Peptide-based vaccine in combination or not with chemotherapy in melanoma patients: a phase II randomized clinical study.

INTERVENTION: Product Name: MelanA/MART‐1: 26‐35 ( 27L) Pharmaceutical Form: Powder for solution for injection INN or Proposed INN: MelanA/MART‐1: 26‐35 ( 27L) Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 250‐ Product Name: NY‐ESO1:157‐165 Pharmaceutical Form: Powder for solution for injection INN or Proposed INN: NY‐ESO1:157‐165 Concentration unit: µg microgram(s) Concentration type: equal Concentration number: 250‐ Trade Name: INTRONA*1F 3MUI 0,5ML Pharmaceutical Form: Solution for injection INN or Proposed INN: Interferon alfa‐2b Concentration unit: Munit million units Concentration type: equal Concentration number: 6‐ Product Name: montanide ISA‐51 Pharmaceutical Form: Emulsion for injection INN or Proposed INN: montanide ISA‐51 Concentration unit: ml millilitre(s) Concentration type: equal Concentration number: .25‐ Trade Name: DETICENE*INFUS 100MG/10ML FL+F Pharmaceutical Form: Powder for infusion* INN or Proposed INN: Dacarbazine Concentration unit: µg/m2 microgram(s)/square meter Concentration type: equal Concentration number: 800‐ CONDITION: advanced melanoma ; MedDRA version: 12.0 Level: HLT Classification code 10027156 Term: Skin melanomas (excl ocular) PRIMARY OUTCOME: Main Objective: To determine whether DTIC plus vaccine administration could prevent relapse and death of patients with high‐risk resected melanoma, thus increasing their DMFS. Patients will be monitored during study and site and interval of relapses will be recorded. The Kaplan±Meier method will be used to calculate plots of estimated distant relapse‐free survival. Cox`s proportional hazards regression will be used to assess the impact of treatment after adjustment for other patient characteristics. Primary end point(s): To determine whether DTIC plus vaccine administration could prevent relapse and death of patients with high‐risk resected melanoma, thus increasing their DMFS. Patients will be monitored during study and site and interval of relapses will be recorded. The Kaplan±Meier method will be used to calculate plots of estimated distant relapse‐free survival. Cox`s proportional hazards regression will be used to assess the impact of treatment after adjustment for other patient characteristics. Secondary Objective: DTH test will be performed as clinical measure of vaccine‐induced immune response. CTL response will be determined by enumerating vaccine‐specific CD8+ T cells in the peripheral blood. The functional properties of CD8+ T cells will also by determined The production of a panel of cytokines will be measured in PBMC of vaccinated patients. Gene expression profiles. Microarray analysis will be also performed on PBMCs before and one day after DTIC administration at selected time points, to identify genes involved in DTIC‐dependent activation of immune responses. Functional study on NKG2D ligands expression. The function of NKG2D receptor in the lysis of tumour cells by NK and CD8+ T cells of tumour patients will be studied. We will measure the levels of soluble NKG2D ligands (MICA, MICB and ULBP1‐4) in the serum of tumour patients. Frequency, type and intensity of adverse events as well as clinically relevant changes in the laboratory parameters INCLUSION CRITERIA: Histologically confirmed AJCC stage IIIb or IIIc or IV (M1a or M1b) disease‐free HLA‐ A*0201melanoma; Adult subjects of >18 years of age; ECOG score 0‐1; Life expectancy of at least 6 months; Hematopoietic, liver and renal normal functions defined as follows: WBC > 3 x 103/μl; platelets > 100 x 103/μl; Hb >10 g/dl; absolute neutrophil count > 1,5 x 103/μl; bilirubin ≤ 2.0 mg/dl; AST, ALT and LDH less than 3 times upper limit of normal; serum creatinine ≤ 2 mg /dl; Fertile females have to practice adequate contraception; Signed informed consent; 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 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range