Safety of Fluvastatin-Celebrex Association in Low-grade and High Grade Optico-chiasmatic Gliomas (FLUVABREX)
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|ClinicalTrials.gov Identifier: NCT02115074|
Recruitment Status : Active, not recruiting
First Posted : April 15, 2014
Last Update Posted : January 1, 2019
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).
|Condition or disease||Intervention/treatment||Phase|
|Glioma||Drug: Fluvastatine Drug: Celebrex||Phase 1|
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).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||21 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Study of Fluvastatin-Celebrex Association for Optico-chiasmatic Low Grade Gliomas and High Grade Gliomas Localized Outside the Brainstem, Relapsed or Refactory, in Children or Young Adults|
|Actual Study Start Date :||June 2014|
|Actual Primary Completion Date :||November 2018|
|Estimated Study Completion Date :||October 2022|
Experimental: Fluvastatine Celebrex
dose escalation for Fluvastatine
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 Name: Celecoxib
- Maximum tolerated dose (MTD) of Fluvastatine combined to a fixed-dose of Celebrex [ Time Frame: 28 days (at the end of the first cycle) ]
The MTD is evaluated according to NCI-CTC v4.0 scale, and is defined as follows:
- grade 3 or 4 neutropenia leading to a delay of therapy superior to 7 days
- grade 3 or 4 thrombocytopenia requiring transfusions over a period superior to 7 days
grade 3 or 4 non-hematologic toxicities, excepted the following events:
- nausea and vomiting despite appropriate symptomatic treatment,
- grade 3 fever, and grade 3 liver toxicity but rapidly reversible,
- grade 3 elevation of creatine phosphokinase (CPK) levels, but rapidly reversible (back <3 X normal within 2 weeks after interruption of treatment)
- Toxicity leading to dose reduction (<75% dose protocol) will also be considered as a DLT, although the grade of toxicity does not in itself justify this classification
- Adverse events [ Time Frame: During all the treatment period, for up to 1 year ]Safety is assessed according to NCI-CTC v4.0 scale
- Efficacy in terms of overall survival [ Time Frame: From date of registration until the date of death from any cause, assessed up to 2 years ]Efficacy is measured according to RANO criteria
- Efficacy in terms of progression-free survival [ Time Frame: After 3, 6, 9 and 12 months of treatment ]Efficacy is measured according to RANO criteria.
- Potential interactions between the two drugs [ Time Frame: Pharmacokinetics: 1 blood sample of 1.5 ml is collected during cycle 1 and at day 1 of the second cycle before fluvastatine and celebrex administration. ]
The Fluvastatin and Celebrex are dosed on the same sample, then compared with pharmacokinetics data from the literature (when drugs are administered alone). The objective is to explore the interaction between the 2 drugs.
Pharmacokinetic analysis is performed by liquid chromatography coupled to mass spectrometry (LC/MS), with UV detection.
- Best response' s distribution during the treatment [ Time Frame: After 3, 6, 9 and 12 months of treatment ]Best response is measured according to RANO criteria.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02115074
|Angers, France, 49933|
|Centre Hospitalier de Bordeaux - Hôpital des Enfants|
|Bordeaux, France, 33076|
|Centre Oscar Lambret|
|Lille, France, 59020|
|Centre Léon Bérard|
|Lyon, France, 69373|
|Hôpital pour enfants La Timone|
|Marseille, France, 13385|
|Centre Hospitalier de Nantes - Hôpital Mère enfants|
|Nantes, France, 44000|
|Paris, France, 75005|
|Centre Hospitalier de Strasbourg|
|Strasbourg, France, 67098|
|Centre Hospitalier de Purpan - Hôpital des Enfants|
|Toulouse, France, 31026|
|Centre Hospitalier de Nancy|
|Vandoeuvre-les-Nancy, France, 54511|
|Institut Gustave Roussy|
|Villejuif, France, 94805|
|Study Director:||Pierre LEBLOND, MD||Centre Oscar Lambret, Lille, France|
|Study Director:||Nicolas ANDRE, MD||Hôpital pour Enfants de " La Timone " AP-HM, Marseille, France|