Safety of Fluvastatin-Celebrex Association in Low-grade and High Grade Optico-chiasmatic Gliomas
Condition: Glioma
MeSH terms: Glioma
Study type: Interventional
Phase: Phase 1

Summary: 
      Optico-chiasmatic gliomas have therapeutic feature since surgical resection plays a secondary
      role. Unlike other sites, many of these tumors are not amenable to complete resection either
      because of anatomical location, and sometimes they only can be biopsied. A substantial number
      of children will have recurrences following resection or will experience progression
      following incomplete tumor removal or biopsy.

      Celebrex is a Cox-2 inhibitor with anti-angiogenic and anti-tumor properties, while statins
      are known to increase the sensitivity of gliomas to anti-tumor agents. Their association
      could be administered for long periods, in the hope of much reduced risk of toxicities.

      This is a national, multicentric, interventional, open-label, non-comparative, and
      non-randomized phase I study evaluating the maximum tolerated dose of the Fluvastatin in
      combination with fixed-dose of Celebrex.

      This project involves 10 SFCE health centers accustomed to phase I / II studies(Société
      Française de Lutte contre les Cancers et Leucémies de l'Enfant et de l'Adolescent - French
      Society for the Fight against Cancer and Leukemia in Children and Adolescents).
    

Detailed description: 
      Dose escalation scheme only concerns Fluvastatin, and is based on a CRML model (Continual
      Reassessment Method Lilelihood approach). Dose associated with a probability of DLT closest
      to 25% will be considered as Recommended Phase 2 Dose (RP2D).

      Escalation phase :

      Patients will be included by cohort of 2. First patient will be included at the first dose
      level of Fluvastatin (2mg/kg/day). The second patient will be included only after sufficient
      time to assess the absence of DLT on first patient. In absence of DLT during the first 28-day
      cycle, dose escalation will be allowed (4, then 6 and 8 mg/kg/day of Fluvastatin).

      The second and all subsequent patients will be treated at the dose level which DLT
      probability is closest to 25%, without skipping step. Intra-patient dose escalation is not
      allowed. Treatment will be administered until progression, or unacceptable toxicity for one
      year. A minimum of 21 patients will be included during the 1st step, including a minimum of 6
      patients receiving RP2D.

      Expansion phase :

      At RP2D, the number of subjects will be increased to reach a total of 14 evaluable patients,
      in order to better characterize RP2D safety. Patients will be included in the expansion phase
      according CRML model as well, to confirm the recommended dose.

      Probabilities of DLT associated with each dose level will be re-estimated by CRML
      progressively, without the need to suspend inclusions. Results could modify RP2D retained
      during 1st step (dose reduction or a dose re-escalation).
    

Intervention name(s): Fluvastatine; Celebrex
Intervention type(s): Drug; Drug
Intervention description(s): Escalation dose : Level 1: 2mg/kg/day. Level 2: 4mg/kg/day. Level 3: 6mg/kg/day. Level 4: 8mg/kg/day.
Per os from D1 to D14 of each 28 day cycle.
Number of Cycles: until progression or unacceptable toxicity develops.; Dose levels : 100 mg twice a day (< 20 kg), 200 mg twice a day (20-50 kg), 400 mg twice a day (> 50 kg)
Per os from D1 to D28 of each 28 day cycle.
Number of Cycles: until progression or unacceptable toxicity develops.
Other intervention name(s): Celecoxib
Intervention MeSH terms: Celecoxib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Low-grade gliomas; high-grade gliomas; optico-chiasmatic; relapsed; refractory