BEVACIZUMAB for Advanced hepatocellular carcinoma|Liver transplant recipient

Inclusion criteria

• {"criterion_text":"- All patients over 18 and under 90 years old: -\twho 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)\n- -\tECOG Performance Status of 0 or 1\n- -\tFor women of childbearing potential and men: agreement to remain abstinent or use effective contraception during treatment and at least: o\t5 months after the end of the treatment with atezolizumab, o\t6 months after the end of the treatment with bevacizumab\n- -\tIf cirrhosis,Child-Pugh class A\n- -\twith HCC recurrence diagnosis according to the EASL diagnostic criteria\n- -\twith advanced HCC not accessible to surgery and locoregional treatment\n- -\twith at least one measurable untreated lesion\n- -\tWith a proposal for Atezo-Beva in first line treatment made in a multidisciplinary meeting\n- -\tECOG Performance Status of 0 or 1\n- -\tFor women of childbearing potential and men: agreement to remain abstinent\n- -\tChild-Pugh class A\n- -\tAdequate 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\tANC ≥ 1.5 x 109/L (1500/µL) without granulocyte colony-stimulating factor support o\tLymphocyte count ≥ 0.5 x 109/L (500/µL) o\tPlatelet count ≥ 75 x 109/L (75,000/µL) without transfusion o\tHemoglobin ≥ 90 g/L (9 g/dL). Patients may be transfused to meet this criterion. o\tAST, ALT ≤ 5 x upper limit of normal (ULN) o\tSerum bilirubin ≤ 3x ULN o\tcreatinine clearance≥40 mL/min (calculated using the Cockcroft-Gault formula) o\tFor patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 2x ULN o\tUrine 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"}

Exclusion criteria

• {"criterion_text":"-\tHistory of ACR within 3 months before starting Atezo-Beva treatment -\tBanff score for acute cellular rejection ≥ 3 on liver biopsy performed before the initiation of the treatment -\tPregnant or breastfeeding woman -\tPatient not affiliated to a beneficiary or entitled social security scheme or to the PUMA -\tPatient not having signed consent -\tHistory of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT-scan -\tHistory of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death -\tUntreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding -\tA prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment. -\tInadequately controlled arterial hypertension -\tPrior history of hypertensive crisis or hypertensive encephalopathy -\tHistory 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 -\tSerious, 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"}
• {"criterion_text":"-\tprior arterial thromboembolic reactions including cerebrovascular accidents, transient ischaemic attacks and myocardial infarctions;"}
• {"criterion_text":"-\tSignificant 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"}
• {"criterion_text":"-\tInadequately controlled arterial hypertension"}
• {"criterion_text":"-\tHistory of leptomeningeal disease"}
• {"criterion_text":"-\tActive tuberculosis"}
• {"criterion_text":"-\tSevere infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia"}
• {"criterion_text":"-\tPrior history of hypertensive crisis or hypertensive encephalopathy"}
• {"criterion_text":"-\tHistory 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"}
• {"criterion_text":"-\tSerious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture"}
• {"criterion_text":"-\tMetastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses"}
• {"criterion_text":"-\tPatient not having signed consent"}
• {"criterion_text":"-\tBanff score for acute cellular rejection ≥ 3 on liver biopsy performed before the initiation of the treatment"}
• {"criterion_text":"-\tPregnant or breastfeeding woman"}
• {"criterion_text":"-\tPatient not affiliated to a beneficiary or entitled social security scheme or to the PUMA"}
• {"criterion_text":"-\tHistory of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT-scan"}
• {"criterion_text":"-\tHistory of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death"}
• {"criterion_text":"-\tUntreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding"}
• {"criterion_text":"-\tA prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment"}
• {"criterion_text":"-\tInadequately 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."}
• {"criterion_text":"-\thypersensitivity to the active substance or to any of the excipients of the SmPC of bevacizumab and the SmPC of atezolizumab"}
• {"criterion_text":"-\thypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies"}

Primary endpoints

• {"endpoint_text":"- Rate of ACR (defined by a Histological Banff score ≥ 5) at 6 months (confirmed by a second external expert center (Pr Calderaro, Mondor hospital).","definition_or_measurement_approach":"ACR defined by a Histological Banff score ≥ 5; assessed at 6 months and confirmation by a second external expert center (Pr Calderaro, Mondor hospital)."}

Secondary endpoints

• {"endpoint_text":"- Rate of ACR (defined by a Histological Banff score ≥ 5) at 24 months and at the end of Atezo-Beva treatment (confirmed by a second external expert center (Pr Calderaro, Mondor hospital).","definition_or_measurement_approach":"ACR defined by Histological Banff score ≥ 5; assessed at 24 months and at end of treatment; confirmation by a second external expert center."}
• {"endpoint_text":"- The PFS defined as the time from inclusion to disease progression according to RECIST 1.1 on imaging (CT-scan) performed every 3 months or death from any cause, whichever occurred first.","definition_or_measurement_approach":"Progression-Free Survival measured from inclusion to progression per RECIST 1.1 on CT scanning every 3 months or death."}
• {"endpoint_text":"- The OS defined by the time from inclusion to death from any cause.","definition_or_measurement_approach":"Overall Survival measured as time from inclusion to death from any cause."}
• {"endpoint_text":"- The ORR at 12 months is defined as the percentage of patients with a confirmed complete or partial response according to RECIST 1.1 criteria on imaging (CT-scan) performed every 3 months.","definition_or_measurement_approach":"Objective Response Rate at 12 months per RECIST 1.1 on CT every 3 months (confirmed complete or partial responses)."}
• {"endpoint_text":"-The Duration of response is defined by the time from first documentation of complete or partial response to disease progression or death according to RECIST 1.1 criteria on imaging (CT-scan) performed every 3 months.","definition_or_measurement_approach":"Duration of Response measured from first documented complete/partial response to progression or death, per RECIST 1.1 on CT every 3 months."}
• {"endpoint_text":"- The time to deterioration of quality of life is defined as the time from inclusion to the first deterioration of quality of life as reported by the patient, with deterioration defined as a decrease from baseline of 10 points or more on the EORTC QLQ–C30 maintained for two consecutive assessments or a decrease of 10 points or more in one assessment followed by death from any cause within 3 weeks. Each quality of life evaluation will be reported by the patient using EORTC QLQ-C30 score fill formed","definition_or_measurement_approach":"Time to deterioration defined as first deterioration ≥10 points on EORTC QLQ–C30 maintained for two consecutive assessments or a single ≥10-point decrease followed by death within 3 weeks; patient-reported using EORTC QLQ-C30."}
• {"endpoint_text":"- Safety and adverse event will be assessed on the basis of the nature, frequency and severity of adverse events according to NCI Common Terminology Criteria for Adverse Events, version 4.0. The management of side effects usually observed under immunotherapy will be managed according to the American Society of Clinical Oncology Clinical Practice Guidelines (33).","definition_or_measurement_approach":"Safety assessed by nature, frequency and severity of AEs per NCI CTCAE v4.0; management per ASCO guidelines."}
• {"endpoint_text":"- DSA will be assessed before the first injection and at D21, M3, M6, M12, M18, M24, and correlated to ACR, the PFS and OS will be evaluated. Dosage of DSA will be centralized in Pr Taupin’s lab (Hôpital Saint Louis, Paris).","definition_or_measurement_approach":"Donor-specific antibodies measured at specified timepoints (pre-dose, D21, M3, M6, M12, M18, M24); correlated with ACR, PFS and OS; assays centralized at specified lab."}

France

Earliest CTIS Part Ii Submission Date

09-11-2024

Latest Decision Or Authorization Date

12-11-2025

Processing Time Days

368

Number Of Sites

11

Number Of Participants

64

Primary sponsor

Full Name

Assistance Publique Hopitaux De Paris

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France