Histologically proven grade 1 glioma/mixed glio-neuronal tumors or pleomorphic xanthoastrocytoma (PXA) confirmed
Conditions
Interventions
Trade Name: MEKINIST
Product Name: MEKINIST
Pharmaceutical Form: Tablet
Trade Name: VELBE
Pharmaceutical Form: Powder for solution for injection
Product Name: Trametinib 5mg poudre pour solution buv
Sponsors
Hôpitaux Universitaires de Strasbourg B.1.2
Eligibility
Sex/Gender
All
Inclusion 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 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 progression • Females of childbearing 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 childbearing 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 60 ml/min for 1.73 m2 • Cardiac function defined as a corrected QT (QTcF) interval < 480 msec, LVEF (left-ventricular-ejection-fraction) = 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 • Gu
Exclusion criteria
Exclusion 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 during all protocol • 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: A 3-year PFS (Progression Free Survival) between the standard treatment (e.g. weekly intra-veinous vinblastine) in the group of non-NF1 PLGG, characterized by a wild-type BRAF gene, to the experimental arm (e.g. daily oral MEK inhibitor, Trametinib (Mekinist©) during 18 courses (e.g. 72 weeks).;Secondary Objective: 1.To evaluate tumor objective response rate (ORR) at 24 and 72 weeks 2.Estimation of overall survival (OS) for each treatment arm 3.Toxicity and safety of the new experimental compound comparatively to the control arm during treatment and until 40 days after last administration of experimental drug 4.Comparing the quality of life (QoL) assessment between a daily oral compound and an IV weekly administration of chemotherapy 5.Homogeneity of treatment effect across molecular strata in each group of treatment 6.Exploratory correlation between visual outcome and the response treatment in patients with optic pathway glioma (OPG) 7.To collect additional data on survival and security for patient benefiting from the switch from the standard arm to Trametinib supply in case of relapse/progression ;Primary end point(s): 3-year progression free survival (PFS) rates comparing both arms (standard vs experimental). The analysis will be based on PFS measured from time of 1st treatment administration up to an event, during the first 3 years of follow-up.;Timepoint(s) of evaluation of this end point: 3 years | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Tumor response at 24 and 72 weeks based on the international and recognized RANO criteria • 3-year OS rates for both arms. The OS calculation will take into account the survival measured from time of 1st treatment administration up to death. • Frequency and description of AE/SAE/SUSAR (Adverse Event/Serious Adverse Event) based on CTCAE criteria focusing on visual disturbances, skin, intestinal and cardiac side effects in the experimental arm compared with the standard control arm • QoL based on specific questionnaires at 24 weeks, at the end of treatment and 3 years after 1st treatment administration in both arms. This analysis is based on PEDsQL questionnaires • 3-year PFS and OS rates according to molecular biomarkers obtained at the entry of the study and based on stratification done at randomization of patients in both arms • 3-year PFS and OS rates according to visual outcome with an analysis of visual function (LogMAR scale) at baseline, at 24 weeks, at the end of treatment and 3 years after 1st treatment administration (both arms are planned to be stratified on locations) • Survival rate (OS, PFS), response rate and AE/SAE/SUSAR rate in the group where a switch from the standard arm to the experimental drug is done at relapse/progression ;Timepoint(s) of evaluation of this end point: 3 years | — |
Countries
France
Contacts
Public ContactEric DEMONSANT
Hôpitaux universitaires de Strasbourg
Outcome results
None listed