Unresectable Stage III MelanomaPhase 2EBINNCT03235245
Immunotherapy With Ipilimumab and Nivolumab Preceded or Not by a Targeted Therapy With Encorafenib and Binimetinib
A Phase 2 study testing Nivolumab + Ipilimumab and Encorafenib + Binimetinib in people with Unresectable Stage III Melanoma and Stage IV Melanoma, run by European Organisation for Research and Treatment of Cancer - EORTC at 38 sites in 9 countries.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Unresectable Stage III Melanoma, Stage IV Melanoma
- What is being tested?
- Nivolumab + Ipilimumab and Encorafenib + Binimetinib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 271 participants
- Where
- 38 sitesin 9 countries
- Study dates
- 30 Oct 2018to Jan 2027
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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])
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- 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
Trial locations and contacts
38 sites in 9 countries.
38 sites in 9 countries
France17 sites
CHU Amiens - Hopital Sud
Amiens
CHRU de Besançon - Hopital Jean Minjoz
Besançon
CHU de Bordeaux - Groupe Hospitalier Saint-André - Hopital Saint-Andre
Bordeaux
Centre Jean Perrin
Clermont-Ferrand
CHU de Dijon - Centre Georges-François-Leclerc
Dijon
CHU de Grenoble - La Tronche - Hôpital A. Michallon
Grenoble
CHRU de Lille
Lille
Centre Hospitalier Lyon Sud
Lyon
Centre Leon Berard
Lyon
Assistance Publique - Hopitaux de Marseille - Hôpital de La Timone (APHM)
Marseille
CHU de Nice - Hopital De L'Archet
Nice
Assitance Publique - Hopitaux de Paris - Hopital Saint-Louis
Paris
CHU Ambroise Pare
Paris
Centre Hospitalier De Pau
Pau
CHU de Saint-Etienne - Hopital Nord
Saint-Priest-en-Jarez
CHU de Tours - Hopital Trousseau
Tours
Gustave Roussy
Villejuif
Italy7 sites
Azienda Ospedaliera Papa Giovanni XXIII
Bergamo
Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"
Naples
IRCCS - Istituto Oncologico Veneto
Padova
IRCCS-Regina Elena National Cancer Center
Roma
Universita Degli Studi Di Siena -Policlinico "le Scotte"
Siena
Azienda Ospedaliera Citta della Salute e della Scienza di Torino
Turin
Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" di Udine
Udine
Germany3 sites
Universitaetsklinikum Heidelberg
Heidelberg
Univ. Mainz - Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz-University Medical Center
Mainz
Universitaetsklinikum Wuerzburg
Würzburg
Spain3 sites
Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia)
Badalona
Hospital Clinic Universitari de Barcelona
Barcelona
Vall d'Hebron Institut d'Oncologia
Barcelona
Denmark2 sites
University Hospitals Copenhagen - Herlev Hospital - University Copenhagen
Herlev
Odense University Hospital
Odense
Finland2 sites
Helsinki University Central Hospital - Dept of Oncology
Helsinki
Tampere University Hospital
Tampere
United Kingdom2 sites
NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre - Gartnavel General Hospital
Glasgow
East & North Hertfordshire NHS Trust - East and North Hertfordshire NHS Trust - Mount Vernon Hospital
Middlesex
Netherlands1 site
The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis
Amsterdam
About this study
Official title: 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.
- Conditions
- Unresectable Stage III Melanoma, Stage IV Melanoma
- Being tested
- Nivolumab + Ipilimumab, Encorafenib + Binimetinib
- Keywords
- cutaneous melanoma, mucosal melanoma, BRAF mutation
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nivolumab + IpilimumabDrug
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.
Encorafenib + BinimetinibDrug
encorafenib 450 mg QD + binimetinib 45 mg BID orally for 12 weeks
| Study group | Role | What they receive |
|---|---|---|
| ARM A: Nivolumab + Ipilimumab | Active comparator | 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. Receives: Drug: Nivolumab + Ipilimumab |
| ARM B: Encorafenib + Binimetinib + Nivolumab + Ipilimumab | Experimental | 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. Receives: Drug: Nivolumab + Ipilimumab; Drug: Encorafenib + Binimetinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression Free Survival (PFS)
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)
Measured: 4.1 years from first patient in
Secondary outcomes (9)
Overall Survival (OS)
OS is defined as the time from the date of randomization to the date of death, whatever the cause.
Measured: 6 years from first patient in
Complete Response (CR) rate
CR will be assessed according to the RECIST criteria (version 1.1)
Measured: 4.1 years from first patient in
Time to Complete Response (CR)
Time to CR is defined as the time from the date of randomization until the occurrence of first CR.
Measured: 4.1 years from first patient in
Duration of Complete Response (CR)
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.
Measured: 4.1 years from first patient in
Best overall response rate
Best overall response will be assessed according to the RECIST criteria (version 1.1)
Measured: 4.1 years from first patient in
Time to best response
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)
Measured: 4.1 years from first patient in
Duration of best response
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)
Measured: 4.1 years from first patient in
Occurrence of adverse events
This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, for adverse event reporting.
Measured: 4.1 years from first patient in
Progression-free survival 2 (PFS2)
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)
Measured: 4.1 years from first patient in
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Aug 2017
- Study start30 Oct 2018
- Primary completion24 Oct 2023
- Study completionJan 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Unresectable Stage III MelanomaStudies of the same condition, open and under way.
- More trials run by European Organisation for Research and Treatment of Cancer - EORTCThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 271 participants (actual)
Sponsor and investigators
- Sponsor type
- Research network
- Responsible party
- Sponsor
- Investigators
- Caroline Robert, Principal investigator, Cancer Institute Gustave Roussy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03235245
- Sponsor's protocol ID
- EORTC-1612-MG
- Other IDs
- 2017-002887-42, 2017
- Acronym
- EBIN
- Status last verified
- Jul 2025
- First submitted
- 27 Jul 2017
- Last updated
- 1 Aug 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: All publications must comply with the terms specified in the EORTC Policy 009 "Release of Results and Publication Policy".
Publications
Robert C, Kicinski M, Dutriaux C, Routier E, Govaerts AS, Buhrer E, Neidhardt EM, Durando X, Baroudjian B, Saiag P, Gaudy-Marqueste C, Ascierto PA, Arance A, Russillo M, Perrot JL, Mortier L, Aubin F, Dalle S, Grange F, Munoz-Couselo E, Mary-Prey S, Amini-Adle M, Mansard S, Lebbe C, Funck-Brentano E, Monestier S, Eggermont AMM, Oppong F, Wijnen L, Schilling B, MandalA M, Lorigan P, van Akkooi ACJ. Combination of encorafenib and binimetinib followed by ipilimumab and nivolumab versus ipilimumab and nivolumab in patients with advanced melanoma with BRAFV600E or BRAFV600K mutations (EBIN): an international, open-label, randomised, controlled, phase 2 study. Lancet Oncol. 2025 Jun;26(6):781-794. doi: 10.1016/S1470-2045(25)00133-0.
PubMed 40449497