Clinical trial NCT02039947
Conditions: Melanoma and Brain Metastases
Keywords: BRAF V600K mutation Metastatic Melanoma BRAF V600R mutation BRAF V600D mutation BRAF V600E mutation Brain metastases BRAF inhibitor Intracranial
Sponsor: Novartis Pharmaceuticals
Start date: 2014-02-21; Completion date: 2018-02-14
Enrollment: 127 participants; Allocation: NON_RANDOMIZED; Intervention model: 

Brief summary:
This is a multi-cohort, open label, Phase II study with Dabrafenib (GSK2118436) and Trametinib (GSK1120212) combination therapy in subject with BRAF mutation-positive melanoma that has metastasized to the brain. This study will evaluate the safety and efficacy of 4 cohorts. Cohorts will consist of; V600 E, D, K, R mutations, metastases to the brain, symptomatic and asymptomatic, with or without prior local (brain) therapy, with or without prior local (brain) therapy, and range of ECOG scores from 0-2.

Detailed description:

Arms: arm 1: Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity. arm 2: Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity arm 3: Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity arm 4: Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity
Interventions: intervention 1: Dabrafenib intervention 2: Trametinib
Intervention descriptions: intervention 1: Dabrafenib will be provided as 50 mg and 75 mg capsules intervention 2: Trametinib will be provided as 0.5 mg and 2.0 mg tablets

Protocol documents:
Prot_001.pdf: 
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  
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V er si o n n u m b er  
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D e v el o p m e nt 
p h a s e  
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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 
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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 
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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  
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Ori gi nal  
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A me n d me nt N o. 4  
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2 0 1 3 N 1 6 8 4 3 7 _ 0 8  
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A me n d me nt N o. 6  
2 0 1 3 N 1 6 8 4 3 7 _ 0 9  
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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. 


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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.  
 


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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 


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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  
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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  
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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. 


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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


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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. 


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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  
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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 


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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. 


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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. 


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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 


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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.  


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 
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 


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 
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/. 


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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: 


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 
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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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, 


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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  


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C o nfi d e nti al 
P a g e 6 8  
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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. 


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C o nfi d e nti al 
P a g e 6 9  
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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 
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m o nt hl y U ntil 
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Di s c  
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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 
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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  
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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  
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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  
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I ncl usi o n / excl usi o n crit eri a4 
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R e gist er s u bj ect  
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C h e mistry a n d H a e m at ol o gy 5 
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Ser u m pr e g n a ncy t est 6 
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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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D e m o gr a p hic d at a  
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Dis e as e c h ar act eristics 9 
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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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Alc o h ol c o ns u m pti o n  
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Past a n d c urr e nt t o b acc o c o ns u m pti o n  
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Cyt oki n e 1 2  
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N e ur ol o gic al ass ess m e nt 1 3  
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C o nfi d e nti al 
  
  
 
                      P a g e 7 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 
 
 
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  
O p ht h al mic Ex a mi n ati o n 1 4  
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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 O G P erf or m a nc e st at us  
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E C G 1 7 
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E C H O 1 8 
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C o nc o mit a nt m e dic ati o ns 2 5  
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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  
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Adv ers e ev e nts 1 9 
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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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Su bj ect c o m pl eti o n or wit h dr a w al  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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D e at h r ec or d (if a p plic a bl e)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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 


N o v arti s 
 
C o nfi d e nti al 
  
  
 
                      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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                      P a g e 7 3  
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        Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
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 


N o v arti s 
 
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                      P a g e 7 4  
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        Pr ot o c ol N o. B R F 1 1 7 2 7 7 
 
 
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. 


8 0  
N o v arti s 
C o nfi d e nti al 
P a g e 8 0  
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 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 


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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 


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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.


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 “ 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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 
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. 


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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.


9 1  
N o v arti s 
C o nfi d e nti al 
P a g e 9 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 
 
 
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 


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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. 


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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 . 


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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, 


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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 


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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. 


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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  
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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. 


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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 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  
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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.  


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C O N FI D E N TI A L  
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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  
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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. 


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C O N FI D E N TI A L  
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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  
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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 
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 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. 


1 3 9  
N o v arti s 
C o nfi d e nti al 
P a g e 1 3 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 
 
 
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. 


1 4 0  
N o v arti s 
C o nfi d e nti al 
P a g e 1 4 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 
 
 
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. 


1 4 1  
N o v arti s 
C o nfi d e nti al 
P a g e 1 4 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 
 
 
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. 


1 4 2  
N o v arti s 
C o nfi d e nti al 
P a g e 1 4 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 
 
 
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 


1 4 3  
N o v arti s 
C o nfi d e nti al 
P a g e 1 4 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 
 
 
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. 


1 4 4  
N o v arti s 
C o nfi d e nti al 
P a g e 1 4 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 
 
 
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. 


1 4 5  
N o v arti s 
C o nfi d e nti al 
P a g e 1 4 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 
 
 
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. 


1 4 6  
N o v arti s 
C o nfi d e nti al 
P a g e 1 4 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 
 
 
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. 


1 4 7  
N o v arti s 
C o nfi d e nti al 
P a g e 1 4 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 
 
 
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. 


1 4 8  
N o v arti s 
C o nfi d e nti al 
P a g e 1 4 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 
 
 
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  
N o v arti s 
C o nfi d e nti al 
P a g e 1 4 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 
 
 
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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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  
N o v arti s 
C o nfi d e nti al 
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  


1 5 7  
N o v arti s 
C o nfi d e nti al 
P a g e 1 5 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 
 
 
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. 


1 5 8  
N o v arti s 
C o nfi d e nti al 
P a g e 1 5 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 
 
 
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. 


1 5 9  
N o v arti s 
C o nfi d e nti al 
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  


1 6 0  
N o v arti s 
C o nfi d e nti al 
P a g e 1 6 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 
 
 
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  
N o v arti s 
C o nfi d e nti al 
P a g e 1 6 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 
 
 
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  
 
 
 
 
 

SAP_000.pdf: 
CONFIDENTIAL
GlaxoSmithKline Group of Companies
BRF117277
1
Division: World Wide Development
Retention Category: GRS019
Information Type: Reporting and Analysis Plan
Compound Number: GSK2118436, GSK1120212 / NCT02039947
Effective Date:
05-Mar-2018
Description: This document details the reporting and analysis plan for BRF117277, a
non-randomized, multi-center Phase II study to evaluate efficacy and safety of combined
therapy with dabrafenib and trametinib in patients with BRAF mutation-positive
melanoma with brain metastases.  Four cohorts based on type of mutation, ECOG
performance score, presence of symptoms and prior local therapy of brain lesions will be
treated.  The primary objective is to assess the intracranial response rate in subjects with
locally confirmed BRAF V600E-mutation positive melanoma that has metastasized to the
brain without symptoms and have not undergone prior local therapy for brain metastases,
ECOG score of 0-1 (Cohort A). Other secondary objectives include intracranial,
extracranial, and overall response in all cohorts, progression-free and overall survival,
duration of intracranial, extracranial, and overall response in all cohorts, and the
incidence and severity of adverse events by cohort.
Subject: Oncology, Reporting and Analysis Plan, melanoma, brain metastases, BRAF
inhibitor, BRAF V600E mutation, BRAF V600K mutation, BRAF V600R mutation, 
BRAF V600D mutation, intracranial
Author’s Name, Title and Functional Area:
 
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.
Title:
Reporting and Analysis Plan for 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 (Amendment 1)


CONFIDENTIAL
GlaxoSmithKline Group of Companies
BRF117277
2
Approved Via E-mail by:
Email approval on file


3
CONFIDENTIAL
GlaxoSmithKline Group of Companies
BRF117277
Revision Chronology
Date
Version
2015-FEB-10
Original
2017-FEB-23
Amendment No. 1
2018-MAR-05
Amendment No. 2


4
CONFIDENTIAL
GlaxoSmithKline Group of Companies
BRF117277
1) Minor correction to typographical errors throughout the document.
2) Title page: Updated description about study objective - to assess the intracranial
response rate in subjects with locally confirmed BRAF V600E-mutation positive
melanoma.
3) Section 2: Updated study objectives to be consistent with the study protocol
amendment No.5 – 1. Primary endpoint amended to allow for locally confirmed BRAF
V600E (followed by central confirmation as with all other cohorts) and 2. Secondary
endpoint number 9: OS changed from 5 to 3 year.
4) Section 3: Updated Study design - Cohort A patient population updated to allow for
locally confirmed BRAF V600E (followed by central confirmation as with all other 
cohorts) and definition of study closure updated from “where all subjects still in
follow up have had at least 5 years follow up…” to “where all subjects still in follow
up have had at least 3 years follow up…”.
5) Updated Protocol reference information from “Protocol Amendment 01, dated 27
April 2014 GlaxoSimthKline Document Number (2013N168168437_01)” to 
“Protocol Amendment 05, dated 13 July 2016 GlaxoSimthKline Document Number 
(2013N168437_07)”.
6) Section 4 and 4.2: reference to 5 year survival changed to 3.
7) Section 5.1: To clarify the significance level at the time of primary analysis, added
“and the primary endpoint test in the primary analysis will be performed at 5% level”.
8)
9) Added section 9.2.15 to clarify how to apply analysis cut-off date.
10) Section 10.3, 10.5 and 10.6: Updated the drug dictionary reference from “GSK Drug
coding dictionary” to “WHODrug coding dictionary”.
11) Section 11.1: added “As a window of 7 days is allowed for scheduling, 7 weeks (or
49 days) will be used for analysis” to clarify the stable disease criteria.
12) As independent reviewer-assessment has been done, removed all the hypothetical
wording (“If done”) removed.


5
CONFIDENTIAL
GlaxoSmithKline Group of Companies
BRF117277
13)Section 11.2: Added detailed derivation rules for the date of last contact.
14)Section 11.2: Added “The duration of intracranial, extracranial, and overall response 
per independent reviewer-assessment will also be summarized. Figures and listings of
duration of independent reviewer-assessed response will also be provided.”.
15)Section 11.2: Added “Frequency of patients with PFS events will be presented and
also separately by types of PFS event, i.e. progression or death.”.
16)Section 11.2: Added “PFS per independent reviewer-assessment will be summarized.
A figure and listing of progression-free survival time per independent reviewer will
also be provided.”
17)Section 12.3: “Summaries of exposure-adjusted incidence rates will be produced for
each AE of special interest” deleted.
18)Section 12.3: Updated the list of adverse event of special interest following 
MedDRA19.1.
19)Section 12.7.1: “A trellis display of LFT shifts from baseline to maximum values will
be provided.” Deleted.
20)Section 12.8: Deleted analysis about neurological exam as the data is not available to
produce these displays.
21)Section 14.1: Modify the Table of Contents for data displays to be consistent with the
updated AESI and the required analysis per team’s discussion and agreement. To be
specific, The following changes have been made,
a.
Updated all AESI related displays to be consistent with the latest MedDRA
19.1.
b. Removed “2.0061 Kaplan-Meier Estimates of Overall Survival at 3 Years by
Cohort” from the list of displays for primary analysis.
c.
Added “2.0061 Kaplan-Meier Estimates of Overall Survival at 3 Years by
Cohort” to the list of displays for end of study analysis.
d. Removed all the displays for Summaries of exposure-adjusted incidence rates
for each AE of special interest.
e.
Updated “1.1220 Summary of Study Treatment Status by Cohort” to “1.1220
Summary of Study Treatment Status for Trametinib by Cohort”.
f.
Added “1.1221 Summary of Study Treatment Status for Dabrafenib by
Cohort”.
g. Removed “3.9020 Summary of Neurological Examinations by Cohort” and 
“30.0340 Listing of Neurological Assessments”.
h. Removed “12.0080 Trellis Display of Patient Profiles of LFT Results by
Cohort”.


CONFIDENTIAL
BRF117277
2
TABLE OF CONTENTS
PAGE
ABBREVIATIONS......................................................................................................................... 4
1.
INTRODUCTION................................................................................................................... 6
2.
STUDY OBJECTIVES AND ENDPOINTS ........................................................................ 6
2.1.
Statistical Hypotheses ............................................................................................. 9
3.
STUDY DESIGN ................................................................................................................... 9
4.
PLANNED ANALYSES ...................................................................................................... 10
4.1.
Interim Analyses..................................................................................................... 10
4.2.
Final Analyses ........................................................................................................ 10
5.
SAMPLE SIZE CONSIDERATIONS.....................................................................................11
5.1.
Sample Size Assumptions .................................................................................... 11
5.2.
Sample Size Sensitivity......................................................................................... 11
5.3.
Sample Size Re-estimation .................................................................................. 11
6.
ANALYSIS POPULATIONS .............................................................................................. 12
6.1.
All Treated Populations ......................................................................................... 12
6.2.
All Enrolled.............................................................................................................. 12
6.3.
Safety Population................................................................................................... 12
6.4.
Analysis Datasets................................................................................................... 12
7.
TREATMENT COMPARISONS........................................................................................ 12
7.1.
Data Display Treatment .............................................................................................13
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES ............................................ 13
8.1.
Multicenter Studies ................................................................................................ 14
8.2.
Other Strata and Covariates................................................................................. 14
8.3.
Examination of Subgroups.................................................................................... 14
8.4.
Multiple Comparisons and Multiplicity................................................................. 14
9.
DATA HANDLING CONVENTIONS................................................................................. 15
9.1.
Premature Withdrawal and Missing Data ........................................................... 15
9.2.
Derived and Transformed Data............................................................................ 15
9.2.1.
Reference dates.................................................................................... 15
9.2.2.
Study Day for Safety Measures .......................................................... 16
9.2.3.
Study Day for Efficacy .......................................................................... 16
9.2.4.
Duration and Elapsed Time ................................................................. 16
9.2.5.
Imputation of Partial Dates................................................................... 17
9.2.6.
Imputation of Missing Exposure End Dates ...................................... 23
9.2.7.
Baseline Definition ................................................................................ 23
9.2.8.
Change from baseline .......................................................................... 24
9.2.9.
Multiple Assessments........................................................................... 24
9.2.10.
Actual Treatment................................................................................... 24
9.2.11.
Extended Loss to Follow-up or Extended Time without an
Adequate Assessment.......................................................................... 24
9.2.12.
Date Associated with Response ......................................................... 25


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3
9.2.13.
Cardiac Scan Modalities (ECHO/MUGA) .......................................... 25
9.2.14.
Derived and Transformed Variables................................................... 25
9.2.15.
Cut-off date ............................................................................................ 27
9.3.
Study Time Periods................................................................................................ 27
9.3.1.
Time in Relation to Treatment............................................................. 27
9.3.2.
Study Time Periods for Concomitant Medications and
Blood and Blood Supportive Care Products...................................... 28
9.4.
Values of Potential Clinical Importance............................................................... 29
9.4.1.
Laboratory Parameters......................................................................... 29
9.4.2.
ECG Parameters:.................................................................................. 29
9.4.3.
Vital Signs .............................................................................................. 30
9.4.4.
Left Ventricular Ejection Fraction........................................................ 31
10. STUDY POPULATION....................................................................................................... 32
10.1.
Disposition of Subjects.......................................................................................... 32
10.2.
Protocol Deviations................................................................................................ 32
10.3.
Demographic and Baseline Characteristics ....................................................... 32
10.4.
Treatment Compliance.......................................................................................... 33
10.5.
Concomitant Medications...................................................................................... 33
34
11. EFFICACY............................................................................................................................ 34
11.1.
Primary Efficacy Analysis...................................................................................... 35
11.2.
Secondary Efficacy Analyses............................................................................... 36
11.3.
Other Efficacy Analyses........................................................................................ 42
12. SAFETY ANALYSES.......................................................................................................... 42
12.1.
Extent of Exposure................................................................................................. 42
12.2.
Adverse Events ...................................................................................................... 43
12.3.
Adverse Events of Special Interest...................................................................... 44
12.4.
Deaths and Serious Adverse Events................................................................... 45
12.5.
Adverse Events Leading to Discontinuation of Study Treatment and
Dose Modifications................................................................................................. 46
12.6.
Pregnancies............................................................................................................ 46
12.7.
Clinical Laboratory Evaluations............................................................................ 46
12.7.1.
Analyses of Liver Function Tests........................................................ 47
12.8.
Other Safety Measures ......................................................................................... 48
50
13. REFERENCES.................................................................................................................... 51
14. ATTACHMENTS ................................................................................................................. 52
14.1.
Table of Contents for Data Display Specifications ............................................ 52
14.1.1.
Data Display Deliverables.................................................................... 62
14.1.2.
Outputs for the Interim Analysis.......................................................... 74
14.2.
Data Display Specifications .................................................................................. 76


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Abbreviations
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical
ATS
All Treated Subjects
CI
Confidence Interval
CR
Complete Response
CTCAE
Common Terminology Criteria for Adverse Events 
CTX
Anti-cancer Therapy Dataset
DIR
Duration of Intracranial Response
DER
Duration of Extracranial Response
DOR
Duration of Overall Response
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Easter Cooperative Oncology Group
eCRF
Electronic Case Report Form
ER
Extracranial Response
GSK
GlaxoSmithKline
IDMC
Independent Data Review Committee
IDSL
Integrated Data Standards Library
IR
Intracranial Response
LDH
Lactate Dehydrogenase
LLN
Lower Limit of Normal
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Medical Affairs
NCI
National Cancer Institutes
OR
Overall Response
OS
Overall Survival
PD
Progressive Disease
PFS
Progression-free Survival
PR
Partial Response
PT
Preferred Term
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SD
Stable Disease
SOC
System Organ Class
SRT
Safety Review Team
ULN
Upper Limit of Normal


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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Mekinist
Tafinlar
Trademarks not owned by the 
GlaxoSmithKline group of companies
SAS


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6
1.
INTRODUCTION
This reporting and analysis plan (RAP) details all planned analyses required for a Clinical
Study Report of study BRF117277. This is a phase II study to evaluate the efficacy and
safety of BRF117277 using a non-randomized, open-label, multiple cohort design.
For further information on the study design, see Protocol Amendment 05, dated 13 July
2017, GlaxoSimthKline Document Number (2013N168437_07).
The content of this RAP is based on the SOP and Information for Authors: Reporting and
Analysis Plans
 effective 23 March 2011.
All decisions regarding final analysis, as defined in this RAP document, have been made
prior to Database Freeze of the study data. Interim analyses are detailed within Section
4.1, where applicable.
2.
STUDY OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To assess the intracranial response (IR) of subjects
with locally confirmed BRAF V600E-mutation
positive melanoma that has metastasized to the
brain without symptoms and have not undergone
prior local therapy for brain metastases, ECOG
score of 0-1 (Cohort A).
IR is defined as the proportion of subjects
with a confirmed intracranial complete
response (CR) or partial response (PR) as per
investigator assessment using modified
RECIST 1.1 guidelines.
Secondary
1.
To assess cohort B for IR of subjects with locally
confirmed BRAF V600E cutaneous melanoma
with metastases to the brain confirmed by MRI,
asymptomatic with prior local therapy for brain
metastases; ECOG score of 0-1.
2.
To assess cohort C for IR of subjects with locally
confirmed BRAF V600 D/K/R cutaneous
melanoma with metastases to the brain confirmed
by MRI, asymptomatic, with or without prior
local therapy; ECOG score of 0-1.
3.
To assess cohort D for IR of subjects with locally
confirmed BRAF V600 D/E/K/R cutaneous
melanoma with metastases to the brain confirmed
by MRI, symptomatic; with or without prior local
therapy; ECOG score of 0-2.
IR is defined as the percentage of subjects
with a confirmed intracranial complete
response (CR) or partial response (PR) as per
investigator assessment using modified
RECIST 1.1 guidelines.


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7
Objectives
Endpoints
4.
To assess Cohorts A, B, C and D for Disease
Control for intracranial, extracranial and overall
response (IDC, EDC and ODC respectively)
5.
To assess Cohorts A, B, C and D for extracranial
response rate (ER)
6.
To assess Cohorts A, B, C and D for overall
response rate (OR)
7.
To assess Cohorts A, B, C and D for duration of
response for intracranial, extracranial and overall
response (DIR, DER and DOR respectively)
8.
To assess Cohorts A, B, C and D for progression-
free survival (PFS)

Intracranial Disease Control (IDC) is
defined as CR+PR+SD for intracranial
disease

Extracranial Disease Control (EDC) is
defined as CR+PR+SD for extracranial
disease

Overall
Disease
Control
(ODC)
is
defined
as
CR+PR+SD
for
overall
disease

Extracranial response (ER), defined as
the percentage of subjects with a best
extracranial response of a confirmed CR
or PR by investigator assessment using
modified RECIST 1.1

Overall response (OR), defined as the
percentage of subjects with a best overall
confirmed response of CR or PR by
investigator assessment

Duration of intracranial, extracranial and
overall response (DIR, DER and DOR),
defined as the time from first
documented evidence of CR or PR until
time of first documented intracranial,
extracranial, or overall disease
progression.

PFS, defined as the interval between first
dose and the earliest date of disease
progression or death due to any cause


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8
Objectives
Endpoints
9.
To assess C Cohorts A, B, C and D for overall
survival (OS) and long-term (particularly 5-
year) OS

Overall survival (OS), defined as the
time from first dose until death due to
any cause
10.  To assess Cohorts A, B, C and D to characterize
the safety of dabrafenib and trametinib
combination therapy.
Assessment of safety of dabrafenib and
trametinib measured by the frequency and
severity of adverse events, skin assessments,
laboratory abnormalities, vital signs, and
assessment data (12-lead electrocardiograms
(ECG), echocardiograms, and clinical
monitoring/observationincluding neurological
examination)


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9
2.1.
Statistical Hypotheses
The primary efficacy objective of this study is to assess the intracranial response (IR) rate
in BRAF V600E mutation positive subjects assessed by Investigators using modified
RECIST 1.1 criteria for Cohort A:

Cohort A: 75 Subjects who are treatment-naive for brain metastases,
asymptomatic and stable on corticosteroids.
The study is designed to provide evidence to support the null hypothesis, H0: IRR ≤ 35%
or to reject it in favor of the alternative hypothesis, HA: IRR ≥ 50% for BRAF V600E
mutation-positive subjects in Cohort A.
This hypothesis will be tested using a one-sided test for superiority with α=0.05. There
will be no other testing; therefore, there will be no adjustment of the Type I error for
multiple testing.
3.
STUDY DESIGN
This study will evaluate the safety and efficacy of 4 cohorts, each receiving the same
treatment. Cohort A: Seventy-five subjects with locally confirmed BRAF V600E
cutaneous melanoma with metastases to the brain confirmed by MRI, asymptomatic,
without prior local (brain) therapy and ECOG score of 0-1. Cohort B: Fifteen subjects
with locally confirmed BRAF V600E cutaneous melanoma with metastases to the brain 
confirmed by MRI, asymptomatic, with prior local (brain) therapy and ECOG score of 0-
1. Cohort C: Up to fifteen subjects with locally confirmed BRAF V600D/K/R cutaneous
melanoma with metastases to the brain confirmed by MRI, asymptomatic, with or
without prior local (brain) therapy and ECOG score of 0-1. Cohort D: Fifteen subjects
with locally confirmed BRAF V600D/E/K or R cutaneous melanoma with metastases to
the brain confirmed by MRI, symptomatic, with or without prior local (brain) therapy and
ECOG score of 0-2.
Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until
evidence of disease progression, death, or unacceptable toxicity. Subjects will be
required to meet all eligibility criteria and return to clinic on a monthly basis for clinical, 
skin and laboratory assessments. Intracranial and extracranial disease will be assessed at
baseline, Week 4, Week 8, and every 8 weeks thereafter.  After Week 40, disease
assessments may be performed every 12 weeks. Response to treatment will be evaluated
using modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
An Independent Data Monitoring Committee (IDMC) will be used in this study.
Protocol-specified guidelines for dose adjustments, interruptions and discontinuation due
to adverse events are provided in Protocol Amendment 05, dated 13 July 2016
GlaxoSimthKline Document Number (2013N168437_07). After discontinuation of study
treatment, subjects will remain in the study for follow-up assessments including monthly
skin assessments up to 6 months and updates on anti-cancer treatment until death.
Subjects who have not died, but are no longer being followed for disease progression or
survival are considered to have withdrawn from the study. The study will be completed
when either all subjects are dead or lost to follow-up, or all subjects still in follow-up


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10
have had at least 3 years follow-up from the date of first dose of study treatment,
whichever is earlier.
4.
PLANNED ANALYSES
In line with ICH E9 [European Medicines Evaluation Agency (CPMP/ICH/3633/96)],
membership of the analysis populations will be determined using the definitions in 
Section 6 of this RAP.
The primary efficacy analysis will be performed when all subjects in Cohort A have had
the opportunity for three (3) post baseline disease assessments. At this time the final
intracranial response analysis will be performed and an interim analysis of PFS and OS
will be provided. The final analysis of PFS, OS, and safety will occur after all subjects
have died or are otherwise lost to follow-up or 3 years from the first dose of study
treatment, whichever is soonest.
4.1.
Interim Analyses
There is a formal interim analysis for futility only with a statistical decision rule in this
trial. For Cohort A, an interim analysis will take place after 22 subjects have been treated
and had the opportunity for at least two disease assessments. The responses used in this
interim analysis do not have to be confirmed.  At least 8 of the 22 subjects must have an
IR (intracranial CR or PR) for the trial to continue.  If 7 or fewer subjects have an IR, this
is evidence that the null hypothesis is true. If accrual is not complete at the time of the
interim analysis, it will continue during this analysis.
An IDMC will review accumulating safety and efficacy data, including the results of the
interim review of safety and efficacy and make recommendations to continue, modify, or
terminate the study if there are concerns regarding safety. The specific responsibilities,
review schedules and composition of the IDMC will be outlined in a separate document,
the IDMC charter. The IDMC will review the study results at least once for efficacy and
futility.  Additional routine reviews of safety data will be scheduled as needed.
4.2.
Final Analyses
The primary analyses will be performed after all subjects in Cohort A have had the
opportunity for three (3) post-baseline disease assessments. This analysis will be
performed after the database is frozen. After all subjects have died or are otherwise lost to
follow-up or 3 years from the first dose of study treatment, whichever is soonest, the End
of Study analysis will be performed on the total cumulated safety data and overall
survival. This analysis will be performed after the End of Study database is frozen. The
displays that will be included in this analysis are listed in Section 14.1.1.


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5.
SAMPLE SIZE CONSIDERATIONS
5.1.
Sample Size Assumptions
The sample size is based on the hypothesized improvement in intracranial response over
study GSK BRF113929 (BREAK-MB) in Cohort A.  A 35% intracranial response (IR) is
not clinically significant over existing therapies. An intracranial response (IR) of 50% is
of clinical significance.
For the primary endpoint cohort (A), 75 BRAF V600E mutation positive subjects will be
enrolled. At the time of the primary efficacy analysis, at least 33 subjects with an IR
(44%) are required to establish that the evidence does not support the null hypothesis.
The sample size is based on a one-sided superiority test of binomial proportions with an
overall Type I error rate 0.05 incorporating an interim analysis with the spending function
proposed by Lan,(1983) with Pocock Boundary. The null hypothesis in Cohort A will be
tested assuming IR of 35% against an IR of 50% using a one-sided test for superiority
with α=0.05 and power=82%. There will be no other testing; therefore, there will be no
adjustment of the Type I error for multiple testing and the primary endpoint test in the
primary analysis will be performed at 5% level.
5.2.
Sample Size Sensitivity
Table 1 shows statistical power for the test of the null hypothesis in Cohort A under the
assumed IR of 35%.  It includes statistical power for scenarios where the alternative
response rate is lower and higher.  All statistical power calculations assume 75 BRAF
V600E mutation positive subjects in the Cohort A All Treated Subjects population.
Table 1
Statistical Power Scenarios with 75 BRAF V600E Mutation Positive
Subjects in Cohort A
IR
Statistical Power
40%
22.9%
45%
53.8%
50%
82.1%
55%
96.2%
5.3.
Sample Size Re-estimation
Sample size re-estimation is not planned for this study.


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6.
ANALYSIS POPULATIONS
6.1.
All Treated Populations
All subjects who receive at least one dose of study medication will comprise the All
Treated subjects (ATS) population.
The V600E population will comprise all BRAF V600E mutation positive subjects in the 
ATS population.
The V600D/K/R population will comprise all BRAF V600D/K/R mutation positive 
subjects in the ATS population.
6.2.
All Enrolled
The All Enrolled population comprises all subjects who were enrolled regardless of
whether they had a dose of study treatment.
6.3.
Safety Population
The safety population is the ATS population.
6.4.
Analysis Datasets
Primary efficacy analyses will be based on investigator-assessed results in the ATS
population. If independent review of efficacy is done, those analysis results will be
secondary.
Safety analyses will use the ATS population.
The V600D/K/R population, defined above and identified in the study protocol as a
population to be used to report on secondary efficacy endpoints by cohorts, will not be 
used.  This change was made to accommodate the small sample size in Cohorts B-D (15
subjects per cohort). Analyses of subgroups of 15 subjects would not generally be
meaningful and are not specified a priori.
7.
TREATMENT COMPARISONS
There are no treatment comparisons. The primary objective will be supported by testing
the null hypothesis in Cohort A. The four cohorts will not be compared statistically for
any endpoint.


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7.1.
Data Display Treatment
The following treatment descriptors will be used on all applicable displays.  Results will
be reported by cohort.
Treatment Group
Data Display
Order of Treatment
Groups
Code
Description
A
Dabrafenib+Trametinib
Dabrafenib+Trametinib
n/a
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis datasets will be created according to CDISC/ADaM standards, and data will be
listed and summarized according to GSK Integrated Data Standards Library (IDSL)
reporting standards. Formatting for dates, times, and decimal places will follow GSK
standards except where specified.
The currently supported versions of SAS, S-Plus software, and TSCG (for figures) will
be used to perform all data analyses, generate tables, figures, and listings.
All data in the database will be presented in by-subject data listings.
All data up to the time of study completion or withdrawal from the study will be included
in the analysis, regardless of duration of treatment.
As the duration of treatment for a given subject will depend on efficacy and tolerability,
the duration of follow-up will vary between subjects. Consequently, there will be no
imputation for missing data.
Use the center ID in summaries and listings, as needed. Summary tables and listings will 
NOT generally be separated by investigator nor will investigator be a factor in any
statistical models.  Unless otherwise stated, all listings will be sorted by center ID,
subject number, cohort, then by visit date.
Unless otherwise stated, continuous variables will be summarized with n, mean, median,
standard deviation, minimum and maximum, and categorical variables will be 
summarized with frequency counts and percentages.
Summaries will be produced by cohort.
All laboratory data will be presented in GSK’s standard units for reporting.
”Worst-case post-baseline” values will be derived using scheduled and unscheduled visits.
Planned times relative to study drug dosing will be used in all tables and summary figures.


14
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Generally, only pre-specified planned times will be used in the summaries, statistical
analyses and calculations of any derived parameters and unscheduled readings will be
listed. However, both unscheduled and scheduled readings will be included in the 
computation of maximum toxicity and in post-baseline shifts displays for labs and in any
listing.
Assessment windows will not be defined for the purpose of classifying measurements
obtained outside scheduled assessment times.
Deviations from the analyses in the RAP will be identified in the CSR.
8.1.
Multicenter Studies
Data from all participating centers will be pooled prior to analysis. It is anticipated that
subject accrual will be spread thinly across centers and summaries of data by center 
would be unlikely to be informative and will not, therefore, be provided. However, a
summary of treated subjects by center will be produced.
8.2.
Other Strata and Covariates
In all efficacy analyses, there is no stratification. There are no formal plans for
investigating any covariates.
8.3.
Examination of Subgroups
There are no formal plans for examining subgroups except reporting adverse events by
sex and age groups (<65 years old and 65 years old).
8.4.
Multiple Comparisons and Multiplicity
The Type I error rate will not be adjusted for multiplicity in secondary or supporting
analyses.


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9.
DATA HANDLING CONVENTIONS
9.1.
Premature Withdrawal and Missing Data
Because study treatment is dependent on the study endpoints (e.g., progression), the
length of treatment for each subject will depend on the efficacy and toxicity of the 
treatment, so the duration of treatment will vary across subjects. Similarly the duration of
follow up will also vary. All available time-to-event data will be analyzed using suitable
statistical methods; subjects with shorter treatment and follow-up due to the natural
history of their disease or medical necessities of the treatment of their disease will not be
considered to have missing time-to-event data. For endpoints which determine the
percentage of responders, subjects with unknown or missing best overall response will be
assumed to be non-responders, and will be included in the denominator when calculating
the percentages.
In the event that the study is terminated, all available data will be listed and a review 
carried out by the study team to assess which statistical analyses are still considered
appropriate.
Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument. These data will be indicated by the use of a “blank” in subject
listing displays. Answers such as “Not applicable” and “Not evaluable” are not
considered to be missing data and should be displayed as such.
Subjects with the designation of treatment relationship for adverse events (AE)s and 
serious adverse events (SAEs) missing will have the worst case assumed to impute the
relationship: if relationship to study treatment is missing it will be assumed to be “Yes”.
There will be no other imputation for missing data other than what’s described in Section
9.2 for partial dates and for missing exposure end dates.
9.2.
Derived and Transformed Data
The following sections provide a general description of the derived and transformed
variables used to describe and analyze the data. Separate analysis dataset specifications
provide full details on all data derivations and transformations including descriptions of
core standard algorithms and standard Oncology algorithms. The analysis dataset
specifications will clearly communicate the content and source of the datasets supporting
the statistical analyses.
9.2.1.
Reference dates
There are three reference dates:
Because age is an eligibility requirement, the reference date for age is the date of 
screening.
The safety reference date is the treatment start date, and will be used to calculate study
day for safety measures.


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The efficacy reference date is the treatment start date and will be used to calculate study 
day for efficacy measures and baseline characteristics (such as time since initial 
diagnosis), as well as efficacy durations.
9.2.2.
Study Day for Safety Measures
If the date of interest occurs on or after the safety reference date then the safety study day
will be calculated as (date of interest - safety reference date) + 1. If the date of interest
occurs before the safety reference date then the safety study day will be calculated as
(date of interest – safety reference date). There is no safety study day 0.
9.2.3.
Study Day for Efficacy
If the date of interest occurs on or after the efficacy reference date then efficacy study day
will be calculated as (date of interest - efficacy reference date) + 1. If the date of interest
occurs prior to the efficacy reference date then efficacy study day will be calculated as
(date of interest – efficacy reference date). There is no efficacy study day 0.
9.2.4.
Duration and Elapsed Time
Durations (e.g., the duration of an adverse event, duration of exposure, etc.) are
calculated as the stop date minus the start date plus one.
For elapsed time (e.g., the time since initial diagnosis):

If the reference date is on or after the event date, then the elapsed time is the
reference date minus the event date + 1.

If the reference date is before the event date then the elapsed time is the reference
date minus the event date.
When reporting time to event (TTE) durations (progression-free survival, duration of
intracranial, extracranial, and overall response, overall survival) in months, divide the
number of days by 30.4375; to report in weeks divide the number of days by 7; to report
in years divide the number of days by 365.25. These algorithms for time to event return
decimal numbers, and ignore the actual numbers of days in the months or years between
start date and stop date. The "year" used in these algorithms is 365.25 days long, and the
"month" is one twelfth of that year.
For converting all other durations (e.g., duration of adverse events, duration of exposure,
age) to weeks, months or years use the following:

To report the duration in weeks, divide the number of days by 7.

To report the duration in months use:
(YEAR(stopdate + 1) - YEAR(startdate)) * 12 + (MONTH(stopdate + 1) -
month(startdate) - 1) + (DAY(stopdate + 1) > = DAY(startdate))

To report the duration in years use:


17
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intck('year', startdate, stopdate + 1) - (month(stopdate + 1) < month(startdate) or
(month(stopdate + 1) = month(startdate) and day(stopdate + 1) < day(startdate)))
The algorithms above for age and duration return whole numbers for months and years,
accurately accounting for the actual numbers of days in the months or years between the
start date and the stop date.
9.2.5.
Imputation of Partial Dates
Imputed partial dates will not be used to derive study day, duration (e.g., duration of
adverse events), or elapsed time variables. In addition, imputed dates are not used for
deriving the last contact date in overall survival analysis dataset.
With the exception of new anti-cancer start date on the Oncology time to event analysis
dataset and exposure end date on the Exposure analysis dataset, imputed dates will also
not be stored on datasets.
Imputed dates will not be displayed in listings. However, where necessary, display
macros may impute dates as temporary variables for the purpose of sorting data in listings 
only. In addition partial dates may be imputed for specific analysis purposes as outlined
below.
The partial date imputation will follow ADaM conventions. The ADaM approach is to
populate the numeric date variables with the imputed date and add a flag variable to the 
dataset that indicates the level of imputation.
The flag variable can contain the values: blank, 'D', 'M', 'Y'.
blank: indicates that no imputation was done
D='Day': indicates that the day portion of the date is imputed
M='Month': indicates that the month and day portions of the date are imputed 
Y='Year': indicates that the entire date (year, month, and day) is imputed
Example of Date Variables:
XYZD_ - character date variable
XYZDT - numeric date variable
XYZDTFL - flag variable
Details on imputing partial dates for specific datasets follow.
Adverse Events (AE):
Imputations in the adverse events dataset are used for slotting events to the appropriate
study time periods and for sorting in data listings.
Dataset
Date
Missing 
Element
Rule


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Dataset
Date
Missing 
Element
Rule
Adverse
Events
(AE)
Start 
Date
day,
month, 
and year

No Imputation for completely missing dates
day,
month

If study treatment start date is missing (i.e. subject did 
not start study treatment), then set start date = January 1.

Else if study treatment start date is not missing:
o
If year of start date = year of study treatment start
date then

If stop date contains a full date and
stop date is earlier than study 
treatment start date then set start date
= January 1.

Else set start date = study treatment
start date.
o
Else set start date = January 1.
day

If study treatment start date is missing (i.e. subject did 
not start study treatment), then set start date = 1st of 
month.

Else if study treatment start date is not missing:
o
If month and year of start date = month and year
of study treatment start date then

If stop date contains a full date and 
stop date is earlier than study
treatment start date then set start 
date= 1st of month.

Else set start date = study treatment
start date.
o
Else set start date = 1st of month.
End
Date

No imputation for partial end dates will be performed
Anti-Cancer Therapy and Radiotherapy:
Start and end dates are generally not imputed.
Imputed partial dates will not be used to derive time since most recent prior therapy. In
addition, the cancer therapy treatment status variable, and not any variables that use
imputed partial dates, will be used to differentiate prior and follow-up anti-cancer therapy
and radiotherapy.


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Dataset
Date
Missing 
Element
Rule
Anti-Cancer
Therapy
Radiotherapy
Start 
Date
day,
month, 
and year

No Imputation for completely missing dates
day,
month

If partial date contains a year only set to January
1st.
day

If partial date contains a month and year set to the
1st of the month.
End
Date

No imputation for partial end dates will be 
performed
Surgery:
The date of surgery or procedure is generally not imputed. However, post treatment
surgery or procedure dates maybe imputed (if necessary) to determine date of new anti-
cancer therapy. In this case only, the date of new anti-cancer therapy (not specific surgery
or procedure date) will be stored on appropriate efficacy datasets. The category for
surgical procedure variable, and not any variables that use imputed partial dates, will be
used to differentiate prior, on, and follow-up surgical procedure data. The derived time in
relation to treatment variables are not needed for reporting of data because the category
for surgical procedure variable can be used. Therefore, imputed dates are not needed for
derivation of time in relation to treatment.
Dataset
Missing 
Element
Rule
Surgical
Procedures
day, month,
and year

No Imputation for completely missing dates
day, month

If partial date contains a year only set to January
1st.
day

If partial date contains a month and year set to the
1st of the month
Concomitant Medication and Blood and Blood Supportive Care Products:
Start and end dates for use in derivation of the reference variables for concomitant 
medication start and end relative to treatment will be imputed. Similarly start and end 
dates for use in derivation of the reference variables for blood and blood supportive care
start and end relative to treatment will be imputed. However these imputed start and end 
dates will not be stored permanently in the analysis datasets.


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The reference variables will be used to differentiate before, during and after for the
concomitant medication or blood or blood supportive care start and end dates. The
derived time in relation to treatment variables are not needed for reporting of these data.


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Dataset
Date
Missing 
Element
Rule
Concomitant 
Medication
Blood and
Blood
Supportive 
Care
Products
Start 
Date
day,
month, 
and year

No Imputation for completely missing dates
day,
month

If study treatment start date is missing (i.e., 
subject did not start study treatment), then set
start date = January 1.

Else if study treatment start date is not missing:
o
If year of start date = year of study
treatment start date then

If stop date contains a full date and 
stop date is earlier than study 
treatment start date then set start 
date = January 1.

Else set start date = study
treatment start date.
o
Else set start date = January 1.
day

If study treatment start date is missing (i.e. 
subject did not start study treatment), then set 
start date = 1st of month.

Else if study treatment start date is not missing:
o
If month and year of start date = month
and year of study treatment start date then

If stop date contains a full date and 
stop date is earlier than study 
treatment start date then set start 
date= 1st of month.

Else set start date = study
treatment start date.
o
Else set start date = 1st of month.
End
Date
day,
month, 
and year

No Imputation for completely missing dates
day,
month

If partial end date contains year only, set end date
= earliest of December 31 or date of last contact.
day

If partial end date contains month and year, set
end date = earliest of last day of the month or date 
of last contact (MSTONE.LCONTDT).


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Time to Event, Response, and Response for Independent Review:
Start dates for follow-up anti-cancer therapy, radiotherapy (where applicable), and
surgical procedures (where applicable) will be temporarily imputed in order to define
event and censoring rules for progression-free survival; intracranial, extracranial, and
overall response rate; and duration of intracranial, extracranial, and overall response (i.e. ,
start date for new anti-cancer therapy). Dates will only be imputed when a month and
year are available but the day is missing. The imputed date(s) will not be stored on the
anti-cancer therapy, radiotherapy, or surgical procedure datasets. The following rules will
be used to impute the date when partial start dates are present on anti-cancer therapy
radiotherapy, and/or surgical procedures dataset[s]:
Dataset
Date
Missing 
Element
Rule
Anti-Cancer
Therapy
Where
applicable:
Radiotherapy
Surgical
Procedures
Start 
Date
day, month,
and year

No Imputation for completely missing dates
day, month

No imputation for missing day and month 
(note the eCRF should only allow for
missing day)
day

If partial date falls in the same month as the 
last dose of study treatment, then assign to 
earlier of (date of last dose of study 
treatment+1, last day of month).

If partial date falls in the same month as the 
subject’s last assessment and the subject’s
last assessment is PD, then assign to earlier 
of (date of PD+1, last day of month).

If both rules above apply, then assign to
latest of the 2 dates

Otherwise, impute missing day to the first of 
the month.
End
Date

No imputation for partial end dates will be
performed


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The date of new anti-cancer therapy is derived as the earliest date of new anti-cancer
therapy (e.g., chemotherapy), radiotherapy (where applicable), or a cancer-related
surgical procedure (where applicable) and will include imputed dates. If the date of new
anti-cancer therapy is an imputed date, then the date of new anti-cancer therapy flag
variable is assigned the value of 'D' to indicate that the day portion of the date is imputed 
(following ADaM convention).
As multiple dates are used to derive the date of new anti-cancer therapy ensure that the
date of new anti-cancer therapy flag is only set to ‘D’ if the derived date is imputed. For
example if the date of new radiotherapy is imputed but the date of new anti-cancer
therapy is prior to date of new radiotherapy and the new anti-cancer therapy date is not a
partial date then the flag should be set to missing as the date used for the new anti-cancer
therapy is not an imputed date.
9.2.6.
Imputation of Missing Exposure End Dates
The rules for imputing missing exposure end dates given in this section apply to both
dabrafenib and trametinib.  The study treatment end date variable will hold the last date
of exposure for either dabrafenib or trametinib, that is, the latest exposure end date across
all study treatments.
In general, completely missing dates are not imputed. However, subjects in oncology
trials may still be on study treatment when analyses are performed and so may have
missing exposure end dates in their last dosing record. Missing exposure end dates for
subjects who are still on study treatment at the time of an analysis will be imputed. For
subjects with missing exposure end dates at the time of data cutoff, the exposure end date
will be imputed to the earliest of: the date of the data cutoff, the date of withdrawal from
the study, or the death date. The imputed exposure end date will be used to calculate
cumulative dose and exposure duration. The imputed exposure end date will be stored in
the exposure analysis dataset and an exposure end date imputation flag variable will be
derived indicating which exposure end date records are imputed. Imputed exposure end
dates will also be stored on the study treatment end date variable.
For subjects who have missing end dates in their last exposure record because they are 
still on study treatment, the on-therapy indicator variables (time in relation to study
treatment) are assigned to on-therapy for all records where the 'dataset'.'date' is after or on
the study treatment start date.
9.2.7.
Baseline Definition
Baseline will be defined as the most recent, non-missing value prior to or on the first
study treatment dose date. For laboratory data, baseline will be defined as the most recent,
non-missing value from a central laboratory prior to or on the first study treatment dose
date. If there are no central labs collected for a subject and lab test prior to or on the first
dose of study treatment, the most recent, non-missing value from a local laboratory prior
to or on the first dose of study treatment will be defined as the baseline value.
For subjects who did not receive study treatment during the study, baseline will be
defined as the latest, non-missing collected value.


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9.2.8.
Change from baseline
Change from baseline will be presented for safety data as described in Section 12.
Change from baseline is calculated as:

For records occurring after baseline: (visit value) – baseline value.
Percent change from baseline is calculated as:

For records occurring after baseline: ((change from baseline) / baseline value) * 100
If either the baseline or visit value is missing, the change from baseline and/or percent
change from baseline is set to missing as well.
9.2.9.
Multiple Assessments
All data will be reported according to the nominal visit date for which it was reported
(that is, no visit windows will be applied during dataset creation). Unscheduled data will
only be included in the display sections that report worst- case post-baseline.
If multiple assessments on different days are reported for the same scheduled assessment,
then the earliest assessment for that scheduled assessment will be analyzed.
If multiple assessments are reported on the same date for the same scheduled planned
time, then the worst-case result will be analyzed, with the exception of laboratory data
reported from both central and local laboratories. If laboratory data is reported from both
central and local laboratories with the same date, then the central laboratory data will be 
analyzed to provide consistency with measurements from other subjects.
Data from all assessments (scheduled and unscheduled), including multiple assessments, 
will be included in listings.
9.2.10.
Actual Treatment
The subjects’ actual treatment will be derived from exposure data. If a subject’s actual
treatment is the same as the assigned treatment, then actual treatment is the assigned
treatment. If a subject receives a study treatment that is different from the assigned
treatment for the entire time of treatment, then actual treatment is the treatment actually
received.
9.2.11.
Extended Loss to Follow-up or Extended Time without an
Adequate Assessment
If two or more consecutive scheduled disease assessments are missed and are then
followed by an assessment of PD or death, PFS will be censored at the last adequate
assessment prior to PD or death. When the scheduled disease assessment is every 8
weeks, a window of 119 days (16 weeks + 7 day window) will be used to determine
whether there was an extended time without adequate assessment. That is, if the time
difference between the PFS event of PD or death and the last adequate assessment is


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more than 119 days, then PFS will be censored at the last adequate assessment prior to 
the PFS event. If the Week 4 and Week 8 disease assessments are both missed or are
inadequate (that is, the first adequate disease assessment is at Week 16), and the Week
16 disease assessment shows progressive disease, then PFS will be set to Day 1.
9.2.12.
Date Associated with Response
For each disease assessment after baseline, determine the dates associated with
intracranial, extracranial, and overall response. For any type of complete response (CR)
or partial response (PR), assign to the latest date within the disease assessments. For any
type of stable disease (SD), Non-CR/Non-PD or Not Evaluable, assign to the earliest date
within the disease assessments. For any type of progressive disease (PD), assign to the
earliest assessment date associated with the progression.
9.2.13.
Cardiac Scan Modalities (ECHO/MUGA)
The same modality (ECHO or MUGA) for determining cardiac scan data (e.g., left
ventricular ejection fraction (LVEF)) should be used to follow a subject throughout the
study. The absolute change from baseline values will not be calculated for any subjects
where the post-baseline value was determined by a cardiac scan modality that is different
than the one used to determine baseline value.
9.2.14.
Derived and Transformed Variables
See Section 11 for details on analyses for intracranial, extracranial, and overall response,
progression-free survival, overall survival, duration of intracranial response, duration of
extracranial response, and duration of overall response.
Prognostic Factors
The prognostic variables below will be added to the following datasets to support 
exploratory analyses:  ADSL, demography, overall response, overall response
independent review (if there is independent review), and time to event datasets.
Baseline ECOG performance status: Baseline ECOG performance status can be 0, 1, or 2,
depending on cohort.  Assign the baseline ECOG performance status value.
Visceral Disease at baseline can be yes or no; assign as follows:
1 = Yes
0 = No
Number of extracranial disease sites at baseline (will be adjusted based on the
distribution of the data if appropriate).  Sum the number of unique sites of disease at
screening and assign as follows:
1 = More than 3
0 = 2 or fewer


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Number of intracranial target lesions at baseline (will be adjusted based on the
distribution of the data if appropriate). Sum the number of intracranial target lesions at
screening and assign as follows:
4 = 5
3 = 4
2 = 3
1 = 2
0 = 1
Number of intracranial non-target lesions at baseline (will be adjusted based on the
distribution of the data if appropriate). Sum the number of intracranial non-target lesions
at screening and assign as follows:
4 = 5 or more
3 = 4
2 = 3
1 = 2
0 = 1
Gender covariate: Assign
1 = Female
0 = Male
AGE (continuous)
Age at baseline categorized as follows: 
1 = More than 65 years old
0 = No more than 65 years old
The time since initial diagnosis of intracranial disease to treatment category:
1 = At least 1 year
0 = Less than 1 year
The time since initial diagnosis of extracranial disease to treatment category:
1 = At least 1 year


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0 = Less than 1 year
Race categorized as follows:
2 = Other
1 = African-American
0 = White
Censoring Date for Progression Free Survival and Duration of Intracranial, Extracranial,
and Overall Response
Date of new anti-cancer therapy flag: If the date of new anti-cancer therapy is an imputed
date, then set to ‘D’. Otherwise set to missing. See Section 9.2.5 for specific rules for
imputing partial dates. As multiple dates are used to derive the date of new anti-cancer
therapy ensure that the flag is only populated if the derived date is imputed. For example,
if the date of new radiotherapy is imputed but the date new anti-cancer therapy is prior to
date of new radiotherapy and the new anti-cancer therapy date is not a partial date then
the flag should be set to missing as the date used for the date of new anti-cancer therapy
is not an imputed date.
9.2.15.
Cut-off date
The analysis cut-off date for the primary analysis of study data will be established. The
primary efficacy analysis will be performed when all subjects in cohort A have had the
opportunity for three (3) post baseline disease assessments. All statistical analyses will be
performed using all data collected in the database up to the data cutoff date. All data with
an assessment date or event start date (e.g. vital sign assessment date or start date of an
adverse event) prior to or on the cut-off date will be included in the analysis. Any data
collected beyond the cut-off date will not be included in the analysis and will not be used
for any derivations. All events with start date before or on the cut-off date and end date
after the cut-off date will be reported as ‘ongoing’. The same rule will be applied to
events starting before or on the cut-off date and not having documented end date. This
approach applies, in particular, to adverse event and concomitant medication reports.
9.3.
Study Time Periods
9.3.1.
Time in Relation to Treatment
Adverse events, serious adverse events, death, laboratory data, vitals, ECG, and
ECHO/MUGA data will be assigned to the study time periods defined below. Partial
dates will be imputed into full dates, if applicable, for slotting data to the appropriate


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categories below (see Section 9.2.5). Flag variables (time in relation to study treatment)
indicating the study time periods will be added to these datasets.
Pre-therapy is defined as the time prior to the subject’s first dose of study treatment.
On-therapy is defined as the time from first dose of study treatment to 30 days after the
last dose date of study treatment.
Extension is defined as the time from overall progression + 1 day to the last dose date of
study treatment.
Post-therapy is defined as any time beyond the on-therapy period if study treatment
stops then, or after the extension period if study treatment is continued beyond initial 
progression.
Some datasets include the first dose day as On-therapy and some exclude the first dose
date as On-Therapy. The first dose day (Day 1) is considered pre-therapy for ECOG,
ECG, vital signs, liver events, lab tests, and cardiac scan. The first dose day (Day 1) is
considered to be On-therapy for adverse events and concomitant medications.
9.3.2.
Study Time Periods for Concomitant Medications and Blood and
Blood Supportive Care Products
Concomitant Medication and Blood and Blood Supportive Care Product start and end
dates will be assigned to study time periods in relation to first dose of study treatment as 
defined below. The start date references time flag variables and end date reference time
flag variables will be added to the concomitant medications and blood and blood 
supportive products datasets, respectively.

Start relative to treatment: Assign to 'BEFORE' if start date is prior to study
treatment start date or if subject has not taken any study treatment or (start date is
missing and end date is before study treatment start date). Else assign to 'DURING'
if the start date falls into the on-therapy period as defined above or if subject is
ongoing (not all study treatment discontinuation records completed) or start date is
missing.  Else assign to 'AFTER' if start date is after the on-therapy period.

End relative to treatment: Assign to 'BEFORE' if end date is prior to study treatment
start date or if subject has not taken any study treatment. Else assign to 'DURING' if
start date falls into the on-therapy period or if subject is ongoing (not all study
treatment discontinuation records completed) or (end date is missing and start
relative to treatment not 'AFTER'). Else assign to 'AFTER' if start date is after the
on-therapy period or (end date is missing and start relative to treatment='AFTER').
Only on-therapy blood and blood supportive care products that start after the start of
study treatment are included in the Blood Products and Blood Supportive Care Product
summaries. Therefore, for summary tables, include blood and blood supportive care
product records where start relative to treatment in ('DURING') and end relative to
treatment in ('DURING','AFTER'). All data will be reported in listings.


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Concomitant medication start relative to treatment and end relative to treatment flags are
used to select data to include in the Concomitant Medication summaries as follows:

Summary of Concomitant Medications: This summary will contain medications 
including those with start date prior to study treatment start date and continue 
(missing end date or end date after study treatment start date) on therapy. Note that
any medications with start date and end date prior to study treatment start date will be
excluded as they are not concomitant. In addition, any medication that was started 
during post-therapy will be excluded. Include concomitant medication records where
start relative to treatment in ('BEFORE','DURING') and end relative to treatment in
('DURING','AFTER').
9.4.
Values of Potential Clinical Importance
9.4.1.
Laboratory Parameters
Reference ranges for all laboratory parameters collected throughout the study are 
provided by the laboratory. A laboratory value that is outside the reference range is
considered either high abnormal (value above the upper limit of the reference range) or
low abnormal (value below the lower limit of the reference range). Note: a high abnormal
or low abnormal laboratory value is not necessarily of clinical concern. The laboratory
reference ranges will be provided on the listings of laboratory data. Clinical laboratory
test results outside of the reference range will be flagged in the listings.
To identify laboratory values of potential clinical importance, National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0) will be used to
assign grades to the relevant laboratory parameters. NCI-CTCAE v4.0 can be found at
http://ctep.cancer.gov/reporting/ctc.html.
For laboratory data which are not listed in the NCI CTCAE v4.0, a summary of values
outside the normal range will be provided.
9.4.2.
ECG Parameters:
The following criteria will be used to flag electrocardiogram (ECG) values that are values 
of potential clinical importance:
To identify QTc (Bazett’s) values of potential clinical importance, NCI-CTCAE v4.0 will
be used to assign grades (see adverse event ‘Electrocardiogram QT corrected interval 
prolonged’). Note that there is a slight inconsistency between CTCAE v4 and ICH E14
(Absolute QTc interval prolongation). It was decided to align with CTCAE for the
oncology standard categories.


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ECG Parameter
Potential Clinical Importance (PCI) Range
Unit
Absolute QTcB interval
450 to <481 (Grade 1)
481 to <501 (Grade 2)
501 (Grade 3)
Msec
Increase from baseline
QTcB
Increase of 31 to 60
Increase of >60
Msec
The following criteria will be used to flag other ECG values that are values of potential 
clinical importance:
ECG Parameter
Potential Clinical Importance (PCI) Range
Unit
PR interval
<110 (L) and >220 (H)
Msec
QRS interval
<75 (L) and >110 (H)
Msec
9.4.3.
Vital Signs
To identify heart rate values of potential clinical importance, NCI-CTCAE v4.0 will be
used to assign categories that align with the grades for ‘Sinus bradycardia’, ‘Sinus
tachycardia’, ‘Supraventricular tachycardia’, and ‘Ventricular tachycardia’.
The following criteria will be used to flag vital sign values that are values of potential 
clinical importance:
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Decrease from baseline
Heart Rate
Decrease to <60
bpm
Increase from baseline
Heart Rate
Increase to >100
bpm
To identify blood pressure values of potential clinical importance, NCI-CTCAE v4.0 will
be used to assign categories that align with the grades for ‘Hypertension’.


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Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Increase from baseline
Systolic Blood Pressure
120 to <140 (Grade 1)
140 to <160 (Grade 2)
160 (Grade 3)
mmHg
Increase from baseline
Diastolic Blood Pressure
80 to <90 (Grade 1)
90 to <100 (Grade 2)
100 (Grade 3)
mmHg
To identify temperature values of potential clinical importance, NCI-CTCAE v4.0 will be
used to assign categories that align with the grades for ‘Hypothermia’ and ‘Fever’.
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Increase from baseline
temperature
Increase to 38
Degrees
C
Decrease from baseline
Diastolic Blood Pressure
Decrease to 35
Degrees
C
9.4.4.
Left Ventricular Ejection Fraction
The following criteria will be used to flag left ventricular ejection fraction (LVEF) values 
that are values of potential clinical importance:
To identify LVEF values of potential clinical importance, NCI-CTCAE v4.0 will be used
to assign categories that align with the grades for ‘Ejection fraction decreased’.
LVEF Parameter
Potential Clinical Importance (PCI) Range
Unit
Absolute change from
baseline LVEF

No change or any increase

Any decrease
o
>0-<10 decrease
o
10-19 decrease
o
20 decrease
o
10 decrease and LLN
o
10 decrease and below LLN
o
>10 decrease and below LLN
o
20 decrease and LLN
o
20 decrease and below LLN
%
Relative change from
baseline LVEF

20 decrease and LLN

20 decrease and below LLN
%


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10.
STUDY POPULATION
Unless otherwise stated, all tables and listings in this section will be based on the All 
Treated Subjects population, and all summaries and data listings will use treatment labels 
as specified in Section 7.
The list of displays for Study Population, including the population to use for each display,
is shown in Section 14 of the RAP.
10.1.
Disposition of Subjects
A summary of the number of subjects in each of the analysis populations described in
Section 6 will be provided. In addition, the number of subjects enrolled will be
summarized for All Treated Subjects population.  Subjects in the All Enrolled population
who are not in the All Treated Subjects population will be listed.
A summary of subject status and reason for study withdrawal will be provided. This
display will show the number and percentage of subjects who withdrew from the study,
including primary reasons for study withdrawal. Reasons for study withdrawal will be
presented in the order they are displayed in the eCRF.
A summary of study treatment status will be provided. This display will show the number
and percentage of subjects who have completed the study, are ongoing, or have
discontinued study treatment and a summary of the primary reasons for discontinuation
of study treatment. Reasons for study treatment discontinuation will be presented in the
order they are displayed in the eCRF. A listing of study treatment discontinuation will be
generated. The listing will include last dose date, and reasons for study treatment
discontinuation.
10.2.
Protocol Deviations
All the protocol deviations will be summarized and list the important 
protocol deviations and will include inclusion/exclusion deviations as well as 
other deviations.
A separate summary and listing of inclusion/exclusion deviations will also be provided.
10.3.
Demographic and Baseline Characteristics
The demographic characteristics (e.g., age, race, ethnicity, sex, baseline height, and
baseline body weight) will be summarized and listed. Age, height and weight will be
summarized using the mean, standard deviation, minimum, median, and maximum. In
addition, age will also be categorized and summarized by <18, 18-64, 65-74, and>74.
The count and percentage will be computed for sex and ethnicity.
Race and racial combinations will be summarized and listed.
Disease history and characteristics (time since initial diagnosis in months, stage at initial 
diagnosis, date of initial diagnosis) at initial diagnosis and screening will be listed.
Separate summaries of disease characteristics at initial diagnosis and screening will be


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provided. Medical conditions present at screening will be listed and will be summarized
by past and current cancer-related categories.
A summary of extracranial disease burden at baseline will be produced.
Substance use, including smoking history and alcohol use, will be summarized and listed.
Prior anti-cancer therapy will be coded using WHODrug coding dictionary, then
summarized by cohort and listed.  A listing of prior anti-cancer therapy will show the
relationship between ATC Level 1, Ingredient, and verbatim text.  A summary of the
number of prior anti-cancer therapy regimens will also be produced.
Prior anti-cancer radiotherapy will be summarized and listed. Prior cancer-related
surgeries will be summarized and listed.
10.4.
Treatment Compliance
A listing of planned and actual treatments will be produced.
A listing of drug accountability data (dispensed and returned) will be produced.
A summary of overall compliance for dabrafenib and trametinib based on the exposure 
data will be produced separately. Percentage overall compliance will be summarized
using the mean, standard deviation, minimum, median, and maximum. In additional,
percentage overall compliance will be categorized and summarized by <80%, 80%-105%,
and >105%.
The calculation of overall compliance is based on the entire interval of dosing for
dabrafenib and trametinib. The formula for daily dose medication is compliance (%) =
[total cumulative actual dose / (duration of study treatment * prescribed dose)]*100
where duration of study treatment is last dose-first dose +1.
A listing of overall compliance will be produced.
In addition, summaries of study treatment exposure and dose modifications (e.g., number
of dose reductions, number of dose interruptions) will further characterize compliance.
These analyses are described in Section 12.1 ‘Extent of Exposure’.
10.5.
Concomitant Medications
Concomitant medications will be coded using WHODrug coding dictionary, summarized,
and listed. The summary of concomitant medications will show the number and
percentage of subjects taking concomitant medications by Ingredient. Multi-ingredient
products will be summarized by their separate ingredients rather than as a combination of
ingredients. Anatomical Therapeutic Chemical (ATC) classification Level 1 (Body
System) information will be included in the dataset created but will not appear on the
listing or summary.


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In the summary of concomitant medications, each subject is counted once within each
unique ingredient. For example, if a subject takes Amoxycillin on two separate occasions,
the subject is counted only once under the ingredient “Amoxycillin”.
In the summary of concomitant medications, the ingredients will be summarized by the
base only, using CMBASECD and CMBASE.
A separate listing of prior and concomitant medications of subjects with diabetes at
baseline (as reporting on the medical history page of the eCRF) will be produced.
Blood products or blood supportive care products with onset date within the on-therapy
window will be included in the summary tables. The frequency and percentage of 
subjects using blood products and blood supportive care products after the start of study 
medication will be provided. Supporting listings will also be provided.
11.
EFFICACY
All efficacy analyses will be based on the ATS population as defined in Section 6 unless
otherwise specified. All analyses will be presented by cohort.
Efficacy assessments are based on modified RECIST 1.1.  Primary assessments will be
based on imaging data. Investigator assessments will be considered as primary
assessments. Independent Reviewer assessments, will be supplementary.
Note: If needed, the IRC charter will have further modifications to RECIST 1.1 because
of additional instructions needed for the independent review. Specifically, instructions
will be provided with respect to ascites, pleural effusion, and subjects with no lesions 
documented at baseline.


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11.1.
Primary Efficacy Analysis
Intracranial Response Rate (IRR) in Cohort A
The intracranial response rate (IRR) is defined as the percentage of subjects achieving a
confirmed intracranial CR or PR from the start of treatment until disease progression or
the start of new anti-cancer therapy. This will be based on investigator-assessed best
intracranial response.
Stable intracranial disease requires meeting the SD criteria at least once after the first
dose of study treatment at a minimum interval of 8 weeks. As a window of 7 days is
allowed for scheduling, 7 weeks (or 49 days) will be used for analysis.
To be assigned a status of intracranial PR or CR, a confirmatory disease assessment for
intracranial disease should be performed not less than 4 weeks after the criteria for
response are first met.
The Independent Reviewer-assessed best intracranial response will also be summarized.
Subjects with Not Evaluable (NE) or missing intracranial response will be treated as non-
responders; i.e., they will be included in the denominator when calculating the percentage.
The exact 95% CI for the intracranial response rate will be calculated for both the interim
and final analysis.
All data relating to intracranial response from the investigator and, if done, the
independent reviewer will be listed, including lesion measurements, response
assessments and best response.
A plot of the maximum percent tumor reduction in intracranial target lesions from
baseline will be provided. The plot will be color-coded for best intracranial response. The
subject number will be indicated on the plot.
Intracranial response will be determined using only intracranial target, non-target, and
new lesions, using the criteria specified in the protocol.
Target
Lesions
Non-Target Lesions
New Lesions
Intracranial
Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not
applicable, and NE=Not Evaluable


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11.2.
Secondary Efficacy Analyses
Intracranial Response (IR) in Cohorts B, C, and D
Intracranial response will be summarized for Cohorts B, C, and D as for Cohort A. 
Extracranial Response (ER) in Cohorts A, B, C, and D
The extracranial response rate (ERR) is defined as the percentage of subjects achieving a
confirmed extracranial CR or PR from the start of treatment until disease progression or
the start of new anti-cancer therapy. This will be based on investigator-assessed best
extracranial response.
Stable extracranial disease requires meeting the SD criteria at least once after the first
dose of study treatment at a minimum interval of 8 weeks. To be assigned a status of 
extracranial PR or CR, a confirmatory disease assessment for extracranial disease should
be performed not less than 4 weeks after the criteria for response are first met.
The Independent Reviewer-assessed best extracranial response will also be summarized.
Subjects with Not Evaluable (NE) or missing extracranial response will be treated as non-
responders; i.e., they will be included in the denominator when calculating the percentage.
The exact 95% CI for the extracranial response rate will be calculated.
All data relating to extracranial response from the investigator and, if done, the
independent reviewer will be listed, including lesion measurements, response 
assessments and best response.
A plot of the maximum percent tumor reduction in extracranial target lesions from
baseline will be provided. The plot will be color-coded for best extracranial response.
The subject number will be indicated on the plot.
Extracranial response will be determined using only extracranial target, non-target, and
new lesions, using the criteria specified in the protocol.
Target
Lesions
Non-Target Lesions
New Lesions
Extracranial
Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not
applicable, and NE=Not Evaluable


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Overall Response (OR) in Cohorts A, B, C, and D
The overall response rate (ORR) is defined as the percentage of subjects achieving a
confirmed overall CR or PR from the start of treatment until disease progression or the
start of new anti-cancer therapy. This will be based on investigator-assessed best overall
response.
Stable disease requires meeting the SD criteria for both intracranial and extracranial
disease at least once after the first dose of study treatment at a minimum interval of 8
weeks.  To be assigned a status of overall PR or CR, a confirmatory disease assessment
for both intracranial and extracranial disease should be performed not less than 4 weeks
after the criteria for response are first met.
The Independent Reviewer-assessed best overall response will also be summarized.
Subjects with Not Evaluable (NE) or missing overall response will be treated as non-
responders; i.e., they will be included in the denominator when calculating the percentage.
The exact 95% CI for the overall response rate will be calculated.
All data relating to overall response from the investigator and, if done, the independent
reviewer will be listed, including lesion measurements, response assessments and best
response.
A plot of the maximum percent tumor reduction in overall target lesions from baseline
will be provided. The plot will be color-coded for best overall response. The subject
number will be indicated on the plot.
Overall response will be determined using both extracranial and intracranial target, non-
target, and new lesions, using the criteria specified in the protocol. Overall target lesion
response is based on all (that is, intracranial and extracranial) target lesions, up to 10 total.
The sum of longest diameters of all intracranial and extracranial target lesions will be
used to determine overall response. Unequivocal new intracranial or extracranial (or 
both) lesions, or unequivocal intracranial or extracranial (or both) non-target lesion
progression indicate overall progression. Target, non-target, and new lesion responses
are combined as for intracranial and extracranial response to determine response at each 
disease assessment and best overall response.

Complete Response (CR): Disappearance of all intracranial and extracranial target
lesions. Any pathological lymph nodes must be <10mm in the short axis.

Partial Response (PR): At least a 30% decrease in the sum of the diameters of
intracranial and extracranial target lesions, taking as a reference, the baseline sum of 
the intracranial and extracranial diameters (e.g. percent change from baseline).

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for progressive disease.

Progressive Disease (PD): At least a 20% increase in the sum of the diameters of
intracranial and extracranial target lesions, taking as a reference, the smallest sum of 
intracranial and extracranial diameters recorded since the treatment started (e.g.,


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percent change from nadir, where nadir is defined as the smallest sum of diameters 
recorded since treatment start). In addition, the sum must have an absolute increase 
from nadir of 5mm.

Not Evaluable (NE): Cannot be classified by one of the five preceding definitions.
Intracranial, Extracranial, and Overall Disease Control in Cohorts A, B, C, and D
The intracranial disease control (IDC), extracranial disease control (EDC), and overall 
disease control (ODC) are defined as CR+PR+SD for intracranial, extracranial, and
overall disease control, respectively. Disease control rates are defined as the percentage
of subjects achieving a confirmed overall CR or PR, or SD for at least 8 weeks from the
start of study treatment, from the start of treatment until disease progression or the start of 
new anti-cancer therapy. This will be based on investigator-assessed responses.
The Independent Reviewer-assessed disease control rate will also be summarized.
Subjects with Not Evaluable (NE) or missing intracranial, extracranial, or overall
response will be treated as non-responders; i.e., they will be included in the denominator
when calculating the percentage.
Exact 95% CIs for the disease control rates will be calculated.
Duration of Intracranial, Extracranial, and Overall Response in Cohorts A, B, C, and D
Duration of intracranial, extracranial, and overall response will be summarized separately
for subjects with a confirmed of intracranial, extracranial, or overall CR or PR and is
defined as the time (in months) from the initial response (CR/PR) to first documented 
disease progression or death due to any cause. This will be based on responses from the
investigator assessment. Censoring rules will follow those of the primary PFS analysis
defined in Section 11.1.
If sample size permits, the median duration of response will be calculated from the 
Kaplan-Meier estimates. First and third quartiles will also be calculated along with
associated 95% confidence intervals if there are a sufficient number of responders who 
subsequently progress or die due to any cause.
Figures and listings of duration of response will also be provided.
The duration of intracranial, extracranial, and overall response per independent reviewer-
assessment will also be summarized. Figures and listings of duration of independent
reviewer-assessed response will also be provided.
Progression-Free Survival in Cohorts A, B, C, and D
Progression-Free survival (PFS) is defined as the interval of time (in months) between the
date of first dose of study treatment and the earliest of the date of overall disease
progression and the date of death due to any cause. Disease progression will be based on
assessments by the investigator.


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The date of documented disease progression will be defined as the date of overall disease
progression based on imaging data. The date of death will be taken from the Record of
Death page. Death on study due to any cause will be used.
Subjects who progressed or died after an extended period without adequate intracranial
and extracranial assessment will be censored at their date of last adequate intracranial and
extracranial assessment prior to progression or death even if subsequent information is
available regarding intracranial or extracranial progression or death. An adequate
assessment is defined as an assessment where the investigator-determined response is CR,
PR, or SD. The date of response at that assessment will be used for censoring. Because
the assessment schedule changes during study treatment, specific rules for identifying
extended loss to follow-up or extended time without an adequate assessment are provided
in Section 9.
If anti-cancer therapy is started without documented overall disease progression or is
started prior to documented overall disease progression, then PFS will be censored at the
date of the last adequate assessment that is on or before the date of initiation of anti-
cancer therapy (i.e., if an assessment occurs on the same day as the start of new anti-
cancer therapy the assessment will be used). The date of response at the last adequate
assessment will be used as the censoring value.
If a subject has only a baseline visit or does not have an adequate assessment that is on or
before the date of initiation of anti-cancer therapy, PFS will be censored at the date of
first dose of study treatment.
If a subject has neither progressed nor died nor started new anti-cancer therapy, then PFS
will be censored at the date of the last adequate assessment defined as an assessment 
where the investigator-assessed response  is CR, PR, SD. The date of response will be
used as the censoring date.
A summary of the assignments for progression and censoring dates for PFS are specified 
in Table 2.
Table 2
Assignments for Progression and Censoring Dates for PFS Analysis
Situation
Date of Event
(Progression/Death) or
Censoring
Outcome
Event (Progression/Death) 
Or Censored
No (or inadequate) baseline
intracranial and extracranial 
tumor assessments and the
subject has not died
First dose of study
treatment
Censored


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Situation
Date of Event
(Progression/Death) or
Censoring
Outcome
Event (Progression/Death) 
Or Censored
No post-baseline
intracranial or extracranial
assessments and the subject
has not died
First dose of study
treatment
Censored
Progression documented
between scheduled visits
Date of assessment of
earliest source of
progression1
Event
No progression (or death)
Date of last adequate
assessment of response2
Censored
New anticancer treatment
started prior to documented
disease progression3
Date of last adequate
assessment of response2 on
or before starting new anti-
cancer therapy
Censored
Death before first PD
assessment (including
death at baseline or prior to 
any adequate assessments)
Date of death
Event
Death between adequate
assessment visits
Date of death
Event
Death or progression after 
more than one missed visit
Date of last adequate
assessment of response2
prior to missed assessments
Censored
1 The earliest of (i) date of radiological assessment showing new intracranial or
extracranial lesion (if progression is based on a new lesion); or (ii) date of radiological
assessment showing unequivocal progression in intracranial or extracranial non target
lesions, or (iii) date of last radiological assessment of measured intracranial and
extracranial lesions (if progression is based on increase in sum of measured intracranial
and extracranial lesions)
2 An adequate assessment is defined as an assessment where the Investigator determined
response is CR, PR, or SD.
3 If PD and new anti-cancer therapy occur on the same day assume the progression was
documented first; e.g., outcome is progression and the date is the date of the assessment
of progression). If anti-cancer therapy is started prior to any adequate assessments,
censoring date should be the date of first dose of study treatment.


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PFS will be summarized using Kaplan-Meier estimates. Frequency of patients with PFS
events will be presented and also separately by types of PFS event, i.e. progression or
death. If there are a sufficient number of progressions or deaths, median PFS, first and
third quartiles, and 95% CIs will be estimated using the Brookmeyer-Crowley method
[Brookmeyer, 1982]. A figure and listing of progression-free survival time will also be
provided.
PFS per independent reviewer-assessment will be summarized. A figure and listing of
progression-free survival time per independent reviewer will also be provided.
Overall Survival in Cohorts A, B, C, and D
Overall Survival (OS) is defined as the interval of time (in months) between the date of 
first dose of study treatment and the date of death due to any cause. For subjects who do 
not die, time of death will be censored at the date of last contact. The date of death should
be taken from that recorded on the Record of Death page. Death on study due to any 
cause will be included.
The date of last contact will be assigned to the latest date of: Exposure, randomization, 
death date, follow-up contact, or any actual assessment/procedure date in any data set.
The following dates will NOT be included in the date of last contact calculations:

Date of birth, date of initial cancer diagnosis, date when metastatic disease was 
first diagnosed, and date of disease staging at screening: These dates are prior to
randomization.

Date of withdrawal from the study: This date may not be associated with an
actual subject visit.

Date of protocol deviation: This date may not be associated with an actual 
assessment.

Date of when dispensed investigational product bottles were returned: This date 
may not be associated with an actual subject visit. For example, a relative could
return un-used drugs.

Date when a sample was analyzed for BRAF mutation: This date is not
associated with an actual subject visit.
If there are no post baseline data then the date of randomization will be the last contact 
date.
Survival will be summarized using the Kaplan-Meier for each cohort. In addition to the
Kaplan-Meier estimates for median overall survival time, the first and third quartiles will
be presented, along with approximate 95% CIs if there are a sufficient number of deaths.
A graph of survival curves and a listing of survival times will also be provided.
Analyses will be conducted at the time of the primary endpoint analysis as well as at the
end of the study.


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11.3.
Other Efficacy Analyses
Summaries of comparisons between Investigator assessment and Independent Reviewer
assessment of the Best intracranial, extracranial and overall Response for each subject
will be provided overall by cohort. Also, a summary of comparison between investigator
assessment and independent reviewer assessment of progression free survival times will
be provided.
Concordance Analysis of Intracranial, Extracranial, and Overall Response Rates
An assessment of the concordance between Independent Reviewer assessment and
Investigator Assessment of the Best Intracranial, Extracranial, and Overall Response for
each subject will be provided overall across all cohorts. The calculation will be based on
the percent agreement (the proportion of response outcomes that agree or match across 
both Independent Reviewer and Investigator Assessments):
Percent Agreement = (Number of matched responders + Number of matched non-
responders) / total number of subjects assessed.
12.
SAFETY ANALYSES
Unless otherwise specified, all the safety analyses will be based on the All Treated
population as defined in Section 6 and summaries will include all events and assessments
collected during the study. All the analyses will be performed by cohort.
The list of displays for safety analyses are shown in Section 14 of the RAP.
12.1.
Extent of Exposure
Extent of exposure to dabrafenib and trametinib will be summarized separately.
The duration of exposure to study treatment in months (from first day to last day of
treatment) will be summarized. Descriptive statistics including mean, median, standard
deviation, minimum, and maximum will be calculated for time on study treatment.
Moreover, time on study treatment will be categorized in different time period: <3
months, 3 months to 6 months, >6 months to 12 months and >12 months.
The subject’s average daily dose, defined as the cumulative dose divided by the duration
of exposure for each subject, will be summarized.
Dose reductions will be summarized by number of reductions and reasons for reductions 
for dabrafenib and trametinib separately. Dose interruptions will be summarized by
number of interruptions, reasons for the interruptions, and interruption duration (days) for
dabrafenib and trametinib separately. The mean, standard deviation, median, minimum
value, and maximum value will be computed for the duration of interruptions as well as
the number and percentage of the interruptions ≤7, 8-14, 15-21 and >21 days.
All the dose reductions and dose interruptions will be listed separately.


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12.2.
Adverse Events
Adverse events (AEs) will be graded according to the CTCAE, Version 4.0. Adverse 
events will be coded to the preferred term (PT) level using the Medical Dictionary for
Regulatory Affairs (MedDRA dictionary).
AE summaries will use the following algorithms for counting subjects:

Preferred term row: Subjects experiencing the same AE preferred term several
times with different grades will only be counted once with the maximum grade.

Any event row: Each subject with at least one adverse event will be counted only
once at the maximum grade no matter how many events they have.
An overview summary of AEs, including counts and percentages of subjects with any AE,
AEs related to study treatment, AEs leading to permanent discontinuation of study
treatment, AE leading to dose reductions, AEs leading to dose interruptions, SAEs, SAEs 
related to study treatment, fatal SAEs, and fatal SAEs related to study treatment will be
produced. The same overview summary will be produced by sex and age groups (<65
and 65 years old)
The frequency and percentage of AEs (all grades) will be summarized and displayed in
two ways: 1) in descending order of total incidence by PT only and 2) in descending
order of total incidence by System Organ Classes (SOC) and PT. In the SOC row, the
number of subjects with multiple events under the same system organ class will be
counted once.
A summary of common (that is, that occurred in strictly 5% of the subjects or above)
non-serious AEs will be provided. No rounding for the percentage will be used in terms
of 5% threshold, e.g., event with 4.9% incidence rate should not be included in this table.
The summary will be displayed by SOC and PT.
A summary of number and percentage of subjects with any adverse events by maximum 
grade will be produced. AEs will be sorted by Preferred term (PT) in descending order of
total incidence.
The relationship between MedDRA SOC, PT, and Verbatim Text will be listed.
A separate summary for dabrafenib related, trametinib related, and dabrafenib and
trametinib related AEs will be provided for study treatment-related AEs. A study
treatment-related AE is defined as an AE for which the investigator classifies the
relationship to study treatment as “Yes”. A worst case scenario approach will be taken to
handle missing relatedness data, i.e. the summary table will include events with the
relationship to study treatment as ‘Yes’ or missing. The summary table will be displayed
in descending order of total incidence by PT only for each drug.
All AEs will be listed. Additionally, a listing of subject IDs for each individual AE will
be produced.


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12.3.
Adverse Events of Special Interest
A comprehensive list of MedDRA terms based on clinical review will be used to identify
each type of events. Changes to the MedDRA dictionary may occur between the start of
the study and the time of reporting and/or emerging data from on-going studies may
highlight additional adverse events of special interest, therefore the list of terms to be 
used for each event of interest and the specific events of interest will be based on the 
safety review team (SRT) agreements in place at the time of reporting.
An overview summary of AEs of special interest, including counts and percentages of 
subjects with any AE, AEs related to study treatment, AEs leading to permanent 
discontinuation of study treatment, AE leading to dose reductions, AEs leading to dose
interruptions, SAEs, SAEs related to study treatment, fatal SAEs, and fatal SAEs related
to study treatment will be produced.
The events of special interest include

Skin related toxicities

Ocular events

Cardiac related events

Hepatic disorders

Pneumonitis/Interstitial lung disease

Bleeding events

Diarrhea

Hypertension

Edema

Hypersensitivity

Pyrexia

Cutaneous squamous cell carcinoma including Keratoacanthoma

Non-Cutaneous Treatment-Emergent Malignancies

New primary melanoma

Pre-renal and Intrinsic Renal Failure

Uveitis

Hyperglycemia

Deep vein thrombosis/pulmonary embolism

Pancreatitis

Neutropenia


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Summaries of the characteristics of each AE of special interest, including the number and
percentage of subjects with these events will be provided for each separately. All
summaries of AEs of special interest will use the number of subjects with the event as the 
denominator when calculating percentages. The summary of event characteristics will 
also be provided, including number of subjects with any event, number of events, number
of subjects with any event that is serious, number of subjects with any event that is
related to study treatment, the outcome of the event, maximum grade and the action taken
for the event. The percentage will be calculated using the number of subjects with the
event as the denominator.  The worst case approach will be applied at subject level for
the event outcome and maximum grade, i.e., a subject will only be counted once as the
worst case from all the events experienced by the subject. For action taken in response to
an event, subjects will be counted once under each action, e.g., if a subject has an event
leading to both study treatment discontinuation and dose reduction, the subject will be
counted once under both actions.
Summaries of onset for cutaneous squamous cell carcinoma including keratoacanthoma, 
and new primary melanomas (that is, AEs of special interest for which duration is not
meaningful) will be produced.  All other AEs of special interest will have summaries of
the onset and duration produced.
In addition, subjects with each AE of special interest will be listed separately by AE of
special interest.
12.4.
Deaths and Serious Adverse Events
Note that if any subject withdraws consent, no data after the date of withdrawing consent,
including death, is supposed to appear in the database.
All deaths will be summarized based on the number and percentage of subjects. This
summary will classify subjects by time of death relative to the last dose of medication 
(>30 days or 30 days). A supportive listing will be generated to provide subject-specific
details on subjects who died.
All SAEs will be tabulated based on the number and percentage of subjects who 
experienced the event. Separate summaries will also be provided for dabrafenib- and
trametinib-related SAEs, fatal SAEs and dabrafenib- and trametinib-related fatal SAEs.
The summary tables will be displayed in descending order of total incidence by PT only.
A dabrafenib- or trametinib-related SAE is defined as an SAE for which the investigator
classifies the relationship dabrafenib or trametinib as “Yes”. A worst case scenario
approach will be taken to handle missing data, i.e. the summary table will include events
with the relationship to study treatment as ‘Yes’ or missing.
SAEs are included in the listing of all adverse events. Separate supportive listings with
subject-level details will be generated for

Fatal SAEs

Non-Fatal SAEs.


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12.5.
Adverse Events Leading to Discontinuation of Study
Treatment and Dose Modifications
The following categories of AEs will be summarized separately in descending order of
total incidence by PT only and separate supportive listings will be generated with subject
level details for those subjects:

AEs Leading to Discontinuation of Study Treatment

AEs Leading to Dose Interruptions

AEs Leadings to Dose Reductions
12.6.
Pregnancies
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE as described in the protocol. If subjects or subjects’ partner become
pregnant while on the study, the information will be included in the narratives and no
separate table or listing will be produced.
12.7.
Clinical Laboratory Evaluations
The assessment of laboratory toxicities will examine the following laboratory tests:
Hematology: White Blood Cell (WBC) count (absolute), Absolute Neutrophil Count
(ANC), Hemoglobin (HGB), Hemoglobin A1C, Hematocrit (HCT), Platelet count,
Basophils, Eosinphils, Lymphocytes, Moncytes, and Neutrophils. Basophils, Eosinphils,
Lymphocytes, Moncytes, and Neutrophils are expressed as percentages. Note that
hematocrit is not gradable by CTCAE v4.0.
Clinical Chemistry: Albumin, Gamma-Glutamyl Transpeptidase (GGT), Urea/Blood
Urea Nitrogen (BUN), Calcium, Creatinine, Glucose, Lactate Dehydrogenase (LDH),
Magnesium, Phosphate, Potassium, and Sodium. BUN and LDH are not gradable by
CTCAE v4.0. For Sodium, Potassium, Calcium, and Glucose there will be two bi-
directional parameters (hyper and hypo) created, and the tests will be graded by CTCAE
v4.0 in both directions.
Liver Function Tests: Aspartateamino transferase (AST), Alanine aminotransferase
(ALT), Alkaline phosphatase, and Total bilirubin (total). All these tests are gradable by
CTCAE v4.0.
Coagulation Tests: Prothrombin time (PT) or International Normalized Ratio (INR), and
activated partial thromboplastin time (APTT). INR and PTT are gradable by CTCAE
v4.0 and PT is not.  Coagulation tests are only done at baseline.
Laboratory grades will be reported using the Common Terminology Criteria for Adverse
Events (CTCAE v4.0).


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Summary of lab by scheduled visits using mean, median, standard deviation, minimum
and maximum will be provided.
Summaries of worst case grade increase from baseline grade will be provided for all the
lab tests that are gradable by CTCAE v4.0. These summaries will display the number and 
percentage of subjects with post-baseline grade increases from their baseline grade. Any
increase in grade from baseline will be summarized along with any increase to a
maximum grade of 3 and any increase to a maximum grade of 4. Missing baseline grade
will be assumed as grade 0. In addition, the summary will include grade increase from
baseline by scheduled visits and worst-case post-baseline. For laboratory tests that are
graded for both low and high values, summaries will be done separately and labeled by
direction, e.g., sodium will be summarized as hyponatremia and hypernatremia.
For lab tests that are not gradable by CTCAE v4.0, summaries of worst case changes
from baseline with respect to normal range will be generated. Decreases to low, changes
to normal or no changes from baseline, and increases to high will be summarized at each 
scheduled visit as well as for the worst case post-baseline. If a subject has a decrease to
low and an increase to high during the same time interval, then the subject is counted in 
both the “Decrease to Low” categories and the “Increase to High” categories. In addition,
the summary will include worst case changes from baseline with respect to normal range
by scheduled visits.
Separate summary tables for hematology, chemistry, and liver function laboratory tests
will be produced. Coagulation test results at baseline will be summarized.
A listing of selected laboratory tests and grades will be provided.  A supporting listing of
laboratory data for subjects with values outside the normal range will be provided. A
separate listing of laboratory data with character values will also be provided.
Detailed derivation of baseline assessment is specified in Section 9.2.7.
Unless otherwise specified, the denominator in percentage calculation at each scheduled
visit will be based on the number of subjects with non-missing value at each particular
visit.
Coagulation tests only collected at baseline. Therefore these tests will not appear in any
summaries of changes from baseline.
12.7.1.
Analyses of Liver Function Tests
Summaries of hepatobiliary laboratory abnormalities including possible Hy’s law cases
will be provided in addition to what has been described above.
Possible Hy’s law cases are defined as any elevated ALT>3×ULN, total
bilirubin≥2×ULN and ALP<3×ULN/missing. Total bilirubin≥2×ULN can be within 28
days following the ALT elevation and if direct bilirubin is available on the same day, it
must be ≥ 35% of total bilirubin. ALP<3xULN/missing means the criteria is satisfied
unless the ALP is ≥3xULN at any time of bilirubin elevation within the 28 days window.


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LFT patient profiles plots for subjects experiencing an ALT, AST or total bilirubin of 
toxicity grade 2 or above will be produced.
A plot of maximum total bilirubin versus maximum ALT will be generated.
12.8.
Other Safety Measures
Unless otherwise specified, the denominator in percentage calculation at each scheduled
visit will be based on the number of subjects with non-missing value at each particular
visit.
Vital Signs
Values of vital signs as well as the change from baseline will be summarized by
scheduled visit using mean, median, standard deviation, minimum and maximum.
In addition vital signs values will be categorized as follows:

Systolic BP (mmHg): Grade 0 (<120), Grade 1 (≥120-<140), Grade 2 (≥140-<160)
and Grade 3 (≥160)

Diastolic BP (mmHg): Grade 0 (<80), Grade 1 (≥80-<90), Grade 2 (≥90-<100), and
Grade 3 (≥100)

Heart rate (beats/min): <60, 60-100, and >100

Temperature (°C): <35, 35<= and <38, ≥38
Summaries of increase in vital signs from the baseline with respect to the categories 
defined above will be performed. These summaries will display the number and
percentage of subjects with any grade increase, increase to grade 2 and increase to grade
3 at each scheduled assessment time and in the worst case post-baseline.
A supportive listing will also be provided.
Performance Status
ECOG performance status will be summarized at baseline and each post-baseline
scheduled visit. Summaries will use frequency and percentage of subjects at each planned
assessment time. A summary of change from baseline by scheduled visits will be
performed, as well as the worst case post-baseline and the best case post-baseline changes
during the study.
A supporting listing will also be provided.
ECG
The summaries for the QTc will use the collected value only.
A summary of the number and percentage of subjects who had normal and abnormal 
(clinically significant and not clinically significant) ECG findings will be displayed by
scheduled visits as well as for the worst case post-baseline.


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The QTc values based on Bazett’s formula will be rounded to the integer and the values
will be categorized into the following ranges: Grade 0 (<450), Grade 1 (450-480), Grade
2 (481-500), and Grade 3 (≥501).  A summary of grade shifts from baseline value for
each scheduled assessment time and in the worst case post-baseline will be provided.
Summaries of grade increase will be provided. These summaries will display the number
and percentage of subjects with any grade increase and increase to grade 3 at each
scheduled assessment time and in the worst case post-baseline.
The changes in QTc values will be categorized into the clinical concern ranges which are
specific to changes in QTc: 31-60 and >60 msec. A summary of change in QTc value will
display the number and percentage of subjects with a change within each range at each
scheduled assessment time and in the worst case post-baseline. Subjects with missing
baseline values will be excluded from this summary.
Listings of abnormal ECG findings and a listing of ECG values will be provided. In
addition, a listing the QTc data for subjects in each cohort an absolute QTcB interval
501 (Grade 3) and an increase from baseline QTcB of >60 at any time in the on-therapy
period (that is, these values do not have to be at the same assessment but the subject must 
be on study treatment or within 30 days of the last dose of study treatment) will be
produced.
A figure plotting the baseline QTc and the worst-case post-baseline values will be
produced. The figure will have reference lines at 450 and 500 msec for both the ordinate
and the abscissa axes. There will be diagonal reference lines at equality (i.e., a 45 degree
line), at equality plus 30 msec, and at equality plus 60 msec.
LVEF
Absolute change from baseline in LVEF will be summarized at each scheduled
assessment time and in the worst case post-baseline. Only the post-baseline assessments
that used the same method (ECHO or MUGA) as the baseline assessments will be used to
derive the change from baseline. The change from baseline will be categorized as
follows:

Any increase

No change

Any decrease:
o 0 - <10% Decrease
o 10 -
<20% Decrease
o ≥20% Decrease

≥10% decrease and ≥LLN

≥10% decrease and < LLN

>10% decrease and < LLN


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
≥20% decrease and ≥LLN

≥20% decrease and < LLN
LVEF results will also be listed with subject level details including absolute change from 
baseline.
Liver Events
For any liver events that occur during the study, the liver event information for RUCUM
score will be summarized, including whether the subject was age 55 or over, whether the 
subject became pregnant, liver imaging normal or not, a biopsy was taken or not, whether 
there was fasting or significant dietary change, whether the subject took any
unconventional medications, timing when the event occurs (while on treatment or after 
stopping treatment) and summary statistics for time from first dose to start of liver event 
and time from last dose to start of liver event. If the number of events does not support a 
summary, then only listings will be produced.
For subjects with multiple events, the first event will be used for the summary tables. All 
events with subject level details will be displayed in a supporting listing.
Ocular Exams
Baseline and Week 4 data will be summarized based on the number and percentage of
subjects who receive an ocular exam. Because post-baseline exams are only performed as
clinically indicated, data beyond Week 4 will only be listed.


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13.
REFERENCES
Brookmeyer R, Crowley J. A confidence interval for the median survival time.
Biometrics, 1982; 38:29-41.
Fleiss, J.L. Statistical Methods for Rates and Proportions (1981), pp. 13-15.
GlaxoSimthKline Document Number 2013N168168437_01, protocol, A Phase II, Open-
Label, Multicentre Study of Dabrafenib plus Trametinib in Subjects with BRAF
Mutation- Positive Melanoma that has Metastasized to the Brain. Effective Date: 27-
APR-2014
GUI_137354: Information for Authors: Reporting and Analysis Plans
Hollander M, Wolfe DA. Nonparametric Statistical Methods. 2nd ed. New York: John 
Wiley & Sons; 1999.
European Medicines Evaluation Agency (CPMP/ICH/3633/96). ICH Topic E9: Statistical
principles for clinical trials. Committee for Proprietary Medicinal Products (CPMP), 
European Agency for the Evaluation of Medicinal Products. London: European
Medicines Evaluation Agency, September 1998
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika, 
1983; 70(3):659-663


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14.
ATTACHMENTS
14.1.
Table of Contents for Data Display Specifications
Table
Study
Pop
1.0010
Summary of Study Populations by Cohort
Table
Study
Pop
1.1010
Summary of Number of Subjects by Centre
Table
Study
Pop
1.1110
Summary of Subject Disposition by Cohort
Table
Study
Pop
1.1220
Summary of Study Treatment Status for Trametinib by Cohort
Table
Study
Pop
1.1221
Summary of Study Treatment Status for Dabrafenib by Cohort
Table
Study
Pop
1.1310
Summary of Inclusion/Exclusion Criteria Deviations
Table
Study
Pop
1.1410
Summary of Protocol Deviations
Table
Study
Pop
1.2010
Summary of Demographic Characteristics by Cohort
Table
Study
Pop
1.2110
Summary of Extracranial Disease Burden at Baseline by Cohort
Table
Study
Pop
1.2020
Summary of Race and Racial Combinations
Table
Study
Pop
1.2120
Summary of Tobacco and Alcohol Use by Cohort
Table
Study
Pop
1.3110
Summary of Past Medical Conditions by Cohort
Table
Study
Pop
1.3111
Summary of Current Cancer-Related Medical Conditions by Cohort
Table
Study
Pop
1.3210
Summary of Disease Characteristics at Initial Diagnosis by Cohort
Table
Study
Pop
1.3220
Summary of Disease Characteristics at Screening by Cohort
Table
Study
Pop
1.3230
Summary of Metastatic Disease at Screening by Cohort
Table
Study
Pop
1.4010
Summary of Coded Anti-Cancer Therapy by Cohort
Table
Study
Pop
1.4020
Summary of Prior Dictionary Coded Anti-Cancer Therapy by
Cohort
Table
Study
Pop
1.4030
Summary of Number of Prior Anti-Cancer Therapy Regimens by
Cohort
Table
Study
Pop
1.4110
Summary of Prior Cancer-Related Surgical Procedures by cohort


53
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confirmation) (modified RECIST 1.1 Criteria) by Cohort
Independent Reviewer-Assessed Best Extracranial Response
(with confirmation) (modified RECIST 1.1 Criteria) by Cohort 
Independent Reviewer-Assessed Best Overall Response (with
confirmation) (modified RECIST 1.1 Criteria) by Cohort
Summary of Comparison of Investigator-Assessed and
Independent Reviewer-Assessed Best Intracranial Response (with
confirmation) (Modified RECIST 1.1 Criteria)
Summary of Comparison of Investigator-Assessed and
Independent Reviewer-Assessed Best Extracranial Response
(with confirmation) (Modified RECIST 1.1 Criteria)
Summary of Comparison of Investigator-Assessed and
Independent Reviewer-Assessed Best Overal Response (with
confirmation) (Modified RECIST 1.1 Criteria)
Comparison of Investigator and BICR Progression-Free Survival 
Timings b y Cohort
Kaplan-Meier Estimates of Investigator-Assessed Duration of
Intracranial Response by Cohort
Kaplan-Meier Estimates of Investigator-Assessed Duration of
Extracranial Response by Cohort
Kaplan-Meier Estimates of Investigator-Assessed Duration of
Overall Response by Cohort
Kaplan-Meier Estimates of Independent Reviewer-Assessed
Duration of Intracranial Response by Cohort
Table
Study
Pop
1.4220
Summary of Duration of Follow-up by Cohort
Table
Study
Pop
1.5010
Summary of Concomitant Medications by Cohort
Table
Study
Pop
1.6010
Summary of Overall Compliance (Dabrafenib) by Cohort
Table
Study
Pop
1.6011
Summary of Overall Compliance (Trametinib) by Cohort
Table
Efficacy
2.0020
Table
Efficacy
2.0022
Table
Efficacy
2.0060
Table
Efficacy
2.1010
Table
Efficacy
2.1012
Table
Efficacy
2.1013
Table
Efficacy
2.1014
Table
Efficacy
2.1015
Table
Efficacy
2.1016
Table
Efficacy
2.1050
Table
Efficacy
2.1051
Table
Efficacy
2.1052
Table
Efficacy
2.2010
Table
Efficacy
2.6010
Table
Efficacy
2.6011
Table
Efficacy
2.6012
Table
Efficacy
2.6013


54
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BRF117277
Table
Efficacy
2.6014
Kaplan-Meier Estimates of Independent Reviewer-Assessed
Duration of Extracranial Response by Cohort
Table
Efficacy
2.6015
Kaplan-Meier Estimates of Independent Reviewer-Assessed
Duration of Overall Response by Cohort
Table
Efficacy
2.7010
Summary of Concordance Between Investigator-Assessed and
Independent Reviewer-Assessed Best Intracranial Response (with
confirmation) (Modified RECIST 1.1 Criteria)
Table
Efficacy
2.7020
Summary of Concordance Between Investigator-Assessed and
Independent Reviewer-Assessed Best Extracranial Response
(with confirmation) (Modified RECIST 1.1 Criteria)
Table
Efficacy
2.7030
Summary of Concordance Between Investigator-Assessed and
Independent Reviewer-Assessed Best Overal Response (with
confirmation) (Modified RECIST 1.1 Criteria)
Table
Safety
3.0010
Summary of Exposure to Dabrafenib by Cohort
Table
Safety
3.0011
Summary of Exposure to Trametinib by Cohort
Table
Safety
3.0040
Summary of Dose Reductions by Cohort (Dabrafenib)
Table
Safety
3.0041
Summary of Dose Reductions by Cohort (Trametinib)
Table
Safety
3.0050
Summary of Dose Interruptions by Cohort (Dabrafenib)
Table
Safety
3.0051
Summary of Dose Interruptions by Cohort (Trametinib)
Table
Safety
3.1010
Adverse Event Overview by Cohort
Table
Safety
3.1020
Summary of All Adverse Events by Cohort (by System Organ
Class)
Table
Safety
3.1030
Summary of All Adverse Events by Cohort (by Preferred Term)
Table
Safety
3.1040
Summary of Common Non-Serious Adverse Events by Cohort
Table
Safety
3.1070
Summary of Adverse Events By Maximum Grade and Cohort
Table
Safety
3.1090
Summary of Adverse Events of Special Interest by Maximum
Grade and Cohort
Table
Safety
3.1110
Summary of Adverse Events Related to Dabrafenib by Cohort
Table
Safety
3.1111
Summary of Adverse Events Related to Trametinib by Cohort
Table
Safety
3.1210
Summary of Serious Adverse Events by Cohort
Table
Safety
3.1220
Summary of Serious Adverse Events By Maximum Grade and
Cohort
Table
Safety
3.1310
Summary of Serious Adverse Events Related to Dabrafenib by 
Cohort


55
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BRF117277
Table
Safety
3.1311
Summary of Serious Adverse Events Related to Trametinib by 
Cohort
Table
Safety
3.1410
Summary of Fatal Adverse Events by Cohort
Table
Safety
3.1420
Summary of Fatal Adverse Events Related to Dabrafenib by 
Cohort
Table
Safety
3.1421
Summary of Fatal Adverse Events Related to Trametinib by Cohort
Table
Safety
3.1510
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment by Cohort
Table
Safety
3.1520
Summary of Adverse Events Leading to Dose Reductions by 
Cohort
Table
Safety
3.1530
Summary of Adverse Events Leading to Dose Interruptions by 
Cohort
Table
Safety
3.1600
Adverse Events of Special Interest Overview by Cohort
Table
Safety
3.1610
Summary of Characteristics of Non-Cutaneous Treatment 
Emergent Malignancies
Table
Safety
3.1611
Summary of Onset of the First Occurrence of Non-Cutaneous 
Treatment Emergent Malignancies
Table
Safety
3.1613
Summary of Characteristics of New Primary Melanoma
Table
Safety
3.1614
Summary of Onset of the First Occurrence of New Primary 
Melanoma
Table
Safety
3.1616
Summary of Characteristics of Cutaneous Squamous Cell
Carcinoma including Keratoacanthoma
Table
Safety
3.1617
Summary of Onset of the First Occurrence of Cutaneous 
Squamous Cell Carcinoma including Keratoacanthoma
Table
Safety
3.1619
Summary of Characteristics of Cardiac Related Events
Table
Safety
3.1620
Summary of Onset and Duration of the First Occurrence of Cardiac 
Related Events
Table
Safety
3.1622
Summary of Characteristics of Hypertension
Table
Safety
3.1623
Summary of Onset and Duration of the First Occurrence of 
Hypertension
Table
Safety
3.1625
Summary of Characteristics of Diarrhea
Table
Safety
3.1626
Summary of Onset and Duration of the First Occurrence of 
Diarrhea
Table
Safety
3.1628
Summary of Characteristics of Ocular Events
Table
Safety
3.1629
Summary of Onset and Duration of the First Occurrence of Ocular
Events
Table
Safety
3.1631
Summary of Characteristics of Pneumonitis/Interstitial lung disease


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BRF117277
Table
Safety
3.1632
Summary of Onset and Duration of the First Occurrence of 
Pneumonitis/Interstitial lung disease
Table
Safety
3.1634
Summary of Characteristics of Skin-Related Toxicities
Table
Safety
3.1635
Summary of Onset and Duration of the First Occurrence of Skin-
Related Toxicities
Table
Safety
3.1637
Summary of Characteristics of Neutropenia
Table
Safety
3.1638
Summary of Onset and Duration of the First Occurrence of 
Neutropenia
Table
Safety
3.1640
Summary of Characteristics of Uveitis
Table
Safety
3.1641
Summary of Onset and Duration of the First Occurrence of Uveitis
Table
Safety
3.1643
Summary of Characteristics of Deep Vein Thrombosis/Pulmonary 
Embolism
Table
Safety
3.1644
Summary of Onset and Duration of the First Occurrence of Deep 
Vein Thrombosis/Pulmonary Embolism
Table
Safety
3.1646
Summary of Characteristics of Edema
Table
Safety
3.1647
Summary of Onset and Duration of the First Occurrence of Edema
Table
Safety
3.1649
Summary of Characteristics of Pre-renal and Intrinsic Renal
Failure
Table
Safety
3.1650
Summary of Onset and Duration of the First Occurrence of Pre-
renal and Intrinsic Renal Failure
Table
Safety
3.1652
Summary of Characteristics of Hepatic Disorders
Table
Safety
3.1653
Summary of Onset and Duration of the First Occurrence of Hepatic 
Disorders
Table
Safety
3.1655
Summary of Characteristics of Pyrexia
Table
Safety
3.1656
Summary of Onset and Duration of the First Occurrence of Pyrexia
Table
Safety
3.1658
Summary of Characteristics of Pancreatitis
Table
Safety
3.1659
Summary of Onset and Duration of the First Occurrence of 
Pancreatitis
Table
Safety
3.1661
Summary of Characteristics of Hyperglycemia
Table
Safety
3.1662
Summary of Onset and Duration of the First Occurrence of 
Hyperglycemia
Table
Safety
3.1664
Summary of Characteristics of Hypersensitivity
Table
Safety
3.1665
Summary of Onset and Duration of the First Occurrence of 
Hypersensitivity


57
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Table
Safety
3.1667
Summary of Characteristics of Bleeding Events
Table
Safety
3.1668
Summary of Onset and Duration of the First Occurrence of 
Bleeding Events
Table
Safety
3.2010
Summary of Deaths by Cohort
Table
Safety
3.3010
Summary of Chemistry Values by Cohort
Table
Safety
3.3011
Summary of Haematology Values by Cohort
Table
Safety
3.3012
Summary of Liver Function Test Values by Cohort
Table
Safety
3.3013
Summary of Baseline Coagulation Test Values by Cohort
Table
Safety
3.3020
Summary of Chemistry Grade Changes from Baseline Grade
Table
Safety
3.3021
Summary of Hematology Grade Changes from Baseline Grade by 
Cohort
Table
Safety
3.3022
Summary of Liver Function Test Grade Changes from Baseline 
Grade by Cohort
Table
Safety
3.3030
Summary of Chemistry Changes from Baseline With Respect to 
the Normal Range
Table
Safety
3.3031
Summary of Hematology Changes from Baseline With Respect to 
the Normal Range
Table
Safety
3.3032
Summary of Liver Function Test Changes from Baseline With 
Respect to the Normal Range
Table
Safety
3.4010
Summary of Vital Signs by Cohort
Table
Safety
3.4020
Summary of Vital Sign Changes from Baseline by Cohort
Table
Safety
3.4030
Summary of Changes in Heart Rate from Baseline by Cohort
Table
Safety
3.4040
Summary of Increases in Systolic Blood Pressure from Baseline by
Cohort
Table
Safety
3.4041
Summary of Increases in Diastolic Blood Pressure from Baseline 
by Cohort
Table
Safety
3.4090
Summary of Left Ventricular Ejection Fraction Change from 
Baseline by Cohort
Table
Safety
3.4110
Summary of ECOG performance Status by Cohort
Table
Safety
3.4120
Summary of Change in ECOG Performance Status from Baseline 
by Cohort
Table
Safety
3.6010
Summary of ECG Findings by Cohort
Table
Safety
3.6030
Summary of Increases in QTc (Bazett's) from Baseline by Cohort


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Table
Safety
3.6040
Summary of Amount of Increase from Baseline Value in QTc 
(Bazett's) by Cohort
Table
Safety
3.6050
Summary of QTc (Bazett's) Shifts from Baseline Value by Cohort
Table
Safety
3.8010
Summary of Liver Chemistry Assessments for Subjects with Liver
Signal/Event by Cohort
Table
Safety
3.8020
Summary of Hepatobiliary Laboratory Abnormalities by Cohort
Table
Safety
3.8030
Summary of Liver Event Information for RUCAM Score by Cohort
Table
Safety
3.9010
Summary of Ophthalmic Examinations by Cohort
Figure
Efficacy
12.0010
Graph of Kaplan Meier Investigator-Assessed Progression Free
Survival Curve by Cohort
Figure
Efficacy
12.0020
Graph of Kaplan Meier Investigator-Assessed Duration of
Intracranial Response Curve by Cohort
Figure
Efficacy
12.0021
Graph of Kaplan Meier Investigator-Assessed Duration of
Extracranial Response Curve by Cohort
Figure
Efficacy
12.0022
Graph of Kaplan Meier Investigator-Assessed Duration of Overall
Response Curve by Cohort
Figure
Efficacy
12.0011
Graph of Kaplan Meier Independent Reviewer-Assessed
Progression Free Survival Curve by Cohort
Figure
Efficacy
12.0023
Graph of Kaplan Meier Independent Reviewer-Assessed Duration
of Intracranial Response Curve by Cohort
Figure
Efficacy
12.0024
Graph of Kaplan Meier Independent Reviewer-Assessed Duration
of Extracranial Response Curve by Cohort
Figure
Efficacy
12.0025
Graph of Kaplan Meier Independent Reviewer-Assessed Duration
of Overall Response Curve by Cohort
Figure
Efficacy
12.0030
Graph of Kaplan Meier Overall Survival Curves by Cohort
Figure
Efficacy
12.0040
Investigator-Assessed Percent Change at Maximum Reduction
from Baseline in Intracranial Tumour Measurement by Cohort
Figure
Efficacy
12.0041
Independent Reviewer-Assessed Percent Change at Maximum
Reduction from Baseline in Intracranial Tumour Measurement by
Cohort
Figure
Safety
12.0050
QTc (Bazett's) Shifts from Baseline to Worst-case Post Baseline
by Cohort
Figure
Safety
12.0060
Figure of LFT Patient Profiles for Possible Hy’s Law Subjects by
Cohort
Figure
Safety
12.0070
Figure of Maximum Total Bilirubin vs Maximum ALT by Cohort –
eDISH Plot
Listing
Study
Pop
21.0010
Listing of Planned and Actual Treatments
Listing
Study
Pop
21.0020
Listing of Subjects Excluded from Analysis Population
Listing
Study
Pop
21.0030
Listing of Reasons for Study Withdrawal


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21.0040
Listing of Dabrafenib Discontinuation Record
21.0041
Listing of Trametinib Discontinuation Record
21.0050
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
21.0060
Listing of Protocol Deviations
21.0070
Listing of Demographic Characteristics
21.0080
Listing of Race
21.0090
Listing of Overall Compliance (Dabrafenib)
21.0091
Listing of Overall Compliance (Tramatinib)
21.0100
Listing of Drug Accountability (Dabrafenib)
21.0101
Listing of Drug Accountability (Tramatinib)
22.0010
Listing of Investigator-Assessed Progression-Free Survival
22.0011
Listing of Independent Reviewer-Assessed Progression-Free
Survival
22.0020
Listing of Overall Survival
22.0030
Listing of Investigator-Assessed Duration of Response
22.0031
Listing of Independent Reviewer-Assessed Duration of Response
22.0040
Listing of Investigator-Assessed Target Lesion Assessments
(modified RECIST 1.1 Criteria)
22.0050
Listing of Investigator.-Assessed Non-Target Lesion Assessments
(modified RECIST 1.1 Criteria)
22.0060
Listing of Investigator-Assessed New Lesions (modified RECIST
1.1 Criteria)
22.0041
Listing of Independent Reviewer-Assessed Target Lesion
Assessments (modified RECIST 1.1 Criteria)
22.0051
Listing of Independent Reviewer-Assessed Non-Target Lesion
Assessments (modified RECIST 1.1 Criteria)
22.0061
Listing of Independent Reviewer-Assessed New Lesions (modified
RECIST 1.1 Criteria)
22.0070
Listing of Investigator-Assessed Tumour Responses (with
confirmation) (modified RECIST1.1 Criteria)
22.0071
Listing of Independent Reviewer.-Assessed Tumour Responses
(with confirmation) (modified RECIST1.1 Criteria)
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Efficacy
Listing
Efficacy
Listing
Efficacy
Listing
Efficacy
Listing
Efficacy
Listing
Efficacy
Listing
Efficacy
Listing
Efficacy
Listing
Efficacy
Listing
Efficacy
Listing
Efficacy
Listing
Efficacy
Listing
Efficacy


60
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BRF117277
23.0010
Listing of Exposure to Dabrafenib
23.0011
Listing of Exposure to Trametinib
23.0020
Listing of Dose Reductions of Dabrafenib
23.0021
Listing of Dose Reductions of Trametinib
23.0030
Listing of Dose Interruptions of Dabrafenib
23.0031
Listing of Dose Interruptions of Trametinib
23.0090
Listing of Relationship Between System Organ Class, Preferred
Term, and Verbatim Text
23.0100
Listing of Subject Numbers for Individual Adverse Events
23.0110
Listing of All Adverse Events
23.0120
Listing of Fatal Serious Adverse Events
23.0130
Listing of Non-Fatal Serious Adverse Events
23.0140
Listing of Adverse Events Leading to Permanent Discontinuation of
Dabrafenib
23.0141
Listing of Adverse Events Leading to Permanent Discontinuation of
Trametinib
23.0150
Listing of Adverse Events that Lead to Dose Interruptions of
Dabrafenib
23.0151
Listing of Adverse Events that Lead to Dose Interruptions of
Trametinib
23.0200
Listing of Non-Cutaneous Treatment Emergent Malignancies
23.0201
Listing of Cardiac-Related Events
23.0202
Listing of Hypertension
23.0203
Listing of Diarrhea
23.0204
Listing of Ocular Events
23.0205
Listing of Pneumonitis/Interstitial lung disease
23.0206
Listing of Skin-Related Toxicities
23.0207
Listing of Neutropenia
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety


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BRF117277
23.0208
Listing of Uveitis
23.0209
Listing of Deep Vein Thrombosis/Pulmonary Embolism
23.0210
Listing of Edema
23.0211
Listing of Pre-renal and Intrinsic Renal Failure
23.0212
Listing of Hepatic Disorders
23.0213
Listing of New Primary Melanoma
23.0214
Listing of Cutaneous Squamous Cell Carcinoma including
Keratoacanthoma
23.0215
Listing of Pyrexia
23.0216
Listing of Pancreatitis
23.0217
Listing of Hyperglycemia
23.0218
Listing of Hypersensitivity
23.0219
Listing of Bleeding Events
23.0250
Listing of Deaths
23.0260
Listing of All Laboratory Data
23.0270
Listing of Laboratory Data for Subjects with Lab Values Outside of
Normal Range
23.0280
Listing of ECOG Performance Status
30.0010
Listing of Tobacco Use
30.0011
Listing of Alcohol Consumption
30.0020
Listing of Past Medical Conditions
30.0021
Listing of Current Cancer-Related Medical Conditions
30.0030
Listing of Disease Characteristics at Initial Diagnosis
30.0040
Listing of Disease Characteristics at Screening
30.0050
Listing of Prior Anti-Cancer Therapy
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop


62
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30.0060
Listing of Prior Anti-Cancer Radiotherapy
30.0070
Listing of Prior Cancer-Cancer Related Surgical Procedures
30.0090
Listing of Concomitant Medications
30.0130
Listing of Subjects with a Difference between Investigator-
Assessed and Independent Reviewer-Assessed Tumour
Response (with confirmation) (modified RECIST 1.1 Criteria)
30.0140
Listing of Subjects with a Difference between Investigator-
Assessed and Independent Reviewer-Assessed Best Tumor
Response
30.0220
Listing of Subject Numbers for Specific Causes of Deaths
30.0240
Listing of Abnormal ECG Findings
30.0250
Listing of ECG Values
30.0270
Listing of Vital Signs
30.0280
Listing of Left Ventricular Ejection Fraction Results
30.0290
Listing of Liver Chemistry Assessments for Subjects with Liver
Signal/Events
30.0300
Listing of Liver Laboratory Tests and Grade
30.0330
Listing of Ophthalmic Examinations
14.1.1.
Data Display Deliverables
All displays in Section 14.1 will be provided at the time of the primary endpoint analysis.
The following displays from Section 14.1 will be provided for the interim analysis:
Table
No.
Title
1.0010
Summary of Study Populations by Cohort
1.1110
Summary of Subject Disposition by Cohort
1.1220
Summary of Study Treatment Status For Trametinib by Cohort
Listing
Study
Pop
Listing
Study
Pop
Listing
Study
Pop
Listing
Efficacy
Listing
Efficacy
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety
Listing
Safety


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1.1221
Summary of Study Treatment Status For Dabrafenib by Cohort
1.2010
Summary of Demographic Characteristics by Cohort
1.2110
Summary of Extracranial Disease Burden at Baseline by Cohort 
1.3220
Summary of Disease Characteristics at Screening By Cohort 
1.4020
Summary of Prior Dictionary Coded Anti-Cancer Therapy by Cohort
1.4030
Summary of Number of Prior Anti-Cancer Therapy Regimens by Cohort
1.5010
Summary of Concomitant Medications by Cohort
2.1009
Investigator-Assessed Best Intracranial Response (with confirmation) (modified
RECIST 1.1 Criteria) for Cohort A (Interim Analysis)
2.1010
Investigator-Assessed Best Intracranial Response (with confirmation) (modified
RECIST 1.1 Criteria) for Cohort A (Primary Analysis)
2.1011
Investigator-Assessed Best Intracranial Response (with confirmation) (modified
RECIST 1.1 Criteria) for Cohorts B, C, and D
2.1012
Investigator-Assessed Best Extracranial Response (with confirmation) (modified
RECIST 1.1 Criteria) by Cohort
2.1013
Investigator-Assessed Best Overall Response (with confirmation) (modified RECIST
1.1 Criteria) by Cohort
3.0010      Summary of Exposure to Dabrafenib by Cohort 
3.0011       Summary of Exposure to Trametinib by Cohort 
3.1010      Adverse Event Overview by Cohort
3.1070
Summary of Adverse Events By Maximum Grade by Cohort
3.1090
Summary of Adverse Events of Special Interest by Maximum Grade and Cohort 
3.1110
Summary of Adverse Events Related to Dabrafenib by Cohort
3.1111
Summary of Adverse Events Related to Trametinib by Cohort 
3.1210
Summary of Serious Adverse Events by Cohort
3.1410
Summary of Fatal Adverse Events by Cohort
3.1510
Summary of Adverse Events Leading to Permanent Discontinuation of Study 
Treatment by Cohort
3.1520
Summary of Adverse Events Leading to Dose Reductions by Cohort


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3.1530
Summary of Adverse Events Leading to Dose Interruptions by Cohort 
3.1600
Adverse Events of Special Interest Overview by Cohort
3.2010
Summary of Deaths by Cohort
3.3020
Summary of Chemistry Grade Changes from Baseline Grade
3.3021
Summary of Hematology Grade Changes from Baseline Grade by Cohort
3.3020
Summary of Liver Function Test Grade Changes from Baseline Grade by Cohort 
3.3030
Summary of Chemistry Changes from Baseline With Respect to the Normal Range 
3.3031
Summary of Hematology Changes from Baseline With Respect to the Normal Range 
3.3032
Summary of Liver Function Test Changes from Baseline With Respect to the Normal
Range
3.4020
Summary of Vital Sign Changes from Baseline by Cohort
3.4040
Summary of Increases in Systolic Blood Pressure from Baseline by Cohort 
3.4090
Summary of Left Ventricular Ejection Fraction Change from Baseline by Cohort
3.6010
Summary of ECG Findings by Cohort
3.6030
Summary of Increases in QTc (Bazett's) by Cohort
3.6040
Summary of Amount of Increase from Baseline Value in QTc (Bazett's) by Cohort 
3.6050
Summary of QTc (Bazett's) Shifts from Baseline Value by Cohort
3.8010
Summary of Liver Chemistry Assessments for Subjects with Liver Signal/Event 
by Cohort
3.8020
Summary of Hepatobiliary Laboratory Abnormalities by Cohort 
3.8030
Summary of Liver Event Information for RUCAM Score by Cohort
The displays for the End of Study analysis will be provided in a separate TFL document:
14.2.
Data Display Specifications
The data display specifications are contained in a separate document. The display mock-
ups are provided as a guideline. The final formats and layouts may be revised due to
potential limitations of the programs and tools used to produce the displays.