B-cell Non-Hodgkin lymphoma (B-NHL) is a cancer of the lymphatic system that originates in the B lymphocytes. The lymphatic system plays a key role in our immune system.“Glo-BNHL” project is aimed at children whose cancer comes back (relapse) or does not respond to standard treatments (refractory).

Despite intensive treatments, the chances of survival for those children are below 30%. Many new treatments have been developed for this type of lymphomas in adults. It is now necessary to identify those that will be most effective in young patients.

In Europe and North America, there are on average only 90 young patients per year who do not respond to standard treatment. Transatlantic collaboration is therefore essential to identify the most effective and least toxic drugs.

The “Glo-BNHL” clinical trial is a global study that aims at evaluating – alone or in combination with existing therapies – the toxicity and efficacy of the most promising new drugs for children to increase the cure rate in these patients.

Given on the one hand the large number of molecules that could be tested in young patients and on the other hand the small number of patients eligible for an experimental clinical trial, only a step-wise approach would ensure the swift evaluation of the most promising treatments. To this end, this programme will create a unique global platform for early clinical trials in relapsed and refractory B-NHL.

The trial will be opened in at least 30 centers in a dozen countries across Europe, North America, Australia and New Zealand with the possibility of further expansion. Participants will be divided into 3 treatment arms, each proposing a different new agent.

In addition to the core objectives of improving survival and quality of life, this trial will focus on improving scientific understanding of the biology of paediatric B-NHL, with the aim of identifying mechanisms of resistance that could be targeted by new therapies.

As current standard treatments are very toxic for young patients, the hope is also to identify new, less harmful frontline treatments, while having ‘rescue’ molecules for children who would relapse.

Last but not least, this platform trial will serve as a reference for other diseases by demonstrating the feasibility of testing multiple new agents in a rare population in a global context using effective novel agent mechanism of action prioritisation.

Ewing’s sarcoma is a malignant bone tumour that most often affects young patients (80% of patients are under 20 years old).Like most paediatric cancers, Ewing’s sarcoma is a rare disease. In Europe, around 600 children and young adults are diagnosed on a yearly basis.

The standard treatment for Ewing’s sarcoma includes chemotherapy and local treatment with radiotherapy or surgery when possible. Despite this heavy treatment, the chances of survival for these young patients, when their disease is metastatic at diagnosis, amount to 30% only and half of the relapses occur already while in treatment. Over the last decades, no new effective drugs have been introduced in the frontline treatment. It is high-time we try to improve the chances of survival for those patients.

The « INTER-EWING-1 » clinical trial is open to patients with metastatic Ewing’s sarcoma. In most cases, innovative treatment is only offered when standard treatment fails. Here, as standard treatment offers only a limited efficacy, the clinical trial will be offered to patients immediately upon diagnosis.

This trial will to study whether adding a new agent called “regorafenib” improves the effectiveness of the standard chemotherapy. It is a drug from the class of enzyme inhibitors; enzymes play a role in many cellular functions, such as cell growth or division. Here, regorafenib will inhibit the multi-targeted tyrosine kinase (TKI).

By inhibiting this enzyme, we are hoping to block the growth of cancer cells. Early clinical data suggest that strategies using multi-targeted TKIs would be among the most effective and could improve treatment in these young patients.

Fight Kids Cancer will allow the funding of the preliminary phase of this trial, with the aim to evaluate the safety of the combination of this drug with chemotherapy and its optimal dosage. The trial will be opened in 15 centres across 5 European countries.

In addition, the « INTER-EWING-1 » project plans to evaluate two other questions aimed at improving standard treatments: the adaptation of radiotherapy doses and the addition of a so-called « maintenance » treatment. These additional issues will be funded through other calls for projects.

Medulloblastoma is a high-risk brain cancer in children. It is the most common brain cancer (20% of brain and spinal cord tumours). Today, treatments cause significant long-term side effects and the rate of incurable relapse remains very high.There is therefore an urgent need to develop more targeted and effective treatments without the side effects of the current approaches.

The translational research project « CARBEMED » aims at identifying a highly innovative treatment strategy that would combine two immunotherapy techniques:

– A new drug from the class of “checkpoint inhibitors”, a technique that prevents cancer cells from going unnoticed (like normal healthy cells) by white blood cells;

– A CAR-T cell therapy treatment that reinforces the natural ability of the immune system to fight cancer: the patient’s own immune cells (T cells) are collected, then genetically manipulated in the laboratory to enable them to recognise and destroy cancer cells. Once modified, these cells are reinjected into the patient.

The effect of this treatment will in the first instance be tested on mice.

This project brings together a team of researchers from three British institutions. Together they bring along the different skills required to deliver on this project: cell therapy, drug treatments, analysis of animal models and translation into clinical trials.

Many other childhood and adult cancers present mechanisms of action that are similar to medulloblastoma. If successful, this combination could therefore benefit these patients as well.

Neuroblastoma is one of the most common solid tumours in children. It is called an extracerebral malignancy because it develops from the nervous system but is not located in the brain (mainly in the abdomen, sometimes along the spine or in the adrenal glands).The translational research project « COMBALK » is aimed at children with high-risk neuroblastoma whose tumour has an alteration in the « ALK » gene and in whom first-line treatment does not work. This represents between 12 to 15% of the neuroblastoma patients.

This project aims at identifying new treatments to improve the cure rate of these young patients whose chances of survival are currently very low.

The researchers found that the ALK protein plays an important role in the growth of cancer cells in patients with a mutation in the « ALK » gene.

Lorlatinib is a targeted therapy that prevents cell division and inhibits the growth of cancer cells. In particular, Lorlatinib inhibits the activity of the ALK protein present in these neuroblastoma patients.

Lorlatinib is now used in first-line treatment in addition to chemotherapy and local treatment. Despite this, many patients develop resistance to this treatment.

This project aims at improving our understanding of the role of the protein ALK and other factors in the development of neuroblastoma in children and at identifying the mechanisms of resistance to this ALK inhibitor. It will then aim at identifying possible new treatments and combinations to overcome those resistances.

Neuroblastoma is one of the most common solid tumours in children. It is characterised as an extracerebral malignancy because it develops from the nervous system but is not located in the brain (mainly in the abdomen, sometimes along the spine or in the adrenal glands).Today, the treatment options available for patients who do not respond to standard treatment or who relapse are not satisfactory. The BEACON-BIO project aims at improving them in the medium term.

Despite intensive treatment, more than one in two patients relapse after frontline treatment and the chances of survival for these patients are below 10%. It is therefore important to improve our understanding of the growth and resistance mechanisms of neuroblastoma to develop more efficient treatments.

To this end, this international collaborative project will attempt to allocate patients into risk groups defined on the basis of their molecular specificities (or biomarkers) and treatment resistance.

A biomarker is an objectively measurable and evaluable characteristic found in blood, body fluids or tissues that can be used as an indicator of the presence of a disease, its progression or response to treatment.

In particular, this project will study the impact of genetic and epigenetic factors in relapse and resistance. Epigenetics is the science that explains why cells with the same genetic code have different functions inside someone’s body.

Finally, this project will seek to identify new combinations of molecules in the hope that they will be more efficient.

These combinations will then be evaluated in the upcoming European platform trial in relapsed and refractory neuroblastoma the European collaborative research groups are currently setting up.

This project aims at identifying news treatment options for children with neuroblastoma. As a result, the project will benefit all children if the study’s conclusions are encouraging.