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: 20.0 Level: PT Classification code 10025650 Term: Malignant melanoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2017-002887-42-ES
- Lead Sponsor
- European Organisation for Research and Treatment of Cancer
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- Not specified
- Target Recruitment
- 270
•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
•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; ac
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