Inclusion Criteria:

- Aged over 18 years

- Patient with histologically or cytologically confirmed melanoma

- Patient with unresectable advanced or metastatic (stage III or IV) melanoma

- Patient with progressive melanoma (any BRAF status is permitted) not responding or
intolerant to previous treatments, including patients with asymptomatic and not
rapidly progressive brain metastases.

- Patient with a minimum of one measurable lesion according to RECIST guideline 1.1

- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2

- Patient having given a written informed consent

Exclusion Criteria:

- Patient eligible for curative treatments and/or any palliative treatments with
demonstrated efficacy, including current treatments for brain metastasis, and
including available BRAF inhibitors as indicated for patients carrying B-RAF mutated
tumours if applicable.

- Patient with history of any other cancer within five years before enrollment (except
cured basal cell carcinoma or cervical cancer in situ)

- Patient with inadequate organ function, defined as:

- Platelet count < 75.103 /L (> grade 2 NCI CTCAE)

- Absolute neutrophil count < 1.109 /L (> grade 2)

- Hemoglobin < 9 g/dL

- INR increased or prolonged activated partial thromboplastin time (aPTT) upper the
limit of normal (ULN) (≥ grade 1)

- Creatinine clearance < 60 mL/min (Cockcroft and Gault formula) (≥ grade 2)

- Patient with ALT > 3 ULN (≥ grade 2) or patient with symptomatic liver metastasis
with ALT > 5 ULN (> grade 2)

- Serum Total Bilirubin > 1.5 ULN (≥ grade 2); Patient with Gilbert's syndrome could be
included if hyperbilirubinemia ≤ 3 ULN

- Not medically controlled coagulation disorder (i.e hemophilia, protein C or S
deficiency…)

- Patient with electronic pacemakers, defibrillators, or any implanted electronic
device

- Any cardiac dysrhythmia (> grade 2) (i.e significant ventricular arrhythmia as
persistent ventricular tachycardia and/or ventricular fibrillation; severe conduction
disorders as atrio-ventricular block 2 and 3, sino-atrial block)

- Recent (less than 6 months) acute vascular diseases (i.e stroke, myocardial
infarction)

- Arterial vascular disorders ≥ grade 2

- Serious, non-healed wound, ulcer or bone fracture

- Significant traumatic injury within 28 days prior to study treatment start or
anticipation of the need for major surgery during study treatment

- Evidence of ongoing or active viral or bacterial infection ( i.e bacterial infection
requiring IV antibiotics)

- Patient with life expectancy less than 3 months

- Prior systemic therapy or any other antineoplastic treatments within the last 4
weeks, including radiotherapy or surgery

- Patients who had participated in another clinical trial in the last 30 days prior to
enrolment in the present clinical trial

- Man and woman of child-bearing age without effective contraception method during the
study and for 3 months after the last administration of Plasmid AMEP (i.e oral
contraception or intra-uterine device for woman; i.e condom for man)

- Pregnant or nursing women

- Any significant disease, including psychiatric and neuromuscular disease, which may
affect the proper evaluation of safety or efficacy or may affect ability to give
informed consent

- Patients unwilling or unable to comply with protocol requirements and scheduled
visits

- For contrast enhanced ultrasound (CEUS): known contraindications to SonoVue as
described in the summary product characteristics (i.e cardiac or pulmonary history,
hypersensitivity to sulphur hexafluoride or to any of the components of SonoVue)

- For the part II: prophylactic phenytoin in combination with dacarbazine.