Conditions: Melanoma
Keywords: MEK inhibitor trametinib Oncology adjuvant melanoma dabrafenib dabrafenib and trametinib combination therapy BRAF mutation-positive melanoma BRAF inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 870
Healthy volunteers: no

Brief summary:
This was a two-arm, randomized, double-blind Phase III study of dabrafenib in combination with trametinib versus two placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk \[Stage IIIa (lymph node metastasis \>1 mm), IIIb or IIIc\] cutaneous melanoma were screened for eligibility. Subjects were randomized to receive either dabrafenib (150 milligram (mg) twice daily \[BID\]) and trametinib (2 mg once daily \[QD\]) combination therapy or two placebos for 12 months.

Detailed description:
This was a two-arm, randomized, double-blind, multi-center, international phase III study of dabrafenib in combination with trametinib versus two matching placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk \[Stage IIIa (lymph node metastasis \>1 mm), IIIb or IIIc\] cutaneous melanoma were screened for eligibility. Subjects were randomized to receive either dabrafenib (150 milligram (mg) twice daily \[BID\]) and trametinib (2 mg once daily \[QD\]). None of the patients had undergone previous systemic anticancer treatment or radiotherapy for melanoma. All the patients had undergone completion lymphadenectomy with no clinical or radiographic evidence of residual regional node disease within 12 weeks before randomization, had recovered from definitive surgery, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. BRAF V600 mutation status was confirmed in primary-tumor or lymph-node tissue by a central reference laboratory. All the patients provided written informed consent.

The primary end point was recurrence-free survival, Overall survival, as the key secondary end point, was to be tested in a hierarchical manner only if the primary end point met the criteria for significance. The overall survival analysis used a preplanned three-look Lan-DeMets group sequential design with an O'Brien-Fleming-type boundary, which was used to determine the significance threshold for the first interim overall survival analysis (two-sided P=0.000019).

Disease assessments included clinical examination and imaging by means of computed tomography, magnetic resonance imaging, or both.) Imaging was performed every 3 months during the first 24 months, then every 6 months until disease recurrence or the completion of the trial. Follow-up for survival began after recurrence and continued through the end of the trial. Adverse events and laboratory values were assessed at screening, on the date of randomization, at least once per month through month 12, and at every visit for disease-recurrence assessment after month 12. Adverse events and laboratory values were graded according to the Common Terminology Criteria for Adverse Events, version 4.0.

Arms:
arm 1: Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months. arm 2: Subjects received matching placebos orally for 12 months

Interventions: intervention 1: Dabrafenib intervention 2: Trametinib intervention 3: Placebos
Intervention descriptions: intervention 1: Each capsule contained 50 mg or 75 mg of free base (present as the mesylate salt) intervention 2: Each tablet contained 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate) intervention 3: The placebo capsules and tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment

Protocol document:
Prot_001.pdf: 


















N o v arti s
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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 ( Cl e a n )
Pr ot o c ol N o. B R F 1 1 5 5 3 2
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 ati o n al N e w Dr u g (I N D) N u m b er
1 1 3, 5 5 7
E ur o p e a n Dr u g R e g ul at ory A ut h oriti es Cli nic al Tri als ( E u dr a C T) N u m b er  
2 0 1 2 -0 0 1 2 6 6 -1 5
U niv ers al Tri al N u m b er ( U T N )
U 1 1 1 1 -1 1 4 8 -3 7 7 8




































N o v arti s
C o nfi d e nti al
P a g e 2 8
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 ( Cl e a n )
Pr ot o c ol N o. B R F 1 1 5 5 3 2 
data ha ve de m o nstrate d M E K acti vati o n at t he ti me of rela pse, t h us t he a d diti o n of a 
M E K i n hi bit or t o da brafe ni b re prese nts a n attracti ve t hera pe utic strate g y  [G oetz , 2 0 1 2].  
Cell li ne data ge nerate d b y  G S K are si milar t o i n vitr o data wit h ot her B R A F/ M E K 
i n hi bit or c o m bi nati o ns [C orc ora n , 2 0 1 0; E mer y , 2 0 0 9].  Si milar t o cell li ne data, i n 
m o use xe n o graft st u dies wit h A 3 7 5 cells w hic h har b or a B R A F V 6 0 0 E m utati o n, t he 
c o m bi nati o n of da brafe ni b a n d tra meti ni b was si g nifica ntl y  better t ha n eit her a ge nt al o ne.
T he c o m bi nati o n i n t he a dj u va nt setti n g als o pre ve nts M E K acti vati o n i n n or mal tiss ues, 
a mec ha nistic si de effect of B R A F m o n ot hera p y, w hic h ca n lea d t o de vel o p me nt of l o w -
gra de s q ua m o us -cell carci n o mas.  T he c o m bi nati o n of B R A F/ M E K i n hi bit ors pre ve nte d 
t he de vel o p me nt of pr oliferati ve s ki n lesi o ns (e pit helial h yper plasia a n d h y per kerat osis of 
t he s ki n, n o n gla n d ular st o mac h a n d/ or f o ot pa ds) o bser ve d i n rats f oll o wi n g treat me nt 
wit h a B R A F i n hi bit or al o ne, s u g gesti n g t hat t he a d diti o n of M E K t o B R A F ma y  
p ote ntiall y  miti gate t he ris k of de vel o pi n g e pit helial pr oliferati ve effects (i.e., c uta ne o us 
s q ua m o us cell carci n o ma) as o bser ve d i n t he cli nic.  O bser vati o ns o n pr oliferati ve s ki n 
effects are si milar t o t h ose p u blis he d wit h a n ot her B R A F/ M E K i n hi bit or c o m bi nati o n 
[Car na ha n , 2 0 1 0].  M ore i m p orta ntl y, e mer ge nce of cli nicall y-si g nifica nt R A S-dri ve n 
t u m ors is far less li kel y t o occ ur w he n t here is c o m bi ne d B R A F/ M E K i n hi biti o n t ha n 
wit h B R A F al o ne [ La c o ut ure, 2 0 1 2].  
T o get her t he precli nical st u dies a n d cli nical data s u p p ort f urt her cli nical e val uati o n of 
da brafe ni b a n d tra meti ni b c o m bi nati o n t hera p y i n s u bjects wit h B R A F -V 6 0 0 E/ K 
m utati o n -p ositi ve mela n o ma i n t he a dj u va nt setti n g.  







































































































































































































































































































SAP_000.pdf: 


















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 ( Cl e a n )
Pr ot o c ol N o. B R F 1 1 5 5 3 2
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 ati o n al N e w Dr u g (I N D) N u m b er
1 1 3, 5 5 7
E ur o p e a n Dr u g R e g ul at ory A ut h oriti es Cli nic al Tri als ( E u dr a C T) N u m b er  
2 0 1 2 -0 0 1 2 6 6 -1 5
U niv ers al Tri al N u m b er ( U T N )
U 1 1 1 1 -1 1 4 8 -3 7 7 8




































N o v arti s
C o nfi d e nti al
P a g e 2 8
Cli ni c al St u d y Pr ot o c ol V er si o n 0 7 ( Cl e a n )
Pr ot o c ol N o. B R F 1 1 5 5 3 2 
data ha ve de m o nstrate d M E K acti vati o n at t he ti me of rela pse, t h us t he a d diti o n of a 
M E K i n hi bit or t o da brafe ni b re prese nts a n attracti ve t hera pe utic strate g y  [G oetz , 2 0 1 2].  
Cell li ne data ge nerate d b y  G S K are si milar t o i n vitr o data wit h ot her B R A F/ M E K 
i n hi bit or c o m bi nati o ns [C orc ora n , 2 0 1 0; E mer y , 2 0 0 9].  Si milar t o cell li ne data, i n 
m o use xe n o graft st u dies wit h A 3 7 5 cells w hic h har b or a B R A F V 6 0 0 E m utati o n, t he 
c o m bi nati o n of da brafe ni b a n d tra meti ni b was si g nifica ntl y  better t ha n eit her a ge nt al o ne.
T he c o m bi nati o n i n t he a dj u va nt setti n g als o pre ve nts M E K acti vati o n i n n or mal tiss ues, 
a mec ha nistic si de effect of B R A F m o n ot hera p y, w hic h ca n lea d t o de vel o p me nt of l o w -
gra de s q ua m o us -cell carci n o mas.  T he c o m bi nati o n of B R A F/ M E K i n hi bit ors pre ve nte d 
t he de vel o p me nt of pr oliferati ve s ki n lesi o ns (e pit helial h yper plasia a n d h y per kerat osis of 
t he s ki n, n o n gla n d ular st o mac h a n d/ or f o ot pa ds) o bser ve d i n rats f oll o wi n g treat me nt 
wit h a B R A F i n hi bit or al o ne, s u g gesti n g t hat t he a d diti o n of M E K t o B R A F ma y  
p ote ntiall y  miti gate t he ris k of de vel o pi n g e pit helial pr oliferati ve effects (i.e., c uta ne o us 
s q ua m o us cell carci n o ma) as o bser ve d i n t he cli nic.  O bser vati o ns o n pr oliferati ve s ki n 
effects are si milar t o t h ose p u blis he d wit h a n ot her B R A F/ M E K i n hi bit or c o m bi nati o n 
[Car na ha n , 2 0 1 0].  M ore i m p orta ntl y, e mer ge nce of cli nicall y-si g nifica nt R A S-dri ve n 
t u m ors is far less li kel y t o occ ur w he n t here is c o m bi ne d B R A F/ M E K i n hi biti o n t ha n 
wit h B R A F al o ne [ La c o ut ure, 2 0 1 2].  
T o get her t he precli nical st u dies a n d cli nical data s u p p ort f urt her cli nical e val uati o n of 
da brafe ni b a n d tra meti ni b c o m bi nati o n t hera p y i n s u bjects wit h B R A F -V 6 0 0 E/ K 
m utati o n -p ositi ve mela n o ma i n t he a dj u va nt setti n g.