Image: A high magnification image of ovarian clear cell carcinoma. Credit: Michael Bonert, CC BY-SA 3.0
At The Institute of Cancer Research we are passionate about working from lab bench to hospital bedside to make the discoveries that defeat cancer – we recognise the importance of fundamental laboratory research, which paves the way for further translational and clinical research.
An innovative new clinical trial, called ATARI, is an important example of discoveries in a lab leading to research that could soon benefit patients.
ATARI is a phase II international clinical trial looking at the effect of a new type of drug, called an ATR inhibitor, on a subset of rare gynaecological cancers. The trial is led by the ICR and The Royal Marsden, and managed by the ICR’s Clinical Trials and Statistics Unit (ICR-CTSU).
Studying which genes control response to a treatment
Professor Chris Lord led the lab research behind the ATARI trial. Chris and colleagues in the CRUK Gene Function Laboratory and the Breast Cancer Now Toby Robins Research Centre were investigating which genes control the response to ATR inhibitors. They identified a gene known as ARID1A, which, when reduced in cells in the lab, resulted in the cells displaying a “profound sensitivity” to ATR inhibitors.
Mutations in the ARID1A gene are commonly found in ovarian clear cell carcinoma (OCCC). OCCC is a rare type of ovarian cancer, which can be particularly aggressive, and has a poorer prognosis than other types. Over 50% of patients with this type of gynae cancer have a mutation in their ARID1A gene, which causes the gene to cease to function as it normally would.
Chris said: “At present, ovarian clear cell carcinoma is hard to treat, and doesn’t respond well to platinum salts or PARP inhibitors, which we would use to treat other types of ovarian cancer. So it’s encouraging to discover that OCCC is sensitive to ATR inhibitors and we are optimistic about the results of this trial.”
Working with industry to advance research
Chris’s team approached the pharmaceutical company AstraZeneca, which was developing ATR inhibitors and was about to take the first one into trials. AstraZeneca saw the potential in the results of Chris and team’s research, and agreed to collaborate: thus, the design of the ATARI trial emerged.
Chris added: “Earlier this year, a team at the ICR published results of a phase I trial of an ATR inhibitor, where one patient with advanced bowel cancer responded remarkably well to the treatment, staying cancer free for more than two years.
“Though he had a different type of cancer, we know that this patient also had an ARID1A mutation, which is commonly found in patients with OCCC, so it will be really interesting to see if similar results occur in the ATARI trial”.
Opening the ATARI trial
The trial opened in November last year at The Royal Marsden, and a further centre at The Christie NHS Foundation Trust in Manchester opened in July 2020. Eventually there will be six UK centres, as well as centres in France and Canada.
The trial is funded by AstraZeneca and the Lady Garden Foundation, and is endorsed by Cancer Research UK. ATARI is a National Cancer Research Institute (NCRI)-led academic collaboration with the European Society of Gynaecological Oncology Trial Groups (ENGOT) and The Gynaecological Cancer InterGroup (GCIG).
The trial’s Chief Investigator is Dr Susana Banerjee, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and Reader in Women’s Cancers at the ICR. The ICR-CTSU Scientific Lead is Professor Judith Bliss, who is also the Director of the Cancer Research UK-funded ICR-CTSU.
The trial will test an ATR inhibitor known as ceralasertib, on its own and in combination with olaparib – a PARP inhibitor, which also has a close connection to the ICR, and Chris in particular.
A world-first trial directing treatment based on ARID1A mutation status
Susana explained the significance of ATARI: “This is a proof of concept trial, and the first time treatment has been directed based on a person’s cancer ARID1A mutation status. Ovarian clear cell carcinoma is a rare form of gynaecological cancer with a particularly poor prognosis, and existing treatments such as chemotherapy are not effective enough for patients with this rare cancer.”
In the first stage of this trial, thirty patients with gynaecological cancers which have come back after previous treatment will be split into three groups, based on the type of cancer they have, and whether or not their cancer has loss of ARID1A.
The first group, ten patients with OCCC or endometrial clear cell cancer who have ARID1A loss, will be treated with ceralasertib, the ATR inhibitor, on its own.
The second group of ten patients with OCCC or endometrial clear cell cancer, who do not have ARID1A loss, will be treated with ceralasertib in combination with olaparib. The third group will be patients with other types of gynaecological cancer, and will be treated with both drugs in combination.
Susana added: “The third cohort of patients include people with other rare forms of gynaecological cancer – this group is important because it provides an option for patients with rare cancers to access new experimental therapies in a trial, an opportunity which they may not otherwise have had.”
Drawing on the expertise of the ICR-CTSU team
International phase II trials, such as ATARI, are a particular area of interest and expertise within the ICR-CTSU, the ICR’s research-led, academic clinical trials unit.
ICR-CTSU have been involved in the design and conduct of a number of similar, international phase II trials including the successful CASPS study, which determined response to treatment in a small patient population with a rare form of sarcoma.
ATARI is what is known as a biomarker-driven trial, meaning that patients are selected based on whether they have a particular characteristic – ARID1A expression status in this case. Selecting patients in this way allows for smaller numbers of patients to determine whether or not a response to treatment occurs.
This is an important aspect to consider during the development of a trial, when assessing rare patient populations such as those within ATARI.
The two-stage design of ATARI allows the recruitment process to be adapted depending on responses observed in the initial stage of the trial, with only those groups of patients demonstrating a sufficient response to treatment proceeding to an expanded second stage.
This design maximises the clinical relevance of trial outcomes, highlighting the patient population most likely to receive benefit from treatment, whilst minimising the number of patients required.
As this is a rare patient population, international involvement is of critical importance, not only to maximise recruitment but also to contribute to international efforts to develop targeted treatment options for people with these rare cancers.
The team at ICR-CTSU, building on their considerable experience in the conduct of international clinical trials, are establishing collaborations with GINECO (France) and the Princess Margaret Cancer Centre Consortium (Canada) to facilitate collaborative partnerships between UK academics and international clinical leaders in the field.
The potential of the ATARI trial
Susana explained that what happens next will depend on how the first stage of the trial plays out.
“Once the first stage is complete, the data will be reviewed independently. If clinical activity is seen in the initial group of patients, we will expand the trial to recruit a further group, and the next stage will commence.
“If the ATARI trial is a success, ceralasertib will hopefully undergo further trials in this setting, and there is potential for this to change the standard of care for women with rare gynaecological cancers.”
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