A phase II study using four medicines (two 'immunotherapy' medicines and two 'target therapy' medicines)in threedifferent sequences ( or arms), to which patients with metastatic (advanced) melanoma with a genetic abnormality willbe randomly allocated, in order to evaluate the best treatment approach for this patient group

Phase 1

• Conditions: Metastatic melanoma with BRAF mutation; MedDRA version: 21.1Level: LLTClassification code 10053571Term: MelanomaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2014-004842-92-SE
• Lead Sponsor: Fondazione Melanoma (ONLUS)

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2018-01-22
• Last Update Posted: 8 July 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 207

Inclusion Criteria

1) Patients of either sex aged b% 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 visitM> 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) b% 1.5 x 10*9/L AND platelet count b% 100 x 10*9/L AND haemoglobin b% 9 g/dL
11) Adequate liver function: total bilirubin b$ 1.5 x upper limit of normal (ULN) AND aspartate aminotransferase (AST)/alanine aminotransferase (ALT) b$ 2.5 X ULN (< 5 x ULN if liver metastases)
12) Adequate renal function: serum creatinine b$ 1.5 mg/dL OR creatinine clearance b% 60 mL/min in males and b% 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:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 5
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 5

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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified