Clinical trial NCT06254248: Safety of Atezolizumab-Bevacizumab in Liver Transplanted Patients With Advanced Hepatocellular Carcinoma
Official title: Safety of Atezolizumab-Bevacizumab in Liver Transplanted Patients With Advanced Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Liver Transplant
Hepatocellular Carcinoma Recurrent
Systemic Treatment
Keywords: HCC
systemic therapy
graft rejection
immunotherapy
Atezolizumab-Bevacizumab
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2024-02-12
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The prognosis of liver transplanted (LT) patients with recurrence of hepatocellular carcinoma (HCC), especially those with progression after locoregional treatment or advanced HCC, remains poor. Current treatment modalities involve tyrosine kinase inhibitors (TKIs) characterized by a low response rate and often poor tolerability. Encouraging findings from the Imbrave 150 study, demonstrating increased survival rates coupled with favorable treatment tolerance, prompt the investigators to consider the potential of offering the combination of treatment with Atezolizumab-Bevacizumab (Atezo-Beva) to patients with LT. No data regarding the safety and efficacy of this new combination are available for patients with LT as they were not included in Imbrave 150. Immunosuppression after LT is low when compared to essentially all other organ recipients, liver recipients are considered with lower immunological risk. However, the use of ICIs has been associated with a risk of hepatic rejection in LT patients. In this study, in order to prevent acute cellular rejection (ACR) occurrence, we propose to adopt a standardized immunosuppressive regimen closed to the one used immediately after LT but with lower therapeutic goals for tacrolimus and everolimus to allow immunotherapy treatment to be effective. The better tolerance of liver grafts will probably lead to less risk of rejection with Atezo-Beva than in other organ transplants.

Detailed description: 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

Eligibility criteria: 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
* ECOG Performance Status of 0 or 1
* For women of childbearing potential and men: agreement to remain abstinent
* Child-Pugh class A

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

Primary outcomes:
measure: Rate of Acute cellular rejection (ACR) (defined by a Histological Banff score ≥ 5) at 6 months (confirmed by an external expert center)
timeFrame: 6 months
Secondary outcomes:
measure: Rate of Acute Cellular Rejection (ACR) at 24 months
timeFrame: 24 months
measure: Rate of Acute Cellular Rejection (ACR) at the end of Atezo-Beva treatment
timeFrame: at the end of treatment
measure: Progression Free Survival (PFS)
timeFrame: between the inclusion and 24 months after the last inclusion
measure: Overall survival (OS)
timeFrame: between the inclusion and 24 months after the last inclusion
measure: Objective Response Rate (ORR)
timeFrame: 12 months
measure: Duration of response
timeFrame: between the inclusion and 24 months after the last inclusion
measure: Time to deterioration of quality of life
timeFrame: between the inclusion and 24 months after the last inclusion
measure: Type, frequency and severity of adverse events and serious adverse events
timeFrame: between the inclusion, at the end of Atezo-Bev treatment and up to 24 months
measure: Donor Specific Antibodies (DSA) median
timeFrame: baseline and at Day 21, 3 Months 6 Months , 12 Months , 18 Months , 24 Months
Other outcomes:
Locations:
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