Immune therapy for brain tumours in children and young adults
U-R-Immune Glioma - A Pilot Study Investigating Upfront Adaptive Immunotherapy Approach in Children, Adolescent and Young Adult (CAYA) Patients with Replication-Repair Deficient (RRD) High-Grade Gliomas (HGG)
Funding
Why this trial
High Grade Glioma, a type of brain cancer also called glioblastoma, is the most lethal cancer among children, adolescents, and young adults. The current treatment, which consists of surgery, radiation, and chemotherapy, commonly causes long-term side effects that dramatically impact the lives of these young patients.
Researchers found that up to 10% of High-Grade Glioma in patients up to 25 years of age is caused by replication-repair deficiency (RRD) – a type of error in the DNA – which results in resistance of the tumour to standard chemotherapies like temozolomide. Children with this type of High-Grade Glioma have extremely poor survival; even with aggressive treatment—consisting of surgery, chemotherapy, and radiation—most survive for 9 to 15 months.
The U-R-Immune Glioma clinical trial aims at giving a treatment that will specifically exploit the vulnerability induced by RRD in the tumour. RRD causes the tumour cells to develop a high number of changes in their genome, a phenomenon called hypermutation.
Why this intervention
A major recent discovery is that hypermutation makes RRD tumours extremely sensitive to drugs called immune checkpoint inhibitors, which are approved for the treatment of other cancers. Immune checkpoint inhibitors block proteins called ‘checkpoints’ that are present on some immune cells, such as T cells, and on some cancer cells. These ‘checkpoints’ keep immune responses from being too strong and sometimes keep T cells from killing cancer cells.
In prior research, the investigators of U-R-Immune Glioma showed radiological responses in >50% of relapsed/refractory RRD-glioblastoma patients treated with immune checkpoint inhibitors as salvage therapy, something unprecedented. Survival for recurrent/progressive RRD hypermutant gliomas with the right immune markers was 80% at 3 years.
That immune checkpoint inhibitors, such as nivolumab, prolong survival in patients with refractory RRD gliomas made the investigators of U-R-Immune Glioma wonder if it could work – and even prevent recurrence – in newly diagnosed patients. In addition, its use may also avoid the short and long-term toxicity of the current standard treatment.
The goal of the U-R Immune Glioma study is to explore whether radiation for progression or recurrence can be delayed or even avoided, by giving upfront nivolumab to young patients with RRD high-grade glioma, who underwent surgery for their tumour. In this trial, patients will have surgery or a biopsy upon progression and will receive treatment consisting of a combination of radiation and nivolumab.
Trial design
This is an open label, single arm pilot study in children, adolescent and young adults with RRD High-Grade Gliomas with favourable immune markers who have not had previous treatment (except for surgery).
The trial consists of two domains:
- In domain 1, the safety and efficacy of nivolumab given to patients who had a total or near total surgical resection of the tumour will be evaluated. All patients showing tumour progression on domain 1 will be able to participate in domain 2.
- In domain 2, patients who need radiation therapy to treat the tumour will be undergoing surgery/biopsy and will then get a combination of radiation therapy and nivolumab, followed by maintenance nivolumab.
18 to 20 patients will be enrolled in total, in Canada, Australia, India, and Jordan.
Partners
Researchers:
- Dr. Uri Tabori, The Hospital for Sick Children (SickKids) Research Institute - Toronto, Canada (Study Principal Investigator)
- Dr. Nirav Thacker, Children’s Hospital of Eastern Ontario (CHEO) - Ottawa, Canada (Co-Study Principal Investigator)
- Dr. Eric Bouffet, The Hospital for Sick Children (SickKids) Research Institute - Toronto, Canada (Co-Principal Investigator leading LMIC)
- Dr. Anirban Das, The Hospital for Sick Children (SickKids) Research Institute - Toronto, Canada (Co-PI lead biological component)
Sponsor:
- The Hospital for Sick Children (SickKids), Toronto, Canada
Other funder:
- Canadian Institutes of Health Research
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