A prospective, open-label, multi-center, Phase I/II study of L19IL2 in combination with Dacarbazine in patients with metastatic melanoma.

A prospective, open-label, multi-center, Phase I/II dose escalation study in which cohorts of 3-6 patients with metastatic melanoma will be assigned to receive escalating doses of L19-IL2 in combination with a fixed dose of Dacarbazine.

After definition of MTD and RD during the phase II part of this study, 60 patients with Stage IV M1a and M1b melanoma will be randomized in a 1:1 ratio to receive open label the combination treatment at the RD (Arm 1) or DTIC monotherapy (Arm 2).

Inclusion Criteria:

1. 18-70 years of age, inclusive
2. Must have histologically or cytologically confirmed cutaneous metastatic melanoma (Stage IV). For the Phase II part only patients with Stage IV M1a or M1b will be enrolled.
3. Must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as identified by CT or MRI scan within 28 days before the first study drug administration.
4. Baseline LDH within normal range
5. Maximal 1 line of previous systemic treatment for metastatic disease (prior adjuvant melanoma therapy, e.g., IFN, is permitted.
6. For women of childbearing potential, a negative pregnancy test within 72 hours prior to the first dose of study treatment.
7. Women with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 12 weeks after the last dose of study medication.
8. Men with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 12 weeks after the last dose of study medication.
9. Must have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
10. Life expectancy of at least three months
11. Adequate organ function: serum creatinine ≤ 1.5 x ULN, total bilirubin ≤ 30 mM/L (or mg/dL, ≤ 2.0 mg/dL), hepatic transaminases ≤ 2.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN.
12. ANC count ≥ 1.5 x 10^9/L, platelet count ≥ 100 x 10^9/L, hemoglobin > 9 g/dL
13. Normal 12-lead ECG and normal bidimensional echocardiogram or MUGA
14. All toxic effects of prior therapy must have resolved to grade ≤1 unless otherwise specified above
15. Willing and able to give written informed consent.

Exclusion Criteria:

1. Pregnant or breastfeeding female
2. Primary ocular melanoma
3. Primary mucosal melanoma
4. Use of any investigational or other anti-cancer drug within 28 days or 5 half-lives, whichever is longer, preceding the first dose of DTIC and L19-IL2
5. Prior radiation to a target lesion, unless there has been clear progression of the lesion since radiotherapy
6. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection
7. History or clinical evidence of brain metastases or leptomeningeal disease
8. Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix
9. Treatment with DTIC within 6 months before start of study
10. Treatment with Ipilimumab within 6 months before start of study
11. Hypersensitivity to DTIC
12. Concomitant use of drugs known to alter cardiac conduction
13. Chronic use of corticosteroids used in the management of cancer or non-cancer-related illness
14. Unstable or serious concurrent uncontrolled medical conditions
15. Inadequately controlled cardiac arrhythmias including atrial fibrillation
16. History of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris
17. Heart insufficiency > grade II NYHA criteria
18. Uncontrolled hypertension
19. Ischemic peripheral vascular disease
20. Active infection or incomplete wound healing.
21. History or evidence of active autoimmune disease.
22. Known history of allergy to intravenously administered proteins/peptides/antibodies
23. History of organ allograft.or allogeneic peripheral blood progenitor cell or bone marrow transplantation
24. Major trauma including surgery within 4 weeks prior to entering the study.
25. Any underlying medical or psychiatric condition which in the opinion of the investigator will make administration of study drug hazardous or hinder the interpretation of study results (e.g. AE).
26. Melanoma patients with BRAF 600 E mutation who are amenable to receive approved treatments able to extend overall survival.