NBTXR3 Crystalline Nanoparticles and Stereotactic Body Radiation Therapy in the Treatment of Liver Cancers

Secondary cancer, Liver metastases Inclusion criteria: * Age ≥ 18 * Written Informed Consent obtained, signed and dated * ECOG performance status 0 or 1 * Life expectancy \> 6 months * Liver metastases from other primary cancers 1) with histologic confirmation of metastases, or 2) History of primary cancer with histology available and lesions in the liver consistent with metastases, or 3) histologic confirmation of primary cancer and a growing enhancing lesion in the liver consistent with a metastasis * Unresectable tumor/s, based on the opinion of an experienced surgeon specializing in hepatic resection, or the patient must be medically inoperable * Patients with extra-hepatic metastases controlled by supportive care or concomitant hormonotherapy are eligible. * Previous liver resection or local treatment (radiofrequency ablative therapy, chemoembolization, microwave treatment…) is permitted * Patients must have recovered from the effects of previous therapy (residual AE grade 0 or 1) * Radiological disease progression according to the investigator evaluation or according to RECIST 1.1 * At least one tumor lesion that can be accurately measured in at least one dimension according to RECIST 1.1 * Normal permeability of hepatic artery evaluated by injected CT-scan (arterial phase) * Total target volume of lesions \< 500cc and \< 50% of the total liver volume * 700 cc of liver volume without tumor involvement and a radiation therapy dose \< 15 Gy * The following laboratory parameters: * Platelet count ≥ 50 x 10\^9/L * Hemoglobin ≥ 8.5 g/dL * Absolute neutrophil count ≥ 1.5 x 10\^9/L, * Prothrombin rate (PR)\> 50% * International Normalized Ratio (INR) \< 1.5 or correctable with vitamin K. Patients receiving anti-coagulation or anti-aggregation therapy must stop temporarily during treatment. * Total bilirubin \<30 μmol/l * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x upper limit of normal * Albumin \>2.5 g/dL * Very low or undetectable HBV DNA and HCV RNA * Serum Creatinine ≤ 1.5 time the upper limit of normal value * Glomerular Filtration Rate \> 44mL/min/1.73m2 * All female patients of childbearing potential must have a negative serum/urinary pregnancy test within the 7 days prior to NBTXR3 administration. Otherwise, Patients must be post-menopausal, surgically sterile, or using 'effective contraception'. The definition of 'effective contraception' will be based on the judgment of the investigator. Exclusion criteria: * Patients with ongoing chronic active viral B or C hepatitis must have received an antiviral treatment with negative or very low viremia before the onset of the radiation therapy * Biliary tract dilatation, biliodigestive anastomosis, bile duct drainage * Uncontrolled extra-hepatic metastatic disease with a symptomatic treatment or well tolerated hormonotherapy (AE 0/1) * Previous cancer cured for less than 2 years * Previous anticancer treatment (chemotherapy or/and biologicals) with a wash out \< 4 weeks * Previous treatment with intra-arterial injection of Y90 loaded microspheres in the same hepatic lobe than the current tumor. * Previous intra-arterial chemotherapy * Prior radiation therapy to the right upper abdomen, precluding re-irradiation of the liver. That is, any previous radiation therapy in which a mean dose to the liver of 15 Gy in conventional fractionation was delivered, or previous doses to critical normal structures that would make re-irradiation unsafe * Impossibility to follow the dosimetry constraints (mean total liver dose \> 15Gy) * Presence of arterio-venous intra tumoral shunting * Encephalopathy related to liver failure * Clinical ascitis * Presence of another scalable tumor disease except cervical carcinoma in situ, treated basal cell carcinoma, or superficial bladder tumors (Ta, Tis \&T1) * Presence of hepato pulmonary syndrome * Auto immune hemolytic anemia * Auto immune disorder, excepted auto immune thyroiditis * Uncontrolled hypertension or congestive heart failure * Active coronary artery disease (myocardial infarction more than 6 months prior to study entry is permitted) * Previous gastrointestinal bleed within the past 2 months * Known syndrome AIDS-related illness or serious non controlled acute or chronic illness * Active, clinically severe bacterial or fungal infections (\> grade 2 NCI-CTCAE, version 5.0) * Complete initial work up earlier than 4 weeks prior to patient registration * Patient whose general health condition does not allow treatment feasibility * Patients unable and/or unwilling to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures * Patients participating in another clinical investigation at the time of signature of the informed consent. Primary cancer: Hepato Cellular Carcinoma - HCC Inclusion criteria: * Age ≥ 18 * Written Informed Consent obtained, signed and dated * ECOG performance status 0 or 1 * Life expectancy \> 3 months * Histological or cytological diagnosis of Hepatocellular cancer or imaging diagnosis by the American Association for the Study of Liver Disease (AASLD) guidelines or European association for the Study of the Liver (EASL) guidelines. * Patients with HCC: * Without main branch or intrahepatic trunk portal vein tumor thrombosis (Vp3 or Vp4, respectively), with progression or recurrence of HCC after surgical or loco-regional treatment * With main branch (right and/or left) or intrahepatic trunk portal vein tumor thrombosis (Vp3 or Vp4, respectively), AND without right atrial involvement. * Recurrent intrahepatic cholangiocarcinoma is eligible only in the phase I part * Liver cirrhosis Child Pugh A - B7 * Previous liver resection or local treatment (radiofrequency ablative therapy, chemoembolization, microwave treatment…) is permitted * Patients with previous treatment with sorafenib or other targeted or systemic therapy are eligible if wash out \> 4 weeks * Patients must have recovered from the effects of previous therapy (residual AE grade 0 or 1) * Radiological disease progression according to the investigator evaluation or according to RECIST 1.1 * At least one tumor lesion that can be accurately measured in at least one dimension according to RECIST 1.1 * Normal permeability of hepatic artery evaluated by injected CT-scan (arterial phase) * Total target volume of lesions \< 500cc and \< 50% of the total liver volume * 700 cc of liver volume without tumor involvement and a radiation therapy dose \< 15 Gy * The following laboratory parameters: * Platelet count ≥ 50 x 10\^9/L * Hemoglobin ≥ 8.5 g/dL * Absolute neutrophil count ≥ 1.5 x 10\^9/L, * Prothrombin rate (PR)\> 50% * International Normalized Ratio (INR) \< 1.5 or correctable with vitamin K * Patients receiving anti-coagulation or anti-agregant therapy must stop temporarily during treatment. * Total bilirubin \<30 μmol/l * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x upper limit of normal * Albumin \>2.5 g/dL * Very low or undetectable HBV DNA and HCV RNA * Serum Creatinine ≤ 1.5 time the upper limit of normal value * Glomerular Filtration Rate \> 44mL/min/1.73m2 * All female patients of childbearing potential must have a negative serum/urinary pregnancy test within the 7 days prior to NBTXR3 administration. Otherwise, Patients must be post-menopausal, surgically sterile, or using 'effective contraception'. The definition of 'effective contraception' will be based on the judgment of the investigator. Exclusion criteria: * Patient suitable for a curative treatment by surgery or local treatment (radiofrequency ablation, microwave treatment, etc.) * Patients with ongoing chronic active viral B or C hepatitis, those patients must have received an antiviral treatment with negativation of the viremia or very low viremia before the onset of the radiation therapy * Biliary tract dilatation, biliodigestive anastomosis, bile duct drainage * Extrahepatic Portal Vein Tumor Thrombosis * Extra-hepatic metastasis * Previous cancer cured for less than 2 years * Previous anticancer treatment (chemotherapy or/and biologicals) with a wash out \< 4 weeks * Previous treatment with intra-arterial injection of Y90 loaded microspheres in the same hepatic lobe than the current tumor. * Previous intra-arterial chemotherapy * Concurrent treatment with any other anticancer therapy, including chemotherapy, immunotherapy, targeted therapy, gene therapy, or patients planning to receive these treatments during the study. Hormonotherapy is permitted * Prior radiation therapy to the right upper abdomen, precluding re-irradiation of the liver. That is, any previous radiation therapy in which a mean dose to the liver of 15 Gy in conventional fractionation was delivered, or previous doses to critical normal structures that would make re-irradiation unsafe * Impossibility to follow the dosimetry constraints (mean total liver dose \> 15Gy) * Presence of arterio-venous intra tumoral shunting * Encephalopathy related to liver failure * Clinical ascitis * Presence of another scalable tumor disease except cervical carcinoma in situ, treated basal cell carcinoma, or superficial bladder tumors (Ta, Tis \&T1) * Presence of hepato pulmonary syndrome * Auto immune hemolytic anemia * Auto immune disorder, excepted auto immune thyroiditis * Uncontrolled hypertension or congestive heart failure * Active coronary artery disease (myocardial infarction more than 6 months prior to study entry is permitted) * Previous gastrointestinal bleed within the past 2 months * Known syndrome AIDS-related illness or serious non- controlled acute or chronic illness * Active, clinically severe bacterial or fungal infections (\> grade 2 NCI-CTCAE, version 5.0) * Complete initial work up earlier than 4 weeks prior to patient registration * Patient whose general health condition does not allow treatment feasibility * Patients unable and/or unwilling to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures * Patients participating in another clinical investigation at the time of signature of the informed consent. Phase I and II parts target the same liver cancer populations (same inclusion and