Clinical Study Phase II of L19IL2 in Combination With Dacarbazine in Patients With Metastatic Melanoma

• Histologically or cytologically confirmed unresectable metastatic (stage IV) non-uveal melanoma
• Age > 18 years
• Measurable disease defined as at least one lesion that can be accurately and serially measured per the modified RECIST criteria. Cutaneous lesions measuring at least 1 cm will be considered measurable.

• Prior therapy for metastatic melanoma:

  • Phase IIa - Dose definition: prior therapy allowed, including prior chemotherapy; previous treatment with DTIC: patients should be treated > 6 months prior to study entry
  • Phase IIb -Activity Evaluation: no prior therapy except radiation. However, if radiation has been administered to a lesion, there must be radiographic evidence of progression of that lesion in order for that lesion to constitute measurable disease or to be included in the measured target lesions
• Fewer than 3 organs involved or cutaneous and/or subcutaneous metastasis only, for PhaseIIb patients
• ECOG performance status \< 2
• Life expectancy of at least 12 weeks
• Absolute neutrophil count > 1.5 x 109/L, hemoglobin > 9.0 g/dL and platelets > 100 x 109/L
• Total bilirubin ≤ 30 µmol/L (or ≤ 2.0 mg/Dl)
• ALT and AST ≤ 2.5 x the upper limit of normal (5.0 x ULN for patients with hepatic involvement with tumor
• LDH \< 2.0 x ULN for Phase IIa patients and normal LDH for the Phase IIb ones.
• Serum creatinine \< 1.5 x ULN
• All toxic effects of prior therapy must have resolved to ≤ Grade 1 unless otherwise specified above
• Negative serum pregnancy test (for women of child-bearing potential only) at screening

Exclusion criteria:

• Primary ocular melanoma
• Evidence of brain metastases, negative CT scan within two months before study commence
• Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (TA, Tis \& Ti) or any cancer curatively treated \< 5 years prior to study entry
• History of HIV infection or chronic hepatitis B or C
• Presence of active infections (e.g. requiring antimicrobial therapy) or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study.
• Inadequately controlled cardiac arrhythmias including atrial fibrillation
• History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
• Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria).
• Uncontrolled hypertension.
• Ischemic peripheral vascular disease (Grade Iib-IV).
• Severe diabetic retinopathy.
• Active autoimmune disease
• History of organ allograft or stem cell transplantation.
• Recovery from major trauma including surgery within 4 weeks prior to administration of study treatment.
• Known history of allergy to IL2, dacarbazine, or other intravenously administered human proteins/peptides/antibodies.
• Breast feeding female.
• Anti-tumor therapy within 4 weeks of the administration of study treatment.
• Previous in vivo exposure to monoclonal antibodies for biological therapy in the 6 weeks before administration of study treatment.
• Previous DTIC treatment in the last 6 months prior to study entry
• Growth factors or immunomodulatory agents within 7 days of the administration of study treatment.
• Patient 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.
• Any conditions that in the opinion of the investigator could hamper compliance with the study protocol.