A trial of AZD6244 and dacarbazine for advanced melanoma in people with a BRAF gene fault

Please note this trial is no longer recruiting patients.

This trial is comparing a combination of AZD6244 and dacarbazine with dacarbazine alone for advanced melanoma in people whose melanoma cells have a change to a gene called BRAF.

The BRAF gene controls production of a protein which affects how cells divide and grow (cell division). In some people the BRAF gene is changed or damaged. This is called a gene mutation. About half of people who have melanoma have a BRAF gene mutation in their cancer cells.

The BRAF protein has an effect on a protein called ‘mitogen activated protein kinase’ MEK, which is another protein involved in cell division. If the BRAF gene is faulty, there will be faulty BRAF protein affecting MEK. This means the cancer cells keep dividing out of control and the cancer grows.

AZD6244 is a new drug that can stop MEK working. It is called a MEK inhibitor.

Doctors may treat advanced melanoma with chemotherapy. A drug they often use is called dacarbazine. In this trial, researchers are looking at adding AZD6244 to chemotherapy.

The aim of the trial is to see if AZD6244 and dacarbazine is better than dacarbazine alone for people who have advanced melanoma and whose melanoma cells have the BRAF gene mutation.

Recruitment

Start 04/08/2009

End 26/02/2010

Phase

Phase 2

Who can enter

You can enter this trial if you

Have advanced melanoma
Have at least one area of melanoma that has not been treated with radiotherapy and is at least 10mm in size, or a lymph node containing melanoma cells that is at least 15mm across and one of these can be seen on a scan
Have a BRAF gene mutation in your melanoma cells (the trial team will test for this by taking blood samples and by looking at a sample of your melanoma if one is available - if not you will need to have a biopsy)
Are well enough to take part in the trial (performance status 0 or 1)
Have satisfactory blood test results
Are at least 18 years old
Are willing to use reliable contraception if there is any chance you or your partner could become pregnant

You cannot enter this trial if you

Have melanoma that started in the eye or in the moist tissues lining the inside of the body, such as the mouth (mucosal melanoma)
Have melanoma that has spread to the brain or has caused spinal cord compression unless this was treated at least 3 months ago, has not caused any problems since then and you are no longer having treatment
Have already had chemotherapy for advanced melanoma – you can take part if you had chemotherapy after surgery to remove your melanoma when it was first diagnosed as long as you didn’t have temozolomide or dacarbazine
Have already had an experimental drug for advanced melanoma apart from interleukin 2, interferon, GM-CSF or a vaccine as long as you had any one of these treatments on its own
Have had any other type of treatment for advanced melanoma in the last month apart from radiotherapy to one area of the body to control symptoms
Have had major surgery in the last 4 weeks
Have already taken part in this study, have had an experimental drug as part of another clinical trial in the last month, or still have side effects from a previous trial
Have had any other type of cancer in the last 5 years apart from non melanoma skin cancer that has been successfully treated or carcinoma in situ of the cervix
Have not recovered from the side effects of any other cancer treatment unless they are mild, apart from hair loss
Have already had drugs that work in a similar way to AZD6244 (Ras, Raf or MEK inhibitors)
Are known to be sensitive to dacarbazine or AZD6244
Cannot swallow or absorb capsules for any reason
Have high blood pressure that cannot be controlled with medication or a heart condition that is cause for concern (the trial doctors can advise you about this)
Have any other serious medical condition
Are known to be hepatitis B, hepatitis C or HIV positive
Are pregnant or breastfeeding

Trial design

This is an international trial. It will recruit about 80 people. The trial is randomised. The people taking part will be put into one of 2 treatment groups by computer. Neither you nor your doctor will be able to decide which group you are in

People in group 1 have dacarbazine and AZD6244
People in group 2 have dacarbazine and a dummy drug (placebo)

You have dacarbazine through a drip into a vein once every 3 weeks. It takes about an hour each time. AZD6244 and the dummy drug are capsules. You take them each day, in the morning and the evening. You must swallow the capsules whole and you cannot eat or drink anything other than water for 2 hours before taking them and for 1 hour afterwards.

Each 3 week period is called a cycle of treatment. You have up to 8 cycles of treatment. But you may continue for longer if the treatment is helping you.

You will be asked to fill out a questionnaire before you start treatment, every 3 weeks during treatment and once more after you finish treatment. The questionnaire will ask about any side effects you have had and about how you have been feeling. This is called a quality of life study.

The trial team will ask your permission to take an extra blood sample. Researchers will study the DNA in your blood. This is to learn more about genetic differences in people with melanoma and how they affect the way people respond to treatment. If you do not want to give this sample for research, you don’t have to. You can still take part in the main study.

Hospital visits

You will see the doctors and have some tests before you start treatment. The tests include

Physical examination
Blood pressure, pulse, weight and height measurement
Blood tests
Pregnancy test (if you are a woman of childbearing age)
Heart trace (ECG)
Echocardiogram
CT scan or MRI scan
Eye examination

If you are having treatment at the Royal Marsden Hospital, you will also have urine tests before you start treatment and at some of your hospital visits during treatment.

On the first day of treatment, you have a blood test before you take the first dose of AZD6244 or placebo, and then between 3 and 6 more blood tests during the next 8 hours. You have ECGs before taking the capsules, and then 2 hours and 4 hours afterwards.

You go to hospital weekly during the first 6 weeks and then once every 3 weeks for as long as you have treatment as part of the trial. At each visit, you have blood tests.

On the day you go hospital in the third week of treatment, you must not take your capsules in the morning. You will take them at the hospital, and you have some extra blood tests and ECGs on that day.

During treatment you have

An ECG every 3 weeks
An echocardiogram after 6 weeks, 12 weeks and then every 3 months
An eye examination every 6 weeks
A CT or MRI scan every 3 months

When you finish treatment, you go back to see the trial doctors a month later. You may need to have more blood tests, an echocardiogram or an ECG.

If you stop treatment because your melanoma has grown, you will see the trial doctor or talk to them by phone every 2 months until the trial has completely finished.

If you stop treatment for any other reason, you will have a CT or MRI scan every 3 months until your melanoma starts to grow again. Then you will see or speak to the trial doctor every 2 months until the trial has completely finished.

Side effects

As AZD6244 is a new drug, there may be some side effects that we don’t know about yet. The possible side effects that researchers do know about include

Rash
Diarrhoea
Swelling of the face or other parts of the body (extremities)
Sickness
Shortness of breath
Increase in blood pressure
Blurred vision
Changes to results of tests that show how well your liver is working (liver function tests)

The side effects of dacarbazine include

Sickness
A drop in the number of blood cells, causing an increased risk of infection, bleeding or bruising problems, tiredness or shortness of breath
Loss of appetite
An allergic reaction to the injection
Diarrhoea
Hair loss
Changes to your liver
Sensitivity to sunlight
Flu like symptoms
Sore mouth and taste changes