Efficacy Evaluation of Atezolizumab, Bevacizumab, and EXL01 in Hepatocellular Carcinoma Patients Resistant to First-Line Immunotherapy

The primary objective of this study is to evaluate the **efficacy** of the combination of atezolizumab and bevacizumab with bacterial supplementation in patients with **hepatocellular carcinoma** (HCC) who have shown progression following first-line immunotherapy. This is clinically relevant as it explores a novel therapeutic approach that could potentially improve outcomes in a patient population with limited treatment options.

Secondary objectives include evaluating the safety of the atezolizumab-bevacizumab combination with bacterial supplementation in the same patient cohort. Assessing safety is crucial to ensure that the treatment regimen is not only effective but also tolerable for patients, thereby providing a comprehensive understanding of its clinical utility.

The clinical trial involves participants diagnosed with **hepatocellular carcinoma** (HCC) who have shown disease progression following first-line immunotherapy with atezolizumab and bevacizumab. The study population includes both male and female subjects aged 18 years and older. Participants are required to have locally advanced, metastatic, or unresectable HCC, as determined by a multidisciplinary team meeting. The trial includes individuals with a Child-Pugh A classification within seven days prior to inclusion and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Participants must have adequate hematological and renal functions, with specific thresholds for hemoglobin, platelets, neutrophils, and creatinine clearance. The disease must be measurable according to RECIST 1.1 criteria. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on these criteria, ensuring a focus on individuals with progressive HCC who meet the specified health and functional requirements.

The clinical trial is designed to evaluate the efficacy of a combination therapy involving **atezolizumab**, **bevacizumab**, and a commensal bacterial strain in patients with **hepatocellular carcinoma** (HCC) who have shown progression after first-line immunotherapy. This is a phase IV, randomized, double-blind, controlled trial. The trial is expected to commence on April 15, 2024, and conclude by January 15, 2026, with an estimated duration of 21 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of HCC, and previous treatment history. The trial will include regular follow-up visits at weeks 6 and 12, and months 6 and 12, to assess the primary endpoints, which include the Objective Response Rate (ORR) and Disease Control Rate (DCR) according to RECIST 1.1, mRECIST, and iRECIST criteria. Secondary endpoints will focus on the frequency of adverse events graded by the NCI-CTCAE classification.

The expected length of participant involvement is up to 12 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The trial will ensure that all participants meet the inclusion criteria, such as having a Child-Pugh A score and adequate hematological and renal functions, to maintain the integrity and safety of the study.

The clinical trial involves the administration of **EXL01**, an experimental medication formulated as a **capsule**. This medication is derived from a **commensal bacterial strain** and is intended for oral administration. Participants will receive a maximum daily dose of one capsule, with the treatment period extending up to 12 months. The compliance of participants with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the study includes the administration of **Avastin** (bevacizumab), a concentrate for solution for infusion. Bevacizumab is a protein-based therapeutic agent, administered via infusion. The maximum daily dose is set at 15 mg/kg, with a treatment duration of up to 12 months. This medication is provided as a standard-of-care therapy and serves as a comparator treatment in the study.

Another non-experimental treatment used in the trial is **Tecentriq** (atezolizumab), also a concentrate for solution for infusion. Atezolizumab is a protein-based agent, administered through infusion. The maximum daily dose is 1200 mg, with a treatment period of up to one month. This medication is utilized in conjunction with the experimental treatment to evaluate its efficacy in combination therapy.

Participant compliance with the administration of both non-experimental treatments will be closely monitored to ensure accurate assessment of the treatment outcomes. The trial aims to evaluate the efficacy of the combination of atezolizumab and bevacizumab with bacterial supplementation in patients with hepatocellular carcinoma who have shown progression following first-line immunotherapy.

The efficacy of the clinical trial titled "MICROBIOTA MODIFICATION FOR IMMUNO-ONCOLOGY IN HEPATOCELLULAR CARCINOMA - 'MOTHER'" will be assessed using several primary endpoints. These include the **Objective Response Rate (ORR)** at week 12, defined as the proportion of patients achieving a Complete Response (CR) or Partial Response (PR) from inclusion to week 12, according to RECIST 1.1 criteria. Additionally, the overall tumor response will be evaluated at weeks 6, 12, and months 6 and 12 using mRECIST, RECIST 1.1, and iRECIST criteria. The Disease Control Rate (DCR) will also be measured, defined as the proportion of patients with CR, PR, or stable disease (SD) at week 12, month 6, and month 12. Progression-Free Survival (PFS) and Overall Survival (OS) will be assessed, with PFS defined as the time from patient inclusion to progression or death from any cause, and OS as the time from inclusion to death from any cause.

Secondary endpoints include the frequency of adverse events, which will be graded according to the latest NCI-CTCAE classification. Adverse events will be monitored from inclusion to 30 days after the last intake of EXL01. The efficacy parameters will be collected and analyzed at specified time points, including week 6, week 12, month 6, and month 12, using validated criteria such as RECIST 1.1, mRECIST, and iRECIST. These assessments will provide comprehensive data on the efficacy of the atezolizumab-bevacizumab combination with bacterial supplementation in patients with progressive hepatocellular carcinoma following first-line immunotherapy.