Clinical trial NCT03235245: Immunotherapy With Ipilimumab and Nivolumab Preceded or Not by a Targeted Therapy With Encorafenib and Binimetinib
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Unresectable Stage III Melanoma
Stage IV Melanoma
Keywords: cutaneous melanoma
mucosal melanoma
BRAF mutation
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
First posted: 2017-08-01
Enrollment: 271
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 4.1 years from first patient in
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: 6 years from first patient in
measure: Complete Response (CR) rate
timeFrame: 4.1 years from first patient in
measure: Time to Complete Response (CR)
timeFrame: 4.1 years from first patient in
measure: Duration of Complete Response (CR)
timeFrame: 4.1 years from first patient in
measure: Best overall response rate
timeFrame: 4.1 years from first patient in
measure: Time to best response
timeFrame: 4.1 years from first patient in
measure: Duration of best response
timeFrame: 4.1 years from first patient in
measure: Occurrence of adverse events
timeFrame: 4.1 years from first patient in
measure: Progression-free survival 2 (PFS2)
timeFrame: 4.1 years from first patient in
Other outcomes:
Locations:
city: Herlev
country: Denmark
facility: University Hospitals Copenhagen - Herlev Hospital - University Copenhagen
city: Odense
country: Denmark
facility: Odense University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital - Dept of Oncology
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Amiens
country: France
facility: CHU Amiens - Hopital Sud
city: Besançon
country: France
facility: CHRU de Besançon - Hopital Jean Minjoz
city: Bordeaux
country: France
facility: CHU de Bordeaux - Groupe Hospitalier Saint-André - Hopital Saint-Andre
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: CHU de Dijon - Centre Georges-François-Leclerc
city: Grenoble
country: France
facility: CHU de Grenoble - La Tronche - Hôpital A. Michallon
city: Lille
country: France
facility: CHRU de Lille
city: Lyon
country: France
facility: Centre Hospitalier Lyon Sud
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Assistance Publique - Hopitaux de Marseille - Hôpital de La Timone (APHM)
city: Nice
country: France
facility: CHU de Nice - Hopital De L'Archet
city: Paris
country: France
facility: Assitance Publique - Hopitaux de Paris - Hopital Saint-Louis
city: Paris
country: France
facility: CHU Ambroise Pare
city: Pau
country: France
facility: Centre Hospitalier De Pau
city: Saint Priest en Jarez
country: France
facility: CHU de Saint-Etienne - Hopital Nord
city: Tours
country: France
facility: CHU de Tours - Hopital Trousseau
city: Villejuif
country: France
facility: Gustave Roussy
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg
city: Mainz
country: Germany
facility: Univ. Mainz - Universitaetsmedizin der Johannes Gutenberg Universitaet Mainz-University Medical Center
city: Wuerzburg
country: Germany
facility: Universitaetsklinikum Wuerzburg
city: Bergamo
country: Italy
facility: Azienda Ospedaliera Papa Giovanni XXIII
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"
city: Padova
country: Italy
facility: IRCCS - Istituto Oncologico Veneto
city: Roma
country: Italy
facility: IRCCS-Regina Elena National Cancer Center
city: Siena
country: Italy
facility: Universita Degli Studi Di Siena -Policlinico "le Scotte"
city: Turin
country: Italy
facility: Azienda Ospedaliera Citta della Salute e della Scienza di Torino
city: Udine
country: Italy
facility: Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia" di Udine
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis
city: Warsaw
country: Poland
facility: Maria Sklodowska-Curie Memorial Cancer Centre
city: Badalona
country: Spain
facility: Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia)
city: Barcelona
country: Spain
facility: Hospital Clinic Universitari de Barcelona
city: Barcelona
country: Spain
facility: Vall d'Hebron Institut d'Oncologia
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde - Beatson West of Scotland Cancer Centre - Gartnavel General Hospital
city: Middlesex
country: United Kingdom
facility: East & North Hertfordshire NHS Trust - East and North Hertfordshire NHS Trust - Mount Vernon Hospital
Study officials:
affiliation: Cancer Institute Gustave Roussy
name: Caroline Robert
role: PRINCIPAL_INVESTIGATOR
References: