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. 2023 Mar 28;15(7):2020.
doi: 10.3390/cancers15072020.

Phase I Study of a Combination of Fluvastatin and Celecoxib in Children with Relapsing/Refractory Low-Grade or High-Grade Glioma (FLUVABREX)

Pierre Leblond  1   2 , Emmanuelle Tresch-Bruneel  3 , Alicia Probst  3 , Nadège Néant  4 , Caroline Solas  4 , Arthur Sterin  5 , Thomas Boulanger  6 , Isabelle Aerts  7 , Cécile Faure-Conter  2 , Anne-Isabelle Bertozzi  8 , Pascal Chastagner  9 , Natacha Entz-Werlé  10 , Emilie De Carli  11 , Marie-Cécile Le Deley  12 , Gauthier Bouche  13 , Nicolas André  5   14   15
Affiliations

Phase I Study of a Combination of Fluvastatin and Celecoxib in Children with Relapsing/Refractory Low-Grade or High-Grade Glioma (FLUVABREX)

Pierre Leblond et al. Cancers (Basel). .

Abstract

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.

Keywords: drug repurposing; high-grade pediatric glioma; low-grade pediatric glioma; phase I trial.

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Conflict of interest statement

G.B., E.T.-B., M.-C.L.D., A.P., N.N., C.S., A.S., T.B., I.A., C.F.-C., A.-I.B., P.C., N.E.-W. and E.D.C. have no conflict of interest to declare. N.A. reports receiving grants and drugs for trials from Bristol Myers Squibb and Pierre Fabre Oncology, receiving travel support from Bristol Myers Squibb for an International Society of Paediatric Oncology meeting and participating as a scientific advisory board member (without receiving personal fees) for Bayer and Bristol Myers Squibb and Partners Therapeutics related to metronomic chemotherapy. P.L. reports receiving drugs for a clinical trial from Pierre Fabre Oncology, receiving drugs and grants for a clinical trial from Bristol Myers Squibb and participating as a scientific advisory board member (receiving personal fees) for AstraZeneca.

Figures

Figure 1
Figure 1
CONSORT diagram.
Figure 2
Figure 2
Sequential inclusion of patients with the allocated dose level.
Figure 3
Figure 3
MRI (T2 gadolinium) of an LGG patient at inclusion (A) and 15 weeks later after 4 cycles of fluvastatin and celecoxib (B). This 8-year-old male patient experienced stable disease and remained on treatment for 23 cycles. A minor response, not meeting the RANO criteria, was observed when comparing the MRI at inclusion (A) with the MRI at week 15 (B).
Figure 4
Figure 4
Kaplan–Meier curves for overall survival (A) and progression-free survival (B) of all 20 patients according to the type of glioma.
See this image and copyright information in PMC

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