A Study of Atezolizumab (Anti-PD-L1 Antibody) plus Bevacizumab versus Active Surveillance as Adjuvant Therapy in Patients with Hepatocellular Carcinoma at High Risk of Recurrence After Surgical Resection or Ablation

1. Why is this study needed?

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. HCC is sometimes diagnosed before it spreads to nearby tissue or to other parts of the body. This means it can often be removed with surgery or with a method of removing cancer cells using heat, known as ‘ablation’. After surgery or ablation, standard of care is for doctors to check people with scans (and sometimes a blood test called AFP) every 3 to 6 months. This is known as ‘active surveillance’. However, currently no treatments are available to prevent or delay HCC from coming back after surgery or ablation.

This study is testing a combination of 2 medicines called atezolizumab and bevacizumab. These medicines are known as ‘immunotherapy’. Immunotherapy is a type of medicine that helps a person’s own immune system attack cancer cells. This combination of medicines is being developed to prevent or delay HCC from coming back after it has been removed.

Atezolizumab with bevacizumab is an experimental combination of medicines. This means health authorities (like the U.S. Food and Drug Administration and European Medicines Agency) have not approved the combination for people who have had HCC removed.

This study aims to compare the effects of atezolizumab combined with bevacizumab versus active surveillance in people who have had HCC removed.

2. Who can take part in the study?

People of at least 18 years of age who have had HCC completely removed with surgery or ablation within the last 3 months can take part in the study. They must be at high-risk of HCC coming back. High risk means having had many or large tumours or those with aggressive features, meaning they form, grow, or spread quickly.

People may not be able to take part in this study if they have had prior treatment for their HCC, have any remaining HCC cells after surgery or ablation or had certain types of HCC. People with certain medical conditions (like heart disease or autoimmune disease), or who have had certain treatments like immunotherapy, will not be able to take part. People who are pregnant, planning to become pregnant during the study, or currently breastfeeding cannot take part.

3. How does this study work?

People will be screened to check if they are able to participate in the study. The screening period will take place from 1 month before the start of treatment or active surveillance.

Everyone who joins this study will be placed into 1 of 2 groups randomly (like flipping a coin) and will either:

• Be given atezolizumab and bevacizumab, as a drip into the vein (infusion) every 3 weeks OR
• Be placed under active surveillance (being closely watched for cancer to come back with no treatment)

Participants will have an equal chance of being placed in either group.

This is an open-label study. This means everyone involved, including the participant and the study doctor, will know the study treatment the participant has been given.

During this study, the study doctor will see participants regularly.

• For participants being treated with atezolizumab plus bevacizumab, patients will visit the clinic every 3 weeks to see how well the treatment is working, monitor for HCC and check for any unwanted effects or symptoms that participants may have.
• For participants in the active surveillance group, contact with the doctor will be a clinic visit or phone call every 3 weeks to monitor for HCC and check for any unwanted effects or symptoms.

Treatment or surveillance will take place for 1 year unless a participant’s HCC comes back, or they have unacceptable unwanted effects. If HCC comes back in a participant under active surveillance, they may be offered atezolizumab and bevacizumab treatment. Participants will have a follow-up visit after 1 month of completing treatment or surveillance, then follow-up visits or telephone calls every 3 months for as long as the participant agrees to it. The study doctor will check on the participant’s wellbeing during follow-up visits or calls.

Total time of participation in the study will be up to 7 and a half years. Participants have the right to stop study treatment and leave the study at any time, if they wish to do so.

4. What are the main results measured in this study?

The main result measured in the study to assess if the medicine has worked is the length of time that people live without their cancer coming back after surgery or ablation for cancer.

Other key results measured in the study include:

• How long participants live, and the number of participants alive at 2 and 3 years after they start the study
• How much time between the start of the study and HCC coming back
• How much time between the start of the study and HCC spreading to nearby tissue 
• The number, type and seriousness of any unwanted effects
• How atezolizumab gets to different parts of the body, how the body changes and gets rid of it, and how it affects the immune system when it is given with bevacizumab

5. Are there any risks or benefits in taking part in this study?

Taking part in the study may or may not make participants feel better. But the information collected in the study can help other people with similar health conditions in the future.

It may not be fully known at the time of the study how safe and how well the study treatment works. The study involves some risks to the participant. But these risks are generally not greater than those related to routine medical care or the natural progression of the health condition. People interested in taking part will be informed about the risks and benefits, as well as any additional procedures or tests they may need to undergo. All details of the study will be described in an informed consent document. This includes information about possible effects and other options of treatment.

Risks associated with the study drugs

Participants may have unwanted effects of the drugs used in this study. These unwanted effects can be mild to severe, even life-threatening, and vary from person to person. During this study, participants will have regular check-ups to see if there are any unwanted effects.

Atezolizumab with bevacizumab

Participants will be told about the known unwanted effects of atezolizumab and bevacizumab and possible unwanted effects based on human and laboratory studies or knowledge of similar medicines.

Known unwanted effects of atezolizumab include cough, pain or discomfort in the head, back pain, joint, muscle or bone pain, frequent watery stools, feeling less hungry than usual and feeling tired or weak.

Known unwanted effects of bevacizumab include high blood pressure, numbness or loss of feeling in the fingers or toes, not having energy or strength, throwing up or wanting to throw up, and frequent watery stools.

Atezolizumab and bevacizumab will be given as a drip into the vein. Known unwanted effects of a drip into the vein include throwing up, wanting to throw up, a feeling of coldness that makes the body shiver, low or high blood pressure, fever, pain or discomfort in the head, frequent watery stools, shortness of breath, and cough.

The study medicine(s) may be harmful to an unborn baby. Women and men must take precautions to avoid exposing an unborn baby to the study treatment.