Summary

Childhood low-grade glioma (LGG) is the most common paediatric central nervous system (CNS) neoplasm. Among LGG hypothalamo-chiasmatic gliomas (HCG) remain a genuine therapeutic challenge. One of the aims of the treatment is to control tumour growth while trying to delay or avoid the use of radiotherapy. Thus chemotherapy is accepted as a first line treatment when surgery is not possible in children aged less than 5 years old and several lines of treatment are usually necessary to obtain a long term control.

Given the chronic nature of many HCG, intensive chemotherapy with potentially serious side effects, after protracted use, including hearing loss, serious infections, and even mutagenesis, should be avoided. As a consequence, for children with multiply recurrent gliomas, there is a need for new less toxic treatment that could be taken for long period of time. Recently, a specific genetic signature of HGC has been unveiled leading to the identification of targets for which agents with potential anticancer effect were available. Therefore, we decided to initiate an non chemotherapeutic agent with a combination of fluvastatin and celecoxib in a phase I/II study in children with refractory or relapsing HCG.

These 2 agents have already been used for the treatment of malignant tumours both in children and adults. Agent 1 used in several multidrug metronomic regimen with an activity in patietns with LGG. Agent 1 mechanism of action is mediated by an antiangiogenic effect. Agent2, is a HMG-coA-réductase inhibitor that can also inhibit the RAS pathway or PPAR alpha. Agent2 has previoulsy showned activity in patients with relapsing or refractory LGG as a single agent and also as part of multidrug regimen. Thus the safety and efficacy of the association of celecoxib and fluvastatine for the treatment of relapsing or refractory GHC in children will be investigated in a phase I/II study. The phase I part will be performed according to a 3+3 model, and according to a a dose escalation model with 4 levels of increase of dose of agent 1 only. (Level 1: X mg/kg/jour— Level r 2: X mg/kg/jour— Level 3: X mg/kg/d— Level 4: X mg/kg/d). Agent2 will be taken at given doses according to the weight (<20 kg:100mg 2X/j—20-50 kg:200mg 2X/j—>50 kg:400mg 2X/j. An intrapatient dose escalation will be perfomed if toxicities ≤ grade 2 are observed. Once the obervation period done, treatment will be taken untill progression, or unacceptable toxicity. A mimimum of 6 patients will be recruited a the last level. Clinical and biological toxicities will be evaluated according to the NCI-Common toxicity criteria AE v4.0. Dose Limiting Toxicity (DLT), will be determined during the first cycle of treatment (28 days) and defined according to Grade 3/4 neutropenia or thrombopenia inducing a delay/stop of over 7 days and all Grade 3/4 non hematological toxicities except for Grade 3 nausea/vomiting, Grade 3 fever and reversible Grade 3 liver toxicity, reversible Grade 3 muscular toxicity, or lastly symptoms associated with disese progression.

DMT determined during the phase I part will be used for the second part (phase I) of the study. This will be a Simon’s 2 steps study (alpha =5%, beta = 10%) evaluating the efficacy of the experimental regimen. 22 patients will be recruited during the first step and if no conclusion regarding efficacy can be drawn, 11 new patients will be recruited. The main efficacy criteria will be PFS at 6 month. Progression can be either clinical (clinical signs of progressions and/or radiological (increase in size >25% for 2 dimensions or appearance of new lesions).`

Overall, the number of recruited patients will range from 28 to 57.

An ancillary studies will be associated with the clinical study. For patients inlcued in the phase I, a PK study of both agents will be performed.

This study is funded by a PHRC grant from the french government and a second grant from Reliable Cancer Therapies