Trametinib for Low-grade glioma | Mixed glio-neuronal tumour | Pleomorphic xanthoastrocytoma (PXA)

Inclusion criteria

• {"criterion_text":"- •\tAge: ≥ 1 month to ≤ 25 years\n- •\tSigned 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.\n- •\tPatient 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\n- •\tHistologically proven grade 1 glioma/mixed glio-neuronal tumors or pleomorphic xanthoastrotoma (PXA) confirmed by local referee and the centrally pathology reviewing\n- •\tDetermination of a negative BRAFv600 mutation by immunohistochemistry and/or molecular methods\n- •\tCollection of fresh frozen tumor tissues and/or paraffin-embedded samples for further molecular biomarker testing\n- •\tSus-tentorial, optic pathway, midline and spine locations allowed\n- •\tKarnofsky or Lansky ≥ 50%\n- •\tCriteria 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.\n- •\tInfants below one year of age with chiasmatic and/or hypothalamic tumor will be treated immediately after surgery, independently from neurological and/or visual evolution\n- •\tFemales 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.\n- •\tPatients must have adequate bone marrow function defined as: absolute neutrophil count (ANC) ≥ 1500/µL; platelets ≥ 100,000/µL and hemoglobin ≥ 9.0 g/dl\n- •\tPatients 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,\n- •\tPatients 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\n- •\tCardiac function defined as a corrected QT (QTcF) interval < 480 msec, LVEF ≥ lower limit of normal (LLN) by echocardiogram (ECHO)\n- •\tAdequate blood pressure control (smaller or equal to the 95th percentile for patient's age, height and gender)\n- •\tPatients are willing and able to comply with scheduled visits, treatment plan, laboratory tests and study procedures\n- •\tGuardians (in case of patients under 18 years) or patient if above 18 years must be affiliated to or a beneficiary of health insurance system.\n- •\tSystematic determination 7q34 duplication status or KIAA1549-BRAF fusion\n- •\tMidline tumors without proven histone H3 mutations\n- •\tDiffuse glioma without IDH1 mutation"}

Exclusion criteria

• {"criterion_text":"- •\tPatients presenting a neurofibromatosis type 1 (NF1) congenital disease\n- •\tPatient having a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C\n- •\tKnown hypersensitivity to drugs or excipients\n- •\tHistory of another malignancy\n- •\tHistory of current uncontrolled infection\n- •\tPure optic nerve glioma, limited to one nerve and without optic chiasma infiltration.\n- •\tCompletely resected tumors\n- •\tPrevious treatment except tumor surgery\n- •\tParticipation in other clinical trials\n- •\tPrior non-surgical therapy for this tumor\n- •\tDiffuse intrinsic pontine glioma (DIPG), even if histologically diagnosed as WHO grade II\n- •\tSubependymal giant astrocytoma (SEGA) in patients with TSC\n- Patients receiving government medical aid (Aide Médicale de l'Etat - AME)\n- •\tPregnancy and lactation"}

Primary endpoints

• {"endpoint_text":"- Therefore, our primary endpoint is the 3-year PFS rates comparing the two arms (standard vs experimental). The analysis will be based on PFS measured from time of 1st treatment administration up to the first event during the first 3 years of follow-up. An event is defined as death for all reasons, progression of a residual tumor, reappearance of a tumor in case of disappearance and/or appearance of new locations in the brain and spine.","definition_or_measurement_approach":"PFS measured from time of first treatment administration up to the first event during the first 3 years of follow-up. Event defined as death from any cause, progression of residual tumor, reappearance of tumor after disappearance and/or appearance of new locations in brain and spine."}

Secondary endpoints

• {"endpoint_text":"- •\tthe tumor response at 24 and 72 weeks 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.","definition_or_measurement_approach":"Tumor response at 24 and 72 weeks assessed using RANO criteria; ORR determined by central independent radiological review; analysis includes patients with at least 24 weeks of completed treatment or earlier discontinuation for progression; responses grouped PD vs CR/PR/SD."}
• {"endpoint_text":"- •\tthe 3-year OS rate: the OS calculation will take into account the survival measured from time of 1st treatment administration up to death.","definition_or_measurement_approach":"Overall survival measured from time of first treatment administration up to death; 3-year OS rate for each arm."}
• {"endpoint_text":"- •\tthe 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 safety assessment will be done by cycle and by patient.","definition_or_measurement_approach":"AEs/SAEs graded per NCI-CTCAE v5.0; frequency and description recorded by cycle and by patient, with specific focus on visual, skin, intestinal and cardiac events."}
• {"endpoint_text":"- •\tthe QoL based on specific questionnaires (PEDs-QoL) at baseline, 24 weeks, at the end of treatment and 3 years after the first treatment administration. The analysis is based on EORTC adapted QOL questionnaires.","definition_or_measurement_approach":"Quality of life assessed using PEDs-QoL / EORTC adapted questionnaires at baseline, 24 weeks, end of treatment, and 3 years after first treatment."}
• {"endpoint_text":"- •\tthe 3-year 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.","definition_or_measurement_approach":"PFS and OS at 3 years stratified by molecular biomarkers obtained via routine molecular analyses (RENOCLIP-LOC) and central histology review."}
• {"endpoint_text":"- •\tthe 3-year PFS and OS rates according to visual outcome in patient with optic pathway glioma with an analysis of visual function (LoqMAR scale) at baseline, at 24 weeks, at the end of treatment and after 3 years of treatment.","definition_or_measurement_approach":"PFS and OS at 3 years correlated with visual outcomes measured by LogMAR scale at baseline, 24 weeks, end of treatment, and 3 years."}
• {"endpoint_text":"- •\tthe data of patients benefiting from the crossover strategy will be collected to obtain information about response rate, PFS and OS for those patients progressing or relapsing on standard arm treatment.","definition_or_measurement_approach":"Outcomes (response rate, PFS, OS) will be collected for patients who cross over from standard to experimental treatment after progression/relapse."}

France

Earliest CTIS Part Ii Submission Date

29-02-2024

Latest Decision Or Authorization Date

03-09-2025

Processing Time Days

552

Number Of Sites

25

Number Of Participants

134

Primary sponsor

Full Name

Les Hopitaux Universitaires De Strasbourg

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France