A clinical trial to compare how safe and effective different doses of mosunetuzumab on its own or in combination with other treatments are in people with chronic lymphocytic leukemia that has not responded to, or has come back after previous treatments

1. Why is the BO43243 clinical trial needed?

Chronic lymphocytic leukemia (CLL) is a type of blood cancer in which the bone marrow makes too many B-cells. B-cells are disease-fighting white cells in blood. The excess B-cells build up and stop the blood, bone marrow and lymph nodes working properly. Standard treatment for CLL includes medicines such as:

• Bruton’s tyrosine kinase inhibitors (BTKi), such as ibrutinib and acalabrutinib. These work by blocking a protein called BTK in CLL cells so they cannot grow as quickly
• Venetoclax, which works by blocking the action of a protein called BCL2. This protein helps keep CLL cells alive. Venetoclax can be given on its own or with:
• Rituximab or obinutuzumab, which are known as ‘immunotherapies’. This is a type of medicine that helps a person’s own immune system attack cancer cells
• Chemotherapy – a medicine that kills cancer cells

Treatment can include stem cell transplant, but age or medical conditions prevent this for most people. Some people have CLL that does not respond to (known as ‘refractory’ CLL) or comes back after (known as ‘relapsed’ CLL) treatment with standard medicines. More treatments for people with CLL are needed when previous treatment has not worked. Mosunetuzumab is a type of immunotherapy. Mosunetuzumab attaches to a marker on some types of CLL cells and another marker on cancer-killing immune cells called T cells. This brings the CLL cells closer to T cells. Mosunetuzumab is an experimental drug – this means health authorities have not approved mosunetuzumab on its own or in combination with other treatments for treating CLL, but mosunetuzumab has been approved to treat follicular lymphoma.

This clinical trial aims to test mosunetuzumab at different doses on its own or in combination with BTKi. This is to understand how safe and how well it works in people with relapsed or refractory CLL and how the body changes and gets rid of mosunetuzumab.

2. How does the BO43243 clinical trial work?

This clinical trial is recruiting people with relapsed or refractory CLL.

People who take part in this clinical trial (participants) will be given increasing doses of the clinical trial treatment mosunetuzumab every week until the target dose is reached. This is either on its own (Group 1), or with BTKi (if they are currently treated with BTKi) until the target dose of mosunetuzumab is reached (Group 2). Treatment will end if their cancer gets worse or they have unacceptable unwanted effects. Participants will stay in the hospital for 2 days after each dose of mosunetuzumab and will be given a medicine called a corticosteroid to lower the chance of unwanted effects. Once the target doses are reached, mosunetuzumab will be given (without needing to stay in hospital after each dose) once every 3 weeks for about 1 year unless a participants’ cancer gets worse, or they have unacceptable unwanted effects. Participants who are currently being treated with a BTKi will continue to be given it for up to 6 weeks from the start of mosunetuzumab treatment.

The clinical trial doctor will see participants at least every 3 weeks. These hospital visits will include checks to see how the participant responds to the treatment and any unwanted effects they may have. Participants will also be seen 1 month after the last dose of clinical trial treatment is given. Then, they will be followed up for as long as they agree to it, about every 3 months for 2 years, then every 6 months. The total time of participation in the clinical trial could be more than 3 years depending on the response to treatment. Participants can stop trial treatment and leave the clinical trial at any time.

3. What are the main endpoints of the BO43243 clinical trial?

The main clinical trial endpoint (the main result measured in the trial) is the number and seriousness of unwanted effects with different doses of mosunetuzumab given alone or with BTKi.

The other clinical trial endpoints include:

• How many people have a reduction of their cancer after treatment
• How many participants have no CLL cells detectable in their blood or bone marrow 2–3 months after the final dose of treatment
• The time between the start of treatment and signs that disease getting worse
• How long people live
• The time between when a person starts the treatment and having a change in disease or treatment
• The number of people who do not have cancer on tests or scans after treatment
• How much time there is between the person’s cancer first responding to treatment and the cancer getting worse
• How study treatment affects the immune system
• How the study treatment gets to different parts of the body, and how the body changes and gets rid of it

4. Who can take part in this clinical trial?

People can take part in this trial if they are over the age of 18 and have relapsed or refractory CLL after at least 2 treatments have failed, including a BTKi and/or venetoclax. People may not be able to take part in this trial if they have certain medical conditions including severe heart, lung or liver disease. People also may not be able to take part if they have had certain treatments including mosunetuzumab. Women cannot take part in this trial if they are pregnant or breastfeeding or are planning to become pregnant during or soon after the clinical trial.

5. What treatment will participants be given in this clinical trial?

Everyone in this clinical trial will join 1 of 2 treatment groups and will be given:

• Group 1 – Increasing doses of mosunetuzumab only, as an injection under the skin (subcutaneous injection) weekly until the target dose is reached, then every 3 weeks for about 1 year
• Group 2 – Increasing doses of mosunetuzumab, given in the same way as Group 1, AND continued treatment with a BTKi (taken as prescribed) for up to 6 weeks from the start of mosunetuzumab treatment

This is an open-label trial, which means everyone involved, including the participant and the clinical trial doctor, will know the clinical trial treatment that the participant has been given. Participants may also receive tocilizumab as drip into a vein given slowly if they experience certain unwanted effects during the clinical trial.

6. Are there any risks or benefits in taking part in this clinical trial?

The safety or effectiveness of the experimental treatment or use may not be fully known at the time of the trial. Most trials involve some risks to the participant. However, it may not be greater than the risks related to routine medical care or the natural progression of the health condition. People who would like to participate will be told about any risks and benefits of taking part in the clinical trial, as well as any additional procedures, tests, or assessments they will be asked to undergo. All of these will be described in an informed consent document (a document that provides people with the information they need to decide to volunteer for the clinical trial).

Risks associated with the clinical trial drugs

Participants may have unwanted effects (an unwanted effect of a drug or medical treatment) from the drugs used in this clinical trial. Unwanted effects can be mild to severe, even life-threatening, and vary from person to person. Participants will be closely monitored during the clinical trial; safety assessments will be performed regularly. Participants will be told about the known unwanted effects of mosunetuzumab and tocilizumab, and possible unwanted effects based on human and laboratory studies or knowledge of similar drugs. Participants will be told about any known unwanted effects of subcutaneous injections and a drip into a vein given slowly.

Potential benefits associated with the clinical trial

Participants' health may or may not improve from participation in the clinical trial. Still, the information collected may help other people with similar medical conditions in the future.