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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Digestive System Diseases [C06]

Trial duration

23 Jan 2026 → ongoing

Decision date (initial)

2025-03-19

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Ministry of Health France

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

We aim 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.

Secondary objectives 1

1. 1-To assess the safety (ACR on histology) at 24 months and at the end of Atezo-Beva treatment. 2-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 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 3-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. 4-To assess the adverse events related to Atezo-Beva treatment in LT patients with recurrent advanced HCC. 5-To assess the evolution of the level of donor specific antibodies (DSA) during Atezo-Beva treatment and its association with ACR, PFS and OS.

Conditions and MedDRA coding

liver transplanted patients with advanced hepatocellular carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 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)
2. - with HCC recurrence diagnosis according to the EASL diagnostic criteria
3. - with advanced HCC not accessible to surgery and locoregional treatment
4. - with at least one measurable untreated lesion
5. - With a proposal for Atezo-Beva in first line treatment made in a multidisciplinary meeting
6. - ECOG Performance Status of 0 or 1
7. - For women of childbearing potential and men: agreement to remain abstinent
8. - Child-Pugh class A
9. - 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
10. - ECOG Performance Status of 0 or 1
11. - 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
12. - If cirrhosis,Child-Pugh class A

Exclusion criteria 22

1. - 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
2. - Patient not having signed consent
3. - History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT-scan
4. - 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
5. - Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding
6. - A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment
7. - 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.
8. - hypersensitivity to the active substance or to any of the excipients of the SmPC of bevacizumab and the SmPC of atezolizumab
9. - hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies
10. - prior arterial thromboembolic reactions including cerebrovascular accidents, transient ischaemic attacks and myocardial infarctions;
11. - 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
12. - Inadequately controlled arterial hypertension
13. - History of leptomeningeal disease
14. - Active tuberculosis
15. - 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
16. - Prior history of hypertensive crisis or hypertensive encephalopathy
17. - 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
18. - Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
19. Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses
20. - Banff score for acute cellular rejection ≥ 3 on liver biopsy performed before the initiation of the treatment
21. - Pregnant or breastfeeding woman
22. - Patient not affiliated to a beneficiary or entitled social security scheme or to the PUMA

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Rate of ACR (defined by a Histological Banff score ≥ 5) at 6 months (confirmed by a second external expert center (Pr Calderaro, Mondor hospital).

Secondary endpoints 8

1. 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).
2. 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.
3. The OS defined by the time from inclusion to death from any cause.
4. 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.
5. -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.
6. 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
7. 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).
8. 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).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Manon ALLAIRE

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Manon ALLAIRE

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications