A study looking at olaparib, AZD6738 and AZD1775 for triple negative breast cancer (VIOLETTE)

Cancer type:

Breast cancer

Status:

Open

Phase:

Phase 2

This study is comparing olaparib on its own and in combination with AZD6738 for triple negative breast cancer that has spread.

To take part in the study, the team want to know if your cancer has changes (mutations Open a glossary item ) in the genes of the HRR (Human Recombination Repair) proteins. For this test, they use a piece of tissue that was taken when you were first diagnosed with breast cancer. Or a piece of tissue that was collected later from a part of the body to which the cancer had spread.

This study was also looking at AZD1775 in combination with olaparib. But this combination is no longer been used.

More about this trial

All cells need to repair DNA Open a glossary item

to survive and grow. The HRR proteins are found in cells and help repair damaged DNA.

Olaparib and AZD6738 can affect how well the HRR proteins work. They work on the HRR proteins and can kill cancer cells.

Cancer cells aren’t as good as normal cells at repairing DNA. So researchers think these drugs could help people with triple negative breast cancer.

In this study the team want to compare:

olaparib
olaparib and AZD6738

The researchers want to find which treatment works best for triple negative breast cancer and what the side effects are.

They were also looking at olaparib and AZD1775. The panel monitoring the safety of people in the study recommended to stop using AZD1775. This was due to the side effects.

Who can enter

The following bullet points list the entry conditions for this study. Talk to your doctor or the study team if you are unsure about any of these. They will be able to advise you.

There are 2 parts to this study.

For part 1 of the study you can join if you:

have triple negative breast cancer
are willing to have a sample of your cancer tissue tested for changes in the HRR protein

For part 2 of the study you may be able to join if all of the following apply. You:

have triple negative breast cancer that has spread to another part the body (metastatic) or has spread into the surrounding tissue and can't be cured
have had at least 1 and no more than 2 chemotherapy treatments that included an anthracycline drug, such as doxorubicin or epirubicin, and, or a taxane drug, such as paclitaxel or docetaxel, since the cancer has spread
have at least 1 area of cancer that can be measured on a scan
have satisfactory blood test results
are able to do everything apart from heavy physical work (performance status 0 or 1)
are able to swallow tablets or capsules
are willing to use 2 reliable types of contraception during treatment and for at least 6 months after if there is any possibility you or your partner could become pregnant
are at least 18 years old.

You cannot join this study if any of the following apply.

Cancer related

You:

have breast cancer that has HER2 proteins (is HER2 positive)
have breast cancer that has receptors for the hormones oestrogen (ER positive) or progesterone (PgR positive)
have cancer that has spread to the brain or spinal cord unless it has been treated with radiotherapy at least 3 weeks before starting treatment in this study and you have no severe side effects. If you are taking steroids it must be a low dose (less than 10mg a day) and have started at least a month ago
have cancer that is pressing against your spinal cord (spinal cord compression ) unless it has been successfully treated and there has been no sign of it for at least 28 days
have had chemotherapy, hormone therapy or a targeted cancer therapy within 3 weeks of starting treatment in this study
have already had treatment with olaparib or similar drug (a PARP inhibitor) unless it was for less than 3 weeks and was finished at least a year ago
have another cancer apart from non melanoma skin cancer , successfully treated carcinoma in situ of the cervix, DCIS , early endometrial cancer or any other solid tumour that was successfully treated and there has been no sign of the cancer for at least 5 years, including lymphoma that didn’t affect the bone marrow
have had a targeted cancer drug as part of a clinical trial in the past 30 days, for an immunotherapy it is 42 days

Medical conditions

You cannot join if any of the following apply. You:

have had heart problems such as congestive heart failure, heart attack or angina that isn’t controlled by medication in the past 6 months or your heart isn’t working well enough
are taking medication or any other substances that affect the CYP enzymes unless they can be stopped before starting treatment
have had major surgery within 2 weeks of starting treatment or you haven’t recovered for previous surgery
still have moderate to severe side effects from any previous cancer treatment apart from hair loss and nerve damage (peripheral neuropathy)
have HIV
have hepatitis B or hepatitis C
have a problem with your digestive system that can affect how well you absorb tablets or capsules

Other

You cannot join if any of the following apply. You:

are allergic to the drugs, or any of their ingredients, used in this study
are pregnant or breastfeeding

Trial design

This is an international phase 2 study.

There are 2 parts to this study.

Part 1

In this part the team test a piece of cancer tissue from when you were diagnosed. This is to find out if your cancer has certain changes in the HRR genes.

Your doctor will tell you the results of the test when they are available. You then can decide to join Part 2.

However, if there are already enough people with your type of change in the HRR gene already taking part it will not be possible for you to go on to Part 2. And your doctor will talk to you about other treatments you might have.

Part 2

In this part the study is open to people with and without the changes in the HRR genes.

You have more tests such as blood tests and scans to find if you are suitable to continue in this part of the study.

If you aren’t suitable, your doctor will tell you about other treatments you might have.

The team might also ask if you are willing to donate any tissue left over from the testing for further research. You don’t have to agree to this.

If you are suitable to continue in the study, you are put into 1 of 3 treatment groups. Neither you nor your doctor can choose which group you are in. This is a randomised study.

The team need about 350 people to join the study. The groups are:

olaparib
olaparib and AZD6738
olaparib and AZD1775 - closed

VIOLETTE trial randomisation diagram

You have treatment in cycles.

Olaparib only
Every 4 weeks is a cycle of treatment. Olaparib tablets are taken twice a day every day.

You can take them with food (a light meal) or without food. You have to take them 12 hours apart.

15540-olaparib-only.png

AZD6738 and olaparib
Every 4 weeks is a cycle of treatment.

AZD6738 are tablets you take once a day.

You take them for the 1st week (7 days) of each 4 week cycle. You must not eat or drink anything, apart from water, for at least 2 hours before taking the tablets and for at least an hour after.

You also take olaparib tablets twice a day every day.

15540-azd6738-and-olaparib.png

AZD1775 and olaparib
The panel monitoring the safety of people in the study recommended to stop using AZD1775. This was due to the side effects. So people are no longer being put into this group.

Everyone in this group could continue having orlaparib only.

Quality of life

You fill in a questionnaire:

before starting treatment
then every 8 weeks while having treatment

The questions ask about your general health and any side effects you might have. This is a quality of life study.

Tissue and blood samples

The team will ask for a piece of cancer tissue taken from when you were first diagnosed. This is to test for certain changes (mutations) in the HRR gene.

They will ask your permission to store any cancer tissue not used for testing. This might be used for future research. You don’t have to agree to do this.

The team will also take some blood samples before and during treatment. They will use these samples to see what happens to the drugs in your body and how these drugs affect your body.

They will also look for substances (biomarkers Open a glossary item

) in your blood that might show how well the treatment is working.

The team will also ask your permission to take a blood sample either:

when you have tests to see if you can join the 2nd part of the study

after you are put into your treatment group for the 2nd part of the study

They will store this sample and may use it to look for certain genes and changes in genes (mutations). You don’t have to agree to this sample being taken if you don’t want to.

Hospital visits

You see the doctor and have tests before taking part. These tests include:

physical examination
blood tests
urine test
heart trace (ECG )
CT scan or MRI scan

You see the doctor 3 times during your first cycle of treatment. If you are taking AZD6738 you have a heart trace done at each visit.

During treatment you see the doctor every 4 weeks. You have a CT scan or MRI scan every 8 weeks.

You see the doctor at the end of treatment and a month later for some of the same tests you had at the start. You then see them every 8 weeks to see how you are.

Side effects

Your doctor and nurse will monitor you closely for any side effects. Let your doctor or nurse know as soon as possible if:

you have severe side effects
your side effects aren’t getting any better
your side effects are getting worse

Early treatment can help manage side effects better.

The most common side effects of AZD1775 include:

a drop in blood cells causing an increased risk of bruising, bleeding and getting an infection
reduced appetite
diarrhoea
feeling or being sick
problems with digestion

You might not have enough fluid in your body (dehydration) or less salts in the blood which doesn’t usually cause any symptoms. But they can sometimes cause:

tiredness
muscle weakness
cramping
irregular heart beats
fits (seizures)

AZD6738 is a new drug and there may be side effects we don’t know about yet. Let your doctor or nurse know as soon as possible if you notice anything that has changed while having AZD6738.

The most common side effect that have been reported so far is a drop in blood cells causing an increased risk of bruising, bleeding and an increased risk of infection.

Other possible side effects might include: