Back to results

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

Primary Purpose

Melanoma

Status

Recruiting

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Encorafenib and Binimetinib

Placebo to match Encorafenib ; Placebo to match Binimetinib

About this trial

This is an interventional treatment trial for Melanoma focused on measuring Melanoma, Stage II, BRAFV600E/K, Adjuvant

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Centro Oncologico Korben
Centro de Investigaciones Medicas Mar del Plata
Fundacion CIDEA
Sanatorio Britanico S.A.
Instituto de Oncologia de Rosario
Hospital Aleman
Instituto Medico Especializado Alexander Fleming
Clinica Adventista Belgrano
Westmead HospitalRecruiting
Melanoma Institute AustraliaRecruiting
Princess Alexandra Hospital
Adelaide Oncology & Haematolog, Calvary North Adelaide Hospital
Box Hill HospitalRecruiting
Austin HealthRecruiting
The Alfred HospitalRecruiting
Hollywood Private Hospital
Sir Charles Gairdner HospitalRecruiting
Landeskrankenhaus - Universitaetsklinikum Graz
Krankenhaus der Elisabethinen LinzRecruiting
Universitätsklinikum St.Pölten-LilienfeldRecruiting
AKH - Medizinische Universität WienRecruiting
Institut Jules BordetRecruiting
ZNA MiddelheimRecruiting
Cliniques Universitaires Saint-LucRecruiting
Universitair Ziekenhuis BrusselRecruiting
UZ GentRecruiting
ZNARecruiting
Vitaz
CHU UCL NamurRecruiting
AMO - Assistência Multidisciplinar em Oncologia
Hospital Erasto Gaertner - Liga Paranaense de Combate ao Câncer
Instituto de Cancer de Londrina
Hospital de Clínicas de Porto Alegre
HGB - Hospital Giovanni Battista - Mãe de Deus Center
Instituto de Oncologia Saint Gallen
CEPON - Centro de Pesquisas Oncológicas de Santa Catarina
Fundação Doutor Amaral Carvalho
CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia
A. C. Camargo Cancer Center
London Health Sciences Centre (LHSC) - Victoria Hospital
Toronto Sunnybrook Hospital
Princess Margaret Cancer Centre
CIUSSS du Centre Ouest de l'lle de Montreal
Fakultni nemocnice Hradec KraloveRecruiting
Fakultni nemocnice OlomoucRecruiting
Fakultni nemocnice OstravaRecruiting
Fakultni nemocnice Kralovske VinohradyRecruiting
Vseobecna fakultni nemocnice v PrazeRecruiting
CHU Nice - Hopital de l Archet 2Recruiting
Hôpital de la TimoneRecruiting
CHU de Dijon - Hôpital du BocageRecruiting
CHU de Bordeaux - Hôpital Saint AndréRecruiting
Institut Claudius Regaud - OncopoleRecruiting
Hôpital Ambroise ParéRecruiting
CRLCC Eugene MarquisRecruiting
CHU Tours - Hôpital TrousseauRecruiting
CHU de Grenoble - Hôpital André MichallonRecruiting
CHU Nantes - Hôtel DieuRecruiting
CHU Saint Etienne - Hôpital NordRecruiting
Hopital Claude Huriez - CHU LilleRecruiting
Hôpital Saint-LouisRecruiting
CAC Clermont-Ferrand Centre Jean PerrinRecruiting
Centre Hospitalier de Pau - Hôpital François MitterrandRecruiting
Centre Hospitalier Lyon SudRecruiting
CHU de Rouen - Hôpital Charles Nicolle
Institut Gustave RoussyRecruiting
CHU Poitiers - Hôpital la MilétrieRecruiting
Universitaetsklinikum HeidelbergRecruiting
Universitaetsklinikum WuerzburgRecruiting
Elbekliniken Buxtehude GmbHRecruiting
Universitaetsklinikum Carl Gustav Carus TU DresdenRecruiting
Universitaetsklinikum Schleswig-HolsteinRecruiting
Universitaetsklinikum Hamburg-EppendorfRecruiting
General Hospital of Athens LaikoRecruiting
Metropolitan HospitalRecruiting
Bioclinic ThessalonikiRecruiting
Anticancer Hospital of Thessaloniki " Theagenio"Recruiting
Interbalkan Hospital of ThessalonikiRecruiting
Semmelweis EgyetemRecruiting
Orszagos Onkologiai IntezetRecruiting
Debreceni EgyetemRecruiting
Petz Aladar Egyetemi Oktato Korhaz
Pecsi TudomanyegyetemRecruiting
Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai KozpontRecruiting
HaEmek Medical CenterRecruiting
Hadassah University Hospital - Ein KeremRecruiting
Rabin Medical Center-Beilinson CampusRecruiting
Chaim Sheba Medical CenterRecruiting
IRCCS Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori "Dino Amadori" - IRSTRecruiting
Ospedale San VincenzoRecruiting
Istituto Nazionale Tumori Fondazione G. PascaleRecruiting
IRCCS Centro di Riferimento Oncologico
Istituto Tumori Giovanni Paolo II IRCCS Ospedale Oncologico BariRecruiting
Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)Recruiting
Azienda Sanitaria Ospedaliera S.Croce e CarleRecruiting
IRCCS Ospedale Policlinico San MartinoRecruiting
Ospedale San RaffaeleRecruiting
Fondazione IRCCS Istituto Nazionale dei TumoriRecruiting
IEO Istituto Europeo di OncologiaRecruiting
IOV - Istituto Oncologico Veneto IRCCSRecruiting
Azienda Ospedaliero Universitaria Policlinico Paolo GiacconeRecruiting
Azienda Ospedaliera di Perugia Ospedale S. Maria della MisericordiaRecruiting
Azienda Ospedaliero Universitaria PisanaRecruiting
Istituto Nazionale Tumori Regina Elena IRCCS
IDI-Istituto Dermopatico dell'Immacolata IRCCSRecruiting
Policlinico Universitario di SassariRecruiting
A.O.U. Senese Policlinico Santa Maria alle ScotteRecruiting
Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di TorinoRecruiting
Azienda Sanitaria Universitaria Friuli CentraleRecruiting
Antoni van LeeuwenhoekRecruiting
Universitair Medisch Centrum Groningen (UMCG)Recruiting
Leids Universitair Medisch CentrumRecruiting
Maastricht University Medical CenterRecruiting
RadboudumcRecruiting
Erasmus MC
UMC Utrecht
IsalaRecruiting
Oslo University HospitalRecruiting
Ålesund Hospital
Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie - Panstwowy Instytut BadawczyRecruiting
Przychodnia Lekarska KomedRecruiting
Centrum Onkologii-Instytut im. M. Sklodowskiej-CurieRecruiting
Wielkopolskie Centrum OnkologiiRecruiting
Centrum Medyczne Pratia PoznanRecruiting
Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut BadawczyRecruiting
Dolnoslaskie Centrum Onkologii
Instituto Português de Oncologia de Lisboa Francisco Gentil, EPE
Centro Hospitalar de Lisboa Norte, E.P.E. - Hospital de Santa Maria
Instituto Português de Oncologia do Porto Francisco Gentil, EPE
Clinical Center "Bezanijska kosa"Recruiting
Institute of Oncology and Radiology of SerbiaRecruiting
Military Medical Academy
Clinical Center KragujevacRecruiting
Clinical Center NisRecruiting
Oncology Institute of Vojvodina
National Hospital Oncology
Johese Clinical Research: Midstream
Sandton Oncology Medical Group
ICO Badalona - Hospital Universitari Germans Trias i Pujol
ICO l'Hospitalet - Hospital Duran i ReynalsRecruiting
Hospital Universitario Virgen de la ArrixacaRecruiting
Hospital Universitari Vall d'HebronRecruiting
Hospital Clinic de BarcelonaRecruiting
Hospital Universitario Reina SofiaRecruiting
Hospital General Universitario Gregorio MarañonRecruiting
Hospital Universitario Ramon y CajalRecruiting
Hospital Universitario 12 de OctubreRecruiting
Centro Integral Oncologico Clara CampalRecruiting
Hospital Regional Universitario de Malaga
Hospital Clinico Universitario de ValenciaRecruiting
Hospital General Universitario de ValenciaRecruiting
Karolinska University HospitalRecruiting
Norrlands UniversitetssjukhusRecruiting
Universitaetsspital ZuerichRecruiting
Royal Preston HospitalRecruiting
Northern Centre for Cancer CareRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm A

Arm B

Arm Description

Encorafenib and Binimetinib

Placebo to match Encorafenib Placebo to match Binimetinib

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Overall survival (OS)

OS is defined as time from randomization to the date of death whatever the cause.

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

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

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

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.

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

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.

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.

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

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).

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

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 .

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

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

Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)_Cmin

Minimum serum concentration (Cmin) will be calculated and reported.

Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)-Cmax

Maximum serum concentration (Cmax) will be calculated and reported.

Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)_AUC

Area under the curve (AUC) will be calculated and reported.

Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-Cmin

Minimum serum concentration (Cmin) will be calculated and reported

Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-Cmax

Maximum serum concentration (Cmax) will be calculated and reported.

Pharmacokinetic (PK) parameter of binimetinib and its metabolite (AR00426032)-AUC

Area under the curve (AUC) will be calculated and reported.

Full Information

NCT ID

NCT05270044

First Posted

February 14, 2022

Last Updated

March 3, 2023

Sponsor

Pierre Fabre Medicament

Collaborators

European Organisation for Research and Treatment of Cancer - EORTC

1. Study Identification

Unique Protocol Identification Number

NCT05270044

Brief Title

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

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Recruiting

Study Start Date

May 2, 2022 (Actual)

Primary Completion Date

March 31, 2027 (Anticipated)

Study Completion Date

May 2, 2035 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pierre Fabre Medicament

Collaborators

European Organisation for Research and Treatment of Cancer - EORTC

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief 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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Melanoma

Keywords

Melanoma, Stage II, BRAFV600E/K, Adjuvant

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

815 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm A

Arm Type

Experimental

Arm Description

Encorafenib and Binimetinib

Arm Title

Arm B

Arm Type

Placebo Comparator

Arm Description

Placebo to match Encorafenib Placebo to match Binimetinib

Intervention Type

Drug

Intervention Name(s)

Encorafenib and Binimetinib

Other Intervention Name(s)

Encorafenib: Braftovi / Binimetinib: Mektovi

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo to match Encorafenib ; Placebo to match Binimetinib

Intervention Description

Encorafenib (6 × 75 mg placebo capsules) QD and binimetinib (3 × 15 mg placebo tablets) BID placebos orally for a maximum of 12 months.

Primary Outcome Measure Information:

Title

Recurrence-free survival (RFS)

Description

Time Frame

Approximately 4.4 years from the accrual of the first patient.

Secondary Outcome Measure Information:

Title

Distant metastasis-free survival (DMFS)

Description

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.

Time Frame

Approximately 6.0 years from first patient in

Title

Overall survival (OS)

Description

OS is defined as time from randomization to the date of death whatever the cause.

Time Frame

Approximately 10 years from first Patient In.

Title

Safety - Incidence, nature, severity and seriousness of treatment emergent adverse events (TEAEs)

Description

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

Time Frame

From the signing of the ICF up to 30 days after end of treatment- approximately 14.5 months

Title

Safety -Incidence, nature and severity of cutaneous malignancies by dermatological examination

Description

Time Frame

From the signing of ICF to study completion- approximately 10 years from last patient in

Title

Safety -Incidence of Serious adverse events (SAEs)

Description

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

Time Frame

From the signing of the ICF to study completion- approximately 10 years from last patient in

Title

Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in physical examination

Description

Time Frame

From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months

Title

Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in vital signs

Description

Time Frame

From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months

Title

Safety and tolerability : Incidence of TEAEs related to notable changes in clinical safety laboratory parameters from baseline.

Description

Time Frame

From the signing of the ICF up to 30 days after end of treatment- approximately up to 14.5 months

Title

Safety and tolerability -Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes from baseline of 12-lead electrocardiograms (ECGs)

Description

Time Frame

From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months

Title

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.

Description

ECHO/MUGA scan assess Left Ventricular Ejection Fraction (LVEF). Changes from baseline of LVEF measurements over time will be reported

Time Frame

From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months

Title

Safety and tolerability - Incidence of treatment-emergent adverse events (TEAEs) related to notable or abnormal changes in ophtalmic examination

Description

Time Frame

From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months

Title

Safety and tolerability-Treatment emergent adverse events (TEAEs) leading to dose interruption, reduction and discontinuation.

Description

Incidence of dose interruptions, dose modifications and discontinuation due to AEs and incidence of AEs requiring additional therapy

Time Frame

On treatment period - 12 months from randomization.

Title

Performance status using the Eastern Co-operative Oncology Group (ECOG) performance status scale.

Description

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 .

Time Frame

From the signing of the ICF up to 30 days after end of treatment-approximately up to 14.5 months

Title

Patient-reported health-related (HRQoL)-European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) .

Description

Time Frame

From the signing of the ICF up to 30 months.

Title

Patient-reported health-related (HRQoL)_European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients (EORTC QLQ-C30)

Description

Time Frame

From the signing of the ICF up to 30 months.

Title

Pharmacokinetic (PK) parameter of encorafenib and its metabolite (LHY746)_Cmin

Description

Minimum serum concentration (Cmin) will be calculated and reported.

Time Frame