Informations générales (source: ClinicalTrials.gov)
A Randomized and Controlled Phase II Protocol in Non NF1 Pediatric and AYA (Adolescent and Young Adults) Patients Bearing a Newly Diagnosed Low Grade Glioma With Wild Type BRAF Gene Comparing a Daily Oral MEK Inhibitor (Trametinib) Versus Weekly Vinblastine for 18 Months (PLGG - MEKTRIC)
Interventional
Phase 2
University Hospital, Strasbourg, France (Voir sur ClinicalTrials)
mai 2022
décembre 2031
30 août 2024
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 ).
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT CURIE | 04/09/2024 13:49:40 | Contacter | |||
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| CLCC INSTITUT GUSTAVE ROUSSY | Samuel ABBOU, MD | Contact (sur clinicalTrials) | |||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| APHM - 13385 - Marseille - France | Nicolas ANDRE, MD | Contact (sur clinicalTrials) | |||
| Centre Leon Berard - 69373 - Lyon - France | Pierre LEBLOND, MD | Contact (sur clinicalTrials) | |||
| Chu Amiens Picardie - 80054 - Amiens - France | Camille KHANFAR, MD | Contact (sur clinicalTrials) | |||
| CHU CAEN - 14 033 - Caen - France | Marianna DEPARIS, MD | Contact (sur clinicalTrials) | |||
| Chu D'Angers - 49933 - Angers - France | Emilie DE CARLI, MD | Contact (sur clinicalTrials) | |||
| Chu de Besancon - 25030 - Besancon - France | Véronique LAITHIER, MD | Contact (sur clinicalTrials) | |||
| Chu de Brest Morvan - 29609 - Brest - France | Liana CARAUSU CARAUSU, MD | Contact (sur clinicalTrials) | |||
| Chu de Nancy - 54500 - Vandoeuvre Les Nancy - France | Pascal CHASTAGNER | Contact (sur clinicalTrials) | |||
| Chu de Nice - 06202 - Nice - France | Gwenaëlle DUHIL DE BENAZE | Contact (sur clinicalTrials) | |||
| CHU de REIMS - 51100 - Reims - France | Grégory GUIMARD | Contact (sur clinicalTrials) | |||
| Chu de Rennes - 35203 - Rennes - France | Chloé PUISEUX | Contact (sur clinicalTrials) | |||
| Chu Dijon Bourgogne - 21079 - Dijon - France | Florent NEUMANN, MD | Contact (sur clinicalTrials) | |||
| Chu Grenoble Alpes - 38043 - Grenoble - France | Anne PAGNIER | Contact (sur clinicalTrials) | |||
| Chu Limoges - 87042 - Limoges - France | Christophe PIGUET | Contact (sur clinicalTrials) | |||
| Chu Montpellier - 34 295 - Montpellier - France | Gilles PALENZUELA | Contact (sur clinicalTrials) | |||
| Chu Poitiers Chu La Miletrie - 86022 - Poitiers - France | Frédéric MILLOT | Contact (sur clinicalTrials) | |||
| Chu Rouen - 76031 - Rouen - France | Aude Marie CARDINE | Contact (sur clinicalTrials) | |||
| Chu Saint Etienne - 42100 - Saint Etienne - France | Sandrine THOUVENIN | Contact (sur clinicalTrials) | |||
| CHU Strasbourg - France - 67091 - Strasbourg - France | Natacha ENTZ-WERLE, MD | Contact (sur clinicalTrials) | |||
| Chu Toulouse - 31 059 - Toulouse - France | Anne Isabelle BERTOZZI | Contact (sur clinicalTrials) | |||
| Chu Tours - 37044 - Tours - France | Marion YVERT | Contact (sur clinicalTrials) | |||
| Clcc Oscar Lambret Lille - 59020 - Lille - France | Sandra RAIMBAULT | Contact (sur clinicalTrials) | |||
| Groupe Hospitalier Pellegrin - 33000 - Bordeaux - France | Céline ICHER, MD | Contact (sur clinicalTrials) | |||
Critères
Tous
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 can understand the impact of clinical
trial and to give consent. For patients above 18 years, their written informed
consent will be obtained.
- Patient may be under guardianship or curatorship (for patient under legal
guardianship, authorization is given by the legal representative of the patient
under guardianship. For patient under curatorship, consent will be obtained from the
adult assisted by his or her legal curator
- Histologically proven grade 1 glioma/mixed glio-neuronal tumors or pleomorphic
xanthoastrocytoma (PXA) confirmed by local referee and the centrally pathology
reviewing
- Determination of a negative BRAFv600 mutation by immunohistochemistry and/or
molecular methods
- Systematic determination 7q34 duplication status or KIAA1549-BRAF fusion
- Midline tumors without proven histone H3 mutations
- Diffuse glioma without IDH1 mutation
- Collection of 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 neurofibromatosis type 1 (NF1) congenital disease
- Pure optic nerve glioma, limited to one nerve and without optic chiasma
infiltration.
- Completely resected tumors
- Previous treatment except tumor surgery
- Pregnancy and lactation
- Participation in other clinical trials
- Prior non-surgical therapy for this tumor
- 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
- Age: ≥ 1 month to ≤ 25 years
- Signed written informed consent prior to study participation of the legal
representatives and the patient if the patient can understand the impact of clinical
trial and to give consent. For patients above 18 years, their written informed
consent will be obtained.
- Patient may be under guardianship or curatorship (for patient under legal
guardianship, authorization is given by the legal representative of the patient
under guardianship. For patient under curatorship, consent will be obtained from the
adult assisted by his or her legal curator
- Histologically proven grade 1 glioma/mixed glio-neuronal tumors or pleomorphic
xanthoastrocytoma (PXA) confirmed by local referee and the centrally pathology
reviewing
- Determination of a negative BRAFv600 mutation by immunohistochemistry and/or
molecular methods
- Systematic determination 7q34 duplication status or KIAA1549-BRAF fusion
- Midline tumors without proven histone H3 mutations
- Diffuse glioma without IDH1 mutation
- Collection of 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 neurofibromatosis type 1 (NF1) congenital disease
- Pure optic nerve glioma, limited to one nerve and without optic chiasma
infiltration.
- Completely resected tumors
- Previous treatment except tumor surgery
- Pregnancy and lactation
- Participation in other clinical trials
- Prior non-surgical therapy for this tumor
- 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