Study goals and procedures: main study
The main aim of this study is to investigate whén CDK4/6 inhibitors (targeted anti-cancer drugs) can best be added to endocrine therapy. The drugs can be added in first line, which means they are added to the first endocrine treatment that a woman receives after she has been diagnosed with advanced breast cancer. CDK4/6 inhibitors can also be added to the so-called second line of treatment. This means that the drugs are added to the second type of endocrine therapy that a woman receives, after failure of previous endocrine therapy.
At this moment, we do not know which strategy (first or second line) is better for patients. We do not know if patients live longer if they receive CDK4/6 inhibitors earlier (i.e. in the first line). In spite of this lack of knowledge, doctors and patients have to choose when to use CDK4/6 inhibitors. This choice is determined by the efficacy (how long can the drug suppress the growth of breast cancer cells) and the disadvantages (side effects, quality of life, the amount of hospital visits).
Study procedures
A total of 1050 patients will be enrolled in this study. All participating patients will be assigned to either treatment group A or treatment group B by means of lottery (or: randomization). The lottery will be carried out by a computer; neither doctors nor patients can influence the outcome of the lottery. Patients assigned to treatment group A will receive a CDK4/6 inhibitor in first line, while patients in treatment group B will receive a CDK4/6 inhibitor in second line.
All medical procedures (i.e. hospital visits, blood checks) during this study are regarded as standard care, which means that no additional procedures are necessary for participation. Every three months, a scan will be performed to evaluate the current status of the disease.
For quality of life and cost-effectiveness analyses, two to three questionnaires are administered every three months of the study period.
Medication
The drugs of interest in this study are so-called CDK4/6 inhibitors. They block proteins that are needed for cell division. Cancer cells divide in a rapid pace, which leads to more and more cancer cells and tumor growth. By blocking proteins that are involved in cell division, CDK4/6 inhibitors can inhibit growth of cancer cells, which may result in stabilization or sometimes even regression of cancer lesions.
Palbociclib (trade name Ibrance®), ribociclib (trade name Kisqali®) and abemaciclib (trade name Verzenios®) are all registered for use in the Netherlands and they are reimbursed via the Dutch national health insurance. DOctors can prescribe either three of these drugs. Thousands of patients worldwide have been previously treated with CDK4/6 inhibitors in combination with endocrine therapy.
In the SONIA study, your doctor will decide with which CDK4/6 inhibitor you will be treated. When it comes to efficacy, the three drugs are highly comparable. The side effects however differ slightly. In general, palbociclib and ribociclib more often cause low white blood counts, whereas abemaciclib more often results in diarrhoea.
Treatment with palbociclib exists of one capsule every day, during three weeks, followed by one week of rest. Treatment with ribociclib follows the same scheme. Abemaciclib is used continuously, patients have to take one tablet twice daily.
Treatment with CDK4/6 inhibitors will be prolonged as longs as the treatment is effective in suppressing cancer cell growth and well tolerated by the patient.
CDK4/6 inhibitors are always combined with standard of care endocrine therapies. In this study, two types of endocrine therapies are used.
Non-steroidal aromatase inhibitors: these drugs inhibit the production of the female sex hormone, estrogen, and thereby inhibit growth of estrogen sensitive breast cancer cells. Two non-steroidal aromatase inhibitors are used in this study: letrozole (trade name Femara®) and anastrozole (trade name Arimidex®). Both are tablets, which have to be taken once daily. Their mechanism of action and side effects are comparable.
Fulvestrant (trade name Faslodex®): this is a so-called selective estrogen receptor degrader (SERD), which causes degradation of the estrogen receptor on breast cancer cells. The estrogen receptor is the part of the cancer cell responsible for estrogen uptake. Because fulvestrant destroys this receptor, no more estrogen is available to the cancer cells, which can lead to growth arrest of the cancer cells. Fulvestrant is administered through an intramuscular injection of which the first three are given with a two week interval (to reach the optimal blood concentration as quick as possible). After the third administration, the injections will be continued monthly.
Study goals and procedures: optional side studies
To answer other relevant questions on the use of CDK4/6-inhibitors, several side studies have been set up. These side studies are optional: patients who do not want to participate in these side studies, can still enroll in the main study.
Side study with extra blood tests
We know from previous studies that many women respond (very) well to endocrine therapy alone and that they derive a long benefit from this treatment. Some women, however, respond better to the combination treatment (endocrine therapy plus CDK4/6 inhibitor). At this point, we are unable to predict which patients have a good chance of responding to endocrine therapy alone or to the combination treatment. We therefore would like to investigate so-called biomarkers. Biomarkers are biological features of breast cancer that can help in understanding the behavior of a certain breast cancer and its susceptibility to anti-cancer treatments. The goal of this biomarkers investigation is to select patients upfront who will or will not benefit from a certain treatment strategy. This will help in preventing over- and undertreatment.
One of our other research goals is to investigate the drug concentration of CDK4/6 inhibitors in the blood and to investigate the effect of this concentration on the occurrence of side effects. Every patient starts with the same dose of CDK4/6 inhibitor, but the uptake and metabolism of the drug is different for each patient. We therefore want to investigate the optimal concentration of CDK4/6 inhibitors for individual patients and the effect of genetic alterations on this concentration.
For the above-mentioned side studies, additional blood samples are needed. Participants are asked to consent for additional blood samples at different time points throughout the course of the study.
Side study with extra imaging (SONImage)
In addition to biomarkers in tissue and blood, it is also possible to improve patient selection with medical imaging. A new type of nuclear scan, the so-called FES-PET-scan, can visualize tumor sensitivity to estrogen (the female sex hormone) in the entire body. Together with a regular FDG-PET-scan (a scan that visualizes glucose metabolism), this FES-PET shows promise in predicting the effect of CDk4/6inhibitors on metastases. It is not yet known whether or not this scan can also predict treatment effect in individual patients. Within SONImage, we want to investigate this further.
For this study, you will be asked to undergo one additional scan (a FES-PET-scan) before start of treatment. This scan can only take place in either the UMC Groningen or the Amsterdam UMC – location VUmc. If you are being treated in a different hospital, your doctor can refer you to one of these hospitals for participation.
Side study with cognitive tests(SONIA EffECT)
Previous research has shown that anti-cancer treatments can have an effect on cognitive functioning. Cognitive functioning is a broad term, that includes focus, memory and planning (amongst others). The endocrine therapy that is used in the first-line of the SONIA study, inhibits the production of estrogen (the female sex hormone) en thereby inhibits tumor growth. Estrogen, however, also plays an important role in brain functioning: estrogens are important in several areas of the brain that are important for cognitive functioning, they help areas of the brain to communicate with each other and they protect the brain against damaging factors. The effect of CDK4/6inhibitors on cognitive functioning is less known. Previous research in patients who suffered from different disease than breast cancer showed a beneficial effect, explained by an anti-inflammatory response in the brain. On the other hand, many patients suffer from fatigue as a side-effect of CDK4/6-inhibitors; fatigue is known to cause a decline in cognitive functioning.
Problems in cognitive functioning can have a significant impact on day-to-day functioning and quality of lige. We therefore want to investigate whether or not treatments used in SONIA have an effect on cognitive functioning. We also want to gain more insight in the occurrence of cognitive problems in women who have just been diagnosed with stage IV breast cancer.
For this study, you will be asked to participate in two online neuropsychological evaluations. One will take place at the beginning of the study, the other evaluation 9 months after study entry.
Information video
This video provides additional information on the SONIA study. Its goal, design and execution are explained to you by the three principle investigators. In addition, a representative of the Dutch Breast Cancer Society (BVN) and a participating patient will express their opinion on the study. Please note: the video is in Dutch.
Participate?
The SONIA study is open for inclusion in several hospitals in the Netherlands. You can discuss the information provided here with your treating physician. He or she will decide if you are eligible for participating in the study, depending on your personal and medical situation.
When you consider participation in the study, you will receive the official subject* information sheet. In this sheet, the study will be explained to you in detail once more.
All study participants will be randomly allocated to one of the two treatment groups. These two groups will then be compared to each other. Subjects will be randomly allocated to a group after they provide consent for participating in the trial; neither you nor your doctor can influence in which treatment group you end up. There are no placebos in the SONIA study, which means that all subjects and their treating physicians know with which drug a subject is being treated at any specific time point.
*When you enter a medical trial, you will be referred to as ‘subject’.
Dutch Breast Cancer Society (Borstkankervereniging Nederland (BVN))
The Dutch Breast Cancer Society (BVN) represents Dutch breast cancer patients and supports the SONIA study. BVN was involved in the study design and collaborates with the SONIA study team throughout the study.
Why does BVN support this study?
BVN feels it is important to investigate at which time point patients benefit the most from the addition of the new drugs. In this respect efficacy is obviously important, but quality of life and impact on a patient’s everyday life (able to carry out daily activities or work, etc.) are also very important parameters. Health care costs will also be taken into account.
On the BVN website, you can find more information on the study (in Dutch):
sonia-studie.nl 