Safety of Atezolizumab-Bevacizumab in Liver Transplanted Patients With Advanced Hepatocellular Carcinoma

Open-label multicentric single-arm two-stage phase 2 trial. Population: Adult LT patients with advanced HCC recurrence with indication to systemic treatment Primary objective: To study the safety (ACR on histology) at 6 months of the first-line Atezo-Beva combination in LT patients with recurrent HCC in association with a standardized immunosuppressive treatment to prevent the risk of liver graft rejection.

Primary endpoint: Rate of Acute cellular rejection (ACR) (defined by a Histological Banff score ≥ 5) at 6 months (confirmed by an external expert center).

Secondary objective:

To study the safety (ACR on histology) at 24 months and at the end of Atezo-Beva treatment in LT patients with recurrent HCC in association with a standardized immunosuppressive treatment to prevent the risk of liver graft rejection.

• To assess the efficacy and tolerance of first-line Atezo-Beva combination in LT patients with advanced HCC in association with a standardized immunosuppressive treatment to prevent the risk of ACR based on:
• the Progression Free Survival (PFS)
• the Overall survival (OS)
• the objective response rate (ORR) (complete and partial response)
• the duration of response
• the quality of life of the patients under Atezo-Beva treatment
• To compare the efficacy (OS and PFS) of LT patients treated by Atezo- Beva treatment to an historical retrospective cohort of LT patients already available treated by TKI as first line (external arm comparison)
• To assess the adverse events related to Atezo-Beva treatment in LT patients with recurrent advanced HCC.
• To assess the evolution of the level of donor specific antibodies (DSA) during Atezo-Beva treatment and its association with ACR, PFS and OS.

Translational research/ancillary studies:

• To assess the association before the first injection between the risk of ACR, PFS, OS and side effects and
• the "Immunome" imaging on tumor sample and non-tumoral liver sample to quantify and regionalize immune populations on pathology (Multispectral Imaging, Mantra)
• the Leukocyte DNA analysis to identify constitutional genetic variants
• To assess the association before the first injection or just before the second injection and at 3 months between the risk of ACR, PFS, OS and side effects and
• the "immunomonitoring" on blood sample (frequency and/or the phenotype of circulating immune cells)
• the presence of tumors cells (liquid biopsies)
• the presence of circulating tumor DNA and the type of mutations
• the presence of circulating proteins
• the profile of circulating exosomes

Inclusion criteria

• 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)
• with HCC recurrence diagnosis according to the EASL diagnostic criteria (33)
• 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
• 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:

• ANC ≥ 1.5 x 109/L (1500/µL) without granulocyte colony-stimulating factor support
• Lymphocyte count ≥ 0.5 x 109/L (500/µL)
• Platelet count ≥ 75 x 109/L (75,000/µL) without transfusion
• Hemoglobin ≥ 90 g/L (9 g/dL). Patients may be transfused to meet this criterion.
• AST, ALT ≤ 5 x upper limit of normal (ULN)
• Serum bilirubin ≤ 3x ULN
• creatinine clearance≥40 mL/min (calculated using the Cockcroft-Gault formula)
• For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 2x ULN
• 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
• 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 :

• 5 months after the end of the treatment with atezolizumab,
• 6 months after the end of the treatment with bevacizumab
• Child-Pugh class A

Exclusion criteria

• History of ACR within 3 months before starting Atezo-Beva treatment
• Banff score for ACR ≥ 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 (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.
• 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
• 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
• 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
• In case of proteinuria > 1g in 24 hours
• History of leptomeningeal disease
• Active tuberculosis
• 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