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