FLUVABREX, a phase I study assessing the safety of the association of fluvastatin in addition to celecoxib in children with refractory optic-pathway glioma

Info

Location: Oscar Lambret Center, Lille, France  -  Hôpital pour enfants de la Timone, Marseille, France and Metronomic Global Health Initiative
Collaboration: Dr Pierre Leblond & Dr Nicolas André

 

Optic-pathway gliomas are rare tumors in the brain accounting for 1 to 5% of all brain tumors in children. They are rarely life-threatening but their growth often causes symptoms so that treatment becomes necessary. The main symptom of optic gliomas is visual impairment because the tumor can affect the optic nerve but, other symptoms, such as a hormonal disturbances, can also occur.

Complete surgical removal of the tumor would be the best option, as is the case for most brain tumors. In practice, however, such surgeries are rarely possible due to the localization of the tumor on the optic pathways. That’s why other treatment strategies are used, despite the relatively small scientific proof of their effectiveness. The current treatment strategy for children with optic glioma symptoms is chemotherapy. In general, the policy should be to postpone radiotherapy for as long as possible, because it can damage the developing brain of a child more and also because it has more long-term effects compared to chemotherapy. Chemotherapy can stop or slow down the growth of this kind of tumors but, unfortunately, in a significant number of patients, the tumor grows back after a few years.

Chemotherapy has many side effects. Therefore, it is important to continue to look for other, low-risk treatment strategies that are better tolerated and potentially have better efficacy profiles. Researchers drew up a list of drugs that are currently being used in clinics for indications other than for the treatment of optic gliomas. They decided to test the combination of the drugs celecoxib and fluvastatin, widely used in adults but less so in children. Both drugs offer a strong biological rationale for being synergistically able to stop or slow progression of optic-pathway gliomas.

Celecoxib is an anti-inflammatory drug that has already been used in combination with chemotherapy in children with cancer. The recommended dose of celecoxib in children is well established.

Fluvastatin is a drug that is used to treat high cholesterol in adults. Fluvastatin has also been used in children with cancer. In order to determine whether the combination of these two drugs is safe in children with optic-pathway gliomas, a clinical trial began in 2013. In addition to evaluating the safety of various doses, the study also assesses response rates on the size and progression of the tumor. Dr Pierre Leblond and Dr Nicolas André are both the principal investigators of this study, in which 10 pediatric oncology departments in France, as well as all members of the Société Française de lutte contre les Cancers et leucémies de l'Enfant et de l'adolescent (SFCE), participate.  So far, 13 patients have been enrolled in the trial (February 2017).

Professional info

Location: Centre Oscar Lambret, Lille, France  -  Hôpital pour enfants de la Timone, Marseille, France and Metronomic Global Health Initiative
Collaboration: Dr Pierre Leblond & Dr Nicolas André

 

Optic-pathway gliomas are rare tumors accounting for 1 to 5% of all brain tumors in children. They are rarely life-threatening but often cause symptoms due to their growth that requires an intervention. Treatment should be initiated from either imaging scan results of the brain or symptoms when it is clear that the tumors have grown. The main symptom of optic gliomas is visual impairment even though other symptoms can occur (such as symptoms related to hormonal disturbance or increased intracranial pressure).

Complete surgical removal would be the best treatment like in most brain tumors. But complete surgery is rarely possible due to the localization of the tumor on the optic pathways. Therefore, other treatment strategies are used, although a rather low level of scientific evidence study results exist about those therapies. The current treatment strategy in children with optic glioma symptoms is chemotherapy to postpone radiotherapy on the developing brain of a child as much as possible.. Chemotherapy appears to have less long-term consequences on neurocognition than radiotherapy. Several drugs alone or in combination have shown they could stop or slow down the progression. Unfortunately, the tumor grows again after a few years in a high amount of patients.

Since chemotherapy is not without toxicity and many children experience their optic gliomas progressing after the use of chemotherapy, it is important to study other low-risk treatment strategies. As a result, investigators summarized the known molecular characteristics of optic-pathway gliomas and assessed the literature to identify possible drugs that could be of potential interest for more research. They developed a list of drugs already used in the clinic for other indications and decided to try a combination of the 2 drugs celecoxib and fluvastatin widely used in adults but less in children. Both drugs 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 regimens. Metronomic provides lower doses every day instead of one shot high dose every 4 weeks. The recommended dose of celecoxib in children is well established.
Fluvastatin is a drug used to treat high cholesterol in adults. Fluvastatin has already been used in children with cancer to determine a recommended dose of 8mg/kg/d, which is higher than the dose used to treat hypercholesterolemia.

In order to verify if the combination of these two drugs is safe in children with optic-pathway gliomas, a clinical trial began in September 2013. In addition to evaluating the safety of several doses of fluvastatin (2, 4, 6 and 8 mg/kg/d) in combination with celecoxib, the study also assesses response rates on the size and progression of the tumor, in up to 24 children with an optic-pathway glioma still progressing despite the prior use of chemotherapy. Dr Pierre Leblond and Dr Nicolas André are principal investigators of this study that will involve 10 pediatric oncology departments in France that are all members of the Société Française de lutte contre les Cancers et leucémies de l'Enfant et de l'adolescent (SFCE). So far, 13 patients have been enrolled in the trial (February 2017).