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)
- Conditions
- BRAF V600 mutation–positive unresectable or metastatic melanoma.MedDRA version: 21.1Level: PTClassification code 10025650Term: Malignant melanomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2017-002887-42-DE
- Lead Sponsor
- EORTC
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 270
• Histologically or cytologically confirmed unresectable stage III/ IV
cutaneous or mucosal melanoma (unknown primary also allowed)
• Presence of BRAF V600E or V600K mutation in tumor tissue prior to
enrolment as per local assessment
• Tumor tissue (FFPE) 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 ULN (< 5x ULN in case of liver
metastases)
• Lipase < 2.0 x the ULN and no radiologic or clinical evidence of
pancreatitis
• 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
• 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)
• 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. 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. 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
• 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
• 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.
• Concomitant administration of strong inducers and inhibitors of P-gp,
glucuronidation, CYP3A4
• Concomitant anticoagulation at therapeutic doses with oral
anticoagulants
• Live vaccines within 30 days prior to the first dose of study therapy.
• 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 or C
• History of Human Immunodeficiency Virus (HIV)
• 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 not allowed
• Active autoimmune disease that has required systemic treatment in
past 2 years. Replacement therapy 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
• 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
• 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.
• Minor surgery 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
• 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
• His
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method