Cryotherapy With in Situ Immunotherapy in Melanoma Metastasis

Inclusion criteria

• Subject with previously treated (or unknown) primary stage IIIB/IIIC melanoma with lymph node metastases, with at least one ≥1 cm3 that is accessible to cryotherapy under interventional radiology (IR), assessed at the inclusion visit (V1).
• ECOG performance status (0 to 2) at the selection visit (V0)
• If woman or man are of reproductive age, they should have no desire to procreate for the duration of their participation in the study, agreeing to use a highly effective contraception method*, with at least one barrier method (condom or diaphragm), and for 5 months after the infusion of Nivolumab for women and 7 months for men
• Leukocytes >2000/mm3, neutrophils >1500/mm3, platelets >100,000/mm3, haemoglobin >9g/dl at the selection visit (V0)
• Total bilirubin <1.5 mg/dl except for patients with Gilbert's syndrome who may have total bilirubin <3.0 mg/dl at the selection visit (V0)
• Liver function: SGOT, SGPT, ALP <2.5 N, if liver metastases SGOT and SGPT <5 N at the selection visit (V0)
• Serum creatinine <1.5 N or creatinine clearance >40 ml/min (using the Cockcroft-Gault equation) at the selection visit (V0)

Exclusion criteria

• Pregnancy (women of childbearing potential : positive blood pregnancy test at the selection visit (V0) or breastfeeding
• History of hypersensitivity to ipilimumab, nivolumab or one of the excipients
• History of severe hypersensitivity to a monoclonal antibody
• History of positive tests for HIV or Acquired Immunodeficiency Syndrome (HIV assessed at the selection visit (V0))
• Positive tests for HCV or HBV indicating an acute or chronic infection at the selection visit (V0)
• Patient presenting with an active, known or suspected autoimmune disease. The following, however, may participate:

• patient with type 1 diabetes or hypothyroidism requiring substitute hormone therapy only;
• patient with psoriasis, vitiligo or alopecia;
• patient with conditions that are not known to reoccur without an exogenous triggering agent.
• History of active neoplasia during the last 3 years with the exception of localised curable cancers considered to be cured, such as basal or squamous cell carcinomas, superficial bladder cancer and prostate, colon or breast carcinoma in situ.
• Active systemic infection
• Patient with a condition requiring systemic steroid treatment (at a dose >10 mg/prednisone equivalent or at unstable dose) or another immunosuppressant within/following 14 days of study drugs administration. Inhaled steroids and treatment for adrenal insufficiency, however, are permitted.
• Contraindication for the cryotherapy procedure as assessed by the radiologist (due to tumour size or proximity to a vascular or nerve structure giving the procedure an unacceptable level of risk) at the inclusion visit (V1)
• Clotting disorder that may interfere with the cryoablation, assessed at the selection visit (V0)
• Contraindication for MRI with gadolinium-based contrast media
• History of uveal melanoma
• Patient having received prior treatment for their melanoma, in particular, patient previously treated with interferon fewer than 3 months ago or with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD-137 or anti-CTLA-4 antibody. Patients who have undergone primary melanoma surgery and the excision of in-transit metastases, as well as adjuvant therapy with interferon if completed over 3 months ago are eligible.
• Contraindication for general and/or local anaesthesia
• Patient operated on under general anaesthesia, within the 4 weeks prior to the planned Nivolumab infusion.
• Patient operated on epidural anaesthesia, within the 72 h prior to the planned Nivolumab infusion.
• History of anterior organ transplantation, including allograft stem cell transplantation.
• History of interstitial lung disease