A substudy to test drug-drug interactions as part of study WO43919: A study to compare inavolisib with fulvestrant versus alpelisib with fulvestrant in patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated breast cancer that has spread and worsened after previous treatments

1. Why is this study needed?

The most common type of breast cancer is hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. HR-positive, HER2-negative breast cancer can spread to nearby cells (known as ‘locally advanced’ cancer) or to other parts of the body (known as ‘metastatic’ cancer). Standard treatment options for people with HR-positive, HER2-negative metastatic breast cancer include hormone therapy (also called endocrine therapy), endocrine therapy combined with a type of drug called a CDK4/6 inhibitor, or chemotherapy. However, in most people with this type of breast cancer, the cancer eventually comes back (known as ‘relapse') because the treatments have stopped working.

Sometimes, cancer cells can have a changed version (also known as a ‘mutation’) of a gene called PIK3CA. Breast cancers with this type of mutation can relapse more quickly after standard treatment has been given. People with cancer often need to take multiple medications at the same time. When different medicines are taken together, they can sometimes change how the body processes each other. This is called a drug-drug interaction (DDI). It can cause medicines to become less effective, or it can lead to unexpected unwanted effects.

This study is testing a medicine called inavolisib given together with fulvestrant. It is being developed to treat people with HR-positive, HER2-negative, PIK3CA-mutated breast cancer whose cancer has worsened during or after treatment with a type of drug called a CDK4/6 inhibitor. This specific combination is experimental. This means health authorities (like the U.S. Food and Drug Administration and European Medicines Agency) have not approved inavolisib (in combination with fulvestrant) for this indication.

This study aims to test how daily doses of inavolisib (given together with fulvestrant) change the amounts of medicines that are broken down by liver proteins (CYP enzymes), such as midazolam, omeprazole, and bupropion, in the body.

2. Who can take part in the study?

People (males / females) of 18 years of age or older can take part in the study if they have HR-positive, HER2-negative, PIK3CA-mutated breast cancer that has spread during or after treatment with a combination of a CDK4/6 inhibitor plus endocrine therapy.

People may not be able to take part in this study if their cancer has spread to the brain or spinal cord or if they have certain other medical conditions, such as diabetes or moderate to severe kidney problems. They may also be unable to take part if they have previously received certain treatments or are unable to swallow pills. 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. During the DDI period, everyone who joins this substudy will be given:

• Midazolam: Twice as a liquid to be swallowed
• Omeprazole and bupropion: Omeprazole as a capsule and bupropion as a tablet, both to be swallowed twice a day
• Inavolisib: As a tablet to be swallowed once every day
• Fulvestrant: As an injection into a muscle (intramuscular) once every two weeks during the first month, then every 4 weeks after the DDI period ends

After the DDI period, participants will have the option to continue taking only inavolisib and fulvestrant to treat their breast cancer. This is a single arm, open-label study. This means all participants receive the same treatment and 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. They will check how the body processes these medicines and look for any unwanted effects participants may have. Participants will have a follow-up visit 1 month after completing the study treatment, during which the study doctor will check on the participant’s well being. Total time of participation in the DDI period will be about 19 days. If participants choose to continue treatment with inavolisib and fulvestrant, they will receive these medicines until their condition gets worse. 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 results measured in the study to assess if inavolisib impacts the liver proteins are the amounts of midazolam, omeprazole, and bupropion, and their broken-down products (metabolites) in the blood over time. Other key results measured in the study include 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 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.

Participants will be told about the known unwanted effects of the drugs and possible unwanted effects based on human and laboratory studies or knowledge of similar medicines. Known unwanted effects of inavolisib include an infection in any part of the urinary tract, low levels of platelets and red blood cells, a high level of sugar in the blood, inflammation of the lining of the mouth, and loose, watery [and more frequent] stools. Known unwanted effects of fulvestrant include allergic reactions, wanting to throw up, sudden feeling of warmth and sweating, rash, muscle, bone or joint pain, feeling tired or weak, and abnormal liver function tests (possible liver damage). Known unwanted effects of midazolam include wanting to throw up, throwing up and sleepiness. Known unwanted effects of omeprazole include loose, watery [and more frequent] stools, belly pain, and throwing up. Known unwanted effects of bupropion include constipation, dry mouth and fast heart beat.

Participants will be told about any known unwanted effects of taking oral tablets. Known unwanted effects of injection include pain or a reaction on the skin where it has been pricked with a needle to give a treatment. The study medicines may be harmful to an unborn baby. Women and men must take precautions to avoid exposing an unborn baby to the study treatment.