A three arms prospective, randomized phase II study to evaluate the best sequential approach with combo immunotherapy (ipilimumab/nivolumab) and combo target therapy (LGX818/MEK162) in patients with metastatic melanoma and BRAF mutatio
- Conditions
- Metastatic melanoma and BRAF mutationMedDRA version: 19.0Level: LLTClassification code 10053571Term: MelanomaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2014-004842-92-IT
- Lead Sponsor
- FONDAZIONE MELANOMA ONLUS
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 230
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 patients. As previous systemic treatmtne for melanoma only interferon is permitted (note that prior adjuvant melanoma therapy is permitted if completed at least 6 weeks prior to randomization, and all related adverse events have either returned to baseline or stabilized).
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 enrolment;
6)Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (appendix 7);
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 fresh sample would be preferable;
8)Female subjects of childbearing potential must have a negative serum pregnancy test result at Baseline and must practice a reliable method 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;
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;
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;
15)Ability to understand study-related patient information and provision of written informed consent for participation in the study.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 115
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 115
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 8 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 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 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)History of Gilbert's syndrome;
9)Inability to regularly access centre facilities for logistical or other reasons;
10)History of poor co-operation, non-compliance with medical treatment, or unreliability;
11)Participation in any interventional drug or medical device study within 30 days prior to treatment start.
12)Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection;
13) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To define the best sequencing combination treatment in primary efficacy variable overall survival (OS).;Secondary Objective: To evaluate the effects of the two sequencing combination treatments on:<br>? Total PFS;<br>? Percentage of patients alive at 2 and 3 years;<br>? Best overall response rate (BORR);<br>? Duration of response (DoR);<br>? Toxicity of the investigational medicinal products (IMPs)<br>? Quality of life and general health status;Primary end point(s): OS is primary endpoint of the study. OS 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 Outcome Measures
Name Time Method