Phase 1 Dose-finding Study of L19TNFα Plus Melphalan Using Isolated Inferior Limb Perfusion (ILP) in Subjects With Intransit Stage III/IV Melanoma

Inclusion Criteria: 1. Subjects aged \>18 years. 2. Histologically or cytologically confirmed intransit stage III/IV melanoma of lower extremity distal to the apex of the femoral triangle 3. ECOG performance status ≤ 2. 4. Subjects must have at least one unidimensional clinically measurable lesion as defined by RECIST criteria (see Section 8). This lesion must not have been irradiated within four weeks during previous treatments. 5. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, and haemoglobin (Hb) ≥ 9.5 g/dl. 6. All acute adverse effects (excluding alopecia) of any prior therapy (including surgery, radiation therapy, chemotherapy) must have been resolved to ≤ Grade 1, except elevated liver transaminases judged to be associated with tumor infiltration (see below) (graded according to National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events, version 3.0 \[CTCAE, v.3.0\]. 7. Alkaline phosphatase (AP), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 2.0 mg/dL unless liver involvement by the tumor, in which case the transaminase levels up to 5 x ULN are allowed. 8. Creatinine ≤ 1.5 ULN or 24 h creatinine clearance ≥ 60 mL/min. 9. Testing negative for acute or chronic infection with hepatitis B or C virus, or human immunodeficiency virus 1 or 2. 10. Negative pregnancy test for females of childbearing potential at the screening visit. 11. Commitment from subject to practice medically appropriate/acceptable method of birth control (e.g., hormonal, condoms or other adequate barrier controls, intrauterine contraceptive device, or sterilization) beginning at the screening visit and continuing until 3 months following the treatment with study drug 12. Able to provide written Informed Consent 13. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures. Exclusion Criteria: 1. Breastfeeding women 2. Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the Investigator, would place the subject at undue risk or interfere with the study. 3. Active autoimmune disease. 4. Cardiac disease as manifested by any of the following: * \> Grade II heart failure, graded per New York Heart Association (NYHA) criteria. * Unstable angina pectoris * Acute or subacute coronary syndromes, including myocardial infarction, occurring with 1 year prior to study treatment * Arrhythmia needing continuous treatment * Ejection fraction less than the institutional lower limit of normal as assessed by multigated radionuclide angiography (MUGA) scan or echocardiogram 5. Uncontrolled hypertension. 6. History of claudication or Ischemic peripheral vascular disease (Grade IIb-IV). 7. Chronic obstructive pulmonary disease or other chronic pulmonary disease with PFTs less than 50% predicted for age. 8. Symptomatic cerebrovascular disease. 9. Active peptic ulcer disease. 10. Concurrent infection of HIV. 11. Severe diabetic retinopathy. 12. Major surgery or trauma within 4 weeks prior to start of study treatment. 13. Hypersensitivity to melphalan or TNFα or other intravenously administered human proteins/peptides/antibodies. 14. Chemotherapy, radiation therapy or therapy with an investigational agent within 4 weeks prior to start of study treatment. 15. Any regional therapy to the affected extremity within 2 months prior to start of study treatment. 16. Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before administration of study treatment. 17. Growth factors or immunomodulatory agents within 7 days prior to the administration of study treatment. 18. Subject requires or is taking corticosteroids or other immunosuppressant drugs on a long-term basis. Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion. 19. Participation in another interventional clinical trial during participation in this trial. 20. Any conditions that in the opinion of the Investigator could hamper compliance with the study protocol.