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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Les Hopitaux Universitaires De Strasbourg

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Mar 2024 → ongoing

Decision date (initial)

2024-03-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Direction générale de l’offre de soins (DGOS) - DGOS N°: PHRCK-19-069)

External identifiers

EU CT number

2023-508531-30-00

EudraCT number

2020-005786-14

ClinicalTrials.gov

NCT05180825

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

improve the current standard treatment regimen expecting a superiority of the experimental arm (e.g. MEK inhibitor, daily Trametinib (Mekinist©)) vs standard therapy (e.g. weekly IV Vinblastine) during a length of 18 courses (4 weeks each, a total of 72 weeks) in the group of non-NF1 PLGGs, characterized by a wild-type BRAF gene. This expected superiority of the 3-year PFS is estimated to 20%.

Secondary objectives 7

1. • To evaluate tumor objective response rate (ORR) at 24 and 72 weeks based on RANO criteria
2. • To estimate overall survival (OS) for each treatment arm at 3 years
3. • To follow the toxicity and safety of the new experimental compound comparatively to the control arm during treatment and at 3 years after starting treatment
4. • To compare the quality of life (QoL) between the 2 arms (e.g. a daily oral compound vs IV weekly administration of chemotherapy)
5. • To evaluate the treatment effect across molecular strata in each group of treatment
6. • To correlate the visual outcome and the response to treatment in patients with OPG
7. • To obtain data on patients having the experimental drug after first progression/relapse on therapy.

Conditions and MedDRA coding

grade 1 glioma/mixed glio-neuronal tumors or pleomorphic xanthoastrocytoma (PXA)

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 21

1. • Age: ≥ 1 month to ≤ 25 years
2. • 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.
3. • 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
4. • Histologically proven grade 1 glioma/mixed glio-neuronal tumors or pleomorphic xanthoastrocytoma (PXA) confirmed by local referee and the centrally pathology reviewing
5. • Determination of a negative BRAFv600 mutation by immunohistochemistry and/or molecular methods
6. • Systematic determination 7q34 duplication status or KIAA1549-BRAF fusion
7. • Midline tumors without proven histone H3 mutations
8. • Diffuse glioma without IDH1 mutation
9. • Collection of fresh frozen tumor tissues and/or paraffin-embedded samples for further molecular biomarker testing
10. • Sus-tentorial, optic pathway, midline and spine locations allowed
11. • Karnofsky or Lansky ≥ 50%
12. • 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.
13. • 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
14. • 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.
15. • 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
16. • 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,
17. • 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
18. • Cardiac function defined as a corrected QT (QTcF) interval < 480 msec, LVEF ≥ lower limit of normal (LLN) by echocardiogram (ECHO)
19. • Adequate blood pressure control (smaller or equal to the 95th percentile for patient's age, height and gender)
20. • Patients are willing and able to comply with scheduled visits, treatment plan, laboratory tests and study procedures
21. • 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.

Exclusion criteria 14

1. • Patients presenting a neurofibromatosis type 1 (NF1) congenital disease
2. • Patient having a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C
3. • Known hypersensitivity to drugs or excipients
4. • History of another malignancy
5. • History of current uncontrolled infection
6. • Pure optic nerve glioma, limited to one nerve and without optic chiasma infiltration.
7. • Completely resected tumors
8. • Previous treatment except tumor surgery
9. • Pregnancy and lactation
10. • Participation in other clinical trials
11. • Prior non-surgical therapy for this tumor
12. • Diffuse intrinsic pontine glioma (DIPG), even if histologically diagnosed as WHO grade II
13. • Subependymal giant astrocytoma (SEGA) in patients with TSC
14. Patients receiving government medical aid (Aide Médicale de l'Etat - AME)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 7

1. • the 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.
2. • the 3-year OS rate: the OS calculation will take into account the survival measured from time of 1st treatment administration up to death.
3. • 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 safety assessment will be done by cycle and by patient.
4. • the 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.
5. • the 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.
6. • the 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.
7. • the 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Les Hopitaux Universitaires De Strasbourg

Sponsor organisation

Les Hopitaux Universitaires De Strasbourg

Address

1 Place De L Hopital, Cs 80426 Cs 80426

City

Strasbourg Cedex

Postcode

67091

Country

France

Scientific contact point

Organisation

Les Hopitaux Universitaires De Strasbourg

Contact name

Natacha ENTZ-WERLE

Public contact point

Organisation

Les Hopitaux Universitaires De Strasbourg

Contact name

Natacha ENTZ-WERLE

Locations

1 EU/EEA country · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 29 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications