Evaluation of Atezolizumab and Bevacizumab Safety in Liver Transplant Recipients with Advanced Hepatocellular Carcinoma

Trial ID: 2024-514400-14-00
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Hepatocellular carcinoma Liver transplant

Objectives

The primary objective of this study is to evaluate the **safety** of the first-line combination of Atezolizumab and Bevacizumab in liver-transplanted patients with recurrent advanced hepatocellular carcinoma (HCC). This assessment focuses on the risk of acute cellular rejection (ACR) on histology at 6 months, in conjunction with a standardized immunosuppressive treatment to prevent liver graft rejection. The clinical relevance of this objective lies in its potential to improve the management of liver-transplanted patients with recurrent HCC by ensuring the safety of this therapeutic regimen.

Secondary objectives include:

Assessing the safety (ACR on histology) at 24 months and at the end of Atezo-Beva treatment.
Evaluating the efficacy and tolerance of the Atezo-Beva combination in liver-transplanted patients with advanced HCC, focusing on progression-free survival (PFS), overall survival (OS), objective response rate (ORR), duration of response, and quality of life.
Comparing the efficacy (OS and PFS) of Atezo-Beva treatment to a historical cohort of liver-transplanted patients treated with tyrosine kinase inhibitors (TKI) as first-line therapy.
Assessing adverse events related to Atezo-Beva treatment in liver-transplanted patients with recurrent advanced HCC.
Evaluating the evolution of donor-specific antibodies (DSA) levels during Atezo-Beva treatment and their association with ACR, PFS, and OS.

Participants

The clinical trial involves **liver transplanted patients with advanced hepatocellular carcinoma**. The study population includes both male and female participants aged between 18 and 90 years. Participants are required to have undergone liver transplantation more than six months prior to the study to mitigate the risk of acute cellular rejection. The trial does not involve a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on specific inclusion criteria, including a diagnosis of hepatocellular carcinoma recurrence according to the European Association for the Study of the Liver (EASL) diagnostic criteria, and the condition must be advanced and not amenable to surgery or locoregional treatment. Participants must have at least one measurable untreated lesion and a proposal for first-line treatment with the Atezo-Beva combination made in a multidisciplinary meeting. Adequate hematologic and end-organ function is required, and participants must agree to remain abstinent or use effective contraception during treatment and for a specified period afterward. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed to evaluate the **safety** of a combination therapy involving **atezolizumab** and **bevacizumab** in liver-transplanted patients with advanced hepatocellular carcinoma. This is an open-label, multicentric, single-arm, two-stage phase 2 trial. The primary objective is to assess the rate of acute cellular rejection (ACR) at six months, defined by a Histological Banff score of 5 or greater, confirmed by an external expert center. Secondary endpoints include the rate of ACR at 24 months, progression-free survival (PFS), overall survival (OS), objective response rate (ORR) at 12 months, duration of response, time to deterioration of quality of life, and safety and adverse events according to NCI Common Terminology Criteria for Adverse Events, version 4.0.

The trial will commence with a screening visit to confirm eligibility based on inclusion criteria, such as age between 18 and 90 years, ECOG Performance Status of 0 or 1, and adequate hematologic and end-organ function. Participants must have undergone liver transplantation more than six months prior and have a diagnosis of recurrent hepatocellular carcinoma according to EASL criteria. The treatment regimen involves intravenous infusion of atezolizumab and bevacizumab, with a maximum treatment period of six months. Follow-up visits will occur every three months to monitor disease progression using RECIST 1.1 criteria via CT scans, assess quality of life, and evaluate safety and adverse events. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Participant involvement is expected to last up to 24 months, with the trial estimated to end by December 2028. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will ensure that all data collection and analysis adhere to rigorous scientific standards to provide reliable and valid results.

Treatment

The clinical trial involves the administration of **Atezolizumab**, an experimental medication formulated as a **solution for infusion**. Atezolizumab is a protein-based therapeutic agent classified under the category "Protein - Other." The medication is administered via **intravenous infusion**. The dosing regimen for Atezolizumab involves a maximum daily dose of 1200 mg, with a total maximum dose of 9600 mg over a treatment period of up to six months. The administration schedule is designed to ensure optimal therapeutic exposure while monitoring for safety and efficacy in the context of the trial.

In conjunction with Atezolizumab, the trial also includes the administration of **Bevacizumab**, another experimental medication provided as a **solution for infusion**. Bevacizumab, like Atezolizumab, is a protein-based therapeutic agent and is administered through **intravenous infusion**. The dosing for Bevacizumab is calculated based on body weight, with a maximum daily dose of 15 mg/kg and a total maximum dose of 15600 mg/kg over a six-month treatment period. The administration of Bevacizumab is coordinated with Atezolizumab to evaluate the safety and potential synergistic effects of the combination therapy in patients with advanced hepatocellular carcinoma.

Both Atezolizumab and Bevacizumab are administered in the context of a standardized immunosuppressive treatment regimen to mitigate the risk of liver graft rejection in liver-transplanted patients. The trial protocol includes rigorous monitoring of participant compliance with the dosing schedules and the assessment of adverse events to ensure participant safety and the integrity of the trial data.

Efficacy

The efficacy of the clinical trial evaluating the safety of Atezolizumab and Bevacizumab in liver-transplanted patients with advanced hepatocellular carcinoma will be assessed using several primary and secondary endpoints. The primary endpoint is the rate of **acute cellular rejection (ACR)**, defined by a Histological Banff score of 5 or greater, at 6 months. This will be confirmed by a second external expert center. Secondary endpoints include the rate of ACR at 24 months and at the end of treatment, progression-free survival (PFS), overall survival (OS), objective response rate (ORR) at 12 months, duration of response, time to deterioration of quality of life, and safety and adverse events.

Progression-free survival is defined as the time from inclusion to disease progression according to RECIST 1.1 criteria on imaging (CT-scan) performed every 3 months or death from any cause. Overall survival is defined as the time from inclusion to death from any cause. The ORR at 12 months is determined by the percentage of patients with a confirmed complete or partial response according to RECIST 1.1 criteria on imaging performed every 3 months. The duration of response is measured from the first documentation of complete or partial response to disease progression or death. The time to deterioration of quality of life is assessed using the EORTC QLQ-C30 score, with evaluations reported by the patient.

Safety and adverse events will be evaluated based on the nature, frequency, and severity of adverse events according to the NCI Common Terminology Criteria for Adverse Events, version 4.0. Additionally, donor-specific antibodies (DSA) will be assessed before the first injection and at specified intervals (D21, M3, M6, M12, M18, M24) and correlated with ACR, PFS, and OS. The dosage of DSA will be centralized in a designated laboratory. These assessments will provide comprehensive data on the efficacy and safety of the treatment regimen in the specified patient population.

Inclusion and Exclusion Criteria

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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
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
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

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Exclusion Criteria

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
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.
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
Inadequately controlled arterial hypertension
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
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
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