Neoadjuvant L19IL2/L19TNF- Pivotal Study

Inclusion Criteria

• •1. Diagnosis of malignant melanoma of the skin with locally advanced disease as defined by clinical stage III B and III C according to AJCC 7th Ed., eligible for complete surgical resection.
• •2. Eligible subjects must have measurable disease and must be candidate for intralesional therapy with at least one injectable cutaneous, subcutaneous, or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
• •3. Prior anti-tumor treatment for the primary melanoma lesion, including surgery and approved adjuvant treatments (e.g., radiotherapy, immune checkpoint inhibitors, BRAF/MEK inhibitors, etc.) is allowed.
• •4. Males or females, age ≥ 18 years.
• •5. ECOG Performance Status/WHO Performance Status ≤ 1.
• •6. Life expectancy of at least 24 months (see paragraph 6.3.1).
• •7. Absolute neutrophil count \> 1.5 x 109/L.
• •8. Hemoglobin \> 9.0 g/dL.
• •9. Platelets \> 100 x 109/L.
• •10. Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/dl).
• •11. ALT and AST ≤ 2.5 x the upper limit of normal (ULN).
• •12. Serum creatinine \< 1.5 x ULN.
• •13. LDH serum level ≤ 1.5 x ULN.
• •14. Documented negative test for HIV, HBV and HCV. For HBV serology, the determination of HBsAg and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (e.g., anti-HBsAg and/or anti-HBc Ab) negative serum HBV-DNA is also required.
• •15. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (v4.03) Grade ≤ 1 unless otherwise specified above.
• •16. Negative pregnancy test at screening for Women Of Childbearing Potential (WOCBP\*). Pregnant women are not allowed to participate to this study. WOCBP must be using, from the screening to three months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, vasectomized partner or sexual abstinence. Pregnancy test will be repeated at the Safety Visit (only WOCBP and only for patients in Arm 1).
• •17. Male patients with WOCBP partners must agree to use simultaneously two acceptable methods of contraception (i.e., spermicidal gel plus condom) from the screening to three months following the last study drug administration.
• •18. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
• •19. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
• •* Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy).
• •20. Patient requiring or 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.
• •21. Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.
• •22. Previous enrolment and randomization in this same study.