Evaluation of Durvalumab and Bevacizumab as Adjuvant Therapy in High-Risk Hepatocellular Carcinoma Post-Curative Resection or Ablation

The primary objective of this Phase III, randomized, double-blind, placebo-controlled, multi-center study is to assess the **efficacy** of **durvalumab** in combination with **bevacizumab** compared to placebo in terms of **recurrence-free survival** (RFS) in patients with **hepatocellular carcinoma** (HCC) who are at high risk of recurrence after curative hepatic resection or ablation. This is clinically relevant as improving RFS could potentially lead to better long-term outcomes for patients with HCC, a condition known for its high recurrence rate post-treatment.

Secondary objectives include:

• Comparing the efficacy of Arm B versus Arm C in terms of RFS.
• Assessing the efficacy of Arm A versus Arm C and Arm B versus Arm C in terms of other efficacy endpoints, including RFS at 24 and 36 months (RFS24, RFS36), time to recurrence (TTR), overall survival (OS), and progression-free survival or time to second progression (RFS/PFS2).

The clinical trial involves a total of **803 participants** diagnosed with **locoregional hepatocellular carcinoma (HCC)**, who have successfully completed curative therapy such as resection or ablation. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a confirmed disease-free status through imaging within 28 days prior to randomization, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and a Child-Pugh score of 5 or 6. The trial also considers lifestyle factors such as the management of HBV and HCV infections, requiring antiviral therapy and adherence to local institutional practices. The population includes vulnerable groups, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographics.

The clinical trial is a **Phase III**, randomized, double-blind, placebo-controlled, multi-center study designed to evaluate the efficacy of **durvalumab** monotherapy or in combination with **bevacizumab** as adjuvant therapy in patients with **hepatocellular carcinoma** (HCC) who are at high risk of recurrence following curative hepatic resection or ablation. The primary objective is to assess recurrence-free survival (RFS), with secondary endpoints including overall survival (OS), time to recurrence (TTR), RFS at 24 and 36 months, and time from randomization to recurrence or progression on subsequent therapy. The trial is expected to commence recruitment on January 15, 2024, and conclude by May 31, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically or cytologically confirmed HCC, disease-free status via imaging within 28 days prior to randomization, and an ECOG performance status of 0-1. Follow-up visits will be scheduled to monitor treatment efficacy and safety, with assessments including imaging studies and laboratory tests to evaluate organ and marrow function. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 12 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. Participants with **HBV** infection must receive antiviral therapy to ensure adequate viral suppression, and those with **HCV** infection will be managed according to local institutional practices. The trial will utilize **intravenous** administration for durvalumab and bevacizumab, with placebo controls implemented to maintain the study's double-blind design.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Durvalumab**, marketed as IMFINZI, is a **concentrate for solution for infusion**. It is administered via **intravenous use**. The active substance, **durvalumab**, is a protein-based therapeutic agent. The maximum treatment period for durvalumab is 12 months. The dosage is measured in milligrams, although specific dosing details are not provided. Participant compliance will be monitored throughout the trial.

**Bevacizumab** is another experimental medication used in this study. It is provided as a **solution for infusion** and administered intravenously. The active substance, **bevacizumab**, is also protein-based. The treatment duration is set for a maximum of 12 months, with dosing in milligrams. Specific dosage amounts are not detailed in the trial documentation.

**Sodium Chloride** is used as a placebo in this trial. It is available as a **solution for infusion** and administered intravenously. The treatment period is up to 12 months, with dosing in milligrams. The placebo is chemically derived, and its role is to serve as a control in the study.

**Dextrose BP** is another placebo used in the trial. It is provided as a **solution for infusion** and administered intravenously. The treatment duration is up to 12 months, with dosing in milligrams. The placebo is used to compare the effects of the experimental treatments.

**Mycophenolate Mofetil** is included as an immunosuppressive agent in the study. It is available in the form of **film-coated tablets** and administered orally. The treatment period is up to 12 months, with dosing in milligrams. This agent is chemically derived and serves as a comparator treatment in the trial.

**Infliximab** is another immunosuppressive agent used in the study. It is provided as a **powder for concentrate for solution for infusion** and administered intravenously. The treatment duration is up to 12 months, with dosing in milligrams. This agent is used to assess its effects in comparison to the experimental treatments.

The efficacy of the clinical trial will be assessed by evaluating the **Recurrence-free survival (RFS)** as the primary endpoint. This involves measuring the time from randomization to the first documented recurrence of hepatocellular carcinoma (HCC) or death from any cause. Secondary endpoints include **Overall survival (OS)**, **Time to recurrence (TTR)**, **RFS at 24 months (RFS24)**, **RFS at 36 months (RFS36)**, and **Time from randomization to recurrence/progression on next therapy (RFS2/PFS2)**. These parameters will provide a comprehensive assessment of the treatment's efficacy in preventing disease recurrence and prolonging survival.

The trial is designed as a Phase III, randomized, double-blind, placebo-controlled, multi-center study. Durvalumab, either as monotherapy or in combination with bevacizumab, will be compared to a placebo. The study will include patients with HCC who are at high risk of recurrence after curative hepatic resection or ablation. The efficacy assessments will be conducted at specified intervals throughout the study duration, with key timepoints including 24 and 36 months for RFS evaluations. The data collected will be analyzed to determine the effectiveness of the treatment regimens in extending recurrence-free and overall survival among the participants.