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Pediatric Low Grade Glioma - MEKinhibitor TRIal vs Chemotherapy (PLGG - MEKTRIC)

Primary Purpose

Grade 1 Glioma, Mixed Glio-neuronal Tumors, Pleomorphic Xanthoastrocytoma

Status

Recruiting

Phase

Phase 2

Locations

France

Study Type

Interventional

Intervention

Trametinib

Vinblastine

About this trial

This is an interventional treatment trial for Grade 1 Glioma

Eligibility Criteria

1 Month - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age: ≥ 1 month to ≤ 25 years

Signed written informed consent prior to study participation of the legal representatives and the patient if the patient is able to understand the impact of clinical trial and to give consent. For patients above 18 years, their written informed consent will be obtained.
Patient could be under guardianship or limited guardianship (for patient under legal guardianship, authorization is given by the legal representative of the patient under guardianship. For patient under limited guardianship, consent will be obtained from the adult under limited guardianship assisted by his or her guardian
Histologically proven grade 1 glioma/mixed glio-neuronal tumors or pleomorphic xanthoastrocytoma (PXA) confirmed by local referee and/or regional RENOCLIP referee and/or national referees in neuropathology (RENOCLIP-LOC panel)
Determination of a negative BRAFv600 mutation by immunohistochemistry and/or molecular methods
Determination of 7q34 duplication status additionally to routinely done FGFR1 and MYB/MYBL1 abnormalities' research
Midline tumors without proven histone H3 mutations
Tumor without IDH1 mutation
Fresh frozen tumor tissues and/or paraffin-embedded samples for further molecular biomarker testing
Sus-tentorial, optic pathway, midline and spine locations allowed
Karnofsky or Lansky ≥ 50%
Criteria for post-surgical treatment: severe visual or neurological symptoms at diagnosis, clinical deterioration of visual or neurological symptoms or radiological progression. The radiological progression is defined as an increase of solid part of the tumor of more than 25% compared to the pre-baseline MRI-imaging over a time period of at least 3 months or the occurrence of new metastatic lesions.
Infants below one year of age with chiasmatic and/or hypothalamic tumor will be treated immediately after surgery, independently from neurological and/or visual evolution
Females of child-bearing potential must be willing to practice highly effective contraception during all treatment and until 6 months after the last dose of study drugs' administration. Additionally, females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to start of study drugs. Boys with reproductive potential must be willing to use condom and consider contraception for partner women of childbearing potential during treatment and until 4 months after the last study drugs' administration.
Patients must have adequate bone marrow function defined as: absolute neutrophil count (ANC) ≥ 1500/µL; platelets ≥ 100,000/µL and hemoglobin ≥ 9.0 g/dl
Patients must have adequate liver function within 7 days prior to screening: bilirubin (sum of unconjugated and conjugated) ≤ 1.5 ULN for age, ALT and AST ≤ 2.5 x upper limit of normal, alkaline phosphatase ≤ 4 x upper limit of normal, INR/PTT < 1.5 x upper limit of normal,
Patients must have adequate renal function within 7 days prior to screening: serum creatinine < 1.5 x upper limit of normal for age and a creatinine clearance > 60 ml/min for 1.73 m2
Cardiac function defined as a corrected QT (QTcF) interval < 480 msec, LVEF ≥ lower limit of normal (LLN) by echocardiogram (ECHO)
Adequate blood pressure control (smaller or equal to the 95th percentile for patient's age, height and gender)
Patients are willing and able to comply with scheduled visits, treatment plan, laboratory tests and study procedures
Guardians (in case of patients under 18 years) or patient if above 18 years must be affiliated to or a beneficiary of health insurance system.

Non-inclusion criteria

Patients presenting a NF1 congenital disease
Pure optic nerve glioma
Completely resected tumors
Previous treatment except tumor surgery
Pregnancy and lactation
Participation in other clinical trials
Prior non-surgical therapy for this indication
Diffuse intrinsic pontine glioma (DIPG), even if histologically diagnosed as WHO grade II
Subependymal giant astrocytoma (SEGA) in patients with TSC
Patient having a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C
Known hypersensitivity to drugs or excipients
History of another malignancy
History of current uncontrolled infection

Sites / Locations

CHU Strasbourg - FranceRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Trametinib experimental arm

Vinblastine control arm

Arm Description

the experimental arm will be Mekinist© (Trametinib) taken orally each day with a 18-course schedule of 4 weeks each.

the control arm will be the weekly intra-venous Vinblastine (Velbe©) during 18 courses of 4 weeks each

Outcomes

Primary Outcome Measures

The primary endpoint is the 3-year PFS (Progression Free Survival rates) comparing the two arms (standard vs experimental).

Secondary Outcome Measures

the OS rate:

the OS calculation will take into account the survival measured from time of 1st treatment administration up to death

the tumor response based on the international and recognized RANO criteria,

the analysis comparing the 2 arms will be based on overall response rate (ORR) by central independent radiological review assessment. The analysis will be conducted in all patients at least at 24 weeks of completed treatment or earlier for the patients who have discontinued for progression reasons. The tumor response will classify the patients in 2 groups: PD subgroup versus CR/PR/SD subgroup.

the tumor response based on the international and recognized RANO criteria,

the frequency and description of AE (adverse event)/SAE (serious adverse event)

based on CTCAE criteria (using NCI-CTCAE version 5.0) focusing on visual disturbances, skin, intestinal and cardiac side effects in the experimental arm compared with the standard control arm.

the PFS and OS rates according to molecular biomarkers obtained with routinely done molecular analyses (RENOCLIP-LOC platform) and after centralized review of each tumor histology.

Full Information

NCT ID

NCT05180825

First Posted

November 25, 2021

Last Updated

August 10, 2023

Sponsor

University Hospital, Strasbourg, France

1. Study Identification

Unique Protocol Identification Number

NCT05180825

Brief Title

Pediatric Low Grade Glioma - MEKinhibitor TRIal vs Chemotherapy

Acronym

PLGG - MEKTRIC

Official Title

A Randomized and Controlled Phase II National Protocol in Non NF1 Pediatric and AYA (Adolescent and Young Adults) Patients Bearing a Wild Type BRAF Gene Newly Diagnosed Comparing a Daily Oral MEK Inhibitor (Trametinib) Versus Weekly Vinblastine During 18 Months

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Recruiting

Study Start Date

May 5, 2022 (Actual)

Primary Completion Date

November 1, 2031 (Anticipated)

Study Completion Date

December 1, 2031 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital, Strasbourg, France

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

Pediatric low-grade glioma (PLGG) is a heterogeneous group of WHO grade I and II brain tumors, associated with a 10-year overall survival of 90%. It is the most common form of primary central nervous system (CNS) tumor arising during childhood, adolescence and young adulthood, accounting for over 30% of CNS tumors in this age group. A large group of PLGG patients will benefit from a complete resection of their tumor. Nevertheless, PLGG can occur anywhere and can be in some locations associated with neurological symptoms, unresectable or radiological progressive tumors that need medical treatments rapidly to avoid long-term sequelae. The current problem during this first line therapy is to improve tumor response, overall survival rate, as well as progression free survival. In our study, we will focus on a specific group of PLGGs without any congenital NF1 mutation and with a wild-type BRAF gene in the tumor. In this subgroup, for instance, the PFS is not increasing anymore above 50% at 3 years independently from the chemotherapeutic scheme. The two current standard therapies are carboplatin plus vincristine during 81 weeks or a weekly IV administration of vinblastine during 70 weeks. The most recent Canadian approach with vinblastine seems to have the same PFS rate, but with a better daily tolerance and less toxicities than the carboplatin/vincristine combination. Therefore, it is becoming the new standard approach in those patients. Nevertheless, we need to improve more their outcome with less recurs and a better first-line tumor response. The recent molecular discoveries involving the Ras/mitogen-activated protein kinase pathway in those PLGG is opening a new era with specific targeted therapies that might be the key to improve their survivals and giving hope to less treatment lines and a better tumor response. Therefore, we designed a prospective open randomized phase II study, named PLGG-MEKTRIC, comparing the experimental arm (a daily MEK inhibitor, Trametinib, Mekinist©) to a standard arm comprising weekly vinblastine during 18 courses of 4 weeks each. The study will enroll 134 patients with a PLGG during childhood, adolescence or young adulthood with no NF1-related disease and without any BRAFv600 mutation located in brain or spine. 67 patients, in each treatment arm, are planned to be enrolled to answer our primary objective. This primary objective will be to determine in the experimental arm a 20% superiority of the 3-year PFS rate in comparison with the standard treatment administered during 18 courses (e.g. 72 weeks). A stratification of the patients will be done in both arms based on molecular tumor results and brain/spine locations to obtain two equivalent arms to be analyzed. The recruitment time will be 36 months and the complete follow-up of each patient will last 3 years. The secondary objectives will be in both arms: the tumor response rate at 24 and 72 weeks of treatment, the 3-year PFS and OS rates and the frequency of AE/SAE/SUSAR (Adverse Event/Serious Adverse Event) based on CTCAE criteria during the 3 years after the first administration. A Quality of Life (QoL) assessment, based on PEDsQL questionnaires, at 24 weeks, at the end of treatment and 3 years after 1st treatment administration in both arms will be part of this study. Finally, 3-year PFS and OS will be analyzed according to molecular biomarkers and visual assessment (LogMar scale) in each arm. An economic analysis is also planned as an ancillary study to determine a cost effectiveness of the best arm and complementary ancillary molecular studies are already organized. In the future, we hope to push forward this new-targeted therapy as a referenced first line treatment of pediatric PLGG to obtain the best tolerance and positive long-term impact and to extend our knowledge of MEK inhibitor impact in molecular subgroups and in optical pathway locations. We also plan to do a "switch" strategy in patients relapsing in standard arm and we will propose systematically to those patients the experimental treatment (MEK inhibitor ).

6. Conditions and Keywords

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

Grade 1 Glioma, Mixed Glio-neuronal Tumors, Pleomorphic Xanthoastrocytoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

134 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Trametinib experimental arm

Arm Type

Experimental

Arm Description

the experimental arm will be Mekinist© (Trametinib) taken orally each day with a 18-course schedule of 4 weeks each.

Arm Title

Vinblastine control arm

Arm Type

Active Comparator

Arm Description

the control arm will be the weekly intra-venous Vinblastine (Velbe©) during 18 courses of 4 weeks each

Intervention Type

Drug

Intervention Name(s)

Trametinib

Intervention Description

Mekinist© (Trametinib) taken orally each day with a 18-course schedule of 4 weeks each.

Intervention Type

Drug

Intervention Name(s)

Vinblastine

Intervention Description

weekly intra-venous Vinblastine (Velbe©) during 18 courses of 4 weeks each

Primary Outcome Measure Information:

Title

The primary endpoint is the 3-year PFS (Progression Free Survival rates) comparing the two arms (standard vs experimental).

Time Frame

At 3 years

Secondary Outcome Measure Information:

Title

the OS rate:

Description

the OS calculation will take into account the survival measured from time of 1st treatment administration up to death

Time Frame

At 3 years

Title

the tumor response based on the international and recognized RANO criteria,

Description

Time Frame

at 24 weeks

Title

the tumor response based on the international and recognized RANO criteria,

Description

Time Frame

at 72 weeks

Title

the frequency and description of AE (adverse event)/SAE (serious adverse event)

Description

based on CTCAE criteria (using NCI-CTCAE version 5.0) focusing on visual disturbances, skin, intestinal and cardiac side effects in the experimental arm compared with the standard control arm.

Time Frame

At the end of Cycle 18 (each cycle is 28 days)

Title

the PFS and OS rates according to molecular biomarkers obtained with routinely done molecular analyses (RENOCLIP-LOC platform) and after centralized review of each tumor histology.

Time Frame

At 3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Month

Maximum Age & Unit of Time

25 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age: ≥ 1 month to ≤ 25 years Signed written informed consent prior to study participation of the legal representatives and the patient if the patient is able to understand the impact of clinical trial and to give consent. For patients above 18 years, their written informed consent will be obtained. Patient could be under guardianship or limited guardianship (for patient under legal guardianship, authorization is given by the legal representative of the patient under guardianship. For patient under limited guardianship, consent will be obtained from the adult under limited guardianship assisted by his or her guardian Histologically proven grade 1 glioma/mixed glio-neuronal tumors or pleomorphic xanthoastrocytoma (PXA) confirmed by local referee and/or regional RENOCLIP referee and/or national referees in neuropathology (RENOCLIP-LOC panel) Determination of a negative BRAFv600 mutation by immunohistochemistry and/or molecular methods Determination of 7q34 duplication status additionally to routinely done FGFR1 and MYB/MYBL1 abnormalities' research Midline tumors without proven histone H3 mutations Tumor without IDH1 mutation Fresh frozen tumor tissues and/or paraffin-embedded samples for further molecular biomarker testing Sus-tentorial, optic pathway, midline and spine locations allowed Karnofsky or Lansky ≥ 50% Criteria for post-surgical treatment: severe visual or neurological symptoms at diagnosis, clinical deterioration of visual or neurological symptoms or radiological progression. The radiological progression is defined as an increase of solid part of the tumor of more than 25% compared to the pre-baseline MRI-imaging over a time period of at least 3 months or the occurrence of new metastatic lesions. Infants below one year of age with chiasmatic and/or hypothalamic tumor will be treated immediately after surgery, independently from neurological and/or visual evolution Females of child-bearing potential must be willing to practice highly effective contraception during all treatment and until 6 months after the last dose of study drugs' administration. Additionally, females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to start of study drugs. Boys with reproductive potential must be willing to use condom and consider contraception for partner women of childbearing potential during treatment and until 4 months after the last study drugs' administration. Patients must have adequate bone marrow function defined as: absolute neutrophil count (ANC) ≥ 1500/µL; platelets ≥ 100,000/µL and hemoglobin ≥ 9.0 g/dl Patients must have adequate liver function within 7 days prior to screening: bilirubin (sum of unconjugated and conjugated) ≤ 1.5 ULN for age, ALT and AST ≤ 2.5 x upper limit of normal, alkaline phosphatase ≤ 4 x upper limit of normal, INR/PTT < 1.5 x upper limit of normal, Patients must have adequate renal function within 7 days prior to screening: serum creatinine < 1.5 x upper limit of normal for age and a creatinine clearance > 60 ml/min for 1.73 m2 Cardiac function defined as a corrected QT (QTcF) interval < 480 msec, LVEF ≥ lower limit of normal (LLN) by echocardiogram (ECHO) Adequate blood pressure control (smaller or equal to the 95th percentile for patient's age, height and gender) Patients are willing and able to comply with scheduled visits, treatment plan, laboratory tests and study procedures Guardians (in case of patients under 18 years) or patient if above 18 years must be affiliated to or a beneficiary of health insurance system. Non-inclusion criteria Patients presenting a NF1 congenital disease Pure optic nerve glioma Completely resected tumors Previous treatment except tumor surgery Pregnancy and lactation Participation in other clinical trials Prior non-surgical therapy for this indication Diffuse intrinsic pontine glioma (DIPG), even if histologically diagnosed as WHO grade II Subependymal giant astrocytoma (SEGA) in patients with TSC Patient having a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C Known hypersensitivity to drugs or excipients History of another malignancy History of current uncontrolled infection

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Natacha ENTZ-WERLE

Phone

03 3 88 12 83 96

Ext

0033

Natacha.entz-werle@chru-strasbourg.fr

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Natacha ENTZ-WERLE

Organizational Affiliation

Hôpitaux Universitaires de Strasbourg

Official's Role

Principal Investigator

Facility Information:

Facility Name

CHU Strasbourg - France

City

Strasbourg

ZIP/Postal Code

67091

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Natacha ENTZ-WERLE, MD

Phone

3 3 88 12 83 96

Ext

0033

Natacha.entz-werle@chru-strasbourg.fr

First Name & Middle Initial & Last Name & Degree

Natacha ENTZ-WERLE, MD

12. IPD Sharing Statement

Learn more about this trial

Pediatric Low Grade Glioma - MEKinhibitor TRIal vs Chemotherapy

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