Immunotherapy With Ipilimumab and Nivolumab Preceded or Not by a Targeted Therapy With Encorafenib and Binimetinib (EBIN)

July 30, 2025 updated by: European Organisation for Research and Treatment of Cancer - EORTC

Combination of Targeted Therapy (Encorafenib and Binimetinib) Followed by Combination of Immunotherapy (Ipilimumab and Nivolumab) vs Immediate Combination of Immunotherapy in Patients With Unresectable or Metastatic Melanoma With BRAF V600 Mutation : an EORTC Randomized Phase II Study (EBIN)

This is a multicenter, 2-arm open-label, randomized comparative phase II study. The objective of this trial is to prospectively evaluate whether a sequential approach with an induction period of 12 weeks with encorafenib + binimetinib followed by combination immunotherapy with nivolumab + ipilimumab improves progression free survival compared to combination immunotherapy nivolumab + ipilimumab alone in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
271

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Denmark
      • Herlev, Denmark
        • University Hospitals Copenhagen - Herlev Hospital - University Copenhagen
      • Odense, Denmark
        • Odense University Hospital
  • Finland
      • Helsinki, Finland
        • Helsinki University Central Hospital - Dept of Oncology
      • Tampere, Finland
        • Tampere University Hospital
  • France
      • Amiens, France
        • CHU Amiens - Hopital Sud
      • Besançon, France
        • CHRU de Besancon - Hopital Jean Minjoz
      • Bordeaux, France
        • CHU de Bordeaux - Groupe Hospitalier Saint-André - Hopital Saint-Andre
      • Clermont-Ferrand, France
        • Centre Jean Perrin
      • Dijon, France
        • CHU de Dijon - Centre Georges-Francois-Leclerc
      • Grenoble, France
        • CHU de Grenoble - La Tronche - Hôpital A. Michallon
      • Lille, France
        • CHRU de Lille
      • Lyon, France
        • Centre Leon Berard
      • Lyon, France
        • Centre Hospitalier Lyon Sud
      • Marseille, France
        • Assistance Publique - Hopitaux de Marseille - Hôpital de La Timone (APHM)
      • Nice, France
        • CHU de Nice - Hôpital de l'Archet
      • Paris, France
        • CHU Ambroise Pare
      • Paris, France
        • Assitance Publique - Hopitaux de Paris - Hopital Saint-Louis
      • Pau, France
        • Centre Hospitalier de Pau
      • Saint Priest en Jarez, France
        • CHU de Saint-Étienne - Hôpital Nord
      • Tours, France
        • CHU de TOURS - HOPITAL TROUSSEAU
      • Villejuif, France
        • Gustave Roussy
  • Germany
      • Heidelberg, Germany
        • Universitaetsklinikum Heidelberg
      • Mainz, Germany
        • Univ. Mainz - Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz-University Medical Center
      • Wuerzburg, Germany
        • Universitaetsklinikum Wuerzburg
  • Italy
      • Bergamo, Italy
        • Azienda Ospedaliera Papa Giovanni XXIII
      • Napoli, Italy
        • Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"
      • Padova, Italy
        • IRCCS - Istituto Oncologico Veneto
      • Roma, Italy
        • IRCCS-Regina Elena National Cancer Center
      • Siena, Italy
        • Universita Degli Studi Di Siena -Policlinico "le Scotte"
      • Turin, Italy
        • Azienda Ospedaliera Città della Salute e della Scienza di Torino
      • Udine, Italy
        • Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" di Udine
  • Netherlands
      • Amsterdam, Netherlands
        • The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis
  • Poland
      • Warsaw, Poland
        • Maria Sklodowska-Curie Memorial Cancer Centre
  • Spain
      • Badalona, Spain
        • Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia)
      • Barcelona, Spain
        • Vall d'Hebron Institut d'Oncologia
      • Barcelona, Spain
        • Hospital Clinic Universitari de Barcelona
  • United Kingdom
      • Glasgow, United Kingdom
        • NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre - Gartnavel General Hospital
      • Middlesex, United Kingdom
        • East & North Hertfordshire NHS Trust - East and North Hertfordshire NHS Trust - Mount Vernon Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Histologically or cytologically confirmed unresectable stage III or IV cutaneous or mucosal melanoma
  • Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment as per local assessment
  • Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. This can be an archived sample if obtained at maximum 3 months prior to randomization and if the patient did not receive treatment since then.
  • Measurable disease per RECIST 1.1 criteria by computed tomography (CT) or Magnetic Resonance Imaging (MRI) of Chest/Abdomen/Pelvis CT and brain CT/MRI performed within 28 days prior to randomization
  • Patients ≥ 18 years of age
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
  • Patients must be able to swallow and retain oral tablets
  • Adequate organ function within 14 days prior to randomization
  • Patients with hyperthyroidism or hypothyroidism but that are stable on hormone replacement can be included.
  • Adequate cardiac function

Exclusion Criteria:

  • Uveal melanoma
  • Any symptomatic brain or leptomeningeal disease. Subjects with brain metastases are eligible if these have been locally treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment and treatment is completed within 28 days prior to first dose of study drug administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
  • Any prior treatment for advanced disease including treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody, anti-LAG-3, anti-TIM-3, anti-IDO, etc or BRAF or MEK inhibitors.
  • History of hypersensitivity to study drugs or any excipient (refer to Investigator's brochures for binimetinib and encorafenib and SmPCs for ipilimumab and nivolumab).
  • Prior adjuvant melanoma therapy with IFN, anti-PD1, anti-PDL1 or anti-CTLA-4 or any other systemic treatment is permitted if completed at least 1 year prior to randomization and all related adverse events have either returned to ≤ 1.
  • Concomitant administration of strong inducers and inhibitors of P-gp, glucuronidation, CYP3A4 (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or St John's Wort [hypericin])
  • Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin)
  • Live vaccines within 30 days prior to the first dose of study therapy. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, H1N1 flu, rabies, BCG, and typhoid vaccine.
  • Current participation or treatment with other investigational agent or use of an investigational device within 4 weeks of the first dose of study treatment
  • Child-Pugh B/C and patients with history of acute or chronic pancreatitis
  • Known history or current evidence of active Hepatitis B (e.g., HBsAg reactive) or C (e.g., HCV RNA [qualitative] is detected) or Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies)
  • Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 15 days prior to the first dose of study treatment
  • Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
  • Autoimmune paraneoplastic syndrome requiring immunosuppressive or dedicated treatment. A specific attention should be given in order to detect any minor myasthenia signs at enrolment; acetylcholine receptor antibodies will be systematically tested when symptoms are suggestive of a myasthenia
  • History of any other hematologic or primary solid tumor malignancy, unless in remission for at least 5 years. A patient with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ or pT1a incidental prostate cancer is eligible
  • Previous allogeneic tissue/solid organ transplant
  • Active infection requiring therapy
  • Major surgery or trauma within 12 weeks prior to first dose of treatment or presence of any non-healing wound. Complete wound healing from major surgery must have occurred one month before the first dose of study treatment.

Minor surgery (including uncomplicated tooth extractions) within 28 days before randomization with complete wound healing at least 10 days before randomization is permitted.

  • Any anticancer treatment within 4 weeks before randomization e.g. radiation, surgery, systemic therapy.
  • Patients with clinically relevant ongoing complications from prior anticancer therapies.
  • Severe or uncontrolled systemic disease or any concurrent condition which in the investigator's opinion makes it undesirable for the patient to participate in the study, or which would jeopardize compliance with the protocol
  • History or current evidence of retinal vein occlusion (RVO) or current risk factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); an ophthalmological assessment is mandatory within 28 days from the first dose of study treatment.
  • History of retinal degenerative disease
  • Impaired gastrointestinal function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)
  • Patients with neuromuscular disorders that are associated with CK > ULN (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
  • Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. Note: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on binimetinib treatment
  • Impaired cardiovascular function or clinically significant cardiovascular diseases
  • Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100mmHg, despite current therapy
  • History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to starting study treatment
  • History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including stroke, transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis, pulmonary emboli, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Active Comparator: ARM A: Nivolumab + Ipilimumab
nivolumab 3 mg/kg q3w + ipilimumab 1 mg/kg q3w for 4 injections followed by nivolumab 480 mg IV q4w until completion of 2 years total treatment or progression. Then treatment will be left at the investigator choice and continued until the 2nd progression.
Drug: Nivolumab + Ipilimumab
nivolumab 3 mg/kg q3w + ipilimumab 1 mg/kg q3w for 4 injections followed by nivolumab 480 mg IV q4w until completion of 2 years total treatment or progression.
Experimental: ARM B: Encorafenib + Binimetinib + Nivolumab + Ipilimumab
encorafenib 450 mg QD + binimetinib 45 mg BID orally for 12 weeks followed, after a week of pause, by nivolumab 3 mg/kg q3w + ipilimumab 1 mg/kg q3w for 4 injections, followed by nivolumab 480 mg IV q4w until completion of 2 years total treatment or progression. Then patients will be rechallenged with encorafenib 450 mg QD + binimetinib 45 mg BID orally continuously until the 2nd progression.
Drug: Nivolumab + Ipilimumab
nivolumab 3 mg/kg q3w + ipilimumab 1 mg/kg q3w for 4 injections followed by nivolumab 480 mg IV q4w until completion of 2 years total treatment or progression.
Drug: Encorafenib + Binimetinib
encorafenib 450 mg QD + binimetinib 45 mg BID orally for 12 weeks

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS)
Time Frame: 4.1 years from first patient in
PRS is defined as the time from the date of randomization until the first date of progression, or until date of death (whatever the cause), whichever occurs first. Progression will be assessed according to the RECIST criteria (version 1.1)
4.1 years from first patient in

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Overall Survival (OS)
Time Frame: 6 years from first patient in
OS is defined as the time from the date of randomization to the date of death, whatever the cause.
6 years from first patient in
Complete Response (CR) rate
Time Frame: 4.1 years from first patient in
CR will be assessed according to the RECIST criteria (version 1.1)
4.1 years from first patient in
Time to Complete Response (CR)
Time Frame: 4.1 years from first patient in
Time to CR is defined as the time from the date of randomization until the occurrence of first CR.
4.1 years from first patient in
Duration of Complete Response (CR)
Time Frame: 4.1 years from first patient in
Duration of CR will be measured from the time measurement criteria for CR are first met until the first date that recurrence is objectively documented.
4.1 years from first patient in
Best overall response rate
Time Frame: 4.1 years from first patient in
Best overall response will be assessed according to the RECIST criteria (version 1.1)
4.1 years from first patient in
Time to best response
Time Frame: 4.1 years from first patient in
Time to best response is defined as the time from the date of randomization until the occurrence of the best response (CR or PR, whichever comes first). CR and PR will be assessed according to the RECIST criteria (version 1.1)
4.1 years from first patient in
Duration of best response
Time Frame: 4.1 years from first patient in
Best response duration will be measured from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented. CR and PR will be assessed according to the RECIST criteria (version 1.1)
4.1 years from first patient in
Occurrence of adverse events
Time Frame: 4.1 years from first patient in
This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, for adverse event reporting.
4.1 years from first patient in
Progression-free survival 2 (PFS2)
Time Frame: 4.1 years from first patient in
PFS2 is defined as the time from randomization to second objective disease progression, or death from any cause, whichever first. The second objective disease progression will be assessed according to the RECIST criteria (version 1.1)
4.1 years from first patient in

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
European Organisation for Research and Treatment of Cancer - EORTC

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Caroline Robert, Cancer Institute Gustave Roussy

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 30, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 24, 2023

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 1, 2027

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 27, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 27, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 1, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 1, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 30, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • EORTC-1612-MG
  • 2017-002887-42 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

All publications must comply with the terms specified in the EORTC Policy 009 "Release of Results and Publication Policy".

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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