A phase III, double-blind, multicenter, randomized study of atezolizumab (anti-PD‑L1 antibody-proteins that form part of body's natural defence against infection or other foreign substances) versus Placebo (a medicine that contains no active ingredients but looks the same as the study drug). This means that it does not have any medicine-related effect on the body.as additional therapy (therapy given after surgery) in patients with high-risk muscle-invasive bladder cancer who are ctDNA positive after surgical removal of the bladder

1. Why is this study needed?

This study is testing a medicine called Atezolizumab and an Investigational Device called Signatera which is a test for circulating tumour DNA (also called ctDNA) . The medicine is being tested as a therapy given after surgery in people with a type of bladder cancer called muscle-invasive bladder cancer (MIBC) who have ctDNA in their blood after surgical removal of the bladder. Circulating tumour DNA is a DNA molecule, which contains genetic information that identifies the tumour. Finding ctDNA in the blood after surgery might mean a patient is at a higher risk of having the cancer return. This study aims to compare the effects of Atezolizumab against a placebo (a substance that looks like the medicine but with no active ingredient) in people with MIBC who have had surgery to remove the bladder, and whose ctDNA test confirmed ctDNA in the blood.

2. Who can take part in the study?

People of 18 years of age or older with high-risk MIBC, can take part in the study if successfully treated with surgery to remove the bladder and the cancer within the last 6 months. People may not be able to take part in this study if they have not fully recovered from surgery, or they have received certain treatments in the past, or within a particular time frame.

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 approximately 6 weeks to complete and is called the pre-screening phase. During this phase a sample of the tumour will be tested for a protein called PDL1. Additionally, we analyze the tumor's DNA using a technique called whole exome sequencing (WES) where pieces of DNA, called genes are identified.

If both PDL1 and WES testing is successful then participants may then move to the Surveillance phase of the study. During the surveillance phase, participants will be monitored through regular blood tests every 6 weeks for up to 6 months (or until 9 months from the date of surgery have passed) and then will continue with blood tests and scans every 3 months for up to 1 year. If the blood tests show fragments of genetic material from the tumour in the blood (ctDNA), and if scans show no evidence that the bladder cancer has come back, participants will be invited to join the treatment phase of the clinical trial. Finding cancer ctDNA in blood after surgery might mean people are at a higher risk of having the cancer return.

If no ctDNA is found in the blood at the end of the Surveillance phase, participants will be offered to move to surveillance follow-up for 4 years, where they will have 4 scans during the first 2 years to check if the cancer returns and then be contacted 4 times for the last 2 years.

For participants who have tested positive for ctDNA they may be eligible to enter the treatment phase.

Everyone who is eligible to receive treatment will be split into 2 groups randomly (like flipping a coin) and given either:

• Atezolizumab, given as an infusion into the vein every 28 days for up to 12 rounds (1 year) of treatment
• OR placebo (non-active medicine) given as an infusion into the vein every 28 days for up to 12 rounds (1 year) of treatment

Participants will have a 2 in 3 chance of being placed in the Atezolizumab group and a 1 in 3 chance of being placed in the placebo group.

This is a ‘placebo-controlled’ clinical trial, which means that one of the groups will be given medicine with no active ingredients (also known as a ‘placebo’). A placebo is used to show that any effects (good or bad) are a result of the active treatment being tested and that the doctor or the participants cannot influence the results of the clinical trial.

This is also a double-blinded study. This means that neither the participants in the study nor the team running it will know which treatment is being given until the study is over. This is done to make sure that the results of the treatment are not affected by what people expected from the received treatment. However, the study doctor can find out which group the participant is in, if the participants' safety is at risk.

During the treatment phase, participants will have scans and blood tests every 9 weeks to see how they are responding to treatment and other regular checks for any potential side effects that they may be having. After completing treatment, participants will still have scheduled assessments to check for signs of cancer every 9 weeks for the first year, every 3 months for the next year and every 6 months for the following 2 years, with one final visit nearly 1 year later. Total time of participation in the study will be about 7 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 a doctor sees the cancer has come back, taken from the time of treatment assignment (randomisation to treatment).

Other key results measured in the study include:

• How long patients with this type of cancer specifically can live.
• How long it takes for the cancer to spread to other parts of the body or for the patient to pass away.
• How the treatment affects patients' daily function and quality of life.
• How many patients have a decrease in ctDNA during treatment.

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
Participants may have unwanted effects of the Atezolizumab and the (Signatera ctDNA test) 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
Participants will be told about the known unwanted effects of Atezolizumab, and possible unwanted effects based on human and laboratory studies or knowledge of similar medicines. Known unwanted effects include joint pain, lack of energy, back pain, cough, decreased appetite, frequent watery stools, shortness of breath, feeling tired or weak, fever, headache, muscle and bone pain. 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.

Signatera (ctDNA test)
Participants will be told about any known unwanted effects of the Signatera test, and where relevant, also potential unwanted effects based on human and laboratory studies or knowledge of similar devices. The Signatera test will be used to check the patient’s blood for circulating tumour DNA. Participants will be told about any known unwanted effects of the Signatera test and, where relevant, potential unwanted effects based on human and laboratory studies or knowledge of similar procedures.