{"id":28805,"date":"2023-04-25T08:00:22","date_gmt":"2023-04-25T08:00:22","guid":{"rendered":"https:\/\/news.cancerresearchuk.org\/?p=25598"},"modified":"2024-11-03T15:12:47","modified_gmt":"2024-11-03T15:12:47","slug":"focus4-learning-from-a-landmark-clinical-trial","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/focus4-learning-from-a-landmark-clinical-trial\/","title":{"rendered":"FOCUS4: Learning from a landmark clinical trial"},"content":{"rendered":"
\"BowelBowel cancer cells under the microscope<\/p>\n

” data-medium-file=”https:\/\/news.cancerresearchuk.org\/wp-content\/uploads\/2023\/04\/FOCUS4-hero-300×168.jpg” data-large-file=”https:\/\/news.cancerresearchuk.org\/wp-content\/uploads\/2023\/04\/FOCUS4-hero.jpg”><\/p>\n

Bowel cancer cells under the microscope<\/p>\n<\/div>\n

After a new treatment has been developed in the lab, it has to be rigorously tested in a clinical trial before it can be used widely in patients.<\/span> <\/span><\/p>\n

Through a clinical trial, researchers can test whether a new treatment is safe, has any side effects, is better than existing treatments, or affects quality of life.<\/span> <\/span><\/p>\n

Just like with every area of cancer research, researchers are constantly working to improve clinical trials, implementing new, ambitious trial designs to make them as effective and efficient as possible.<\/span> <\/span><\/p>\n

And when a trial comes to an end, it presents an opportunity to reflect on its successes and areas for improvement.<\/span> <\/span><\/p>\n

FOCUS4<\/span><\/a> was a large-scale, multi-arm multi-stage, randomised trial investigating a range of new treatments in people newly diagnosed with advanced or metastatic colorectal cancer. <\/span> <\/span><\/p>\n

Funded by us and the Efficacy and Mechanism Evaluation Programme, a partnership between the Medical Research Council (MRC) and the National Institute for Health and Care Research, the trial ran for almost 7 years, starting to recruit participants in January 2014 and closing in October 2020.<\/span> <\/span><\/p>\n

One of the first clinical trials of its kind, FOCUS4 was what\u2019s called a stratified, adaptive trial. It was both a trial of treatments for colorectal cancer, and a trial of its own methodology, one that hadn\u2019t been done in colorectal cancer before, or any solid tumours for that matter.<\/span> <\/span><\/p>\n

Though stratified trials are becoming more common, back in 2011 when FOCUS4 was conceived by the <\/span>NCRI Colorectal Group<\/span><\/a>, they were still relatively novel, particularly on the scale FOCUS4 was aiming for.<\/span> <\/span><\/p>\n

But before we dive into the specifics of FOCUS4, let\u2019s answer a question you might have on your mind. <\/span> <\/span><\/p>\n

What\u2019s a stratified trial?<\/h2>\n

Luckily, it\u2019s not quite as complicated as it might sound. So, let\u2019s break it down.<\/span> <\/span><\/p>\n

Cancers are caused by mutations, small changes to our DNA that accumulate over time and can result in uncontrolled replication of cells \u2013 the growth of a tumour. Some mutations that cause cancers to begin are random, and a cancer may start growing simply because a cell has acquired one too many for it to function normally.<\/span> <\/span><\/p>\n

However, mutations in some genes are associated with an increased likelihood of developing particular types of cancer. For example, a mutation in a gene called <\/span>EGFR<\/span><\/i> that causes it to make too much of a particular protein, also called EGFR, is associated with lung<\/span> cancers.<\/span> <\/span><\/p>\n

But because we know about these relationships, we have specific drugs that target these mutations, often counteracting the effect that the mutation has on a cell. To continue the previous example, drugs like <\/span>erlotinib<\/span><\/a> and <\/span>gefitinib<\/span><\/a> both inhibit the activity of the EGFR protein, which slows down cancer growth.<\/span> <\/span><\/p>\n

That means if we can analyse a sample of a person\u2019s tumour and identify what mutations appear in its DNA, we can try to match these people with a drug that might be more effective in treating it.<\/span> <\/span><\/p>\n

Therefore, if a new drug is developed that targets cancers with certain mutations, we can analyse the tumour of patients to make sure they have that mutation before they\u2019re accepted onto the trial to test it.<\/span> <\/span><\/p>\n

And we can do this for multiple drugs within the same trial, matching patients with different mutations to different drugs that need testing in separate trial arms that run concurrently.<\/span> <\/span><\/p>\n

In short, running a stratified trial is like running multiple smaller trials at once, all under the header of one big trial.<\/span> <\/span><\/p>\n

What about adaptive?<\/h2>\n

The adaptive part means that trial arms can be opened or closed reactively throughout the course of the trial. <\/span> <\/span><\/p>\n

For example, if a trial runs three groups each testing a different drug on a different mutation, but midway through the trial it\u2019s obvious that one of these drugs is having no effect, that arm of the trial can be closed early, and patients can be reassigned to a different trial arm if appropriate.<\/span> <\/span><\/p>\n

On the flipside, if while the trial is running a fourth drug is developed that needs testing, a new arm can be opened to allow for that to happen in parallel with the others. Similarly, if new science suggests another type of mutation might be responsive to a drug already being tested, the trial can broaden the eligibility criteria to include the new mutation.<\/span> <\/span><\/p>\n

Making the trial design adaptive means we can make sure time and resources are being used more effectively. By closing a trial arm that might not be working, we can free up space for the testing of another drug should it come along.<\/span> <\/span><\/p>\n

And if that weren\u2019t enough, FOCUS4 also used what\u2019s called a seamless design in relation to the <\/span>phase of the clinical trial<\/span><\/a>. <\/span> <\/span><\/p>\n

Usually, new treatments would go through several clinical trials sequentially, from phase 1, which broadly tests a drug\u2019s safety and works out the correct dosage, through phase 2 to see if the drug demonstrates promise in a small, tightly controlled trial, to phase 3, testing its efficacy against the current standard of care.<\/span> <\/span><\/p>\n

In FOCUS4, the trial was designed to move seamlessly from phase 2 into phase 3 if a drug was showing early promise of benefit, continuing recruitment into phase 3 while retaining the patients already enrolled. <\/span> <\/span><\/p>\n

Seamless design trials are more efficient, avoiding the time and costs involved in setting up multiple back-to-back trials. <\/span> <\/span><\/p>\n

So, those are the basic principles of the trial design. Let\u2019s get into what FOCUS4 did. <\/span> <\/span><\/p>\n

The procedure<\/h2>\n

\u201cPatients who are stable and responding to their first line chemotherapy in the UK would typically be considered for a treatment break,\u201d says Professor Louise Brown, who was project lead of FOCUS4. <\/span> <\/span><\/p>\n

\u201cPrevious work we\u2019ve done has demonstrated that it\u2019s safe, in terms of overall survival, to give people a break, and just monitor their tumour so that if it shows signs of coming back, you can immediately restart that first line chemotherapy. <\/span> <\/span><\/p>\n

\u201cBut that also opened up an opportunity for us to say, \u2018in that treatment break, let\u2019s see if we can test new drugs.\u2019\u201d<\/span> <\/span><\/p>\n

To do that, FOCUS4 ran three stratified trial arms, called B, C and D, each testing one drug in patients with certain mutations after the standard 16 weeks of chemotherapy when patients would be starting a treatment break. <\/span> <\/span><\/p>\n

They were measuring what\u2019s called progression-free survival (PFS), meaning how long a patient lives before their cancer gets bigger.<\/span> <\/span><\/p>\n