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

Stage IV Melanoma Clinical Trial

— EBIN  

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03235245
• Other study ID #: EORTC-1612-MG
• Secondary ID: 2017-002887-42
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 30, 2018
• Est. completion date: January 2027

Study information

• Verified date: May 2024
• Source: European Organisation for Research and Treatment of Cancer - EORTC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 progression free survival compared to combination immunotherapy nivolumab + ipilimumab alone in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 271
• Est. completion date: January 2027
• Est. primary completion date: October 24, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Melanoma
• Stage IV Melanoma
• Unresectable Stage III Melanoma

Intervention

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.
• Encorafenib + Binimetinib
encorafenib 450 mg QD + binimetinib 45 mg BID orally for 12 weeks

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
European Organisation for Research and Treatment of Cancer - EORTC

Countries where clinical trial is conducted

Denmark,  Finland,  France,  Germany,  Italy,  Netherlands,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Overall Survival (OS)	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
Secondary	Complete Response (CR) rate	CR will be assessed according to the RECIST criteria (version 1.1)	4.1 years from first patient in
Secondary	Time to Complete Response (CR)	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
Secondary	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.	4.1 years from first patient in
Secondary	Best overall response rate	Best overall response will be assessed according to the RECIST criteria (version 1.1)	4.1 years from first patient in
Secondary	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)	4.1 years from first patient in
Secondary	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)	4.1 years from first patient in
Secondary	Occurrence of adverse events	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
Secondary	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)	4.1 years from first patient in