A phase II study using four medicines (two 'immunotherapy' medicines and two 'target therapy' medicines)in three different sequences ( or arms), to which patients with metastatic (advanced) melanoma with a genetic abnormality will be randomly allocated, in order to evaluate the best treatment approach for this patient group.
- Conditions
- Metastatic melanoma with BRAF mutationMedDRA version: 20.0 Level: LLT Classification code 10053571 Term: Melanoma System Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2014-004842-92-GB
- Lead Sponsor
- Fondazione Melanoma (ONLUS)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- Not specified
- Target Recruitment
- 207
A subject is eligible for the study if all of the following criteria are met:
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) Patients who are treatment naive for metastatic disease. Previous adjuvant treatment, including checkpoint inhibitors anti CTLA-4, anti PD-1/PDL-1 are allowed except for stage IV (if completed at least 6 weeks prior to randomisation, and all related adverse events have either returned to baseline or stabilised). BRAF inhibitor treatment in an adjuvant setting is not permitted.
4) Measurable disease by computed tomography (CT) or Magnetic Resonance Imaging (MRI) as 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
7) Tumour 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 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. Additional pregnancy tests must be performed every six weeks during the Combo-Immuno and every four weeks during the 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
10) Adequate bone marrow haematological function: absolute neutrophil count (ANC) = 1.5 x 10*9/L AND platelet count = 100 x 10*9/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 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: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 0
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 0
A subject is excluded from the study if any of the following criteria are met:
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 (past or present evidence of retinopathy, central serous retinopathy [CSR], occlusion of retinal vein [RVO], retinal degenerative disease) or ophthalmopathy, which according to the ophthalmologic evaluation at baseline could be considered a risk factor for CSR / RVO (e.g. cupping of the optic disc, visual field defect, intraocular pressure (e.g. central intraocular pressure > 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 tumour 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 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)
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