E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic melanoma and BRAF mutation |
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E.1.1.1 | Medical condition in easily understood language |
Black skin cancer (melanoma) with pathological change of the BRAF gene |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053571 |
E.1.2 | Term | Melanoma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To define the best sequencing combination treatment in primary efficacy variable overall survival (OS). |
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E.2.2 | Secondary objectives of the trial |
• 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 |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biological markers (biomarker study). The objective of the biomarkers ancillary study is to focus on understanding mechanisms of action/resistance. In particular, the ancillary study: • Will inform how to sequence targeted RAF/MEK agents with immunotherapy agents (i.e. ipilumumab and nivolumab) in melanoma; • Will be hypothesis-generating only. |
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E.3 | Principal 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 (< 5 x ULN if liver metastases); 12) Adequate renal function: serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min in males and ≥ 50 mL/min in females (calculated according to Cockroft-Gault formula); 13) Serum calcium levels, international normalised ratio (INR) and partial thromboplastin time were within normal limits; 14) Life expectancy of at least 3 months; |
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E.4 | Principal 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.
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E.5 End points |
E.5.1 | 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. |
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E.5.1.1 | 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. |
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E.5.2 | 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)
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E.5.2.1 | 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
France |
Poland |
Sweden |
Spain |
Switzerland |
Germany |
Greece |
Italy |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Treatment duration will be until the second PD (2 years estimated). It is expected that the study will start (First Patient FirsT Visit Date)on November 2016, and the study will end (Last Patient Last Visit) on June 2021. The date of study end is dependent on the clinical course of the disease and may therefore occur earlier than indicated. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |