Adjuvant Encorafenib and Binimetinib in High-risk Stage II Melanoma With a BRAF Mutation.

Melanoma Clinical Trial

— COLUMBUS-AD  

Official title:

Adjuvant Encorafenib & Binimetinib vs. Placebo in Fully Resected Stage IIB/C BRAF V600E/K Mutated Melanoma: a Randomized Triple-blind Phase III Study in Collaboration With the EORTC Melanoma Group

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05270044
• Other study ID #: W00090GE303/EORTC-2139-MG
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: May 2, 2022
• Est. completion date: May 2, 2035

Study information

• Verified date: November 2023
• Source: Pierre Fabre Medicament
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the Columbus-AD study is to evaluate the efficacy and safety of 12 months of encorafenib in combination with binimetinib in adjuvant setting of BRAF V600E/K mutant stage IIB/C melanoma versus the current standard of care (surveillance).

Description:

This is a randomized triple-blind placebo-controlled international multicenter phase III superiority clinical trial. Participants with completely resected cutaneous melanoma and documented BRAF V600E/K status by central assay will be randomized 1 to 1 to receive either treatment with encorafenib and binimetinib or their two placebos for 12 months. Patients will be stratified according to the stage of the disease according to AJCC version 8 between: - stage IIB (i.e., pT3b or pT4a) - stage IIC (i.e., pT4b). The long-term evaluation of all endpoints (including information about the occurrence of new treatment-related adverse events, if any) will take place 10 years from the randomization of the last patient.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 815
• Est. completion date: May 2, 2035
• Est. primary completion date: March 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Pre-Screening

• Male or female = 18 years of age;
• Surgically resected, with tumour free margins, and histologically/pathologically confirmed new diagnosis of stage II (pT3b-pT4bN0) cutaneous melanomaa;
• Sentinel node (SN) biopsy within 14 weeks from initial diagnosis of melanoma.
• Sentinel node (SN) staged node negative (pN0);
• Available tumour sample for central determination of the BRAF V600E/K mutation. Screening
• Melanoma confirmed centrally to be BRAF V600E/K mutation-positive;
• Participant still free of disease as evidenced by the required baseline imaging and physical/dermatological assessments performed respectively within 6 weeks and 2 weeks before randomization (Day 1);
• No more than 12 weeks elapsed between full surgical resection (including SLNB) and randomization;
• Recovered from definitive surgery (e.g., complete wound healing, no uncontrolled wound infections or indwelling drains);
• ECOG performance status of 0 or 1;
• Adequate haematological function as defined as Absolute neutrophil count (ANC) = 1.5 x 109/L, Platelets = 100 x 109/L and Hemoglobin = 9.0 g/dL;
• Adequate renal function as defined as Serum creatinine = 1.5 × ULN; or calculated creatinine clearance = 50 mL/min;
• Adequate electrolytes, defined as serum potassium and magnesium levels within institutional normal limits;
• Adequate hepatic function as defined as Serum total bilirubin = 1.5 x ULN and < 2 mg/dL, Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) = 2.5 x ULN;
• Adequate cardiac function as defined as LVEF = 50% as determined by MUGA scan or echocardiogram and Mean triplicate QTcF value = 480 msec and no history of QT syndrome;
• Adequate coagulation function, defined as INR =1.5× ULN unless the patient is receiving anticoagulant therapy as long as PT or aPTT is within the therapeutic range;
• Negative serum ß-HCG test (female patient of childbearing potential only) performed within 3 days prior to Day 1;
• Female patients of child-bearing potential and male patients must agree to follow the protocol's contraception guidance during the treatment period and for =30 days after last administration. Exclusion Criteria: Pre-screening
• Unknown ulceration status;
• Uveal and mucosal melanoma;
• Clinically apparent metastases (N+/M1);
• Microsatellites, satellites and/or in-transit metastases,
• Local (scar) recurrences. Screening
• Breast feeding women;
• Pregnant women;
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO;
• History of thromboembolic or cerebrovascular events = 12 weeks prior to randomization;
• History of previous or concurrent malignancy within preceding 3 years or any condition with a life expectancy of less than 5 years;
• Participants with a prior cancer associated with RAS mutation;
• Prior systemic anticancer therapy for melanoma or radiotherapy for melanoma;
• Hypersensitivity to the study drugs or to any of the excipients;
• Participants with severe lactose intolerance (e.g., Rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption);
• Impaired cardiovascular function or clinically significant cardiovascular diseases;
• Neuromuscular disorders that are associated with CK > ULN (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy);
• Non-infectious pneumonitis and Interstitial Lung Disease;
• Positive SARs-CoV-2 or variants of SARs-CoV2 RT-PCR test at screening or suspected to be infected with SARs-CoV2 or variants of SARsCoV2 with confirmation pending;
• Active bacterial, fungal, or viral infection, including, but not limited to HBV, HCV, and known HIV or AIDS-related illness, or an infection requiring systemic therapeutic treatment within 2 weeks prior to randomization.

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Encorafenib and Binimetinib
Encorafenib 450 mg (6 × 75 mg capsules) once daily (QD) and binimetinib 45 mg (3 x 15 mg tablets) twice daily (BID) orally for a maximum of 12 months.
• Placebo to match Encorafenib ; Placebo to match Binimetinib
Encorafenib (6 × 75 mg placebo capsules) QD and binimetinib (3 × 15 mg placebo tablets) BID placebos orally for a maximum of 12 months.

Locations

Country	Name	City	State
Argentina	Centro Oncologico Korben	Caba	Buenos Aires
Argentina	Fundacion CIDEA	Ciudad Autonoma Bs As	Ciudad Autonoma Buenos Aires
Argentina	Clinica Adventista Belgrano	Ciudad Autonoma Buenos Aires
Argentina	Hospital Aleman	Ciudad Autonoma Buenos Aires
Argentina	Instituto Medico Especializado Alexander Fleming	Ciudad Autonoma Buenos Aires
Argentina	Centro de Investigaciones Medicas Mar del Plata	Mar Del Plata	Buenos Aires
Argentina	Instituto de Oncologia de Rosario	Rosario	Santa Fe
Argentina	Sanatorio Britanico S.A.	Rosario	Santa Fe
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Austin Health	Heidelberg	Victoria
Australia	Hollywood Private Hospital	Nedlands	Western Australia
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
Australia	Adelaide Oncology & Haematolog, Calvary North Adelaide Hospital	North Adelaide	South Australia
Australia	The Alfred Hospital	Prahran	Victoria
Australia	Westmead Hospital	Sydney	New South Wales
Australia	Melanoma Institute Australia	Wollstonecraft	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Austria	Landeskrankenhaus - Universitaetsklinikum Graz	Graz
Austria	Krankenhaus der Elisabethinen Linz	Linz
Austria	Universitätsklinikum St.Pölten-Lilienfeld	St. Pölten
Austria	AKH - Medizinische Universität Wien	Vienna
Belgium	Institut Jules Bordet	Anderlecht
Belgium	ZNA Middelheim	Antwerpen
Belgium	Universitair Ziekenhuis Brussel	Brussel
Belgium	Cliniques Universitaires Saint-Luc	Brussels
Belgium	UZ Gent	Gent
Belgium	ZNA	Merksem
Belgium	Vitaz	Sint-Niklaas
Belgium	CHU UCL Namur	Yvoir
Brazil	Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer	Curitiba	Paraná
Brazil	CEPON - Centro de Pesquisas Oncológicas de Santa Catarina	Florianópolis	Santa Catarina
Brazil	Fundação Doutor Amaral Carvalho	Jaú	Sao Paulo
Brazil	Instituto de Cancer de Londrina	Londrina	Paraná
Brazil	HGB - Hospital Giovanni Battista - Mãe de Deus Center	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital de Clínicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul
Brazil	AMO - Assistência Multidisciplinar em Oncologia	Salvador	Bahia
Brazil	Instituto de Oncologia Saint Gallen	Santa Cruz Do Sul	Rio Grande Do Sul
Brazil	CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia	Santo André	Sao Paulo
Brazil	A. C. Camargo Cancer Center	São Paulo	Sao Paulo
Canada	London Health Sciences Centre (LHSC) - Victoria Hospital	London	Ontario
Canada	CIUSSS du Centre Ouest de l'lle de Montreal	Montréal	Quebec
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
Canada	Toronto Sunnybrook Hospital	Toronto	Ontario
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Králové
Czechia	Fakultni nemocnice Olomouc	Olomouc
Czechia	Fakultni nemocnice Ostrava	Ostrava - Poruba
Czechia	Fakultni nemocnice Kralovske Vinohrady	Praha 10
Czechia	Vseobecna fakultni nemocnice v Praze	Praha 2
France	CHU de Bordeaux - Hôpital Saint André	Bordeaux	Gironde
France	Hôpital Ambroise Paré	Boulogne-Billancourt	Hauts De Seine
France	CHU Tours - Hôpital Trousseau	Chambray-lès-Tours	Indre Et Loire
France	CAC Clermont-Ferrand Centre Jean Perrin	Clermont-Ferrand	Puy De Dome
France	CHU de Dijon - Hôpital du Bocage	Dijon	Cote dÝOr
France	CHU de Grenoble - Hôpital André Michallon	La Tronche	Isere
France	Hopital Claude Huriez - CHU Lille	Lille cedex	Nord
France	Hôpital de la Timone	Marseille cedex 5	Bouches-du-Rhône
France	CHU Nantes - Hôtel Dieu	Nantes Cedex 1	Loire Atlantique
France	CHU Nice - Hopital de l Archet 2	Nice cedex 3	Alpes Maritimes
France	Hôpital Saint-Louis	Paris Cedex 10	Paris
France	Centre Hospitalier de Pau - Hôpital François Mitterrand	Pau cedex	Pyrenees Atlantiques
France	Centre Hospitalier Lyon Sud	Pierre Bénite cedex	Rhone
France	CHU Poitiers - Hôpital la Milétrie	Poitiers	Vienne
France	CRLCC Eugene Marquis	Rennes cedex	Ille Et Vilaine
France	CHU de Rouen - Hôpital Charles Nicolle	Rouen	Seine Maritime
France	CHU Saint Etienne - Hôpital Nord	Saint Etienne Cedex 2	Loire
France	Institut Claudius Regaud - Oncopole	Toulouse	Haute Garonne
France	Institut Gustave Roussy	Villejuif cedex	Val De Marne
Germany	Elbekliniken Buxtehude GmbH	Buxtehude	Niedersachsen
Germany	Universitaetsklinikum Carl Gustav Carus TU Dresden	Dresden	Sachsen
Germany	Universitaetsklinikum Hamburg-Eppendorf	Hamburg
Germany	Universitaetsklinikum Heidelberg	Heidelberg	Baden Wuerttemberg
Germany	Universitaetsklinikum Schleswig-Holstein	Kiel	Schleswig Holstein
Germany	Universitaetsklinikum Wuerzburg	Wuerzburg	Bayern
Greece	General Hospital of Athens Laiko	Athens
Greece	Metropolitan Hospital	Néo Fáliro
Greece	Anticancer Hospital of Thessaloniki " Theagenio"	Thessaloníki
Greece	Bioclinic Thessaloniki	Thessaloníki
Greece	Interbalkan Hospital of Thessaloniki	Thessaloníki
Hungary	Orszagos Onkologiai Intezet	Budapest
Hungary	Semmelweis Egyetem	Budapest
Hungary	Debreceni Egyetem	Debrecen
Hungary	Petz Aladar Egyetemi Oktato Korhaz	Gyor
Hungary	Pecsi Tudomanyegyetem	Pécs
Hungary	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont	Szeged
Italy	IRCCS Centro di Riferimento Oncologico	Aviano	Pordenone
Italy	Istituto Tumori Giovanni Paolo II IRCCS Ospedale Oncologico Bari	Bari
Italy	Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)	Bergamo
Italy	Azienda Sanitaria Ospedaliera S.Croce e Carle	Cuneo
Italy	IRCCS Ospedale Policlinico San Martino	Genova
Italy	IRCCS Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori "Dino Amadori" - IRST	Meldola	Forli - Cesena
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano
Italy	IEO Istituto Europeo di Oncologia	Milano
Italy	Ospedale San Raffaele	Milano
Italy	Istituto Nazionale Tumori Fondazione G. Pascale	Naples	Napoli
Italy	IOV - Istituto Oncologico Veneto IRCCS	Padova
Italy	Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone	Palermo
Italy	Azienda Ospedaliera di Perugia Ospedale S. Maria della Misericordia	Perugia
Italy	Azienda Ospedaliero Universitaria Pisana	Pisa
Italy	IDI-Istituto Dermopatico dell'Immacolata IRCCS	Roma
Italy	Istituto Nazionale Tumori Regina Elena IRCCS	Roma
Italy	Policlinico Universitario di Sassari	Sassari
Italy	A.O.U. Senese Policlinico Santa Maria alle Scotte	Siena
Italy	Ospedale San Vincenzo	Taormina	Messina
Italy	Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino	Torino
Italy	Azienda Sanitaria Universitaria Friuli Centrale	Udine
Netherlands	Antoni van Leeuwenhoek	Amsterdam
Netherlands	Universitair Medisch Centrum Groningen (UMCG)	Groningen
Netherlands	Leids Universitair Medisch Centrum	Leiden
Netherlands	Maastricht University Medical Center	Maastricht
Netherlands	Radboudumc	Nijmegen
Netherlands	Erasmus MC	Rotterdam
Netherlands	UMC Utrecht	Utrecht
Netherlands	Isala	Zwolle
Norway	Ålesund Hospital	Ålesund
Norway	Oslo University Hospital	Oslo
Poland	Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie - Panstwowy Instytut Badawczy	Gliwice
Poland	Przychodnia Lekarska Komed	Konin
Poland	Centrum Onkologii-Instytut im. M. Sklodowskiej-Curie	Kraków
Poland	Wielkopolskie Centrum Onkologii	Poznan
Poland	Centrum Medyczne Pratia Poznan	Skórzewo
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy	Warszawa
Poland	Dolnoslaskie Centrum Onkologii	Wroclaw
Portugal	Centro Hospitalar de Lisboa Norte, E.P.E. - Hospital de Santa Maria	Lisboa
Portugal	Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE	Lisboa
Portugal	Instituto Português de Oncologia do Porto Francisco Gentil, EPE	Porto
Romania	S.C Medisprof S.R.L	Cluj-Napoca
Romania	S.C Centrul de Oncologie Sf. Nectarie S.R.L	Craiova
Romania	Institutul Regional de Oncologie Iasi	Iasi
Serbia	Clinical Center "Bezanijska kosa"	Belgrade
Serbia	Institute of Oncology and Radiology of Serbia	Belgrade
Serbia	Military Medical Academy	Belgrade
Serbia	Clinical Center Kragujevac	Kragujevac
Serbia	Clinical Center Nis	Niš
Serbia	Oncology Institute of Vojvodina	Sremska Kamenica
South Africa	National Hospital Oncology	Bloemfontein	Free State
South Africa	Johese Clinical Research: Midstream	Centurion	Gauteng
South Africa	Sandton Oncology Medical Group	Johannesburg	Gauteng
Spain	ICO Badalona - Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitario Reina Sofia	Córdoba
Spain	Hospital Universitario Virgen de la Arrixaca	El Palmar	Murcia
Spain	ICO l'Hospitalet - Hospital Duran i Reynals	L'Hospitalet De Llobregat	Barcelona
Spain	Centro Integral Oncologico Clara Campal	Madrid
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Regional Universitario de Malaga	Málaga
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital General Universitario de Valencia	Valencia
Sweden	Karolinska University Hospital	Stockholm
Sweden	Norrlands Universitetssjukhus	Umeå
Switzerland	Universitaetsspital Zuerich	Zuerich
United Kingdom	Northern Centre for Cancer Care	Newcastle Upon Tyne	Tyne & Wear
United Kingdom	Royal Preston Hospital	Preston	Lancashire

Sponsors (2)

Lead Sponsor	Collaborator
Pierre Fabre Medicament	European Organisation for Research and Treatment of Cancer - EORTC

Countries where clinical trial is conducted

Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Czechia,  France,  Germany,  Greece,  Hungary,  Italy,  Netherlands,  Norway,  Poland,  Portugal,  Romania,  Serbia,  South Africa,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recurrence-free survival (RFS)	RFS is defined as the time between the date of randomization and the date of 1) first recurrence (local, regional, or a distant metastasis), 2) new melanoma that is known to be either ulcerated, thick (Breslow thickness>1 mm) or requiring a treatment other than surgery or 3) death (whatever the cause), whichever occurs first.	Approximately 4.4 years from the accrual of the first patient.
Secondary	Distant metastasis-free survival (DMFS)	DMFS is defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first.	Approximately 6.0 years from first patient in
Secondary	Overall survival (OS)	OS is defined as time from randomization to the date of death whatever the cause.	Approximately 10 years from first Patient In.
Secondary	Safety - Incidence, nature, severity and seriousness of treatment emergent adverse events (TEAEs)	Incidence nature and severity of adverse events and SAEs graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0	From the signing of the ICF up to 30 days after end of treatment- approximately 14.5 months
Secondary	Safety -Incidence, nature and severity of cutaneous malignancies by dermatological examination	This is to monitor for the possible development of keratoacanthoma and/or squamous cell carcinoma and new primary melanoma, as these have been reported to occur with selective BRAF inhibitor treatment. Incidence, nature and severity of new cutaneous malignancies (kerantoacanthoma, squamous cell carcinoma and new primary melanoma) will be recorded and graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0	From the signing of ICF to study completion- approximately 10 years from last patient in
Secondary	Safety -Incidence of Serious adverse events (SAEs)	Incidence nature and severity of serious adverse events will be recorded and graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0	From the signing of the ICF to study completion- approximately 10 years from last patient in
Secondary	Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in physical examination	Standard physical examinations on cardiovascular, respiratory, gastrointestinal, dermatological, ophthalmological and neurological systems will be performed and will be evaluated based on normal/abnormal and clinical significance observations. Number of participants with TEAEs related to abnormal or clinical significance observations to the physical examinations after the start of study drug will be reported.	From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months
Secondary	Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in vital signs	Clinically notable elevated values: Systolic blood pressure (BP): = 160 mmHg and an increase = 20 mmHg from baseline; Diastolic BP: = 100 mmHg and an increase = 15 mmHg from baseline; Heart rate: = 100 beats/min (bpm) with increase from baseline of = 15 bpm; Body temperature [°C] = 38°C). Clinically notable low values: Systolic BP: <120 mmHg with decrease from baseline of = 20 mmHg; Diastolic BP: < 80 mmHg with decrease from baseline of = 15 mmHg; Heart rate: <50 bpm with decrease from baseline of = 15 bpm; Body temperature [°C]: = 35 °C	From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months
Secondary	Safety and tolerability : Incidence of TEAEs related to notable changes in clinical safety laboratory parameters from baseline.	incidence of treatment-emergent adverse events (TEAEs) related to notable changes in clinical safety laboratory parameters from baseline.; Number of participants with clinically notable shift from baseline in laboratory parameter values based on national cancer institute common terminology criteria (NCI-CTCAE) grade, Version 5.0 will be graded from Grades 1 to 5. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death. Clinically notable shift is defined as a worsening from baseline by at least 2 grades, or to grade 3 or above.	From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months
Secondary	Safety and tolerability -Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes from baseline of 12-lead electrocardiograms (ECGs)	12-lead ECGs will be obtained using an internationally recognized 12-lead cardiograph. Clinically notable ECG values: QT [millisecond (ms)] and QT interval (ms) corrected for heart rate using Fridericia's formula (QTcF) intervals (ms): increase from baseline > 60 ms, new > 450 ms, new > 480 ms, new > 500 ms.	From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months
Secondary	Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes from baseline of echocardiogram or multigated acquisition (ECHO/MUGA) scans.	ECHO/MUGA scan assess Left Ventricular Ejection Fraction (LVEF). Changes from baseline of LVEF measurements over time will be reported	From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months
Secondary	Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in ophtalmic examination	Changes from baseline and worse value on ophthalmic examination over time will be reported.; a full ophthalmic examination by an ophthalmologist will be performed (at baseline an end of treatment) including best corrected visual acuity (BCVA), slit lamp examination, intraocular pressure (IOP), dilatedfundoscopy and optical coherence tomography (OCT). Retinal examination is required to identify findings associated with retinal pigment epithelial detachments (RPED), serous detachment of the retina and RVO (OCT and angiography).; the investigator will also monthly monitor visual assesment (general inspection of the eyes, examination of motility and alignment, visual disturbance including diminished central vision, blurred vision or loss of vision).	From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months
Secondary	Safety and tolerability-Treatment emergent adverse events (TEAEs) leading to dose interruption, reduction and discontinuation.	Incidence of dose interruptions, dose modifications and discontinuation due to AEs and incidence of AEs requiring additional therapy	On treatment period - 12 months from randomization.
Secondary	Performance status using the Eastern Co-operative Oncology Group (ECOG) performance status scale.	Changes from baseline and worse value on Eastern Cooperative Oncology Group (ECOG) Scale with a range from 0 to 5 with lower score mean a lower functional impairment, 5 corresponding to death .	From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months
Secondary	Patient-reported health-related (HRQoL)-European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) .	To determine if there is any change from baseline during the treatment and every 6 months thereafter up to 30 months in the European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) questionnaire scores.; EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The descriptive system has five dimension (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), each is rated according to a five-point verbal rating scale (VRS): 1. no problems, 2. slight problems, 3. moderate problems, 4. severe problems and 5. extreme problems) and translated into a five-digit number that describes the participant's health state	From the signing of the ICF up to 30 months.
Secondary	Patient-reported health-related (HRQoL)_European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients (EORTC QLQ-C30)	To determine if there is any change from baseline during the treatment and every 6 months thereafter up to 30 months in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients (EORTC QLQ-C30) questionnaire scores EORTC QLQ-C30 consists of fifteen multi-item scales: five functional scales (physical, role, cognitive, emotional and social); nine symptom/items scales (fatigue, pain, nausea, vomiting, dyspnea, insomnia, apetite loss, constipation, diarrhae and financial difficulties) and a global health and Quality of Life (QoL) scale. Each scale in the questionnaire will be scored (0 to 100). High scores represents a high health/quality of life	From the signing of the ICF up to 30 months.
Secondary	Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)_Cmin	Minimum serum concentration (Cmin) will be calculated and reported.	From randomization up to 11 months
Secondary	Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)-Cmax	Maximum serum concentration (Cmax) will be calculated and reported.	From randomization up to 11 months
Secondary	Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)_AUC	Area under the curve (AUC) will be calculated and reported.	From randomization up to 11 months
Secondary	Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-Cmin	Minimum serum concentration (Cmin) will be calculated and reported	From randomization up to 11 months
Secondary	Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-Cmax	Maximum serum concentration (Cmax) will be calculated and reported.	From randomization up to 11 months
Secondary	Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-AUC	Area under the curve (AUC) will be calculated and reported.	From randomization up to 11 months