Design on trial – immune-oncology challenges

There has been a boom in immune-oncology treatment research over the last five years. It’s a field that not only offers researchers and clinical trial designers significant challenges, but could also lead to greater rewards.

“Various things about immune treatments make them different to small-molecule therapeutics,” explains Peter Johnson of the University of Southampton’s Clinical Trials Unit and chief clinician at Cancer Research UK. Johnson is a medical oncologist specialising in the treatment of lymphoma. His main research interest is in immunotherapy, which is using the body’s own immune system to fight cancer.

His extensive experience leading lymphoma clinical trials encompasses everything from large international studies involving hundreds of patients from around the world, to first-in-man trials of new antibody treatments developed by labs in Southampton and elsewhere.

“Firstly, the mechanistic uncertainty that surrounds immunotherapies means we don’t have reliable biomarkers for selecting patients,” he says.

“This makes it hard to pinpoint the patients most likely to benefit from immune-oncology treatments, but current research suggests only a minority of patients may be suitable. The approvals so far have been for quite broad population patients with particular tumour types.

“Sometimes approvals have been contingent on expression of the relevant antigen – for example, whether it’s PD1 or PD-L1, but that’s not always the case.”

The other great unknown is toxicity, a significant barrier that has resulted in some trials being paused. “As immune-oncology treatments are becoming more potent, we are growing more aware of the need to recognise their increasing toxicity,” notes Johnson.

This links back to the need for improved mechanistic understanding and accurate patient selection. “The field is expanding more rapidly than our mechanistic understanding,” Johnson explains, “and we are often having to play catch-up as the clinical trials are developed and this makes it more complex.”

The professor advocates a cautious approach to trial design in order to facilitate more detailed studies of biomarkers.

“I understand the commercial imperative to move towards an approval as quickly as possible,” he says. “However, I think there is room for detailed mechanistic work to understand the characteristics of the tumour and the features of the immune system, while at the same time making sure that as many people as possible benefit in the shortest possible time.”

Johnson also states that investment in clinical evaluation leads to positive gains in terms of more successful treatments and better patient outcomes.

“We’ve so often seen clinical trials of small molecule therapies end up with results that we don’t understand,” he explains. “It’s extremely disappointing when a very complex field like immune-oncology follows the same pattern and gets rushed to large-scale clinical testing that ignores mechanistic understanding.”

Very large-scale trials are often not compatible with immune-oncology research Johnson adds. “It depends on the question that’s being asked, but large-scale international studies tend to have fairly simplistic clinical readouts. Trials that are going to tell us how these drugs are really going to work are probably going to be conducted in only one or two countries, where they can do the tissue handling and the complex analysis that’s required to a high level.

“For example, with immunotherapies there’s a need for detailed analysis on fresh tumour biopsies to fully understand at a monocular level what the effects of a treatment are, and this is much more difficult with large-scale studies. You inevitably need a small number of laboratories for this kind of complex testing, and shipping samples over large distances is logistically very complex.”

The challenges of trial design

Johnson describes trial design as “absolutely crucial” to the success of the research. “I think it is very important that trials in immune-oncology are designed to tell us about the mechanisms, what’s actually happening, and how best to select patients,” he adds.

“One of my big concerns in this field is that we don’t derive enough understanding about how the treatments are working in the trials that we conduct. It’s important to make sure that, even if the clinical experiment fails, the read-outs still provide enough useful information to help design and improve trials in the future.”

Facilities and trial infrastructure

There is now increasing collaboration within immune-oncology. “One of the exciting developments in immune-oncology over the last few years has been the increasing willingness of pharmas to partner for clinical trials with academic researchers who have a detailed understanding of the immune network and how it’s controlled. These companies want to make sure they’re doing better experiments.

“For example, Cancer Research UK’s centre for trial development has a rapidly expanding portfolio of studies that are being undertaken with commercial partners.

“Unfortunately, that’s still not universally the case but the industry increasingly recognises that academic insight into mechanisms can help achieve better trial design.”

The UK has a well-developed network of experimental cancer medicine centres offering the facilities and infrastructure to facilitate immune-oncology research and trials that meet international regulatory standards.

“The UK is an excellent environment for this kind of research, which is why we’ve seen such an expansion in recent years,” observes Johnson.

Engagement and trial protocols

The professionalisation of clinical research over the last 20 years has also been positive.

“It’s important that clinical trials are conducted to the highest integrity,” states Johnson. “We need to make sure that, when we conduct our trials, we ensure that participants are engaged in something meaningful.”

In immune-oncology – as with cancer research generally in the UK – patient supply is good in terms of clinical research recruitment. “Around 20% of people in the UK who get cancer will take part in a clinical trial and that’s an outstanding figure when you compare it with global statistics or to the number in the US, which is under 3%,” reveals Johnson. “However, patient selection when you’re designing a trial is vital. It is also crucial to consider how strictly the inclusion and exclusion criteria are drawn. Many trials fail because those criteria are badly drawn without a proper appreciation of the population of patients for whom the trial might be suitable.”

The key to developing an effective trial design is to ensure protocols are effective from a clinical perspective but also flexible enough to minimise disruptions for the patient. Trials need to be designed sensibly to avoid compliance issues trumping patient preferences.

“There are some aspects of the ways in which clinical trials are organised –particularly some regulatory compliance issues – that make it much more complicated for patients than it needs to be,” reckons Johnson, noting that it would help if trials allowed patients to fulfil more of their trial obligations closer to home. “For example, there is an inevitable requirement for regular blood tests or biochemical tests.

“These are absolutely standard and could be done at any hospital. However, because they’re part of a clinical trial, the patient is asked to travel to the site where the trial is being conducted.

“This is not always a precondition from the regulatory authority – it’s often trial sponsors, or designers, being over-cautious about compliance. If the sponsors of the trial haven’t confirmed that a particular laboratory is fully compliant with their standards, they worry the data will be non-admissible.

“This is an issue for discussion between the regulators and the people who design the trial protocols. Trial designers need to try to push back against unnecessary regulatory issues that burden the patient without improving the quality of the research.”

The future of trial design

Johnson argues future clinical trial design should make better use of new technology. “I think we can be much cleverer about how we collect information. We live in an age in which the great majority of patients who take part in clinical trials have some form of mobile communication device – yet, in most cases, we still rely on them coming into clinics. They sit down, talk about how they’re feeling and what their side effects have been like and we transcribe it into a database.

“I would much prefer to run a trial in which my patients were touching in remotely via a mobile device so I can check their daily reports and adverse events remotely. I’d feel much more confident about that than waiting for them to ring up a research helpline out of hours when they’ve got a serious problem. I think there’s a lot more we can do with technology in this way.”

Johnson concludes that while smart technology requires investment to guarantee safety and accuracy, he believes its use would ultimately deliver cost and time savings. “We really do need to modernise the way we run trials in this regard.”