The BEACON 2 trial aim to test two promising treatments that combine chemotherapy with new anti-cancer medicines (respectively bevacizumab and dintutuximab beta) to cure children with relapsed neuroblastoma with fewer side effects. 

Despite intensive treatments, the chances of survival for children with neuroblastoma that has come back remain unacceptably low, with less than 20% of children achieving long term cure. Only one type of drug has ever been developed specifically for neuroblastoma and it is critical to develop new medicines for this aggressive cancer. 

The two promising treatments that combine chemotherapy with new anti-cancer medicines that will be tested in the BEACON 2 trial are respectively targeting the blood vessels that help the tumours grow and directly the tumour cells via an antibody that binds on a molecule found on the surface of neuroblastoma cells. In the latest, it will allow the child’s own immune system to recognise and kill the tumours cells. 

The Beacon2 trial will confirm which of these two treatments is better in a larger group of patients. This is an essential step to change practice, so that the treatment can be given by doctors widely across Europe after the trial. It will also develop new combinations of drugs that improve the efficacy of immunotherapy, curing more children with fewer side effects. 

Despite the current intensive treatments, the chances of survival for children with neuroblastoma that has come back (in relapse) remain unacceptably low, with less than 20% of children achieving a long-term cure while the treatment causes severe long-term side effects for survivors.As a result, today’s challenge is to reduce the side effects of the treatment while retaining and improving its efficacy to cure more patients.

An international team of computer scientists, biologists, and clinicians will collaborate to build computer models of patients (Digital Twins), which will allow the design of personalised therapies that are more efficient and less toxic than the current therapies.

The technique of digital Twins is already successfully used in engineering, where engineers build, test, and improve a computer model so that they can build the best version of the real machine.

The team will start by building “DigiTwins” of mouse models with neuroblastoma. These mouse models are very similar to the human disease and have been successfully used to develop and test new drugs for neuroblastoma. They allow to perform a comprehensive molecular analysis, where changes in the genome, in the expression of genes (epigenetics), in the production of proteins and of metabolites (which supply building blocks for the body) will be measured. The team will then use advanced computational methods to combine these molecular data and construct the Digital Twin models. Every neuroblastoma mouse will have a corresponding DigiTwin computer model, which can be used to try out different treatments virtually on the computer so that the best possible individual treatment can be identified. These treatments then will be tested in the mice.

Once the accuracy of the DigiTwin models in mice is ascertained, it will be translated to humans. The accuracy of these human DigiTwin models will be evaluated against the treatment outcomes of these patients.

The final objective of DigiTwins project is to pave the way for future clinical studies, where DigiTwins can provide better and more personalised treatments for neuroblastoma patients.

Leukaemia and lymphoma are the most common haematological malignancies in children and constitute almost half of all paediatric cancer cases. High-risk patients, who do not respond to standard therapy or suffer from relapse (when the disease comes back), only have a 27% survival rate.The HEM-iSMART is a personalised medicine trial in which children with relapsed leukaemia or lymphoma will receive a treatment corresponding to the specific genetic alteration(s) present in their tumour. It aims at recruiting sixty patients in total.

Continuous research in cancer genetics and rapid development of new techniques to analyse tumour material have facilitated the development of drugs that specifically target mutations found in cancer cells.
When tumour cells are mutated, they produce mutated proteins that, in turn, promote cancer development and progression, and can lead to resistance of the tumour cells to standard treatment.

Targeted drugs could revert the activity of altered proteins, stop cancer growth or induce tumour cell death. As a result, such drugs could increase the chances of survival for children with relapsed leukaemia or lymphoma.

The HEM-iSMART trial aims at testing four new therapies, each one matching a specific genetic alteration present in the tumour of the patients. This new approach, the first to tackle this issue at a European level, will be carried out in collaboration with the International Leukaemia Target Board (ILTB).

Leukaemia is a cancer of the blood where the patient’s own system turns malignant: the white blood cells grow anarchically and surpass the red blood cells in the blood stream – causing extreme fatigue, bruising and ultimately, the patient’s death.Acute lymphoblastic leukaemia or ALL is the most common type of blood cancer – lymphoblastic refers to the type of white blood cells that has mutated. Today, about 90% of the children with ALL will survive. As a result, childhood ALL can almost be considered as a curable disease. Unfortunately, this is not true for all patients diagnosed with ALL, especially not for infants, i.e., children under 1 year of age.

This project pursues two objectives. First of all, it aims at understanding the mechanisms which make infant ALL so aggressive. It has already been demonstrated that most of the babies diagnosed with ALL carry a leukaemia-specific mutation in the MLL gene. Understanding the MLL gene is thus the key to better treatments.

Second, it will attempt to identify new treatment options by targeting these mechanisms and providing evidence to show that these newly identified treatments could be efficient when applied to patients in the clinic.

The findings of this project will be discussed with the clinical trial groups that set up clinical studies in ALL: the INTERFANT/UKALL consortium.

The project’s findings could be used to improve the risk stratification between the patients and test the identified treatments in an international clinical setting. This could allow more personalised, effective, and kind treatments for infants with ALL in the future.

Today, when a child with cancer runs out of standard treatment options, they will seek treatment in the framework of a clinical trial in the hope to cure or at least to extend their life.In the framework of a clinical trial, all the data about the effect of the tested drug are recorded with the specific intent to determine whether the tested drug is effective and its toxicity is acceptable. Unfortunately, today, there are not enough relevant clinical trials for most of the children for which the current treatments are not effective.

More often than not, as a result, those children with cancer will be treated with a novel drug off-label, in the framework of a compassionate use or medical need programme. In such a case, the clinical data of the patients are lost, when in fact we would need to detect unnecessary toxicity or remarkable efficacy.

This is exactly what the SACHA international registry will do: collect real-life data about innovative therapies administered outside clinical trials to children, adolescents and young adults with paediatric malignancies. These real-life data will help to: 1) recommend the halt of the prescription of the drugs that show to be ineffective or have an unacceptable toxicity, 2) support the development of paediatric clinical trials when new anti-tumour activity is observed.

SACHA international is built on the previous experience of the SACHA France pilot initiated by the French Society of Paediatric Oncology (SFCE) that has included more than 280 patients since March 2020, confirming the feasibility of this type of registry. SACHA International is an initiative from the Innovative Therapies for Children with Cancer (ITCC) Consortium and plans to include 500 patients per year over three years in several European countries, as well as Australia and New Zealand.