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

NCT03235245 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: EORTC-1612-MG2017-002887-42
• Study Type: interventional
• Target: 271
• Locations: 9 countries
• Sites: 38

Brief 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 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

Keywords

cutaneous melanoma; mucosal melanoma; BRAF mutation

Outcome Measures

Primary Outcomes (1)

• 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)

  4.1 years from first patient in

Secondary Outcomes (9)

• Overall Survival (OS)

  6 years from first patient in

• Complete Response (CR) rate

  4.1 years from first patient in

• Time to Complete Response (CR)

  4.1 years from first patient in

• Duration of Complete Response (CR)

  4.1 years from first patient in

• Best overall response rate

  4.1 years from first patient in

Study Arms (2)

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.

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.

Drug: Nivolumab + Ipilimumab; Drug: Encorafenib + Binimetinib

Interventions

Nivolumab + Ipilimumab DRUG

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.

ARM A: Nivolumab + Ipilimumab; ARM B: Encorafenib + Binimetinib + Nivolumab + Ipilimumab

Encorafenib + Binimetinib DRUG

encorafenib 450 mg QD + binimetinib 45 mg BID orally for 12 weeks

ARM B: Encorafenib + Binimetinib + Nivolumab + Ipilimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• European Organisation for Research and Treatment of Cancer - EORTC: lead

Study Sites (38)

University Hospitals Copenhagen - Herlev Hospital - University Copenhagen

Herlev, Denmark

Location

Odense University Hospital

Odense, Denmark

Location

Helsinki University Central Hospital - Dept of Oncology

Helsinki, Finland

Location

Tampere University Hospital

Tampere, Finland

Location

CHU Amiens - Hopital Sud

Amiens, France

Location

CHRU de Besançon - Hopital Jean Minjoz

Besançon, France

Location

CHU de Bordeaux - Groupe Hospitalier Saint-André - Hopital Saint-Andre

Bordeaux, France

Location

Centre Jean Perrin

Clermont-Ferrand, France

Location

CHU de Dijon - Centre Georges-François-Leclerc

Dijon, France

Location

CHU de Grenoble - La Tronche - Hôpital A. Michallon

Grenoble, France

Location

CHRU de Lille

Lille, France

Location

Centre Hospitalier Lyon Sud

Lyon, France

Location

Centre Leon Berard

Lyon, France

Location

Assistance Publique - Hopitaux de Marseille - Hôpital de La Timone (APHM)

Marseille, France

Location

CHU de Nice - Hopital De L'Archet

Nice, France

Location

Assitance Publique - Hopitaux de Paris - Hopital Saint-Louis

Paris, France

Location

CHU Ambroise Pare

Paris, France

Location

Centre Hospitalier De Pau

Pau, France

Location

CHU de Saint-Etienne - Hopital Nord

Saint-Priest-en-Jarez, France

Location

CHU de Tours - Hopital Trousseau

Tours, France

Location

Gustave Roussy

Villejuif, France

Location

Universitaetsklinikum Heidelberg

Heidelberg, Germany

Location

Univ. Mainz - Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz-University Medical Center

Mainz, Germany

Location

Universitaetsklinikum Wuerzburg

Würzburg, Germany

Location

Azienda Ospedaliera Papa Giovanni XXIII

Bergamo, Italy

Location

Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"

Napoli, Italy

Location

IRCCS - Istituto Oncologico Veneto

Padua, Italy

Location

IRCCS-Regina Elena National Cancer Center

Roma, Italy

Location

Universita Degli Studi Di Siena -Policlinico "le Scotte"

Siena, Italy

Location

Azienda Ospedaliera Citta della Salute e della Scienza di Torino

Turin, Italy

Location

Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" di Udine

Udine, Italy

Location

The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis

Amsterdam, Netherlands

Location

Maria Sklodowska-Curie Memorial Cancer Centre

Warsaw, Poland

Location

Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia)

Badalona, Spain

Location

Hospital Clinic Universitari de Barcelona

Barcelona, Spain

Location

Vall d'Hebron Institut d'Oncologia

Barcelona, Spain

Location

NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre - Gartnavel General Hospital

Glasgow, United Kingdom

Location

East & North Hertfordshire NHS Trust - East and North Hertfordshire NHS Trust - Mount Vernon Hospital

Middlesex, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 40449497 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Nivolumab; Ipilimumab; encorafenib; binimetinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Caroline Robert

  Cancer Institute Gustave Roussy

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2017
• First Posted: August 1, 2017
• Study Start: October 30, 2018
• Primary Completion: October 24, 2023
• Study Completion (Estimated): January 1, 2027
• Last Updated: August 1, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share

Locations

FR (17); PL (1); FI (2); DE (3); NL (1); DK (2); GB (2); ES (3); IT (7)