Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD).

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01682083
• Collaborator: (none)
• Enrollment: 870
• Locations: 210
• Arms: 2
• Anticipated Duration (Months): 119.7
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: Dabrafenib; Drug: Trametinib; Drug: Placebos	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 870 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: COMBI-AD: A Phase III Randomized Double Blind Study of Dabrafenib (GSK2118436) in COMBInation With Trametinib (GSK1120212) Versus Two Placebos in the ADjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection
• Actual Study Start Date: Jan 8, 2013
• Actual Primary Completion Date: Jun 30, 2017
• Anticipated Study Completion Date: Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dabrafenib and trametinib Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.	Drug: Dabrafenib; Each capsule contained 50 mg or 75 mg of free base (present as the mesylate salt); Other Names: GSK2118436 ; Drug: Trametinib; Each tablet contained 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate); Other Names: GSK1120212
Placebo Comparator: Dabrafenib and trametinib placebos Subjects received matching placebos orally for 12 months	Drug: Placebos; The placebo capsules and tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment

Outcome Measures

Primary Outcome Measures

1. Relapse-free Survival (RFS) [Approximately 3.5 years]

   Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause.

Secondary Outcome Measures

1. Overall Survival [approximately 3.5 years]

   Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo

2. Distant Metastasis-free Survival [approximately 3.5 years]

   Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event.

3. Freedom From Relapse [approximately 3.5 years]

   Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis more than 1 mm), IIIb or IIIc cutaneous melanoma determined to be V600E/K mutation positive by a central laboratory. Patients presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible.

• Surgically rendered free of disease no more than 12 weeks before randomization.

• Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling drains).

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

• Adequate hematologic, hepatic, renal and cardiac function.

Key Exclusion Criteria:

• Known mucosal or ocular melanoma or the presence of unresectable in-transit metastases.

• Evidence of distant metastatic disease.

• Prior systemic anti-cancer treatment and radiotherapy for melanoma; prior surgery for melanoma is allowed.

• History of another malignancy or concurrent malignancy including prior malignant melanoma. Exceptions to this include: Patients who have been disease-free for 5 years or patients with a history completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ, multiple primary melanomas, or other malignancies for which the patient has been disease free for > 5 years.

• History or current evidence of cardiovascular risk.

• History or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Birmingham	Alabama	United States	35243
2	Novartis Investigative Site	Tucson	Arizona	United States	85719
3	Novartis Investigative Site	San Francisco	California	United States	94115
4	Novartis Investigative Site	San Francisco	California	United States	94143
5	Novartis Investigative Site	Aurora	Colorado	United States	80045
6	Novartis Investigative Site	Farmington	Connecticut	United States	06030
7	Novartis Investigative Site	Fort Myers	Florida	United States	33916
8	Novartis Investigative Site	Lake Worth	Florida	United States	33461
9	Novartis Investigative Site	Orlando	Florida	United States	32806
10	Novartis Investigative Site	Saint Petersburg	Florida	United States	33705
11	Novartis Investigative Site	Stuart	Florida	United States	34994
12	Novartis Investigative Site	Tampa	Florida	United States	33612
13	Novartis Investigative Site	Atlanta	Georgia	United States	30322
14	Novartis Investigative Site	Atlanta	Georgia	United States	30341
15	Novartis Investigative Site	Indianapolis	Indiana	United States	46202
16	Novartis Investigative Site	Baltimore	Maryland	United States	21237
17	Novartis Investigative Site	Lutherville-Timonium	Maryland	United States	21093
18	Novartis Investigative Site	Boston	Massachusetts	United States	02114
19	Novartis Investigative Site	Ann Arbor	Michigan	United States	48019
20	Novartis Investigative Site	Morristown	New Jersey	United States	07960
21	Novartis Investigative Site	Winston-Salem	North Carolina	United States	27157
22	Novartis Investigative Site	Cincinnati	Ohio	United States	45242
23	Novartis Investigative Site	Columbus	Ohio	United States	43210
24	Novartis Investigative Site	Portland	Oregon	United States	97213
25	Novartis Investigative Site	Pittsburgh	Pennsylvania	United States	15232
26	Novartis Investigative Site	Nashville	Tennessee	United States	37203
27	Novartis Investigative Site	Nashville	Tennessee	United States	37232-5536
28	Novartis Investigative Site	Dallas	Texas	United States	75230
29	Novartis Investigative Site	Murray	Utah	United States	84107
30	Novartis Investigative Site	Seattle	Washington	United States	98109
31	Novartis Investigative Site	Capital Federal	Buenos Aires	Argentina	C1426ANZ
32	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	C1050AAK
33	Novartis Investigative Site	Viedma	Río Negro	Argentina	R8500ACE
34	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000KZE
35	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires		Argentina	C1025ABH
36	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires		Argentina	C1121ABE
37	Novartis Investigative Site	Santa Fe		Argentina	3000
38	Novartis Investigative Site	Gateshead	New South Wales	Australia	2290
39	Novartis Investigative Site	North Sydney	New South Wales	Australia	2060
40	Novartis Investigative Site	Tweed Heads	New South Wales	Australia	2485
41	Novartis Investigative Site	Westmead	New South Wales	Australia	2145
42	Novartis Investigative Site	Greenslopes	Queensland	Australia	4120
43	Novartis Investigative Site	Milton	Queensland	Australia	4064
44	Novartis Investigative Site	Woolloongabba	Queensland	Australia	4102
45	Novartis Investigative Site	Adelaide	South Australia	Australia	5000
46	Novartis Investigative Site	Box Hill	Victoria	Australia	3128
47	Novartis Investigative Site	Heidelberg	Victoria	Australia	3084
48	Novartis Investigative Site	Melbourne	Victoria	Australia	3004
49	Novartis Investigative Site	Nedlands	Western Australia	Australia	6009
50	Novartis Investigative Site	Graz		Austria	8036
51	Novartis Investigative Site	Innsbruck		Austria	6020
52	Novartis Investigative Site	Linz		Austria	A-4010
53	Novartis Investigative Site	Salzburg		Austria	A-5020
54	Novartis Investigative Site	Wels		Austria	A-4600
55	Novartis Investigative Site	Wien		Austria	1090
56	Novartis Investigative Site	Wien		Austria	A-1030
57	Novartis Investigative Site	Wien		Austria	A-1220
58	Novartis Investigative Site	Brussels		Belgium	1200
59	Novartis Investigative Site	Leuven		Belgium	3000
60	Novartis Investigative Site	Liege		Belgium	4000
61	Novartis Investigative Site	Wilrijk		Belgium	2610
62	Novartis Investigative Site	Goiania	Goiás	Brazil	74605-030
63	Novartis Investigative Site	Curitiba	Paraná	Brazil	81520-060
64	Novartis Investigative Site	Ijui	Rio Grande Do Sul	Brazil	98700-000
65	Novartis Investigative Site	Rio De Janeiro		Brazil	22 260-020
66	Novartis Investigative Site	São Paulo		Brazil	01323-900
67	Novartis Investigative Site	Edmonton	Alberta	Canada	T6G 1Z2
68	Novartis Investigative Site	Hamilton	Ontario	Canada	L8V 5C2
69	Novartis Investigative Site	Oshawa	Ontario	Canada	L1G 2B9
70	Novartis Investigative Site	Ottawa	Ontario	Canada	K1H 8L6
71	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9
72	Novartis Investigative Site	Montreal	Quebec	Canada	H2W 1S6
73	Novartis Investigative Site	Quebec		Canada	G1R 2J6
74	Novartis Investigative Site	Brno		Czechia	656 53
75	Novartis Investigative Site	Hradec Kralove		Czechia	500 05
76	Novartis Investigative Site	Olomouc		Czechia	775 20
77	Novartis Investigative Site	Praha 10		Czechia	100 34
78	Novartis Investigative Site	Praha 2		Czechia	128 08
79	Novartis Investigative Site	Zlin		Czechia	76275
80	Novartis Investigative Site	Arhus C		Denmark	8000
81	Novartis Investigative Site	Herlev		Denmark	2730
82	Novartis Investigative Site	Odense		Denmark	5000 C
83	Novartis Investigative Site	Bordeaux		France	33075
84	Novartis Investigative Site	Boulogne-Billancourt		France	92100
85	Novartis Investigative Site	Brest cedex		France	29609
86	Novartis Investigative Site	Dijon		France	21079
87	Novartis Investigative Site	Grenoble		France	38043
88	Novartis Investigative Site	Lille		France	59037
89	Novartis Investigative Site	Marseille cedex 5		France	13385
90	Novartis Investigative Site	Montpellier cedex 5		France	34295
91	Novartis Investigative Site	Nice		France	06202
92	Novartis Investigative Site	Paris Cedex 10		France	75475
93	Novartis Investigative Site	Paris		France	75006
94	Novartis Investigative Site	Pierre-Benite cedex		France	69495
95	Novartis Investigative Site	Reims Cedex		France	51092
96	Novartis Investigative Site	Rennes Cedex		France	35042
97	Novartis Investigative Site	Toulouse cedex 9		France	31059
98	Novartis Investigative Site	Tours Cedex 9		France	37044
99	Novartis Investigative Site	Villejuif cedex		France	94805
100	Novartis Investigative Site	Freiburg	Baden-Wuerttemberg	Germany	79104
101	Novartis Investigative Site	Heidelberg	Baden-Wuerttemberg	Germany	69120
102	Novartis Investigative Site	Heilbronn	Baden-Wuerttemberg	Germany	74078
103	Novartis Investigative Site	Mannheim	Baden-Wuerttemberg	Germany	68167
104	Novartis Investigative Site	Tuebingen	Baden-Wuerttemberg	Germany	72076
105	Novartis Investigative Site	Ulm	Baden-Wuerttemberg	Germany	89081
106	Novartis Investigative Site	Muenchen	Bayern	Germany	80337
107	Novartis Investigative Site	Muenchen	Bayern	Germany	80804
108	Novartis Investigative Site	Nuernberg	Bayern	Germany	90419
109	Novartis Investigative Site	Regensburg	Bayern	Germany	93053
110	Novartis Investigative Site	Wuerzburg	Bayern	Germany	97080
111	Novartis Investigative Site	Darmstadt	Hessen	Germany	64297
112	Novartis Investigative Site	Kassel	Hessen	Germany	34125
113	Novartis Investigative Site	Marburg	Hessen	Germany	35043
114	Novartis Investigative Site	Wiesbaden	Hessen	Germany	65199
115	Novartis Investigative Site	Schwerin	Mecklenburg-Vorpommern	Germany	19049
116	Novartis Investigative Site	Buxtehude	Niedersachsen	Germany	21614
117	Novartis Investigative Site	Hannover	Niedersachsen	Germany	30625
118	Novartis Investigative Site	Aachen	Nordrhein-Westfalen	Germany	52074
119	Novartis Investigative Site	Bochum	Nordrhein-Westfalen	Germany	44791
120	Novartis Investigative Site	Bonn	Nordrhein-Westfalen	Germany	53127
121	Novartis Investigative Site	Essen	Nordrhein-Westfalen	Germany	45122
122	Novartis Investigative Site	Koeln	Nordrhein-Westfalen	Germany	50937
123	Novartis Investigative Site	Muenster	Nordrhein-Westfalen	Germany	48149
124	Novartis Investigative Site	Mainz	Rheinland-Pfalz	Germany	55131
125	Novartis Investigative Site	Homburg	Saarland	Germany	66421
126	Novartis Investigative Site	Magdeburg	Sachsen-Anhalt	Germany	39120
127	Novartis Investigative Site	Quedlinburg	Sachsen-Anhalt	Germany	06484
128	Novartis Investigative Site	Kiel	Schleswig-Holstein	Germany	24105
129	Novartis Investigative Site	Luebeck	Schleswig-Holstein	Germany	23538
130	Novartis Investigative Site	Erfurt	Thueringen	Germany	99089
131	Novartis Investigative Site	Gera	Thueringen	Germany	07548
132	Novartis Investigative Site	Berlin		Germany	10117
133	Novartis Investigative Site	Berlin		Germany	10249
134	Novartis Investigative Site	Berlin		Germany	13585
135	Novartis Investigative Site	Athens		Greece	11527
136	Novartis Investigative Site	Thessaloniki		Greece	54622
137	Novartis Investigative Site	Thessaloniki		Greece	564 29
138	Novartis Investigative Site	Jerusalem		Israel	91120
139	Novartis Investigative Site	Ramat Gan		Israel	52621
140	Novartis Investigative Site	Roma	Lazio	Italy	00167
141	Novartis Investigative Site	Genova	Liguria	Italy	16132
142	Novartis Investigative Site	Bergamo	Lombardia	Italy	24127
143	Novartis Investigative Site	Milano	Lombardia	Italy	20133
144	Novartis Investigative Site	Milano	Lombardia	Italy	20141
145	Novartis Investigative Site	Candiolo	Piemonte	Italy	10060
146	Novartis Investigative Site	Pisa	Toscana	Italy	56126
147	Novartis Investigative Site	Padova	Veneto	Italy	35128
148	Novartis Investigative Site	Shizuoka		Japan	411-8777
149	Novartis Investigative Site	Tokyo		Japan	104-0045
150	Novartis Investigative Site	Amsterdam		Netherlands	1066 CX
151	Novartis Investigative Site	Amsterdam		Netherlands	1081 HV
152	Novartis Investigative Site	Groningen		Netherlands	9713 GZ
153	Novartis Investigative Site	Leeuwarden		Netherlands	8934 AD
154	Novartis Investigative Site	Maastricht		Netherlands	6229 HX
155	Novartis Investigative Site	Nijmegen		Netherlands	6525 GA
156	Novartis Investigative Site	Rotterdam		Netherlands	3015 GD
157	Novartis Investigative Site	Auckland		New Zealand	0622
158	Novartis Investigative Site	Alesund		Norway	6026
159	Novartis Investigative Site	Oslo		Norway	0310
160	Novartis Investigative Site	Gdansk		Poland	80-215
161	Novartis Investigative Site	Konin		Poland	62-500
162	Novartis Investigative Site	Poznan		Poland	60-693
163	Novartis Investigative Site	Warszawa		Poland	02-781
164	Novartis Investigative Site	Warszawa		Poland	04-125
165	Novartis Investigative Site	Chelyabinsk		Russian Federation	454087
166	Novartis Investigative Site	Moscow		Russian Federation	115478
167	Novartis Investigative Site	Moscow		Russian Federation	143423
168	Novartis Investigative Site	Ryazan		Russian Federation	390011
169	Novartis Investigative Site	St. Petersburg		Russian Federation	191104
170	Novartis Investigative Site	St. Petersburg		Russian Federation	197758
171	Novartis Investigative Site	St. Petersburg		Russian Federation
172	Novartis Investigative Site	Volgograd		Russian Federation	400138
173	Novartis Investigative Site	Badalona		Spain	08916
174	Novartis Investigative Site	Barcelona		Spain	08035
175	Novartis Investigative Site	Barcelona		Spain	08036
176	Novartis Investigative Site	Cartagena		Spain	30202
177	Novartis Investigative Site	Las Palmas De Gran Canaria		Spain	35016
178	Novartis Investigative Site	Madrid		Spain	28034
179	Novartis Investigative Site	Madrid		Spain	28041
180	Novartis Investigative Site	Madrid		Spain	28046
181	Novartis Investigative Site	Malaga		Spain	29010
182	Novartis Investigative Site	Palma de Mallorca		Spain	07198
183	Novartis Investigative Site	Pamplona		Spain	31008
184	Novartis Investigative Site	San Sebastian		Spain	20014
185	Novartis Investigative Site	Santander		Spain	39008
186	Novartis Investigative Site	Sevilla		Spain	41014
187	Novartis Investigative Site	Valencia		Spain	46014
188	Novartis Investigative Site	Goteborg		Sweden	SE-413 45
189	Novartis Investigative Site	Lund		Sweden	SE-221 85
190	Novartis Investigative Site	Stockholm		Sweden	SE-171 76
191	Novartis Investigative Site	Uppsala		Sweden	SE-751 85
192	Novartis Investigative Site	Basel		Switzerland	4031
193	Novartis Investigative Site	Chur		Switzerland	7000
194	Novartis Investigative Site	Zurich		Switzerland	8091
195	Novartis Investigative Site	Taichung		Taiwan	404
196	Novartis Investigative Site	Taipei		Taiwan	100
197	Novartis Investigative Site	Taoyuan		Taiwan	333
198	Novartis Investigative Site	Northwood	Middlesex	United Kingdom	HA6 2RN
199	Novartis Investigative Site	Exeter		United Kingdom	EX2 5DW
200	Novartis Investigative Site	Glasgow		United Kingdom	G12 0YN
201	Novartis Investigative Site	Guildford		United Kingdom	GU2 7XX
202	Novartis Investigative Site	Leeds		United Kingdom	LS9 7TF
203	Novartis Investigative Site	London		United Kingdom	NW3 2QG
204	Novartis Investigative Site	London		United Kingdom	SW3 6JJ
205	Novartis Investigative Site	London		United Kingdom	W1G 6AD
206	Novartis Investigative Site	Manchester		United Kingdom	M20 4BX
207	Novartis Investigative Site	Newcastle upon Tyne		United Kingdom	NE7 7DN
208	Novartis Investigative Site	Norwich		United Kingdom	NR4 7UY
209	Novartis Investigative Site	Preston		United Kingdom	PR2 9HT
210	Novartis Investigative Site	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Study Protocol - May 31, 2017
• Statistical Analysis Plan - May 31, 2017

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01682083
• Other Study ID Numbers: 115532; 2012-001266-15; CDRB436F2301
• First Posted: Sep 10, 2012
• Last Update Posted: Aug 31, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: MEK inhibitor; trametinib; Oncology; adjuvant melanoma; dabrafenib; dabrafenib and trametinib combination therapy; BRAF mutation-positive melanoma; BRAF inhibitor
• Additional relevant MeSH terms: Melanoma; Trametinib; Dabrafenib

Study Results

Participant Flow

Recruitment Details	The study was conducted in 169 centers across 25 countries. Results reported have the data cut-off as of 30 June 2017.
Pre-assignment Detail	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.

Arm/Group Title	Dabrafenib and Trametinib Combination Therapy	Dabrafenib and Trametinib Placebos
Arm/Group Description	Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.	Subjects received matching placebos orally for 12 months
Period Title: Overall Study
STARTED	438	432
COMPLETED	331	277
NOT COMPLETED	107	155

Baseline Characteristics

Arm/Group Title	Dabrafenib and Trametinib Combination Therapy	Dabrafenib and Trametinib Placebos	Total
Arm/Group Description	Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.	Subjects received matching placebos orally for 12 months	Total of all reporting groups
Overall Participants	438	432	870
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	50.4 (14.17)	50.5 (13.14)	50.4 (13.66)
Sex: Female, Male (Count of Participants)
Female	195 44.5%	193 44.7%	388 44.6%
Male	243 55.5%	239 55.3%	482 55.4%
Race/Ethnicity, Customized (Count of Participants)
White	432 98.6%	427 98.8%	859 98.7%
Asian	6 1.4%	5 1.2%	11 1.3%

Outcome Measures

1. Primary Outcome

Title	Relapse-free Survival (RFS)
Description	Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause.
Time Frame	Approximately 3.5 years

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population

Arm/Group Title	Dabrafenib and Trametinib Combination Therapy	Dabrafenib and Trametinib Placebos
Arm/Group Description	Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.	Subjects received matching placebos orally for 12 months
Measure Participants	438	432
Relapsed (event)	163 37.2%	247 57.2%
Died	3 0.7%	1 0.2%
Censored, follow-up ended	43 9.8%	35 8.1%
Censored, follow-up ongoing	229 52.3%	149 34.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dabrafenib and Trametinib Combination Therapy, Dabrafenib and Trametinib Placebos
	Comments	The null hypothesis, H0: λ = 1 or reject it in favor of the alternative hypothesis, HA: λ ≠ 1, where λ is the hazard ratio (HR) of combination therapy relative to placebo.
	Type of Statistical Test	Superiority
	Comments	Hazard ratio is obtained from the stratified Pike estimator. A hazard ratio <1 indicates a lower risk with Dabrafenib + Trametinib compared with Placebo.
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio, log
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo
Time Frame	approximately 3.5 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Dabrafenib and Trametinib Combination Therapy	Dabrafenib and Trametinib Placebos
Arm/Group Description	Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.	Subjects received matching placebos orally for 12 months
Measure Participants	438	432
Died (event)	60 13.7%	93 21.5%
Censored, follow-up ended	47 10.7%	62 14.4%
Censored, follow-up ongoing	331 75.6%	277 64.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dabrafenib and Trametinib Combination Therapy, Dabrafenib and Trametinib Placebos
	Comments	Hazard ratio is obtained from the stratified Pike estimator.
	Type of Statistical Test	Superiority
	Comments	A hazard ratio <1 indicates a lower risk with dabrafenib + trametinib compared with Placebo.
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Log Rank
	Comments	the two-sided threshold for significance at this first interim analysis was p=0.000019
Method of Estimation	Estimation Parameter	Hazard Ratio, log
	Estimated Value	0.57
	Confidence Interval	(2-Sided) 95%; 0.42 to 0.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Distant Metastasis-free Survival
Description	Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event.
Time Frame	approximately 3.5 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Dabrafenib and Trametinib Combination Therapy	Dabrafenib and Trametinib Placebos
Arm/Group Description	Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.	Subjects received matching placebos orally for 12 months
Measure Participants	438	432
Number of Subjects - Relapsed	106 24.2%	150 34.7%
Number of Subjects - died	4 0.9%	2 0.5%
Number of Subjects - censored, follow-up ended	99 22.6%	131 30.3%
Number of Subjects - follow-up ongoing	229 52.3%	149 34.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dabrafenib and Trametinib Combination Therapy, Dabrafenib and Trametinib Placebos
	Comments	Hazard ratio is estimated using Pike estimator.
	Type of Statistical Test	Superiority
	Comments	A hazard ratio <1 indicates a lower risk with Dabrafenib + Trametinib compared with Placebo.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio, log
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.40 to 0.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Freedom From Relapse
Description	Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.
Time Frame	approximately 3.5 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Dabrafenib and Trametinib Combination Therapy	Dabrafenib and Trametinib Placebos
Arm/Group Description	Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.	Subjects received matching placebos orally for 12 months
Measure Participants	438	432
Number of Subjects - relapsed	163 37.2%	247 57.2%
Number of Subjects - died	2 0.5%	0 0%
Number of Subjects - censored, follow-up ended	44 10%	36 8.3%
Number of Subjects - censored, follow-up ongoing	229 52.3%	149 34.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dabrafenib and Trametinib Combination Therapy, Dabrafenib and Trametinib Placebos
	Comments	Hazard ratio is estimated using Pike estimator.
	Type of Statistical Test	Superiority
	Comments	A hazard ratio <1 indicates a lower risk with Dabrafenib + Trametinib compared with Placebo.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.57
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events (AEs) were collected from the time the first dose of study treatment is administered until 30 days after discontinuation of study treatment. Serious AEs (SAEs) were reported over the same time period as AEs except SAEs assessed as related to study participation, study treatment or concomitant medication were recorded from the time a subject consents to participate in the study up to and including any follow-up contact.
Adverse Event Reporting Description	All cause mortality provided for the treatment period only.
Arm/Group Title	Dabrafenib + Trametinib Combination Therapy		Dabrafenib and Trametinib Placebos
Arm/Group Description	Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.		Subjects received matching placebos orally for 12 months
All Cause Mortality
	Dabrafenib + Trametinib Combination Therapy		Dabrafenib and Trametinib Placebos
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/435 (0.9%)		1/432 (0.2%)
Serious Adverse Events
	Dabrafenib + Trametinib Combination Therapy		Dabrafenib and Trametinib Placebos
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	155/435 (35.6%)		44/432 (10.2%)
Blood and lymphatic system disorders
Febrile neutropenia	2/435 (0.5%)		0/432 (0%)
Haemorrhagic anaemia	1/435 (0.2%)		0/432 (0%)
Neutropenia	1/435 (0.2%)		0/432 (0%)
Pancytopenia	1/435 (0.2%)		0/432 (0%)
Cardiac disorders
Atrial fibrillation	1/435 (0.2%)		0/432 (0%)
Atrioventricular block second degree	1/435 (0.2%)		0/432 (0%)
Cardiac ventricular thrombosis	0/435 (0%)		1/432 (0.2%)
Tachycardia	0/435 (0%)		1/432 (0.2%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion	0/435 (0%)		1/432 (0.2%)
Eye disorders
Chorioretinopathy	5/435 (1.1%)		0/432 (0%)
Iritis	1/435 (0.2%)		0/432 (0%)
Macular oedema	1/435 (0.2%)		0/432 (0%)
Retinal detachment	2/435 (0.5%)		0/432 (0%)
Uveitis	2/435 (0.5%)		0/432 (0%)
Visual acuity reduced	1/435 (0.2%)		0/432 (0%)
Gastrointestinal disorders
Abdominal pain	1/435 (0.2%)		0/432 (0%)
Abdominal pain upper	0/435 (0%)		1/432 (0.2%)
Diarrhoea	1/435 (0.2%)		0/432 (0%)
Gastrooesophageal reflux disease	1/435 (0.2%)		0/432 (0%)
Inguinal hernia	1/435 (0.2%)		0/432 (0%)
Pancreatic toxicity	1/435 (0.2%)		0/432 (0%)
Pancreatitis	1/435 (0.2%)		0/432 (0%)
Proctalgia	0/435 (0%)		1/432 (0.2%)
Retroperitoneal haematoma	1/435 (0.2%)		0/432 (0%)
Vomiting	4/435 (0.9%)		0/432 (0%)
General disorders
Asthenia	1/435 (0.2%)		0/432 (0%)
Chills	13/435 (3%)		0/432 (0%)
Fatigue	2/435 (0.5%)		0/432 (0%)
Influenza like illness	3/435 (0.7%)		0/432 (0%)
Pyrexia	67/435 (15.4%)		4/432 (0.9%)
Systemic inflammatory response syndrome	1/435 (0.2%)		0/432 (0%)
Hepatobiliary disorders
Drug-induced liver injury	1/435 (0.2%)		0/432 (0%)
Hepatic haemorrhage	0/435 (0%)		1/432 (0.2%)
Hepatotoxicity	1/435 (0.2%)		0/432 (0%)
Hyperbilirubinaemia	1/435 (0.2%)		0/432 (0%)
Infections and infestations
Abscess jaw	1/435 (0.2%)		0/432 (0%)
Cellulitis	5/435 (1.1%)		1/432 (0.2%)
Cholecystitis infective	1/435 (0.2%)		0/432 (0%)
Epstein-Barr virus infection	1/435 (0.2%)		0/432 (0%)
Erysipelas	8/435 (1.8%)		1/432 (0.2%)
Febrile infection	1/435 (0.2%)		0/432 (0%)
Gastroenteritis	1/435 (0.2%)		0/432 (0%)
Groin abscess	1/435 (0.2%)		0/432 (0%)
Groin infection	1/435 (0.2%)		0/432 (0%)
Herpes zoster	0/435 (0%)		1/432 (0.2%)
Influenza	2/435 (0.5%)		0/432 (0%)
Lower respiratory tract infection	3/435 (0.7%)		0/432 (0%)
Parvovirus infection	1/435 (0.2%)		0/432 (0%)
Pharyngitis	1/435 (0.2%)		0/432 (0%)
Pneumonia	3/435 (0.7%)		0/432 (0%)
Post procedural infection	0/435 (0%)		1/432 (0.2%)
Rash pustular	1/435 (0.2%)		0/432 (0%)
Retinitis	1/435 (0.2%)		0/432 (0%)
Salpingitis	1/435 (0.2%)		0/432 (0%)
Sepsis	4/435 (0.9%)		0/432 (0%)
Soft tissue infection	0/435 (0%)		1/432 (0.2%)
Subcutaneous abscess	0/435 (0%)		1/432 (0.2%)
Upper respiratory tract infection	1/435 (0.2%)		0/432 (0%)
Urinary tract infection	0/435 (0%)		1/432 (0.2%)
Urosepsis	1/435 (0.2%)		0/432 (0%)
Vulval abscess	1/435 (0.2%)		0/432 (0%)
Wound infection	0/435 (0%)		1/432 (0.2%)
Injury, poisoning and procedural complications
Limb injury	0/435 (0%)		1/432 (0.2%)
Post procedural haemorrhage	0/435 (0%)		1/432 (0.2%)
Seroma	1/435 (0.2%)		1/432 (0.2%)
Upper limb fracture	0/435 (0%)		1/432 (0.2%)
Investigations
Alanine aminotransferase increased	3/435 (0.7%)		0/432 (0%)
Aspartate aminotransferase increased	2/435 (0.5%)		0/432 (0%)
Blood creatine phosphokinase increased	1/435 (0.2%)		0/432 (0%)
Ejection fraction decreased	13/435 (3%)		5/432 (1.2%)
Right ventricular systolic pressure increased	0/435 (0%)		1/432 (0.2%)
Transaminases increased	1/435 (0.2%)		0/432 (0%)
Troponin increased	1/435 (0.2%)		0/432 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/435 (0.2%)		0/432 (0%)
Dehydration	4/435 (0.9%)		0/432 (0%)
Diabetes mellitus inadequate control	0/435 (0%)		1/432 (0.2%)
Hyperglycaemia	2/435 (0.5%)		0/432 (0%)
Hyponatraemia	1/435 (0.2%)		0/432 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/435 (0.2%)		0/432 (0%)
Intervertebral disc protrusion	1/435 (0.2%)		0/432 (0%)
Myopathy	1/435 (0.2%)		0/432 (0%)
Pain in extremity	1/435 (0.2%)		0/432 (0%)
Rhabdomyolysis	2/435 (0.5%)		0/432 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acanthoma	0/435 (0%)		1/432 (0.2%)
B-cell lymphoma	1/435 (0.2%)		0/432 (0%)
Basal cell carcinoma	0/435 (0%)		1/432 (0.2%)
Bladder transitional cell carcinoma	0/435 (0%)		1/432 (0.2%)
Bowen's disease	2/435 (0.5%)		2/432 (0.5%)
Colon adenoma	1/435 (0.2%)		0/432 (0%)
Endometrial adenocarcinoma	2/435 (0.5%)		0/432 (0%)
Focal nodular hyperplasia	1/435 (0.2%)		0/432 (0%)
Keratoacanthoma	1/435 (0.2%)		1/432 (0.2%)
Lentigo maligna	0/435 (0%)		1/432 (0.2%)
Malignant melanoma	1/435 (0.2%)		3/432 (0.7%)
Malignant melanoma in situ	0/435 (0%)		1/432 (0.2%)
Prostate cancer	1/435 (0.2%)		0/432 (0%)
Renal cancer	0/435 (0%)		1/432 (0.2%)
Salivary gland adenoma	0/435 (0%)		1/432 (0.2%)
Squamous cell carcinoma	3/435 (0.7%)		3/432 (0.7%)
Squamous cell carcinoma of skin	1/435 (0.2%)		1/432 (0.2%)
Nervous system disorders
Amyotrophic lateral sclerosis	0/435 (0%)		1/432 (0.2%)
Carpal tunnel syndrome	0/435 (0%)		1/432 (0.2%)
Demyelinating polyneuropathy	1/435 (0.2%)		0/432 (0%)
Dizziness	2/435 (0.5%)		0/432 (0%)
Facial paralysis	1/435 (0.2%)		0/432 (0%)
Headache	4/435 (0.9%)		0/432 (0%)
Loss of consciousness	1/435 (0.2%)		0/432 (0%)
Meningoradiculitis	1/435 (0.2%)		0/432 (0%)
Migraine	1/435 (0.2%)		1/432 (0.2%)
Paraesthesia	1/435 (0.2%)		0/432 (0%)
Peripheral sensorimotor neuropathy	1/435 (0.2%)		0/432 (0%)
Presyncope	2/435 (0.5%)		0/432 (0%)
Seizure	1/435 (0.2%)		0/432 (0%)
Psychiatric disorders
Mental status changes	1/435 (0.2%)		0/432 (0%)
Obsessive-compulsive disorder	0/435 (0%)		1/432 (0.2%)
Renal and urinary disorders
Acute kidney injury	2/435 (0.5%)		0/432 (0%)
Calculus urinary	1/435 (0.2%)		0/432 (0%)
Nephrotic syndrome	1/435 (0.2%)		0/432 (0%)
Renal colic	1/435 (0.2%)		0/432 (0%)
Reproductive system and breast disorders
Ovarian disorder	1/435 (0.2%)		0/432 (0%)
Priapism	1/435 (0.2%)		0/432 (0%)
Testicular mass	0/435 (0%)		1/432 (0.2%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/435 (0.2%)		0/432 (0%)
Lung disorder	1/435 (0.2%)		0/432 (0%)
Pleural effusion	1/435 (0.2%)		0/432 (0%)
Pulmonary embolism	3/435 (0.7%)		1/432 (0.2%)
Pulmonary hypertension	1/435 (0.2%)		0/432 (0%)
Skin and subcutaneous tissue disorders
Erythema nodosum	1/435 (0.2%)		0/432 (0%)
Panniculitis	1/435 (0.2%)		0/432 (0%)
Rash generalised	1/435 (0.2%)		0/432 (0%)
Vascular disorders
Embolism	0/435 (0%)		1/432 (0.2%)
Hypotension	6/435 (1.4%)		0/432 (0%)
Lymphoedema	0/435 (0%)		1/432 (0.2%)
Vascular occlusion	1/435 (0.2%)		0/432 (0%)
Other (Not Including Serious) Adverse Events
	Dabrafenib + Trametinib Combination Therapy		Dabrafenib and Trametinib Placebos
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	414/435 (95.2%)		340/432 (78.7%)
Blood and lymphatic system disorders
Neutropenia	34/435 (7.8%)		4/432 (0.9%)
Eye disorders
Dry eye	22/435 (5.1%)		13/432 (3%)
Vision blurred	27/435 (6.2%)		16/432 (3.7%)
Gastrointestinal disorders
Abdominal pain	34/435 (7.8%)		23/432 (5.3%)
Abdominal pain upper	30/435 (6.9%)		27/432 (6.3%)
Constipation	51/435 (11.7%)		27/432 (6.3%)
Diarrhoea	143/435 (32.9%)		65/432 (15%)
Dry mouth	41/435 (9.4%)		15/432 (3.5%)
Dyspepsia	24/435 (5.5%)		26/432 (6%)
Nausea	172/435 (39.5%)		88/432 (20.4%)
Vomiting	120/435 (27.6%)		43/432 (10%)
General disorders
Asthenia	58/435 (13.3%)		42/432 (9.7%)
Chills	158/435 (36.3%)		19/432 (4.4%)
Fatigue	204/435 (46.9%)		122/432 (28.2%)
Influenza like illness	66/435 (15.2%)		29/432 (6.7%)
Oedema peripheral	58/435 (13.3%)		19/432 (4.4%)
Pyrexia	248/435 (57%)		44/432 (10.2%)
Infections and infestations
Folliculitis	24/435 (5.5%)		9/432 (2.1%)
Nasopharyngitis	41/435 (9.4%)		48/432 (11.1%)
Urinary tract infection	26/435 (6%)		8/432 (1.9%)
Investigations
Alanine aminotransferase increased	64/435 (14.7%)		6/432 (1.4%)
Aspartate aminotransferase increased	61/435 (14%)		7/432 (1.6%)
Blood alkaline phosphatase increased	31/435 (7.1%)		1/432 (0.2%)
Blood lactate dehydrogenase increased	22/435 (5.1%)		1/432 (0.2%)
Metabolism and nutrition disorders
Decreased appetite	47/435 (10.8%)		25/432 (5.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	119/435 (27.4%)		61/432 (14.1%)
Back pain	38/435 (8.7%)		34/432 (7.9%)
Muscle spasms	39/435 (9%)		13/432 (3%)
Myalgia	70/435 (16.1%)		40/432 (9.3%)
Pain in extremity	60/435 (13.8%)		38/432 (8.8%)
Nervous system disorders
Dizziness	34/435 (7.8%)		33/432 (7.6%)
Dysgeusia	29/435 (6.7%)		12/432 (2.8%)
Headache	169/435 (38.9%)		102/432 (23.6%)
Respiratory, thoracic and mediastinal disorders
Cough	73/435 (16.8%)		33/432 (7.6%)
Dyspnoea	30/435 (6.9%)		17/432 (3.9%)
Epistaxis	41/435 (9.4%)		2/432 (0.5%)
Oropharyngeal pain	39/435 (9%)		15/432 (3.5%)
Skin and subcutaneous tissue disorders
Alopecia	24/435 (5.5%)		18/432 (4.2%)
Dermatitis acneiform	54/435 (12.4%)		10/432 (2.3%)
Dry skin	55/435 (12.6%)		32/432 (7.4%)
Erythema	48/435 (11%)		14/432 (3.2%)
Hyperhidrosis	30/435 (6.9%)		7/432 (1.6%)
Night sweats	23/435 (5.3%)		11/432 (2.5%)
Palmar-plantar erythrodysaesthesia syndrome	24/435 (5.5%)		6/432 (1.4%)
Pruritus	40/435 (9.2%)		29/432 (6.7%)
Rash	106/435 (24.4%)		47/432 (10.9%)
Rash maculo-papular	31/435 (7.1%)		11/432 (2.5%)
Vascular disorders
Hypertension	49/435 (11.3%)		35/432 (8.1%)
Lymphoedema	34/435 (7.8%)		24/432 (5.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.