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)

• Histologically or cytologically confirmed unresectable stage III/ 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 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: • Absolute neutrophil count
(ANC) >= 1.5 x 109/L (>= 1500 per mm3) • Lymphocyte count >= 1.0 x 109/L (>= 1000
per mm3) • Platelet count >= 100 x 109/L (>= 100,000 per mm3) • Hemoglobin >= 9.0
g/dL (>= 5.59 mmol/l) • Total bilirubin <= 1.5 x institutional upper limit of
normal (ULN) or direct bilirubin <= ULN for patients with total bilirubin levels
> 1.5 x ULN. • AST (SGOT)/ALT (SGPT) <= 2.5 x institutional upper limit of
normal (< 5x ULN in case of liver metastases) • Lipase < 2.0 x the ULN and no
radiologic or clinical evidence of pancreatitis • Serum phosphorus, calcium,
magnesium and potassium within normal ranges as per local lab values •
Creatinine <= 1.5 x ULN or calculated creatinine clearance >= 60 mL/min for
patient with creatinine levels > 1.5 x institutional laboratory value
(according to Cockroft-Gault, Appendix D in protocol); • International
Normalized Ratio (INR) or Prothrombin Time (PT) and Activated Partial
Thromboplastin Time (aPTT) <= 1.5 x ULN Note: patients receiving anticoagulant
therapy (have to be shifted to low molecular weight heparin (LMWH) before
treatment start; as warfarin and related 4-hydroxycoumarin-containing molecules
are not permitted) are eligible if their PT or INR or PTT is within the
recommended range for the desired level of anticoagulation. • Patients with
hyperthyroidism or hypothyroidism but that are stable on hormone replacement
can be included. • Adequate cardiac function: • left ventricular ejection
fraction (LVEF) >= 50% as determined by a multigated acquisition (MUGA) scan or
echocardiogram, • 12-lead ECG (in triplicate [2-5 minutes apart]). Single ECG
should be obtained after the patient has been in a supine position for 5
minutes and recorded while the patient remains in that position on which QTcF
must be <470 ms. • Women of child bearing potential (WOCBP) must have a
negative serum (preferred) or urine pregnancy test within 72 hours prior to
registration.Note: women of childbearing potential are defined as premenopausal
females capable of becoming pregnant (i.e. females who have had evidence of
menses in the past 12 months, with the exception of those who had prior
hysterectomy). However, women who have been amenorrheic for 12 or more months
are still considered to be of childbearing potential if the amenorrhea is
possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian
suppression or other reasons.• Patients of childbearing / reproductive
potential should use adequate birth control measures, as defined by the
investigator, during the study treatment period and after the study treatment:
• for at least 5 months for a woman and 7 months for a man after the last study
treatment (nivolumab and ipilimumab or nivolumab alone). • for a period of at
least 2 months after last dose of encorafenib and binimetinib Note: A highly
effective method of birth control is defined as a method which results in a low
failure rate (i.e. less than 1% per year) when used consistently and correctly.
Such methods include: • Combined (estrogen and progestogen containing) hormonal
contraception associated with inhibition of ovulation (oral, intravaginal,
transdermal) • Progestogen-only hormonal contraception associated with
inhibition of ovulation (oral, injectable, implantable) • Intrauterine device
(IUD) • Intrauterine hormone-releasing system (IUS) • Bilateral tubal occlusion
• Vasectomized partner • Sexual abstinence Note: for patient that will receive
ENCO: there is a potential for ENCO to induce CYP3A4, which may reduce the
effectiveness of hormonal contraception methods. • Female patients must not be
breast feeding during the trial treatment and for a period of at least 5 months
after treatment discontinuation. • Subject is willing and able to comply with
the protocol for the duration of the study including undergoing treatment and
scheduled visits and examinations including follow up. • Before patient
registration/randomization and before any related study activity, written
informed consent must be given according to ICH/GCP, and national/local
regulations}e* *8@ Changes are the following (ref. prot v3.0 and v4.0 tracked
changes) : - Serum phosphorus, total calcium, total magnesium and potassium
within normal ranges as per local lab values; in case of small variation
(+/-10%) in phosphorus, calcium or magnesium, the patient may be considered
eligible and the decision will be left to the investigator - Serum total
bilirubin <= 1.5 x institutional upper limit of normal (ULN) or direct bilirubin
<= ULN for patients with total bilirubin levels > 1.5 x ULN. - AST (SGOT)/ALT
(SGPT) <= 2.5 x ULN (< 5x ULN in case of liver metastases) - Creatinine <= 1.5 x
ULN or calculated creatinine clearance >= 60 mL/min for patient with creatinine
levels > 1.5 x ULN (according to Cockroft-Gault formula, Appendix D);

• 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 4 weeks after
end of treatment. 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 returned to grade <= 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) • History of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies)
• Chronic use of immunosuppressive agents and/or systemic corticosteroids or
any use in the last 2 weeks prior to the first dose of study treatment •
Corticosteroid use as premedication for IV contrast allergies/reactions is
allowed • Conditions requiring systemic treatment with <10 mg daily prednisone
equivalents or equivalent doses of any other corticosteroid are allowed •
History of interstitial lung disease (ILD) OR pneumonitis (other than chronic
obstructive pulmonary disease (COPD) exacerbation) that has required oral or IV
steroids are allowed • 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 • 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. Changes are the following (ref. prot
v3.0 and v4.0 tracked changes) : - 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 6 months prior to randomization and all related adverse
events have returned to grade <= 1. - History of interstitial lung disease (ILD)
OR pneumonitis (other than chronic obstructive pulmonary disease (COPD)
exacerbation) that has required oral or IV steroids are not allowed