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

Melanoma Clinical Trial

— COMBI-AD  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01682083
• Other study ID #: 115532
• Secondary ID: 2012-001266-15CD
• Status: Completed
• Phase: Phase 3
• Start date: January 8, 2013
• Est. completion date: July 31, 2023

Study information

• Verified date: August 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 870
• Est. completion date: July 31, 2023
• Est. primary completion date: June 30, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Melanoma

Intervention

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

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Capital Federal	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	Santa Fe
Argentina	Novartis Investigative Site	Viedma	Río Negro
Australia	Novartis Investigative Site	Adelaide	South Australia
Australia	Novartis Investigative Site	Box Hill	Victoria
Australia	Novartis Investigative Site	Gateshead	New South Wales
Australia	Novartis Investigative Site	Greenslopes	Queensland
Australia	Novartis Investigative Site	Heidelberg	Victoria
Australia	Novartis Investigative Site	Melbourne	Victoria
Australia	Novartis Investigative Site	Milton	Queensland
Australia	Novartis Investigative Site	Nedlands	Western Australia
Australia	Novartis Investigative Site	North Sydney	New South Wales
Australia	Novartis Investigative Site	Tweed Heads	New South Wales
Australia	Novartis Investigative Site	Westmead	New South Wales
Australia	Novartis Investigative Site	Woolloongabba	Queensland
Austria	Novartis Investigative Site	Graz
Austria	Novartis Investigative Site	Innsbruck
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Wels
Austria	Novartis Investigative Site	Wien
Austria	Novartis Investigative Site	Wien
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Brussels
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Belgium	Novartis Investigative Site	Wilrijk
Brazil	Novartis Investigative Site	Curitiba	Paraná
Brazil	Novartis Investigative Site	Goiania	Goiás
Brazil	Novartis Investigative Site	Ijui	Rio Grande Do Sul
Brazil	Novartis Investigative Site	Rio De Janeiro
Brazil	Novartis Investigative Site	São Paulo
Canada	Novartis Investigative Site	Edmonton	Alberta
Canada	Novartis Investigative Site	Hamilton	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Oshawa	Ontario
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Czechia	Novartis Investigative Site	Brno
Czechia	Novartis Investigative Site	Hradec Kralove
Czechia	Novartis Investigative Site	Olomouc
Czechia	Novartis Investigative Site	Praha 10
Czechia	Novartis Investigative Site	Praha 2
Czechia	Novartis Investigative Site	Zlin
Denmark	Novartis Investigative Site	Arhus C
Denmark	Novartis Investigative Site	Herlev
Denmark	Novartis Investigative Site	Odense
France	Novartis Investigative Site	Bordeaux
France	Novartis Investigative Site	Boulogne-Billancourt
France	Novartis Investigative Site	Brest cedex
France	Novartis Investigative Site	Dijon
France	Novartis Investigative Site	Grenoble
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Marseille cedex 5
France	Novartis Investigative Site	Montpellier cedex 5
France	Novartis Investigative Site	Nice
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris Cedex 10
France	Novartis Investigative Site	Pierre-Benite cedex
France	Novartis Investigative Site	Reims Cedex
France	Novartis Investigative Site	Rennes Cedex
France	Novartis Investigative Site	Toulouse cedex 9
France	Novartis Investigative Site	Tours Cedex 9
France	Novartis Investigative Site	Villejuif cedex
Germany	Novartis Investigative Site	Aachen	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bochum	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Bonn	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Buxtehude	Niedersachsen
Germany	Novartis Investigative Site	Darmstadt	Hessen
Germany	Novartis Investigative Site	Erfurt	Thueringen
Germany	Novartis Investigative Site	Essen	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Freiburg	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Gera	Thueringen
Germany	Novartis Investigative Site	Hannover	Niedersachsen
Germany	Novartis Investigative Site	Heidelberg	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Heilbronn	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Homburg	Saarland
Germany	Novartis Investigative Site	Kassel	Hessen
Germany	Novartis Investigative Site	Kiel	Schleswig-Holstein
Germany	Novartis Investigative Site	Koeln	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Luebeck	Schleswig-Holstein
Germany	Novartis Investigative Site	Magdeburg	Sachsen-Anhalt
Germany	Novartis Investigative Site	Mainz	Rheinland-Pfalz
Germany	Novartis Investigative Site	Mannheim	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Marburg	Hessen
Germany	Novartis Investigative Site	Muenchen	Bayern
Germany	Novartis Investigative Site	Muenchen	Bayern
Germany	Novartis Investigative Site	Muenster	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Nuernberg	Bayern
Germany	Novartis Investigative Site	Quedlinburg	Sachsen-Anhalt
Germany	Novartis Investigative Site	Regensburg	Bayern
Germany	Novartis Investigative Site	Schwerin	Mecklenburg-Vorpommern
Germany	Novartis Investigative Site	Tuebingen	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Ulm	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Wiesbaden	Hessen
Germany	Novartis Investigative Site	Wuerzburg	Bayern
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Thessaloniki
Greece	Novartis Investigative Site	Thessaloniki
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Ramat Gan
Italy	Novartis Investigative Site	Bergamo	Lombardia
Italy	Novartis Investigative Site	Candiolo	Piemonte
Italy	Novartis Investigative Site	Genova	Liguria
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Padova	Veneto
Italy	Novartis Investigative Site	Pisa	Toscana
Italy	Novartis Investigative Site	Roma	Lazio
Japan	Novartis Investigative Site	Shizuoka
Japan	Novartis Investigative Site	Tokyo
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Groningen
Netherlands	Novartis Investigative Site	Leeuwarden
Netherlands	Novartis Investigative Site	Maastricht
Netherlands	Novartis Investigative Site	Nijmegen
Netherlands	Novartis Investigative Site	Rotterdam
New Zealand	Novartis Investigative Site	Auckland
Norway	Novartis Investigative Site	Alesund
Norway	Novartis Investigative Site	Oslo
Poland	Novartis Investigative Site	Gdansk
Poland	Novartis Investigative Site	Konin
Poland	Novartis Investigative Site	Poznan
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Warszawa
Russian Federation	Novartis Investigative Site	Chelyabinsk
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Ryazan
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	Volgograd
Spain	Novartis Investigative Site	Badalona
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Cartagena
Spain	Novartis Investigative Site	Las Palmas De Gran Canaria
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga
Spain	Novartis Investigative Site	Palma de Mallorca
Spain	Novartis Investigative Site	Pamplona
Spain	Novartis Investigative Site	San Sebastian
Spain	Novartis Investigative Site	Santander
Spain	Novartis Investigative Site	Sevilla
Spain	Novartis Investigative Site	Valencia
Sweden	Novartis Investigative Site	Goteborg
Sweden	Novartis Investigative Site	Lund
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Uppsala
Switzerland	Novartis Investigative Site	Basel
Switzerland	Novartis Investigative Site	Chur
Switzerland	Novartis Investigative Site	Zurich
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taoyuan
United Kingdom	Novartis Investigative Site	Exeter
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	Guildford
United Kingdom	Novartis Investigative Site	Leeds
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Newcastle upon Tyne
United Kingdom	Novartis Investigative Site	Northwood	Middlesex
United Kingdom	Novartis Investigative Site	Norwich
United Kingdom	Novartis Investigative Site	Preston
United Kingdom	Novartis Investigative Site	Southampton
United States	Novartis Investigative Site	Ann Arbor	Michigan
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Aurora	Colorado
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Birmingham	Alabama
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Novartis Investigative Site	Columbus	Ohio
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Farmington	Connecticut
United States	Novartis Investigative Site	Fort Myers	Florida
United States	Novartis Investigative Site	Indianapolis	Indiana
United States	Novartis Investigative Site	Lake Worth	Florida
United States	Novartis Investigative Site	Lutherville-Timonium	Maryland
United States	Novartis Investigative Site	Morristown	New Jersey
United States	Novartis Investigative Site	Murray	Utah
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Novartis Investigative Site	Orlando	Florida
United States	Novartis Investigative Site	Pittsburgh	Pennsylvania
United States	Novartis Investigative Site	Portland	Oregon
United States	Novartis Investigative Site	Saint Petersburg	Florida
United States	Novartis Investigative Site	San Francisco	California
United States	Novartis Investigative Site	San Francisco	California
United States	Novartis Investigative Site	Seattle	Washington
United States	Novartis Investigative Site	Stuart	Florida
United States	Novartis Investigative Site	Tampa	Florida
United States	Novartis Investigative Site	Tucson	Arizona
United States	Novartis Investigative Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Czechia,  Denmark,  France,  Germany,  Greece,  Israel,  Italy,  Japan,  Netherlands,  New Zealand,  Norway,  Poland,  Russian Federation,  Spain,  Sweden,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Relapse-free Survival (RFS)	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.	Approximately 3.5 years
Secondary	Overall Survival	Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo	approximately 3.5 years
Secondary	Distant Metastasis-free Survival	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.	approximately 3.5 years
Secondary	Freedom From Relapse	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.	approximately 3.5 years