Efficacy of Daromun Neoadjuvant Intratumoral Treatment in Clinical Stage IIIB/C Melanoma Patients

Inclusion Criteria:

1. Diagnosis of clinical stage IIIB and IIIC (AJCC v7) metastatic melanoma, eligible forcomplete surgical resection of all metastases (surgically resectable).
2. Eligible subjects must have measurable disease and must be candidate for intralesionaltherapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregatehave a longest diameter of ≥ 10 mm.
3. Males or females, age ≥ 18 years.
4. ECOG Performance Status/WHO Performance Status ≤ 1.
5. Life expectancy of > 24 months.
6. Absolute neutrophil count > 1.5 x 109/L.
7. Hemoglobin > 9.0 g/dL.
8. Platelets > 100 x 109/L.
9. Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl).
10. ALT and AST ≤ 2.5 x the upper limit of normal (ULN).
11. Serum creatinine < 1.5 x ULN .
12. LDH serum level ≤ 1.5 x ULN.
13. Documented negative test for HIV, HBV and HCV. For HBV serology, the determination ofHBsAg, and anti-HBcAg Ab is required. In patients with serology documenting previousexposure to HBV negative serum HBV-DNA is also required.
14. All acute toxic effects (excluding alopecia) of any prior therapy must have resolvedto National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above.
15. All women of childbearing potential (WOCBP) must have negative pregnancy test resultsat the screening. WOCBP must be using, from the screening to three months followingthe last study drug administration, highly effective contraception methods. WOCBP andeffective contraception methods are defined by the "Recommendations for contraceptionand pregnancy testing in clinical trials" issued by the Head of Medicine Agencies'Clinical Trial Facilitation Group and which include, for instance, progesterone-onlyor combined (estrogen- and progesterone-containing) hormonal contraception associatedwith inhibition of ovulation, intrauterine devices, intrauterine hormone-releasingsystems, bilateral tubal occlusion, vasectomized partner or sexual abstinence.Pregnancy test will be repeated at the safety visit (only WOCBP and only for patientsin Arm 1).
16. Male patients with WOCBP partners must agree to use simultaneously two acceptablemethods of contraception (i.e. spermicidal gel plus condom) from the screening tothree months following the last study drug administration.
17. Evidence of a personally signed and dated informed consent document indicating thatthe subject has been informed of all pertinent aspects of the study.
18. Willingness and ability to comply with the scheduled visits, treatment plan,laboratory tests and other study procedures.

Exclusion Criteria:

1. Uveal melanoma or mucosal melanoma
2. Evidence of distant metastases at screening.
3. Previous or concurrent cancer that is distinct in primary site or histology from thecancer being evaluated in this study except: cervical carcinoma in situ, treated basalcell carcinoma, superficial bladder tumors (Ta, Tis & T1), second primary melanoma insitu or any cancer curatively treated ≥ 5 years prior to study entry.
4. Presence of active infections (e.g. requiring antimicrobial therapy) or other severeconcurrent disease, which, in the opinion of the investigator, would place the patientat undue risk or interfere with the study.
5. History within the last year of acute or subacute coronary syndromes includingmyocardial infarction, unstable or severe stable angina pectoris.
6. Inadequately controlled cardiac arrhythmias including atrial fibrillation.
7. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
8. LVEF ≤ 50% and/or abnormalities observed during baseline ECG and Echocardiograminvestigations that are considered as clinically significant by the investigator.
9. Uncontrolled hypertension.
10. Ischemic peripheral vascular disease (Grade IIb-IV).
11. Severe diabetic retinopathy.
12. Active autoimmune disease.
13. History of organ allograft or stem cell transplantation.
14. Recovery from major trauma including surgery within 4 weeks prior to enrollment.
15. Known history of allergy to IL2, TNF, or other human proteins/peptides/antibodies orany other constituent of the product.
16. Breast feeding female.
17. Anti-tumor therapy (except small surgery) within 4 weeks before enrollment.
18. Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6weeks before enrollment.
19. Planned administration of growth factors or immunomodulatory agents within 7 daysbefore enrollment.
20. Patient requiring or taking corticosteroids or other immunosuppressant drugs on along-term basis. Limited use of corticosteroids to treat or prevent acutehypersensitivity reactions is not considered an exclusion criterion.
21. Any conditions that in the opinion of the investigator could hamper compliance withthe study protocol.
22. Previous enrolment and randomization in the same study.