Immunization Strategy With Intra-tumoral Injections of Pexa-Vec With Ipilimumab in Metastatic / Advanced Solid Tumors.

Inclusion Criteria:

* Male or female patients aged ≥ 18 years at time of inform consent signature
* Histologically confirmed, advanced/metastatic solid tumor refractory or relapsing to/after standard therapy or the patient has refused or does not tolerate standard therapy. Any tumor types can be considered in Part A except hepatocellular carcinoma (HCC). In part B, tumor types may include melanoma, MSI-High colorectal carcinoma (CRC), head and neck tumors, gastric cancers, triple negative breast cancers and mesothelioma.
* Tumor status (as determined by radiology evaluation): At least one injectable site ≥2cm and ≤8 cm in diameter and one distant non-injected measurable site (target site).

NotaBene: for the DL5 and DL6, depending of the size of the injectable lesions, patients should present more than 1 injectable lesion (See Appendix 3). Of note, patients with only one injectable lesion with a diameter = 2 cm are not eligible for theses 2 DLs.

* PS ECOG 0 or 1
* Minimal wash-out period for prior anti-cancer regimens (i.e. chemotherapy, immunotherapy, or radiation therapy) \> 3 weeks before Week 1 day 1.
* Resolution (i.e. ≤ Grade 1) of all toxicity related to prior anti-cancer treatment with exceptions of alopecia Grade 2, neuropathy Grade 2 and according to biological values presented in Criteria I8.
* No major surgery within 4 weeks prior Week 1 day 1
* Laboratory requirements:

  1. Absolute neutrophil count (ANC) ≥ 1 x 109/L
  2. Lymphocytes ≥1 x 109/L
  3. Platelets ≥ 100 x 109/L;
  4. Hemoglobin ≥ 90 g/L
  5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 3 x ULN (if patient exhibits liver metastasis, up to 5 x ULN acceptable) and total bilirubin ≤ 3mg/dL
  6. Serum creatinine ≤1.5 x ULN or creatinine clearance is ≥60 mL/min according to Cockcroft-Gault formula
  7. International normalized ratio (INR) ≤1.7
  8. Serum chemistries within normal limits (high or low) or Grade 1 (with exception of sodium, potassium, glucose, calcium, upon Investigator discretion)
* Life expectancy \> 3 months
* Negative pregnancy test for women of child-bearing potential within 72 hours before Week 1 Day 1
* Men and women of reproductive potential must be willing to double barrier methods of contraception during the treatment period and for up to 6 weeks after last Pexa Vec administration.
* Patient should understand, sign, and date the written voluntary informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol.
* Patients must be covered by a medical insurance.

Exclusion Criteria:

* Known significant immunodeficiency due to underlying illness (e.g., HIV/AIDS) and/or immune-suppressive medication including systemic corticosteroids and/or blood CD4+ T-cells \< 200/µL.
* History of auto-immunity or untreated wounds from infection or inflammatory skin conditions. Ancient auto-immunity with stable endocrine oral substitution and vitiligo could be considered eligible by investigators.
* Experience of a severe systemic reaction or side-effect as a result of a previous smallpox vaccination
* Ongoing severe inflammatory skin condition (as determined by the investigator) requiring medical treatment
* History of severe eczema (as determined by the investigator) requiring medical treatment
* Severe or unstable cardiac disease, including significant coronary artery disease requiring angioplasty or stenting within the preceding 12 months, unless well-controlled and on stable medical therapy for at least 3 months
* Medical conditions, per the investigator's judgment, that predispose the patient to untoward medical risk of tachycardia, or hypotension during or following treatment with Pexa-Vec
* Previous treatment with Pexa-Vec or other vaccinia vector based treatment
* Tumor tissue sample not available for biological studies (from the initial diagnosis and/or relapse) at time of inclusion
* History of allergic reactions attributed to one of the compound of ipilimumab or compound of similar composition (as per Yervoy SPC® - see Appendix 5)
* Hepatitis C virus therapy including interferon/pegylated interferon or ribavirin or by extension any other hepatitis C virus therapy that cannot be discontinued within 14 days prior to any Pexa Vec injection. Sponsor should be consulted if the patient is taking any other antiviral medications to determine eligibility and/or to determine wash-out duration.
* Significant bleeding event within the last 12 months that places the patient at risk for IT injection procedure based on Investigator assessment
* Anticoagulant or anti-platelet medication that cannot be interrupted prior to IT injections (as listed in the protocol).
* Inability to suspend treatment with anti-hypertensive medication (including but not limited to: diuretics, beta-blockers, angiotensin converting enzyme \[ACE\] inhibitors, aldosterone antagonists, etc.) for 48 hours prior to and 48 hours after each Pexa Vec injection.
* Prior malignancy except for the following: basal or squamous cell skin cancer, in situ cervical cancer, or other cancer adequately treated from which the patient has been disease-free for at least 3 years
* Active brain metastasis (treated and stable brain metastasis accepted).
* Any prior or planned organ transplant (e.g., liver transplant) or allogeneic hematopoietic stem cell transplantation.
* Pregnant or breastfeeding women
* Household contact exclusions for patients enrolled: Women who are pregnant or nursing an infant, Children \< 1 year old, People with skin disease (e.g. eczema, atopic dermatitis and related diseases…), Immunocompromised hosts (severe deficiencies in cell-mediated immunity, including AIDS, organ transplant recipients, hematologic malignancies).