Ezurpimtrostat autophagy inhibitor in association with Atezolizumab-Bevacizumab in first line treatment of unresectable hepatocellular carcinoma, a phase 2b randomized trial. ABE-LIVER
- Trial ID
- 2022-502078-17-00
- Protocol
- 38RC210434 ABE LIVER
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **efficacy** of Ezurpimtrostat in combination with the standard of care, Atezolizumab-Bevacizumab, compared to the standard of care alone, as a first-line treatment in patients with unresectable hepatocellular carcinoma. This evaluation is clinically relevant as it aims to determine whether the addition of Ezurpimtrostat can enhance treatment outcomes in this patient population, potentially offering a more effective therapeutic option.
Secondary objectives include:
- Assessing the tumor response under the combination of Ezurpimtrostat with Atezolizumab-Bevacizumab.
- Evaluating the impact on Overall Survival (OS) and the duration of response.
- Assessing the Alpha-fetoprotein (AFP) response at 3, 6, and 12 months.
- Evaluating the overall survival rate and progression-free survival rate at 6 and 12 months.
- Assessing the safety and quality of life, including time to deterioration, using EORTC QLQ-C30 and HCC 18 scores.
- Investigating the predictive value of CD4/CD8 intratumor infiltrate and PPT1 baseline expression on tumor response and survival outcomes.
- Conducting pharmacokinetic and pharmacodynamic studies of Ezurpimtrostat in association with Atezolizumab-Bevacizumab.
- Biobanking peripheral blood mononuclear cell (PBMC) serum and plasma samples for further ancillary studies.
- Collecting socio-demographic data for ancillary studies.
Participants
The clinical trial involves participants diagnosed with **unresectable hepatocellular carcinoma**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a life expectancy of at least 12 weeks and must demonstrate adequate hematologic, renal, and hepatic function prior to the administration of the investigational drug, Ezurpimtrostat. The trial does not include a vulnerable population. Participants must have a histologically confirmed diagnosis of non-resectable or metastatic hepatocellular carcinoma, with no prior systemic therapy for advanced disease. The trial population was selected based on specific inclusion criteria, such as the presence of a measurable tumor per RECIST v1.1 criteria and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Lifestyle considerations, such as the requirement for antiviral therapy in hepatitis B virus-positive patients, are also taken into account. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **Ezurpimtrostat** in combination with standard care, comprising **Atezolizumab** and **Bevacizumab**, as a first-line treatment for patients with unresectable hepatocellular carcinoma. This is a phase 2b randomized, double-blind, controlled trial. The trial is expected to last until May 2026, with recruitment having commenced in November 2022. Participants will be randomly assigned to receive either the combination therapy or the standard care alone, with the primary endpoint being progression-free survival, assessed by centralized tumor response evaluation according to RECIST version 1.1.
The study involves several key visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, life expectancy, and adequate organ function. Following successful screening, participants will undergo baseline assessments before the initiation of treatment. Regular follow-up visits will be scheduled to monitor the safety and efficacy of the treatment, assess tumor response, and collect pharmacokinetic and pharmacodynamic data. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
Participant involvement is anticipated to last for a maximum of three months, corresponding to the treatment period. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or any other reason deemed appropriate by the investigator. The trial will also assess secondary endpoints such as overall survival, duration of response, and quality of life, providing a comprehensive evaluation of the treatment's impact on patients with unresectable hepatocellular carcinoma.
Treatment
The clinical trial involves the administration of several experimental medications, primarily focusing on the treatment of unresectable hepatocellular carcinoma. **Oyavas** is a concentrate for solution for infusion containing **bevacizumab** as the active substance. It is administered via **intravenous infusion** at a dosage of 15 mg/kg, with a maximum treatment period of 3 months. The pharmaceutical form is a concentrate for solution for infusion, and the product is manufactured by STADA ARZNEIMITTEL AG.
**Zirabev** is another concentrate for solution for infusion, also containing **bevacizumab**. It is administered intravenously at a dosage of 15 mg/kg, with a maximum treatment period of 3 months. The product is manufactured by PFIZER EUROPE MA EEIG.
**Abevmy** is a concentrate for solution for infusion with **bevacizumab** as the active ingredient. It is administered via intravenous infusion at a dosage of 15 mg/kg, with a maximum treatment period of 3 months. The product is manufactured by MYLAN IRE HEALTHCARE LIMITED.
**Tecentriq** is a concentrate for solution for infusion containing **atezolizumab**. It is administered via intravenous infusion at a dosage of 1200 mg, with a maximum treatment period of 3 months. The product is manufactured by ROCHE REGISTRATION GMBH.
**Avastin** is a concentrate for solution for infusion with **bevacizumab** as the active substance. It is administered via intravenous infusion at a dosage of 15 mg/kg, with a maximum treatment period of 3 months. The product is manufactured by ROCHE REGISTRATION GMBH.
**Alymsys** is a concentrate for solution for infusion containing **bevacizumab**. It is administered intravenously at a dosage of 15 mg/kg, with a maximum treatment period of 3 months. The product is manufactured by MABXIENCE RESEARCH S.L.
**Aybintio** is a concentrate for solution for infusion with **bevacizumab** as the active ingredient. It is administered via intravenous infusion at a dosage of 15 mg/kg, with a maximum treatment period of 3 months. The product is manufactured by SAMSUNG BIOEPIS NL B.V.
**MVASI** is a concentrate for solution for infusion containing **bevacizumab**. It is administered intravenously at a dosage of 15 mg/kg, with a maximum treatment period of 3 months. The product is manufactured by AMGEN TECHNOLOGY (IRELAND) UC.
**GNS561** is a hard capsule containing the active substance **GNS561**. It is administered orally at a dosage of 200 mg, with a maximum treatment period of 3 months. The product is manufactured by GENOSCIENCE PHARMA.
All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The trial aims to assess the efficacy of Ezurpimtrostat in combination with standard-of-care therapy, which includes Atezolizumab and Bevacizumab, compared to standard-of-care therapy alone.
Efficacy
The efficacy of the investigational treatment in this clinical trial will be assessed using several key endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, which is defined as the time from randomization to the occurrence of disease progression or death from any cause, whichever occurs first. Progression events will be evaluated based on centralized tumor response assessment according to RECIST version 1.1, with analyses conducted by the CHU Grenoble Alpes Statistics department.
Secondary endpoints include the assessment of tumor response under the combination of Ezurpimtrostat with Atezolizumab-Bevacizumab in the first-line setting for unresectable hepatocellular carcinoma. Additional secondary endpoints involve evaluating the impact of this combination on Overall Survival (OS), the duration of response, and the Alpha-fetoprotein (AFP) response at 3, 6, and 12 months. The overall survival rate and progression-free survival rate at 6 and 12 months will also be assessed. Safety, quality of life (using the EORTC QLQ-C30 score), and time to deterioration (TTD) will be evaluated. The predictive value of CD4/CD8 intratumor infiltrate and PPT1 baseline expression on tumor response and survival outcomes will be analyzed. Pharmacokinetic (PK) and pharmacodynamics (PD) studies of Ezurpimtrostat in association with Atezolizumab-Bevacizumab will be conducted, along with peripheral blood mononuclear cell (PBMC) biobanking for further ancillary studies.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Males or females ≥ 18 years of age
- Histologically confirmed (liver biopsy within 6 previous months) and documented non resectable or metastatic HCC
- Patients with a BCLC C status, as per the Barcelona Clinic Liver Cancer (BCLC) staging system
- No prior systemic therapy for advanced HCC
- Liver tumor burden < 50% of the liver (per Investigator judgment)
- Child-Pugh A (≤ 6) without any history of cirrhotic decompensation within the past 6 months
- Antiviral therapy required in hepatitis B virus patients (Hepatitis B antigen positive)
- Presence of a measurable tumor per RECIST v1.1 criteria
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
- Life expectancy ≥ 12 weeks
- In case of cirrhosis, last esophageal varices detection by esogastroduodenal endoscopy have to be performed within last the 6 months before inclusion and since macro-vascular invasion diagnosis
- Adequate hematologic function prior to the first dose of Ezurpimtrostat, defined as: 12.1. Absolute neutrophils count ≥ 1500 cells/μL 12.2. Hemoglobin ≥ 9 g/dL with no transfusion within 4 weeks prior to first planned dose of Ezurpimtrostat 12.3. Platelet count > 50,000/μL with no transfusion within 2 weeks prior to first planned dose of Ezurpimtrostat
- Adequate renal function prior to first dose, defined as 13.1. Serum creatinine < 1.5 × Upper limit of normal (ULN) 13.2. Creatinine clearance ≥ 30 mL/min/m2 (by Cockroft-Gault equation of 24-hour urine) if creatinine ≥ 1.5 × ULN
- Adequate hepatic function prior to first dose, defined as AST/ALT ≤ 5 × ULN
- Women patients of childbearing potential must have a negative serum pregnancy test at screening and baseline, and be willing to use a highly effective contraception. The patient should be advised to continue the contraception for at least 6 months following the completion of dosing. Women with cessation for > 24 months of previously occurring menses, or women of any age who have had a hysterectomy, or have had both ovaries removed will be considered to be of non-childbearing potential
- Male patients of reproductive potential must be willing to use one acceptable method of contraception, as judged by Investigator and Sponsor, and/or to refrain from donating sperm from the time of screening through at least 6 months following the completion of dose administration
- Amenable to computed tomography (CT) with 3 or 4 phase liver or magnetic resonance imaging (MRI) of abdomen and pelvis, and CT of chest, or MRI of whole body, for initial tumor size measurements and subsequent follow-up
- Absence of other clinically relevant abnormalities (i.e., those which require medical intervention) for all screening laboratory test results as judged by the Investigator and Sponsor
- Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
- Able to understand and provide written informed consent
- Patients covered by Health Insurance System
Exclusion Criteria
- Any known history of encephalopathy ≤ 6 months prior to first planned dose of treatment
- Severe or uncontrolled renal condition
- Untreated chronic hepatitis B
- Untreated HCV infection
- Known history of immunodeficiency diseases (e.g., active HIV)
- Use of any prohibited concomitant medications within 14 days of the Baseline/Day 1 visit
- Contraindication to additional liver biopsy planned between C4 and C5
- Contraindication to iodinated contrast agent infusion
- Known current alcohol (> 20g/ Day in women and > 30g/ Day in men) or substance abuse
- Malabsorption issues (e.g., gastric bypass or gastrectomy patients)
- History of leptomeningeal disease
- Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high-risk for bleeding
- Active or history of autoimmune disease
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan
- Known active tuberculosis
- History of malignancy other than HCC within 3 years prior to screening, with the exception of adequately treated skin basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, in-situ carcinoma of the uterine cervix, or prostate cancer that is controlled by hormone therapy (patients may continue hormone therapy while on study)
- Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within at least 6 months after the last dose of treatment
- Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
- Uncontrolled tumor-related pain
- Uncontrolled or symptomatic hypercalcemia
- Treatment with systemic immunostimulatory agents
- Prior history of hypertensive crisis or hypertensive encephalopathy
- Known esophageal varices with recent history of bleeding (within previous 6 months)
- Evidence of bleeding diathesis or significant coagulopathy
- History of intestinal obstruction and/or clinical signs or symptoms of gastrointestinal (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
- Known clinically significant or life threatening organ or systemic disease such that in the opinion of the Investigator, the significance of the disease will compromise the patient's participation in the trial
- Known intolerance or hypersensitivity to the active ingredient or to one of the components of the study drug
- Persistent toxicities related to prior treatment of grade greater than 1
- Subjects with active infection
- History of bone marrow allograft or solid organ transplant
- Subjects requiring corticosteroid therapy at a dose equivalent to more than 10 mg of prednisone equivalent dose per day (corticosteroid administration is permitted by a route resulting in minimal systemic exposure [cutaneous, rectal, articular, ocular or inhalation] is authorized)
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
- Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies
- History of gastrointestinal perforations and fistulae
- Uncontrolled or symptomatic proteinuria
- Active aneurysm considered as unstable and/or at high risk of complication
- Subject in exclusion period for another study
- Subject who cannot be contacted in case of emergency
- All protected persons: pregnant or parturient women, breastfeeding mothers, persons deprived of liberty by judicial or administrative decision, persons subject to a legal protection measure
- Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
- Chronic treatment with immunosuppressive agents (like steroids) ≤ 6 weeks prior to first planned dose of treatment
- Major surgical procedures, open biopsy or significant traumatic injury ≤ 4 weeks prior to first dose of treatment or anticipation of major surgical procedure during the course of the trial, minor surgical procedures ≤ 1 week of first planned dose (the surgical wound must be fully healed)
- Local therapy to liver within 28 days prior to initiation of study treatment or non-recovery from side effects of any such procedure
- Any clinically significant cardiovascular condition as judged by the Investigator (such as New York Heart Association Class II or greater cardiac failure, myocardial infarction, or cerebrovascular accident within 3 months prior to Day 1 of Cycle 1, uncontrolled arterial hypertension, unstable arrhythmia, or unstable angina)
- Patients who experienced immune-mediated pericardial disorders during previous treatment by immune checkpoint blockade therapies, including anti-CTLA4, anti-PD1, and anti-PDL1 therapeutic antibodies
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 07 Nov 2022 | 196 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Oyavas 25 mg/mL concentrate for solution for infusion 400 mg | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 15 | 3 | PRD8834501 |
Zirabev 25 mg/ml concentrate for solution for infusion. | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 15 | 3 | PRD7082677 |
Abevmy 25 mg/mL concentrate for solution for infusion. | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 15 | 3 | PRD9171925 |
Tecentriq 1,200 mg concentrate for solution for infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1200 | 3 | PRD5434939 |
Alymsys 25mg/mL concentrate for solution for infusion. | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 15 | 3 | PRD8838613 |
Avastin 25 mg/ml concentrate for solution for infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 15 | 3 | PRD2153902 |
Avastin 25 mg/ml concentrate for solution for infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | IV INFUSION | 15 | 3 | PRD2153901 |
Aybintio 25 mg/ml concentrate for solution for infusion. | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 15 | 3 | PRD8313460 |
MVASI 25 mg/mL concentrate for solution for infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 15 | 3 | PRD5803006 |
MVASI 25 mg/mL concentrate for solution for infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 15 | 3 | PRD5803005 |