D H)  
M a g n esi u m  
P h os p h at e  
P ot assi u m  
S o di u m  
T ot al  Bilir u bi n b  
T ot al  Pr ot ei n  
H e m at ol o g y  P ar a m et er s  
W hit e  Bl o o d  C ell  ( W B C) C o u nt  ( a bs ol ut e) 
A bs ol ut e  n e utr o p hil  ( A N C) c o u nt 
H e m o gl o bi n 
H e m o gl o bi n  A 1 C 
H e m at ocrit  
I nt er n ati o n al N or m aliz e d  R ati o  (I N R; at  Scr e e ni n g  o nly )a  
Pl at el et  C o u nt  
Pr ot hr o m bi n  Ti m e  ( P T; at  Scr e e ni n g  o nly )a  
P arti al  T hr o m b o pl asti n  Ti m e  ( P T T; at  Scr e e ni n g  o nly )a  
A ut o m at e d  W B C  Diff er e nti al  ( ex pr ess e d as  %): 
B as o p hils  
E osi n o p hils  
Ly m p h ocyt es 
M o n ocyt es 
N e utr o p hils  
Ot h er  t e st s 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
9 5  
 
 
A myl as e  a n d  li p as e [ m o nit or vi a l oc al l a b or at ory w h er e  a p pr o pri at e  t o ev al u at e  c ert ai n A Es  (i. e., a b d o mi n al p ai n,  
p a ncr e atitis,  etc.)]  
s er u m β -h C G  ( h u m a n c h ori o nic g o n a d otr o p hi n)  
F or  s u bj ects wit h  a  hist ory  of  c hr o nic H B V  a n d/ or  H C V,  t h e f oll o wi n g t ests will  b e  p erf or m e d  at  Scr e e ni n g:  
 
Vir al  h e p atitis  s er ol o gy; 
 
H e p atitis  B  s urf ac e a nti g e n  a n d  H e p atitis  B  c or e a nti b o dy  (I g M); a n d/ or  
 
H e p atitis  C  R N A  
a.  
C o a g ul ati o n p a n el  t o b e  d o n e  at  Scr e e ni n g o nly. 
b.  
Bilir u bi n fr acti o n ati o n is r ec o m m e n d e d if t ot al bilir u bi n is > 2 x t h e u p p er  li mit of  n or m al ( U L N). 
c. 
If s er u m cr e ati ni n e is > 1. 5  m g/ d L, cr e ati ni n e cl e ar a nc e s h o ul d b e  c alc ul at e d usi n g t h e st a n d ar d 
C ockcr oft- G a ult f or m ul a [ A p p e n dix 3 ]. 
7. 4. 5. O p ht h al mi c E x a mi n ati o n  
S u bjects are re q uire d t o h a ve a sta n d ar d o p ht hal mi c e x a mi nati o n c o n d ucte d 
b y  a n o p ht hal m ol o gist pri or t o first d ose ( baseli ne), wee k 4( M o nt h 1), wee k 
2 4 ( M o nt h 6) a n d  a n n uall y t hereaft er u nless cli nicall y i n dicate d s o o ner.  
A d diti o nal o p ht hal mic e xa mi nati o ns will be perf or me d o nl y as 
s y m pt o matic all y w arra nte d. 
T he e x a m will i ncl u de vis ual ac uit y ( best c orrecte d), t o n o metr y (i ntra oc ular press ur e 
meas ure me nt), vis u al fiel d e x a mi nati o n, slit la m p bi o micr osc o p y of t he a nt eri or se g me nt 
( wit h s pecial atte nti o n t o i nfla m mati o n) a n d t he p osteri or se g me nt, a n d i n direct 
f u n d osc o pic e x a mi nati o n wit h s pecial atte nti o n t o p ossi ble reti nal a b n or malities.  O ptical 
c o here n ce t o m o gra p h y is str o n gl y rec o m me n de d at sc he d ule d visits, a n d if reti nal 
a b n or malities are s us p ect e d or n ote d. Ot her t y p es of a n cillar y t esti n g i ncl u di n g c ol or 
f u n d us p h ot o gra p h y a n d fl u orescei n a n gi o gra p h y are als o r ec o m me n d e d if cli nicall y 
i n dicate d. 
7. 4. 6. Vit al Si g n s  
Vital si g n meas ur e me nts will i ncl u de s yst olic a n d diast olic bl o o d press ure, b o d y 
te m perat ur e, p ulse rate, b o d y w ei g ht, a n d hei g ht ( o nl y at Scree ni n g). B o d y t e m perat ur e, 
wei g ht a n d hei g ht meas ure me nts s h o ul d be rec or d e d i n t he metric scale. 
See Secti o n 5. 8. 3. 2. 1  f or details o n m o nit ori n g of h y perte nsi o n. 
7. 4. 7. P h y si c al E x a mi n ati o n s  
C o m plete p h ysical e x a mi nati o n is i n dicate d at scree ni n g a n d disc o nti n uati o n a n d will 
i ncl u de assess me nts of e yes, n e ur ol o gical a n d car di o vasc ular s yste ms, l u n gs, a b d o m e n, 
a n d a n y ot h er areas wit h si g ns a n d s y m pt o ms of disease, a n d of t he hea d, nec k, ears, 
n ose,  m o ut h, t hr oat, t h yr oi d, l y m p h n o des, e xtre mities, a n d a f ull s ki n e x a m t o assess 
c uta ne o us mali g na nci es a n d pr oliferati ve s ki n dise ases. Der mat ol o gic s ki n e x a ms ma y 
be referre d t o a Der mat ol o gist, if nee d e d. 
If p ossi ble, t he sa me p h ysicia n s h o ul d perf or m eac h e x a mi nati o n f or t he d urati o n of t he 
st u d y t o e ns ure c o nsiste n c y b et wee n e val uati o ns (i.e., if t he s u bject is referre d t o a 
Der mat ol o gist f or t he Scree ni n g e x a mi nati o n, t he Der mat ol o gist s h o ul d d o all f oll o w- u p 
der mat ol o gi c s ki n assess me nts). 
Ne ur ol o gical e x a ms s h o ul d be perf or m e d b y t h e I n vesti gat or as per t h e sc he d ule i n 
(Ta ble 1 9 ). Alter nati vel y, s u bjects ma y be referre d t o a Ne ur ol o gist, at t he discreti o n of 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
9 6  
 
 
t he I n v esti gat or. 
A t h or o u g h n e ur ol o gical assess me nt is re q uire d at baseli ne f oc usi n g o n: 
• 
Me ntal stat us 
• 
Cra nial ner ves 
• 
M ot or s yste m 
• 
Se ns or y s yst e m 
• 
T he dee p te n d o n refle x es 
• 
C o or di nati o n a n d t he cere bell u m 
• 
Gait 
Ne ur ol o gical S y m pt o ms ma y i ncl u de t he f oll o wi n g ( b ut are n ot li mite d t o): 
• 
Hea dac he 
• 
Na usea a n d/ or v o miti n g 
• 
Verti g o a n d/ or dizzi ness 
• 
Restless ness a n d/ or irrita bilit y 
• 
Fati g ue or slee pless ness 
• 
Heari n g l oss 
• 
M uscle wea k n ess 
• 
Bala n ce pr o bl e ms 
• 
S peec h pr o ble ms 
• 
Ot hers 
7. 4. 8. El e ctr o c ar di o gr a m s ( E C G)  
T wel ve ( 1 2)-lea d E C Gs will be o btai ne d usi n g a n E C G mac hi ne t hat a ut o maticall y 
calc ulates h eart rate a n d meas ures P R, Q R S, Q T, R R a n d Q Tc B i nter vals. 
At eac h assess me nt, a si n gle 1 2 -lea d E C G will be perf or me d b y q u alifie d site pers o n nel 
after t he s u bject has reste d i n a se mi-rec u m be nt or s u pi ne p ositi o n f or at least 5 mi n utes. 
T w o c o pies of t he E C G traci n g s h o ul d be o btai ne d at t he ti me of t he E C G; t he first c o p y 
will be ke pt i n t he s u bject’s me dical c hart a n d t he sec o n d c o p y will be ke pt i n t he st u d y 
file f or retr os pecti ve c ollecti o n b y t he S p o ns or if necessar y.  See Secti o n 5. 8. 3. 3  f or d ose 
m o dificati o ns g ui d eli nes if Q Tc pr ol o n gati o n occ urs. 
7. 4. 9. E c h o c ar di o gr a m s ( E C H O)  
Ec h ocar di o gra ms ( E C H O) will be perf or me d t o assess car diac ejecti o n fracti o n. T he 
ec h ocar di o gra p h er’s e val uati o n s h o ul d i ncl u de a n e val uati o n f or left ve ntric ular ejecti o n 
fracti o n. C o pies of all E C H O sca ns will be ce ntrall y c ollecte d f or re vie w. C ollecti o n 
details will be A g M e d Net I m a gi n g Ac q uisiti o n G ui deli nes. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
9 7  
 
 
7. 6. 2. B R A F m ut ati o n a s s a y  
S u bjects i n  A L L c o h orts ma y be e nr olle d bas e d o n certifie d assa y l ocal test res ults. 
T he tiss ue re q uire m e nts f or t he B R A F m utati o n assa y e val u ati n g p atie nt eli gi bilit y f or t h e 
st u d y m a y be pr o vi de d i n t he S P M. 
A d diti o nal bi o mar kers relate d t o t he acti vit y of d a brafe ni b a n d tra meti ni b ma y als o b e 
a nal yz e d as des cri be d i n Secti o n 7. 6 . 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
9 8  
 
 
8.   
D A T A M A N A G E M E N T 
Data Ma na ge me nt will i de ntif y a n d i m ple me nt t he m ost effecti ve d ata ac q uisiti o n a n d 
ma na ge me nt strat e g y f or eac h cli nical trial pr ot oc ol a n d deli ver datas ets t hat s u p p ort t he 
pr ot oc ol o bjecti ves. 
F or t his st u d y, s u bject data will be e ntere d i nt o t he electr o nic case re p ort f or ms (e C R Fs), 
tra ns mitte d electr o nicall y t o N o vartis ( or desi g nee), a n d be c o m bi ne d wit h d ata fr o m 
ot her s o urces i n a vali dat e d data s yst e m. 
Cli nical data ma na ge me nt will be perf or me d i n acc or da nce wit h a p plica bl e sta n dar ds 
a n d data cl ea ni n g pr oce d ures wit h t he o bjecti ve of res ol vi n g err ors a n d i nc o nsiste ncies 
i n t he data w hic h w o ul d ot her wise i m pact o n t he a nal ysis a n d re p orti n g o bjecti ves, or t he 
cre di bilit y of t h e Cli nical St u d y R e p ort.  All A Es a n d c o nc o mita nt me dicati o ns ter ms 
will be c o de d usi n g t h e Me dical Dicti o nar y f or R e g ul at or y Acti vities ( Me d D R A) a n d a 
c ust o m me dicati o n dicti o nar y. 
T he e C R Fs (i ncl u di n g q u eries a n d a u dit trails) will be retai ne d b y N o vartis, a n d c o pies 
will be se nt t o t he i n vesti gat or t o mai ntai n as t he i n vesti gat or c o p y.  
9.   
D A T A A N A L Y SI S A N D S T A TI S TI C A L C O N SI D E R A TI O N S 
9. 1.  
H y p ot h e se s  
T he pri mar y effi cac y o bj ecti ve of t his st u d y is t o assess t he i ntracra nial res p o nse (I R) rate 
i n B R A F V 6 0 0 E m utati o n p ositi ve s u bjects assesse d b y I n v esti gat ors usi n g m o difie d 
R E CI S T 1. 1 criteria f or C o h ort A: 
 
C o h ort A: 7 5 S u bjects w h o are tr eat me nt- nai v e f or brai n metastas es, 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
9 9  
 
 
as y m pt o matic a n d sta ble o n c ortic oster oi ds. 
T he st u d y is desi g ne d t o pr o vi de e vi de nce t o s u p p ort t he n ull h y p ot hesis, H 0: I R R ≤ 3 5 % 
or t o reject it i n fa v or of t he alter nati ve h y p ot hesis, H A : I R R ≥ 5 0 % f or B R A F V 6 0 0 E 
m utati o n- p ositi ve s u bjects i n C o h ort A. 
T he n ull h y p ot hesis is base d o n res ults of B R F 1 1 3 9 2 9 ( B R E A K- M B), a st u d y of 
da brafe ni b i n t w o c o h orts of patie nts wit h hist ol o gicall y c o nfir me d metast atic 
mela n o ma t o t he brai n [L o n g , 2 0 1 2]. T he I R i n p atie nts wit h n o pri or l ocal 
treat me nt f or brai n metastases was 3 9 %; i n patie nts wit h pri or l ocal treat me nt, t he 
I R w as 3 1 %. 
W hile t he B R E A K- M B  trial de m o nstrate d acti vit y i n patie nts wit h acti ve brai n 
metastases, all of t he p atie nts i n t hat trial were as y m pt o matic fr o m C N S disease. 
Ve m urafe ni b, a n ot her ele cti ve i n hi bit or of o nc o ge nic B R A F ki n ase t hat s pecificall y 
tar gets ca n cer cells har b ori n g m utate d B R A F V 6 0 0, was rece ntl y st u die d i n a c o h ort of 2 4 
patie nts wit h s y m pt o mati c brai n metastas es.  Me di a n P F S i n t he brai n was 4. 3 m o nt hs 
a n d f or ot her sites was 4. 6 m o nt hs. I n a d diti o n, a n i m pr o ve me nt i n perf or m a nce stat us 
( decrease fr o m bas eli ne of at least 1 p oi nt of E C O G sc ore) was s ee n i n 8 3. 3 % of patie nts, 
a n d 6 6. 7 % re p orte d a re d ucti o n of ≥3 0 % (c o m pare d wit h baseli ne d ose) or c o m plete 
disc o nti n uati o n of c ortic oster oi ds. 
T his c urre nt trial is e x pecte d t o b uil d u p o n t he c urre nt b o d y of e vi de nce of t ar gete d 
t hera p y i n m ela n o ma brai n metastases t hr o u g h a n e val uati o n of t he c o m bi nati o n of 
da brafe ni b a n d tr a meti ni b i n patie nts wit h V 6 0 0- m utati o n p ositi ve mela n o ma brai n 
metastases. 
T he alter nati ve h y p ot hesis was selecte d as t he I R t hat w o ul d be cli nicall y rele va nt f or t his 
c o m bi nati o n t hera p y.  T h e st u d y is desi g ne d t o ha ve 8 2 % statistical p o wer t o detect a n I R 
of 5 0 % i n V 6 0 0 E m utati o n- p ositi ve s u bjects w h o recei ve da brafe ni b i n c o m bi nati o n wit h 
tra meti ni b i n C o h ort A. 
T his h y p ot hesis will be t este d usi n g a o ne-si de d test f or s u peri orit y wit h α = 0. 0 5. T here 
will be n o ot her testi n g; t heref ore, t here will be n o a dj ust me nt of t he T y p e I err or f or 
m ulti ple testi n g. 
9. 2.  
St u d y D e si g n C o n si d er ati o n s  
9. 2. 1. S a m pl e Si z e A s s u m pti o n s  
T he sa m ple size is base d o n t he h y p ot hesize d i m pr o ve me nt i n i ntracra nial res p o nse o ver 
st u d y G S K B R F 1 1 3 9 2 9 ( B R E A K- M B) i n C o h ort A.  3 5 % i ntracra nial res p o nse (I R) is 
n ot cli nicall y si g nifica nt o ver e xisti n g t hera pies.  A n i ntracra nial res p o nse (I R) of 5 0 % is 
of cli nical si g nifi ca nce. 
F or t he pri m ar y e n d p oi nt c o h ort ( A), 7 5 B R A F V 6 0 0 E m utati o n p ositi ve s u bjects will be 
e nr olle d.  At t he ti me of t he pri mar y effi cac y a n al ysis, at least 3 3 s u bjects wit h a n IR 
( 4 4 %) are re q uire d t o est a blis h t hat t he e vi de nce d oes n ot s u p p ort t he n ull h y p ot hesis. 
T he sa m ple siz e is base d o n a o ne-si de d s u peri orit y tri al of bi n o mial pr o p orti o ns wit h a n 
o verall T y pe I err or rate 0. 0 5 i nc or p orati n g a n i nt eri m a nal ysis wit h al p ha-s pe n di n g 
f u ncti o n pr o p ose d b y La n ; 1 9 8 3 wit h P oc oc k B o u n dary.  T he n ull h y p ot hesis i n C o h ort A 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 0 0  
 
 
will be teste d ass u mi n g I R of 3 5 % a gai nst a n I R of 5 0 % usi n g a o n e-si de d t est f or 
s u peri orit y wit h a = 0. 0 5 a n d p o wer = 8 2 %. Sa m ple Size Se nsiti vit y 
Ta ble 2 5  s h o ws statistical p o wer f or t he test of t he n ull h y p ot hesis i n C o h ort A u n der t he 
ass u me d I R of 3 5 % a n d f or sce nari os w here t he alt er nati ve res p o nse rate is l o wer a n d 
hi g her, ass u mi n g 7 5 B R A F V 6 0 0 E m utati o n p ositi ve s u bjects. 
T a bl e 2 5  
St ati sti c al P o w er S c e n ari o s wit h 7 5 B R A F V 6 0 0 E M ut ati o n P o siti v e S u bj e ct s i n 
C o h ort A  
I R 
St ati sti c al P o wer  
4 0 %  
2 2. 9 %  
4 5 %  
5 3. 8 %  
5 0 %  
8 2. 1 %  
5 5 %  
9 6. 2 %  
 
9. 2. 2. S a m pl e Si z e R e- e sti m ati o n  
N o f or mal sa m ple siz e r e-esti mati o n is pla n ne d. 
9. 3.  
D at a  A n aly s i s C o n si d er ati o n s 
9. 3. 1. A n al y si s P o p ul ati o n s  
All s u bjects w h o recei ve at least o ne d ose of st u d y me dicati o n will c o m prise t he All 
Treate d S u bjects ( A T S) p o p ulati o n. 
T he V 6 0 0 E p o p ulati o n will c o m prise all B R A F V 6 0 0 E m utati o n p ositi ve s u bjects 
w h o recei ve at least o ne d ose of st u d y tr eat me nt. 
T he V 6 0 0 D/ K/ R p o p ulati o n will c o m prise all B R A F V 6 0 0 D/ K/ R m utati o n 
p ositi ve s u bjects w h o recei ve at least o ne d os e of st u d y treat me nt.  
9. 3. 2. A n al y si s D at a S et s  
T he pri mar y dat asets f or effic ac y will c o m prise efficac y d ata fr o m s u bjects i n t he 
V 6 0 0 E p o p ulati o n fr o m C o h ort A. T he V 6 0 0 D/ K/ R p o p ulati o n will als o be use d t o 
re p ort o n sec o n dar y effi cac y e n d p oi nts b y c o h orts. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 0 1  
 
 
T he data sets f or assessi n g all safet y e n d p oi nts will i ncl u de all safet y data c ollecte d 
o n s u bjects i n t he A T S p o p ulati o n. 
9. 3. 3. Tr e at m e nt C o m p ari s o n s  
Treat me nt c o m paris o ns are n ot a p plica ble f or t his st u d y.  T h e pri mar y o bj ecti ve will 
be s u p p orte d b y testi n g t he n ull h y p ot hesis i n C o h ort. A. T he f o ur c o h orts will n ot 
be c o m pare d statisticall y f or a n y e n d p oi nt. 
. 3. 4. I nt eri m A n al y si s 
T here is a f or mal i nteri m a nal ysis f or f utilit y o nl y wit h a statistical decisi o n r ule i n t his 
trial.  F or C o h ort A, a n i nteri m a nal ysis will ta ke place after 2 2 s u bjects ha v e bee n 
treate d a n d h a d t he o p p ort u nit y f or at least t w o disease ass ess me nts.  T he res p o nses 
use d i n t his i nteri m a nal ysis d o n ot ha ve t o be c o nfir me d.  At least 8 of t he 2 2 s u bjects 
m ust ha ve a n  I R (i ntracra nial C R or P R) f or t he trial t o c o nti n ue.  If 7 or fe wer s u bjects 
ha ve a n I R, t his is e vi de n ce t hat t he n ull h y p ot h esis is tr ue.  If accr ual is n ot c o m plete at 
t he ti me of t he i nteri m a nal ysis, it will c o nti n ue d uri n g t his a nal ysis. 
A n I D M C will re vie w acc u m ulati n g safet y a n d efficac y dat a, i ncl u di n g t he res ults of t he 
i nteri m re vie w of s afet y a n d effi cac y a n d ma ke rec o m me n dati o ns t o c o nti n ue, m o dif y, or 
ter mi nate t he st u d y if t here are c o n cer ns re gar di n g safet y. T he I D M C will r e vie w t he 
st u d y res ults at least o nc e f or efficac y a n d f utilit y.  A d diti o nal r o uti ne re vie ws of safety 
data will be sc he d ule d as nee de d.  T h e I D M C r es p o nsi bilities a n d re vie w sc he d ules are 
o utli ne d i n t he I D M C C harter. 
9. 3. 5. K e y El e m e nt s of  A n al ysi s Pl a n  
Data will be liste d a n d s u m marize d acc or di n g t o t he N o vartis’ re p orti n g sta n dar ds, 
w here a p plica ble.  C o m plete details will be d oc u me nte d i n t he Re p orti n g a n d A nal ysis 
Pla n ( R A P).  A n y de viati o ns fr o m, or a d diti o ns t o, t he ori gi nal a nal ysis pla n descri be d 
i n t his pr ot oc ol will be d oc u me nte d i n t he R A P a n d fi nal st u d y re p ort. 
As it is a ntici pate d t hat accr ual will be s prea d t hi nl y acr oss ce ntres a n d s u m maries of data 
b y ce ntre w o ul d be u nli k el y t o be i nf or mati ve, dat a fr o m all partici p ati n g ce ntres will be 
p o ole d pri or t o a nal ysis. 
All data u p t o t he ti me of st u d y c o m pleti o n/ wit h dra wal fr o m t he st u d y will be i ncl u de d i n 
a nal ys es, r e gar dl ess of d urati o n of treat me nt. 
T he le n gt h of treat me nt f or eac h s u bj ect will de pe n d o n t he efficac y a nd  t o xicit y of t he 
treat me nt, s o t he d urati o n of treat me nt a n d f oll o w- u p will var y a m o n g s u bjects.  All 
a vaila ble ti me-t o -e ve nt d ata will be a nal yz e d usi n g a p pr o priate statistical met h o ds; 
s u bjects wit h s h orter treat me nt a n d f oll o w- u p d ue t o t he nat ural hist or y of t heir disease or 
me dical necessities of t he treat me nt of t heir disease will n ot be c o nsi dere d t o ha ve 
missi n g data.  C o nse q ue ntl y t h ere will be n o i m p utati o n f or missi n g ti m e-t o-e ve nt data. 
De m o gra p hic a n d baseli n e c haract eristics will be s u m marize d acc or di n g t o c urre nt 
N o vartis sta n dar ds. 
F or t he a nal ysis of o verall s ur vi val, t he last date of k n o w n c o ntact will be use d f or t h ose 
s u bjects w h o ha ve n ot di e d at t he ti me of a n al ysis; s uc h s u bjects will be c o nsi dere d 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 0 2  
 
 
ce ns ore d. 
F o r t he a nal ysis of P F S, if t he s u bject recei ve d s u bse q ue nt a nti-ca n cer t hera p y pri or t o t he 
date of d oc u me nt e d pr o gressi o n or deat h, pr o gressi o n free-s ur vi v al will be ce ns ore d at t he 
last a de q uate assess me nt (t hat is, t he last assess me nt i n w hic h t he visit le vel res p o nse is 
C R, P R, or S D) pri or t o t he i nitiati o n of t hat a nti-ca ncer t h era p y.  Ot her wis e, if t he s u bject 
d oes n ot ha ve a d o c u me nte d date of pr o gressi o n or deat h, pr o gressi o n-free s ur vi val will 
be ce ns or e d at t he d ate of t he last a de q uate assess me nt.  F urt her d etails o n r ules f or 
ce ns ori n g will be pr o vi de d i n t he R A P. 
T here will be n o a dj ust me nts of t he T y pe I err or rate f or m ulti plicit y. 
9. 3. 5. 1.  
Effi c a c y A n al y s e s 
9. 3. 5. 1. 1.  
Pri m ar y A n al y si s  
T he I R is d efi ne d as t he perce nt a ge of s u bjects w h o ha ve a b est c o nfir me d i ntracra nial 
c o m plete or partial res p o nse b y i n vesti gat or assess me nt. S u bjects w h o ha ve a n 
i ntracra ni al res p o nse of N E ( n ot e val ua bl e) or a missi n g res p o nse will be treate d as n o n- 
res p o n ders, i.e., t h e y will be i ncl u de d i n t he de n o mi nat or w he n cal c ulati n g t he 
p erce nta ge.  T he pri mar y effic ac y a n al ysis will be perf or me d w he n all s u bjects i n c o h ort 
A ha ve ha d t h e o p p ort u nit y f or t hree ( 3) p ost baseli ne disease ass ess me nts.  At least 3 3 
of 7 5 V 6 0 0 E s u bjects ( 4 4 %) m ust s h o w a n i ntracra nial res p o nse f or t he n ull h y p ot hesis 
t o be reject e d.  T he I R, al o n g wit h e xact t w o-si de d 9 5 % c o nfi de n ce i nter val, will be 
re p orte d.  I n v esti gat or- assesse d I R will be c o nsi dere d t he pri mar y a n al ysis. 
Sec o n d ar y A n al yses  
Sec o n dar y effi cac y e n d p oi nts are liste d i n [ Ta ble 1 ] a n d Secti o n 2 .  Eac h will be 
a nal yz e d se paratel y as o utli ne d i n t his ta ble. 
T he o ver all res p o nse r ate ( O R R) , d efi ne d as t he perce nt a ge of s u bjects wit h a c o nfir me d 
o verall C R or P R b y i n vesti gat or ass ess me nt usi n g t he R E CI S T 1. 1 criteria. T o deter mi ne 
t he o verall res p o nse, all t ar get a n d n o n-tar get lesi o ns will be assesse d usi n g m o difie d 
R E CI S T 1. 1 criteria.  S u bjects w h o ha ve a n o verall res p o nse of N E ( n ot e v al ua ble) or a 
missi n g res p o nse will be treate d as n o n-res p o n ders, i.e. t he y will be i ncl u de d i n t he 
de n o mi nat or w he n calc ul ati n g t he perce nta ge. O verall res p o ns e will be det er mi ne d usi n g 
R E CI S T 1. 1.  R ules f or assi g ni n g eac h s u bject’s visit-le vel best o verall res p o nse are gi v e n 
i n Secti o n 7. 3. 2. 1 0 .  A t w o-si de d 9 5 % c o nfi de n ce i nter val will be re p orte d al o n g wit h t he 
p oi nt esti mate. 
T he d ur ati o n of res p o nse f or i ntracra nial, e xtracra nial, a n d o verall res p o ns e will be 
s u m marize d descri pti vel y usi n g K a pla n- Meier q uartiles, al o n g wit h t w o-si de d 9 5 % 
c o nfi de nce i nter vals.  O nl y t he s u bset of s u bjects w h o s h o w a c o m plete or partial t u m o ur 
res p o nse will be i ncl u de d i n t hese a nal ys es.  Ce ns ori n g r ul es f or d urati o n of res p o nse will 
use t he r ules f or P F S. Ca uti o n s h o ul d be e x ercise d w hile i nter preti n g t he res ults d ue t o 
p ossi ble c o m peti n g ris ks. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 0 3  
 
 
Pr o g ressi o n free s ur vi v al ( P F S), defi n e d as t he ti me fr o m t he first d ose of da brafe ni b 
a n d tra meti ni b t o t he earliest of deat h or pr o gressi o n, will be s u m m arize d usi n g Ka pl a n- 
Meier q uartile esti mates al o n g wit h t w o -si de d 9 5 % c o nfi de n ce i nter vals.  If a s u bject 
recei v es s u bse q ue nt a nti- ca ncer t hera p y pri or t o t h e date of d o c u me nte d pr o gressi o n or 
deat h, pr o gressi o n free-s ur vi val will be ce ns ore d at t he last a de q uat e assess me nt (t hat is, 
t he last assess me nt i n w hic h t he visit le vel res p o ns e is C R, P R, or S D) pri or t o t he 
i nitiati o n of t hat a nti-ca ncer t hera p y.  Ot her wise, if t he s u bject d oes n ot ha ve a 
d oc u me nte d date of pr o gressi o n or deat h, pr o gressi o n- free s ur vi val will be ce ns ore d at 
t he date of t he last a de q u ate assess me nt. 
O ver all s ur vi v al ( O S): O S, defi ne d as t he ti me t o deat h f or a n y reas o n, will be 
s u m marize d usi n g Ka pla n- Meier q uartile esti mates al o n g wit h t w o-si de d 9 5 % c o nfi de n ce 
i nter vals.  O S will be ce ns ore d usi n g t h e date of l ast k n o w n c o ntact f or t h os e w h o are 
ali ve at t he ti me of a n al ysis. Als o of i nterest will be t he tail of t he O S c ur v e, wit h t he 3 - 
year O S esti mate of parti c ular i nterest. 
All res p o nses are i n vesti gat or-assess e d.  If necess ar y, i n de pe n d e nt ce ntr al r e vie w will be 
perf or me d u n der c harter if t here is a re q uire me nt. 
9. 3. 5. 2.  
S af et y A n al y s e s  
T he A T S p o p ulati o n will be use d f or t h e a nal ysis of safet y data. All safet y meas ures will 
be a nal yz e d se p aratel y f or eac h c o h ort a n d als o a g gre gatel y if a p pr o priate.  Safet y 
a nal ys es m a y als o be re p orte d f or t he V 6 0 0 E a n d V 6 0 0 D/ K/ R a nal ysis p o p ulati o ns f or 
eac h c o h ort.  C o m plete d etails of t he safet y a nal ys es will be pr o vi de d i n t he R A P. 
T his st u d y, or a si n gle c o h ort t here of, ma y be st o p pe d at a n y ti me if e x cessi ve t o xicities 
wit h t he st u d y treat me nt are o bser ve d. 
9. 3. 5. 2. 1.  
E xt e nt of E x p o s ur e  
T he n u m ber of s u bjects a d mi nistere d st u d y me dicati o n will be s u m marize d acc or di n g t o 
t he d urati o n of t hera p y. S u m maries of d ose a n d d ose i nte nsit y will be pr o vi de d as 
a p pr o priate f or da brafe ni b a n d tra meti ni b. 
9. 3. 5. 2. 2.  
A d v er s e E v e nt s  
A d verse e ve nts ( A Es) will be c o de d usi n g t h e sta n dar d Me dical Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A) a n d gr o u pe d b y s yste m or ga n class. A Es will be 
gra de d b y t he i n vesti gat or acc or di n g t o t he N C I- C T C A E ( versi o n 4. 0) [N C I, 2 0 0 9]. 
E ve nts will be s u m marize d b y fre q u e n c y a n d pr o p orti o n of t otal s u bjects, b y s yste m 
or ga n cl ass a n d preferre d ter m. Se parate s u m maries will be gi ve n f or all A Es, dr u g- 
relate d A Es, s eri o us A Es a n d A Es lea di n g t o disc o nti n uati o n of st u d y treat me nt. 
If t he A E is liste d i n t he N CI C T C A E ( v ersi o n 4. 0) ta ble, t he ma xi m u m gra de will be 
s u m marize d. 

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C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 0 4  
 
 
C haracteristics of t he f oll o wi n g A Es of s pecial i nt erest will be s u m marize d se parat el y : 
n o n- mela n o ma s ki n lesi o ns, p yre xia, car diac e ve nts, a nae mia, a n d n e utr o pe nia.  I n 
partic ular, t he rate of n o n- mela n o ma s ki n lesi o ns will be calc ulate d as t he perce nt a ge of 
s u bjects wit h t he a p peara nce of a n y n o n - mela n o ma s ki n lesi o ns after t he st art of 
treat me nt.  E x act t w o-si de d 9 5 % c o nfi d e nce i nter vals f or t he rate of n o n- mela n o ma s ki n 
lesi o ns i n eac h ar m will als o be prese nte d.  Details will be gi ve n i n t he R A P. 
T he i nci de nce of deat hs a n d t he pri mar y ca us e of deat h will be s u m marize d. 
9. 3. 5. 2. 3.  
Cli ni c al L a b or at or y E v al u ati o n s  
Hae mat ol o g y a n d cli nic al c he mistr y dat a will be s u m marize d at eac h sc he d ule d 
assess me nt acc or di n g t o N CI C T C A E gra de ( v ersi o n 4. 0) .  T he pr o p orti o n of val ues l yi n g 
o utsi de t he refere n ce ra n ge will als o be prese nt e d f or la b orat or y tests t hat are n ot gra d e d 
beca use t h ere are n o ass o ciate d N CI C T C A E ( versi o n 4. 0) criteria.  S u m maries will 
i ncl u de data fr o m sc he d ule d assess me nts o nl y, a n d all data will be re p orte d acc or di n g t o 
t he n o mi nal visit date f or w hic h it was rec or de d; n o visit wi n d o ws will be a p plie d. 
U nsc he d ule d d ata will be i ncl u de d i n “ p ost- baseli ne” s u m maries w hic h will ca pt ure a 
w orst case acr oss all sc he d ule d a n d u nsc he d ule d visits after t he first d ose of st u d y 
me dicati o n.  F urt her details will be pr o vi de d i n t he R A P. 
9. 3. 5. 2. 4.  
Ot h er S af et y M e a s ur e s  
T he res ults of sc h e d ule d assess me nts of vital si g ns, 1 2-lea d E C G, ec h o car di o gra m a n d 
E C O G perf or ma nce stat us will be s u m marize d.  S u m maries will i ncl u de data fr o m 
sc he d ule d ass ess me nts o nl y.  All data will be re p orte d acc or di n g t o t he n o mi nal visit date 
f or w hic h it was r ec or de d; n o visit wi n d o ws will be a p plie d.  All data will b e liste d. 
F urt her d etails will be pr o vi de d i n t he R A P. 
9. 3. 5. 2. 5.  
M e a s ur e of A gr e e m e nt b et w e e n I n Vitr o Di a g n o sti c (I V D) S cr e e ni n g A s s a y 
a n d R e s p o n s e G e n eti c s, I n c. ( R GI) S cr e e ni n g A s s a y f or D et er mi ni n g B R A F 
V 6 0 0 E or V 6 0 0 K M ut ati o n- P o siti v e S u bj e ct s  
A sec o n d ar y o bje cti ve of t he st u d y is t he de vel o p me nt a n d vali dati o n of a B R A F i n vitr o 
dia g n ostic (I V D) assa y.  T he cli nical assa y v ali dati o n will deter mi ne t he e xte nt of 
a gree m e nt bet wee n t he I V D assa y t o detect B R A F m utati o ns a n d t he Res p o nse Ge netics, 
I n c. ( R GI) assa y t o detect B R A F m utati o ns.  Effi cac y res ults of s u bjects deter mi ne d t o be 
B R A F m utati o n- p ositi ve b y t he I V D assa y will be descri be d t o ill ustrate c o m para bilit y t o 
t he res ults fr o m all s u bje cts e nr olle d i n t he trial (t hat is, t h ose deter mi ne d t o be B R A F 
m uta nt b y  t h e R GI assa y ). A p pr o priate statistical met h o ds [U S  F D A , 2 0 0 7] will be use d; 
t hese met h o ds will be o utli ne d f urt her i n t he R A P. All a vaila ble tiss ue sa m ples will be use d 
i n t he assa y vali dati o n.  Meas ures of p ositi ve perce nt a gree me nt a n d n e gati ve perce nt 
a gree m e nt will be re p ort e d, as well as t he t w o-si d e d 9 5 % c o nfi d e nce i nter vals.  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 0 5  
 
 
1 0.  
S T U D Y C O N D U C T C O N SI D E R A TI O N S 
1 0. 1.  P o sti n g  of  I nf or m ati o n o n  P u bli cl y A v ail a bl e Cli ni c al Tri al   
  
R e gi st er s 
St u d y i nf or mati o n fr o m t his pr ot oc ol will be p oste d o n p u blicl y a vaila bl e cli nical trial 
re gisters bef ore e nr ol me nt of s u bjects be gi ns. 
1 0. 2.   
R e g ul at or y a n d  Et hi c al C o n si d er ati o n s, I n cl u di n g t h e I nf or m e d 
C o n s e nt  Pr o c e s s 
Pri or t o i nitiati o n of a st u d y site, N o vartis will o btai n fa v o ura ble o pi ni o n/a p pr o val fr o m 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 0 6  
 
 
t he a p pr o priat e re g ulat or y a ge n c y t o c o n d uct t he st u d y i n acc or da n ce with  I C H G o o d 
Cli nical Practice ( G C P) a n d a p plica ble c o u ntr y-s p ecific re g ulat or y re q uire me nts i ncl u di n g 
t h ose re q uire d u n d er a U S I N D. 
T he st u d y will be c o n d u cte d i n acc or d a nce wit h all a p plica ble re g ul at or y re q uire me nts. 
T he st u d y will be c o n d u cte d i n acc or d a nce wit h G C P, all a p plica ble s u bject pri vac y 
re q uire me nts, a n d t h e g ui di n g pri nci ples of t h e Declarati o n of Helsi n ki 2 0 0 8, i ncl u di n g, 
b ut n ot li mite d t o: 
 
I R B/I E C r e vie w a n d fa v o ura ble o pi ni o n/a p pr o val of st u d y pr ot oc ol a n d a n y 
s u bse q ue nt a me n d me nts. 
 
S u bject i nf or me d c o nse nt. 
 
I n v esti gat or re p orti n g re q uire me nts. 
N o vartis will pr o vi de f ull details of t he a b o ve pr oce d ures, eit her ver ball y, i n writi n g, or 
b ot h. 
Writte n i nf or me d c o nse nt m ust be o btai ne d fr o m eac h s u bject pri or t o partici pati o n i n t he 
st u d y. 
I n a p pr o vi n g t he cli nic al pr ot oc ol t he I E C/I R B a n d, w here re q uire d, t he a p plica ble 
re g ulat or y a ge n c y are als o a p pr o vi n g t he o pti o nal assess me nts 
 
 u nless ot her wis e i n dicate d. 
W here 
per mitte d b y re g ulat or y a ut h orities, a p pr o val of t h e o pti o nal assess me nts ca n occ ur after 
a p pr o val is o btai ne d f or t he rest of t he st u d y.  If s o, t he n t he writte n a p pr o val will clearl y 
i n dicate a p pr o val of t he o pti o nal assess me nts is bei n g deferre d a n d t he st u d y, e x ce pt f or 
t he o pti o nal assess me nts, ca n be i nitiate d.  W he n t he o pti o nal assess me nts are n ot 
a p pr o ve d, t he n t he a p pr o val f or t he rest of t he st u d y will clearl y i n dicate t his a n d 
t heref ore, t he o pti o nal assess me nts will n ot be c o n d ucte d. 
1 0. 3.  Q u ali t y C o ntr ol ( St u d y M o nit ori n g) 
I n acc or da n ce wit h a p pli ca ble re g ulati o ns, G C P, a n d N o vartis pr oce d ures, N o vartis 
pers o n nel ( or d esi g nate d Cli nical Researc h Or ga nisati o n [ C R O]) will c o ntact t he site 
pri or t o t he start of t he st u d y t o re vi e w wit h t he site staff t he pr ot oc ol, st u d y 
re q uire me nts, a n d t h eir res p o nsi bilities t o satisf y re g ul at or y, et hical, a n d N o vartis 
re q uire me nts.  W he n re vie wi n g d ata c ollecti o n pr o ce d ures, t h e disc ussi o n will i ncl u de 
i de ntificati o n, a gree me nt a n d d oc u me ntati o n of data ite ms f or w hic h t he C R F will ser ve 
as t he s o urce d oc u me nt. 
N o vartis ( or desi g n ate d C R O) pers o n nel will m o nit or t he st u d y t o e ns ure t hat t he:  
 
Data are a ut he ntic, acc urate, a n d c o m plete. 
 
Safet y a n d ri g hts of s u bjects are b ei n g pr otecte d. 
 
St u d y is c o n d u cte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot o c ol a n d a n y ot her 
st u d y a gree me nts, G C P, a n d all a p plica ble re g ulat or y re q uire m e nts. 
T he i n vesti gat or a n d t he hea d of t he me di cal i nstit uti o n ( w here a p plica ble) a grees t o 
all o w t he m o nit or direct access t o all rele va nt d o c u me nts.  

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C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 0 7  
 
 
1 0. 4.  Q u ali t y A s s ur a n c e 
T o e ns ure c o m plia n ce wit h G C P a n d all a p plica ble re g ulat or y re q uire m e nts, N o vartis ma y 
c o n d uct a q ualit y ass ur a n ce assess me nt a n d/ or a u dit of t he site rec or ds, a n d t he re g ulat or y 
a ge ncies ma y c o n d uct a re g ul at or y i ns pecti o n at a n y ti me d uri n g or after c o m pleti o n of 
t he st u d y. I n t he e v e nt of a n assess me nt, a u dit or i ns pecti o n, t he i n vesti gat or (a n d 
i nstit uti o n) m ust a gree t o gra nt t he a d vis or(s), a u dit or(s) a n d i ns pect or(s) direct access t o 
all rele va nt d oc u m e nts a n d t o all ocate t heir ti me a n d t he ti me of t heir staff t o disc uss t he 
c o n d uct of t he st u d y,  a n y fi n di n gs/rele va nt iss ues a n d t o i m ple me nt a n y c orrecti ve a n d/ or 
pre ve ntati ve acti o ns t o a d dress a n y fi n di n gs/iss ues i de ntifie d. 
1 0. 5.  St u d y a n d Sit e  Cl o s ur e 
T he st u d y will be c o nsi d ere d cl os e d w he n all c o h ort A s u bjects still i n f oll o w u p ha ve 
ha d t he o p p ort u nit y f or at least 3 years f oll o w- u p fr o m t he date of first d ose of st u d y 
treat me nt or 7 0 % of c o h ort A patie nts ha ve die d or are l ost t o f oll o w u p,  w hic he ver is 
earlier
U p o n c o m pleti o n or ter mi nati o n of t he st u d y, t he N o vartis pers o n nel ( or desi g nate d C R O ) 
m o nit or will c o n d uct site cl os ure acti vities wit h t he i n vesti gat or or site staff (as 
a p pr o priate), i n acc or da n ce wit h a p plica ble re g ulati o ns, I C H G C P, a n d N o vartis Sta n dar d 
O perati n g Pr oce d ures. 
N o vartis reser ves t he ri g ht t o te m p oraril y s us pe n d or ter mi nate t he st u d y at a n y ti me f or 
reas o ns i ncl u di n g ( b ut n ot li mite d t o) safet y iss ues, et hical iss ues, or se vere n o n- 
c o m plia nce.  If N o vartis deter mi nes t hat s uc h acti o n is re q uire d, N o vartis will disc uss t he 
reas o ns f or ta ki n g s uc h acti o n wit h t he i n vesti gat or or hea d of t he me dical i nstit uti o n 
( w here a p plica bl e).  W he n feasi ble, N o v artis will pr o vi de a d va n ce n otice t o t he 
i n vesti gat or or h ea d of t he me dical i nstit uti o n of t he i m pe n di n g acti o n. 
If a st u d y is s us pe n de d or ter mi nate d f or s afet y re as o ns, N o vartis will pr o m ptl y i nf or m all 
i n vesti gat ors, hea ds of t h e me dical i nstit uti o ns ( w here a p plica ble), a n d/ or i nstit uti o ns 
c o n d ucti n g t h e st u d y. N o vartis will als o pr o m ptl y i nf or m t he rele va nt re g ul at or y 
a ut h orities of t he s us pe nsi o n/ter mi nati o n al o n g wit h t he reas o ns f or s uc h acti o n.  W here 
re q uire d b y a p plica ble re g ulati o ns, t he i n vesti gat or or hea d of t he me dical i nstit uti o n m ust 
i nf or m t he I R B/I E C pr o m ptl y a n d pr o vi de t he reas o n(s) f or t h e s us pe nsi o n/ter mi nati o n. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 0 8  
 
 
1 0. 6.  R e c or d s R et e nti o n 
F oll o wi n g cl os ure of t he st u d y, t he i n vesti gat or or hea d of t he me di cal i nstit uti o n ( w here 
a p plica ble) m ust mai ntai n all site st u d y rec or ds (e x ce pt f or t h ose re q uire d b y l ocal 
re g ulati o ns t o be mai ntai ne d else w here) i n a safe a n d sec ure l ocati o n.  T he rec or ds m ust 
be easil y accessi ble w h e n nee de d (e. g., f or a N o vartis a u dit or re g ulat or y i ns pecti o n) a n d 
m ust be a vaila ble f or re vi e w i n c o nj u ncti o n wit h assess me nt of t he facilit y, s u p p orti n g 
s yste ms, a n d rele v a nt site staff. 
W here per mitte d b y l o cal la ws/re g ulati o ns or i nstit uti o n al p olic y, s o me or all of t he 
rec or ds ma y b e mai ntai n e d i n a f or mat ot her t ha n har d c o p y (e. g., micr ofic he, sca n ne d, 
electr o nic); h o we ver, ca uti o n m ust be e x ercise d bef ore s uc h acti o n is ta ke n.  T he 
i n vesti gat or m ust e ns ur e t hat all re pr o d ucti o ns are le gi ble a n d are a tr u e a n d acc urate c o p y 
of t he ori gi nal.  I n a d diti o n, t he y m ust meet accessi bilit y a n d retrie val sta n dar ds, i ncl u di n g 
re ge nerati o n of a h ar d c o p y, if re q uire d.  T he i n v esti gat or m ust als o e ns ure t hat a n 
acce pta ble bac k - u p of t he re pr o d u cti o ns e xists a n d t hat t here is a n acce pt a ble q ualit y 
c o ntr ol pr oce d ure i n place f or creati n g t he re pr o d u cti o ns. 
T he i n vesti gat or m ust n otif y N o v artis o f a n y c ha n ges i n t he arc hi val arra n ge me nts, 
i ncl u di n g, b ut n ot li mite d t o arc hi val of rec or ds at a n off-site facilit y or tra nsfer of 
o w ners hi p of t he rec or ds i n t he e ve nt t hat t he i n vesti gat or is n o l o n ger ass ociate d wit h t he 
site. 
Esse ntial d oc u me nts ( writte n a n d electr o ni c) s h o ul d be retai ne d f or a p eri o d of n ot less t ha n 
fiftee n ( 1 5) years fr o m t h e c o m pleti o n of t he Cli nical Trial u nless N o vartis pr o vi des 
writte n per missi o n t o dis p ose of t he m or, re q uires t heir rete nti o n f or a n a d diti o nal peri o d of 
ti me beca use of a p plica bl e la ws, re g ul ati o ns a n d/ or g ui deli nes. 
1 0. 7.  Pr o vi si o n of St u d y R e s ult s  t o I n v e sti g at or s, P o sti n g of I nf or m ati o n 
o n P u bli cl y A v ail a bl e Cli ni c al Tri al s R e gi st er s a n d P u bli c ati o n  
W here re q uir e d b y a p plica ble re g ulat or y re q uir e me nts, a n i n vesti gat or si g n at or y will be 
i de ntifie d f or t he a p pr o val of t he cli nical st u d y re p ort.  T he i n vesti gat or will be pr o vi de d 
reas o na bl e access t o statistical ta bles, fi g ures, a n d rele va nt r e p orts a n d will ha ve t he 
o p p ort u nit y t o re vie w t h e c o m plete st u d y res ults at a N o v artis site or ot h er m ut uall y- 
a greea ble l ocati o n. 
N o v artis will als o pr o vi d e t he i n vesti gat or wit h t he f ull s u m mar y of t he st u d y res ults. 
T he i n vesti gat or is e nc o ura ge d t o s hare t he s u m mar y res ults wit h t he st u d y s u bjects, as 
a p pr o priate. 
N o v artis ai ms t o p ost a res ults s u m mar y t o t he N o vartis Cli nical Trial Res ults we bsite 
w w w. n o vartiscli nicaltrials.c o m a n d ot her p u blicl y a vaila ble re gisters n o later t ha n 1 2  
m o nt hs after t he last s u bject’s last visit ( L S L V) [t his a p plies t o eac h dat a a nal ysis p has e f or 
st u dies wit h m ulti ple p hases, e. g., pri mar y a nal ysis, f oll o w u p a nal ysis etc]. I n a d diti o n, t he 
ai m is t o s u b mit a ma n uscri pt t o a peer- re vie we d j o ur nal f or p u blicati o n wit hi n 1 8 m o nt hs 
of L S L V. N o v artis als o ai ms t o p u blis h t he f ull st u d y pr ot oc ol o n t he N o v artis Cli nical 
Trial Res ults we bsite ( w w w. n o vartiscli nicaltrials. c o m) at t he ti me t he res ults of t he st u d y 
are p u blis he d as a ma n us cri pt i n t he scie ntific literat ure.  
W he n ma n uscri pt p u blicati o n i n a peer- revie we d j o ur nal is n ot feasi ble, f urt her st u d y 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 0 9  
 
 
i nf or mati o n will be p oste d t o t he N o vartis Cli nical Trial Res ults we bsite 
( w w w. n o vartiscli nicaltrials.c o m)t o s u p ple me nt t he res ults s u m mar y. 
1 0. 8.  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 (I D M C) 
A n I D M C will be utiliz e d i n t his st u d y t o e ns ure e xter nal o bjecti ve me dical a n d/ or 
statistical re vie w of safet y a n d/ or efficac y iss ues i n or der t o pr otect t he et hi cal a n d safety 
i nterests of s u bjects a n d t o pr otect t he scie ntific v ali dit y of  t he st u d y.  T h e s c he d ule of a n y 
pla n ne d i nteri m a nal ysis a n d t he a nal ysis pla n f or I D M C r e vie w is des cri be d i n t he 
c harter, w hic h is a vaila bl e u p o n re q uest.  
1 1.  
R E F E R E N C E S 
A gar wala S S, Kir k w o o d J M, G ore M et al. Te m oz ol o mi de f or t he Treat me nt of Brai n 
Metastases Ass ociat e d Wit h Metastatic Mela n o ma: A P hase II St u d y.  J o ur n al of Cli nic al 
O nc ol o gy 2 0 0 4; 2 2( 1 1): 2 1 0 1- 2 1 0 7.  
Alcalá A M, Fla hert y, K T. B R A F i n hi bit ors f or t he treat me nt of metastatic mela n o ma: 
cli nical trials a n d mec h a nis ms of resista nce.  Cli n Ca ncer Res 2 0 1 2; 1 8( 1): 3 3 - 3 9. 
Bala g ula Y, H ust o n K B, B usa m KJ, et al. Der mat ol o gic si de effects ass o ciate d wit h t he 
M E K 1/ 2 i n hi bit or sel u meti ni b ( A Z D 6 2 4 4, A R R Y- 1 4 2 8 8 6). I n vest Ne w Dr u gs 2 0 1 0; 2 9: 
1 1 1 4- 1 1 2 1 
B e ns o n A B, Aja ni J A, Catala n o R B, E n gel ki n g C, K or n bla u S M, Marte ns o n Jr J A, 
Mc Call u m R, Mitc hel E P, O’ D orisi o T M, V o kes E E, & Wa dler S.  Rec o m me n de d 
G ui deli nes f or t he Treat me nt of Ca ncer Treat me nt-I n d uce d Diarr hea.  J o ur n al of Cli nic al 
O nc ol o gy . 2 0 0 4; 2 2: 2 9 1 8- 2 9 2 6. 
Br o o ks S M, Wer k E E, Ac her ma n SJ, S ulli va n I, T hras her K.  A d verse Effects of 
P he n o bar bital o n C ortic oster oi d Meta b olis m i n Patie nts wit h Br o nc hial Ast h ma. Ne w 
E n gl a n d J o ur n al of Me dici ne 1 9 7 2; 2 8 6: 1 1 2 5- 8.  
Car na ha n J, Beltra n PJ, Ba bij C, et al.  Selecti ve a n d p ote nt Raf i n hi bit ors para d o xicall y 
sti m ulate n or mal cell pr oliferati o n a n d t u m o ur gr o wt h.  M ol Ca ncer T her 2 0 1 0; 
9( 8): 2 3 9 9- 2 4 1 0.  
Carr oll KJ.  Bac k t o basi cs: e x plai ni n g sa m ple size i n o utc o me trials, are statisticia ns 
d oi n g a t h or o u g h j o b? P har m Stat 2 0 0 9; 8( 4): 3 3 3- 3 4 5. 
C ha p ma n P B, Ha us c hil d A, R o bert C, et al. I m pr o ve d s ur vi val wit h ve m urafe ni b i n 
mela n o ma wit h B R A F V 6 0 0 E M utati o n. N E n gl J Me d 2 0 1 1; 3 6 4: 2 5 0 7- 1 6.  
C orc ora n R B, Dias- Sa nta gat a D, Ber get h o n K, Iafrate AJ, Settle ma n J, E n gle ma n J A. 
B R A F ge ne a m plificati o n ca n pr o m ote ac q uire d resista nce t o M E K i n hi bit ors i n ca ncer 
cells har b ori n g t he B R A F V 6 0 0 E m utati o n. Sci Si g nal 2 0 1 0; 3( 1 4 9):ra 8 4.  
Cra n mer D, J eter J M, M or ga n S S et al.  W h ol e-Brai n Ra diati o n T hera p y  i n Mela n o ma: 
A n O pe n Q uesti o n.  T he L a ncet O nc ol o gy  2 0 1 0; 1 1( 1): 1 3.  
Da vies H, Bi g n ell, G. R., C o x, C., Ste p he ns, P., E d ki ns, S., et al. M utati o ns of t he B R A F 
Ge ne i n H u ma n Ca ncer. N at ure  2 0 0 2; 4 1 7: 9 4 9- 9 5 4.  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 1 0  
 
 
Da vies M A, Li u P, McI nt yre S, et al. Pr o g n ostic fact ors f or s ur vi val i n mela n o ma patie nts 
wit h brai n metastases. Ca ncer 2 0 1 1; 1 1 7: 1 6 8 7 - 9 6. 
D u m mer R, Ri n der k nec ht J, G ol di n ger S. M., Wa g ner I, Mitc hell L, Ver o nese M. L., Nic k 
S, P. Hilfi ker P a n d G o b bi S; Meeti n g A bstract 8 5 4 8 A S C O 2 0 1 3; A n o pe n -la bel pil ot 
st u d y of ve m urafe ni b i n pre vi o usl y tr eate d met astatic mela n o ma patie nts wit h brai n 
metastases. 
E g ger m o nt A M, R o bert C. Ne w dr u gs i n mela n o ma: it’s a w h ole ne w w orl d . E ur J 
Ca ncer 2 0 1 1; 4 7: 2 1 5 0- 2 1 5 7 
Eise n T, A h ma d T,  Fl a h ert y K T, G ore M,  K a ye S et al.  S orafe ni b i n A d va nce d 
Mela n o ma: A P hase II R a n d o mise d Disc o nti n uati o n Trial A nal ysis.  Britis h J o ur n al of 
C a ncer 2 0 0 6; 9 5( 5): 5 8 1 – 5 8 6.  
Eise n ha uer E A, T herasse P, B o gaerts J, Sc h wartz L H, Sar ge nt D, F or d R, Da nce y J, 
Ar b uc k S, G w yt her S, M o o ne y M, R u bi nstei n L, S ha n kar L, D o d d L, Ka pl a n R, 
Lac o m be D, Ver weij J.  Ne w Res p o nse E v al uati o n Criteria i n S oli d T u m o urs:  Re vise d 
R E CI S T g ui deli nes ( versi o n 1. 1).  E ur o pe a n J o ur n al of C a ncer . 2 0 0 9; 4 5: 2 2 8- 2 4 7. 
E m er y C M, Vija ye n dra n K G, Zi pser M C, et al.  M E K 1 m utati o ns c o nfer resista nce t o M E K 
a n d B- R A F i n hi biti o n.  Pr oc Natl Aca d Sci U S A 2 0 0 9; 1 0 6( 4 8): 2 0 4 1 1 -2 0 4 1 6.  
Falc h o o k G, I nfa nte J R, Fec h er L A, et al. T he oral M E K 1/ 2 i n h ibit or G S K 1 1 2 0 2 1 2 
de m o nstrates ear ly efficac y si g nals. A n n als of O nc ol o g y 2 0 1 0; 2 1 ( 8): 4 9 5 0.  
Fife K M, C ol ma n M H, Ste ve ns G N, Firt h I C,  M o o n D et al. Deter mi na nts of O utc o me i n 
Mela n o ma Patie nts wit h Cere bral M etastases. J o ur n al of Cli nic al O nc ol o gy 2 0 0 4; 2 2: 
1 2 9 3- 1 3 0 0. 
F la hert y K T, P uza n o v I, Ki m K B, et al.  I n hi biti o n of m utate d, acti vate d B R A F i n 
metastatic mela n o ma.  N E n gl J Me d 2 0 1 0; 3 6 3( 9): 8 0 9- 8 1 9.  
Fla hert y K T, R o bert C, Herse y P, Nat ha n P, Gar be C, Mil he m M, De mi d o v L V, Hassel 
J C, R ut k o ws ki P, M o hr P, D u m mer R, Trefzer U, Lar ki n J, Uti kal J, Dre n o B, N ya k as M, 
Mi d dlet o n M R, Bec ker J C, Case y M, S her ma n J L, W u F S, O uellet D, Marti n A, Patel K, 
Sc ha de n d orf D, M E T RI C St u d y Gr o u p; N E n gl J Me d 2 0 1 2; 3 6 7: 1 0 7 - 1 1 4J ul y 1 2, 
2 0 1 2 D OI: 1 0. 1 0 5 6/ N EJ M oa 1 2 0 3 4 2 1 
Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 1 N 1 2 6 8 1 1 _ 0 0: G S K 1 1 2 0 2 1 2 + G S K 2 1 1 8 4 3 6 
(tra meti ni b a n d da brafe ni b), I n vesti gat or’s Br oc h ure. 1 5-F E B- 2 0 1 2. 
Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 1 N 1 2 6 8 1 1 _ 0 1 G S K 1 1 2 0 2 1 2 + G S K 2 1 1 8 4 3 6. 
I n v esti gat or's Br oc h ure Versi o n 2. Re p ort Dat e 1 7- M A Y- 2 0 1 3. 
Gla x o S mit h Kli ne D oc u me nt N u m ber C M 2 0 1 0/ 0 0 0 1 0/ 0 2: G S K 2 1 1 8 4 3 6 ( da brafe ni b) 
I n v esti gat or’s Br oc h ure. 2 0-M a y- 2 0 1 1. 
Gla x o S mit h Kli ne D oc u me nt N u m ber C M 2 0 1 0/ 0 0 0 1 0/ 0 3 St u d y I D G S K 2 1 1 8 4 3 6 
I n v esti gat or's Br oc h ure. . Re p ort Date 0 3-M a y- 2 0 1 3. 
Gla x o S mit h Kli ne D oc u me nt N u m ber H M 2 0 0 9/ 0 0 1 5 1/ 0 2: G S K 1 1 2 0 2 1 2 (tra meti ni b) 
I n v esti gat or’s Br oc h ure. 2 3-J un - 2 0 1 1. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 1 1  
 
 
Gla x o S mit h Kli ne D oc u me nt N u m ber R M 2 0 0 9/ 0 0 0 0 6 4/ 0 2 St u d y I D G S K 2 1 1 8 4 3 6. 
I n v esti gat or Br oc h ure. Re p ort Date 2 7-M a y- 2 0 1 0. 
G or de n A, Os ma n I, Gai W, et al. A nal ysis of B R A F a n d N- R A S m utati o ns i n metastatic 
mela n o ma tiss ues. Ca ncer Res. 2 0 0 3; 6 3: 3 9 5 5- 3 9 5 7. 
G or d o n M S, I nfa nte J R, Messers mit h W, et al. T he oral M E K 1/ M E K 2 i n hi bit or, 
G S K 1 1 2 0 2 1 2, effecti vel y i n hi bits t he M A P K pat h wa y: p h ar mac o ki netic, 
p har mac o d y n a mic, a n d cli nical res p o nse relati o ns hi p. 2 2 N D E O R T C- N C I- A A C R 
S y m p osi u m: M olec ular Tar gets a n d Ca ncer T hera pe utics 2 0 1 0, a bstract 3 7 3. 
Ha usc hil d A, Gr o b JJ, De mi d o v L V,  J o u ar y T, G utz mer R, Mill war d M, R ut k o ws ki P, 
Bla n k C U, Miller Jr W H, Kae m p ge n E, M artí n- Al garra S, Karasze ws k a B, Ma uc h C, 
C hiari o n- Sile ni V, Marti n A, S wa n n S, Ha ne y P, Mira k h ur B, G uc kert M E, G o o d ma n V, 
C ha p ma n P B, Da brafe ni b i n B R A F- m utate d met astatic mela n o ma: a m ultice ntre, o p e n- 
la bel, p hase 3 ra n d o mise d c o ntr olle d trial, T he La ncet,  2 8 J ul y–3  A u g ust 2 0 1 2, Pa ges 
3 5 8- 3 6 5, I S S N 0 1 4 0 - 6 7 3 6 
H o di F S, O’ Da y SJ, Mc Der m ott D F, We ber R W, S os ma n J A, Haa ne n J B, G o nzales R, 
R o bert C, Sc ha de n d orf D, Hassel J C, A kerle y W, va n de n Eert we g h AJ, L ut z k y J, 
L ori ga n P, Va u bel J M, Li nette G P, H o g g D, Otte ns meier C H, Le b be C, Pes c hel C, Q uirt 
I, Clar k JI, W olc h o k J D, We ber J S, Tia n J, Yelli n MJ, Nic h ol G M, H o os A, Ur ba WJ; 
I m pr o v e d S ur vi val wit h I pili m u ma b i n Patie nts wit h Metastatic Mela n o ma; N E n gl J 
Me d. 2 0 1 0 A u g 1 9; 3 6 3( 8): 7 1 1- 2 3  
H o n g D S, V e nce L, Falc h o o k G, er al.  B R A F( V 6 0 0) I n hi bit or G S K 2 1 1 8 4 3 6 Tar gete d 
I n hi biti o n of M uta nt B R A F i n Ca ncer Patie nts D oes N ot I m pair O verall I m m u ne 
C o m pete nc y. Cli n Ca ncer Res A pril 1 5, 2 0 1 2 1 8; 2 3 2 6 
H o u be n R, Bec ker J C, Ka p pel A, et al. C o nstit uti ve acti vati o n of t he Ras- Raf si g nalli n g 
p at h w a y i n metastatic mela n o ma is ass ociate d wit h p o or pr o g n osis. J Carci n o g. 2 0 0 4; 
3: 6. 
H u nc hare k M, Ca u bet J F, Mc Garr y R.  Si n gle-a ge nt D T I C vers us c o m bi nati o n 
c he m ot hera p y wit h or wit h o ut i m m u n ot hera p y i n metastatic mela n o ma: a meta-a nal ysis 
of 3 2 7 3 patie nts fr o m 2 0 ra n d o mize d trials.  Mela n o ma Res 2 0 0 1; 1 1( 1): 7 5- 8 1.  
J a mes L P, Letzi g L, Si m ps o n P M, Ca p parelli E, R o berts D W, Hi ns o n J A, Da ver n TJ, Lee 
W M. P har mac o ki netics of Aceta mi n o p he n- Pr otei n A d d uct i n A d ults wit h Aceta mi n o p he n 
O ver d ose a n d Ac ute Li v er Fail ure. Dr u g M eta b Dis p os 2 0 0 9; 3 7( 8): 1 7 7 9 - 1 7 8 4. 
Ki m K, Le wis K, Pa vlic k A, et al., A p has e II st u d y of t he M E K 1/ M E K 2 i n hi bit or 
G K S 1 1 2 0 2 1 2 i n metastatic B R A F- V 6 0 0 E or K m uta nt c uta ne o us mela n o m a patie nts 
pre vi o usl y tr eate d wit h or wit h o ut a B R A F i n hi bit or. Pi g me nt Cell Res. 2 0 1 1; 2 4: 1 0 2 1. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 1 2  
 
 
Ki n d P.  T he E ur o Q o L Q uesti o n naire: A n I n de x of Healt h - Relate d Q ualit y o f Lif e, 
Q ualit y of Lif e a n d P har mac oec o n o mics i n Cli nical trials, Sec o n d E diti o n, 1 9 9 6; p p 1 9 1 - 
2 0 0.  
Kirsc h ner M, Hel m ke B, Starz H, et al. Pre p o n d e ra nce of t he o n c o ge nic V 5 9 9 E a n d 
V 5 9 9 K m utati o ns i n t he B -raf ki nase d o m ai n is e n ha nce d i n mela n o ma l y m p h n o de 
metastases.  Mela n o ma R es. 2 0 0 5; 1 5: 4 2 7 -4 3 4.  
K or n E L, Li u P Y, Lee SJ, et al.  Met a-a naly sis of p hase II c o o perati ve gr o u p trials i n 
metastatic sta ge I V m ela n o ma t o deter mi ne pr o gressi o n-free a n d o verall s ur vi val 
be nc h mar ks f or f ut ur e p h ase II tri als.  J Cli n O nc ol 2 0 0 8; 2 6( 4): 5 2 7 -5 3 4.  
K u mar R, A n geli ni S, Cze ne K, et al. B R A F m utati o ns i n metastatic mela n o ma: a 
p ossi ble ass ociati o n wit h cli nical o u tc o me. Cli n Ca ncer R es. 2 0 0 3; 9: 3 3 6 2- 3 3 6 8. 
Lac o ut ure M E, A na d kat MJ, Be nsa d o u n RJ, et al, Cli nical practice g ui deli n es f or t he 
pre ve nti o n a n d tr eat me nt of E G F R i n hi bit or-ass ociate d der mat ol o gic t o xicities. S u p p ort 
Care Ca ncer 2 0 1 1; 1 9: 1 0 7 9- 1 0 9 5.  
Lac o ut ure M E, S he n h o n g W, R o bert C, et al. E v ol vi n g strate gies f or t he ma na ge me nt of 
ha n d-f o ot s ki n reacti o n ass ociate d wit h t h e m ultitar gete d ki nase i n hi bit ors s orafe ni b a n d 
s u niti ni b.  T he O nc ol o gist 2 0 0 8; 1 3: 1 0 0 1- 1 0 1 1. 
La n K K G, De Mets D L.  Discrete se q u e ntial b o u n daries f or cli nical trials.  Bi o metri ka 1 9 8 3; 
7 0( 3): 6 5 9- 6 6 3.  
Le Gal F, G or die n E, Aff ola bi D, Ha nsli k T, All o ui C, Dé n y P, Ga ult E.  Q ua ntificati o n of 
He patitis Delta Vir us R N A i n Ser u m b y C o nse ns us Real- Ti m e P C R I n dicat es Differe nt 
Patter ns of Vir ol o gi cal Res p o nse t o I nt erfer o n T h era p y i n C hr o nicall y I nfecte d Patie nts.  J 
Cli n Micr o bi ol. 2 0 0 5; 4 3( 5): 2 3 6 3 – 2 3 6 9.  
Li br a M, Mala p o nte G, Na v ola nic P M, et al. A nal y sis of B R A F m utati o n i n pri mar y a n d 
metastatic mela n o ma. Cell C y cle 2 0 0 5; 4: 1 3 8 2 -1 3 8 4.  
Li n os E, S wetter S M, C o c k b ur n M G, et al. I ncreasi n g b ur de n of mela n o ma i n t he U nite d 
States. J I n vest D er mat ol. 2 0 0 9; 1 2 9 ( 7): 1 6 6 6- 1 6 7 4. 
Li p w ort h A D, R o bert C, Z h u A X. Ha n d- F o ot S y n dr o me ( Ha n d- F o ot S ki n Reacti o n, 
Pal mar- Pla ntar Er yt hr o d ys est hesia); F o c us o n S orafe ni b a n d S u niti ni b. O nc ol o gy. 2 0 0 9; 
7 7: 2 5 7- 7 1.  
L o n g G V, S os ma n J A, Da u d AI, et al: P hase II t hr ee-ar m ra n d o mise d st u d y of t he B R A F 
i n hi bit or da brafe ni b al o n e vs c o m bi nati o n wit h M E K 1/ 2 i n hi bit or tra meti ni b i n patie nts 
wit h B R A F V 6 0 0 m utati o n- p ositi ve metastatic mela n o ma. 2 0 1 2 E S M O C o n gress. 
A bstract L B A 2 7. Prese nt e d Se pte m ber 2 9, 2 0 1 2 
Majer M., Sa ml o ws ki W. E. Ma na ge me nt of M etastatic Mela n o ma Patie nts wit h Brai n 
Metastases. C urre nt O nc ol o gy Re p orts 2 0 0 7 9( 5): 4 1 1- 4 1 6.  
Mar g oli n K, Er nst off M S, Ha mi d O, et al. I pili m u ma b i n patie nts wit h mela n o ma a n d 
brai n metastases: a n o p e n-la bel, p hase 2 trial. La n cet O nc ol 2 0 1 2; 1 3: 4 5 9 - 6 5. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 1 3  
 
 
Mc Lella n B, Kerr H. C uta ne o us t o xicities of t he m ulti ki nase i n hi bit ors s orafe ni b a n d 
s u niti ni b. Der mat ol o gic T hera p y 2 0 1 1; 2 4: 3 9 6- 4 0 0. 
Mc Willia ms R R, Ra o R D, B uc k n er J C, Li n k MJ, Mar k o vic S, et al. Mela n o ma-I n d u ce d 
Brai n Met astases. Ex p ert Revie ws i n A ntic a ncer T her a p y . 2 0 0 8; 8( 5): 7 4 3- 5 5. 
N C I. C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) versi o n 4. 0. D H H S, 
N C I, NI H, Bet hes da, M D; 2 0 0 9. 
Nissa n M H, S olit D B, T he “ S W O T” of B R A F i n hi biti o n i n mela n o ma: B R A F i n hi bit ors, 
M E K i n hi bit ors or b ot h? C urr O nc ol Re p 2 0 1 1; 1 3: 4 7 9- 4 8 7.  
O’ Brie n P C, Fle mi n g T R. M ulti ple Testi n g Pr oce d ures f or Cli nical Triasls. Bi o metrics. 
1 9 7 9; 3 5: 5 4 9- 5 5 6. 
O ke n M. M, Creec h, R. H, T or me y, D. C., H ort o n, J., Da vis, T. E., Mc Fa d de n, E. T., 
Car b o ne, P. P. T o xicit y a n d Res p o nse Criteria of t he Easter n C o o perati ve O nc ol o g y 
Gr o u p. A meric a n J o ur n al of Cli nic al O nc ol o gy. 1 9 8 2; 5: 6 4 9- 6 5 5. 
O m h olt K, Platz A, Ka nter L, et al. N R A S a n d B R A F m utati o ns arise earl y d uri n g 
mela n o ma pat h o ge n esis a n d are preser ve d t hr o u g h o ut t u m o ur pr o gressi o n. Cli n Ca ncer 
Res. 2 0 0 3; 9: 6 4 8 3- 6 4 8 8. 
Ra bi n R, de C harr o F.  E Q- 5 D: a meas ure of healt h stat us fr o m t he E ur o Q ol Gr o u p.  A n n  
Me d 2 0 0 1; 3 3( 5): 3 3 7 -3 4 3.  
Ries L A G, Mel bert D, Kra pc h o M et al (e ds). S E E R ca ncer statistics re vie w 1 9 7 5 -2 0 0 5: 
Nati o nal Ca ncer I nstit ute, Bet hes d a M D, htt p://seer.ca ncer. g o v/csr/ 1 9 7 5 _ 2 0 0 5/, base d o n 
N o ve m ber 2 0 0 7 S E E R d ata s u b missi o n, p oste d t o t he S E E R we b site, 2 0 0 8. 
R o bert C, Ar na ult J P, Mate us C. R A F i n hi biti o n a n d i n d ucti o n of s q ua m o us cell 
carci n o ma. C urr O pi n O n c ol 2 0 1 1; 2 3 ( 2): 1 7 7 - 1 8 2. 
R o bert C, T h o mas L, B o n dare n k o I et al. I pili m u ma b pl us dacar bazi ne f or pre vi o usl y 
u ntreate d metastatic m ela n o ma 2 0 1 1. N E n g J Me d; 3 6 4: 2 5 1 7- 2 6.  
Sa ml o ws ki W E, Wats o n G A, Wa n g M, Ra o G, Kli m o P et al. M ulti m o dalit y Treat me nt 
of Mela n o ma Brai n met astases I nc or p orati n g Stere otactic Ra di os ur ger y ( S R S). C a ncer  
2 0 0 7; 1 0 9( 9): 1 8 5 5- 6 2.  
Sa m ps o n J H, Carter J HJr, Frie d ma n A H, Sei gler H F. De m o gra p hics, pr o g n osis, a n d 
t hera p y i n 7 0 2 patie nts wit h brai n metastases fr o m mali g na nt mela n o m a. J Ne ur os ur g. 
1 9 9 8 ; 8 8 : 1 1 -2 0 . 
S o n da k V K, Fla h ert y L E. I m pr o v e d o utc o mes f or patie nts wit h metastatic mela n o ma. Nat  
Re v Cli n O nc ol 2 0 1 1; 8: 5 1 3 -5 1 5.  
Sta u dt M,  Lasit hi ota kis K, Leiter U, M eier F, Ei ge ntler T, et al.  Det er mi na nts of S ur vi val 
i n Patie nts wit h Brai n Metastases fr o m C uta ne o us Mela n o ma. Britis h J o ur n al C a ncer 2 0 1 0; 
1 0 2( 8): 1 2 1 3 -8.  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 1 4  
 
 
Trefzer U, Mi n or D, Ri bas A et al. B R E A K- 2: a P hase II A trial of t he selecti ve B R A F 
ki nase i n hi bit or G S K 2 1 1 8 4 3 6 i n patie nts wit h B R A F m utati o n - p ositi ve ( V 6 0 0 E/ K) 
metastatic mela n o ma. Pi g me nt Cell Res. 2 0 1 1; 2 4: 1 0 2 0. 
U. S. F o o d a n d Dr u g A d mi nistrati o n ( U S F D A). St atistic al G ui d a nce o n Re p orti n g Res ults 
fr o m St u dies Ev al u ati n g Di a g n ostic Tests. F D A, Sil ver S pri n g, M D; 2 0 0 7. 
w w w.f da. g o v/ Me di cal De vices/ De vice R e g ulati o na n d G ui da nce/ G ui da nce D oc u me nt 
s/ uc m 0 7 1 1 4 8. ht m. Accesse d 9 Se pte m ber 2 0 1 0. 
Wa n P T, Gar nett MJ, R oe S M, Lee S, Nic ulesc u- D u vaz D, et al. Mec ha nis m of Acti vati o n 
of t he R A F - E R K Si g nali n g Pat h wa y b y O nc o ge ni c M utati o ns of B- R A F. C ell.  2 0 0 4; 1 1 6: 
8 5- 8 6 7. 
W e ber J, K. Fla hert y, J. I nfa nte, G. Falc h o o k, R. Keff or d, A. Da u d, O. Ha mi d, R. 
G o nzalez, R. K u dc ha d kar, D. La wre nce, H. A. B urris III, G. V. L o n g, A. Al gazi, K. 
Le wis, K. B. Ki m, I. P uza n o v, P.  S u n, S.  Little, K. Patel, J. S os ma n; U p date d safet y a n d 
effic ac y res ults fr o m a P hase I/II st u d y of t he oral B R A F i n hi bit or da brafe ni b 
( G S K 2 1 1 8 4 3 6) c o m bi ne d wit h t he oral M E K ½ i n hi bit or tra meti ni b ( G S K 1 1 2 0 2 1 2) i n 
patie nts wit h B R A Fi- n aï ve metastatic mela n o ma, J o ur nal of Cli nical O nc ol o g y 3 0, 2 0 1 2 
(s u p pl; a bstr 8 5 1 0) 
Well br oc k C., Karasari des M., Marais R. T he R A F Pr otei ns Ta ke Ce ntre Sta ge. N at ure 
Revie ws i n M olec ul ar Cell Bi ol o gy. 2 0 0 4; 5: 8 7 5- 8 8 5 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 1 5  
 
 
1 2.   
A P P E N DI C E S 
1 2 .1 . A p p e n di x  1 : 
M el a n o m a  of  t h e S ki n  St a gi n g
 
R ef er e nc e: A merica n J oi nt C o m mittee o n  Ca ncer. ( 2 0 0 9). 7t h E diti o n of AJ C C 
Mela n o ma Sta gi n g S yste m.  Retrie ve d 1 9 A pril 2 0 1 2 fr o m 
w w w.ca n cersta gi n g. or g/sta gi n g/ p osters/ mel a n o ma 8. 5 x 1 1. p df.  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 1 6  
 
 
1 2. 2.  A p p e n di x 2: E a st er n C o o p er ati v e O n c ol o g y Gr o u p ( E C O G) 
P erf or m a n c e St at u s  
A cti vit y St at u s 
D e s cri pti o n  
0 
F ully activ e, a bl e t o c arry o n all pr e-dis e as e p erfor ma nce 
wit h o ut r estricti o n. 
1 
R estrict e d i n p hysic ally str en u ous activity b ut a m b ulat ory a n d 
a bl e t o c arry o ut w ork of a li g ht or s e d e ntary n at ure, e. g., li g ht 
h o use w ork, offic e w ork. 
2 
A m b ul atory a nd c a p a ble of all s elf-c ar e but un abl e to carry o ut 
a ny w ork activiti es.   U p a nd a b out m or e t h an 5 0 % of w aki n g 
h o urs. 
3 
C a p a ble of o nly li mit e d self-c ar e, c o nfi n ed to b e d or c h air m or e 
t h a n 5 0 % of w aki ng h o urs. 
4 
C o m pl et ely disa bl ed.  C an not c arry o n a ny s elf-car e. Tot ally 
c o nfi ne d to b e d or c h air. 
5 
D e a d.  
Refere nce: 
O ke n M M, Creec h R H, T or me y D C, et al.  T o xicit y a n d res p o nse criteria of t he Easter n 
C o o perati ve O nc ol o g y Gr o u p.  A m J Cli n O nc ol 1 9 8 2; 5( 6): 6 4 9- 6 5 5.  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 1 7  
 
 
1 2. 3.  A p p e n di x 3: C o c k cr oft-G a ult  F or m ul a 
T o deter mi ne eli gi bilit y f or t he st u d y, i n vesti gat ors s h o ul d calc ulate a s u bject’s creati ni ne 
cleara nce b y t he C oc kcr oft- Ga ult f or m ula as f oll o ws [ C oc kcr oft , 1 9 7 6]: 
Cr Cl f or m al es ( mL/ mi n) =  
( 1 4 0 - a g e  [y e ars]) × ( wei g ht [kg]) 
 
  
7 2 × (s er u m cr eati ni ne [ m g/d L]) 
Cr C L f or f e m al es ( mL/ mi n) =  
 
0. 8 5 × ( 1 4 0 - a g e  [y e ars]) × ( wei g ht [k g]) 
 
   
7 2 × (s er u m cr eati ni ne [ m g/d L]) 
F or SI u nit s:  
Cr Cl f or m al es ( mL/ mi n) =  
( 1 4 0 - a g e  [y e ars]) × ( wei g ht [kg]) × 1. 2 3 
(s er u m cr e ati ni n e [m ol/ L]) 
Cr C L f or f e m al es ( mL/ mi n) =  
( 1 4 0 - a g e  [y e ars]) × ( wei g ht [kg]) × 1. 0 5 
(s er u m cr e ati ni n e [m ol/ L]) 
Cr Cl = cr e ati ni ne cl ear a nc e; SI = Systè m e Int er nati o nal d’ U nit és.  
 
Re fere nce: 
C oc kcr oft D W, Ga ult M H.  Pre dicti o n of creati ni ne cleara nce fr o m s er u m creati ni ne. 
Ne p hr o n 1 9 7 6; 1 6( 1): 3 1- 4 1.  

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 1 8  
 
 
1 2. 4.  A p p e n di x 4: Q T i nt er v al o n el e ctr o c ar di o gr a m c orr e ct e d u si n g 
t h e B a z ett’ s f or m ul a ( Q T c B) 
Bazett's f or m ula use d t o c orrect Q T i nter val f or h eart rate is:  
Q Tc B   Q T 
R R  
w here Q Tc B is t he Q T i nter val c orrect e d f or h eart rate, R R is t he i nter val fr o m t he o nset 
of o ne Q R S c o m ple x t o t he o nset of t he ne xt Q R S c o m ple x, me as ure d i n sec o n ds , ofte n 
deri ve d fr o m t he h eart rat e ( H R) as 6 0/ H R, a n d Q T is t he Q T i nter val me as ure d i n 
millisec o n ds . 
Refere nce:  
Bazett H C.  A n a nal ysis of t he ti me-relati o ns of el ectr ocar di o gra ms. Heart 1 9 2 0; 7: 3 5 3-
3 7 0.

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 1 9  
 
 
1 2. 5.  A p p e n di x 5: N e w Y or k H e art A s s o ci ati o n ( N Y H A) G ui d eli n e s  
T he Ne w Y or k Heart Ass ociati o n F u ncti o nal Classificati o n pr o vi des a si m ple wa y of 
classif yi n g t he e xte nt of heart fail ure [ T he Criteri a C o m mittee of t he Ne w Y or k Heart 
Ass ociati o n , 1 9 9 4].  It pl aces s u bjects i n 1 of 4 cat e g ories base d o n t he le vel of li mitati o n 
e x perie nce d d uri n g p h ysi cal acti vit y: 
F u n cti o n al C a p a cit y  
O bj e cti ve A ss e ss m e nt  
Cl a s s  I: Su bj ects wit h c ar diac dis eas e b ut wit h o ut r es ulti n g 
li mit ati o n of p hysic al activity. Or di n ary p hysic al activity d o es 
n ot ca us e u nd u e f atig u e, pal pit ati o n, dys pn ea, or a n ginal 
p ai n.  
A: N o o bj ectiv e evi de nc e of 
c ar di ov asc ular dis e ase. 
Cl a s s  II: Su bj ects wit h c ardi ac dis eas e r esulti n g i n sli g ht 
li mit ati o n of p hysic al activity.  T h ey ar e c o mfort a ble at r est. 
Or di n ary p hysical activity r es ults i n f ati g ue, pal pit ati o n, 
dys p ne a, or a n g in al pai n. 
B: O bj ectiv e evid e nce of 
mi ni m al c ar di ov asc ul ar 
dis e as e.  
Cl a s s  III: S u bjects wit h car di ac dis eas e r esulti n g in m ark e d 
li mit ati o n of p hysic al activity. T h ey ar e c o mfort a ble at rest.  
L ess th a n or di nary p hysic al activity c a uses f ati g ue, 
p al pit a tion, dysp ne a, or a n gi n al p ain.  
C: O bj ectiv e evid e nce of 
m o d er ately s ev er e 
c ar di ov asc ular dis e ase. 
Cl a s s  I V: S u bjects wit h car di ac dis eas e r esulti n g in 
i n a bility t o carry o n a ny p hysic al activity wit h out disco mf ort. 
Sy m pt o ms of h eart f ail ure or t h e a n gi n a l sy ndr o m e m ay b e 
pr es e nt ev en at r est.  If a ny p hysic al activity is u nd ert ake n, 
disc o mf ort is i ncr e ase d.  
D: O bj ectiv e evid e nce ofsever e 
c ar di ov asc ular dis e ase. 
Refere nce:  
T he Criteria C o m mittee of t he Ne w Y or k Heart Ass ociati o n.  N o me nclat ure a n d criteria 
f or dia g n osis of diseas es of t he heart a n d great vessels.  9t h e d.  B ost o n, Mass: Little, 
Br o w n, & C o; 1 9 9 4: 2 5 3- 2 5 6.

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 2 0  
 
 
 
1 2. 6.  A p p e n di x 6: Li v er C h e mi str y M o nit ori n g, I nt err u pti o n St o p pi n g 
a n d  F oll o w- u p  Crit eri a 
P h a s e II Li v er S af et y Al g orit h m s 
 
 
 
 
 
 

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 2 1  
 
 
1 2. 7.  A p p e n di x 7: Li v er S af et y Dr u g  R e st art or  R e c h all e n g e G ui d eli n e s 
1.   
Dr u g restart ma y be c o nsi dere d f or a s u bject e x hi biti n g c o m pelli n g b e nefit f or a 
critical me dici ne f oll o wi n g dr u g-i n d uce d li ver i nj ur y, if fa v ora ble be n efit: ris k 
a n d n o alter nati ve m e dici ne a vaila ble.  It a p plies t o P hase I-I V st u dies (e x cl u di n g 
healt h y v ol u nteer st u dies; e xa m ple of p hase I st u dies are o n c ol o g y st u dies). 
2.   
I n P has e III-I V, dr u g rest art ma y be c o nsi dere d f or li ver safet y e ve nts wit h a clear 
u n derl yi n g ca use (e. g. biliar y, p a ncreatic e ve nts, h y p ote nsi o n, ac ute viral 
he p atitis), if n ot ass ociate d wit h dr u g-i n d uce d li ver i nj ur y, alc o h olic he patitis, or 
h y pers e nsiti vit y (fe ver, ras h or e osi n o p hilia) a n d dr u g n ot ass ociate d wit h H L A 
ge n etic mar k er of li ver i nj ur y) w he n  li ver c he mistries ha ve i m pr o ve d t o n or mal 
or are wit hi n 1. 5 x baseli ne a n d A L T < 3 x U L N.  
Li v er E v e nt s P o s si bl y R el at e d t o I P - Dr u g R e st art/ R e c h all e n g e F oll o wi n g P o s si bl e  
Dr u g-i n d u c e d Li v er I nj ur y C h all e n g e G ui d eli n e s  
F oll o wi n g dr u g-i n d uce d li ver i nj ur y, dr u g rest art or rec h alle n ge is ass oci ate d wit h a  
1 3 % m ort alit y acr oss all dr u gs i n pr os pecti ve st u dies 1 Cli nical o utc o mes var y b y dr u g, 
wit h nearl y 5 0 % fatalit y wit h hal ot ha ne rea d mi nistere d i n o ne m o nt h of i nitial i nj ur y. 
H o we ver, s o me dr u gs sel d o m res ult i n rec urre nt li ver i nj ur y or fat alit y.  Ris k fact ors f or a 
fatal dr u g restart/rec halle n ge o ut c o me i ncl u de: h y perse nsiti vit y1 wit h i nitial li ver i nj ur y 
(e. g. fe v er, ras h, e osi n o p hilia), ja u n dice or bilir u bi n 2 x U L N or I N R > 1. 5 s u g gesti n g 
se vere li ver i nj ur y, pri or I P-relat e d se vere or fatal dr u g restart/rec halle n ge 2, 3 or e vi de nce of 
dr u g-relat e d precli nical lia bilit y / mit oc h o n drial i m pair me nt 3

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 2 2  
 
 
N o v arti s D e ci si o n Pr o c e s s f or Dr u g R e st art A p pr o v al or Di s a p pr o v al ( al s o s e e Fi g ur e 
1 ) 
 
 
 
Pri nci pal I n vesti gat or ( PI) re q uests c o nsi d erati o n of dr u g restart f or a s u bject 
recei vi n g c o m p elli n g be n efit fr o m a critical or life-sa vi n g dr u g, w h o e x hi bits li ver 
c he mistr y ele vati o n meeti n g s u bject st o p pi n g criteria, wit h n o alter nati ve tr eat me nt 
 
N o vartis Gl o bal Cli nical Lea d & Cli nical Safet y P h ysicia n.t o r e vie w t he 
s u bject’s restart/rec h alle n ge ris k fact ors & c o m plete c hec klist (Ta ble 2 6 ).

2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
1 2 3  
 
 
 
T a bl e 2 6  
C h e c kli st f or dr u g r e c h all e n g e f or criti c al m e di ci n e  
( F oll o wi n g dr u g -i n d u c e d li v er i nj ur y, dr u g re c h all e n g e i s a s s o ci at e d wit h 1 3 % m ort alit y 
a cr o s s all dr u g s i n pr o s p e cti v e st u di e s)  
 
Y e s  
N o  
C o m p elli n g b e n efit  of t h e i n v e sti g ati o n al pr o d u ct (I P)  f or t hi s s u bj e ct  
a n d  n o  alt er n ati v e  t h er a py .  Pr o vi d e bri ef e x pl a n ati o n : 
 
 
R el ati v e b e n efi t-ri sk  f a v or a ble f or dr u g r e st art/r e c h all e n g e , aft er 
c o n si d eri n g t h e  f ollo wi n g hi g h ri s k f a ct ors : 
 
 
• 
I niti al li v er i nj ur y e v e nt i n cl u d e d: 
 
 
–  f e v er, r a s h, e o si n o p hili a, or h y p er s e n siti vit y 
 
 
–  or bilir u bi n  2 x U L N ( dir e ct bilir u bi n > 3 5 % of t ot al)  
 
 
• 
S u bj e ct  c urr e ntl y  e x hi bit s A L T  3 x U L N , bilir u bi n  2 x U L N  ( dir e ct 
bilir u bi n > 3 5 % of t ot al, if a v ail a bl e), or  I N R 1. 5  
 
 
• 
S e v er e or f at al r e st art/r e c h all e n g e h a s e arli er b e e n o b s er v e d wit h I P  
If y e s, pl e a s e pr o vi d e bri ef e x pl a n ati o n : 
 
 
• 
I P a s s o ci at e d wit h k n o w n pr e cli ni c al h e p ati c li a bilit y/ i nj ur y 
 
 
 
Pri n ci p al I n v e sti g at or ( PI) A cti o n s:  
 
T he PI  m ust o btai n Et hics C o m mittee or Instit uti o nal Re vie w B o ar d re vie w of dr u g 
rei nitiati o n, as re q uire d. 
 
PI m ust disc uss t he p ossi ble be nefits a n d ris ks of dr u g rei nitiati o n wit h t he s u bject. 
 
T he s u bject m ust si g n i nf or me d c o nse nt wit h a clear descri pti o n of p ossi ble be nefits 
a n d ris ks of dr u g a d mi nistrati o n, i ncl u di n g rec urre nt li ver i nj ur y or d eat h. C o nse nt 
m ust be rec or d e d i n t he st u d y c hart. 
 
T he dr u g m ust be rei nitiate d at N o vartis a p pr o ve d d ose(s).  
 
Li ver c he mistries s h o ul d be f oll o we d t wice wee kl y u ntil sta bl e. 
 
T he Et hics C o m mittee or I nstit uti o nal Re vie w B oar d m ust be i nf or me d of t he 
s u bject’s o utc o me, as r e q uire d. 
 
N o vartis t o be n otifie d of a n y a d verse e v e nts, as p er Secti o n 7. 4. 2 . 

1 2 4  
N o v arti s 
C o nfi d e nti al 
P a g e 1 2 4 
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Fi g ur e 2  
N o v arti s pr o c e s s f or dr u g r e st art aft er p o s si bl e dr u g-i n d u c e d li v er 
i nj ur y 
 
 
R ef er e n c e s:  
 
A n dra de RJ, R o bles M, L uce na MI.  R ec halle n ge i n dr u g -i n d uce d li ver i nj ury : t he 
attracti ve hazar d.  E x pert O pi n Dr u g Saf. 2 0 0 9; 8: 7 0 9 -7 1 4.  
 
H u nt, C M.  Mit oc h o n drial a n d i m m u n oaller gic i nj ur y i ncreas e ris k of p ositi ve dr u g 
rec halle n ge after dr u g-i n d uce d li ver i nj ur y: A s yste matic re vie w.  He p at ol. 
2 0 1 0; 5 2: 2 2 1 6- 2 2 2 2 
 
Pa pa y JI, Cli nes D, Rafi R, Y ue n N, Britt S D, Wals h J S, H u nt C M.  Dr u g-i n d uce d 
li ver i nj ur y f oll o wi n g p ositi ve dr u g rec h alle n ge.  R e g ul T o x P har m. 2 0 0 9; 5 4: 8 4- 9 0.

1 2 5  
N o v arti s 
C o nfi d e nti al 
P a g e 1 2 5 
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Dr u g R e st art G ui d eli n e s 
N o v arti s D e ci si o n Pr o c e s s f or Dr u g R e st art A p pr o v al or Di s a p pr o v al ( al s o s e e 
Fi g ur e 2 ) 
 Pri nci pal I n v esti gat or ( PI) re q uests c o nsi d erati o n of dr u g rei nitiati o n f or a s u bject  
sta ble or i m pr o vi n g o n i n vesti gati o nal pr o d u ct (I P), w h o e x hi bits li ver c he mistr y 
ele vati o n meeti n g s u bject st o p pi n g criteri a, w hic h is tra nsie nt, n o n -dr u g -relate d, a n d 
res ol ves. 
 G S K Me dical M o nit or & Cli nical Safet y P h ysicia n t o re vie w t he s u bject’s 
dia g n osis,  restart ris k fact ors & c o m plete c hec klist (T a ble 2 7 ). 
T a bl e 2 7 C h e c kli st f or P h a s e III dr u g r e st art  
a ft er w ell -e x pl ai n e d li v er i nj ur y ( e. g. bili ar y, p a n cr e ati c, h y p ot e n si v e e v e nt s, C H F, 
a c ut e vir al h e p atiti s), li v er c h e mi stri e s i m pr o vi n g t o n or m al or  1. 5 x b a s eli n e a n d 
A L T < 3 x U L N.  
 
Y e s  
N o  
I s s u bj e ct st a bl e or i m pr o vi n g o n t h e i n v e sti g ati o n al pr o d u ct  (I P) ? 
 
 
D o  n ot  r e st art if t h e f oll o wi n g ri s k f a ct or s at i niti al li v er i nj ury : 
 
 
 
F e v er, r a s h, e o si n o p hili a, or h y p er s e n siti vit y  
 
 
 
D r ug -i n d u c e d li v er i nj ur y 
 
 
 
A l c o h oli c h e p atiti s ( A S T > A L T, t y pi c all y < 1 0 x U L N) 
 
 
 
I P a s s o ci at e d wit h li v er i nj ur y a n d a n H L A g e n eti c m ar k er ( e. g. 
l a p ati ni b, a b a c a vir, a m o xi cilli n/ cl a v ul a n at e) 
 
 
Pri n ci p al I n v e sti g at or ( PI) A cti o n s  
 
 
T he PI  m ust o btai n Et hics C o m m. or I nstit uti o nal Re vie w B o ar d re vie w of dr u g 
rei nitiati o n, as re q uire d. 
 
 
PI m ust disc uss t he be nefits a n d ris ks of dr u g rei nitiati o n wit h t he s u bject. 
 
 
T he s u bject m ust si g n i nf or me d c o nse nt wit h a clear descri pti o n of p ossi ble be nefits 
a n d ris ks of dr u g a d mi nistrati o n, i ncl u di n g rec urre nt li ver i nj ur y or d eat h. C o nse nt 
m ust be rec or d e d i n t he st u d y c hart. 
 
 
Li ver c he mistries s h o ul d be f oll o we d wee kl y u ntil sta ble. 
 
 
T he Et hics C o m mittee or I nstit uti o nal Re vie w B oar d m ust be i nf or me d of t he 
patie nt’s o utc o me, as r e q uire d. 
 
 
N o vartis t o be n otifie d of a n y a d verse or seri o us a d verse e v e nts, as per Secti o n 
7. 4. 2. 6  a n d Secti o n 7. 4. 2. 7 . 
 

1 2 6  
N o v arti s 
C o nfi d e nti al 
P a g e 1 2 6 
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Fi g ur e 3  
N o v arti s pr o c e s s f or dr u g r e st art a p pr o v al s 
 
Refere nces: 
 A n dra de RJ, R o bles M, L uce na MI. R ec halle n ge i n dr u g-i n d u ce d li ver i nj ur y: t he 
attracti ve hazar d. E x pert O pi n Dr u g Saf. 2 0 0 9; 8: 7 0 9- 7 1 4.  
 H u nt, C M. Mit oc h o n drial a n d i m m u n oaller gic i nj ur y i ncrease ris k of p ositi ve dr u g 
rec halle n ge after dr u g-i n d uce d li ver i nj ur y: A s yst e matic re vie w. He p at ol. 
2 0 1 0; 5 2: 2 2 1 6- 2 2 2 2. 
 Pa pa y JI, Cli nes D, Rafi R, Y ue n N, Britt S D, Wals h J S, H u nt C M. Dr u g-i n d uce d 
li ver i nj ur y f oll o wi n g p ositi ve dr u g rec halle n ge. Re g ul T o x P har m. 2 0 0 9; 5 4: 8 4- 9 0. 


1 2 7  
N o v arti s 
C o nfi d e nti al 
P a g e 1 2 7 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 

1 2 8  
N o v arti s 
C o nfi d e nti al 
P a g e 1 2 8 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9  
  
  
  
  
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 

1 2 9  
N o v arti s 
C o nfi d e nti al 
P a g e 1 2 9 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9  
  
  
  
  
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 

1 3 0  
N o v arti s 
C o nfi d e nti al 
P a g e 1 3 0 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9  
  
  
  
  
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 

1 3 1  
N o v arti s 
C o nfi d e nti al 
P a g e 1 3 1 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
 

1 3 2  
N o v arti s 
C o nfi d e nti al 
P a g e 1 3 2 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9  
  
  
  
  
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
1 2. 9 . 1  
E x cl u si o n Crit eri a 
 
S u bjects wit h hist or y of HI V are e x cl u de d fr o m t his t he st u d y. ( Secti o n 4. 1. 3 ) 
 
S u bjects u n der g uar dia ns hi p / u n der s u per visi o n (a n ot her pers o n is res p o nsi ble, 
deci de f or t he patie nt) or de pri ve d of li bert y (i n pris o n f or e x a m ple) will be e x cl u de d 
fr o m t his st u d y. 
 
S u bjects prese nti n g u n c orrect e d electr ol yt e a b n or malities (i ncl u di n g ma g n esi u m) 
  
ca n n ot be all o w e d. 
 
S u bjects ta ki n g me dicati o ns k n o w n t o i n d uce Q T pr ol o n gati o n are e x cl u d e d fr o m t his 
st u d y. 
1 2. 9. 2  
V al v ul ar t o xi cit y cit eri a  
G ui deli nes f or V al v ul ar T o xicit y f or S u bjects E nr olle d i n Fr a nce  
 
S u bjects w h o ha ve a n as y m pt o matic, m o derate re g ur gitati o n or ste n osis b y 
E C H O ( Gra d e 2 mitral/tric us pi d/a ortic val v ular t o xicit y per C T C A E v 4. 0) 
s h o ul d te m p oraril y disc o nti n ue da brafe ni b a n d ha ve a re p eat e val uati o n b y 
E C H O wit hi n 1 wee k.  E C H O s h o ul d be re peate d e ver y 1 - 2 wee ks f or 4 wee ks 
or u ntil val ve rec o v er y t o baseli ne. 
o  If t he val ve rec o v ers t o baseli ne a n y ti me d uri n g t he ne xt 4 wee ks, after 
c o ns ultati o n a n d a p pr o val of t he N o vartis Gl o bal Cli nical L ea d, t he s u bject 
ma y be restarte d o n da brafe ni b at a re d u ce d d ose(s). F or s uc h s u bjects, 
m o nit ori n g of t he val v e via E C H O will t he n be perf or me d 2 a n d 4 wee ks 
after rec h alle n ge, a n d e v er y 4 wee ks t hereafter f or 1 2 wee ks a n d t he n per 
pr ot oc ol.  
o  If re p eat E C H O d oes n ot re veal val v e rec o ver y t o baseli ne wit hi n 4 wee ks, 
t he n t he s u bject s h o ul d per ma ne ntl y disc o nti n ue d a brafe ni b. T he val ve 
s h o ul d c o nti n ue t o be m o nit ore d via E C H O e ver y 4 wee ks f or 1 6 wee ks or 
u ntil res ol uti o n. 
 
S u bjects wit h a Gra de 3 or 4 (s y m pt o matic, se v ere re g ur gitati o n/ste n osis b y 
i ma gi n g, wit h s y m pt o ms c o ntr olle d b y  m e dical i nter ve nti o n) val v ular t o xicit y 
m ust disc o nti n ue da brafe ni b.  Val v ular t o xicit y s h o ul d c o nti n ue t o be m o nit ore d 
e v er y 4 wee ks f or 1 6 w ee ks or u ntil res ol uti o n.  If rec o ver y occ urs (ret ur n t o 
baseli ne via i ma gi n g A N D s y m pt o m r es ol uti o n) wit hi n 4 wee ks, t he s u bject ma y 
restart da brafe ni b at a re d uce d d ose aft er c o ns ultati o n a n d a p pr o val of t he 
N o vartis  Gl o bal Cli nical L ea d. F or s u c h s u bjects, m o nit ori n g of t he val v e via 
E C H O will t he n be perf or me d 2 a n d 4 wee ks after rec halle n ge, a n d e ver y 4 
wee ks t hereaft er f or 1 2 w ee ks a n d t he n per pr ot oc ol. 
E C H O m ust be perf or me d at baseli ne a n d at f oll o w- u p visit(s).  C o pies of all E C H O(s) 
a n d car di ol o g y c o ns ultati o ns perf or me d o n s u bjects w h o e x perie nce a val v ular t o xicit y 
will be re q uire d b y N o vartis f or re vie w. 

1 3 3  
N o v arti s 
C o nfi d e nti al 
P a g e 1 3 3 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9  
  
  
  
  
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
1 2. 9. 2  
N o n- c ut a n e o u s s e c o n d ar y/r e c urr e nt m ali g n a n c y  
Pri or t o i nitiati o n of st u d y treat me nt s u bjects s h o ul d u n der g o a hea d a n d nec k 
e x a mi nati o n wit h mi ni mall y vis ual i ns pecti o n of oral m uc osa a n d l y m p h n o de pal pati o n, 
as well as c hest/a b d o me n C o m p ut e d T o m o gra p h y ( C T) sca n. D uri n g treat m e nt s u bjects 
s h o ul d be m o nit ore d as cli nicall y a p pr o priate w hi c h ma y i n cl u de a h ea d a n d nec k 
e x a mi nati o n e ver y 3 m o nt hs a n d a c hest/a b d o me n C T sca n e ver y 6 m o nt hs. A nal 
e x a mi nati o ns a n d pel vic e x a mi nati o ns are rec o m me n de d bef ore t he start of a n d at t he e n d 
of treat me nt or w h e n c o nsi dere d cli nicall y i n dicat e d. C o m plete bl o o d cell c o u nts s h o ul d 
be perf or me d as cli nicall y i n dicate d. F oll o wi n g disc o nti n uati o n of da brafe ni b m o nit ori n g 
f or n o n-c uta ne o us sec o n dar y/rec urre nt mali g n a ncies s h o ul d c o nti n ue f or u p t o 6 m o nt hs 
or  u ntil i nitiati o n of a n ot her a nti- ne o plastic t hera p y, w hic h e ver c o mes first. A n y n o n- 
c uta ne o us sec o n dar y/r ec urre nt mali g na nc y s h o ul d be re p ort e d as a pr ot oc ol-s pecific S A E 
a n d treate d acc or di n g t o sta n dar d cli nical pr actice. 

1 3 4  
N o v arti s 
C o nfi d e nti al 
P a g e 1 3 4 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9  
  
  
  
  
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
1 2. 1 0.   
A p p e n di x 1 0:  Pr ot o c ol C h a n g e s f or A m e n d m e nt 0 1  
A me n d me nt N u m ber 0 1 
T his a me n d me nt is a p plica ble t o all i n vesti gati o nal st u d y sites i n all c o u ntries. 
A d mi nistrati ve c ha n ges i ncl u di n g u p dat e d S p o ns or C o ntact i nf or mati o n. 
S e c o n d ar y O bj e cti v e s  
Previ o us:  
# 7.  o verall s ur vi val ( O S) 
Revise d:  
# 7.  o verall s ur vi val ( O S) a n d l o n g-ter m ( p artic ularl y 5 - year) O S 
Re as o n f or c h a n g e: A d diti o n of l o n g ter m over all s urviv al. 
St u d y  D e si g n 
Previ o us:  
S ur vi val a n d ne w a nti- ca ncer t hera p y f oll o w- u p will c o nti n ue u ntil 7 0 % of t he t otal 
e nr olle d p o p ulati o n has die d or bee n l ost t o f oll o w- u p. At s uc h ti me t he st u d y will be 
cl ose d. S u bjects w h o me et t he i ncl usi o n/e xcl usi o n criteria f or t he r oll o ver st u d y will 
ha ve t he o pti o n t o r oll o ver i nt o G S K 1 1 4 1 4 4 r oll- o ver st u d y. 
Revise d:  
After treat me nt disc o nti n uati o n, s u bjects will be f oll o we d f or s ki n assess m e nts, s ur vi val, 
safet y, a n d disease pr o gressi o n as a p plica ble. S ur vi val a n d ne w a nti-ca ncer t hera p y 
f oll o w- u p will c o nti n ue u ntil eit her all s u bjects are dea d or l ost t o f oll o w- u p, or all 
s u bjects still i n f oll o w- u p ha ve ha d at least 5  years of f oll o w- u p, w hic he ver is earlier. At 
s uc h ti me t he st u d y will be cl ose d. 
Re as o n f or c h a n g e:  
S ur vi val f oll o w- u p peri o d has bee n e xte n de d i n or der t o c ollect a d diti o nal l o n g-ter m 
o verall s ur vi val data. 

1 3 5  
N o v arti s 
C o nfi d e nti al 
P a g e 1 3 5 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9  
  
  
  
  
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
S e cti o n  1. 1  B a c k gr o u n d 
A d diti o n:  
Da brafe ni b, a n ot her s mall m olec ule B R A F-i n hi bit or recei ve d F D A- a p pr o val i n Ma y 2 0 1 3 
a n d E M A a p pr o val i n A u g ust 2 0 1 3. 
Re as o n f or c h a n g e:  
U p date d i nf or mati o n a v aila ble 
S e cti o n  1. 1  B a c k gr o u n d 
A d diti o n:  
I n J a n 2 0 1 4 t he c o m bi nati o n of da brafe ni b a n d tra meti ni b recei ve d F D A a p pr o val, a n d i n 
Fe br u ar y 2 0 1 4 t he c o m bi nati o n recei v e d a p pr o val i n A ustralia. 
Re as o n f or c h a n g e: A p pr o v al i n U nite d St ates a n d A ustr ali a  
T a bl e 1  
St u d y O bj e cti v e s a n d E n d p oi nt s  
Previ o us:  
T o assess C C o h orts A, B, C a n d D f or o verall s ur vi val ( O S) 
Revise d:  
T o assess C C o h orts A, B, C a n d D f or o verall s ur vi val ( O S) a n d l o n g-ter m ( partic ularl y 5 -
year) O S 
Re as o n f or c h a n g e:  
A d diti o n of l o n g ter m o v erall s ur vi val. 
S T U D Y  D E SI G N 
Previ o us: C o h ort A, B, C:  
S u bjects w h o are recei vi n g c o n c o mita nt c ortic ost er oi ds m ust be o n a sta bl e or decreasi n g 
d ose f or at least 3  w ee ks pri or t o first d ose of st u d y tr eat me nt.  ( Refer t o Secti o n 6. 3 
Ca uti o nar y M e dicati o ns). 
Revise d: C o h ort A, B, C:  
S u bjects w h o are recei vi n g c o n c o mita nt c ortic ost er oi ds m ust be o n a sta bl e or decreasi n g 
d ose f or at least 1 m o nt h pri or t o first d ose of st u d y treat me nt.  ( Refer t o Secti o n 6. 3 
Ca uti o nar y M e dicati o ns). 
Re as o n f or c h a n g e:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
S T U D Y  D E SI G N 
Previ o us:  
Pr ot oc ol-s pecifie d g ui deli nes f or d ose a dj ust me nts, i nterr u pti o ns a n d disc o nti n uati o n d ue 
t o a d vers e e ve nts are pr o vi de d bel o w.  After disc o nti n uati o n of st u d y treat me nt, s u bjects 
will re mai n i n t he st u d y f or f oll o w - u p assess me nts i ncl u di n g m o nt hl y s ki n assess me nts 
u p t o 6 m o nt hs a n d u p dates o n a nti-ca ncer treat m e nt u ntil deat h.  S u bjects w h o ha ve n ot 
die d, b ut are n o l o n ger bei n g f oll o w e d f or dise ase pr o gressi o n or s ur vi val are c o nsi d ere d 

1 3 6  
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C o nfi d e nti al 
P a g e 1 3 6 
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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
t o ha ve wit h dra w n fr o m t he st u d y. T he st u d y will be c o m plete d w he n eit h er all s u bjects 
are dea d or l ost t o f oll o w- u p, or all s u bjects still i n f oll o w- u p ha ve ha d at least 5 years 
f oll o w- u p, w hic he ver is earlier. 
Revise d:  
Pr ot oc ol-s pecifie d g ui deli nes f or d ose a dj ust me nts, a n d disc o nti n uati o n d ue t o a d verse 
e ve nts are pr o vi de d bel o w.  After disc o nti n uati o n of st u d y tr eat me nt, s u bjects will re mai n 
i n t he st u d y f or f oll o w- u p assess me nts i ncl u di n g m o nt hl y s ki n assess me nts u p t o 6 
m o nt hs a n d u p dates o n a nti-ca ncer treat me nt u ntil deat h.  S u bjects w h o ha v e n ot die d, b ut 
are n o l o n ger bei n g f oll o we d f or dise ase pr o gressi o n or s ur vi val are c o nsi d ere d t o ha ve 
wit h dra w n fr o m t he st u d y. T he st u d y will be c o m plete d w he n eit her all s u bjects are d ea d 
or l ost t o f oll o w- u p, or all s u bjects still i n f oll o w- u p ha ve ha d at least 5  years f oll o w- u p 
fr o m t he date of first d ose of st u d y treat me nt, w hi c he ver is earlier. 
Re as o n f or c h a n g e:  
S ur vi val f oll o w- u p peri o d has bee n e xte n de d i n or der t o c ollect a d diti o nal l o n g-ter m 
o verall s ur vi val data. 
4. 1. 2  I n cl u si o n Crit eri a  
Previ o us: Criteri a # 5:  
 
Pri or T M X f or brai n metastases a n d a d j u va nt I F N are acce pta ble a n d d o es n ot c o u nt 
t o war d t he t w o pre vi o us s yste mic tr eat me nt re gi me ns. 
 
Revise d:  
Pri or te m oz ol o mi de f or brai n metastases a n d a dj u va nt i nterfer o n are acce pta ble a n d d oes 
n ot c o u nt t o war d t he t w o pre vi o us s yste mic treat me nt re gi me ns. 
Re as o n f or c h a n g e:  
Clarificati o n of T M X a n d I F N 
Previ o us: Criteri a # 6:,  
M ust be a ble t o u n der g o M RI a n d ha v e at least o n e meas ura ble i ntracra nial lesi o n f or 
w hic h all of t he f oll o wi n g criteria h a ve t o be met: 
 
F or tar get lesi o ns wit h dia meter of > 0. 5c m b ut  1 c m d oc u me nte d meas ure me nt 
b y a n e ur ora di ol o gist. 
 
F or all lesi o ns wit h a dia m eter of  3c m b ut  4 c m d oc u me nte d meas ure me nt b y 
a ne ur ol o gist. 
Revise d:  
M ust be a ble t o u n der g o M RI a n d ha v e at least o n e meas ura ble i ntracra nial lesi o n f or 
w hic h all of t he f oll o wi n g criteria h a ve t o be met: 
 
F or tar get lesi o ns wit h dia meter of > 0. 5c m b ut  1 c m d oc u me nte d meas ure me nt 
b y a n e ur ora di ol o gist/a p pr o priatel y q ualifie d ra di ol o gist / ne ur os ur ge o n is 
re q uire d. 
 
F or all lesi o ns wit h a dia meter of  3c m b ut  4 c m d oc u me nte d meas ure me nt b y 
a ne ur ora di ol o gist / a p pr o priatel y q u alifie d ra di ol o gist / ne ur os ur ge o n is r e q uire d. 
Re as o n f or c h a n g e:  
T y p o gra p hical c orrecti o n of ne ur ol o gist t o ne ur ora di ol o gist a n d t he a d diti o n of 
a p pr o priatel y q u alifie d ra di ol o gist / ne ur os ur ge o n b ase d u p o n c o u ntr y re q uir e me nts.  

1 3 7  
N o v arti s 
C o nfi d e nti al 
P a g e 1 3 7 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9  
  
  
  
  
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
4. 1. 2  I n cl u si o n Crit eri a  
Previ o us:  
T a bl e 2  
D efi niti o n s f or A d e q u at e B a s eli n e Or g a n F u n cti o n  
S y ste m 
La b orat or y  Val ues  
He mat ol o gi c  
A N C  
 1. 2 ×  1 0 9/ L 
He m o gl o bi n  
 9 g/ d L  
Platelet c o u nt  
 1 0 0 x  1 0 9/ L 
P T/ IN R a a n d P T T  
 1. 5 x U L N  
He patic  
Al b u mi n  
 2. 5 g/ d L  
T otal bilir u bi n  
 1. 5 x U L N  
A S T a n d A L T  
 2. 5 x  U L N  
Re nal  
Ser u m creati ni n e b  
 1. 5 m g/ d L  
Car diac  
Left Ve ntric ul ar Eje cti o n fracti o n  
( L V E F)c  
≥ L L N  b y  E C H O  
A b bre viati o ns: A L T = ala ni ne tra nsa mi nase; A N C = a bs ol ute ne utr o p hil 
c o u nt; A S T = as partate a mi n otra nsferas e; I N R = i nter nati o nal n or malize d rati o; 
L L N = l o wer li mit of n or mal; P T = pr ot hr o m bi n ti me; P T T = partial 
t hr o m b o plasti n ti me; U L N = u p per li mit of n or mal. 
a. 
S u bjects recei vi n g a ntic o a g ul ati o n treat me nt ma y be all o we d t o 
partici pate wit h I N R est a blis he d wit hi n t he t hera p e utic ra n ge pri or t o 
ra n d o mizati o n. 
b.  If ser u m creati ni ne is > 1. 5 m g/ d L, cal c ulate creati ni ne cleara nce usi n g 
sta n dar d C oc k cr oft- G a ult f or m ula.  Creati ni ne cleara nce m ust be  50 
m L/ mi n t o be eli gi ble. See A p pe n di x 3. 
c. 
E C H O sca ns m ust be use d t hr o u g h o ut t he st u d y 

1 3 8  
N o v arti s 
C o nfi d e nti al 
P a g e 1 3 8 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9  
  
  
  
  
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Revise d:  
T a bl e 2  
D efi niti o n s f or A d e q u at e B a s eli n e Or g a n F u n cti o n  
S y ste m 
La b orat or y  Val ues  
He mat ol o gi c  
A N C  
 1. 2 ×  1 0 9/ L 
He m o gl o bi n  
 9 g/ d L  
Platelet c o u nt  
 1 0 0 x  1 0 9/ L 
P T/ IN R a a n d P T T  
 1. 3 x U L N  
He patic  
 
 
T otal bilir u bi n  
 1. 5 x U L N c  
A S T a n d A L T  
 2. 5 x  U L N 
Re nal  

Ser u m creati ni n e b 
 1. 5 m g/ d L 
Car diac  

Left Ve ntric ul ar  
Ejecti o n fracti o n  
( L V E F)d 
≥ L L N  b y  E C H O 
A b bre viati o ns: A L T = ala ni ne tra nsa mi nase; A N C = a bs ol ute ne utr o p hil c o u nt; A S T 
= as part ate a mi n otra nsf erase; I N R = i nter nati o nal n or malize d rati o; L L N = l o wer 
li mit of n or mal; P T = pr ot hr o m bi n ti me; P T T = partial t hr o m b o plasti n ti me; U L N = 
u p per li mit of n or mal. 
a) S u bjects recei vi n g a ntic o a g ul ati o n treat me nt ma y be all o we d 
t o partici pate wit h I N R esta blis he d wit hi n t he t hera pe utic 
ra n ge pri or t o e nr oll me nt. 
b) If ser u m creati ni ne is > 1. 5 m g/ d L, cal c ulate creati ni ne cleara nce 
usi n g sta n dar d C oc kcr oft- Ga ult f or m ula ( A p pe n di x 3).  Creati ni ne 
cleara nce m ust be  5 0  m L/ mi n t o be eli gi ble. 
c) E x ce pt s u bjects wit h k n o w n Gil bert’s s y n dr o me. 
d) E C H O sca ns m ust be use d t hr o u g h o ut t he st u d y 
Re as o n f or c h a n g e:  
Al b u mi n re m o ve d, P T/I N R a a n d P T T was u p date d fr o m  1. 5 x U L N t o  1. 3 x U L N t o 
ali g n wit h t he u p dat e d asset sta n dar d la n g ua ge f or t he da brafe ni b a n d tra meti ni b 
c o m bi nati o n. 
4. 1. 2  I n cl u si o n Crit eri a  
Previ o us:  
W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g n a nc y test wit hi n 1 4 
da ys of first d ose of st u d y treat me nt a n d a gree t o use effecti ve c o ntrace pti o n t hr o u g h o ut 
t he treat me nt peri o d a n d f or 4 m o nt hs after t he l ast d ose of st u d y tr eat me nt. 
N O T E: Oral c o ntrace pti ves are n ot r elia ble d ue t o p ote ntial dr u g- dr u g i nt eracti o n 
wit h da braf e ni b 
Revise d:  
W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g n a nc y test wit hi n 1 4 
da ys pri or t o e nr oll me nt a n d a gree t o use effecti ve c o ntrace pti o n, as defi ne d i n Secti o n 
7. 4. 3. 1 fr o m 1 4 da ys pri or t o e nr oll me nt, t hr o u g h o ut t he treat me nt peri o d, a n d f or 4 
m o nt hs after t he last d ose of st u d y treat me nt. 

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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Re as o n f or c h a n g e:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
4. 1. 3  E x cl u si o n Crit eri a 
Previ o us:  
2.   
Pri or treat me nt wit h a n y B R A F i n hi bit or (i ncl u di n g b ut n ot 
li mite d t o da brafe ni b, ve m urafe ni b, L G X 8 1 8, or a n y B R A F 
m uta nt selecti ve a ge nt) or a n y M E K i n hi bit or (i ncl u di n g b ut n ot 
li mite d t o tra meti ni b, A Z D 6 2 4 4, a n d R D E A 1 1 9). 
4.   
A nti-ca ncer t hera p y (c h e m ot hera p y wit h dela ye d t o xicit y, e xte nsi ve 
ra diati o n t hera p y, i m m u n ot hera p y, bi ol o gic t hera p y, or maj or 
s ur ger y) or i n vesti gati o n al a nti-ca ncer t hera p y wit hi n 3 wee ks, or 
c he m ot hera p y wit h o ut d ela ye d  t o xicit y wit hi n t he 2 wee ks of 
starti n g st u d y tr eat me nt. ( N ote: I pili m u ma b treat me nt m ust e n d at 
least 8 wee ks pri or t o d osi n g. 
8.   
Hist or y of a n ot her mali g na nc y. 
E xce pti o n: S u bjects w h o ha ve bee n dise as e-free f or 3 years (i.e. s u bjects wit h 
sec o n d mali g na n cies t hat are i n d ole nt or d efi niti vel y tr eate d at least 3 years) or 
s u bjects wit h a hist or y of c o m pletel y resecte d n o n- mela n o ma s ki n ca ncer. 
Revise d:  
2.   
Pri or treat me nt wit h a B R A F i n hi bit or or a M E K i n hi bit or. 
3.   
K n o w n oc ular or pri mar y m uc osal mela n o ma 
4.   
Pri or s yste mic a nti- ca ncer treat me nt ( c he m ot hera p y, i m m u n ot hera p y, 
bi ol o gic t hera p y, v acci n e t hera p y, wit hi n t he last 3 wee ks, or 
che m ot hera p y wit h o ut d ela ye d  t o xicit y wit hi n t he last 2 wee ks prece di n g 
t he first d ose of t he c o m bi nati o n.  Pri or s yste mic tr eat me nt i n t he a dj u va nt 
setti n g is all o we d (s a me ti meli nes as a b o ve). ( N ote: I pili m u ma b treat me nt 
m ust e n d at least 8 wee ks pri or t o e nr oll me nt.) 
9.   
Hist or y of mali g na n c y wit h c o nfir me d acti vati n g R A S m utati o n at a n y 
ti me.  
N ote : Pr os pecti ve R A S testi n g is n ot re q uir e d. H o we ver, if t h e res ults of pre vi o us R A S 
testi n g are k n o w n, t he y m ust be use d i n assessi n g eli gi bilit y. 
Re as o n f or c h a n g e: U p dat e d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t he 
da brafe ni b a n d tra m eti ni b c o m bi nati o n. 
Re m ov al of:  
Ac ute i nfecti o n re q uiri n g i ntra ve n o us a nti bi otics. 
Re as o n f or c h a n g e:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 

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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Previ o us:  
A hist or y or c urre nt e vi d e nce/ris k of reti nal vei n o ccl usi o n ( R V O) or reti nal pi g me nt 
e pit helial detac h me nt ( R P E D) i ncl u di n g: 
 
Prese nce of pre dis p osi n g fact ors t o R V O or R P E D (e. g., u nc o ntr olle d 
gla u c o ma or oc ul ar h y p erte nsi o n, u nc o ntr olle d h y perte nsi o n, 
u nc o ntr olle d dia betes mellit us, or a hist or y of h y p er visc osit y or 
h y p erc o a g ula bilit y s y n dr o mes); or  
 
Visi ble reti nal pat h ol o g y as assesse d b y o p ht hal mic e x a mi nati o n t hat is 
c o nsi dere d a ris k fact or f or R V O or R P E D s uc h as: 
i.  
E vi de nce of ne w o ptic disc c u p pi n g; 
ii.  
E vi de nce of ne w vis ual fi el d defects o n a ut o mate d peri metr y; 
iii.  
I ntr a oc ular press ure > 2 1 m m H g as me as ure d b y t o n o gra p hy.  
Revise d:  
A hist or y or c urre nt e vi d e nce of reti nal vei n occl usi o n ( R V O) 
Re as o n f or c h a n g e:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
4. 2. 1  P er m a n e nt Di s c o nti n u ati o n fr o m St u d y Tr e at m e nt  
Previ o us:  
S ur vi val a n d ne w a nti- ca ncer t hera p y f oll o w- u p will c o nti n ue u ntil eit her all s u bjects are 
dea d, wit h dra w n c o nse nt or l ost t o f oll o w- u p, or all s u bjects still i n f oll o w- u p ha ve ha d at 
least 5 years f oll o w- u p, w hic he ver is earlier. At s uc h ti me t he st u d y will b e cl ose d. 
Revise d:  
S ur vi val a n d ne w a nti- ca ncer t hera p y f oll o w- u p will c o nti n ue u ntil eit her all s u bjects are 
dea d, wit h dra w n c o nse nt or l ost t o f oll o w- u p, or all s u bjects still i n f oll o w- u p ha ve ha d at 
least 5 years f oll o w- u p fr o m t he date of first d ose of st u d y tr eat me nt, w hic he ver is 
earlier.. At s u c h ti me t he st u d y will be cl ose d. 
Re as o n f or c h a n g e:  
Clarificati o n t hat 5 years f oll o w u p is fr o m t he dat e of first d ose of st u d y tr eat me nt. 
4. 2. 1. S u bj e ct C o m pl eti o n a n d Wit h dr a w al  
Previ o us:  
A s u bject will be c o nsi d ere d t o ha ve c o m plete d t h e st u d y if t he s u bject dies d uri n g t he 
st u d y tr eat me nt or f oll o w- u p peri o d or has ha d at least 5 years f oll o w- u p fr o m t he e n d of 
t he trial. T he ca us e of deat h will be d oc u me nte d i n t he e C R F. 
Revise d:  
A s u bject will be c o nsi dere d t o ha ve c o m plete d t h e st u d y if t he s u bject dies d uri n g t he 
st u d y treat me nt or f oll o w- u p peri o d or has ha d at least 5 years f oll o w- u p fr o m t he date of 
first d ose of st u d y tr eat m e nt at t he e n d of t he trial. T he ca us e of deat h will be d oc u me nte d 
i n t he e C R F. 

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Re as o n f or c h a n g e:  
Clarificati o n t hat 5 years f oll o w u p is fr o m t he dat e of first d ose of st u d y tr eat me nt. 
5. 2. 1  D a br af e ni b a n d Tr a m eti ni b C o m bi n ati o n  
Previ o us:  
B ot h st u d y tr eat me nts s h o ul d be a d mi nistere d i n t he m o r ni n g at a p pr o xi matel y t he s a me 
ti me e v er y d a y.  T he s ec o n d d ose of da brafe ni b ( 1 5 0 m g) s h o ul d be a d mi nistere d 
a p pr o xi matel y 1 2 h o urs after t he m or ni n g d ose.  St u d y m e dicati o n s h o ul d be ta ke n orall y 
wit h a p pr o xi matel y 2 0 0  m L of water u n der fasti n g c o n diti o ns, eit her 1 h o ur bef ore or 2 
h o urs after a m eal.  If a d mi nistrati o n of tra meti ni b is i nterr u pte d or per m a ne ntl y 
disc o nti n ue d, a d mi nistrati o n of da brafe ni b ma y be c o nti n ue d.  If a d mi nistrati o n of 
da brafe ni b is i nterr u pte d, or per ma n e ntl y disc o nti n ue d, a d mi nistrati o n of tra meti ni b ma y 
c o nti n ue. 
Revise d:  
W he n a d mi nistere d i n c o m bi nati o n, ta ke t he o nce- da ily d ose of tr a meti ni b at 
a p pr o xi matel y t he sa me ti me eac h d a y wit h eit her t he m or ni n g d ose or t he e ve ni n g d os e 
of da brafe ni b.  T he s ec o n d d ose of da brafe ni b ( 1 5 0 m g) s h o ul d be a d mi nistere d 
a p pr o xi matel y 1 2 h o urs after t he m or ni n g d ose.  St u d y m e dicati o n s h o ul d be ta ke n orall y 
wit h a p pr o xi matel y 2 0 0  m L of water u n der fasti n g c o n diti o ns, eit her 1 h o ur bef ore or 2 
h o urs after a meal. 
Re as o n f or c h a n g e:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
5. 2. 1  D a br af e ni b a n d Tr a m eti ni b C o m bi n ati o n  
Previ o us:  
S u bjects s h o ul d a bstai n fr o m i n gesti o n of a n y f o o d or dri n k c o ntai ni n g gra pefr uit a n d 
gra pefr uit j uice, Se ville ora n ges, or p o m mel os wit hi n 7 da ys pri or t o d osi n g u ntil 
treat me nt disc o nti n uati o n, as t h ese ha v e bee n s h o w n t o i n hi bit C Y P 3 A 4 acti vit y. 
Revise d:  
Re m o ve d 
Re as o n f or c h a n g e:  
T his restricti o n is n o l o n ger re q uir e d. 
5. 8  
D o s e  M o difi c ati o n G ui d eli n e s  
Previ o us:  
Wit h t he e x ce pti o ns of p yre xia (li kel y relate d t o d a brafe ni b); a n d decrease d L V E F, R V O 
(reti nal vei n occl usi o n), a n d R P E D (li kel y relat e d t o tra meti ni b), t he g ui da nce s u g gests 
t hat b ot h t hera pies be re d uce d, i nterr u pt e d or disc o nti n ue d si m ulta ne o usl y i n res p o nse t o 
t o xicities t hat are c o nsi dere d b y t h e i n vesti gat or t o be treat me nt r elate d. 

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C o nfi d e nti al 
P a g e 1 4 2 
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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Revise d:  
Wit h t he e x ce pti o ns of p yre xia a n d n e w pri mar y R A S- m utati o n p ositi ve n o n-c uta ne o us 
mali g na n cies(li kel y rel ate d t o da brafe ni b); a n d d ecreas e d L V E F, R V O (reti nal vei n 
occl usi o n), R P E D, a n d p ne u m o nitis (li kel y relate d t o tra meti ni b), t he g ui d a nce s u g gests 
t hat b ot h t hera pies be re d uce d, i nterr u pt e d or disc o nti n ue d si m ulta ne o usl y i n res p o nse t o 
t o xicities t hat are c o nsi dere d b y t h e i n vesti gat or t o be treat me nt r elate d. 
Re as o n f or c h a n g e:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
T a bl e 3  
C at e g ori e s of D o s e M o difi c ati o n G ui d eli n e s  
Previ o us:  
 
A d verse E v e nt  
Da brafe ni b  
Tra meti ni b  
Vis ual C ha n ges ( R V 0)  
 
X  
P ne u m o nitis  
X  
X  
Revise d:  
 
A d verse E v e nt  
Da brafe ni b  
Tra meti ni b  
Vis ual C ha n ges  
 
X  
P ne u m o nitis  
 
X  
 
Re as o n f or c h a n g e:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
T a bl e 5  
D o s e M o difi c ati o n G ui d eli n e s f or E v e nt s C o n si d er e d R el at e d t o 
St u d y Tr e at m e nt ( D a br af e ni b a n d Tr a m eti ni b C o m bi n ati o n 
Tr e at m e nt)  
Previ o us:  
D ose M o dific ati o n G ui deli nes f or E ve nts C o nsi dere d Rel ate d t o St u d y Tre at me nt  
( D a br afe ni b a n d Tr a meti ni b C o m bi n ati o n Tre at me nt) 
C T C A E 
Gr a de  
Acti o n a n d D ose M o dific ati o n  
Gra de  1  
 C o nti n ue  st u d y treat me nt at c urre nt d ose le vel 
 M o nit or cl osel y  
 Pr o vi de s u p p orti ve care acc or di n g t o i nstit uti o nal sta n dar ds  
Gra de  2  
 I nterr u pt st ud y treat me nt if cli nicall y i n dicate d  
 M o nit or cl osel y  
 Pr o vi de s u p p orti ve c are acc or di n g t o i nstit uti o nal sta n dar ds 
 W he n  t o xicit y res ol ves t o gra de 1 or b aseli ne, restart st u dy  
treat me nt at c urre nt d ose le vel 

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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
C T C A E 
Gr a de  
Acti o n a n d D ose M o dific ati o n  
Gra d e 3  
 I nterr u pt st ud y  treat me nt 
 M o nit or cl osel y  
 Pr o vi de s u p p orti ve care acc or di n g t o i nstit uti o nal sta n dar ds  
 W he n t o xicit y  res ol ves t o gra de 1 or b aseli ne, restart st u dy  
treat me nt re d uce d b y o ne d ose le vel  
 If t he gra d e 3 t o xicit y rec urs, i nterr u pt st u d y tr eat me nt 
 W he n  t o xicit y res ol ves t o gra de 1 or b aseli ne, restart st u dy  
treat me nt re d uce d b y a n ot her d ose le vel  
Gra de  4  
 I nterr u pt st ud y  treat me nt 
 M o nit or cl osel y 
 Pr o vi de s u p p orti ve care acc or di n g t o i nstit uti o nal sta n dar ds  
 Restart wit h st u d y  treat me nt re d uce d b y o ne d ose le vel o nce  
t o xicit y res ol ves t o gra de 1 or baseli ne 
 If t he gra d e 4 t o xicit y rec urs, eit her per m a ne ntl y disc o nti n ue 
st u d y tre at me nt or, if t he s u bject is cli nicall y b e n efiti n g, 
disc uss c o nti n uati o n of st u d y treat me nt wit h t he G S K a me dical 
m o nit or.  
 
Revise d:  
D ose M o dific ati o n G ui deli nes f or E ve nts C o nsi dere d Rel ate d t o St u d y Tre at me nt  
( D a br afe ni b a n d Tr a meti ni b C o m bi n ati o n Tre at me nt). 
C T C A E 
Gr a de  
Acti o n a n d D ose M o dific ati o n a, b  
Gr a de 1 o r  
Gr a de  2 
t oler a ble 
C o nti n ue st u d y tre at me nt at s a me d ose le vel ( n o d ose  
m o dific ati o n)  a n d m o nit or a s cli ni cally i n di cat e d.  
Gr a de 2 (I nt oler a ble) o r Gr a de  3  
1 st, 2n d  or  
3 rdocc urre n ce  
I nterr u pt st ud y treat me nt u ntil t o xicit y res ol ves t o ≤ gra de 1 t he n 
restart at ne xt l o wer d ose le vel 
4 th  or  greater  
occ urre nce  
Disc o nti n ue treat me nt.  
Gr a de  4  
1 st occ urre nce  
I nterr u pt st ud y treat me nt u ntil t o xicit y  res ol ves t o ≤ gra de 1 or 
baseli ne t he n restart at ne xt l o wer d ose le vel or disc o nti n ue at 
discreti o n of i n vesti gat or  
2 n d  occ urre nce  I nterr u pt st ud y treat me nt u ntil t o xicit y  res ol ves t o ≤ gra de 1 or 
baseli ne t he n restart at t w o d ose le vels l o wer t ha n t he starti n g d os e or 
disc o nti n ue at discre ti o n of i n vesti gat or a n d after disc ussi o n wit h t he 
me dical m o nit or.  
3 rd  occ urre nce  Disc o nti n ue treat me nt  
Treat me nt s h o ul d be disc o nti n ue d if m ore t ha n 3 d ose re d ucti o ns are re q uir e d 
A p pr o val fr o m t he G S K Me dical M o nit or is re q uire d t o restart st u d y treat me nt after 
≥2 1  da ys. 

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W he n a n i n di vi d ual’s a d verse reacti o ns are u n der effecti ve ma na ge me nt, d ose r e- 
escalati o n f oll o wi n g t he sa me d osi n g ste ps as de- escalati o n ma y be c o nsi dere d. T h e 
da brafe ni b d ose s h o ul d n ot e x cee d 1 5 0 m g t wice dail y a n d t he tra meti ni b s h o ul d 
n ot e x cee d 2 m g o n ce dail y.  
Re as o n f or c h a n g e:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
T a bl e 6  
D o s e M o difi c ati o n G ui d eli n e s a n d St o p pi n g Crit eri a f or L V E F 
D e cr e a s e 
Previ o us:  
D ose M o dific ati o n G ui deli nes a n d St o p pi n g Criteri a f or L V E F Decre as e  
D ose M o dificati o n G ui deli nes a n d St o p pi n g Criteria f or L V E F  
 
Cli nic  
L V E F -dr o p  ( %) or  
C T C A E  gr a de  
Acti o n  a n d  D ose  M o dific ati o n  
As y m pt o matic  
A bs ol ute  decrease  of  > 1 0 %  i n 
L V E F  c o m pare d  t o baseli ne 
a n d  ej ecti o n fracti o n bel o w  
t he i nstit uti o n’s L L N  
• 
I nterr u pt tra meti ni b a n d  da brafe ni b  a n d re p eat 
E C H O  w it hin  2 we e k sa  
• 
If t he L V E F rec o vers wit hi n 4 wee ks ( defi ne d as 
L V E F ≥L L N a n d  a bs ol ute decrease ≤1 0 % 
c o m pare d t o baseli ne) c o ns ult wit h t he G S K 
me dical m o nit or a n d re q uest a p pr o val f or 
restart. 
• 
Restart treat me nt wit h tra meti ni b or place b o 
re d uce d d ose b y o ne d ose le vel. 
• 
Restart da brafe ni b at pre vi o us d ose le vel b 
• 
Re peat E C H O 2 , 4 , 8 a n d 1 2 wee ks after re -
start; c o nti n ue i n i nter vals of 1 2 wee ks 
t hereafter.  
• 
If L V E F d oes n ot rec o ver wit hi n 4 wee ks  
• 
C o ns ult wit h car di ol o gist . 
• 
P er ma ne ntl y disc o nti n ue tra meti ni b . 
Re peat E C H O after 2, 4, 8,  1 2,  a n d  1 6  
w ee ks or  u ntil  res ol uti o n. 
• 
C o ns ult  wit h  G S K  me dical  m o nit o rd. 
 
S y m pt o matic c  
Gra d e  3:  restin g  L V E F  3 9 -
2 0 %  or  > 2 0 %  a bs ol ute 
re d ucti o n fr o m baseli ne  
 
Per m a ne ntl y  disc o nti n ue  tr a meti ni b. 
 
Disc o nti n ue  d a br afe ni b  
 
Re p ort  as  S A E  
 
C o ns ult  wit h  c ar di ol o gist  
 
Re peat  E C H O  after  2, 4, 8, 1 2,  a n d  1 6 wee ks  
or  u ntil  res ol uti on e  
Gra d e  4:  resti n g L V E F  < 2 0 %  
A b bre viati o ns:  C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; 
E C H O = ec h ocar di o gra m; G S K = Gla x o S mit h Kli ne; L L N = l o wer li mit of 
n or mal; L V E F = l eft ve ntric ular ej ecti o n fracti o n; 
a) If E C H O d oes n ot s h o w L V E F rec o ver y aft er 2 wee ks, re p eat E C H O 2 we e ks 
later. 

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P a g e 1 4 5 
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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
b) If rec urre nt e pis o des of L V E F re d ucti o n occ ur da brafe ni b m o n ot hera p y, c o ns ult 
me dical m o nit or. 
c) S y m pt o ms m a y i ncl u de: d ys p nea, ort h o pe n ea, a n d ot her si g ns a n d s y m pt o ms of 
p ul m o nar y c o n gesti o n a n d e de m a. 
d) 
O nce L V E F rec o v ers, restarti n g da brafe ni b m o n ot hera p y ca n be c o nsi dere d i n 
c o ns ultati o n wit h G S K me dical m o nit or. 
e) 
O nce L V E F rec o v ers, i ncl u di n g res ol uti o n of s y m pt o ms, restart of da brafe ni b 
m o n ot hera p y o nl y ca n b e c o nsi dere d i n c o ns ultati o n wit h G S K me dical m o nit or. 
Revise d:  
D ose M o dific ati o n G ui deli nes a n d St o p pi n g Criteri a f or L V E F Decre as e  
D ose M o dificati o n G ui deli nes a n d St o p pi n g Criteria f or L V E F  
 
Cli nic  
L V E F -dr o p  ( %) or  
C T C A E  gr a de  
Acti o n  a n d  D ose  M o dific ati o n  
As y m pt o matic  
A bs ol ute  decrease  of  > 1 0 %  i n 
L V E F  c o m pare d  t o baseli ne 
a n d  ej ecti o n fracti o n bel o w  
t he i nstit uti o n’s L L N  
• 
I nterr u pt tra meti ni b a n d re peat E C H O 
wit hi n 2 wee ksa, b  
• 
If t he L V E F  re c o ve r s wit hi n  4 w ee ks 
( defi ne d as L V E F  ≥L L N  a n d   a bs ol ute 
decrease  ≤1 0 %  c o m pare d  t o baseli ne)  
• 
C o ns ult  wit h  t he G S K  me dical 
m o nit or  a n d  re q uest a p pr o val  f or 
restart 
• 
If a p pr o ve d, restart treat me nt wit h 
tram eti ni b  re d uce d b y  o ne  d ose le vel  
• 
Re peat  E C H O  at 2  , 4 , 8 a n d 1 2 
wee ks  after  re-start; c o nti n ue  i n 
i nter vals o f 1 2  w ee ks t hereafter. 
• 
If L V E F  d oes  n ot  rec o ver  w it hi n 
4 wee ks . 
• 
C o ns ult  wit h  car di ol o gist  
• 
Per m a ne ntl y  disc o nti n ue  
t r am eti ni b  
• 
Re p ort  as  S A E  
• 
Re peat  E C H O  after  2,  4,  8,  1 2,  a n d 1 6  
• 
w ee ks or  u n til res ol uti o n 
S y m pt o matic c  
Gra d e  3:  resti n g L V E F  3 9 -2 0 %  
or  > 2 0 %  a bs ol ute re d ucti o n  
fr o m baseli ne  
• 
Per m a ne ntl y  disc o nti n ue  tr a meti ni b 
• 
I nterr u pt d a br afe ni b .d  
• 
Re p ort  as  S A E  
• 
C o ns ult  wit h  c ar di ol o gist  
 
Re peat  E C H O  after  2, 4, 8, 1 2,  a n d  1 6 
wee ks  or  u ntil  res oluti o n b,d  
Gra d e  4:  resti n g L V E F  < 2 0 %  
A b bre viati o ns: C T C A E = C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts; E C H O = 
ec h ocar di o gra m; G S K = Gla x o S mit h Kli ne; L L N = l o wer li mit of  n or mal; L V E F = left 
ve ntric ular ej ecti o n fracti o n; 
a) If E C H O d oes n ot s h o w L V E F rec o ver y after 2 wee ks, re pe at E C H O 2 w e e ks later. 
b) 
If rec urre nt e pis o des of  L V E F re d ucti o n occ ur i n s u bj ects rec ei vi n g da brafe ni b m o n ot hera p y, 
c o ns ult me dical m o nit or. 
d) 
S y m pt o ms ma y i ncl u de: d ys p nea, ort h o pe nea, a n d ot her si g ns a n d s y m pt o ms of  p ul m o nar y 
c o n gesti o n a n d e d e m a.  
c) 
O nce L V E F rec o vers, i ncl u di n g res ol uti o n of  s y m pt o ms, rest art of  da brafe ni b m o n ot hera p y o nl y 
ca n be  c o nsi dere d i n c o ns ultati o n wit h G S K me dical m o nit or. 

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P a g e 1 4 6 
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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Re as o n f or c h a n g e:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f o r t he da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
T a bl e 8  
Wit h h ol di n g a n d St o p pi n g Crit eri a f or Q T c B- Pr ol o n g ati o n  
Previ o us:  
Wit h h ol di n g a n d St o p pi n g Criteri a f or Q Tc- Pr ol o n g ati o n  
Q T c-Pr ol o n g ati o n a  
Acti o n a n d D ose M o dific ati o n  
 Q Tc B  ≥5 0 1 msec  
 I nterr u pt st ud y treat me nt u ntil Q Tc B  
pr ol o n gati o n res ol ves t o gra de 1 or 
baseli ne  
 Restart at c urre nt d ose le velb  
 If e ve nt r ec urs, per ma n e ntl y dis c o nti n ue 
st u dy  tr eat me nt 
A b bre viati o ns: msec = millisec o n ds; Q Tc B = Q T i nter val o n electr ocar di o gra m 
c orrecte d usi n g t he Bazett’s f or m ula 
a.   Base d o n a vera ge Q Tc val ue of tri plicat e E C Gs.  F or e x a m ple, if a n E C G 
de m o nstrates a pr ol o n ge d Q T i nter val, o btai n t w o or m ore E C Gs o ver a bri ef 
peri o d, a n d t he n use t h e a vera ge d Q Tc v al ues of t h e t hree E C Gs t o deter mi n e if 
st u d y tr eat me nts s h o ul d be i nterr u pte d or dis c o nti n ue d. 
b.   If t he Q Tc pr ol o n gati o n res ol ves t o gra d e 1 or baseli ne, t he s u bject ma y res u me 
st u d y tr eat me nt if t he i n v esti gat or a n d G S K me dical m o nit or a gree t h at t he 
s u bject will be nefit fr o m f urt her tr eat me nt. 
Revise d:  
Wit h h ol di n g a n d St o p pi n g Criteri a f or Q Tc B- Pr ol o n g ati o n  
Q T c-
Pr ol o n g ati o n a  
Acti o n a n d D ose M o dific ati o n  
 
Q Tc B  ≥5 0 1 
msec  
 
I nterr u pt all st ud y tr eat m e nts u ntil Q Tc B  
pr ol o n gati o n res ol ves t o gra de 1 or b aseli ne  
 
Test ser u m p otassi u m, calci u m, p h os p h or us a n d ma g n esi u m. If 
a b n or mal c orrect p er r o uti ne cli nical practice t o wit hi n n or mal 
li mits. 
 
Re vie w c o nc o mita nt me dicati o n usa ge f or a ge nts t hat pr ol o n g 
Q Tc.  
 
If e ve nt r es ol ves, restart st u d y treat me nt at c urre nt d ose le velb  
 If e ve nt d oes n ot res ol v e, per m a ne ntl y disc o nti n ue st u d y 
tre at me nts.  C o nsi der e v al u ati o n wit h c ar di ol o gist.  
 
If e ve nt rec urs, per m a ne ntl y disc o nti n ue st u d y tre at me nts.  
C o nsi der e v al u ati o n wit h c ar di ol o gist.  
A b bre viati o ns:  msec = millisec o n ds; Q Tc B = Q T i nter val o n electr o car di o gra m 
c orrecte d usi n g t he Bazett’s f or m ula 
a)  Base d o n a vera ge Q Tc val ue of tri plicat e E C Gs.  F or e x a m ple, if a n E C G 
de m o nstrates a pr ol o n ge d Q T i nter val, o btai n t w o or m ore E C Gs o ver a bri ef 
peri o d, a n d t he n use t h e a vera ge d Q Tc v al ues of t h e t hree E C Gs t o deter mi n e if 
st u d y tr eat me nts s h o ul d be i nterr u pte d or dis c o nti n ue d. 

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P a g e 1 4 7 
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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
b)  If t he Q Tc pr ol o n gati o n res ol ves t o gra d e 1 or baseli ne, t he s u bject ma y res u me 
st u d y tr eat me nt if t he i n v esti gat or a n d G S K me dical m o nit or a gree t h at t he s u bject 
will be nefit fr o m f urt her treat me nt. 
Re as o n f or c h a n g e:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
5. 8. 4. 3.  
G ui d eli n e s f or c u S C C a n d n e w c a s e s of s e c o n d ar y m el a n o m a s  
Previ o us:  
C uta ne o us s q ua m o us cell carci n o mas h a ve b ee n o bser ve d i n s u bjects treate d wit h 
da brafe ni b a n d t he c o m bi nati o n of da brafe ni b a n d tra meti ni b (see da brafe ni b a n d 
tra meti ni b c o m bi nati o n I B); [ Gla x o S mit h Kli ne D oc u me nt N u m ber 
2 0 1 1 N 1 2 6 8 1 1 _ 0 0. 2 0 1 2]. T hese treat me nt-relate d c u S C C s h o ul d be s ur gicall y 
re m o ve d acc or di n g t o i nstit uti o nal practice.  D ose m o dificati o ns or i nterr u pti o ns 
of t he st u d y tr eat me nt are n ot re q uire d f or c u S C C.  Occ urre nce of c u S C C m ust be 
re p orte d as a n S A E. S u b mit c u S C C t u m o ur tiss ue f or a nal ysis  a n d as directe d i n 
t he S P M. 
Revise d:  
1 2. 9. 1. 1  
G ui d eli n e s f or c u S C C a n d tr e at m e nt e m er g e nt m el a n o m a s  
C uta ne o us s q ua m o us cell carci n o mas h a ve b ee n o bser ve d i n s u bjects treate d wit h 
da brafe ni b a n d t he c o m bi nati o n of da brafe ni b a n d tra meti ni b (see da brafe ni b a n d 
tra meti ni b c o m bi nati o n I B); [ Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 1 N 1 2 6 8 1 1 _ 0 0, 
2 0 1 2]. T hese treat me nt-relate d c u S C C s h o ul d be s ur gicall y re m o ve d acc or di n g t o 
i nstit uti o nal practice.  D ose m o dificati o ns or i nterr u pti o ns of t he st u d y treat me nt are n ot 
re q uire d f or c u S C C.  Occ urre nce of c u S C C m ust be re p ort e d as a n S A E. Pat h ol o g y re p ort 
s h o ul d be place d i n s u bje ct c hart 
Ne w Pri m a r y Mel a n o m a : Ne w pri mar y mela n o mas ha ve bee n re p orte d i n patie nts 
treate d wit h da brafe ni b. T hese were i de ntifie d pri maril y wit hi n t he first 5 m o nt hs of 
t hera p y a n d di d n ot re q uire treat me nt m o dificati o n ot her t ha n e x cisi o n. M o nit ori n g f or 
s ki n lesi o ns s h o ul d occ ur as descri be d f or c u S C C. Ne w pri mar y ca ncers a n d treat me nt- 
e mer ge nt mali g na nci es, wit h t he e x ce pti o n of basal cell carci n o ma ( B C C) s h o ul d be 
rep orte d as a S A E.  B C C s h o ul d be re p orte d as a n A E or S A E base d o n t he discreti o n of 
t he i n vesti gat or. A bi o ps y of t he n e w mali g na n c y s h o ul d be ta ke n, w here p ossi ble, a n d 
s u b mitte d f or f urt her a nal yses.  Testi n g of t hes e bi o psies ma y i ncl u de R A S m utati o n 
testi n g a n d a n al ysis of pr otei ns relate d t o t he acti o n of da brafe ni b.  G e n o mic alterati o ns, 
w hic h i ncl u de b ut n ot li mite d t o D N A, R N A a n d pr otei n a nal ysis of t h ese bi o ps y 
s peci me ns ma y b e perf or me d, a n d w o ul d be restricte d t o t he a nal ysis of p at h wa y 
m utati o ns k n o w n t o be ass ociate d wit h, a n d rele va nt t o, B R A F- m uta nt t u m ors or pat h wa y 
acti vati o n. 
E val uate f or s y m pt o ms or cli nical si g ns of n o n-c ut a ne o us, ne w pri mar y/rec urre nt 
mali g na n cies bef ore i nitiati o n of treat me nt, peri o dicall y d uri n g tr eat me nt, or as cli nicall y 
i n dicate d. F oll o wi n g disc o nti n uati o n of st u d y treat me nt, m o nit ori n g f or n o n-c uta ne o us 
sec o n dar y/r ec urre nt mali g na n cies s h o ul d c o nti n ue f or u p t o 6 m o nt hs or u ntil i niti ati o n of 
a n ot her a nti- ne o plastic t h era p y. A b n or mal fi n di n gs s h o ul d be ma na ge d acc or di n g t o 
cli nical practices. 

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P a g e 1 4 8 
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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Re as o n f or c h a n g e:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n 
5. 8. 5. 1.  
G ui d eli n e s f or P yr e xi a  
Previ o us:  
E pis o des of p yre xia ha ve bee n o bser ve d i n s u bjects recei vi n g da brafe ni b m o n ot hera p y or 
i n c o m bi nati o n wit h tra meti ni b (see da brafe ni b a n d da brafe ni b a n d tra m eti ni b 
c o m bi nati o n I Bs); [ Gla x o S mit h Kli ne D oc u me nt N u m ber C M 2 0 1 0/ 0 0 0 1 0/ 0 2 2 0 1 1 a n d 
Gla x o S mit h Kli ne D oc u me nt N u m ber 2 0 1 1 N 1 2 6 8 1 1 _ 0 0. 2 0 1 2]. I n  a mi n orit y of cases t he 
p yre xia was acc o m p a nie d b y s y m pt o ms s uc h as s e vere c hills, de h y drati o n, h y p ot e nsi o n, 
diz zi ness or wea k ness. 
P yre xia acc o m pa nie d b y h y p ote nsi o n, or de h y drati o n re q uiri n g I V fl ui ds, or se vere 
ri g ors/c hills s h o ul d be re p orte d as a n S A E as per Secti o n 7. 4. 2. 6. 
S u bjects s h o ul d be i nstr ucte d o n t he i m p orta nce of i m me diatel y re p orti n g fe brile 
e pis o des.  I n t he e v e nt of a fe ver, t he s u bject s h o ul d be i nstr ucte d t o ta ke n o n-ster oi dal 
a nti- p yretics - i b u pr ofe n ( preferre d) or acet a mi n o p he n/ paraceta m ol as a p pr o priate t o 
c o ntr ol fe ver.  I n s u bjects e x perie nci n g p yr e xia ass ociate d wit h ri g ors, se vere c hills, 
de h y drati o n,  h y p ote nsi o n, etc., re n al f u ncti o n s h o ul d be m o nit ore d caref ull y (see Secti o n 
5. 8. 5. 3). 
G ui deli nes re gar di n g m a na ge me nt a n d d ose m o dificati o ns f or p yre xia c o nsi dere d t o be 
relate d t o st u d y tr eat me nt are pr o vi d e d i n Ta ble 1 1.  
T a bl e 1 1  
M a n a g e m e nt a n d  D o s e M o difi c ati o n G ui d eli n e s f or P yr e xi a 
A d verse  
E ve nt  
A d verse E ve nt  M a n a ge me nt  
Acti o n a n d D ose  M o dific ati o n  
P y re xia 
1 st E ve nt b: 
 Cli nical e val uati o n f or i nfecti o n 
a n d h y p erse nsiti vit y c  
 La b orat or y  w or k -u p c 
 H y drati o n as re q uir e d d  
 Bl o o d sa m ple f or c yt o ki n e 
a nalysise 
 A d mi nister a nti -p y retic 
treat me nt (acet a mi n o p he n is 
reco m me n de d as first li ne 
a nt i-p yretic bef ore m o vi n g 
i nt o i b u pr ofen ) cli nicall y 
i n dicate d a n d c o nti n ue 
pr o p h y la ctic treat me ntf 
1 st E ve nt:  
 I nterr u pt d a br afe ni b 
 C o nti n ue tra meti ni b  
 O nce  p y re xia res ol ves t o 
baseli ne, restart 
da brafe ni b at t he sa me 
d ose le vel  
o  If fe v er was 
ass ociate d wit h 
de h y drati o n or 
h y p ote nsi o n, 
re d uce 
d a br afe ni b b y 
o ne d ose le vel  

1 4 9  
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C o nfi d e nti al 
P a g e 1 4 9 
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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
A d verse  
E ve nt  
A d verse E ve nt  M a n a ge me nt  
Acti o n a n d D ose  M o dific ati o n  
a 
2 n d  E ve nt g  
 Cli nical e val uati o n f or i nfecti o n 
a n d h y p erse nsiti vit y c  
 La b orat or y  w or k -u p c 
 H y drati o n as re q uir e d d  
 Bl o o d sa m ple f or c yt o ki n e 
a nalysise 
 Wit hi n  3  da y s of o ns et of 
p y re xi a 
o  O pti mize a nti -p yretic 
t herap y  
o  C o nsi der oral 
c ortic oster oi ds (i.e., 
pre d nis o ne 1 0 m g) f or at 
least 5  d a y s or as 
cli nicall y i n dicat e df 
S u bse q ue nt E ve nts : 
 Cli nical e val uati o n f or i nfecti o n 
a n d h y p erse nsit i vity c  
 La b orat or y  w or k -u p c 
 H y drati o n as re q uir e d d  
 Bl o o d sa m ple f or c yt o ki n e 
a nalysise 
 wit hi n 3 da y s of o nset of 
p y re xi a: 
o  O pti miz e oral c ortic oster oi d 
d ose as cli nicall y  i n dicat e d 
f or recalcitr a nt p yre xia g  
o  If c ortic oster oi ds ha v e bee n 
ta pere d a n d p y re xi a rec urs, 
restart ster oi ds 
o  If c ortic oster oi ds ca n n ot be 
ta pere d c o ns ult me dical m o nit or 
2 n d  E ve nt:  
 I nterr u pt d a br afe ni b 
 C o nti n ue tra meti ni b  
 O nce  p y re xia res ol ves t o 
baseli ne, restart  da brafe ni b 
at t he sa me d ose le vel  
o  If fe v er was 
ass ociate d wit h 
de h y drati o n or 
h y p ote nsi o n, 
re d uce 
d a b r afe ni b b y 
o ne d ose le vel  
 
 
S u bse q ue nt E ve nts:  
 I nterr u pt d a br afe ni b 
 C o nti n ue tra meti ni b  
 O nce  p y re xia res ol ves t o 
baseli ne, restart 
da brafe ni b re d uce d b y 
o ne d ose le vel h  
 If da brafe ni b m ust be 
re d uce d t o < 5 0 m g BI D, 
per ma ne ntl y 
disc o nti n ue 
d a br afe ni b. 
Tr a m eti ni b m a y be 
c o nti n ue d 
a. 
P yre xia is defi ne d as a b o d y te m perat ure e q ual t o or a b o ve 3 8. 5 Celsi us or 1 0 1. 3 ○ 
Fa hre n heit. 
b.  F or s u bjects e x perie nci n g p yr e xia c o m plicate d b y ri g ors, s e vere c hills, etc., a cli nical 
e val uati o n a n d la b orat or y w or k- u p is ma n dat or y f or eac h e ve nt; a nti- p yretic treat me nt 
s h o ul d be starte d i m me diatel y at t he first occ urre n ce a n d pr o p h yl actic a nti- p yretic 
treat me nt is rec o m me n d e d 
c. 
T h or o u g h cli nical e x a mi nati o n f or si g ns a n d s y m pt o ms of i nfecti o n or 
h y pers e nsiti vit y is re q uir e d; la b orat o r y w or k- u p s h o ul d i ncl u de f ull- bl o o d-c o u nt, 
electr ol ytes, creati ni ne, bl o o d urea nitr o ge n ( B U N), C-reacti ve pr otei n ( C R P), li ver- 
f u ncti o n tests, bl o o d c ult ure, a n d uri n e c ult ure. 

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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
d.  
Oral h y drati o n s h o ul d be e nc o ura ge d i n s u bjects wit h o ut e vi de nce of de h y drati o n. 
I ntr a ve n o us h y drati o n is rec o m me n de d i n s u bjects e x perie nci n g p yre xia c o m plicate d 
b y de h y drati o n/ h y p ote nsi o n. 
e. 
Bl o o d sa m ple f or c yt o ki n e a nal ysis s h o ul d be ta ke n i m me diatel y at t he first 
occ urre nce of fe ver (i.e. w he n t he s u bject visits t he cli nic) a n d aft er t he fe v er has 
disa p peare d (i.e. d uri n g t he ne xt r o uti ne visit), sa m ples m ust be se nt t o t he ce ntral 
la b orat or y. 
f. 
A nti- p yretic tr eat me nt m a y i ncl u d e aceta mi n o p he n, i b u pr ofe n, or s uita ble a nti- p yretic 
me dicati o n acc or di n g t o i nstit uti o nal sta n dar ds. Pr o p h ylactic a nti- p yretic tr eat me nt 
ma y be disc o nti n ue d after t hree d a ys i n t he a bse nce of p yre xia  
g. I n s u bject e x perie nci n g p yre xia c o m plicat e d b y ri g ors, s e vere c hills, etc., w hic h 
ca n n ot be c o ntr olle d wit h a nti- p yretic me di cati o n, oral c ortic oster oi ds s h o ul d be 
starte d at t he 2 n d e v e nt a n d d oses s h o ul d be gra d u all y i ncrease d f or s u bs e q ue nt 
e ve nts. 
h.  
Da brafe ni b s h o ul d be re d uce d b y o n e d ose le vel after t hree e pis o des of p yr e xia 
c o m plicate d b y ri g ors, se vere c hills, etc., w hic h ca n n ot be ma na ge d b y best 
s u p p orti ve care a n d i ncreasi n g d oses of oral ster oi ds. Escalati o n of da brafe ni b is 
all o we d if n o e pis o de of p yre xia is o bser ve d i n t he 4 wee ks s u bs e q ue nt t o d ose 
re d ucti o n. 
Revise d:  
E pis o des of p yre xia ha ve bee n o bser ve d i n s u bjects recei vi n g da brafe ni b m o n ot h era p y, 
a n d is i ncreas e d i n i nci de nce a n d se v erit y i n s u bjects recei vi n g d a brafe ni b i n c o m bi nati o n 
wit h tra meti ni b (see da brafe ni b a n d da brafe ni b a n d tra meti ni b c o m bi nati o n I Bs); 
[ Gla x o S mit h Kli ne D oc u me nt N u m ber C M 2 0 1 0/ 0 0 0 1 0/ 0 2 2 0 1 1 a n d Gla x o S mit h Kli ne 
D oc u me nt N u m ber 2 0 1 1 N 1 2 6 8 1 1 _ 0 0. 2 0 1 2]. I n  a mi n orit y of cases t he p yr e xia was 
acc o m pa ni e d b y s y m pt o ms s uc h as se vere c hills, de h y drati o n,  h y p ote nsi o n, dizzi ness or 
wea k ness. 
S u bjects s h o ul d be i nstr ucte d o n t he i m p orta nce of i m me diatel y re p orti n g fe brile 
e pis o des.  I n t he e v e nt of a fe ver, t he s u bject s h o ul d be i nstr ucte d t o ta ke a nti- p yretics 
(e. g. i b u pr ofe n or aceta mi n o p he n/ paraceta m ol) as a p pr o priate t o c o ntr ol fe v er.  T he use 
of oral c ortic ost er oi ds s h o ul d be c o nsi dere d i n t h ose i nsta nces i n w hic h a nti- p yretics are 
i ns ufficie nt.  M o nit or ser u m creati ni ne a n d ot h er e vi de nce of re nal f u n cti o n d uri n g a n d 
f oll o wi n g se vere e ve nts of p yre xia (see Secti o n 5. 8. 5. 3). 
G ui deli nes re gar di n g m a na ge me nt a n d d ose m o dificati o ns f or p yre xia c o nsi dere d t o be 
relate d t o st u d y tr eat me nt are pr o vi d e d i n Ta ble 1 1. 

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T a bl e 1 1  
M a n a g e m e nt a n d  D o s e M o difi c ati o n G ui d eli n e s f or P yr e xi aa, b  
A d verse  
E ve nt  
A d verse E ve nt M a n a ge me nt  
Acti o n a n d D ose  M o dific ati o n  
P y re xia a 
All E ve nts:  
 Cli nical e val uati o n f or 
i nfecti o n a n d hy perse nsiti vit y c  
 La b orat or y  w or k -u p c 
 H y drati o n as re q uir e d d  
1 st E ve nt b: 
 A d mi nister a nti -p y retic 
treat me nt as cli nicall y i n dicate d 
a n d i nitiate pr o p h y l actic 
treat me nt if ass oci ate d wit h 
ri g ors, re nal f ail ure, d eh y d rati o n 
or h y p ote nsi o n e 
2 n d  E ve nt f 
 Wit hi n  3  da y s of o ns et of 
p y re xi a  
o  O pti miz e a nti -p yretic 
t herap y  
o  C o nsi der oral 
c ortic oster oi ds (i.e., 
pre d nis o ne 1 0 m g) f or at 
least 5  d a y s or as cli nicall y 
i n dicate df 
 
 
 
S u bse q ue nt E ve nts : 
 Wit hi n  3  da y s of o ns et 
of p y re xi a: 
o  O pti miz e oral 
c ortic oster oi d d ose as 
cli nicall y i n dicat e d f or 
recal citra nt p yre xia f 
o  If c ortic oster oi ds ha v e 
bee n ta pere d a n d p y re xia 
rec urs, restart ster oi ds 
o  If c ortic oster oi ds ca n n ot be 
ta pere d c o ns ult me dical 
m o nit or  
1 st E ve nt:  
 I nterr u pt 
d a br afe ni b  
 C o nti n ue tra meti ni b  
 O nce  p y re xia res ol ves t o 
baseli ne, restart da brafe ni b at 
t he sa me d ose le vel  
o  If fe v er was ass ociat e d 
wit h ri g ors, re nal f ail ure, 
de h y drati o n or 
h y p ote nsi o n, re d uce 
d a br afe ni b b y o ne d ose 
le velg  
 
2 n d  E ve nt:  
 I nterr u pt d a br afe n d 
 C o nti n ue tra meti ni b  
 O nce  p y re xia res ol ves t o 
baseli ne, restart da brafe ni b at 
t he sa me d ose le vel 
o  If fe v er was ass ociat e d 
wit h ri g ors, re nal f ail ure, 
de h y drati o n or 
h y p ote nsi o n,  re d uce 
d a br afe ni b b y o ne d ose 
le velg  
 
S u bse q ue nt E ve nts:  
 I nterr u pt 
d a br afe ni b  
 C o nti n ue tra meti ni b  
 O nce  p y re xia res ol ves t o 
baseli ne, restart 
da brafe ni b  
re d uce d b y o ne d ose 
le velg  
 If da brafe ni b m ust be 
re d uce d t o < 5 0 m g 
BI D, per ma ne ntl y  
Disc o nti n ue 
d a br afe ni b. Tr a meti ni b 
m a y be c o nti n ue d  
a. 
P yre xia is defi ne d as a b o d y  te m perat ure e q ual t o or  a b o ve 3 8. 5 Celsi us or  1 0 1. 3º Fa hre n heit. 

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b. 
F or s u bj ects e x perie nci n g p yre xia c o m plicate d b y  ri g ors, se vere c hills, etc., a cli nical e val uati o n 
a n d la b orat or y wor k- u p  is ma n dat or y f or eac h e ve nt; a nti- p yr etic treat me nt s h o ul d be  starte d 
i m me diatel y at t he first occ urre nce a n d pr o p h ylactic a nti- p yr etic treat me nt is rec o m me n de d 
c. 
T h or o u g h cli nical e xa mi nati o n f or si g ns a n d s y m pt o ms of  i nfecti o n or  h y perse nsiti vit y is 
re q uire d; la b orat or y w or k-u p  s h o ul d i ncl u de f ull- bl o o d-c o u nt, electr ol ytes, creati ni ne, bl o o d 
urea nitr o ge n ( B U N), C-reacti ve pr otei n ( C R P), li ver-f u ncti o n tests, bl o o d c ult ure, a n d uri ne 
c ult ure. 
d. 
Oral h y drati o n s h o ul d be  e nc o ura ge d i n s u bj ects wit h o ut e vi de nce of  de h y drati o n. I ntra ve n o us 
h y drati o n is rec o m me n de d i n s u bj ects e x perie nci n g p yre xia c o m plicate d b y 
de h y drati o n/ h y p ote nsi o n. 
e. 
A nti- p yretic treat me nt ma y i ncl u de aceta mi n o p he n, i b u pr ofe n, or  s uita ble a nti- p yreti c 
me dicati o n acc or di n g t o i nstit uti o nal sta n dar ds. Pr o p h ylactic a nti- p yretic treat me nt ma y be 
disc o nti n ue d after t hree da ys i n t he a bse nce of  p yre xia 
f. 
 I n s u bj ect e x perie nci n g p yre xi a c o m plicate d b y  ri g ors, se vere c hills, etc., w hic h ca n n ot be 
c o ntr olle d wit h a nti- p yretic me dicati o n, oral c ortic oster oi ds s h o ul d be  starte d at t he 2 n d e ve nt 
a n d d oses s h o ul d be  gra d uall y i ncrease d f or s u bse q ue nt e ve nts. 
g. 
Da brafe ni b s h o ul d be  re d uce d b y  o ne d ose le vel aft er t hree e pis o des of  p yre xia c o m plicate d b y  
ri g ors, se vere c hills, etc., w hic h ca n n ot be  ma na ge d b y  best s u p p orti ve care a n d i ncreasi n g 
d oses of  oral ster oi ds. Escalati o n of  da brafe ni b is all o we d if n o  e pis o de of  p yre xia is o bser ve d 
i n t he 4 wee ks s u bse q u ent  t o d ose re d ucti o n. 
Re as o n f or c h a n g e:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
5. 8. 5. 4.  
G ui d eli n e s f or Vi s u al C h a n g e s  
Previ o us:  
E pis o des of vis ual c ha n ges ha ve bee n o bser ve d i n s u bjects recei vi n g d a brafe ni b, 
tra meti ni b or t he c o m bi nati o n of b ot h t hera pies. T he ca usal relati o ns hi p bet wee n a 
c ha n ge i n visi o n a n d t he st u d y treat me nt s h o ul d b e caref ull y e x pl ore d a n d a n 
o p ht hal m ol o gist s h o ul d be c o ns ulte d. S pecial atte nti o n s h o ul d be gi ve n t o reti nal (e. g., 
C S R) or reti nal vei n a b n or malities (e. g., R V O). F or e ve nts of vis ual c ha n ges re gar dless 
of se verit y, a bl o o d sa m ple f or P K a n al ysis m ust be dra w n as cl ose as p ossi ble t o t he 
ti me of t he e ve nt. 
G ui deli nes re gar di n g m a na ge me nt a n d d ose re d u cti o n f or vis ual c ha n ges c o nsi dere d t o be 
relate d t o st u d y tr eat me nt are pr o vi d e d i n Ta ble 3 4 

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T a bl e 1 4  
M a n a g e m e nt a n d D o s e M o difi c ati o n G ui d eli n e s f or Vi s u al C h a n g e s  
C T C
A E 
Gr a
de a  
A d v ers e E ve n t M a n a ge m e nt  
Acti o n  a n d  D ose  M o dific ati o n  
Gra d e 1  
 
C o ns ult  o p ht hal m ol o gist wit hi n  7  
da ys  of  o nset  
 
E xcl u de  C S R  or  R V O  
 
C o ns ult  reti nal s pecialist i n case 
of  C S R  or  R V O  
 
Re p ort  R V O  as S A E  
 
C o nti n ue  f oll o w u p 
e xa mi nati o n(s)  b y  reti nal 
s pecialist f or C S R  a n d  R V O  
 
C o nti n ue  st u d y treat me nt at t he sa me  d ose  
le vel u ntil o p ht hal m o l o gic e xa mi nati o n  ca n 
be  c o n d ucte d b  
 
If o p ht hal m ol o gic  e xa mi nati o n ca n n ot  be  
perf or me d  wit hi n  7  da ys  of  o nset,  
i nterr u pt st u d y treat me nt u ntil C S R  a n d  
R V O  ca n be e xcl u de d  a n d  s y m pt o ms 
res ol ve 
 
Restart  tra meti ni b at sa me d os e le vel  
 
C S R:  I nterr u pt tra meti ni b u ntil s y m pt o ms  
res ol ve a n d  e xa m b y reti nal  s pecialist 
s h o ws res ol uti o n
 
Restart  wit h  tra meti ni b re d uce d b y o ne  d ose  
le vel 
 
R V O:  Per m a ne ntl y  disc o nti n ue 
t r am eti ni b  
Gra d e  2 
a n d  Gr a d e 
3  
 
C o ns ult  o p ht hal m ol o gist 
i m me diatel y 
 
E xcl u de  C S R  a n d  R V O  
 
C o ns ult  reti nal s pecialist i n case 
of  R V O  or  C S R  f or f oll ow -u p  
e xa m 
 
Re p ort  R V O  as S A E  
 
C o nti n ue  f oll o w u p 
e xa mi nati o n(s)  b y  reti nal 
s pecialist f or C S R  a n d  R V O  
 
I nterr u pt tr a meti ni b u ntil  si g ns a n d 
s y m pt o ms ha ve  res ol ve d t o baseli ne 
 
Restart  wit h  tra meti ni b re d uce d b y o ne  d ose  
le vel 
 
C S R:  I nterr u pt tra meti ni b u ntil s y m pt o ms 
res ol ve a n d  e xa m b y reti nal  s pecialist 
s h o ws res ol uti o n Restart tra meti ni b 
re d uce d b y  o ne  d ose  le vel 
 
R V O:  Per m a ne ntl y  disc o nti n ue 
t r am eti ni b  
Gra d e 4  
 
C o ns ult  o p ht hal m ol o gist 
i m me diatel y 
 
E xcl u de  C S R  a n d  R V O  
 
Re p ort  R V O  as S A E  
 
C o nti n ue  f oll o w u p 
e xa mi nati o n(s)  b y  reti nal 
s pecialist f or C S R  a n d  R V O  
 
Per m a ne ntl y  disc o nti n ue t r am eti ni b  
C S R = ce ntral ser o us reti n o pat y; C T C A E = C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts; R V O = 
reti nal vei n occl usi o n; S A E = seri o us a d verse e ve nt 
a. 
Refers t o C T C A E Versi o n 4. 0 ‘ E ye dis or ders – Ot her, s pecif y 
b. 
If vis ual c ha n ges are clearl y u nrelate d t o st u d y treat me nt (e. g., aller gic c o nj u ncti vitis), m o nit or 
cl osel y b ut o p ht hal mic e xa mi nati o n is n ot re q uire d. 

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Revise d:  
E pis o des of vis ual c ha n ges ha ve bee n o bser ve d i n s u bjects recei vi n g tr a meti ni b, 
da brafe ni b, a n d c o m bi nati o n t hera p y.  A n o p ht hal m ol o gist s h o ul d be c o ns ulte d if c ha n ges 
i n visi o n de vel o p.  H o we ver, if t he vis ual c ha n ges are cl earl y u nrel ate d t o st u d y treat me nt 
(e. g., aller gi c c o nj u ncti vitis), t he n m o nit or cl osel y as it ma y be reas o n a ble t o defer 
o p ht hal mic e x a mi nati o n. 
Treat me nt wit h da brafe ni b has bee n ass o ciate d wit h t he de vel o p me nt of u veitis, i ncl u di n g 
iritis. M o nit or patie nts f or vis ual si g ns a n d s y m pt o ms (s uc h as, c ha n ge i n visi o n, 
p h ot o p h o bia a n d e ye pai n) d uri n g t h era p y. S peci al atte nti o n s h o ul d be gi ve n t o reti nal 
fi n di n gs ( e. g., reti nal pi g me nt e pit helial detac h me nt ( R P E D) or reti n o vasc ular 
a b n or malities (i.e., bra nc h or ce ntr al reti nal vei n o ccl usi o ns ( R V O).  F or e v e nts of vis ua l 
c ha n ges (re gar dless of se verit y) f or w hi c h a n o p ht hal mic e x a mi nati o n is c o n d ucte d, a 
bl o o d sa m ple f or P K a nal ysis m ust be dra w n as cl ose as p ossi ble t o t he ti me of t he e v e nt. 
G ui deli nes re gar di n g m a na ge me nt a n d d ose re d u cti o n f or vis ual c ha n ges a n d/ or 
o p ht hal mic e x a mi nati o n fi n di n gs c o nsi dere d t o be relate d t o st u d y treat me nt are pr o vi de d 
i n Ta ble 1 4. 
T a bl e 1 4  
M a n a g e m e nt a n d  D o s e M o difi c ati o n G ui d eli n e s f or Vi s u al C h a n g e s 
a n d/ or O p ht h al mi c E x a mi n ati o n Fi n di n g s  
C T C A E 
Gr a de a  
A d verse E ve nt  M a n a ge me nt  Acti o n a n d D ose M o dific ati o n  
Gra de 1 b  
 
C o ns ult o p ht hal m ol o gist 
wit hi n  7 da ys of o nset  

 
If dilate d f u n d us e xa mi nati o n ca n n ot be 
perf or me d wit hi n 7 da ys  of o nset, i nterr u pt 
tra meti ni b u ntil R P E D a n d R V O ca n be 
e xcl u de d b y reti na 
s pecialist/ o pht hal m ol o gist . If s u bject is 
recei vi n g tra meti ni b/ da brafe ni b 
c o m bi nati o n t hera p y da brafe ni b ma y be 
c o nti n ue d. 
 
If R P E D a n d R V O e xcl u de d, c o nti n ue 
( or restart) tra meti ni b at sa me d ose le vel 
 
If R P E D s us pecte d or dia g n ose d: 
see R P E D d ose m o dificati o n Ta ble 1 5   
bel o w;  re p ort as S A E if di a g n ose d.  
 
If R V O dia g n ose d: P er m a ne ntl y 
disc o nti n ue tr a meti ni b a n d  re p ort as 
S A E.  
Gra de 2 
a n d Gra de 
3  
 
C o ns ult 
o p ht hal m ol o gist 
i m me diatel y 
 
I nterr u pt tra meti ni b.  If 
s u bj ect is recei vi n g 
tra meti ni b/ da brafe ni b 
c o m bi nati o n t hera p y 
da brafe ni b m a y be 
c o nti n ue d. 

 
If R P E D a n d R V O e xcl u de d, restart 
tra meti ni b at sa me d ose 
le vel. 
 If R P E D dia g n ose d, see R P E D  d ose 
m o dificati o n ta ble bel o w;  re p ort as S A E. 
 
If R V O dia g n ose d: P er m a ne ntl y 
disc o nti n ue  tr a meti ni b a n d  re p ort as 
S A E  

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C T C A E 
Gr a de a  
A d verse E ve nt  M a n a ge me nt  Acti o n a n d D ose M o dific ati o n  
Gra de 4  
 
C o ns ult 
o p ht hal m ol o gist 
i m me diatel y 
 
I nterr u pt tra meti ni b. If 
s u bj ect is recei vi n g 
tra meti ni b/ da brafe ni b 
c o m bi nati o n t hera p y 
da brafe ni b  m a y be 
c o nti n ue d. 
 
If R P E D a n d R V O e xcl u de d, m a y 
c o nsi der restarti n g tra meti ni b at  
sa me or re d uce d d ose after 
disc ussi o n wit h st u d y me dical 
m o nit or  
 
If R V O  or  R P E D  di a g n ose d, 
per m a ne ntl y disc o nti n ue tr a meti ni b 
a n d re p ort as S A E.  
A b bre viati o ns: R P E D = reti nal pi g me nt e pit helial detac h me nt; C T C A E = C o m m o n 
T er mi n ol o g y Criteria f or A d verse E ve nts; R V O = reti nal vei n occl usi o n; S A E = seri o us 
a d verse e ve nt 
a)  
Refers t o C T C A E Versi o n 4. 0 ‘ E ye dis or ders – Ot her, s pecif y’ 
b)  
If vis ual c ha n ges are clearl y u nrelate d t o st u d y treat me nt (e. g., aller gic c o nj u ncti vitis), 
m o nit or cl osel y b ut o p ht hal mic e xa mi nati o n is n ot re q uire d.  
T a bl e 1 5  
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 tr a m eti ni b f or r eti n al pi g m e nt 
e pit h eli al d et a c h m e nt s ( R P E D) a  
C T C A E Gr a de  
Acti o n a n d D ose M o dific ati o n  
Gra d e 1 R P E D ( A sy m pt o matic;  cli nical 
or  dia g n ostic o bs er vati o ns o nl y ) 
 C o nti n ue treat me nt wit h reti nal 
e val uati o n m o nt h ly u ntil res ol uti o n. If  
R P E D w orse ns f oll o w i nstr ucti o ns 
bel o w  
Gra d e 2 -3  R P E D  ( Sy m pt o matic wit h  mil d 
t o m o derate decrease i n vis ual ac uity ; 
li miti n g i nstr u me ntal A D L) 
 I nterr u pt tra m eti ni b 
 Reti nal e val uat i o n m o nt hl y 
 If i m pr o ve d t o ≤ Gra d e 1, restart 
trameti ni b at l o wer d ose (re d uce d b y  
0. 5 m g) or dis c o nti n ue i n patie nts 
ta ki n g tra m eti ni b 1 m g d ail y 
Refers t o C T C A E Versi o n 4. 0 ‘ Reti n o pat h y’ 
L a n g u a ge f or O p ht h al m ol o gic E x a m descri pti o n  
O p ht h al m ol o gic E x a m  
At certai n ti me p oi nts i n t he trial a n d if vis ual c ha n ges d e vel o p, a n e ye e x a m is i n dicate d. 
( Refer t o Secti o n 5. 8. 5. 4  f or vis ual c ha n ges st o p pi n g criteria).  T he e x a m will i ncl u de 
best c orrecte d vis ual a c uit y,  t o n o metr y, slit la m p bi o micr osc o pic e x a mi nati o n, vis ual 
fiel d e x a mi nati o n, a n d dilate d i n direct f u n d osc op y wit h s pecial atte nti o n t o reti nal 
a b n or malities.  O ptical c o here nce t o m o gra p h y is str o n gl y rec o m me n de d at sc he d ule d 
visits, a n d if reti nal a b n or malities are s us pecte d. Ot her t y p es of a n cillar y testi n g i ncl u di n g 
c ol or f u n d us p h ot o gra p h y a n d fl u orescei n a n gi o gra p h y are als o rec o m me n d e d if cli nicall y 
i n dicate d. 
Re as o n f or c h a n ge:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 

1 5 6  
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P a g e 1 5 6 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9  
  
  
  
  
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Ta ble 3 7  
Ma na ge me nt a n d D ose M o dificati o n G ui deli nes f or P ne u m o nitis 
5. 8. 5. 5.  
G ui d eli n e s f or P n e u m o niti s  
A d diti o n:  
P ne u m o nitis has bee n o bser ve d i n s u bjects r ecei vi n g da brafe ni b a n d tra m eti ni b. T o 
re d uce t h e ris k of p ne u m o nitis, s u bjects will be m o nit ore d cl osel y f or s y m pt o ms, 
e val uate d wit h i ma gi n g a n d f u ncti o nal tests. D ose m o dificati o n a n d s u p p orti ve care 
g ui deli nes f or p ne u m o nitis are descri be d i n Ta ble 1 6. 
T a bl e 1 6  
M a n a g e m e nt a n d D o s e M o difi c ati o n G ui d eli n e s f or P n e u m o niti s  
C T C A E  
Gr a de  
A d verse E ve nt  M a n a ge me nt  
Acti o n a n d D ose M o dific ati o n  
Gr a de  1  
 C T sc a n ( hi g h - res ol uti o n wit h 
l u n g wi n d o ws) rec o m me n de d 
 
Cli ni c al  e v al u ati o n a n d 
l a b or at or y w ork - u p f or 
i nfecti o n 
 M o nit ori n g of o x y ge n ati o n vi a 
p uls e-o xi metr y rec o m me n de d  
 C o ns ult ati o n of p ul m o n ol o gist 
rec o m me n de d  
 C o nti n ue st u d y tre at me nt at 
c urre nt d ose  
C T C A E 
Gr a de  
A d verse E ve nt M a n a ge me nt 
Acti o n a n d D ose M o dific ati o n 
Gr a de  2  
 C T sc a n ( hi g h - res ol uti o n wit h 
l u n g wi n d o ws) 
 Cli nic al e v al u ati o n a n d 
l a b or at or y w or k -u p f or  
i nfecti o n 
 C o ns ult p ul m o n ol o gist  
 P ul m o n ar y f u ncti o n tests – if 
< n or m al, r e pe at e ver y 8 
w ee ks u ntil ≥ n or m al  
 Br o nc h osc o p y wit h bi o ps y  
a n d/ or B A L rec o m me n de d . 
 S y m pt o m ati c t her a p y 
i ncl u di n g c ortic oster oi ds if 
cli nic all y i n dic ate d  
 I nterr u pt tr a meti ni b u ntil 
rec o v er y t o g r a de ≤1  
 Rest art wit h st u d y tre at me nt 
re d uce d b y o ne d ose le vel  
 Esc al ati o n t o pre vi o us d ose 
le vel after 4 wee ks a n d 
c o ns ult ati o n wit h me dic al 
m o nit or p ossi ble  
 If n o rec o ver y t o gr a de ≤1 
wit hi n 4 wee ks, per m a ne ntl y 
disc o nti n ue st u d y tre at me nt  

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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
C T C A E  
Gr a de  
A d verse E ve nt  M a n a ge me nt  
Acti o n a n d D ose M o dific ati o n  
Gr a de  3  
 C T sc a n ( hi g h - res ol uti o n w it h 
l u n g wi n d o ws). 
 Cli nic al e v al u ati o n a n d 
l a b or at or y w ork - u p f or 
i nfecti o n. 
 C o ns ult p ul m o n ol o gist.  
 P ul m o n ar y f u ncti o n tests -if 
< n or m al, r e pe at e ver y 8 
w ee ks u ntil ≥ n or m al  
 Br o nc h osc o p y wit h bi o ps y 
a n d/ or B A L if p ossi ble.  
 S y m pt o m ati c t her a p y 
i ncl u di n g c ortic oster oi ds as 
cli nic all y i n dic ate d.  
 
 I nterr u pt tr a meti ni b u ntil 
rec o v er y t o gr a de ≤1  
 After c o ns ult ati o n wit h 
me dic al m o nit or, st u d y 
tre at me nt m a y be rest arte d 
re d uce d b y o ne d ose le vel.  
 If n o rec o ver y t o g r a de  ≤1 
wit hi n 4 wee ks, per m a ne ntl y 
disc o nti n ue st u d y t re at me nt.  
Gr a de  4  
 S a me as g r a de 3 
 Per m a ne ntl y disc o nti n ue 
tr a meti ni b
 
B A L = br o nci oal ve ol ar la va ge; C T = c o m p ute d t o m o gra p h y; C T C A E = C o m m o n 
Ter mi n ol o g y Criteri a f or A d verse E v e nts 
A b bre viati o ns:  C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d verse E v e nts; 
E C H O = ec h o car di o gra m; G S K = Gla x o S mit h Kli ne; L L N = l o w er li mit of 
n or mal; L V E F = l eft ve ntric ular ej ecti o n fracti o n; 
a) If E C H O d oes n ot s h o w L V E F rec o ver y aft er 2 wee ks, re p eat E C H O 2 wee ks 
later. 
b) If rec urre nt e pis o des of L V E F re d ucti o n occ ur da brafe ni b m o n ot hera p y, 
c o ns ult me dical m o nit or. 
c) S y m pt o ms m a y i ncl u de: d ys p nea, ort h o pe n ea, a n d ot her si g ns a n d s y m pt o ms 
of p ul m o nar y c o n gesti o n a n d e d e m a.  
d) 
O nce L V E F rec o v ers, restarti n g da brafe ni b m o n ot hera p y ca n be c o nsi dere d i n 
c o ns ultati o n wit h G S K me dical m o nit or. 
e) 
O nce L V E F rec o v ers, i ncl u di n g res ol uti o n of s y m pt o ms, restart of da brafe ni b 
m o n ot hera p y o nl y ca n b e c o nsi dere d i n c o ns ultati o n wit h G S K me dical 
m o nit or.  
Re as o n f or c h a n g e: O mitt e d fr o m pr ot oc ol V 0 0  
T he i n vesti gat or m ust be i nf or me d as s o o n as p ossi ble a b o ut a n y m e dicati o n ta ke n fr o m 
t he ti me of scree ni n g u ntil 3 0 da ys after t he l ast d ose of st u d y tr eat me nt wit h t he 
e x ce pti o n of ne w a nti-ca ncer t hera p y, if t a ke n after st u d y treat me nt disc o nti n uati o n; 
t hese will be d oc u me nte d u ntil st u d y c o m pleti o n/ wit h dra wal or deat h. A n y c o nc o mita nt 
me dicati o n(s), i ncl u di n g dietar y s u p ple me nts, ta ke n d uri n g t he st u d y will be rec or de d i n 
t he e C R F. T he mi ni m u m re q uire me nt is t hat dr u g na me, d ose, t he dat es of 
a d mi nistrati o n a n d reas o n f or me dicati o ns will be rec or d e d. A d diti o nall y, a c o m plete 
list of all pri or a nti-ca ncer t hera pies will be rec or de d i n t he e C R F. 

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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Patie nts s h o ul d recei ve f ull s u p p orti ve care d uri n g t he st u d y, i ncl u di n g tra nsf usi o ns of 
bl o o d a n d bl o o d pr o d ucts, a n d treat me nt wit h a nti bi otics, a nti-e metics, a nti- Diarr heals, 
a n d a nal gesics, a n d ot her care as dee me d a p pr o pri ate, a n d i n acc or d a nce wit h t heir 
i nstit uti o nal g ui deli nes. Use of a ntic o a g ula nts s uc h as warfari n is per mitte d pr o vi de d t hat 
I N R is m o nit ore d i n a cc or da nce wit h l ocal i nstit uti o nal practice. 
W hile patie nts are o n st u d y treat me nt, palliati ve ra diati o n t hera p y is per mitte d f or n o n- 
tar get lesi o ns t hat are eit her ne w or pres e nt at bas eli ne. T he t otal d ose ma y n ot e x cee d 3 0 
G y. 
Revise d:  
T he i n vesti gat or m ust be i nf or me d as s o o n as p ossi ble a b o ut a n y m e dicati o n ta ke n fr o m 
t he ti me of scree ni n g u ntil 3 0 da ys after t he l ast d ose of st u d y treat me nt.  A n y 
c o nc o mita nt me dicati o n(s), i ncl u di n g dietar y s u p ple me nts, ta ke n d uri n g t he st u d y will be 
rec or de d i n t he e C R F.  T he mi ni m u m re q uire me nt is t hat dr u g na m e, d ose, a n d t he dates 
of a d mi nistrati o n are t o b e rec or de d.  A d diti o nall y, a c o m plete list of all pri or s ur gical 
pr oce d ures will be rec or d e d i n t he e C R F. 
S u bjects s h o ul d recei ve f ull s u p p orti ve care d uri n g t he st u d y, i ncl u di n g tr a nsf usi o ns of 
bl o o d a n d bl o o d pr o d ucts, a n d treat me nt wit h a nti bi otics, a nti-e metics, a nti- diarr heals, 
a n d a nal gesics, a n d ot her care as dee me d a p pr o pri ate, a n d i n acc or d a nce wit h t heir 
i nstit uti o nal g ui deli nes.  Use of a ntic oa g ula nts s u c h as warfari n is per mitte d h o we ver, 
ca uti o n s h o ul d be e x ercise d a n d a d diti o nal I nter nati o nal N or malize d Rati o (I N R) 
m o nit ori n g is rec o m me n de d w he n da brafe ni b is use d c o nc o mita ntl y wit h warfari n. 
W hile patie nts are o n st u d y treat me nt, palliati ve ra diati o n t hera p y is per mitte d f or n o n 
tar get lesi o ns t hat are eit her ne w or pres e nt at bas eli ne. 
Ra diati o n s ki n i nj ur y has bee n re p orte d wit h c o nc urre nt use of d a brafe ni b a n d ra diati o n. 
It is rec o m me n de d t hat d a brafe ni b be hel d f or se v e n da ys bef ore a n d t w o d a ys after X R T 
i n s u bjects recei vi n g da brafe ni b m o n ot hera p y or i n c o m bi nati o n wit h tra meti ni b. T hese 
rec o m me n dati o ns ca n be m o difie d base d o n t he p h ysicia n’s assess me nt of t he ris k of 
ra diati o n s ki n i nj ur y. 
Re as o n f or c h a n ge:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
T he t otal d ose ma y n ot e x cee d 3 0 G y. 
Revise d:  
Ra diati o n s ki n i nj ur y has bee n re p orte d wit h c o nc urre nt use of da brafe ni b a n d ra diati o n. 
It is rec o m me n de d t hat d a brafe ni b be hel d f or se v e n da ys bef ore a n d t w o d a ys after X R T 
i n s u bjects recei vi n g da brafe ni b m o n ot hera p y or i n c o m bi nati o n wit h tra meti ni b. T hese 
rec o m me n dati o ns ca n be m o difie d base d o n t he p h ysicia n’s assess me nt of t he ris k of 
ra diati o n s ki n i nj ur y. 
Re as o n f or c h a n ge:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 

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P a g e 1 5 9 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9  
  
  
  
  
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Previ o us:  
T a bl e 1 8  
M e di c ati o n s t o b e u s e d wit h C a uti o n  
U S E WI T H C A U TI O N: C o nce n tr ati o ns of t hese dr u gs m a y be i ncre ase d or 
decre ase d b y d a br afe ni b  
Cl ass/ T her a pe utic  Are a  
Mil d/ M o der ate C Y P 3 A a n d C Y P 2 C 8  
A ntiarr h y t h mics 
Diltiaze m, vera pa mil  
A nti bi otic  
Er y t hr om yci n  
A ntif u n gal  
Fl uc o naz ole  
Miscella ne o us  
A pre pita nt, ci meti di ne, m o ntel u kast  
U S E 
WI T H C A U TI O N: C o -a d mi nistr ati o n of t hese dr u gs wit h st u d y tre at me nt 
m a y res ult i n l oss of effic ac y.  M o nit or s u bjects f or l oss of effic ac y or s u bstit ute 
wit h a n ot her me dic ati o n.  
Cl ass/ T her a pe utic  Are a  
C Y P 3 A 4, C Y P 2 B 6, C Y P 2 C 8, C Y P 2 C 9, or C Y P 2 C 1 9  
S u bstr ates t h at M a y be Affecte d b y I n d ucti o n  
A nal gesics  
Alfe nta nil, b u pre n or p hi n e, celec o xi b, c o dei ne, 
fe nta ny l, met ha d o ne, ox yc o d o ne  
A ntiarr h y t h mics 
Dis o p y ra mi de, dr o ne d ar o ne, me xileti ne, 
pr o pafe n o n e, q ui ni di ne  
A nti bi otics  
C hl ora m p he nic ol, d o x y cy cli ne, ery t hr om yci n, m o xifl o x aci n  
A ntic oa g ula nts/ 
A nti platelets  
Cil ostaz ole, warfari n  
A ntic o n v ulsa nts  
Di val pr oe x, la m otri gi ne, val pr oate, z o nisa mi de  
A nti de pressa nts a n d  
A nti ps y c h otics  
Ari pi praz ole, b u pr o pi o n, b us pir o ne, desi pra mi ne, 
hal o peri d ol, mirtaza pi ne, pi m ozi de, q uetia pi ne, 
traz o d o ne, a mitri ptyli ne, cl o mi pra mi ne, i mi pra mi ne 
U S E WI T H C A U TI O N: C o nce n tr ati o ns of t hese dr u gs m a y be i ncre ase d or 
decre ase d b y d a br afe ni b  
A nti dia betics  
Gl y b uri de, s a x a gli pti n, t ol b uta mi de, nate gli ni de, 
pi o glitaz o ne, re pa gli ni de, r osi glitaz o ne 
A ntif u n gals  
Cas p of u n gi n, fl u c o naz ole, ter bi nafi n e  
A nti hista mi nes  
Aste miz ole, c hl or p he nira mi ne, e basti ne  
A nti h y perte nsi ves  
A ml o di pi ne, diltiaze m, fel o di pi ne, nife di pi ne, 
nil va di pi ne, nis ol di pi ne, vera pa mil  
A nti mi grai ne A ge nts  
Dier g ota mi ne,  eletri pta n, er g ota mi ne  
C ortic oster oi ds  
De x a met has o ne, met h y l pre d nis ol o ne, oral b u des o ni de 
Erectile D y sf u n cti o n 
A ge nts  
Sil de nafil, ta dalafil, var de nafil  
H M G -C o A Re d uctase 
I n hi bit ors 
At or vastati n, l o vastati n, si m vastati n, ceri vastati n  

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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Cl ass/ T her a pe utic  Are a  
Mil d/ M o der ate C Y P 3 A a n d C Y P 2 C 8  
H y p n otics a n d Se d ati ves  
Al praz ola m, br otiz ola m, diaze pa m, estaz ola m, 
mi daz ola m, triaz ola m, z ol pi de m, z o picl o ne  
I m m u n os u p pr essa nts 
E ver oli m us, sir oli m us, tacr oli m us  
Miscella ne o us  
A pre pita nt, cisa pri d e, darife naci n, dis o p yra mi de, 
lefl u n o mi de, met h o he xital, oral c o ntrace pti ves, q ui ni ne, 
ra niti di ne, s olife naci n, s ulfasalazi ne, tra ma d ol, t ol va pta n, 
c hl or o q ui ne, z o picl o ne  
Selecti ve Al d oster o ne 
Bl oc kers  
E plere n o ne  
A b bre viati o ns: C Y P = c yt oc hr o me P 4 5 0; H M G- C o A = 3- h y dr o x y- 3 - met h yl gl utar yl- 
c oe nz yme  A.  
Q uesti o ns re gar di n g c o nc o mita nt me dicati o ns s h o ul d be directe d t o t he G S K Me dical 
M o nit or f or clarifi cati o n. 
 
Revise d:  
T a bl e 1 8  
M e di c ati o n s t o b e u s e d wit h C a uti o n  
U S E WI T H C A U TI O N: C o nce ntr ati o ns of t hese dr u gs m a y be i ncre ase d or 
decre ase d b y d a br afe ni b  
Cl ass/ T her a pe utic  
Are a  
Mil d/ M o der ate C Y P 3 A a n d C Y P 2 C 8  
A ntiarr h y t h mics 
Diltiaze m, vera pa mil  
A nti bi otic  
Er y t hr om yci n  
A ntif u n gal  
Fl uc o naz ole  
Miscella ne o us  
A pre pita nt  
U S E WI T H C A U TI O N: C o -a d mi nistr ati o n of t hese dr u gs  wit h st u d y tre at me nt 
m a y res ult i n l oss of effic ac y.  M o nit or s u bjects f or l oss of effic ac y or s u bstit ute 
wit h a n ot her me dic ati o n.  
Cl ass/ T her a pe utic  
Are a  
C Y P 3 A 4, C Y P 2 B 6, C Y P 2 C 8, C Y P 2 C 9, or C Y P 2 C 1 9  
S u bstr ates t h at M a y be Affecte d b y I n d ucti o n  
A nal gesics  
Alfe nta nil, b u pre n or p hi n e, celec o xi b, c o dei ne, fe nta n y l, 
met ha d o ne, o x yc o d o ne  
A ntiarr h y t h mics 
Dis o p y ra mi de, dr o ne d ar o ne, me xileti ne, pr o pafe n o ne, 
q ui ni di ne  
A nti bi otics  
C hl ora m p he nic ol, d o x y cy cli ne, er y t hr om yci n, 
m o xifl o x aci n  
A ntic oa g ula nts/ 
A nti platelets  
Cil ostaz ole, warfari n  
A ntic o n v ulsa nts  
Di val pr oe x, la m otri gi ne, val pr oate, z o nisa mi de  
A nti de pressa nts a n d  
A nti ps y c h otics  
Ari pi praz ole, b u pr o pi o n, b us pir o ne, desi pra mi ne, 
hal o peri d ol, mirtaza pi ne, pi m ozi de, q uetia pi ne, 
traz o d o ne, a mitri pty li ne, cl o mi pra mi ne, i mi pra mi ne 

1 6 1  
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C o nfi d e nti al 
P a g e 1 6 1 
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Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
A nti dia betics  
Gl y b uri de, s a x a gli pti n, t ol b uta mi de, nate gli ni de, 
pi o glitaz o ne, re pa gli ni de, r osi glitaz o ne  
Cl ass/ T her a pe utic  
Are a  
Mil d/ M o der ate C Y P 3 A a n d C Y P 2 C 8  
A ntif u n gals  
Cas p of u n gi n, fl u c o naz ole, ter bi nafi n e  
A nti hista mi nes  
Aste miz ole, c hl or p he nira mi ne, e basti ne  
A nti h y perte nsi ves  
A ml o di pi ne, diltiaze m, fel o di pi ne, nife di pi ne, 
nil va di pi ne, nis ol di pi ne, vera pa mil  
A nti mi grai ne A ge nts  
Dier g ota mi ne, eletri pta n, er g ota mi ne  
C ortic oster oi ds  
De x amet has o ne, met h yl pre d nis ol o ne, oral b u des o ni de 
Erectile D y sf u n cti o n 
A ge nts  
Sil de nafil, ta dalafil, var de nafil  
H M G -C o A Re d uctase 
I n hi bit ors 
At or vastati n, l o vastati n, si m vastati n, r os u vastati n, 
pra vastati n  
H y p n otics a n d Se d ati ves  Al praz ola m, br otiz ola m, diaze pa m, estaz ola m, 
mi daz ola m, triaz ola m, z ol pi de m, z o picl o ne  
I m m u n os u p pr essa nts 
E ver oli m us, sir oli m us, tacr oli m us  
Miscella ne o us  
A pre pita nt, cisa pri d e, darife naci n,  di g o xi n,  dis o p y ra mi de, 
lefl u n o mi de, met h o he xital, oral c o ntrace pti ves, q ui ni ne, 
ra niti di ne, s olife naci n, s ulfasalazi ne, tra ma d ol, t ol va pta n, 
c hl or o q ui ne, z o picl o ne  
Selecti ve Al d oster o ne 
Bl oc kers  
E plere n o ne  
U S E WI T H C A U TI O N: C o -a d mi nistr ati o n of dr u gs t h at i ncre ase g astric p H 
s h o ul d be use d wit h c a uti o n w he n a d mi nistere d wit h d a br afe ni b as e x p os ure t o 
d a br afe ni b m a y be decre ase d  
p H alteri n g a ge nts  
de xla ns o praz ole. es o me praz ole, fa m oti di ne, ila praz ole, 
la ns o praz ole, o me praz ole, pa nt o praz ole, ra b e praz ole, 
ra niti di ne 
A b bre viati o ns: C Y P = c yt oc hr o me P 4 5 0; H M G- C o A = 3- h y dr o x y- 3 - m et h yl gl ut ar yl-
c oe nz yme  A.  
Q uesti o ns re gar di n g c o nc o mita nt me dicati o ns s h o ul d be directe d t o t he G S K Me dical 
M o nit or f or clarifi cati o n. 
Re as o n f or c h a n ge:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 

N o v arti s 
 
C o nfi d e nti al 
  
  
 
                      P a g e 1 7 3 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
  
  
 
        Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
T a bl e 1 9  
Ti m e a n d E v e nt s T a bl e  
Previ o us:  
St u d y Assess me nts 1  
S creen -2  
 
W eek  1 -2  
W eek  4  
W eek  8  
W eek  1 2  
W eek  1 6  
W eek  2 0  
W eek  2 4  
W eek  2 8  
 
W eek  3 2  
 
W eek  3 6  
a n d  th en  
M o n th l y 
U n til 
U n sch  
Disc  
F w p 1 9  
C o n c 
In f or me d c o nse nt 
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T u m o ur tiss ue sa m ple f or  B R A F V 6 0 0 m utati o n 3  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ntr acra nial tar get a n d n o n – tar get lesi o n assess me nt a n d 
res p o nse 2 1  
 
X   
 
X  
 
X   
 
X   
 
X   
 
X   
 
X  
 
 
X   
 
E xtracra nial tar get a n d n o n -tar get lesi o n assess me nt a n d 
res p o nse 2 2  
 
X   
 
X  
 
X   
 
X   
 
X   
 
X   
 
X  
 
 
X   
 
In cl usi o n / e x cl usi o n criteri a 4  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re gister s u bject  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C he mistr y  a n d Hae m at ol o g y 5  
X  
X  
X  X  X  X  X  X  X  
X  
X  
X  
 
X   
 
Ser u m pre g na n c y  test6  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C oa g ulati o n  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h y sic al e x a mi nati o n 
X   
 
 
 
 
 
 
 
 
 
 
 
X   
 
Hei g h t7  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wei g ht, Te m p, B P, Res p a n d H R
8  
X  
X  
X  X  X  X  X  X  X  
X  
X  
X  
X  
X   
 
De m o gra p hic d ata  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease c h aracteristics 9  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri or a nti -ca ncer t hera p y , ra di ot herap y  a n d s ur gical  
pr oce d ures  
 
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past a n d c urre nt me dical c o n diti o ns, fa mil y  hist or y  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alc o h ol c o ns u m pti o n  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

N o v arti s 
 
C o nfi d e nti al 
  
  
 
                      P a g e 1 7 4 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
  
  
 
        Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
 
St u d y Assess me nts 1  
S creen -2  
 
W eek  1 -2  
W eek  4  
W eek  8  
W eek  1 2  
W eek  1 6  
W eek  2 0  
W eek  2 4  
W eek  2 8  
 
W eek  3 2  
 
W eek  3 6  
a n d  th en  
M o n th l y 
U n til 
U n sch  
Disc  
F w p 1 9  
C o n c 
Past a n d c urre nt t o bacc o c o ns u m pti o n  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C y to ki n e 1 2  
X   
X   
 
 
 
 
 
 
 
 
 
 
 
 
Ne ur ol o gical ass ess me nt 1 3  
X   
X  X   
X   
X   
X   
X  
 
X   
 
O p ht hal mic E xa mi nati o n 1 4  
X   
X   
 
 
 
 
 
 
 
 
 
 
 
 
Der mat ol o gic s ki n assess me nt 1 5  
X   
X    X   X    X   X    X   X     X   X    X    
  X   X   
Dis pe nse oral st u d y treat me nt a n d assess c o m plia nc e 1 6  
 
   X   X    X   X    X   X    X   X     X   X    X    
 
 
 
E C O G Perf or ma n ce stat us  
X  
X  
X  X  X  X  X  X  X  
X  
X  
X  
X  
X   
 
E C G 1 7  
X   
X  X  X   
 
X   
 
X   
 
X   
 
E C H O 1 8  
X   
X   
X   
 
 
 
 
 
 
 
X   
 
C o nc o mita nt me dicati o ns  
X  
X  
X  X  X  X  X  X  X  
X  
X  
X  
X  
X   
 
Bl o o d pr o d ucts a n d bl o o d s u p p orti ve care pr o d ucts  
X  
X  
X  X  X  X  X  X  X  
X  
X  
X  
X  
X   
 
A d verse e ve nts 1 9  
X  
X  
X  X  X  X  X  X  X  
X  
X  
X  
X  
X  
X  
X  
F oll o w -u p c o ntact, a nti -ca ncer t h erap y 2 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X   
S u bject c o m pleti o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Deat h rec or d  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  

N o v arti s 
 
C o nfi d e nti al 
  
  
 
                      P a g e 1 7 5 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
  
  
 
        Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
 
Revise d:  
Ti m e a n d E v e nt s T a bl e  
 
St u d y Assess me nts 1  
S creen -2  
D a y 1  
W eek  4  
W eek  8  
W eek  1 2  
W eek  1 6  
W eek  2 0  
W eek  2 4  
W eek  2 8  
W eek  3 2  
W eek  3 6  
th en  
M o n th l y 
U n sch ed u led  
Dis co n tin u ed  
F o ll ow  u p 9  
C o n clu si o n 
In f or me d c o nse nt 
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T u m o ur tiss ue sa m ple f or B R A F V 6 0 0 m utati o n 3  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ntr acra nial tar get a n d n o n – tar get lesi o n assess me nt a n d 
res p o nse 2 1  
 
X   
 
X  
 
X   
 
X   
 
X   
 
X   
 
X   
 
X   
 
E xtracra nial tar get a n d n o n -tar get lesi o n assess me nt a n d 
res p o nse 2 2  
 
X   
 
X  
 
X   
 
X   
 
X   
 
X   
 
X   
 
X   
 
In cl usi o n / e x cl usi o n criteri a 4  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re gister s u bject  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C he mistr y  a n d Hae m at ol o g y 5  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
X   
 
Ser u m pre g na n c y  test6  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C oa g ulati o n  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h y sic al e x a mi nati o n 
X   
 
 
 
 
 
 
 
 
 
 
 
X   
 
Hei g h t7  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wei g ht, Te m p, B P, Res p a n d H R 8  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
 
De m o gra p hic d ata  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease c h aracteristics 9  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri or a nti -ca ncer t hera p y , ra di ot herap y  a n d s ur gical  
pr oce d ures  
 
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past a n d c urre nt me dical c o n diti o ns, fa mil y  hist or y  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alc o h ol c o ns u m pti o n  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

N o v arti s 
 
C o nfi d e nti al 
  
  
 
                      P a g e 1 7 6 
Cl i ni c al St u d y Pr ot o c ol V er si o n 0 7 
  
  
 
        Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
St u d y Assess me nts 1  
S creen -2  
D a y 1  
W eek  4  
W eek  8  
W eek  1 2  
W eek  1 6  
W eek  2 0  
W eek  2 4  
W eek  2 8  
W eek  3 2  
W eek  3 6  
th en  
M o n th l y 
U n sch ed u led  
Dis co n tin u ed  
F o ll ow  u p 9  
C o n clu si o n 
Past a n d c urre nt t o bacc o  c o ns u m pti o n  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C y t o ki ne 1 2  
X   
X   
 
 
 
 
 
 
 
 
 
 
 
 
Ne ur ol o gical ass ess me nt 1 3  
X   
X  
X   
X   
X   
X   
X   
X   
 
O p ht hal mic E xa mi nati o n 1 4  
X   
X   
 
 
 
 
 
 
 
 
 
 
 
 
Der mat ol o gic s ki n assess me nt 1 5  
X   
X    X   X    X   X    X   X    X   X    X    
  X   X   
Dis pe nse oral st u d y treat me nt a n d assess c o m plia nc e 1 6  
 
  X   X    X   X    X   X    X   X    X   X    X    
 
 
 
E C O G Perf or ma n ce stat us  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
 
E C G 1 7  
X   
X  
X  
X   
 
X   
 
X   
 
X   
 
E C H O 1 8  
X   
X   
X   
 
X   
 
X   
 
X   
 
C o nc o mita nt me dicati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
 
Bl o o d pr o d ucts a n d bl o o d s u p p orti ve care pr o d ucts  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
 
A d verse e ve nts 1 9  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
F oll o w -u p c o ntact, a nti-ca ncer t h erap y 2 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X   
S u bject c o m pleti o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Deat h rec or d  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  

N o v arti s 
C o nfi d e nti al 
P a g e 1 7 7 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Re as o n f or c h a n ge:  
Wee k 1 was u p date d t o Da y 1; F o ot n otes u p dates; S u bjects w h o ha ve u n der g o n e l ocal 
B R A F testi n g a n d w h o are B R A F V 6 0 0 E or V 6 0 0 K m utati o n p ositi ve- V 6 0 0 K was 
re m o ve d as t his was a t y p o gra p hical err or; clarifi cati o n t hat patie nts m ust wait f or B R A F 
m utati o n stat us c o nfir mati o n fr o m ce ntral testi n g b ef ore first d ose f or c o h ort A; 
O p ht hal m ol o g y E x a m: A n o p ht hal mic e x a mi nati o n was u p date d fr o m will be perf or me d 
at Scree ni n g t o pri or t o first d ose; First d ose of st u d y me dicati o n m ust be wit hi n 7 2 h o urs 
of ra n d o mizati o n was del ete d; F oll o w- u p c o ntact: All s u bjects w h o per ma n e ntl y 
disc o nti n ue st u d y treat me nt will be f oll o we d f or s ur vi val, der mat ol o gic s ki n assess me nts 
a n d ne w a nti- ca ncer t hera pies (i ncl u di n g ra di ot hera p y a n d s ur ger y) e v er y m o nt h f or 6 
m o nt hs after st u d y tr eat m e nt disc o nti n uati o n –  ( or u ntil a ne w ca n cer  treat me nt is 
i nitiate d) was a d de d f or clarificati o n; E C H O e x a ms i n t he ta ble were c orrecte d t o 
scree ni n g, w ee ks 4, 1 2 a n d t he n e ver y 1 2 wee ks i n cl u di n g disc o nti n uati o n visit . 
Ta ble 1 9 F o ot n otes  
Previ o us f o ot n ote # 2:  
Scree ni n g pr oce d ures ma y b e  p erf or m e d 1 4  d a ys pri or t o first d ose of st u d y dr u g, e x ce pt 
f or t u m o ur assess me nts w hic h ma y be perf or me d 2 8 da ys pri or t o first d ose of st u d y dr u g, 
a n d ec h o car di o gra ms a n d E C Gs w hic h ma y be p erf or me d 3 5 da ys pri or t o t he first d ose 
of st u d y dr u g.  S u bjects w h o ha ve u n der g o ne l ocal B R A F t esti n g a n d w h o are B R A F 
V 6 0 0 E or V 6 0 0 K m utati o n p ositi ve, ma y be gi n scree ni n g pr oce d ures b ut sites still nee d 
t o se n d i n tiss ue sa m ple t o t he ce ntral la b orat or y f or ce ntr al testi n g f or c o h ort assi g n me nt. 
Be gi n ni n g wit h W ee k 1 visit, all assess me nt visits ha ve a  7  d a y visit wi n d o w f or 
fle xi ble sc he d uli n g. 
Revise d f o ot n ote # 2:  
Scree ni n g pr oce d ures ma y b e  p erf or m e d 1 4  d a ys pri or t o first d ose of st u d y dr u g, e x ce pt 
f or t u m o ur assess me nts w hic h ma y be perf or me d 2 8 da ys pri or t o first d ose of st u d y dr u g, 
a n d ec h o car di o gra ms a n d E C Gs w hic h  ma y be perf or me d 3 5 da ys pri or t o t he first d ose 
of st u d y dr u g.  S u bjects w h o ha ve u n der g o ne l ocal B R A F t esti n g a n d w h o are B R A F 
V 6 0 0 E or V 6 0 0 K m utati o n p ositi ve, ma y be gi n scree ni n g pr oce d ures h o we ver, m ust 
wait f or B R A F m utati o n stat us c o nfir mati o n fr o m ce ntral testi n g bef ore first d ose f or 
c o h ort A.  F or C o h orts B, C, a n d D sites still nee d t o se n d i n tiss ue sa m ple t o t he ce ntral 
la b orat or y f or retr os p ecti ve testi n g. Be gi n ni n g wit h Da y 1 visit, all visits ha ve a  3  da y 
visit wi n d o w a n d sca ns will ha ve  7  da ys f or fle xi ble sc he d uli n g. 
Re as o n f or C h a n ge:  
T y p o gra p hical err ors 
Ta ble 1 9 F o ot n ote 
Previ o us f o ot n ote # 1 4:  
O p ht hal m ol o g y E x a m: A n o p ht hal mic e x a mi nati o n will be perf or me d at Scree ni n g a n d 
wee k 4; aft er wee k 4, a d diti o nal o p ht hal mic e x a mi nati o ns will be perf or me d o nl y as 
s y m pt o maticall y warra nt e d.  Refer t o Secti o n 7. 4. 5 f or details. 
Revise d f o ot n ote # 1 4:  
2 5. O p ht hal m ol o g y E x a m: A n o p ht hal mic e x a mi nati o n will be perf or me d pri or t o first 
d ose a n d wee k 4; after wee k 4, a d diti o nal o p ht hal mic e x a mi nati o ns will be perf or me d 
o nl y as s y m pt o maticall y warra nte d.  Refer t o Secti o n 7. 4. 5 f or details 
 

N o v arti s 
C o nfi d e nti al 
P a g e 1 7 8 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Re as o n f or C h a n ge:  
U p date d ti mi n g of e x a m fr o m pref or me d at scree ni n g t o pri or t o f orst d ose t o all o w m ore 
fle xi ble sc he d uli n g. 
Ta ble 1 9 F o ot n ote 
Previ o us f o ot n ote # 1 6:  
Dis pe nsati o n of St u d y Treat me nt: Dis pe nse a 4- 6  wee k s u p pl y of  t he st u d y me dicati o n 
wit h i nstr ucti o ns.  Rec or d d ose re d ucti o ns, d ose i nterr u pti o ns/ dela ys a n d/ or d ose 
escalati o ns. First d ose of st u d y me dicati o n m ust be wit hi n 7 2 h o urs of ra n d o mizati o n . 
Revise d f o ot n ote # 1 6:  
Dis pe nsati o n of St u d y Treat me nt: Dis pe nse a 4- 6  wee k s u p pl y of  t he st u d y me dicati o n 
wit h i nstr ucti o ns.  Rec or d d ose re d ucti o ns, d ose i nterr u pti o ns/ dela ys a n d/ or d ose 
escalati o ns. First d ose of st u d y me dicati o n m ust be wit hi n 7 2 h o urs of ra n d o mizati o n. 
Re as o n f or C h a n ge:  
T his restricti o n is n o l o n ger re q uir e d. 
Ta ble 1 9 F o ot n ote 
Previ o us f o ot n ote # 2 0:  
F oll o w- u p c o ntact: All s u bjects w h o per ma n e ntl y disc o nti n ue st u d y treat me nt will be 
f oll o we d f or s ur vi v al, der mat ol o gic s ki n assess me nts a n d ne w a nti-ca n cer t hera pies 
(i ncl u di n g ra di ot hera p y a n d s ur ger y) e v er y m o nt h f or 6 m o nt hs after st u d y treat me nt 
disc o nti n uati o n. 
Revise d f o ot n ote # 1 6:  
F oll o w- u p c o ntact: All s u bjects w h o per ma n e ntl y disc o nti n ue st u d y treat me nt will be 
f oll o we d f or s ur vi v al, der mat ol o gic s ki n assess me nts a n d ne w a nti-ca n cer t hera pies 
(i ncl u di n g ra di ot hera p y a n d s ur ger y) e v er y m o nt h f or 6 m o nt hs after st u d y treat me nt 
disc o nti n uati o n or u ntil a ne w ca n cer  treat me nt is i nitiate d 
Re as o n f or C h a n ge:  
Clarificati o n of f oll o w u p u ntil disc o nti n uati o n or ne w ca n cer treat me nt i nitiate d 
7. 2. 1. 1.  
S e c o n d ar y E n d p oi nt s  
Previ o us:  
o verall s ur vi val ( O S) 
Revise d:  
o verall s ur vi val ( O S) a n d l o n g-ter m ( p artic ularl y 5- ye ar) O S 
Re as o n f or c h a n ge:  
A d diti o n of l o n g ter m o v erall s ur vi val. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 7 9 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
7. 4. 2. 2  
D efi niti o n of a S A E  
Previ o us:  
 
La b orat or y a b n or malities as refere n ce d i n Secti o n 7. 4. 2. 3. 
 
L V E F t hat me ets st o p pi n g criteria Secti o n 5. 8. 3. 1. 
 
C S R or R V O 
 
P yre xia acc o m pa nie d b y h y p ote nsi o n, or de h y drati o n re q uiri n g I V fl ui ds, or se vere 
ri g ors/c hills 
Revise d:  
 
S y m pt o matic L V E F decrease t hat meets st o p pi n g criteria or as y m pt o matic L V E F 
decrease t hat d o es n ot rec o ver, as o utli ne d as L V E F g ui da nce ( Secti o n 5. 8. 3. 1) 
    La b orat or y a b n or malities as refere n ce d i n Secti o n 7. 4. 2. 3. 
 
L V E F t hat me ets st o p pi n g criteria Secti o n 5. 8. 3. 1. 
    C S R or R V O 
    P yre xia acc o m pa nie d b y h y p ote nsi o n, or de h y drati o n re q uiri n g I V fl ui ds, or se vere 
ri g ors/c hills 
Re as o n f or c h a n ge:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
7. 4. 4. 1.  
Pr e g n a n c y T e sti n g a n d Pr e v e nti o n  
A d diti o n:  
N ote: Fre nc h/ Ger ma n s u bjects: n o c o ntrace pti o n f or me n is re q uire d 
Re as o n f or c h a n ge:  
Ali g n me nt wit h E ur o pea n la bel 
Cli nic al C he mistr y P a r a met ers  
Al b u mi n 
Al kali ne P h os p hatase 
Ala ni ne Tra ns a mi nase ( A L T) or Ser u m Gl uta mic P yr u vic Tra nsa mi nase ( S G P T) 
As partate A mi n otra nsferase ( A S T) or Ser u m Gl uta mic O xal oacetic Tra nsa mi nase 
( S G O T) 
Ga m ma- Gl uta m yl Tr a ns pe pti dase ( G G T) 
Bicar b o nate 
Bl o o d Urea Nitr o ge n ( B U N) or urea 
Calci u m C hl ori de 
Creati ni ne c 
Gl uc ose (ra n d o m) 
Lactate D e h y dr o ge n ase ( L D H) 
Ma g n esi u m 
P h os p hate 
P otassi u m 
S o di u m  
T otal Bilir u bi n b  
T otal Pr otei n  
 
 

N o v arti s 
C o nfi d e nti al 
P a g e 1 8 0 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Revise d: 
 
Cli nic al C he mistr y P a r a meters  
Al b u mi n 
Al kali ne P h os p hatase 
Ala ni ne Tra ns a mi nase ( A L T) or Ser u m Gl uta mic P yr u vic Tra nsa mi nase 
( S G P T) 
As partate A mi n otra nsferase ( A S T) or Ser u m Gl uta mic O xal oacetic 
Tra nsa mi nase ( S G O T)  
 
Ga m ma- Gl uta m yl Tr a ns pe pti dase ( G G T) 
Bl o o d Urea Nitr o ge n ( B U N) or urea 
Calci u m 
Creati ni ne c 
Gl uc ose (ra n d o m) 
Lactate D e h y dr o ge na se ( L D H) 
Ma g n esi u m 
P h os p hate 
P otassi u m 
S o di u m 
T otal Bilir u bi n b  
T otal Pr otei n  
 
Re as o n f or c h a n ge:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
S u bjects are re q uir e d t o ha ve a sta n d ar d o p ht hal mi c e x a mi nati o n perf or me d b y a n 
o p ht hal m ol o gist at baseli ne, at wee k 4 a n d as cli nicall y warra nte d per pr ot o c ol’s 
g ui da n ce. 
Revise d:  
S u bjects are re q uire d t o h a ve a sta n d ar d o p ht hal mi c e x a mi nati o n perf or me d b y a n 
o p ht hal m ol o gist at pri or t o first d ose, at wee k 4 a n d as cli nicall y warra nte d per pr ot oc ol’s 
g ui da n ce. 
Re as o n f or c h a n ge:  
U p date d t o ali g n wit h t he u p date d asset sta n dar d la n g ua ge f or t h e da brafe ni b a n d 
tra meti ni b c o m bi nati o n. 
9. 3. 3. Tr e at m e nt C o m p ari s o n s  
Previ o us:  
T here are n o tr eat me nt c o m paris o ns. T he pri mar y o bjecti ve will be s u p p ort e d b y testi n g 
t he n ull.).  T he t hree c o h orts will n ot be c o m pare d statisticall y f or a n y e n d p oi nt. 
Revise d:  
T here are n o tr eat me nt c o m paris o ns. T he pri mar y o bjecti ve will be s u p p ort e d  b y testi n g 
t he n ull h y p ot hesis i n C o h ort A T he t hree c o h orts will n ot be c o m pare d statisticall y f or 
a n y e n d p oi nt. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 8 1 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Re as o n f or c h a n ge:  
Clarificati o n of c o h ort A 
A d diti o n of A p pe n di x 9 f or Fre nc h a n d Ger m a n c o u ntr y s pecific re q uire me nts 
1 2. 9  
A pp e n d i x 9: C o u ntr y S p e cifi c R e q uir e m e nt s 
 
 
 
1 2. 9  
E x cl u si o n Crit eri a 
 
S u bjects wit h hist or y of HI V are e x cl u de d fr o m t his t he st u d y. ( Secti o n 4. 1. 3) 
 
S u bjects u n der g uar dia ns hi p / u n der s u per visi o n (a n ot her pers o n is res p o nsi ble, 
deci de f or t he patie nt) or de pri ve d of li bert y (i n pris o n f or e x a m ple) will be e x cl u de d 
fr o m t his st u d y. 
 
S u bjects t hat prese nt wit h electr ol yt e a b n or maliti es are e x cl u de d fr o m t his st u d y. 
 
S u bjects ta ki n g me dicati o ns k n o w n t o i n d uce Q T pr ol o n gati o n are e x cl u de d fr o m t his 
st u d y. 
1 2. 9.  V al v ul ar t o xi cit y cit eri a 
G ui deli nes f or V al v ul ar T o xicit y f or S u bjects E nr olle d i n Fr a nce  
 
S u bjects w h o ha ve a n as y m pt o matic, m o derate re g ur gitati o n or ste n osis b y  
E C H O ( Gra d e 2 mitral/tric us pi d/a ortic val v ular t o xicit y per C T C A E v 4. 0) 
s h o ul d te m p oraril y disc o nti n ue da brafe ni b a n d ha ve a re p eat e val uati o n b y 
E C H O wit hi n 1 wee k.  E C H O s h o ul d be re peate d e ver y 1 - 2 wee ks f or 4 wee ks 
or u ntil val ve rec o v er y t o baseli ne. 
o  If t he val ve rec o v ers t o baseli ne a n y ti me d uri n g t he ne xt 4 wee ks, after 
c o ns ultati o n a n d a p pr o val of t he G S K me dical m o nit or, t he s u bject ma y b e 
restarte d o n d a brafe ni b at a re d uce d d ose(s). F or s uc h s u bjects, 
m o nit ori n g of t he val ve via E C H O will t he n be perf or me d 2 a n d 4 wee ks 
after rec halle n ge, a n d e v er y 4 wee ks t h ereafter f or 1 2 wee ks a n d t he n p er 
pr ot oc ol.  
o  If re p eat E C H O d oes n ot re veal val v e rec o ver y t o baseli ne wit hi n 4 wee ks, 
t he n t he s u bject s h o ul d per ma ne ntl y disc o nti n ue d a brafe ni b. T he val ve 
s h o ul d c o nti n ue t o be m o nit ore d via E C H O e ver y 4 wee ks f or 1 6 wee ks or 
u ntil res ol uti o n. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 8 2 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
T a bl e  2 9 
Wit h h ol di n g  a n d  St o p pi n g Crit eri a f or Q T c B - Pr ol o n g ati o n 
Previ o us:  
Q T c -
Pr ol o n g ati o n a 
A cti o n a n d D o s e M o difi c ati o n  
 
Q Tc B  ≥5 0 1 
ms ec  
4)  I nt err u pt all st u dy tr e at me nts until Q Tc B pr ol o n g ati o n r es olv es t o gr a de 1 
or b as eli n e  
5)  T e st  s er u m p ot assi u m, c alci u m, p h os p h or us a n d m a g nesi u m. If a b nor m al 
c orr ect p er r o uti n e cli nic al pr actic e t o wit hi n n or m al li mits. 
6)  R evi e w c o nc o mit a nt m e dic ation  us ag e f or a g e nts  t h at pr ol o ng Q Tc. 
7)  If ev e nt res olv es, r estart st udy tr e at m e nt at curr e nt d os e lev elb 
8)  If ev e nt d o es n ot r es olv e, p er m a n e ntly disco nti n ue st udy tr eat m e nts. 
9)  C o nsi d er ev alu ati on wit h car diol o gist.  
1 0)  If ev ent r ecurs, p er man e ntly disc o nti nu e st u dy tr e at me nts. 
C o ns i d er eval u ati o n with c ar di ol o gist. 
 
 
Q Tc B  ≥5 0 1 
ms ec 
1 1)  I nt err u pt all st u d y tre at m e nt s u ntil  Q T c B pr ol o n gati o n re s ol v e s t o 
gr a d e 1 or b a s eli n e  
1 2)  T e st  s er u m p ot as si u m, cal ci u m, p h o s p h or u s a n d m a g n esi u m. If 
a b n or m al c orr e ct p er r o uti ne cli ni c al pr acti c e t o wit hi n n or m al li mit s.  
1 3)  R e vi e w  c o n c o mit a nt m e di cati o n  u s a g e f or a g e nt s t hat pr ol o n g Q T c.  
1 4)  If e v e nt r e s olv e s, r e st art st u d y tr e at m e nt at l o w er d o s e le v el or 
c urr e nt. d o s e l e v e lb  
1 5)  If e v e nt d o e s n ot r e s ol v e, p er m a n e ntl y di s c o nti n u e st u dy tr e at m e nt s. 
C o n si d er e v al u ati o n wit h car di ol o gi st.  
1 6)  If e v e nt re c ur s, p er m a ne ntl y di s c o nti n u e st u d y tr eat m e nt s. 
C o n si d er e v al u ati o n wit h c ar di ol o gi st.  
 
Revise d:  
Re as o n f or c h a n ge: T o be i n li ne wit h l a bel  
T a bl e  3 0 
M a n a g e m e nt a n d  D o s e M o difi c ati o n G ui d eli n e s f or 
P n e u m o niti s  
Re m o val of f o ot n otes as t he y di d n ot pert ai n t o t he p ne u m o nitis g ui deli nes 

N o v arti s 
C o nfi d e nti al 
P a g e 1 8 3 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
A p p e n di x 6: Li v er C h e mi str y M o nit ori n g, I nt err u pti o n St o p pi n g a n d  
F oll o w- u p  Crit eri a  
 
Previ o us : 
 
Revise d:  
P h a s e II Li v er S af et y Al g orit h m s  
 
 
A L T > 3 x U L N 
C o nti n u e I P 
O bt ai n t wi c e m o nt hl y li v er 
c h e mi stri e s u ntil n or m ali s e d 
or  b a c k t o b a s eli n e v al u e s 
 
N o A L T > 3 x U L N or  bilr u bi n > 2 x U L N ? 
Y e s 
 
 
Y e s 
 
pl u s Bilir u bi n > 2 x U L N 
N otif y G S K wit hi n 2 4 h t o 
di s c u s s s u bj e ct s af et y 
C o nti n u e I P 
C h e c k li v er c h e mi str y 
w e e kl y f or 4 w e e k s 
Y e s  
( > 3 5 % dir e ct) (or  pl u s 
N o  
I N R > 1. 5, if m e a s ur e d)* 
 
Y e s 
 
A L T > 5 x U L N N o  
 
Y e s 
H e p atiti s 
s y m pt o m s 
or  r a s h ? 
N o  
 
 
Y e s 
A bl e t o m o nit or 
w e e kl y f or 4  
w k s ?  
N o**  
Y e s 
•I n str u ct s u bj e ct t o st o p i n v e sti g ati o n al pr o d u ct (I P) 
• N otif y G S K + arr a n g e cli ni c al f oll o w u p wit hi n 2 4 h  
• P erf or m li v er c h e mi stri e s a n d li v er e v e nt f oll o w u p  
a s s e s s m e nt s ( s er ol o g y, P K  s a m pl e et c a s  i n pr ot o c ol) 
• R e p ort a s  a n  S A E  ( e x cl. h e p ati c i m p air m e nt or  cirr h o si s 
st u di e s) + a n d c o m pl et e li v er e v e nt C R F, S A E  d at a 
c oll e cti o n t o ol, + li v er i m a gi n g +/ or bi o p s y C R F s if t e st s 
p erf or m e d. 
• O bt ai n t wi c e w e e kl y li v er c h e mi stri e s u ntil r e s ol v e d, 
st a bili s e d or  r et ur n e d t o b a s eli n e v al u e s 
• C o n s ult ati o n wit h h e p at ol o gi st/ s p e ci ali st r e c o m m e n d e d 
•Wit h dr a w s u bj e ct fr o m st u d y aft er li v er c h e mi str y 
m o nit ori n g c o m pl et e + d o  n ot r e- c h all e n g e wit h I P 
 
•I n str u ct s u bj e ct t o st o p i n v e sti g ati o n al pr o d u ct (I P) 
• N otif y G S K + arr a n g e cli ni c al f oll o w u p wit hi n 2 4-7 2 h  
• P erf or m li v er c h e mi stri e s a n d li v er e v e nt f oll o w u p  
a s s e s s m e nt s ( s er ol o g y, P K  s a m pl e et c a s  i n pr ot o c ol) 
• C o m pl et e li v er e v e nt C R F, S A E  d at a c oll e cti o n t o ol if 
a p pr o pri at e, + li v er i m a gi n g +/ or bi o p s y C R F s if t h e s e 
t e st s p erf or m e d. 
• O bt ai n w e e kl y li v er c h e mi stri e s [** a s f ar a s  p o s si bl e] 
u ntil r e s ol v e d, st a bili s e d or  r et ur n e d t o b a s eli n e 
•Wit h dr a w s u bj e ct fr o m st u d y aft er li v er c h e mi str y 
m o nit ori n g c o m pl et e + d o  n ot r e- c h all e n g e wit h I P 
*I N R v al u e n ot a p pli c a bl e t o p ati e nt s o n  a nti c o a g ul a nt s 

N o v arti s 
C o nfi d e nti al 
P a g e 1 8 4 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Re as o n f or c h a n ge:  
A p pe n di x 6 –  re m o val of P hase III t o I V al g orit h m a n d place me nt of p h as e II al g orit h m. 
 
S u bjects wit h a Gra de 3 or 4 (s y m pt o matic, se vere re g ur gitati o n/ste n osis b y 
i ma gi n g, wit h s y m pt o ms c o ntr olle d b y m e dical i nter ve nti o n) val v ular t o xicit y 
m ust disc o nti n ue da brafe ni b.  Val v ular t o xicit y s h o ul d c o nti n ue t o be m o nit ore d 
e v er y 4 wee ks f or 1 6 w ee ks or u ntil res ol uti o n.  If rec o ver y occ urs (ret ur n t o 
baseli ne via i ma gi n g A N D s y m pt o m r es ol uti o n) wit hi n 4 wee ks, t he s u bject ma y 
restart da brafe ni b at a re d uce d d ose aft er c o ns ultati o n a n d a p pr o val of t he G S K 
me dical m o nit or. F or s uc h s u bjects, m o nit ori n g of t he val ve via E C H O will t he n 
be perf or me d 2 a n d 4 wee ks after rec halle n ge, a n d e ver y 4 wee ks t hereaft er f or 
1 2 wee ks a n d t h e n per pr ot oc ol. 
E C H O m ust be perf or me d at baseli ne a n d at f oll o w- u p visit(s).  C o pies of all E C H O(s) 
a n d car di ol o g y c o ns ultati o ns perf or me d o n s u bjects w h o e x perie nce a val v ular t o xicit y 
will be re q uire d b y G S K f or re vie w. 
1 2. 9  N o n - c ut a n e o u s s e c o n d ar y/r e c urr e nt m ali g n a n c y 
Pri or t o i nitiati o n of st u d y treat me nt s u bjects s h o ul d u n der g o a hea d a n d nec k 
e x a mi nati o n wit h mi ni mall y vis ual i ns pecti o n of oral m uc osa a n d l y m p h n o de pal pati o n, 
as well as c hest/a b d o me n C o m p ute d T o m o gra p h y ( C T) sca n. D uri n g treat m e nt s u bjects 
s h o ul d be m o nit ore d as cli nicall y a p pr o priate w hi c h ma y i n cl u de a h ea d a n d nec k 
e x a mi nati o n e ver y 3 m o nt hs a n d a c hest/a b d o me n C T sca n e v er y 6 m o nt hs. A nal 
e x a mi nati o ns a n d pel vic e x a mi nati o ns are rec o m me n de d bef ore t he start of a n d at t he e n d 
of treat me nt or w h e n c o nsi dere d cli nicall y i n dicat e d. C o m plete bl o o d cell c o u nts s h o ul d 
be perf or me d as cli nicall y i n dicat e d. F oll o wi n g disc o nti n u ati o n of da brafe ni b m o nit ori n g 
f or n o n-c uta ne o us sec o n dar y/rec urre nt mali g n a ncies s h o ul d c o nti n ue f or u p t o 6 m o nt hs 
or  u ntil i nitiati o n of a n ot her a nti- ne o plastic t hera p y, w hic h e ver c o mes first. A n y n o n- 
c uta ne o us se c o n dar y/r ec urre nt mali g na nc y s h o ul d be re p orte d as a pr ot oc ol-s pecific S A E 
a n d treate d acc or di n g t o sta n dar d cli nical pr actice. Reas o n f or c h a n ge: 
C o u ntr y-s pecifi c u p dates as re q ueste d b y t h e Fre n c h re g ulat or y a ge n c y. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 8 5 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
1 2. 1 1.   
A p p e n di x 1 1 : Pr ot o c ol C h a n g e s f or A m e n d m e nt 0 2  
A me n d me nt N u m ber 0 2 
T his a me n d me nt is a p plica ble t o all i n vesti gati o nal st u d y sites i n  Fr a nce o nl y. 
A d mi nistrati ve c ha n ges i ncl u di n g u p dat e d S p o ns or C o ntact i nf or mati o n. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 8 6 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Previ o us:  
T a bl e 1 6  
M a n a g e m e nt a n d D o s e M o difi c ati o n G ui d eli n e s f or P n e u m o niti s  
C T C A E 
Gr a d e  
A d v er s e E v e nt M a na g e m e nt  
A cti o n a n d D o s e M o difi c ati o n  
Gr a d e 1  
• 
C T s c a n ( hi g h - r e s ol uti o n wit h l u n g 
wi n d o w s) r e c o m m e n de d . 
• 
Cli ni c al e v al uati o n a n d  la b orat ory 
w or k - u p f or i nf e cti o n . 
• 
M o nit ori n g of o x y ge n ati o n vi a 
p ul s e -o xi m etr y r ec o m m e n de d . 
• 
C o n s ult ati o n  of p ul m o n ol o gist 
r e c o m m e n d e d 
 
• 
C o nti n u e  tr a m eti ni b at 
c urr e nt d o s e  
Gr a d e 2  
• 
C T s c a n ( hi g h - r e s ol uti o n wit h l u n g 
wi n d o w s)  
• 
Cli ni c al e v al uati o n a n d la b orat ory 
w or k -u p f or i nf e cti o n  
• 
C o n s ult p ul m o n ol o gi st  
• 
P ul m o n ar y f u n cti o n t est s – if < 
n or m al, r e p e at e ver y 8 we e ks u ntil 
≥ n or m al  
• 
Br o n c h o s c o p y wit h bi o p s y a n d/ or 
B A L r e c o m m e n d e d . 
• 
S y m pt o m ati c t h era py i n cl u di n g 
c orti c o st er oi d s if cli ni c ally 
i n di c at e d. 
 
• 
I nt err u pt tr a m eti ni b u ntil 
r e c o v er y t o gra d e ≤1  
• 
R e st art  wit h 
tr a m eti ni br e d u ce d b y o n e 
d o s e l e v el  
• 
E s c al ati o n t o pr e vi o u s 
d o s e l e v el aft er 4 we e k s 
a n d c o n s ult ati o n wit h 
m e di c al m o nit or p o s si bl e . 
• 
If n o re c o v er y t o gra d e ≤1 
wit hi n 4 w e e k s, 
p er m a n e ntl y di sc o nti n u e 
tr a m etini b  
 
Gr a d e 3  
• 
C T s c a n ( hi g h - r e s ol uti o n wit h l u n g 
wi n d o w s)  
• 
Cli ni c al e v al uati o n a n d la b orat ory 
w or k - u p f or i nf e cti o n  
• 
C o n s ul p ul m o n ol o gist.  
• 
P ul m o n ar y f u n cti o n t est s -if < 
n or m al, r e p e at e ver y 8 we e ks u ntil 
≥ n or m al.  
• 
Br o n c h o s c o p y wit h bi o p s y a n d/ or 
B A L  if p o s si bl e 
• 
S y m pt o m ati c t h era py i n cl u di n g 
c orti c o st er oi d s a s cli ni c all y 
i n di c at e d 
• 
I nt err u pt tr a m eti ni b u ntil 
r e c o v er y t o gra d e ≤1  
• 
Aft er c o n s ult ati o n wit h 
m e di c al  m o nit or, 
tr a m eti ni b m a y be 
r e st art e d r e d u c e d b y o n e 
d o s e l e v el . 
• 
 
If n o re c o v er y t o 
gr a d e ≤1 wit hi n 4 w e ek s, 
p er m a n e ntl y di sc o nti n u e 
tr a m eti ni b tr e at m e nt 
 
Gr a d e 4  
• 
S a m e a s gr a d e 3 
• 
P er m a n e ntl y di s c o nti n u e 
tr a m eti ni b
 
B A L = br o nci o alv e ol ar l av a g e; C T  = c o m p ut e d t o m o gr a p hy; C T C A E = C o m m o n T er mi n ol o gy Crit eri a f or Adv ers e 
Ev e nts 
A b br evi ati o ns: C T C A E = C o m m o n T er mi n ol o gy Crit eri a f or Adv ers e Ev e nts; E C H O = ec h oc ar di o gr a m; G S K = 
Gl ax o S mit h Kli n e; L L N  = l o w er li mit of  n or m al; L V E F = l eft v e ntric ul ar ej ecti o n fr acti o n; 
a)  If E C H O d o es  n ot  s h o w L V E F r ec ov ery aft er  2 w e eks, r e p e at E C H O 2 w e eks l at er. 
b)  If r ec urr e nt e pis o d es of  L V E F r e d ucti o n occ ur d a br af e ni b m o n ot h er a py, c o ns ult m e dic al m o nit or. 
c) 
Sy m pt o ms m ay i ncl u d e: dys p n e a, ort h o p e n e a, a n d  ot h er  si g ns a n d  sy m pt o ms of  p ul m o n ary c o n g esti o n a n d 
e d e m a.  
d)  
O nc e L V E F r ec ov ers, r est arti n g d a br af e ni b m o n ot h er a py c a n b e  c o nsi d er e d i n c o ns ult ati o n wit h G S K m e dic al 
m o nit or. 
e)  
O nc e L V E F r ec ov ers, i ncl u di n g r es ol uti o n of  sy m pt o ms, r est art of  d a br af e ni b m o n ot h er a py o nly c a n be 
c o nsi d er e d i n c o ns ult ati o n wit h G S K m e dic al m o nit or. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 8 7 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Revise d:  
Re m o val of f o ot n otes. 
T a bl e 1 6  
M a n a g e m e nt a n d D o s e M o difi c ati o n G ui d eli n e s f or P n e u m o niti s  
C T C A E  
Gr a d e  
A d v ers e  E v e n t M a n a g e m e nt  
A cti o n  a n d  D o s e  M o difi c ati o n  
Gr a d e  
1  
• 
C T  s c a n  ( hi g h- re s ol uti o n wit h  
l u n g wi n d o w s ) re c o m m e n d e d. 
• 
Cli ni c al  e v al u ati o n  a n d l a b orat ory  
w or k -u p  f or i nf e cti o n. 
• 
M o nit ori n g  of o x y g e n ati o n  vi a  p ul s e - 
o xi m etr y  r e c o m m e n d e. 
• 
C o n s ult ati o n  of p ul m o n ol o g ist 
re c o m m e n d e d. 
 
• 
C o nti n u e  tra m eti ni b at c urre nt  d o s e  
Gr a d e  
2  
• 
C T  s c a n  ( hi g h- re s ol uti o n wit h  l u n g 
wi n d o w s).  
• 
Cli ni c al  e v al u ati o n  a n d l a b orat ory  w or k -
u p  f or i nf e cti o n 
• 
C o n s ult  p ul m o n ol o gi st  
• 
P ul m o n ar y  f u n cti o n t e sts  – if < n or m al, 
re p e at e v er y  8  w e e k s u nti l ≥ n or m al  
• 
Br o n c h o s c o p y  wit h bi o p s y  a n d/ or  B A L 
re c o m m e n d e d. 
• 
S y m pt o m ati c  t h er a p y i n cl u di n g 
c orti c o st er oi d s  if cli ni c all y i n di c at e d. 
• 
I nt err u pt tra m eti ni b u ntil  re c o ver y t o gra d e 
≤1  
• 
R e st art  wit h  tra m eti ni b b e  re d u c e d b y o n e  
d o s e  l e v el 
• 
Es c al ati o n t o pre vi o u s d o s e l e vel aft er 4 
w e e k s a n d c o n s ult ati o n wit h me di c al 
m o nit or p o s si bl e.  
• 
If n o  re c o v ery t o gra d e  ≤1  wit hi n  4 
w e e k s,  p er m a n e ntl y  di s c o nti n ue 
tra m eti ni b
Gr a d e  
3  
• 
C T  s c a n  ( hi g h- re s ol uti o n wit h  l u n g 
wi n d o w s)  
• 
Cli ni c al  e v al u ati o n  a n d l a b orat ory  w or k -
u p  f or i nf e cti o n 
• 
C o n s ult  p ul m o n ol o gi st  
• 
P ul m o n ar y  f u n cti o n t e sts -if <  n or m al,  
re p e at e v er y 8  w e e k s  u ntil  ≥ n or m al  
• 
Br o n c h o s c o p y  wit h bi o p s y  a n d/ or  B A L  
if p o s si bl e  
• 
S y m pt o m ati c  t h er a p y i n cl u di n g 
c orti c o st er oi d s  a s cli ni c all y  i n di c at e d. 
• 
I nt err u pt tra m eti ni b u ntil  re c o ver y t o gra d e 
≤1  
• 
Aft er  c o n s ult ati o n  wit h  m e di c al  m o nit or, 
tra m eti ni b m a y  b e  re st art e d re d u c e d b y  
o n e  d o s e  l e v el 
• 
If n o  re c o v ery t o gra d e  ≤1  wit hi n  4 w e e k s,  
p er m a n e ntl y  di s c o nti n u e tra m eti ni b  
tre at m e nt 
Gr a d e  
4  
• 
S a m e  a s  gra d e  3  
• 
Per m a n e ntl y  di s c o nti n u e  tra m eti ni b 
 
Re as o n f or c h a n ge:  
Re m o val of f o ot n otes as t he y di d n ot pert ai n t o t he p ne u m o nitis g ui deli nes.  

N o v arti s 
C o nfi d e nti al 
P a g e 1 8 8 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
T a bl e 2 9  
Wit h h ol di n g a n d St o p pi n g Crit eri a f or Q T c B- Pr ol o n g ati o n  
Previ o us:  
 
Q T c -
Pr ol o n g ati o n a 
A cti o n a n d D o s e M o difi c ati o n  
 
Q Tc B  ≥5 0 1 
ms ec  
 
I nt err u pt all stu dy tre at m ents until Q Tc B pr ol o n g ati o n r es olv es t o gr a de 1 
or b as eli n e . 
 
T est s eru m p ot assi u m, c alci u m, p h os p h or us a n d m a g nesi u m. If 
a b n or m al c orr ect p er ro uti ne cli nic al pr actice t o wit hi n n or m al li mits. 
 
R evi e w c o nc o mit a nt m e dic ation  us ag e f or a g e nts t h at pr ol o ng Q Tc.  
 
If ev e nt res olv es, r estart st udy tr e at m e nt at curr e nt d os e lev elb  
 
If ev e nt d o es n ot r es olv e, p er m a n e ntly disco nti n ue st udy tr eat m e nts. 
C o nsi d er ev alu ati on wit h car diol o gist.  
 
If ev ent r ecurs, p er man e ntly disc o nti nu e st u dy tr e at me nts. 
C o nsi d er eval u ati o n with c ar di ol o gist.  
Revise d:  
Q T c -
Pr ol o n g ati o n a 
A cti o n a n d D o s e M o difi c ati o n  
 
Q Tc B  ≥5 0 1 
ms ec  
 
I nt err u pt all stu dy tre at m ents until Q Tc B pr ol o n g ati o n r es olv es t o  gr a de 1  
or  b as eli n e  
 
T est s eru m p ot assi u m, c alci u m, p h os p h or us a n d m a g nesi u m. If  
a b n or m al c orr ect p er ro uti ne cli nic al pr actice t o wit hi n n or m al li mits.  
 
R evi e w c o nc o mit a nt m e dic ation  us ag e f or a g e nts t h at pr ol o ng Q Tc.  
 
If ev e nt res olv es, r estart st udy tr e at m e nt at l o w er d os e l evel or c urr e nt 
d os e lev e lb 
 
If ev e nt d o es n ot r es olv e, p er m a n e ntly disco nti n ue st udy tr eat m e nts. 
C o nsi d er ev alu ati on wit h car diol o gist.  
 If ev ent r ecurs, p er ma ne ntly disc o nti nu e st u dy tr e at me nts. 
C o nsi d er eval u ati o n with c ar di ol o gist.  
Re as o n f or c h a n ge:  
T o be i n li ne wit h la bel. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 8 9 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
A p p e n di x 6:  Li v er C h e mi str y M o nit ori n g, I nt err u pti o n St o p pi n g a n d F oll o w- u p  
Crit eri a  
Previ o us : 
P h a s e III-I V Li v er S af et y Al g orit h m s  
 
 
A L T > 3 x U L N 
Y e s 
 
pl u s 
bilir u bi n > 2 x  
C o nti n u e I P 
O bt ai n t wi c e 
m o nt hl y li v er 
c h e mi stri e s u ntil 
n or m ali s e d or 
b a c k t o b a s eli n e 
v al u e s  
 
Y e s 
 
 
A L T < 3 x U L N  
+ bilir u bi n  
< 2 x U L N 
aft er ≤ 4 
w k s ?  
N o  
 
N otif y G S K wit hi n 2 4 h 
t o di s c u s s s u bj e ct 
s af et y  
C o nti n u e I P 
C h e c k li v er c h e mi str y 
w e e kl y f or 4 w e e k s  
 
N o  
 
 
 
Y e s 
 
 
A bl e t o 
m o nit or 
N o  
w e e kl y f or  
4 w e e k s ? 
Y e s 
U L N ( > 3 5 % 
dir e ct) ( or   N o  
pl u s I N R > 1. 5, 
if m e a s ur e d)* 
 
H e p atiti s 
s y m pt o m s N o  
or  r a s h ? 
 
A L T   N o  
> 8 x U L N 
A L T  
> 5 x U L N  
b ut  
< 8 x U L N  
 
Y e s 
 
A bl e t o 
m o nit or 
w e e kl y f or 
> 2 w k s ?  
 
Y e s 
A L T > 5  
a n d  
< 8 x U L N 
f or > 2 
w k s  
A L T > 3 x U L N  
N o  b ut  < 5 x U L N 
+ bilir u bi n 
< 2 x U L N + n o 
s y m pt o m s 
 
Y e s  
Y e s 
Y e s  
N o ** 
 
Y e s 
N o  
 
•I n str u ct s u bj e ct t o st o p i n v e sti g ati o n al pr o d u ct (I P) 
• N otif y G S K + arr a n g e cli ni c al f oll o w u p wit hi n 2 4 h  
• P erf or m li v er c h e mi stri e s a n d li v er e v e nt f oll o w u p  
a s s e s s m e nt s ( s er ol o g y, P K  s a m pl e et c a s  i n pr ot o c ol) 
• R e p ort a s  S A E  ( e x cl. h e p ati c i m p air m e nt or  cirr h o si s 
st u di e s) + c o m pl et e li v er e v e nt C R F, S A E d at a c oll e cti o n 
t o ol, + li v er i m a gi n g +/ or bi o p s y C R F s if t e st s p erf or m e d. 
• O bt ai n t wi c e w e e kl y li v er c h e mi stri e s u ntil r e s ol v e d, 
st a bili s e d or  r et ur n e d t o b a s eli n e v al u e s 
• C o n s ult ati o n wit h h e p at ol o gi st/ s p e ci ali st r e c o m m e n d e d 
•Wit h dr a w s u bj e ct fr o m st u d y aft er li v er c h e mi str y 
m o nit ori n g c o m pl et e + d o  n ot r e- c h all e n g e wit h I P 
 
•I n str u ct s u bj e ct t o st o p i n v e sti g ati o n al pr o d u ct (I P) 
• N otif y G S K + arr a n g e cli ni c al f oll o w u p wit hi n 2 4-7 2 h  
• P erf or m li v er c h e mi stri e s a n d li v er e v e nt f oll o w u p  
a s s e s s m e nt s ( s er ol o g y, P K  s a m pl e et c a s  i n pr ot o c ol) 
• C o m pl et e li v er e v e nt C R F, S A E  d at a c oll e cti o n t o ol if 
a p pr o pri at e, + li v er i m a gi n g +/ or bi o p s y C R F s if  t e st s 
p erf or m e d. 
• O bt ai n w e e kl y li v er c h e mi stri e s [** a s f ar a s  p o s si bl e] 
u ntil r e s ol v e d, st a bili s e d or  r et ur n e d t o b a s eli n e 
•Wit h dr a w s u bj e ct fr o m st u d y aft er li v er c h e mi str y 
m o nit ori n g c o m pl et e + d o  n ot r e- c h all e n g e wit h I P 
*I N R v al u e n ot a p pli c a bl e t o p ati e nt s o n  a nti c o a g ul a nt s  

N o v arti s 
C o nfi d e nti al 
P a g e 1 9 0 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Revise d:  
P h a s e II Li v er S af et y Al g orit h m s  
 
 
A L T > 3 x U L N 
C o nti n u e I P 
O bt ai n t wi c e m o nt hl y li v er 
c h e mi stri e s u ntil n or m ali s e d 
or  b a c k t o b a s eli n e v al u e s 
 
N o A L T > 3 x U L N or  bilr u bi n > 2 x U L N ? 
Y e s 
 
 
Y e s 
 
pl u s Bilir u bi n > 2 x U L N 
N otif y G S K wit hi n 2 4 h t o 
di s c u s s s u bj e ct s af et y 
C o nti n u e I P 
C h e c k li v er c h e mi str y 
w e e kl y f or 4 w e e k s 
Y e s  
( > 3 5 % dir e ct) (or  pl u s 
N o  
I N R > 1. 5, if m e a s ur e d)* 
 
Y e s 
 
A L T > 5 x U L N N o  
 
Y e s 
H e p atiti s 
s y m pt o m s 
or  r a s h ? 
N o  
 
 
Y e s 
A bl e t o m o nit or 
w e e kl y f or 4  
w k s ?  
N o**  
Y e s 
•I n str u ct s u bj e ct t o st o p i n v e sti g ati o n al pr o d u ct (I P) 
• N otif y G S K + arr a n g e cli ni c al f oll o w u p wit hi n 2 4 h  
• P erf or m li v er c h e mi stri e s a n d li v er e v e nt f oll o w u p  
a s s e s s m e nt s ( s er ol o g y, P K  s a m pl e et c a s  i n pr ot o c ol) 
• R e p ort a s  a n  S A E  ( e x cl. h e p ati c i m p air m e nt or  cirr h o si s 
st u di e s) + a n d c o m pl et e li v er e v e nt C R F, S A E  d at a 
c oll e cti o n t o ol, + li v er i m a gi n g +/ or bi o p s y C R F s if t e st s 
p erf or m e d. 
• O bt ai n t wi c e w e e kl y li v er c h e mi stri e s u ntil r e s ol v e d, 
st a bili s e d or  r et ur n e d t o b a s eli n e v al u e s 
• C o n s ult ati o n wit h h e p at ol o gi st/ s p e ci ali st r e c o m m e n d e d 
•Wit h dr a w s u bj e ct fr o m st u d y aft er li v er c h e mi str y 
m o nit ori n g c o m pl et e + d o  n ot r e- c h all e n g e wit h I P 
 
•I n str u ct s u bj e ct t o st o p i n v e sti g ati o n al pr o d u ct (I P) 
• N otif y G S K + arr a n g e cli ni c al f oll o w u p wit hi n 2 4-7 2 h  
• P erf or m li v er c h e mi stri e s a n d li v er e v e nt f oll o w u p  
a s s e s s m e nt s ( s er ol o g y, P K  s a m pl e et c a s  i n pr ot o c ol) 
• C o m pl et e li v er e v e nt C R F, S A E  d at a c oll e cti o n t o ol if 
a p pr o pri at e, + li v er i m a gi n g +/ or bi o p s y C R F s if t h e s e 
t e st s p erf or m e d. 
• O bt ai n w e e kl y li v er c h e mi stri e s [** a s f ar a s  p o s si bl e] 
u ntil r e s ol v e d, st a bili s e d or  r et ur n e d t o b a s eli n e 
•Wit h dr a w s u bj e ct fr o m st u d y aft er li v er c h e mi str y 
m o nit ori n g c o m pl et e + d o  n ot r e- c h all e n g e wit h I P 
*I N R v al u e n ot a p pli c a bl e t o p ati e nt s o n  a nti c o a g ul a nt s 
  

N o v arti s 
C o nfi d e nti al 
P a g e 1 9 1 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
Re as o n f or c h a n ge:  
A p pe n di x 6 –  re m o val of P hase III t o I V al g orit h m a n d place me nt of p h as e II al g orit h m. 
1 2. 1 2.   
A p p e n di x 1 2 : Pr ot o c ol C h a n g e s f or A m e n d m e nt 0 3  
A me n d me nt N u m ber 0 3 
T his a me n d me nt is a p plica ble t o all i n vesti gati o nal st u d y sites i n all c o u ntries. 
1)  
Re vise d list of a ut h ors 
2)  
Clarificati o n Pr ot oc ol A me n d me nt 2 is a c o u ntr y-s pecific a m e n d me nt as re q ueste d 
b y t he Fre nc h re g ulat or y a ge n c y. 
3)  
Mi n or a d mi nistrati ve c ha n ges a n d c orrecti o n t o t y p o gra p hical err ors t hr o u g h o ut 
t he d oc u me nt. 
4)  
Ta ble of C o nte nts U p dat e d wit h Secti o n 1. 3, A p pe n di x 1 1 a n d 1 2 refere nces. 
5)  
Secti o n 1. 3 hea der a d de d f or clarit y bet w ee n st u d y a n d d os e rati o nal e. 
6)  
 St u d y d esi g n re vise d f or clarit y ar o u n d tr eat me nt disc o nti n uati o n a n d f oll o w u p 
of s u bjects. 
7)  
E x cl usi o n HI V re m o ve d per Marc h 2 0 1 4 u p dates t o I nc/ E x c (c o m bi nati o n). 
8)  
 Per ma ne nt disc o nti n uati o n fr o m st u d y tr eat me nt re vise d f or clarit y ar o u n d 
treat me nt disc o nti n uati o n a n d f oll o w u p of s u bjects. 
9)  
 D osa ge a n d a d mi nistrati o n secti o n re vise d bas e d o n c o m bi nati o n d osa ge 
a n d a d mi nistrati o n Marc h 2 0 1 4. 
1 0) 
Ta ble 3 a d de d f o ot n otes f or c o nsiste nc y acr oss M E K/ B R A F pr ot oc ols. 
1 1) 
D ose Le vel Re d u cti o n G ui deli nes re vise d f or c o nsiste nc y acr oss M E K/ B R A F 
  
pr ot oc ols. 
1 2) 
Ta ble 6 s u pers cri pt b a n d c a d de d t o s y m pt o matic L V E F f or c o nsiste nc y acr oss 
  
M E K/ B R A F pr ot oc ols. 
1 3) 
Ta ble 7 well c o ntr olle d B P re vise d f or c o nsiste n c y acr oss M E K/ B R A F pr o t oc ols. 
1 4) 
Secti o n 5. 8. 4 a d de d ‘ kerat oaca nt h o ma f or c o nsiste nc y acr oss M E K/ B R A F 
pr ot oc ols. 
1 5) 
Secti o n 5. 8. 4. 3 a d de d ‘ kerat oaca nt h o ma f or c o nsiste nc y acr oss M E K/ B R A F 
  
pr ot oc ols. 
1 6) 
Ta ble 1 1 re vise d d a brafe ni b d ose re d ucti o n f or c o nsiste nc y acr oss M E K/ B R A F 
  
pr ot oc ols. 
1 7) 
Secti o n 5. 8. 5. 4 a d de d refere nce Secti o n 7. 5. 5. 
1 8) 
Ta ble 1 4 a d de d f o ot n ote f or P K refere nce. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 9 2 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
1 9) 
Ta ble 1 6 a d de d f o ot n otes f or c o nsiste nc y acr oss M E K/ B R A F pr ot oc ols. 
2 0) 
Secti o n 6. 1 re vise d f or cl arit y t o ti me re q uire me nts f or c o nc o mita nt me dicati o ns. 
2 1) 
Ta ble 1 7 hea d er re vise d f or clarit y o n pr o hi bite d me dicati o ns. 
2 2) 
Ta ble 1 9 re vise d f or cl arit y o n re q uire d ass ess me nts. 
2 3) 
Secti o n 7. 3. 2. 1 re vise d f or c o nsiste nc y bet w ee n u p date d I ma ge Ac q uisiti o n 
  
G ui deli nes f or Brai n M RI. 
2 4) 
 Secti o n 7. 3. 2. 2 re vise d f or clarit y ar o u n d treat me nt disc o nti n uati o n a n d f oll o w u p 
of s u bjects. 
2 5) 
 Secti o n 7. 5. 3. 1 re vise d seri u m pre g na nc y t est t o 7 da ys pri or t o e nr ol me nt 
i n acc or d a nce wit h Oct 2 0 1 4 safet y g ui da nce. 
2 6) 
 Secti o n 7. 5. 5 re vise d wit h ne w o p ht hal mic criteria fr o m J ul y 2 0 1 4 tra meti ni b 
safet y g ui da nce. 
2 7) 
Secti o n 9. 2. 1 re vise d wit h descri pti o n o n h o w sa m ple siz e of 7 5 was calc ulate d. 
2 8) 
Secti o n 9. 3. 3 Treat me nt c o m paris o n clarifie d as N A f or t his st u d y. 
2 9) 
Ta ble 2 5 re vise d f or cl arit y bet wee n r o w 1 a n d r o w 2 i n a s u peri orit y bi n o mial trial. 
3 0) 
Secti o n 9. 3. 5. 1. 1 Sec o n dar y A nal yses a d de d li ne f or clarificati o n t o i nter pretati o n. 
3 1) 
A p pe n di x 1 1 a d de d t o reflect a me n d me nt 0 2 c h a n ges. 
3 2) 
A p pe n di x 1 2 a d de d t o reflect a me n d me nt 0 3 c h a n ges. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 9 3 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
1 2. 1 3.   
A p p e n di x 1 3 : Pr ot o c ol C h a n g e s f or A m e n d m e nt 0 4  
T his a me n d me nt is a p plica ble t o all i n vesti gati o nal st u d y sites i n all c o u ntries: 
1.  
U p dati n g c o ntact det ails of Me dical M o nit or. 
2.  
Ta ble 1 St u d y O bjecti ves – 1. Pri mar y e n d p oi nt a me n de d t o all o w f or l ocall y 
c o nfir me d B R A F V 6 0 0 E (f oll o we d b y ce ntral c o nfir mati o n as wit h all ot her 
c o h orts) a n d 2 sec o n dar y e n d p oi nt n u m ber 9 O S c ha n ge d fr o m 5 t o 3 year. 
3.  Secti o n 3 St u d y d esi g n – c o h ort A patie nt p o p ulati o n u p date d t o all o w f or l ocall y 
c o nfir me d B R A F V 6 0 0 E (f oll o we d b y ce ntral c o nfir mati o n as wit h all ot her 
c o h orts). A n d defi niti o n of st u d y cl os ure u p d ate d fr o m “ w here all s u bjects still i n 
f oll o w u p ha ve ha d at least 5 years f oll o w u p …” t o “ w here all s u bjects still i n 
f oll o w u p ha ve ha d at least 3 years f oll o w u p …” 
4.  Secti o n 3. 1 Disc ussi o n of Desi g n – pri m ar y efficac y o bjecti ve e n d p oi nt a me n de d 
t o all o w f or l ocall y c o nfir me d B R A F V 6 0 0 E (f oll o we d b y ce ntral c o nfir mati o n as 
wit h all ot her c o h orts) 
5.  Secti o n 4. 1. 2 I n cl usi o n Criteria 4 u p date d t o all o w f or l ocall y c o nfir me d B R A F 
V 6 0 0 E (f oll o we d b y ce ntral c o nfir mati o n as wit h all ot her c o h orts) a n d I ncl usi o n 
criteria 1 0 - peri o d f or c o ntrace pti o n a me n de d fr o m 1 4 da ys pri or t o b aseli ne t o 7 
da ys t o be c o nsiste nt wit h all ot her secti o ns of pr ot oc ol a n d c urre nt I B 7 safet y 
u p date. 
6.  Secti o n 4. 2. 1 refere nce t o 5 year s ur vi val c ha n ge d t o 3. 
7.  Secti o n 4. 2. 2 refere nce t o 5 year s ur vi val c ha n ge d t o 3. 
8.  Secti o n 5. 2, 1 D u plicate d se nte nce d elete d. 
9.  Secti o n 5. 8. 1 A me n de d fr o m d ose re d u cti o ns bel o w 5 0 t o d ose re d ucti o ns bel o w 7 5 
m g BI D. 
1 0.  Ta ble 5 “ or great er occ urre nce” delet e d. 
1 1.  Ta ble 1 9 Ti me a n d E v e nts Ta ble –  f o ot n otes 2 a n d 3 a me n de d t o all o w f or l ocall y 
c o nfir me d B R A F V 6 0 0 E (f oll o we d b y ce ntral c o nfir mati o n as wit h all ot he r 
c o h orts). 
1 2.  Secti o n 7. 2. 1. 1 sec o n dar y e n d p oi nt refere nce t o 5 year s ur vi val c ha n ge d t o 3. 
1 3.  7. 4. 3. 1 Pre g n a nc y T esti n g a n d Pre ve nti o n –  secti o n u p date d peri o d f or 
c o ntrace pti o n a me n de d fr o m 1 4 da ys pri or t o b aseli ne t o 7 da ys t o be c o nsiste nt 
wit h all ot her secti o ns of pr ot oc ol a n d c urre nt I B 7 safet y u p date. 
1 4.  7. 6. 2 B R A F m utati o n ass a y s ecti o n a me n de d t o all o w f or l ocall y c o nfir me d B R A F 
V 6 0 0 E (f oll o we d b y ce ntral c o nfir mati o n as wit h all ot her c o h orts). 
1 5.  Secti o n 9. 3. 5. 1. 1 Pri mar y A nal ysis refere n ce t o 5 year s ur vi val c ha n ge d t o 3. 
1 6.  Secti o n 1 0. 5 St u d y a n d Site Cl os ure refere n ce t o 5 year s ur vi val c ha n ge d t o 3. 
1 7.  A p pe n di x 1 3 a d de d t o reflect a me n d me nt 0 4 c h a n ges. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 9 4 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
1 2 . 14.  
A p p e n di x 1 3 : Pr ot o c ol C h a n g e s f or A m e n d m e nt 0 5  ( d at e d 
1 3 -J ul - 2 0 1 6) fr o m A m e n d m e nt 0 4 ( d at e d 14 D e c 2 0 1 5) 
T his a me n d me nt is a p plica ble t o all i n vesti gati o nal st u d y sites i n all c o u ntries.  
 
A me n d me nt S u m mar y of Mai n C ha n ges: Gl o bal C ha n ges 
 
Secti o n(s)  
C h a n ge  
R ati o n ale  
Hea der/ F o oter  
C ha n ge d as per N o vartis Re q uire me nts  
C ha n ge i n st u d y 
s p o ns ors hi p fr o m G S K t o 
N o vartis  
Title Pa ge  
Title Pa ge re place d as p er N o vartis 
Re q uire me nts  
C ha n ge i n st u d y 
s p o ns ors hi p fr o m G S K t o 
N o vartis  
S p o ns or 
I nf or mati o n Pa ge  
G S K c o ntact i nf or mati o n has bee n 
re place d wit h N o vartis c o ntact details  
C ha n ge i n st u d y 
s p o ns ors hi p fr o m G S K t o 
N o vartis  
S p o ns or 
si g nat or y 
C ha n ge of s p o ns or si g nat or y  
C ha n ge i n st u d y 
s p o ns ors hi p fr o m G S K t o 
N o vartis  
M ulti ple  
T he ter m ‘ G S K me dical m o nit or’ has 
bee n re pl ace d b y N o vartis Gl o bal 
Cli nical  Lea d  
C ha n ge i n st u d y 
s p o ns ors hi p fr o m G S K t o 
N o vartis  
M ulti ple  
Refere n ces t o G S K c o n c o mita nt 
me dicati o ns delete d  
C ha n ge i n st u d y 
s p o ns ors hi p fr o m G S K t o 
N o vartis  
M ulti ple  
Refere n ces t o Gla x o S mit h Kli ne or its 
staff re pl ace d wit h wit h t hat of N o vartis 
a n d its a ut h orize d a ge nts  
T o ali g n wit h t he c h a n ge 
of s p o ns ors hi p fr o m G S K 
t o N o vartis. 
M ulti ple  
Ma ke a d mi nistrati ve c h a n ges  
T o ali g n wit h t he c h a n ge 
of s p o ns ors hi p fr o m G S K 
t o N o vartis. 
 
A m e n d m e nt D et ail s: 
 
S e cti o n:   
Li st of a b br e vi ati o n s:   
Te xt a d de d: 
Cli nical Researc h Or ga ni zati o n ( C R O)  
Gl o bal Cli nical Pr o gra m Hea d ( G C P H) 
Reas o n f or c h a n ge: 
C ha n ge i n st u d y s p o ns ors hi p a n d t o bri n g i nt o li ne wit h N o vartis pr ocesses   

N o v arti s 
C o nfi d e nti al 
P a g e 1 9 5 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
S e cti o n 5. 4 : 
Tr e at m e nt A s si g n m e nt:   
 
Te xt c ha n ge d: 
 
U p o n o btai ni n g c o ns e nt fr o m t he s u bject f or t he st u d y t h e s u bject will be re gistere d 
i nt o t he Re gistrati o n a n d Me dicati o n Or deri n g S yste m ( R A M O S), t he G S K 
i nteracti ve v oic e res p o ns e s yste m (I V R S), b y t he i n vesti gat or or a ut h orize d site staff 
t o re gister a n d rec or d s u bject acti vit y. St u d y-s pecific i nstr ucti o nal w or ks heets will be 
pr o vi de d f or t he us e of R A M O SI V R S. 
O nce t he tar get n u m ber of eac h c o h ort has b ee n e nr olle d, t hat c o h ort will be cl ose d t o 
f urt her e nr ol me nt a n d R A M O SI V R S will n o l o n ger all o w a s u bject t o be e ntere d. 
 
Reas o n f or c h a n ge: 
C ha n ge i n st u d y s p o ns ors hi p a n d t o bri n g i nt o li ne wit h N o vartis pr ocesses   
S e cti o n 7: St u d y A s s e s s m e nt s a n d pr o c e d ur e s: 
 
T a bl e 1 9 Ti m e a n d E v e nt s t a bl e: 
 
Te xt c ha n ge d: 
 
Se nte nce a d d e d t o F o ot n ote 1 9 - Adv ers e ev e nts a n d S eri o us Adv ers e Ev e nts will b e  r ec or d e d f or m t h e 
ti m e of  first d os e of  st u dy tr e at m e nt is a d mi nist er e d u ntil 3 0  d ays aft er disc o nti n u ati o n of  st u dy tr e at m e nt.  All S A Es 
ass ess e d as r el at e d t o st u dy p artici p ati o n ( e. g. r el at e d t o st u dy pr oc e d ur es) s h o ul d b e c oll ect e d fr o m ti m e of 
i nf or m e d c o ns e nt. Pl e as e r ef er t o s ecti o n 7. 4. 2. 6 f or r e p orti n g ti m eli n es. Seri o us a dv ers e ev e nts will  b e c oll ect e d 
ov er t h e s a m e ti m e p eri o d as  A E’s  exc e pt S A Es ass ess e d rel at e d t o st u dy p artici p ati o n ( e. g. pr ot oc ol m a n d at e d 
pr oc e d ur es, i nv asiv e t ests, or  c h a n g e i n existi n g th er a py),  st u dy tr e at m e nt, or  a G S K c o nc o mit a nt m e dic ati o n w hic h 
m ust b e  r ec or d e d fr o m t h e s u bj ects c o ns e nts t o p artici p at e i n t h e st u dy u p  t o a n d  i ncl u di n g a ny f oll o w- u p c o nt act. 
Reas o n f or c h a n ge: 
C ha n ge i n st u d y s p o ns ors hi p a n d t o bri n g i nt o li ne wit h N o vartis pr ocesses   
S e cti o n 7. 4. 2. 5:  
Ti m e P eri o d a n d Fr e q u e n c y f or d et e cti n g A E s a n d 
S A E s: 
Te xt c ha n ge d: 
All S A Es a n d  Aa d vers e e ve nts ( A Es) will be c ollecte d fr o m t he ti me t he first d ose of 
st u d y treat me nt is a d mi nistere d u ntil 3 0 da ys after disc o nti n uati o n of st u d y treat me nt 
re gar dl ess of i nitiati o n of a ne w a nti-ca ncer t hera p y or  tra nsfer t o h os pice. 
Seri o us a d verse e ve nts ( S A Es) will be c ollecte d o ver t he sa me ti me peri o d as state d 
a b o ve f or A Es.  I n a d diti o n, Fr o m t he ti me a s u bject c o nse nts t o partici pate i n a n d 
c o m pletes t he st u d y ( See Secti o n 4. 2), a n y all S A Es assesse d as rel ate d t o st u d y 
partici pati o n (e. g., pr ot o c ol- ma n date d pr oce d ures, i n vasi ve tests, or c ha n ge i n e xisti n g 
t hera py) , st u d y tr eat me nt, or a G S K c o n c o mita nt me dicati o n, m ust be rec or de d fr o m 
t he ti me a s u bject c o nse nts t o partici pate i n t he st u d y u p t o a n d i ncl u di n g a n y f oll o w- u p 

N o v arti s 
C o nfi d e nti al 
P a g e 1 9 6 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
c o ntact.  All S A Es  will be re p ort e d pr o m ptl y t o G S K N o vartis wit hi n 2 4 h o urs, as 
i n dicate d i n Secti o n 7. 4. 2. 6. 
 
Reas o n f or c h a n ge: 
C ha n ge i n st u d y s p o ns ors hi p a n d t o bri n g i nt o li ne wit h N o vartis pr ocesses   
S e cti o n 7. 4. 2. 6:  
Pr o m pt R e p orti n g of S eri o u s A d v er s e E v e nt s a n d 
Ot h er E v e nt s t o G S K N o v arti s  
T a bl e 2 3 Ti m e Fr a m e s f or R e p orti n g S A E s a n d Ot h er E v e nt s  
Te xt c ha n ge d: 
Pr e g n a ncy  
2 w e eks  2 4 
h o urs  
Pr e g n a ncy  n otific ati o n 
f or m 
2  w e eks  
Pr e g n a ncy  f oll o w-
u p f or m  
 
Reas o n f or c h a n ge: 
C ha n ge i n st u d y s p o ns ors hi p a n d t o bri n g i nt o li ne wit h N o vartis pr ocesses   
S e cti o n  7. 4. 3. 2: Pr e g n a n c y R e p orti n g: 
 
Te xt c ha n ge d: 
 
T o e ns ure s u bject safet y, eac h pre g na n c y m ust be re p orte d t o G S K N o vartis wit hi n 2 
wee ks 2 4 h o urs of l ear ni n g of its occ urre nce.   
 
Reas o n f or c h a n ge: 
C ha n ge i n st u d y s p o ns ors hi p a n d t o bri n g i nt o li ne wit h N o vartis pr ocesses   
S e cti o n 8. D at a M a n a g e m e nt: 
Te xt a d de d: 
Data Ma na ge me nt will i de ntif y a n d i m ple me nt t he m ost effecti ve d ata ac q uisiti o n a n d 
ma na ge me nt strat e g y f or eac h cli nical trial pr ot oc ol a n d deli ver datas ets t hat s u p p ort 
t he pr ot oc ol o bjecti ves. 
 
Te xt c ha n ge d: 
Ma na ge me nt of c Cli nical data ma na ge me nt will be perf or me d i n acc or d a nce wit h 
a p plica ble G S K sta n dar ds a n d data clea ni n g pr oce d ures wit h t he o bjecti ve of res ol vi n g 
err ors a n d i nc o nsiste ncies i n t he data w hic h w o ul d ot her wise i m pact o n t h e a nal ysis 
a n d re p orti n g o bje cti ves, or t he cre di bilit y of t he Cli nical St u d y Re p ort. t o e ns ure t he 
i nte grit y of t he d ata, e. g., re m o vi n g err ors a n d i nc o nsiste ncies i n t he data.  All 
A E d verse e ve nts a n d c o n c o mita nt me dicati o ns ter ms will be c o de d usi n g t he Me dical 
Dicti o nar y f or Re g ulat or y A cti vities ( Me d D R A) a n d a n i nter nal vali date d a c ust o m 
me dicati o n dicti o nar y, G S K Dr u g. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 9 7 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
 
I n all cases, s u bject i nitials will n ot be c ollecte d or tra ns mitte d t o G S K i n acc or da nce 
wit h G S K p olic y. 
 
Reas o n f or c h a n ge: 
C ha n ge i n st u d y s p o ns ors hi p a n d t o bri n g i nt o li ne wit h N o vartis pr ocesses   
S e cti o n 1 0. 2  
R e g ul at or y a n d Et hi c al C o n si d er ati o n s, I n cl u di n g t h e 
I nf or m e d C o n s e nt Pr o c e s s:  
Te xt c ha n ge d: 
Pri or t o i nitiati o n of a st u d y site, N o vartis G S K will o btai n fa v o ura ble 
o pi ni o n/a p pr o val fr o m t he a p pr o pri ate re g ul at or y a ge n c y t o c o n d uct t he st u d y i n 
acc or d a nce w ith  I C H G o o d Cli nical Practice ( G C P) a n d a p plica ble c o u ntr y-s pecific 
re g ulat or y re q uire me nts i ncl u di n g t h ose re q uire d u n der a U S I N D. 
T he st u d y will be c o n d ucte d i n acc or d a nce wit h I C H G C P, all a p plica ble s u bject 
pri vac y re q uire me nts, a n d t he et hical g ui di n g pri nci ples t hat are o utli ne d i n of t he 
Declarati o n of Helsi n ki 2 0 0 8, i ncl u di n g, b ut n ot li mite d t o: 
 I nstit uti o nal Re vie w B oar d (I R B)/I n de p e n de nt Et hics C o m mittee (IE C ) re vie w 
a n d fa v o ura ble o pi ni o n/a p pr o val of st u d y pr ot oc ol a n d a n y s u bse q ue nt 
a me n d me nts. 
Reas o n f or c h a n ge: 
C ha n ge i n st u d y s p o ns ors hi p a n d t o bri n g i nt o li ne wit h N o vartis pr ocesses   
S e cti o n 1 0. 3. 
Q u alit y C o ntr ol ( St u d y M o nit ori n g ) 
Te xt c ha n ge d 
I n acc or da n ce wit h a p pli ca ble re g ulati o ns, G C P, a n d N o vartis G S K pr oce d ures, 
N o vartis pers o n nel ( or desi g nate d Cli nical Researc h Or ga nisati o n [ C R O]) will 
c o ntact t he site will be c o ntacte d pri or t o t he start of t he st u d y t o re vie w wit h t he site 
staff t he pr ot oc ol, st u d y re q uire me nts, a n d t heir res p o nsi bilities t o satisf y re g ulat or y, 
et hical, a n d N o v artis G S K  re q uire m e nts.  W he n re vie wi n g data c ollecti o n 
pr oce d ures, t he disc ussi o n will i ncl u de i de ntificati o n, a gree m e nt a n d d oc u me ntati o n 
of data ite ms f or w hi c h t he C R F will ser ve as t he s o urce d oc u m e nt. 
T he i n vesti gat or a n d t he hea d of t he me di cal i nstit uti o n ( w here a p plica ble) a grees t o 
all o w t he m o nit or direct access t o all rele va nt d o c u me nts a n d t o all ocate t h eir ti me 
a n d t he ti me t o t heir staff t o m o nit or t o disc uss fi n di n gs a n d a n y iss ues. 
N o vartis ( or desi g n ate d C R O) pers o n nel will m o nit or t he st u d y t o e ns ure t hat t he:  
M o nit ori n g visits will be c o n d ucte d i n a ma n ner t o e ns ure t hat t he: 
• St u d y is c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot o c ol a n d a n y 
ot her st u d y a gree me nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire m e nts. 

N o v arti s 
C o nfi d e nti al 
P a g e 1 9 8 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
T he i n vesti gat or a n d t he hea d of t he me di cal i nstit uti o n ( w here a p plica ble) a grees t o 
all o w t he m o nit or direct access t o all rele va nt d o c u me nts. 
Reas o n f or c h a n ge: 
C ha n ge i n st u d y s p o ns ors hi p a n d t o bri n g i nt o li ne wit h N o vartis pr ocesses   
S e cti o n 1 0. 5. 
St u d y a n d Sit e Cl o s ur e:   
Te xt c ha n ge d: 
U p o n c o m pleti o n or ter mi nati o n of t he st u d y, t he N o vartis pers o n nel ( or desi g nate d 
C R O) m o nit or will c o n d uct site cl os ure acti vities wit h t he i n vesti gat or or site staff (as 
a p pr o priate), i n acc or da n ce wit h a p plica ble re g ulati o ns, I C H G C P, a n d N o vartis 
G S K Sta n dar d O perati n g Pr oce d ures. 
Reas o n f or c h a n ge: 
C ha n ge i n st u d y s p o ns ors hi p a n d t o bri n g i nt o li ne wit h N o vartis pr ocesses   
 
S e cti o n 1 0. 6.  
R e c or d s R et e nti o n: 
Te xt c ha n ge d: 
G S K will i nf or m t he i n vesti gat or of t he ti me p eri o d f or retai ni n g t he site rec or ds i n 
or der t o c o m pl y wit h all a p plica ble re g ulat or y re q uire me nts.  T he mi ni m u m rete nti o n 
ti me will meet t he strictest sta n dar d a p plica ble t o a partic ular site, as dictat e d b y l ocal 
la ws/re g ulati o ns, G S K sta n dar d o perati n g pr oce d ures, a n d/ or i nstit uti o nal 
re q uire me nts. 
Esse ntial d oc u me nts ( writte n a n d electr o ni c) s h o ul d be retai ne d f or a p eri o d of n ot less 
t ha n fiftee n ( 1 5) years fr o m t he c o m pleti o n of t he Cli nical Trial u nless N o vartis 
pr o vi des writte n per missi o n t o dis p ose of t he m or, re q uires t heir rete nti o n f or a n 
a d diti o nal peri o d of ti me beca use of a p plica ble la ws, re g ulati o ns a n d/ or g ui deli nes. 
 
Reas o n f or c h a n ge: 
C ha n ge i n st u d y s p o ns ors hi p a n d t o bri n g i nt o li ne wit h N o vartis pr ocesses   
S e cti o n 1 0. 7.  
Pr o vi si o n of St u d y R e s ult s t o I n v e sti g at or s, P o sti n g of 
I nf or m ati o n o n P u bli cl y A v ail a bl e Cli ni c al Tri al s R e gi st er s a n d 
P u bli c ati o n:   
 
Te xt c ha n ge d: 
N o v artis G S K ai ms t o p ost a res ults s u m mar y t o t he N o v artis G S K Cli nical St u d y 
Re gister Trial Res ults we bsite w w w. n o vartiscli nicaltrials.c o m a n d ot her p u blicl y 
a vaila ble re gisters n o later t ha n 1 2 8  m o nt hs after t he last s u bject’s last visit ( L S L V) 
[t his a p plies t o eac h data a nal ysis p hase f or st u dies wit h m ulti ple p hases, e. g., pri mar y 

N o v arti s 
C o nfi d e nti al 
P a g e 1 9 9 
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
a nal ysis, f oll o w u p a nal ysis etc]. I n a d diti o n, t he ai m is t o s u b mit a ma n uscri pt t o a 
peer- re vie we d j o ur n al f or p u blicati o n wit hi n 1 8 m o nt hs of L S L V. N o vartis G S K als o 
ai ms t o p u blis h t he f ull st u d y pr ot oc ol o n t he N o v artis G S K Cli nical St u d y 
Re gister Trial Res ults we bsite ( w w w. n o vartiscli nicaltrials.c o m) at t he ti me t he res ults 
of t he st u d y are p u blis he d as a ma n uscri pt i n t he scie ntific literat ur e. 
 
Reas o n f or c h a n ge: 
C ha n ge i n st u d y s p o ns ors hi p a n d t o bri n g i nt o li ne wit h N o vartis pr ocesses   
 
A p p e n di x 1 5 : Pr ot o c ol C h a n g e s f or A m e n d m e nt 0 7 ( a n d 6 o n G S K 
t e m pl at e o nl y) 
 
P a g e 2 2 l ast P ar a gr a p h  
Fr o m: 
St u d y cl os ure is defi ne d b y  w h ere all s u bjects still i n f oll o w u p ha ve ha d at least 3 years 
f oll o w- u p fr o m t he date of first d ose of st u d y treat me nt, w hic he ver is earli er. 
 
T o: 
 
 St u d y cl os ur e is d efi ne d b y  w h ere all c o h ort A s u bjects still i n f oll o w u p ha ve ha d t he 
o p p ort u nit y f or at least 3 years f oll o w- u p fr o m t he date of first d ose of st u d y treat me nt or 
7 0 % of c o h ort A p atie nts ha ve die d or are l ost t o f oll o w u p, w hic he ver is earlier.  
 
Reas o n f or c h a n ge 
 
T h e ext e nsi o n is r e q uir e d d u e t o i m m at urit y of c o h ort A d at a, t h e pri m ary effic acy p o p ul ati o n, 
w hic h is a r es ult of sl o w r ecr uit m e nt i n t his c o h ort.   
 
Pa ge 3 4 l ast para gra p h 
 
Fr o m:  
 
St u d y cl os ur e is defi ne d b y  w h ere all s u bjects still i n f oll o w u p ha ve h a d at least 3 years 
f oll o w- u p fr o m t he date of first d ose of st u d y treat me nt, w hic he ver is earli er. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 9
9  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
2 0 0  
 
 
T o  
 
St u d y cl os ure is defi ne d b y  w h ere all c o h ort A s u bjects still i n f oll o w u p ha ve ha d t he 
o p p ort u nit y f or at least 3 years f oll o w- u p fr o m t he date of first d ose of st u d y treat me nt or 
7 0 % of c o h ort A p atie nts ha ve die d or are l ost t o f oll o w u p, w hic he ver is earlier 
 
Reas o n f or c h a n ge 
 
T h e ext e nsi o n is r e q uir e d d u e t o i m m at urit y of c o h ort A d at a, t h e pri m ary effic acy p o p ul ati o n, 
w hic h is a r es ult of sl o w r ecr uit m e nt i n t his c o h ort.   
 
Pa ge 1 0 8 s ecti o n 1 0. 5 
 
Fr o m: 
 
T he st u d y will be c o nsi d ere d cl os e d w he n 7 0 % of t he t otal e nr olle d st u d y p o p ulati o n has 
die d or bee n l ost t o f oll o w- u p, w hic h is esti mate d t o be a p pr o xi matel y 3  ye ars after t he 
start of t he st u d y. 
 
T o: 
 
T he st u d y will be c o nsi d ere d cl os e d w he n all c o h ort A s u bjects still i n f oll o w u p ha ve 
ha d t he o p p ort u nit y f or at least 3 years f oll o w- u p fr o m t he date of first d ose of st u d y 
treat me nt or 7 0 % of c o h ort A patie nts ha ve die d or are l ost t o f oll o w u p, w hic he ver is 
earlier 
 
Reas o n f or c h a n ge 
 
T h e ext e nsi o n is r e q uir e d d u e t o i m m at urit y of c o h ort A d at a, t h e pri m ary effic acy p o p ul ati o n, 
w hic h is a r es ult of sl o w r ecr uit m e nt i n t his c o h ort.   
 
Pa ge 3 5 p ara gra p h 5 
 
 
Fr o m:  
T he st u d y is desi g ne d t o ha ve 8 4 %  statistical p o wer t o detect a n I R of 5 0 % i n V 6 0 0 E 
m utati o n- p ositi ve s u bjects w h o recei ve da brafe ni b i n c o m bi nati o n wit h tra meti ni b i n 
C o h ort A.   
T o: 
 
T he st u d y is desi g ne d t o ha ve 8 2 %  statistical p o wer t o detect a n I R of 5 0 % i n V 6 0 0 E 
m utati o n- p ositi ve s u bjects w h o recei ve da brafe ni b i n c o m bi nati o n wit h tra meti ni b i n 
C o h ort A.   
 
Reas o n f or c h a n ge –  t y p o gra p hical err or b et wee n pr ot oc ol a n d S A P. 
 
Pa ge  1 0 8 p ara gra p h 4 
 

2 0 1 3 N 1 6 8 4 3 7 _ 0 9
9  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
2 0 1  
 
 
Fr o m 
 
T he st u d y is desi g ne d t o ha ve 8 4 %  statistical p o wer t o detect a n I R of 5 0 % i n V 6 0 0 E 
m utati o n- p ositi ve s u bjects w h o recei ve da brafe ni b i n c o m bi nati o n wit h tra meti ni b i n 
C o h ort A. 
 
 
T o  
 
T he st u d y is desi g ne d t o ha ve 8 2 %  statistical p o wer t o detect a n I R of 5 0 % i n V 6 0 0 E 
m utati o n- p ositi ve s u bjects w h o recei ve da brafe ni b i n c o m bi nati o n wit h tra meti ni b i n 
C o h ort A. 
 
 
Reas o n f or c h a n ge –  t y p o gra p hical err or b et wee n pr ot oc ol a n d S A P. 

2 0 1 3 N 1 6 8 4 3 7 _ 0 9  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
 
 
7 6  
 
 
 
 
Pa ge 7 1 Ta ble 1 9 Fr o m 
 
 
St u d y Assess me nts 1  
S creen -2  
D a y 1  
W eek  4  
W eek  8  
W eek  1 2  
W eek  1 6  
W eek  2 0  
W eek  2 4  
W eek  2 8  
W eek  3 2  
W eek  3 6  
th en  
M o n th l y 
U n sch ed u led  
Dis co n tin u ed  
F o ll ow  u p 9  
C o n clu si o n 
In f or me d c o nse nt 
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T u m o ur tiss ue sa m ple f or B R A F V 6 0 0 m utati o n 3  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ntr acra nial tar get a n d n o n – tar get lesi o n assess me nt a n d 
res p o nse 2 1  
 
X   
 
X  
 
X   
 
X   
 
X   
 
X   
 
X   
 
X   
 
E xtracra nial tar get a n d n o n -tar get lesi o n assess me nt a n d 
res p o nse 2 2  
 
X   
 
X  
 
X   
 
X   
 
X   
 
X   
 
X   
 
X   
 
In cl usi o n / e x cl usi o n criteri a 4  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re gister s u bject  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C he mistr y  a n d Hae m at ol o g y 5  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
X   
 
Ser u m pre g na n c y  test6  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C oa g ulati o n  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h y sic al e x a mi nati o n 
X   
 
 
 
 
 
 
 
 
 
 
 
X   
 
Hei g h t7  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wei g ht, Te m p, B P, Res p a n d H R
8  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
 
De m o gra p hic d ata  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease c h aracteristics 9  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri or a nti -ca ncer t hera p y , ra di ot herap y  a n d s ur gical  
pr oce d ures  
 
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past a n d c urre nt me dical c o n diti o ns, fa mil y  hist or y  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

2 0 1 3 N 1 6 8 4 3 7 _ 0 9  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
 
 
7 7  
 
 
Alc o h ol c o ns u m pti o n  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R e as o n f or c h a n g e –  c orr ecti o n of tr a nscri pti o n err or c arri e d fr o m pr ot oc ol a m e n d m e nt 4 
 
  
S ecti o n 7. 4. 3. 1 Fr o m: 
 
W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g n a nc y test wit hi n 7 da ys pri or t o e nr oll me nt a n d a gree t o use effecti ve 
c o ntrace pti o n, S u bjects wit h a p ositi ve pre g na nc y test res ult m ust be e x cl u de d fr o m t he st u d y.   
T o  
W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m pre g n a nc y test wit hi n 1 4 da ys pri or t o e nr oll me nt a n d a gree t o use effecti ve 
c o ntrace pti o n, S u bjects wit h a p ositi ve pre g na nc y test res ult m ust be e x cl u de d fr o m t he st u d y.   
 
R e as o n f or c h a n g e: - c orr ecti o n of err or c arri e d fr o m pr ot oc ol a m e n d m e nt 4 
 
 

7 8  
2 0 1 3 N 1 6 8 4 3 7 _ 0 9  
C O N FI D E N TI A L  
B R F 1 1 7 2 7 7  
 
 
 
St u d y Assess me nts 1  
S creen -2  
D a y 1  
W eek  4  
W eek  8  
W eek  1 2  
W eek  1 6  
W eek  2 0  
W eek  2 4  
W eek  2 8  
W eek  3 2  
W eek  3 6  
th en  
M o n th l y 
U n sch ed u led  
Dis co n tin u ed  
F o ll ow  u p 9  
C o n clu si o n 
Past a n d c urre nt t o bacc o c o ns u m pti o n  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C y t o ki ne 1 2  
X   
X   
 
 
 
 
 
 
 
 
 
 
 
 
Ne ur ol o gical ass ess me nt 1 3  
X   
X  
X   
X   
X   
X   
X   
X   
 
O p ht hal mic E xa mi nati o n 1 4  
X   
X   
 
 
 
 
 
 
 
 
 
 
 
 
Der mat ol o gic s ki n assess me nt 1 5  
X   
X    X   X    X   X    X   X    X   X    X    
  X   X   
Dis pe nse oral st u d y treat me nt a n d assess c o m plia nc e 1 6  
 
  X   X    X   X    X   X    X   X    X   X    X    
 
 
 
E C O G Perf or ma n ce stat us  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
 
E C G 1 7  
X   
X  
X  
X   
 
X   
 
X   
 
X   
 
E C H O 1 8  
X   
X   
X   
 
X   
 
X   
 
X   
 
C o nc o mita nt me dicati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
 
Bl o o d pr o d ucts a n d bl o o d s u p p orti ve care pr o d ucts  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
 
A d verse e ve nts 1 9  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
F oll o w -u p c o ntact, a nti -ca ncer t h erap y 2 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X   
S u bject c o m pleti o n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
Deat h rec or d  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  

N o v arti s 
C o nfi d e nti al 
P a g e 7 9  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
 
 
T o: 
 
 
 
St u d y A s s e s s m e nt s 1 
Scr e e n -2 
D a y 1  
W e e k 4  
W e e k 8  
W e e k 1 2  
W e e k 1 6  
W e e k 2 0  
W e e k 2 4  
W e e k 2 8  
W e e k 3 2  
W e e k 3 6  
W e e k 4 0 t h e n 
m o nt hl y U ntil 
Tre at m e nt 
Di s c  
1. 2.  
Tre at m e nt  
Di s c 2 6 
F oll o w u p 9   2 7 
C o n cl u si o n  
I nf or m e d c o ns e nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T u m o ur tiss u e s a m pl e f or B R A F V 6 0 0 
m ut ati o n 3  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ntr acr a ni al t ar g et a n d n o n – t ar g et l esi o n 
ass ess m e nt a n d r es p o ns e 2 1   2 7  
X  
 
X  
X  
 
X  
 
X  
 
X  
 
X  
X  
 
 
Extr acr a ni al t ar g et a n d n o n -t ar g et l esi o n 
ass ess m e nt a n d r es p o ns e 2 2     2 7  
X  
 
X  
X  
 
X  
 
X  
 
X  
 
X  
X  
 
 
I ncl usi o n / excl usi o n crit eri a4 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R e gist er s u bj ect  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C h e mistry a n d H a e m at ol o gy 5 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
S er u m pr e g n a ncy t est6 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o a g ul ati o n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P hysic al ex a mi n ati o n  
X  
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
H ei g ht 7  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
W ei g ht, T e m p, B P, R es p a n d H R 8 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
D e m o gr a p hic d at a  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dis e as e c h ar act eristics 9 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri or a nti -c a nc er t h er a py, r a di ot h er a py a n d 
s ur gic al pr oc e d ur es 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P ast a n d c urr e nt m e dic al c o n diti o ns, f a mily 
hist ory  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alc o h ol c o ns u m pti o n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P ast a n d c urr e nt t o b acc o c o ns u m pti o n  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyt oki n e 1 2  
X  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
N e ur ol o gic al ass ess m e nt 1 3  
X  
 
X  
X  
 
X  
 
X  
 
X  
 
X  
X  
 
 
O p ht h al mic Ex a mi n ati o n 1 4  
X  
 
X  
 
 
 
 
X  
 
 
 
 
 
 
 
D er m at ol o gic ski n ass ess m e nt 1 5 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
Dis p e ns e or al st u dy tr e at m e nt a n d ass ess 
tr e at m e nt c o m pli a nc e1 6 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
E C O G P erf or m a nc e st at us  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
E C G 1 7 
X  
 
X  
X  
X  
 
 
X  
 
 
X  
 
X  
 
 
E C H O 1 8 
X  
 
X  
 
X  
 
 
X  
 
 
X  
 
X  
 
 
C o nc o mit a nt m e dic ati o ns 2 5  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
Bl o o d pr o d ucts a n d bl o o d s u p p ortiv e c ar e 
pr o d ucts  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
A dv ers e ev e nts 1 9 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
F oll o w -u p m o nt hly d er m at ol o gic ski n 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 

8 0  
N o v arti s 
C o nfi d e nti al 
P a g e 8 0  
Cli ni c al St u d y Pr ot o c ol V er si o n 0 9 
Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
St u d y A s s e s s m e nt s 1 
Scr e e n -2 
D a y 1  
W e e k 4  
W e e k 8  
W e e k 1 2  
W e e k 1 6  
W e e k 2 0  
W e e k 2 4  
W e e k 2 8  
W e e k 3 2  
W e e k 3 6  
W e e k 4 0 t h e n 
m o nt hl y U ntil 
Tre at m e nt 
Di s c  
1. 2.  
Tre at m e nt  
Di s c 2 6 
F oll o w u p 9   2 7 
C o n cl u si o n  
ass ess m e nt c o nt act, a nti -c a nc er t h er a py 2 0 
S urviv al F oll o w -u p, a nti -c a nc er t h er a py 2 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
S u bj ect c o m pl eti o n or wit h dr a w al  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
D e at h r ec or d (if a p plic a bl e)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X