Anti-inflammatory and cholesterol inhibitor as repurposed drugs for children's optic nerve cancer
A phase I study assessing the safety of the association of fluvastatin in addition to celecoxib in children with refractory optic-pathway glioma (Fluvabrex).
- Paediatric cancer
- Brain cancer
Why this trial?
Optic-pathway gliomas are rare tumours accounting for 1 to 5% of all brain tumours in children. They are rarely life-threatening, but often cause symptoms that require intervention. The main symptom of optic gliomas is visual impairment; however, other symptoms can also occur. Complete surgical removal is the best treatment. Unfortunately, complete resection is rarely possible due to the localisation of the tumour on the optic pathways.
As a result, other treatment strategies supported by only a low level of scientific evidence are often used.
Why this drug?
The current treatment strategy in children with optic glioma symptoms is chemotherapy, to postpone radiotherapy on the child’s developing brain for as long as possible. Several chemotherapies have displayed the ability to stop or slow the progression of optic glioma. Unfortunately, the tumour will often return after a few years. Since chemotherapy is not without toxicity and many children experience tumour progression after chemotherapy, it is important to search for other low-risk treatment strategies.
In this search, researchers summarised the known molecular characteristics of optic-pathway gliomas and examined the literature to identify drugs that could be of potential interest based on their mechanism of action. Two of the drugs identified are celecoxib and fluvastatin, widely used in adults but less often in children. Both offer a strong biological rationale for being synergistically able to stop or slow progression of optic-pathway gliomas.
Celecoxib is an anti-inflammatory drug from the COX-2 inhibitor family. In children with cancer, celecoxib has been used in combination with chemotherapy in metronomic (lower dose but more frequent administration) regimens. Its recommended dose in children is well-established.
Fluvastatin is a drug used to treat high cholesterol in adults, but has already been used in children with cancer. The recommended dose in children is 8 mg/kg/d, higher than the dose used to treat hypercholesterolemia.
This clinical trial is needed to first determine the best dose of the 2 drugs when combined, and assess the safety of the combination. After this has been established, future trials need to be performed to be able to conclude whether the combination of these drugs has an effect on the growth of the tumour in these patients.
This trial is a phase I, open label, multi-centric trial to assess whether the combination of fluvastatin and celecoxib is safe in children with optic-pathway gliomas. 35 children will be recruited and treated in 11 French centres.
In addition to evaluating the safety of several doses of fluvastatin (2, 4, 6 and 8 mg/kg/d) in combination with celecoxib, response rates based on the size of the tumour will also be assessed.
The first results of a phase I study with fluvastatin/celecoxib in children with glioma were presented during the conference of the International Society of Paediatric Oncology (SIOP) in Lyon in October 2019.
As preclinical and clinical data support the anticancer activity of fluvastatin and celecoxib in low grade gliomas (LGG), a phase I trial was designed to evaluate the combination in children with relapsing or refractory glioma. Twenty patients were included. The combination of the two drugs displayed very limited toxicity with interesting preliminary activity in patients with LGG.
A phase 2 study in patients with LGG should be encouraged, and support of the Anticancer Fund is currently being discussed with the French paediatric oncologists.
- Dr Pierre Leblond, Centre Oscar Lambret, Lille, France (Coordinating Investigator)
- Dr Nicolas André, Hôpital pour Enfants de “La Timone” AP-HM, Marseille, France (Sub Investigator)
- Centre Oscar Lambret, Lille, France
- Société Française de lutte contre les Cancers et leucémies de l'Enfant et de l'adolescent (SFCE)
More info on clinicaltrials.gov: NCT02115074
Ferris, J.S., et al. (2012). HMG CoA reductase inhibitors, NSAIDs and risk of glioma. Int J Cancer, 131(6), E1031-7. doi: 10.1002/ijc.27536
Gao, J., et al. (2010). Combined inhibitory effects of Celebrex and fluvastatin on the growth of human hepatocellular carcinoma xenografts in nude mice. J Int Med Res., 38(4),1413- 1427. doi:10.1177/147323001003800423
Last updated: January 2020