Vaccination With Autologous Dendritic Cells Loaded With Autologous Tumor Lysate or Homogenate Combined With Immunomodulating Radiotherapy and/or Preleukapheresis IFN-alfa in Patients With Metastatic Melanoma: a Randomized "Proof-of-principle" Phase II Study

Prior treatment

• Patients who have positive tests to HCV, HBV, HIV, or syphilis (specific blood testing must be performed within 30 days before any GMP-regulated activity (leukapheresis and collection of tumor biopsies to be used for tumor lysate/homogenate preparation).
• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
• Other known malignant neoplastic diseases in the patient's medical history with a disease-free interval of less than 3 years (except for previously treated basal cell carcinoma and in situ carcinoma of the uterine cervix);
• Any contraindication to undergo leukapheresis as evaluated by transfusionist (e.g. severe anemia, piastrinopenia, oral anticoagulant therapy).

Other illness

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements (on physician's judgment).

Other

• Patients with unresectable or metastatic melanoma BRAF V600 mutation-positive eligible to Vemurafenib cannot be enrolled in first line, unless they refuse this treatment.
• Patients eligible for Ipilimumab treatment, cannot be enrolled unless they refuse this treatment.
• Patients with known progressing and/or symptomatic brain metastases.

• Signed Written Informed Consent: patients must be willing and able to give written informed consent, that have to be given before starting of screening procedure.
• Availability of autologous tumor tissue fulfilling acceptance criteria prescribed by the "Product Specification File".
• Patients must have histologically or cytologically confirmed malignant unresectable stage III or stage IV melanoma;
• Patients must have a minimum of two lesions, one of which must be measurable,(i.e. that can be accurately measured in two perpendicular dimensions, with at least 1 diameter \>20 mm and the other dimension \>10 mm with conventional techniques or at least 10 x 10 mm with spiral CT scan).
• Patients carrying BRAF mutation-positive melanoma must have received previous Vemurafenib, unless they are not eligible or refuse the treatment.
• Patients treated with previous first line therapy must have received Ipilimumab, unless they are not eligible or refuse the treatment.
• Pretreated brain metastases which have been clinically stable for at least 6 months and not requiring corticosteroids are allowed;
• ECOG performance status 0-1;
• Negative screening tests for HIV, HBV HCV and syphilis not older than 30 days before performing any of the GMP-regulated activities required (leukapheresis, collection of tumor biopsies to be used for tumor lysate/homogenate preparation);
• Prior lines of chemotherapy, immunotherapy or biological therapy (e.g. inhibitors of B-Raf or c-Kit, Ipilimumab, etc.) for advanced disease are allowed (patients must have lasted prior treatments at least 4 weeks before the first vaccine dose);
• Men and women aged 18-70 years.
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up 8 weeks after the study, in order to minimize the risk of pregnancy;
• Patients must have normal organ and marrow function as defined below:
  • leukocytes \>1,500/microL
  • absolute neutrophil count \>1,000/microL
  • platelets \>80,000/microL
  • total bilirubin within 2 x ULN
  • AST(SGOT)/ALT(SGPT) \<2.5 x ULN
  • creatinine ≤ 2 mg/dl