A Phase I/Ib study evaluating single-agent inavolisib and inavolisib plus atezolizumab in PIK3CA-mutated cancers

Background and study aims:

Cancer is a disease in which abnormal cells divide without control and can invade nearby tissues. Cancers that are known collectively as head and neck cancers usually begin in the squamous cells (a flat cell that looks like a fish scale under a microscope) that form the moist, inner lining of the head and neck (for example, those inside the mouth, throat, and voice box). The risk factors for head and neck squamous cell carcinoma (HNSCC) include tobacco use, alcohol consumption, and infection with human papillomavirus (HPV). Studies of HNSCC tumors show that there is a frequent occurrence of a mutation in the PIK3CA gene. PIK3CA is a gene that controls a message telling cells to grow and multiply. This message is often involved in cancer when cells lose the ability to turn it off. This messaging system is called the PI3K cancer pathway. Inavolisib, the drug that is being studied, is designed to block the wrong messaging from the mutated PIK3CA gene and, therefore, block the PI3K cancer pathway described above. Inavolisib is an experimental drug, which means health authorities have not approved inavolisib for the treatment of cancer. In this study, inavolisib will be tested with or without a drug called atezolizumab. Atezolizumab has been approved by health authorities for several cancers, but not for recurrent and/or metastatic HNSCC (cancer that has come back and/or spread to other organs).

The main aims of this study are:

• To evaluate the effects, good or bad, of inavolisib alone or inavolisib plus atezolizumab in participants with PIK3CA-mutated, recurrent, and/or metastatic HNSCC cancer
• To determine how safe and tolerable inavolisib is when given alone or in combination with atezolizumab in participants with PIK3CA-mutated, recurrent, and/or metastatic HNSCC cancer
• To assess the anti-tumor activity of inavolisib when given alone or in combination with atezolizumab in participants with PIK3CA-mutated, recurrent, and/or metastatic HNSCC cancer
• To determine how the body absorbs, distributes, and eliminates inavolisib when given alone or in combination with atezolizumab

Who can participate?

People aged at least 18 years with a confirmed diagnosis of recurrent and/or metastatic HNSCC that has been previously treated with systemic therapy.

What does the study involve?

The duration of participation in the study will depend on the participant's tolerance of and response to the treatment, this could range from 1 day to more than 24 months.

The study involves three parts:

• (Pre-)Screening (to see if the participants are eligible for the study): The participants will be asked to share a blood sample (about 1½ tablespoons) to determine whether it is positive for an eligible PIK3CA mutation. Some sites may initially test only for the presence of a PIK3CA mutation (pre-screening).
• Treatment Phase: The participants will receive study treatment in 21-day cycles (each 21-day period is called a “cycle”). The participants will have clinic visits twice a week for the first cycle, two clinic visits during cycles 2 and 3, and then once per cycle thereafter while the participants are receiving treatment. The clinic may contact the participants by telephone mid-cycle to check their condition. Clinic visits may last 1-5 hours.
• Follow-up (to check on the participant after treatment is finished): Following study treatment discontinuation, participants will be followed for safety for 30 days after final study treatment (30-day safety follow-up, including a 30-day follow-up visit), or until the start of another anti-cancer therapy, whichever occurs first. There will be additional hyperglycemia (high blood sugar) follow-up, if required, which will be monitored until resolution or for 90 days, whichever is sooner

Participants will be enrolled into two separate groups namely:

• Arm A: Participants in this group will receive inavolisib tablets, to be taken by mouth, once daily, on Days 1−21 of each cycle.
• Arm B: Participants in this group will receive inavolisib tablets, to be taken by mouth, once daily and atezolizumab given as an infusion (into the vein) once every 3 weeks (21 days).

The treatment will continue until the cancer worsens, the participants have medically unacceptable side effects, or if the participants decide to withdraw from the study.

What are the possible benefits and risks of participating?

Participants may not receive any direct medical benefit from participating in this study, but the information collected will help other people who have a similar medical condition in the future. Participants may have side effects from the drugs or procedures used in this study; these may range from mild to severe and even life-threatening, and they can vary from person to person. The side effects associated with inavolisib, based on human and laboratory studies or knowledge of similar drugs, are listed below. There may be side effects that are not known at this time.

Known side effects:

1. Hyperglycemia (increased blood sugar levels)

2. Diarrhea (loose stools)

3. Decreased appetite

4. Vomiting

5. Nausea

6. Decreased weight

7. Constipation

8. Flatulence (gas)

9. Rash

10. Mucosal inflammation/stomatitis (inflammation of the lining of the mouth or ulcers of the lip or mouth)

Potential side effects:

1. Eye disorder (eye pain or sensitivity to light, blurred vision, cataract which may cause cloudiness of the eye)

2. Colitis (inflammation [swelling and redness] of the large bowel [colon])

3. Possible harm to a developing fetus, including birth defects and/or miscarriage

4. Pneumonitis (inflammation of the lungs that may cause difficulty breathing and can be life-threatening)

5. Depressed immune function (low levels of white blood cells that may lead to increased risk of infections, low levels of platelets)

6. In males, reduced fertility or permanent sterility

Among the side effects known to be associated with atezolizumab, the following would require more attention:

1. Inflammation of the intestines (colitis), thyroid gland, adrenal glands, pituitary gland, liver, brain and surrounding membranes, lungs (pneumonitis), pancreas (pancreatitis), kidneys, blood vessels (vasculitis), muscles, eye, or heart muscle (myocarditis)

2. Nerve damage

3. Reactions associated with infusion (events occurring during or within 1 day of infusion); symptoms may include fever, chills, shortness of breath, and sudden reddening of the face, neck, or chest

4. Condition of high levels of sugar in the blood

5. Severe skin or mucosal reactions

6. Development of special antibodies to atezolizumab by the immune system

7. Potential to cause harm to a developing fetus

8. Breakdown of red blood cells (autoimmune hemolytic anemia)

9. Allergic reactions may occur with atezolizumab and typically occur while it is being given into the vein or shortly after it has been given. Symptoms could include nausea, vomiting, skin reactions (hives or rash), difficulty breathing, or low blood pressure. These reactions could be mild or severe and might lead to death or permanent disability.

10. In rare situations, an immune reaction can occur with administration of atezolizumab. This reaction can cause side effects related to severe inflammation and/or severe infection

There may be some risks associated with the procedures performed during the study:

1. The tumor tissue sample (biopsy) can cause pain, redness, swelling, excessive bleeding, bruising, or draining at the needle site. Abnormal wound healing, fever, infection, and allergic reaction to the medication used to numb the skin over the biopsy site can also occur

2. The screening test for PIK3CA mutations in a blood sample to establish eligibility for the study can rarely produce an incorrect test result. If the enrolment in the study is based on an incorrect test result (“false positive”), the participant may be less likely to respond to the study treatment

3. For blood samples, drawing blood can cause pain, bruising, or infection where the needle is inserted. The participants may experience dizziness, fainting, or upset stomach when their blood is drawn

4. Tumor assessments involving a computed tomography (CT) scan, a magnetic resonance imaging (MRI) scan, or a bone scan may have the following risks:

4.1. The participant may have an allergic reaction to a tracer or contrast agent

4.2. Oral and rectal contrast agents may cause nausea, constipation, diarrhea, and abdominal bloating

4.3. Injected contrast agents may cause nausea, headache, hives, temporary low blood pressure, chest pain, back pain, fever, weakness, and seizures. There may be pain, bruising, or infection at the injection site

4.4. CT and MRI scanners may cause some anxiety and claustrophobia (fear of being in small places)

4.5. Although there are no known long-term harmful effects from the radiation of a single scan, the risk of harmful effects from multiple scans over a period is not known

4.6. Reports indicate that deposits of gadolinium-based contrast agents may remain in the brain long after MRI scan completion in some participants undergoing four or more scans. The implications of this are unknown.

There may be a risk in exposing an unborn child to the study drug, and all risks are not known at this time. Women and men must take precautions to avoid exposing an unborn child to the study drug. Participants who are pregnant, become pregnant or are currently breastfeeding cannot take part in this study.