A Phase III Multicenter Randomized Open-Label Study of Atezolizumab and Bevacizumab as Adjuvant Therapy in High-Risk Hepatocellular Carcinoma Post-Resection or Ablation

The primary objective of this Phase III, multicenter, randomized, open-label study is to evaluate the **efficacy** of atezolizumab plus bevacizumab compared with active surveillance in patients with high-risk **hepatocellular carcinoma** (HCC) following surgical resection or ablation. The primary endpoint is recurrence-free survival (RFS) as determined by an Independent Review Facility (IRF). This is clinically relevant as it aims to determine whether the combination therapy can effectively reduce the risk of cancer recurrence, which is a significant concern in high-risk HCC patients.

Secondary objectives include:

• Evaluating the efficacy of atezolizumab plus bevacizumab compared with active surveillance based on overall survival (OS), RFS after randomization as determined by the investigator and by an IRF, time to recurrence (TTR), IRF-assessed RFS and investigator-assessed RFS rate after randomization, and OS rate at 24 months and 36 months, as well as time to extrahepatic spread or macrovascular invasion after randomization.
• Assessing the safety of atezolizumab plus bevacizumab compared with active surveillance.
• Characterizing the pharmacokinetic (PK) profile of atezolizumab when administered in combination with bevacizumab.
• Evaluating the immune response to atezolizumab.

The clinical trial involves a total of **596 participants** diagnosed with **high-risk hepatocellular carcinoma (HCC)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific criteria, including a first diagnosis of HCC and having undergone curative resection or ablation within 4-12 weeks prior to randomization. All participants are required to have fully recovered from surgical procedures within 4 weeks before randomization and must exhibit an ECOG Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Additionally, participants must have a Child-Pugh Class A status, reflecting well-compensated liver function. The trial includes individuals considered a vulnerable population, emphasizing the need for careful monitoring and ethical considerations. Lifestyle factors such as diet and physical activity are not specified, but the absence of macrovascular invasion (MVI) and the high risk for HCC recurrence are significant considerations in the selection process.

The clinical trial is a **Phase III**, multicenter, randomized, open-label study designed to evaluate the efficacy of **atezolizumab** plus **bevacizumab** compared to active surveillance in patients with high-risk **hepatocellular carcinoma** (HCC) following surgical resection or ablation. The primary objective is to assess recurrence-free survival (RFS) as determined by an Independent Review Facility (IRF). Secondary endpoints include overall survival (OS) rates at 24 and 36 months, time to recurrence, and incidence and severity of adverse events. The trial is expected to run from March 2020 to July 2027, with a maximum treatment period of 12 months for each participant.

Participants will be randomly assigned to receive either the combination therapy or active surveillance. The study involves several key visits: an initial screening visit to confirm eligibility based on criteria such as a first diagnosis of HCC, high risk for recurrence, and an ECOG Performance Status of 0 or 1. Follow-up visits will occur regularly to monitor treatment effects, adverse events, and disease progression. The end-of-study visit will evaluate the final outcomes and collect data on long-term survival and recurrence rates.

Participant involvement is expected to last up to 12 months, with conditions for early termination including significant adverse events or disease progression. The trial will utilize **intravenous infusion** as the route of administration for the investigational products, which have been re-packed and re-labeled for clinical trial use. The study aims to provide valuable insights into the potential benefits of atezolizumab and bevacizumab as adjuvant therapy in reducing the risk of HCC recurrence.

The clinical trial involves the administration of **Tecentriq** (atezolizumab), a **concentrate for solution for infusion**. Tecentriq is provided in a dosage of 1,200 mg and is administered via **intravenous infusion**. The maximum daily dose is 1,200 mg, with a total maximum dose of 20.40 grams over the treatment period. The treatment is scheduled to be administered over a maximum period of 12 months. Tecentriq has been re-packed and re-labeled specifically for use in this clinical trial. The active substance, atezolizumab, is a protein of non-human origin, classified under the ATC code L01FF05.

Additionally, the trial includes the administration of **Avastin** (bevacizumab), also a **concentrate for solution for infusion**. Avastin is administered at a concentration of 25 mg/ml, with a maximum daily dose of 15 mg/kg and a total maximum dose of 255 mg/kg over the treatment period. Similar to Tecentriq, Avastin is administered via **intravenous infusion** and is scheduled for a maximum treatment period of 12 months. The product has been re-packed and re-labeled for clinical trial use. Bevacizumab, the active substance in Avastin, is also a protein of non-human origin, and it is classified under the ATC code L01FG01.

In this study, the experimental treatment involves the combination of atezolizumab and bevacizumab, compared against active surveillance as the non-experimental treatment. The primary objective is to evaluate the efficacy of the combination therapy in terms of recurrence-free survival in patients with hepatocellular carcinoma at high risk of recurrence following surgical resection or ablation. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed primarily through the **recurrence-free survival (RFS)** as evaluated by an Independent Review Facility (IRF). This primary endpoint will provide a measure of the time patients remain free from disease recurrence following treatment with atezolizumab plus bevacizumab compared to active surveillance. Secondary endpoints include overall survival (OS) rates at 24 and 36 months, time to recurrence (TTR), time to extrahepatic spread (EHS) or macrovascular invasion, and RFS as determined by both the investigator and IRF, particularly in the PD-L1-high subgroup. Additionally, the incidence and severity of adverse events will be monitored, with severity classified according to the NCI CTCAE v5.0.

Changes from baseline in targeted vital signs and clinical laboratory test results will also be evaluated. Serum concentrations of atezolizumab at specified timepoints and the prevalence and incidence of anti-drug antibodies (ADAs) to atezolizumab will be measured. The efficacy assessments will be conducted at various timepoints throughout the study, including at 24 and 36 months post-randomization. These comprehensive evaluations will provide a robust analysis of the treatment's efficacy in patients with hepatocellular carcinoma at high risk of recurrence after surgical resection or ablation.