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.
Name: Nivolumab + Ipilimumab
Description: nivolumab 3 mg/kg q3w + ipilimumab 1 mg/kg q3w for 4 injections followed by nivolumab 480 mg IV q4w until completion of 2 years total treatment or progression.Type: DrugARM A: Nivolumab + Ipilimumab ARM B: Encorafenib + Binimetinib + Nivolumab + Ipilimumab
Name: Encorafenib + Binimetinib
Description: encorafenib 450 mg QD + binimetinib 45 mg BID orally for 12 weeksType: DrugARM B: Encorafenib + Binimetinib + Nivolumab + Ipilimumab
Description: PRS is defined as the time from the date of randomization until the first date of progression, or until date of death (whatever the cause), whichever occurs first. Progression will be assessed according to the RECIST criteria (version 1.1)
Measure: Progression Free Survival (PFS) Time: 4.1 years from first patient inDescription: OS is defined as the time from the date of randomization to the date of death, whatever the cause.
Measure: Overall Survival (OS) Time: 6 years from first patient inDescription: CR will be assessed according to the RECIST criteria (version 1.1)
Measure: Complete Response (CR) rate Time: 4.1 years from first patient inDescription: Time to CR is defined as the time from the date of randomization until the occurrence of first CR.
Measure: Time to Complete Response (CR) Time: 4.1 years from first patient inDescription: Duration of CR will be measured from the time measurement criteria for CR are first met until the first date that recurrence is objectively documented.
Measure: Duration of Complete Response (CR) Time: 4.1 years from first patient inDescription: Best overall response will be assessed according to the RECIST criteria (version 1.1)
Measure: Best overall response rate Time: 4.1 years from first patient inDescription: Time to best response is defined as the time from the date of randomization until the occurrence of the best response (CR or PR, whichever comes first). CR and PR will be assessed according to the RECIST criteria (version 1.1)
Measure: Time to best response Time: 4.1 years from first patient inDescription: Best response duration will be measured from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented. CR and PR will be assessed according to the RECIST criteria (version 1.1)
Measure: Duration of best response Time: 4.1 years from first patient inDescription: This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, for adverse event reporting.
Measure: Occurrence of adverse events Time: 4.1 years from first patient inDescription: PFS2 is defined as the time from randomization to second objective disease progression, or death from any cause, whichever first. The second objective disease progression will be assessed according to the RECIST criteria (version 1.1)
Measure: Progression-free survival 2 (PFS2) Time: 4.1 years from first patient inAllocation: Randomized
Parallel Assignment
There are 2 SNPs
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. --- V600E ---
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 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. --- V600E ---
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. --- V600E --- --- V600K ---
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 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. --- V600E --- --- V600K ---