MIRV STUDY – New clinical trial combining chemotherapy and targeted therapies from diagnosis onwards

Project context

New clinical trial combining chemotherapy and targeted therapies (MEK inhibitor mirdametinib) from diagnosis onwards.

Low-grade paediatric gliomas are the most common brain tumours and usually require intravenous chemotherapy. Unfortunately, most tumours progress and other therapeutic avenues must be explored.

Thanks to an initial study (TRAM-01) supported by the Paediatric Research Foundation in 2017, Dr. Perreault’s team, in collaboration with other research centres, demonstrated the effectiveness of targeted therapies for these patients in cases of recurrence. To improve patient care, response and quality of life, Dr. Perreault has set up a new clinical trial (MIRV study) that combines chemotherapy and targeted therapies (MEK inhibitor mirdametinib) from the time of diagnosis.

This multicentre study will be conducted in nine Canadian paediatric oncology centres and will include 50 patients.

Objectives

The primary objective is to determine the effectiveness of this combination in terms of tumour reduction. In addition, the research team will evaluate several secondary objectives, including side effects, neurological progression and quality of life during treatment. Analyses using artificial intelligence will also be used to evaluate the radiological response of tumours (gliomas).

Some statistics

• Low-grade pedriatic gliomas are the most common brain tumours in children (51.2%), and more than 50% of these tumours are refractory to conventional chemotherapy. Tumour progression is associated with significant morbidity, and there is an urgent need for more effective therapeutic approaches. Recent studies have shown that more than 90% of (low-grade pedriatic gliomas) could respond to targeted therapies.

• Currently the largest international clinical trial conducted with MEKi (trametinib) for the treatment of gliomas (TRAM-01 study).

Expected outcomes

• This study has already achieved its primary objectives and has successfully demonstrated that trametinib (MEKi) induces a response in 48% of patients with PLGG.

• Given the promising results observed in the TRAM-01 study, the research team is developing a new Canadian multicentre Phase I/II clinical trial to evaluate the efficacy of targeted therapy as an adjunct to standard chemotherapy for newly diagnosed pediatric glioma patients. Dr. Perreault hypothesises that combining these two approaches will increase efficacy and response rates (at least 60%) in these patients.

• Current data and clinical experience suggest that this combination would be effective and well tolerated.

• For this study (MIRV study), mirdametinib (MEKi) was chosen for its ability to induce an excellent response rate with relatively few side effects. This drug is manufactured by SpringWorks Therapeutics, which supported this study by providing mirdametinib in kind. Vinblastine is the standard chemotherapy treatment in Canada for paediatric gliomas.

Hypothesis

Dr. Perreault’s team postulates that the combination of mirdametinib and vinblastine will induce a response in more than 60% of patients newly diagnosed with PLGG.

Originality of the project – expected results

• This is the first international study to propose a combination of targeted therapy (MEKi) and chemotherapy for patients newly diagnosed with pediatric glioma.

• This clinical trial will also include innovative outcomes such as quality of life, neurological function, and volumetric analysis. Quality of life is a priority for this population and is now included in the evaluation of the efficacy of new drugs. Researchers are interested in tumour response, but improved neurological function is the ultimate goal for these patients and their families.

• The only study on low-grade gliomas to include a questionnaire on neurological function. Finally, measuring tumour volume will enable better assessment of tumour response. Semi-automatic and artificial intelligence techniques will be used to assess volumetric response.

• Biological studies should reveal associations between the response to targeted therapies and certain genetic abnormalities found in these tumours.

• Every year in Canada, more than 120 children are diagnosed with glioma. While some patients can be cured by surgery alone, more than 70% of them require additional treatment due to the inaccessibility of the tumour, which prevents complete resection, for example in the optic pathways. In these cases, glioma is associated with significant morbidity as the tumour progresses.

• The research team is convinced that the combination of chemotherapy and targeted therapy will prove more effective while remaining well tolerated.

Impact on children’s health

• The research team is already a leader in the field of neuro-oncology, specifically in the treatment of paediatric glioma. This has led to clinical and basic research collaborations with more than nine centres across Canada.

• With this new study, she will consolidate the neuro-oncology research structure at CHU Sainte-Justine and continue to develop better treatments and care for children with brain tumours. This study will serve as a model for the Canadian Pediatric Cancer Consortium to develop clinical trial infrastructure in pediatric oncology in Canada. This will facilitate the development of new oncology trials and increase access to innovative therapies for children with cancer.

Potential impact on student training

• This study will make a valuable contribution to student training. At least six students will be involved in the MIRV study.
• A PhD student will be involved in the biological aspect of the trial (liquid biopsy, DNA methylation profiling, exome sequencing).
• A PhD student will be involved in the volumetric analysis of pediatric gliomas.
• Medical students, fellows, and other graduate students will actively participate in the analysis of data from this comprehensive study, focusing on aspects such as quality of life and neurological progression.