Safety of Atezolizumab/Bevacizumab in liver transplanted patients with advanced hepatocellular carcinoma (IMMUNO-TH)

Prior treatment

• prior arterial thromboembolic reactions including cerebrovascular accidents, transient ischaemic attacks and myocardial infarctions;
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
• Prior history of hypertensive crisis or hypertensive encephalopathy
• A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment

Other illness

• History of ACR within 3 months before starting Atezo-Beva treatment - Banff score for acute cellular rejection ≥ 3 on liver biopsy performed before the initiation of the treatment - Pregnant or breastfeeding woman - Patient not affiliated to a beneficiary or entitled social security scheme or to the PUMA - Patient not having signed consent - History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT-scan - History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death - Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding - A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment. - Inadequately controlled arterial hypertension - Prior history of hypertensive crisis or hypertensive encephalopathy - History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration - Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses
• Inadequately controlled arterial hypertension
• History of leptomeningeal disease
• Active tuberculosis
• History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration
• Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
  • Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT-scan
• History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
• Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding
• Inadequately controlled arterial hypertension (defined as systolic blood pressure (BP) ≥ 160 mmHg and/or diastolic blood pressure > 100 mmHg), based on an average of ≥ 3 BP readings on ≥ 2 sessions Anti-hypertensive therapy to achieve these parameters is allowable.
• hypersensitivity to the active substance or to any of the excipients of the SmPC of bevacizumab and the SmPC of atezolizumab
• hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies

Other

• Patient not having signed consent
• Banff score for acute cellular rejection ≥ 3 on liver biopsy performed before the initiation of the treatment
• Pregnant or breastfeeding woman
• Patient not affiliated to a beneficiary or entitled social security scheme or to the PUMA

• All patients over 18 and under 90 years old: - who underwent LT more than 6 months ago (to prevent the higher risk of ACR which exists within the first months after LT and to deal with populations with a lowered immunosuppressive regimen long after LT)
• ECOG Performance Status of 0 or 1
• For women of childbearing potential and men: agreement to remain abstinent or use effective contraception during treatment and at least: o 5 months after the end of the treatment with atezolizumab, o 6 months after the end of the treatment with bevacizumab
• If cirrhosis,Child-Pugh class A
• with HCC recurrence diagnosis according to the EASL diagnostic criteria
• with advanced HCC not accessible to surgery and locoregional treatment
• with at least one measurable untreated lesion
• With a proposal for Atezo-Beva in first line treatment made in a multidisciplinary meeting
• ECOG Performance Status of 0 or 1
• For women of childbearing potential and men: agreement to remain abstinent
• Child-Pugh class A
• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment, unless otherwise specified: o ANC ≥ 1.5 x 109/L (1500/µL) without granulocyte colony-stimulating factor support o Lymphocyte count ≥ 0.5 x 109/L (500/µL) o Platelet count ≥ 75 x 109/L (75,000/µL) without transfusion o Hemoglobin ≥ 90 g/L (9 g/dL). Patients may be transfused to meet this criterion. o AST, ALT ≤ 5 x upper limit of normal (ULN) o Serum bilirubin ≤ 3x ULN o creatinine clearance≥40 mL/min (calculated using the Cockcroft-Gault formula) o For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 2x ULN o Urine dipstick for proteinuria < 2+ (within 7 days prior to initiation of study treatment). Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate <1 g of protein in 24 hours