A clinical trial to compare the effectiveness and safety of RO7771950 in combination with trastuzumab and capecitabine, versus tucatinib in combination with trastuzumab and capecitabine in people with locally advanced or metastatic breast cancer that is HER2-positive

1. Why is this study needed?

HER2, also known as human epidermal growth factor receptor 2, is a protein involved in normal cell growth. It can be made in larger than normal amounts by some types of cancer cells, including breast cancer, and cause cancer cells to grow more quickly. Breast cancer can sometimes be diagnosed as “locally advanced unresectable” (cancer that has spread to nearby tissue, and cannot be removed by surgery) or “metastatic” (cancer that has spread to other parts of the body). HER2-positive breast cancer is more likely to spread to the brain than HER2-negative breast cancer. Because of this, researchers are looking for better treatment options for people whose cancer has spread to the brain.

This study is testing a medicine called RO7771950 in combination with trastuzumab and capecitabine. It is being developed to treat HER2-positive breast cancer that may or may not have spread to the brain.

RO7771950 is an experimental medicine. Although trastuzumab and capecitabine are approved for HER2-positive breast cancer, their combination with RO7771950 is considered experimental in this study.This means health authorities (like the U.S. Food and Drug Administration and European Medicines Agency) have not approved RO7771950 (in combination with trastuzumab and capecitabine) for the treatment of HER2-positive breast cancer.

This study aims to find out how well RO7771950 works compared to tucatinib when both are given together with the medicines, trastuzumab and capecitabine, in people with HER2-positive breast cancer.

2. Who can take part in the study?

People (males / females) of 18 years of age or older with HER2-positive breast cancer that has spread to nearby tissue and cannot be removed by surgery, or that has spread to other parts of the body, can take part in the study.

People may not be able to take part in this study if they have certain other medical conditions, such as liver or heart disease, infections, or if they are receiving other cancer treatments. People who are pregnant, planning to become pregnant, or currently breastfeeding cannot take part in the study.

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 up to 4 weeks before the start of treatment. This study will be carried out in two stages:
Stage 1: This stage will help find the best dose of RO7771950 to be used for Stage 2. The study treatment will be given in 21-day cycles, which means treatment is repeated every 3 weeks.

Everyone who joins this stage will be split up into 3 groups randomly (like rolling a die) and given either:

• RO7771950 (low dose), as tablets (to be swallowed), twice a day, for every day of the cycle
• RO7771950 (high dose), as tablets, twice a day, for every day of the cycle
• Tucatinib, given as tablets, twice a day, for every day of the cycle

Stage 2: Everyone who joins this stage will receive either:

• RO7771950 (at a dose selected from Stage 1), given as tablets, twice a day for every day of the cycle, or
• Tucatinib, given as tablets, twice a day for every day of the cycle

In both stages, all the participants will also receive:

• Trastuzumab, either as an injection under the skin (subcutaneous injection) or a drip into the vein (intravenous infusion), on the first day of each cycle, and 
• Capecitabine, as tablets, twice a day for the first 14 days of each cycle.

Participants will have an equal chance of being placed in any of the groups.

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 every 1 or 2 weeks for 9 weeks and then every 3 weeks thereafter. They will see how well the treatment is working and ask about any unwanted effects participants may have. Participants will have follow-up visits every 3 months after completing the study treatment, during which the study doctor will check on the participant’s well being. The total time of participation in the study will be about 33 months. 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 how long participants live without their cancer getting worse. Other key results measured in the study include how long participants whose cancer has spread to the brain live before their cancer gets worse, and how long all participants live overall. The study also looks at how many participants respond to the treatment, how long they respond for, changes in symptoms and daily functioning and the number and seriousness of any unwanted effects.

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 medicines
Participants may have unwanted effects of the medicines 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.

RO7771950 has had limited testing in humans. Therefore, the unwanted effects of this medicine are not fully known now. Participants will be told about the possible unwanted effects based on laboratory studies or knowledge of similar medicines. Known unwanted effects include abnormal liver blood tests, pain or discomfort in the head, wanting to throw up, throwing up, loose, watery [and more frequent] stools, and decrease in red blood cells.

Participants will be told about the known unwanted effects of tucatinib, trastuzumab, and capecitabine and possible unwanted effects based on human and laboratory studies or knowledge of similar medicines. Known unwanted effects of tucatinib include abnormal liver blood tests, pain or discomfort in the head, throwing up, loose, watery [and more frequent] stools, inflammation and sores in the mouth and pain in joints. Known unwanted effects of trastuzumab include fever, throwing up, wanting to throw up, loose, watery [and more frequent] stools, muscle pain, and decrease in red and white blood cells. Known unwanted effects of capecitabine include inflammation and sores or ulcers in the lining of the mouth, esophagus, or intestines, bleeding in the intestines, dry mouth, back and joint pain, and difficulty breathing.

Trastuzumab will be given as a drip into the vein or an injection under the skin. Known unwanted effects of infusion or injection include low or high blood pressure, fever, pain or discomfort in the head, and a reaction on the skin where it has been pricked with a needle to give a treatment.

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.