Safety of Atezolizumab-Bevacizumab in Liver Transplanted Patients With Advanced Hepatocellular Carcinoma (IMMUNO-TH)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Liver Transplant; Hepatocellular Carcinoma Recurrent; Systemic Treatment
• Intervention / Treatment: Drug: Systemic therapy

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

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Manon Allaire, MD; Phone Number: +33 142127064; Email: manon.allaire@aphp.fr
• Study Contact Backup: Name: Anne Bissery; Phone Number: +33 142162432; Email: anne.bissery@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Atezo-Beva combination; first-line Atezo-Beva combination in LT patients with advanced HCC in association with a standardized immunosuppressive treatment to prevent the risk of acute cellular rejection

Drug: Systemic therapy; Atezolizumab-Bevacizumab every 3 weeks until progression or side effects in combination with Standardized immunosuppressive treatment: Tacrolimus (objective 5-7 ng/ml) Mycophenolate Mofetil 1000 mg per day Corticosteroids at least 5 mg per day Everolimus will be continued if already started before the inclusion (objective 5-7 ng/ml). If everolimus has not been started prior to inclusion, do not start it, but adopt the following protocol: corticoids + Tacrolimus + Cellcept.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Acute cellular rejection (ACR) (defined by a Histological Banff score ≥ 5) at 6 months (confirmed by an external expert center)	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	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Acute Cellular Rejection (ACR) at 24 months	Rate of ACR (defined by a Histological Banff score ≥ 5) at 24 months (confirmed by a second external expert center.	24 months
Rate of Acute Cellular Rejection (ACR) at the end of Atezo-Beva treatment	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.	at the end of treatment
Progression Free Survival (PFS)	The Progression Free Survival (PFS) is 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.	between the inclusion and 24 months after the last inclusion
Overall survival (OS)	The Overall survival (OS) defined by the time from inclusion to death from any cause	between the inclusion and 24 months after the last inclusion
Objective Response Rate (ORR)	The Objective Response Rate (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.	12 months
Duration of response	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.	between the inclusion and 24 months after the last inclusion
Time to deterioration of quality of life	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 every 6 months until 24 months after the initiation of the treatment.	between the inclusion and 24 months after the last inclusion
Type, frequency and severity of adverse events and serious adverse events	They 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	between the inclusion, at the end of Atezo-Bev treatment and up to 24 months
Donor Specific Antibodies (DSA) median	DSA will be assessed and correlation to ACR, the PFS and OS will be evaluated	baseline and at Day 21, 3 Months 6 Months , 12 Months , 18 Months , 24 Months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): May 15, 2024
• Primary Completion (Estimated): May 15, 2028
• Study Completion (Estimated): December 15, 2028

Study Registration Dates

• First Submitted: January 12, 2024
• First Submitted That Met QC Criteria: February 9, 2024
• First Posted (Actual): February 12, 2024

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 9, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: immunotherapy; HCC; systemic therapy; graft rejection; Atezolizumab-Bevacizumab
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: APHP230899

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No