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Safety of Fluvastatin-Celebrex Association in Low-grade and High Grade Optico-chiasmatic Gliomas (FLUVABREX)

Primary Purpose

Glioma

Status

Completed

Phase

Phase 1

Locations

France

Study Type

Interventional

Intervention

Fluvastatine

Celebrex

About this trial

This is an interventional treatment trial for Glioma focused on measuring Low-grade gliomas, high-grade gliomas, optico-chiasmatic, relapsed, refractory

Eligibility Criteria

6 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Histologically confirmed recurrent or progressive primary hypothalamic-chiasmatic low grade glioma, and not warranting a biopsy or surgery
Histologically confirmed recurrent or progressive primary hypothalamic-chiasmatic high grade glioma, or in complete remission after a new exeresis, excepted brainstem gliomas
Relapsed or refractory disease after at least 1 line adjuvant treatment including radiation therapy, but not surgery
Measurable lesions according to RANO criteria for the patients with low grade glioma and for the patients with high grade glioma included in RP2D level (Recommended Phase 2 Dose).
Non-measurable lesions according to RANO criteria for patients with high grade glioma included in the dose escalation step.
Age > 6 years and < 21 years old
Lansky score > 70 or WHO score < 2 (neurological conditions associated with the disease should not be taken into consideration)
Haematological conditions: ANC > 1000/mm3 and platelets > 75000/mm3
Creatinine < 1.5 x normal for age or calculated clearance > 70 ml/mn/1.73m2
Hepatic function: Total bilirubin < 3 N and SGOT and SGPT < 4 N
Muscle enzymes : CPK < 2 N
No organ toxicity superior to grade 2 according to NCI-CTCAE v4.0
No allergy, hypersensibility to one of the compounds of the treatment
Patients able to swallow capsules
Life expectancy at least > 6 months for low grade gliomas and > 3 months for high grade gliomas
Patient affiliated with a health insurance system
Effective contraception for patients (male and female) with reproductive potential throughout the treatment period
Written informed consent of patient and/or parents/guardians prior to the study participation

Exclusion Criteria:

Chemotherapy within 21 days before D1 of experimental treatment. This period may be shortened in case of previous chemotherapy with vincristine (2 weeks), or extended in case of targeted therapies (4 weeks), or treatment by nitrosoureas (6 weeks)
Radiotherapy within 6 months before D1 of experimental treatment
Peptic ulcer disease, or gastrointestinal bleeding
Known hypersensitivity to sulfonamides.
History of asthma, acute rhinitis, nasal polyps, angioedema, urticaria or other allergic-type reactions induced by acetylsalicylic acid or NSAIDs , including COX-2 inhibitors (cyclo-oxygenase- 2)
Inflammatory bowel disease.
Known congestive heart failure (NYHA II- IV)
Ischemic proven, peripheral and/or history of arterial stroke (including transient ischemic attack)
Pregnancy or breast feeding woman
Known allergy to experimental treatment
Organ toxicity superior to grade 2 according to NCI-CTCAE v4.0
Active infection
Pre-existing muscle pathology
Unsuitable for medical follow-up (geographic, social or mental reasons)

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Fluvastatine Celebrex

Arm Description

dose escalation for Fluvastatine

Outcomes

Primary Outcome Measures

Maximum tolerated dose (MTD) of Fluvastatine combined to a fixed-dose of Celebrex

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

Secondary Outcome Measures

Adverse events

Safety is assessed according to NCI-CTC v4.0 scale

Efficacy in terms of overall survival

Efficacy is measured according to RANO criteria

Efficacy in terms of progression-free survival

Efficacy is measured according to RANO criteria.

Potential interactions between the two drugs

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

Best response is measured according to RANO criteria.

Full Information

NCT ID

NCT02115074

First Posted

March 26, 2014

Last Updated

February 9, 2022

Sponsor

Centre Oscar Lambret

Collaborators

Anticancer Fund, Belgium

1. Study Identification

Unique Protocol Identification Number

NCT02115074

Brief Title

Safety of Fluvastatin-Celebrex Association in Low-grade and High Grade Optico-chiasmatic Gliomas

Acronym

FLUVABREX

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2022

Overall Recruitment Status

Completed

Study Start Date

June 2014 (Actual)

Primary Completion Date

November 2018 (Actual)

Study Completion Date

January 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Centre Oscar Lambret

Collaborators

Anticancer Fund, Belgium

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Glioma

Keywords

Low-grade gliomas, high-grade gliomas, optico-chiasmatic, relapsed, refractory

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

20 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Fluvastatine Celebrex

Arm Type

Experimental

Arm Description

dose escalation for Fluvastatine

Intervention Type

Drug

Intervention Name(s)

Fluvastatine

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Celebrex

Other Intervention Name(s)

Celecoxib

Intervention Description

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.

Primary Outcome Measure Information:

Title

Maximum tolerated dose (MTD) of Fluvastatine combined to a fixed-dose of Celebrex

Description

Time Frame

28 days (at the end of the first cycle)

Secondary Outcome Measure Information:

Title

Adverse events

Description

Safety is assessed according to NCI-CTC v4.0 scale

Time Frame

During all the treatment period, for up to 1 year

Title

Efficacy in terms of overall survival

Description

Efficacy is measured according to RANO criteria

Time Frame

From date of registration until the date of death from any cause, assessed up to 2 years

Title

Efficacy in terms of progression-free survival

Description

Efficacy is measured according to RANO criteria.

Time Frame

After 3, 6, 9 and 12 months of treatment

Title

Potential interactions between the two drugs

Description

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.

Title

Best response' s distribution during the treatment

Description

Best response is measured according to RANO criteria.

Time Frame

After 3, 6, 9 and 12 months of treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

6 Years

Maximum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Histologically confirmed recurrent or progressive primary hypothalamic-chiasmatic low grade glioma, and not warranting a biopsy or surgery Histologically confirmed recurrent or progressive primary hypothalamic-chiasmatic high grade glioma, or in complete remission after a new exeresis, excepted brainstem gliomas Relapsed or refractory disease after at least 1 line adjuvant treatment including radiation therapy, but not surgery Measurable lesions according to RANO criteria for the patients with low grade glioma and for the patients with high grade glioma included in RP2D level (Recommended Phase 2 Dose). Non-measurable lesions according to RANO criteria for patients with high grade glioma included in the dose escalation step. Age > 6 years and < 21 years old Lansky score > 70 or WHO score < 2 (neurological conditions associated with the disease should not be taken into consideration) Haematological conditions: ANC > 1000/mm3 and platelets > 75000/mm3 Creatinine < 1.5 x normal for age or calculated clearance > 70 ml/mn/1.73m2 Hepatic function: Total bilirubin < 3 N and SGOT and SGPT < 4 N Muscle enzymes : CPK < 2 N No organ toxicity superior to grade 2 according to NCI-CTCAE v4.0 No allergy, hypersensibility to one of the compounds of the treatment Patients able to swallow capsules Life expectancy at least > 6 months for low grade gliomas and > 3 months for high grade gliomas Patient affiliated with a health insurance system Effective contraception for patients (male and female) with reproductive potential throughout the treatment period Written informed consent of patient and/or parents/guardians prior to the study participation Exclusion Criteria: Chemotherapy within 21 days before D1 of experimental treatment. This period may be shortened in case of previous chemotherapy with vincristine (2 weeks), or extended in case of targeted therapies (4 weeks), or treatment by nitrosoureas (6 weeks) Radiotherapy within 6 months before D1 of experimental treatment Peptic ulcer disease, or gastrointestinal bleeding Known hypersensitivity to sulfonamides. History of asthma, acute rhinitis, nasal polyps, angioedema, urticaria or other allergic-type reactions induced by acetylsalicylic acid or NSAIDs , including COX-2 inhibitors (cyclo-oxygenase- 2) Inflammatory bowel disease. Known congestive heart failure (NYHA II- IV) Ischemic proven, peripheral and/or history of arterial stroke (including transient ischemic attack) Pregnancy or breast feeding woman Known allergy to experimental treatment Organ toxicity superior to grade 2 according to NCI-CTCAE v4.0 Active infection Pre-existing muscle pathology Unsuitable for medical follow-up (geographic, social or mental reasons)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pierre LEBLOND, MD

Organizational Affiliation

Centre Oscar Lambret, Lille, France

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Nicolas ANDRE, MD

Organizational Affiliation

Hôpital pour Enfants de " La Timone " AP-HM, Marseille, France

Official's Role

Study Director

Facility Information:

Facility Name

CHU Angers

City

Angers

ZIP/Postal Code

49933

Country

France

Facility Name

Centre Oscar Lambret

City

Lille

ZIP/Postal Code

59020

Country

France

Facility Name

Centre Léon Bérard

City

Lyon

ZIP/Postal Code

69373

Country

France

Facility Name

Hôpital pour enfants La Timone

City

Marseille

ZIP/Postal Code

13385

Country

France

Facility Name

Institut Curie

City

Paris

ZIP/Postal Code

75005

Country

France

Facility Name

Centre Hospitalier de Strasbourg

City

Strasbourg

ZIP/Postal Code

67098

Country

France

Facility Name

Centre Hospitalier de Purpan - Hôpital des Enfants

City

Toulouse

ZIP/Postal Code

31026

Country

France

Facility Name

Centre Hospitalier de Nancy

City

Vandoeuvre-les-Nancy

ZIP/Postal Code

54511

Country

France

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Safety of Fluvastatin-Celebrex Association in Low-grade and High Grade Optico-chiasmatic Gliomas

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Safety of Fluvastatin-Celebrex Association in Low-grade and High Grade Optico-chiasmatic Gliomas (FLUVABREX)

Glioma

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial