A blueprint for faster, fairer drug development in rare childhood cancers

Article by Adam Green, freelance journalist

The challenge of rare diseases

Childhood cancers are, in most cases, now curable thanks to breakthroughs in paediatric medicine. Behind the headlines, complex machinery and logistics are required to generate the evidence to support new treatments. The limiting factor is not scientific imagination, or generating hypotheses, but the practical challenge of generating credible, robust evidence. This is particularly the case where there are small numbers of people with a condition, who may live in different countries with very different healthcare service infrastructure. This data needs to be generated and aggregated to make it meaningful enough to translate to clinical practice.

The University of Birmingham is tackling this challenge through Glo-BNHL, an international platform trial for children and adolescents with relapsed or refractory B-cell non-Hodgkin lymphoma. Amos Burke, Professor of Paediatric Oncology at the University of Birmingham and an Honorary Consultant Paediatric Oncologist at Birmingham Women’s and Children’s Hospital, directs the Cancer Research UK Clinical Trials Unit (CRCTU) and is Chief Investigator of the Glo-BNHL project. He explains that their work is an example of what research excellence looks like: not only addressing a clinical conundrum but building capability to deliver complex trials that regulators and industry can act on.

A cure for all children

Survival rates for children newly diagnosed with mature B-cell non-Hodgkin lymphoma (NHL) now exceed 90%. However, for those whose disease comes back or fails to respond, outcomes are much worse, with fewer than 30% surviving.

Clinical research in adult lymphoma has produced a growing pipeline of novel therapies, including immune-based approaches, but these do not automatically translate to paediatric settings. Regulators and research sponsors normally require a formal, agreed plan for how the drug will be developed and studied in children, which may include specification of the trials that need to be conducted. This will include the age range of participants, the doses of drug, the specific safety monitoring and the outcomes to be evaluated. Until that plan is in place, the existing data can’t simply be “re-used” to justify approval for use in children.

Conducting trials for treatments of rare cancers is further limited by small populations. In the case of refractory B-Cell NHL in children, Professor Burke explains that between Europe and the whole of America, there are only around 50-70 children per year with refractory B-Cell NHL who would realistically be recruited to a trial. The challenge is how to translate therapeutic cancer treatments that have been tested in adult populations to children with the same disease, in a way that is feasible globally and economically viable for the companies that produce treatments.

Working with the regulators

Regulatory frameworks are finally evolving to accelerate translation. “The biggest challenge is that this type of cancer is very rare, which makes it hard to run traditional clinical trials. Because there are so few patients, researchers need to use flexible and innovative trial designs to generate robust evidence to support these new therapies,” said a spokesperson for the European Medical Agency (EMA).

In Europe, paediatric medicines development sits within a dedicated regulatory framework. In the US, legislation such as the Pediatric Research Equity Act shapes expectations of paediatric research. For companies, this means that there are obligations and incentives to work with research partners to develop treatments for paediatric cancers. For Universities, this means an opportunity to provide evidence in a form that can be readily translated by industry partners to produce and distribute medicines at scale.

Glo-BNHL uses a platform design with one overarching infrastructure that can test several treatments in the same rare disease population. This is something like the difference between building a pop-up shop and building a marketplace.

Traditional clinical trials are like pop-up stalls. They are set up for one product, run for a set period, and then at the study’s completion the infrastructure winds down and the next trial begins from scratch. A platform trial is more like a marketplace. Once the governance, approvals, data systems, and international network are established, different treatment “stalls” can open, close, and be replaced without rebuilding the whole structure each time.

This matters when eligible patient numbers are extremely small, as in the case of B-cell NHL. Using a platform means that duplication can be reduced, and the set-up time for each therapy is shortened. This makes it more realistic for industry partners to test candidate drugs in children without reinventing the wheel for each program.

“Platform trials can be very helpful for developing new medicines for children, especially in cancer,” said an EMA spokesperson. “These academic-led platform trials provide a smart, efficient, and flexible way to test treatments. That’s why EMA is actively involved in international initiatives focused on improving and expanding platform trials for paediatric oncology research.”

For the Glo-BNHL platform, the initial categories of treatment are bispecific antibodies, antibody-drug conjugates with chemotherapy, and CAR-T cells. Each tackle B-cell NHL in different ways. Bispecific antibodies are engineered proteins that act as a molecular bridge to attach lymphoma cells to immune cells, so that the immune system can destroy the malignant cells. Antibody-drug conjugates are more like guided missiles, where the antibody has a potent drug attached to it. It seeks out lymphoma cells and the attached drug is taken into the lymphoma cell, causing damage from within. CAR-T cells are a more individualised approach, whereby T-cells from the child’s blood are reprogrammed to recognise a specific marker on the lymphoma cell and reintroduced. Other categories of treatment will be added if they prove promising in adult studies. On the trial, children can move from one treatment to another if it doesn’t work or is unsuitable. This flexibility can help children reach ‘consolidation therapy’, the phase intended to lock in a remission and reduce the likelihood of the lymphoma recurring.

The trial design has another strategically important feature. It uses Bayesian statistical methods, which are particularly valuable when patient numbers are small. Bayesian reasoning is used widely to make predictions without waiting for huge numbers to accumulate. This is the approach taken in weather forecasting, for example. This allows evidence to be updated iteratively, so as time goes on, the data supports earlier decisions about whether a treatment looks promising or should be stopped. This is scientifically important, but also has an ethical context. If treatments under investigation are not working, or have burdensome side effects, the analysis reduces the number of children exposed to therapies that are unlikely to help.

“Fit for filing” regulatory-grade evidence

Another strand of the project’s strategic appeal is its ambition to be “fit for filing”. Many academic trials end with a journal paper, and real-world impact then depends on whether the findings are noticed, cited, trusted and acted on.

The Glo-BNHL project has a different end-point in mind. The evidence is usable as soon as it is generated, because it already meets industry-grade standards for data quality, assurance and trial conduct, such as “100% source verification” with every datapoint checked against the original records. This matters in paediatric oncology, where recruitment is slow and patient numbers are small. Any delay to the usability of findings can be costly and sometimes ethically hard to justify. “Fit for filing” means the dataset can move directly into regulatory decision-making, rather than waiting for a publication to translate into a regulatory-ready package. In practice, Glo-BNHL combines stewardship of the clinical network and control of the trial design with the level of data assurance regulators and industry require. The platform approach has received positive regulatory feedback in Europe. The European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) and Paediatric Committee (PDCO) have documented their support of the Glo-BNHL platform, in particular the merit of using a master protocol to allocate patients in a rare disease setting.

Birmingham's clinical trials expertise

Birmingham is a leading global hub in clinical trial design and innovation; its credibility rests on an ecosystem of skills, data and infrastructure which has proven especially valuable in paediatric cancer research. The Cancer Research UK Clinical Trials Unit (CRCTU) at the University of Birmingham is one of Cancer Research UK’s network of funded clinical trials units. The University describes CRCTU as designing and delivering trials across all phases and collaborating nationally and internationally, with an emphasis on innovative design approaches suitable for small patient groups. In paediatric oncology specifically, CRCTU is the largest of Cancer Research UK’s two dedicated units for children’s cancers and is responsible for the majority of academic childhood cancer trials in the UK.

Glo-BNHL is still early in its initial seven-year mission, but already illustrates a delivery model with huge potential. The vision is of a global clinical community coordinated around a rare disease problem. Current partnerships include Innovative Therapies for Children with Cancer (ITCC) and European Intergroup for Childhood NHL (EICNHL) in Europe; Children’s Oncology Group (COG) and C17 in North America; and the Australia and New Zealand Children’s Haematology and Oncology Group (ANZCHOG). The platform structure enables testing of multiple treatments and the academic sponsorship model means that evidence produced is of regulatory grade. Together, these components can address the translation of promising therapies to children with cancer.