Metastatic melanoma and BRAF mutation MedDRA version: 21.1 Level: LLT Classification code 10053571 Term: Melanoma System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Opdivo
Product Name: Nivolumab (Opdivo)
Product Code: BMS-936558
Pharmaceutical Form: Solution for injection
INN or Proposed INN: NIVOLUMAB
Other descriptive name: NIVOLUMAB
Concentration
Sponsors
Fondazione Melanoma ONLUS
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1) Patients of either sex aged = 18 years; 2) Histologically confirmed stage III (unresectable) or stage IV melanoma with the BRAF V600 mutation. Patients with mucosal melanoma (but not those with ocular melanoma) are eligible for study participation; 3) Treatment naïve for metastatic disease patients. Previous adjuvant treatment, included checkpoint inhibitors anti CTLA-4, anti PD-1/PDL-1 is allowed, except for stage IV (if completed at least 6 weeks prior to randomization, and all related adverse events have either returned to baseline or stabilized). BRAF inhibitor treatment in adjuvant setting is not permitted. 4) Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) per RECIST 1.1 criteria; 5) Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrollment; 6) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1; 7) Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. An archive sample is mandatory at the screening visit; however, a new sample collection would be preferable; 8) Female subjects of childbearing potential must have a negative pregnancy test result at baseline and must practice two highly effective methods of contraception for the total study duration plus 23 weeks (i.e. 30 days plus the time required for nivolumab to undergo five half lives) after the last dose of nivolumab and ipilimumab and 30 days after the last dose of binimetinib and encorafenib for female subjects. Additional pregnancy testing must be performed every 6 weeks during the treatment Combo-Immuno and every 4 weeks during the treatment Combo-Target, as well as at the end of the systemic exposure; 9) Men who are sexually active with women of childbearing potential must practice a reliable method of contraception for the total study duration plus 31 weeks (i.e. 80 days plus the time required for nivolumab to undergo five half lives) after the last dose of nivolumab and ipilimumab and 90 days after the last dose of binimetinib and encorafenib; 10) Adequate bone marrow haematological function: absolute neutrophil count (ANC) = 1.5 x 109/L AND platelet count = 100 x 109/L AND haemoglobin = 9 g/dL; 11) Adequate liver function: total bilirubin = 1.5 x upper limit of normal (ULN) AND aspartate aminotransferase (AST)/alanine aminotransferase (ALT) = 2.5 X ULN (=65 years) yes F.1.3.1 Number of subjects for this age range 115
Exclusion criteria
Exclusion criteria: 1) Active brain metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete and 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; 2) Subjects with active, known or suspected autoimmune disease; 3) Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment; 4) Prior treatment for stage III (unresectable) or stage IV melanoma with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) antibody; 5) Female subjects who are pregnant (positive pregnancy test), breast-feeding, or who are of childbearing potential and not practicing a reliable method of birth control; 6) Evidence of 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, or would interfere with the results of the study; 7) Patients with a history of uncontrolled cardiovascular or interstitial lung disease and evidence or risk of retinal vein occlusion or central serous retinopathy (patients with a history of cardiovascular or interstitial lung disease and evidence or risk of retinal vein occlusion or central serous retinopathy (past or present evidence of rethinophaty central serous retinopathy - CSR -, occlusion of retinal - RVOo retinal degenerative disease) or ophthalmopathy, which according to the ophthalmologic evaluation at baseline could be considered a risk factor for CSR / RVO ( eg. cupping of the optic disc, visual field defect, intraocular pressure - (eg: central IOP - > 21 mmHg); 8) Previous or concurrent malignancy. Exceptions: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to study entry; or other solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry 9) History of Gilbert's syndrome; 10) Inability to regularly access centre facilities for logistical or other reasons; 11) History of poor co-operation, non-compliance with medical treatment, or unreliability; 12) Participation in any interventional drug or medical device study within 30 days prior to treatment start. 13) Positive test for human immunodeficiency virus (HIV), hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection; 14) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). 15) Receipt of live vaccine within 30 days prior to study drug administration. 16) History of severe or life-threatening skin adverse events or reactions to drugs.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To define the best sequencing combination treatment in primary efficacy variable overall survival (OS).;Secondary Objective: • Total PFS; • 3, 4 and 5 years PFS rate; • Percentage of patients alive at 3, 4 and 5 years; • Best overall response rate (BORR); • Duration of response (DoR); • Toxicity of the investigational medicinal products (IMPs) • Quality of life and general health status defined by: o Health-related quality of life (HRQoL), by means of the 30-item European Organisation for Research and Treatment of Care quality of life questionnaire (EORTC QLQ-C30); o General health status, by means of the European Quality of Life 5- Dimensions(EQ-5D) questionnaire; o Impairment of work productivity and activity, by means of the Work Productivity and Activity Impairment: General Health (WPAI:GH) questionnaire;Primary end point(s): Overall Survival is primary endpoint of the study (OS). It will be calculated as the time from the date of randomization until the date of death from any cause.;Timepoint(s) of evaluation of this end point: Any patient not know to have died at the time of data analysis will be censored at the time of the last recorded date on which the patient was know to be alive. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Total PFS; • 3, 4 and 5 years PFS rate; • Percentage of patients alive at 3, 4 and 5 years; • Best overall response rate (BORR); • Duration of response (DoR); • Biological markers (biomarkers ancillary study); • Health-related quality of life (HRQoL; • General health status; • Impairment of work productivity and activity. Safety endpoints: Toxicity of the IMPs (NCI CTC-AE Version 4.03 criteria); • Adverse events (AEs) and serious adverse events (SAEs); • Vital signs (weight, BMI, heart rate, blood pressure); • Laboratory safety parameters (haematology, blood chemistry, urinalysis) ;Timepoint(s) of evaluation of this end point: Total PFS calculated from the date of randomization until the date of the second progression. 3 years PFS rate; 3-years mean value calculated from the date of randomization. Percentage of patients alive at 3 years: will be measured as a number (expressed as a percentage) of patients in 3. year. BORR: from the date of randomization until the study end DoR calculated as the time from the date of the first documented response (CR or PR) until the date of the first documented progression or death due to underlying cancer. Biomarkers ancillary study: at study end. Health-related quality of life (HRQoL), General health status and Impairment of work productivity and activity: by means of a questionnaires - every visit Safety Secondary Endpoints- throughout the study | — |
Countries
Austria, France, Germany, Greece, Italy, Poland, Spain, Sweden, Switzerland, United Kingdom
Contacts
Public ContactPaola Schiavo
Fondazione Melanoma ONLUS
Outcome results
None listed