COMBI-APlus: Study of Dabrafenib+Trametinib in the Adjuvant Treatment of Stage III BRAF V600+ Melanoma After Complete Resection to Evaluate the Impact on Pyrexia Related Outcomes

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03551626
• Collaborator: (none)
• Enrollment: 556
• Locations: 100
• Arm: 1
• Actual Duration (Months): 36.6
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is an open-label Phase IIIb study of dabrafenib in combination with trametinib in the adjuvant treatment of melanoma after complete resection to evaluate the impact on pyrexia related outcomes of an adapted pyrexia AE-management algorithm, as well as safety, efficacy and health-related outcomes.

Approximately 600 subjects will be enrolled to receive dabrafenib (150 mg BID) and trametinib (2 mg once daily) combination therapy for 12 months. At enrollment, subjects will be instructed on the pyrexia management algorithm.

This study consists of two Periods for Enrolled subjects:

• Treatment Period - subjects will receive up to 12 months of treatment.

• Follow-up Period - subjects will be followed through 24 months from their first dose date for relapse, and through end of study for overall survival. Follow-up will start once treatment is complete or is prematurely discontinued and continue through the end of the study, regardless of disease recurrence.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 556 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: COMBI-APlus: Open-label, Phase IIIb Study of Dabrafenib in COMBInation With Trametinib in the Adjuvant Treatment of Stage III BRAF V600 Mutation-positive Melanoma After Complete Resection to Evaluate the Impact on Pyrexia Related Outcomes of an Adapted Pyrexia AE-management Algorithm (Plus)
• Actual Study Start Date: Aug 29, 2018
• Actual Primary Completion Date: Oct 5, 2020
• Actual Study Completion Date: Sep 16, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dabrafenib and trametinib combination therapy Subjects will receive dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.	Drug: Dabrafenib; Supplied as dabrafenib 50 mg, 75 mg Capsules for oral use; Drug: Trametinib; supplied as trametinib 0.5mg, 2.0mg tablets for oral use

Outcome Measures

Primary Outcome Measures

1. Change from baseline in composite rate of pyrexia related events [Baseline up to 12 months]

   The composite rate of grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia by 12 months in overall treated subjects

Secondary Outcome Measures

1. Relapse free survival (RFS) from the first dose to disease recurrence or death from any cause [Baseline up to approximately 24 months]

   RFS is defined as the time from the date of first dose of the study medication to the date of disease recurrence or death due to any cause.

2. Overall Survival (OS) from the first dose to date of death due to any cause [Baseline up to approximately 24 months]

   OS is defined as the time from date of the first dose of study medication to date of death due to any cause.

3. Percentage of patients who require management of pyrexia [Baseline up to 12 months]

   Percentage of patients who experienced pyrexia and required intervention

4. The percentage of participants who permanently discontinued treatment due to any Adverse event [Baseline up to 12 months]

   Participants who permanently discontinued treatment due to any Adverse event during treatment

5. Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Total Score (FACT-M MS) [Baseline up to 24 months]

   QoL assessed using Function Assessment Cancer Therapy-melanoma (FACT-M) assessment tool. This includes the FACT-Melanoma subscale (FACT-M MS) questionnaire -specific subscale consists of 16 questions for Melanoma Subscale (MS) and 8 questions for Melanoma Surgery Scale (MSS).Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M Total Score (FACT-M TS) ranges from 0 to 172 and is derived as follows: FACT-M TS= PWB Score + SWB Score + EWB Score + FWB Score + MS Score. Higher scores represent a better quality of life.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Completely resected histologically confirmed cutaneous melanoma stage IIIA (LN metastasis >1 mm), IIIB, IIIC, IIID [AJCC (ed 8)]

• V600E/K mutation positive using a validated local test

• Subjects presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible.

• Subjects who have previously had Stage III melanoma at any time are not eligible.

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

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

Exclusion Criteria:

• Uveal or mucosal melanoma

• Evidence of metastatic disease including unresectable in-transit metastasis

• Received any prior adjuvant or neoadjuvant treatment, including but not limited to chemotherapy, checkpoint inhibitors, targeted therapy [e.g., BRAF and/or MEK inhibitors], biologic therapy, vaccine therapy, investigational treatment, or radiotherapy for melanoma

• Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers and any completely resected carcinoma in situ

• History or current evidence of cardiovascular risk

• A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Rosario	Sante Fe	Argentina	S200KZE
2	Novartis Investigative Site	Buenos Aires		Argentina	C1125ABE
3	Novartis Investigative Site	Cordoba		Argentina	X5004BAL
4	Novartis Investigative Site	Woolloongabba	Queensland	Australia	4102
5	Novartis Investigative Site	Cairns		Australia	QLD 4870
6	Novartis Investigative Site	Rio de Janeiro	RJ	Brazil	20220410
7	Novartis Investigative Site	Porto Alegre	RS	Brazil	90035-003
8	Novartis Investigative Site	Sao Paulo	SP	Brazil	01246 000
9	Novartis Investigative Site	Calgary	Alberta	Canada	T2N 4N2
10	Novartis Investigative Site	Edmonton	Alberta	Canada	T6G 1Z2
11	Novartis Investigative Site	Hamilton	Ontario	Canada	L8V 5C2
12	Novartis Investigative Site	London	Ontario	Canada	N6A 4L6
13	Novartis Investigative Site	Ottawa	Ontario	Canada	K1H 8L6
14	Novartis Investigative Site	Toronto	Ontario	Canada	M4N 3M5
15	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 1Z6
16	Novartis Investigative Site	Montreal	Quebec	Canada	H3T 1E2
17	Novartis Investigative Site	Quebec		Canada	G1R 2J6
18	Novartis Investigative Site	Brno	Czech Republic	Czechia	656 53
19	Novartis Investigative Site	Ostrava Poruba	Czech Republic	Czechia	708 52
20	Novartis Investigative Site	Prague 8	Czech Republic	Czechia	180 00
21	Novartis Investigative Site	Zlin	Czech Republic	Czechia	762 75
22	Novartis Investigative Site	Hradec Kralove	CZE	Czechia	500 05
23	Novartis Investigative Site	Prague	Prague 1	Czechia	11000
24	Novartis Investigative Site	Olomouc		Czechia	775 20
25	Novartis Investigative Site	Praha		Czechia	12808
26	Novartis Investigative Site	Helsinki		Finland	9
27	Novartis Investigative Site	Tampere		Finland	FIN-33521
28	Novartis Investigative Site	Turku		Finland	20520
29	Novartis Investigative Site	Pierre Benite Cedex	Cedex 02	France	69495
30	Novartis Investigative Site	Limoges cedex	Haute Vienne	France	87000
31	Novartis Investigative Site	Rennes Cedex	Ille Et Vilaine	France	35062
32	Novartis Investigative Site	Besancon Cedex		France	25030
33	Novartis Investigative Site	Bobigny Cedex		France	93009
34	Novartis Investigative Site	Bordeaux Cedex		France	33075
35	Novartis Investigative Site	Boulogne Billancourt		France	92104
36	Novartis Investigative Site	Clermont Ferrand		France	63003
37	Novartis Investigative Site	Dijon		France	21034
38	Novartis Investigative Site	Grenoble Cedex 9		France	38043
39	Novartis Investigative Site	Lille Cedex		France	59037
40	Novartis Investigative Site	Lorient Cedex		France	56322
41	Novartis Investigative Site	Marseille Cedex 05		France	13885
42	Novartis Investigative Site	Montpellier		France	34295
43	Novartis Investigative Site	Nice Cedex		France	06202
44	Novartis Investigative Site	Paris Cedex 10		France	75475
45	Novartis Investigative Site	Poitiers		France	86021
46	Novartis Investigative Site	Reims		France	51092
47	Novartis Investigative Site	Toulouse Cedex 9		France	31059
48	Novartis Investigative Site	Villejuif Cedex		France	94800
49	Novartis Investigative Site	Athens		Greece	115 27
50	Novartis Investigative Site	Athens		Greece	18547
51	Novartis Investigative Site	Athens		Greece	GR 115 22
52	Novartis Investigative Site	Thessaloniki		Greece	54622
53	Novartis Investigative Site	Budapest		Hungary	H 1122
54	Novartis Investigative Site	Pecs		Hungary	7623
55	Novartis Investigative Site	Szeged		Hungary	H 6725
56	Novartis Investigative Site	Jerusalem		Israel	9112001
57	Novartis Investigative Site	Ramat Gan		Israel	52621
58	Novartis Investigative Site	Bergamo	BG	Italy	24127
59	Novartis Investigative Site	Meldola	FC	Italy	47014
60	Novartis Investigative Site	Antella - Bagno A Ripoli	FI	Italy	50011
61	Novartis Investigative Site	Genova	GE	Italy	16132
62	Novartis Investigative Site	Milano	MI	Italy	20133
63	Novartis Investigative Site	Milano	MI	Italy	20141
64	Novartis Investigative Site	Modena	MO	Italy	41124
65	Novartis Investigative Site	Palermo	PA	Italy	90127
66	Novartis Investigative Site	Padova	PD	Italy	35100
67	Novartis Investigative Site	Roma	RM	Italy	00128
68	Novartis Investigative Site	Roma	RM	Italy	00167
69	Novartis Investigative Site	Torino	TO	Italy	10126
70	Novartis Investigative Site	Udine	UD	Italy	33100
71	Novartis Investigative Site	Napoli		Italy	80131
72	Novartis Investigative Site	Sapporo-city	Hokkaido	Japan	060-8543
73	Novartis Investigative Site	Chuo ku	Tokyo	Japan	104 0045
74	Novartis Investigative Site	Riga		Latvia	LV 1079
75	Novartis Investigative Site	Vilnius		Lithuania	LT-08660
76	Novartis Investigative Site	Oslo		Norway	0379
77	Novartis Investigative Site	Ålesund		Norway	NO-6026
78	Novartis Investigative Site	Gdansk		Poland	80 952
79	Novartis Investigative Site	Warszawa		Poland	02 781
80	Novartis Investigative Site	Wroclaw		Poland	53 413
81	Novartis Investigative Site	Porto		Portugal	4200-072
82	Novartis Investigative Site	Moscow		Russian Federation	115478
83	Novartis Investigative Site	Moscow		Russian Federation	143423
84	Novartis Investigative Site	Omsk		Russian Federation	644013
85	Novartis Investigative Site	St Petersburg		Russian Federation	197758
86	Novartis Investigative Site	Bratislava		Slovakia	812 50
87	Novartis Investigative Site	Kosice		Slovakia	04191
88	Novartis Investigative Site	Ljubljana		Slovenia	1000
89	Novartis Investigative Site	Goteborg		Sweden	SE-413 45
90	Novartis Investigative Site	Orebro		Sweden	701 85
91	Novartis Investigative Site	Stockholm		Sweden	SE 171 76
92	Novartis Investigative Site	Umea		Sweden	SE 901 85
93	Novartis Investigative Site	Izmir		Turkey	35040
94	Novartis Investigative Site	Bristol	Avon	United Kingdom	BS2 8ED
95	Novartis Investigative Site	Northwood	Middlesex	United Kingdom	HA6 2RN
96	Novartis Investigative Site	Sheffield	South Yorkshire	United Kingdom	S10 2JF
97	Novartis Investigative Site	Cambridge		United Kingdom	CB2 2QQ
98	Novartis Investigative Site	Leeds		United Kingdom	LS9 7TF
99	Novartis Investigative Site	Manchester		United Kingdom	M20 4BX
100	Novartis Investigative Site	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03551626
• Other Study ID Numbers: CDRB436F2410; 2018-000168-27
• First Posted: Jun 11, 2018
• Last Update Posted: Oct 15, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: dabrafenib; trametinib; adjuvant; Stage III melanoma; combination treatment; pyrexia
• Additional relevant MeSH terms: Melanoma; Fever; Hyperthermia; Trametinib; Dabrafenib

Study Results

No Results Posted as of Oct 15, 2021