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

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Melanoma
• Intervention / Treatment: Drug: Encorafenib and Binimetinib; Drug: Placebo to match Encorafenib ; Placebo to match Binimetinib

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 815
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Ciudad Autonoma Buenos Aires, Argentina, C1118AAT
    • Hospital Aleman
  • Ciudad Autonoma Buenos Aires, Argentina, C1426ANZ
    • Instituto Médico Especializado Alexander Fleming
  • Ciudad Autonoma Buenos Aires, Argentina, C1430EGF
    • Clinica Adventista Belgrano
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1426
      • Centro Oncológico Korben
    • Mar Del Plata, Buenos Aires, Argentina, B7600FYK
      • Centro de Investigaciones Medicas Mar del Plata
  • Ciudad Autonoma Buenos Aires
    • Ciudad Autonoma Bs As, Ciudad Autonoma Buenos Aires, Argentina, C1121ABE
      • Fundacion Cidea
  • Santa Fe
    • Rosario, Santa Fe, Argentina, 2000
      • Sanatorio Britanico S.A.
    • Rosario, Santa Fe, Argentina, S2000KZE
      • Instituto de Oncología de Rosario
• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2145
      • Westmead Hospital
    • Wollstonecraft, New South Wales, Australia, 2065
      • Melanoma Institute Australia
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • South Australia
    • North Adelaide, South Australia, Australia, 5006
      • Adelaide Oncology & Haematolog, Calvary North Adelaide Hospital
  • Victoria
    • Box Hill, Victoria, Australia, 3128
      • Box Hill Hospital
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
    • Prahran, Victoria, Australia, 3181
      • The Alfred Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
    • Nedlands, Western Australia, Australia, 6009
      • Hollywood Private Hospital
• Austria
  • Graz, Austria, 8036
    • Landeskrankenhaus - Universitaetsklinikum Graz
  • Linz, Austria, 4020
    • Krankenhaus der Elisabethinen Linz
  • St. Pölten, Austria, 3100
    • Universitätsklinikum St.Pölten-Lilienfeld
  • Vienna, Austria, 1090
    • AKH - Medizinische Universität Wien
• Belgium
  • Anderlecht, Belgium, 1070
    • Institut Jules Bordet
  • Antwerpen, Belgium, 2020
    • ZNA Middelheim
  • Brussel, Belgium, 1090
    • Universitair Ziekenhuis Brussel
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Gent, Belgium, 9000
    • UZ Gent
  • Merksem, Belgium, 2170
    • ZNA
  • Sint-Niklaas, Belgium, 9100
    • VITAZ
  • Yvoir, Belgium, 5530
    • CHU UCL Namur
• Brazil
  • Bahia
    • Salvador, Bahia, Brazil, 41950-640
      • AMO - Assistência Multidisciplinar em Oncologia
  • Paraná
    • Curitiba, Paraná, Brazil, 81520-060
      • Hospital Erasto Gaertner - Liga Paranaense de Combate Ao Câncer
    • Londrina, Paraná, Brazil, 86015-520
      • Instituto de Cancer de Londrina
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-903
      • Hospital de Clínicas de Porto Alegre
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90110-270
      • Hgb - Hospital Giovanni Battista - Mae de Deus Center
    • Santa Cruz Do Sul, Rio Grande Do Sul, Brazil, 96810-110
      • Instituto de Oncologia Saint Gallen
  • Santa Catarina
    • Florianópolis, Santa Catarina, Brazil, 88034-000
      • CEPON - Centro de Pesquisas Oncológicas de Santa Catarina
  • Sao Paulo
    • Jaú, Sao Paulo, Brazil, 17210-120
      • Fundacao Doutor Amaral Carvalho
    • Santo André, Sao Paulo, Brazil, 09060-870
      • Cepho - Centro de Estudos E Pesquisas de Hematologia E Oncologia
    • São Paulo, Sao Paulo, Brazil, 01509-900
      • A. C. Camargo Cancer Center
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre (LHSC) - Victoria Hospital
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Cancer Centre
    • Toronto, Ontario, Canada, M4N 3M5
      • Toronto Sunnybrook Hospital
  • Quebec
    • Montréal, Quebec, Canada, H3T 1E2
      • CIUSSS du Centre Ouest de l'lle de Montreal
• Czechia
  • Hradec Králové, Czechia, 500 05
    • Fakultni nemocnice Hradec Kralove
  • Olomouc, Czechia, 79900
    • Fakultni nemocnice Olomouc
  • Ostrava - Poruba, Czechia, 708 52
    • Fakultni nemocnice Ostrava
  • Praha 10, Czechia, 100 34
    • Fakultni nemocnice Kralovske Vinohrady
  • Praha 2, Czechia, 128 08
    • Vseobecna Fakultni Nemocnice V Praze
• France
  • Alpes Maritimes
    • Nice cedex 3, Alpes Maritimes, France, 06202
      • CHU Nice - Hopital de l Archet 2
  • Bouches-du-Rhône
    • Marseille cedex 5, Bouches-du-Rhône, France, 13385
      • Hopital de La Timone
  • Cote dÝOr
    • Dijon, Cote dÝOr, France, 21079
      • CHU de Dijon - Hopital du Bocage
  • Gironde
    • Bordeaux, Gironde, France, 33075
      • CHU de Bordeaux - Hopital Saint Andre
  • Haute Garonne
    • Toulouse, Haute Garonne, France, 31059
      • Institut Claudius Regaud - Oncopole
  • Hauts De Seine
    • Boulogne-Billancourt, Hauts De Seine, France, 92100
      • Hopital Ambroise Pare
  • Ille Et Vilaine
    • Rennes cedex, Ille Et Vilaine, France, 35042
      • CRLCC Eugene Marquis
  • Indre Et Loire
    • Chambray-lès-Tours, Indre Et Loire, France, 37170
      • CHU Tours - Hôpital Trousseau
  • Isere
    • La Tronche, Isere, France, 38700
      • CHU de Grenoble - Hôpital André Michallon
  • Loire
    • Saint Etienne Cedex 2, Loire, France, 42055
      • CHU Saint Etienne - Hôpital Nord
  • Loire Atlantique
    • Nantes Cedex 1, Loire Atlantique, France, 44093
      • CHU Nantes - Hôtel Dieu
  • Nord
    • Lille cedex, Nord, France, 59037
      • Hopital Claude Huriez - CHU Lille
  • Paris
    • Paris Cedex 10, Paris, France, 75010
      • Hôpital Saint-Louis
  • Puy De Dome
    • Clermont-Ferrand, Puy De Dome, France, 63000
      • CAC Clermont-Ferrand Centre Jean Perrin
  • Pyrenees Atlantiques
    • Pau cedex, Pyrenees Atlantiques, France, 64046
      • Centre Hospitalier de Pau - Hôpital François Mitterrand
  • Rhone
    • Pierre Bénite cedex, Rhone, France, 69495
      • Centre Hospitalier Lyon Sud
  • Seine Maritime
    • Rouen, Seine Maritime, France, 76031
      • CHU de Rouen - Hôpital Charles Nicolle
  • Val De Marne
    • Villejuif cedex, Val De Marne, France, 94805
      • Institut Gustave Roussy
  • Vienne
    • Poitiers, Vienne, France, 86021
      • CHU Poitiers - Hôpital la Milétrie
• Germany
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf
  • Baden Wuerttemberg
    • Heidelberg, Baden Wuerttemberg, Germany, 69120
      • Universitaetsklinikum Heidelberg
  • Bayern
    • Wuerzburg, Bayern, Germany, 97080
      • Universitaetsklinikum Wuerzburg
  • Niedersachsen
    • Buxtehude, Niedersachsen, Germany, 21614
      • Elbekliniken Buxtehude GmbH
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Universitaetsklinikum Carl Gustav Carus Tu Dresden
  • Schleswig Holstein
    • Kiel, Schleswig Holstein, Germany, 24105
      • Universitaetsklinikum Schleswig-Holstein
• Greece
  • Athens, Greece, 11527
    • General Hospital of Athens Laiko
  • Néo Fáliro, Greece, 18547
    • Metropolitan Hospital
  • Thessaloníki, Greece, 54622
    • Bioclinic Thessaloniki
  • Thessaloníki, Greece, 57001
    • Interbalkan Hospital of Thessaloniki
  • Thessaloníki, Greece, 54639
    • Anticancer Hospital of Thessaloniki " Theagenio"
• Hungary
  • Budapest, Hungary, 1122
    • Orszagos Onkologiai Intezet
  • Budapest, Hungary, 1085
    • Semmelweis Egyetem
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem
  • Győr, Hungary, 9023
    • Petz Aladár Egyetemi Oktató Kórház
  • Pécs, Hungary, 7632
    • Pecsi Tudomanyegyetem
  • Szeged, Hungary, 6720
    • Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ
• Italy
  • Bari, Italy, 70124
    • Istituto Tumori Giovanni Paolo Ii Irccs Ospedale Oncologico Bari
  • Bergamo, Italy, 24127
    • Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)
  • Cuneo, Italy, 12100
    • Azienda Sanitaria Ospedaliera S.Croce e Carle
  • Genova, Italy, 16132
    • IRCCS Ospedale Policlinico San Martino
  • Milano, Italy, 20132
    • Ospedale San Raffaele
  • Milano, Italy, 20133
    • Fondazione IRCCS Istituto Nazionale dei Tumori
  • Milano, Italy, 20141
    • Ieo Istituto Europeo Di Oncologia
  • Padova, Italy, 35128
    • IOV - Istituto Oncologico Veneto IRCCS
  • Palermo, Italy, 90127
    • Azienda Ospedaliero Universitaria Policlinico Paolo Giaccone
  • Perugia, Italy, 06156
    • Azienda Ospedaliera Di Perugia Ospedale S. Maria Della Misericordia
  • Pisa, Italy, 56126
    • Azienda Ospedaliero Universitaria Pisana
  • Roma, Italy, 00144
    • Istituto Nazionale Tumori Regina Elena Irccs
  • Roma, Italy, 00167
    • IDI-Istituto Dermopatico dell'Immacolata IRCCS
  • Sassari, Italy, 07100
    • Policlinico Universitario di Sassari
  • Siena, Italy, 53100
    • A.O.U. Senese Policlinico Santa Maria alle Scotte
  • Torino, Italy, 10126
    • Azienda Ospedaliero-Universitaria Citta della Salute e della Scienza di Torino
  • Udine, Italy, 33100
    • Azienda Sanitaria Universitaria Friuli Centrale
  • Forli - Cesena
    • Meldola, Forli - Cesena, Italy, 47014
      • IRCCS Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori "Dino Amadori" - IRST
  • Messina
    • Taormina, Messina, Italy, 98039
      • Ospedale San Vincenzo
  • Napoli
    • Naples, Napoli, Italy, 80131
      • Istituto Nazionale Tumori Fondazione G. Pascale
  • Pordenone
    • Aviano, Pordenone, Italy, 33081
      • IRCCS Centro di Riferimento Oncologico
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Antoni van Leeuwenhoek
  • Groningen, Netherlands, 9713 GZ
    • Universitair Medisch Centrum Groningen (Umcg)
  • Leiden, Netherlands, 2333 ZA
    • Leids Universitair Medisch Centrum
  • Maastricht, Netherlands, 6202 AZ
    • Maastricht University Medical Center
  • Nijmegen, Netherlands, 6525 GA
    • Radboudumc
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus MC
  • Utrecht, Netherlands, 3508 GA
    • UMC Utrecht
  • Zwolle, Netherlands, 8025 AB
    • Isala
• Norway
  • Oslo, Norway, 0424
    • Oslo University Hospital
  • Ålesund, Norway, 6017
    • Alesund Hospital
• Poland
  • Gliwice, Poland, 44-102
    • Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie - Panstwowy Instytut Badawczy
  • Konin, Poland, 62-500
    • Przychodnia Lekarska KOMED
  • Kraków, Poland, 31-115
    • Centrum Onkologii-Instytut im. M. Sklodowskiej-Curie
  • Poznań, Poland, 61-866
    • Wielkopolskie Centrum Onkologii
  • Skórzewo, Poland, 60-185
    • Centrum Medyczne Pratia Poznan
  • Warszawa, Poland, 02-781
    • Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy
  • Wrocław, Poland, 53-413
    • Dolnoslaskie Centrum Onkologii
• Portugal
  • Lisboa, Portugal, 1649-035
    • Centro Hospitalar de Lisboa Norte, E.P.E. - Hospital de Santa Maria
  • Lisboa, Portugal, 1099-023
    • Instituto Portugues de Oncologia de Lisboa Francisco Gentil, EPE
  • Porto, Portugal, 4200-072
    • Instituto Português de Oncologia do Porto Francisco Gentil, EPE
• Romania
  • Cluj-Napoca, Romania, 400641
    • S.C Medisprof S.R.L
  • Craiova, Romania, 200542
    • S.C Centrul de Oncologie Sf. Nectarie S.R.L
  • Iasi, Romania, 700483
    • Institutul Regional de Oncologie Iasi
• Serbia
  • Belgrade, Serbia, 11000
    • Military Medical Academy
  • Belgrade, Serbia, 11000
    • Institute of Oncology and Radiology of Serbia
  • Belgrade, Serbia, 11000
    • Clinical Center "Bezanijska kosa"
  • Kragujevac, Serbia, 34000
    • Clinical Center Kragujevac
  • Niš, Serbia, 18000
    • Clinical Center Nis
  • Sremska Kamenica, Serbia, 21204
    • Oncology Institute of Vojvodina
• South Africa
  • Free State
    • Bloemfontein, Free State, South Africa, 9301
      • National Hospital Oncology
  • Gauteng
    • Centurion, Gauteng, South Africa, 1692
      • Johese Clinical Research: Midstream
    • Johannesburg, Gauteng, South Africa, 2196
      • Sandton Oncology Medical Group
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clínic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Córdoba, Spain, 14004
    • Hospital Universitario Reina Sofia
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de octubre
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Madrid, Spain, 28050
    • Centro Integral Oncologico Clara Campal
  • Málaga, Spain, 29010
    • Hospital Regional Universitario de Málaga
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
  • Valencia, Spain, 46014
    • Hospital General Universitario de Valencia
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • ICO Badalona - Hospital Universitari Germans Trias i Pujol
    • L'Hospitalet De Llobregat, Barcelona, Spain, 08908
      • Ico L'Hospitalet - Hospital Duran I Reynals
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Hospital Universitario Virgen de la Arrixaca
• Sweden
  • Stockholm, Sweden, 17176
    • Karolinska University Hospital
  • Umeå, Sweden, 901 87
    • Norrlands Universitetssjukhus
• Switzerland
  • Zuerich, Switzerland, 8091
    • Universitaetsspital Zuerich
• United Kingdom
  • Lancashire
    • Preston, Lancashire, United Kingdom, PR2 9HT
      • Royal Preston Hospital
  • Tyne & Wear
    • Newcastle Upon Tyne, Tyne & Wear, United Kingdom, NE7 7DN
      • Northern Centre for Cancer Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 β-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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Encorafenib and Binimetinib	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.; Other Names: Encorafenib: Braftovi / Binimetinib: Mektovi
Placebo Comparator: Arm B; Placebo to match Encorafenib Placebo to match Binimetinib	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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.
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
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
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
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
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
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
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
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
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
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.
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
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.
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.
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Pierre Fabre Medicament
• Collaborators: European Organisation for Research and Treatment of Cancer - EORTC
• Investigators: Study Chair: Alexander C.J. van AKKOOI, MD, PhD, European Organisation for Research and Treatment of Cancer - EORTC

Study record dates

Study Major Dates

• Study Start (Actual): May 2, 2022
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): May 2, 2035

Study Registration Dates

• First Submitted: February 14, 2022
• First Submitted That Met QC Criteria: February 25, 2022
• First Posted (Actual): March 8, 2022

Study Record Updates

• Last Update Posted (Actual): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 21, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Melanoma; Adjuvant; Stage II; BRAFV600E/K
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma
• Other Study ID Numbers: W00090GE303/EORTC-2139-MG

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to de-identified patient-level data in response to scientifically valid research proposals will be provided 30 days after CHMP opinion. All requests from qualified researchers for access to Columbus AD clinical data and information will be managed through a dedicated Pierre Fabre portal.
• IPD Sharing Time Frame: Study protocol/Informed Consent Form will be made available in Clinical Trial.gov 30 days after the time of CHMP opinion or up to a maximum of 1 year after the end of the trial whichever is earlier.; CSR and SAP: 30 days after the time of CHMP opinion or up to a maximum of 1 year after the end of the trial whichever is earlier.
• IPD Sharing Access Criteria: Pierre Fabre corporate portal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No