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.
- Histologically or cytologically confirmed unresectable stage III or IV cutaneous or
- Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment as per
- 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
- 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
- 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
- Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg,
- 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)
- 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
- Any anticancer treatment within 4 weeks before randomization e.g. radiation, surgery,
- Patients with clinically relevant ongoing complications from prior anticancer
- 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
- Patients with neuromuscular disorders that are associated with CK > ULN (e.g.,
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal
- 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
- 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