Trametinib for Pediatric Neuro-oncology Patients With Refractory Tumor and Activation of the MAPK/ERK Pathway.

NCT03363217 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: Trametinib study TRAM-01
• Study Type: interventional
• Target: 114
• Locations: 1 country
• Sites: 7

Brief Summary

This is a phase 2, open-label, interventional clinical trial that will study the response rate of pediatric glioma and plexiform neurofibroma (PN) to oral administration of trametinib. Patients meeting all inclusion criteria for a given study group will receive the study medication at a daily dose of 0.025 mg/kg up to a total of 18 cycles, in 28-day cycles. A total of 150 patients will be recruited as part of this clinical study. Patients aged between 1 month (corrected age) and 25 years old will be eligible, in order to include a maximum of patients affected by low-grade glioma (LGG) and PN. This study includes four groups: patients with neurofibromatosis type 1 (NF1) and LGG, NF1 patients with PN, patients with LGG with a B-Raf Serine/Threonine-protein Kinase/Proto-oncogene Encoding B-Raf (BRAF) fusion and patients with glioma of any grade with activation of the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinases (MAPK/ERK) pathway. All patients except patients with PN must have failed at least one line of treatment. The study will also explore the molecular mechanisms behind tumor development, progression and resistance to treatment. Furthermore, this study will also explore important aspects for patients with brain tumors by including assessment of quality of life and neuropsychological evaluation.

Conditions

Low-grade Glioma; Plexiform Neurofibroma; Central Nervous System Glioma

Keywords

Glioma; Optic Pathway Glioma; Low grade glioma; MAPK/ERK; Plexiform Neurofibroma; Neurofibromatosis Type 1; Central Nervous System; CNS; Brain Tumor; LGG; NF1; KIAA1549-BRAF; Mitogen-activated Protein Kinase (MEK) inhibitor; Trametinib

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate

  Determination of the objective response rate of daily trametinib as a single agent for treatment of progressing/refractory low-grade tumors with MAPK/ERK pathway activation.

  From date of treatment start until the date of first documented progression, up to completion of treatment (504 treatment days).

Secondary Outcomes (6)

• Time to Progression

  From date of treatment start up to 3 years following completion of treatment (504 treatment days).

• Progression Free Survival

  From date of treatment start up to 3 years following completion of treatment (504 treatment days).

• Overall Survival

  From date of treatment start up to 3 years following completion of treatment (504 treatment days).

• Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability).

  From treatment start until 30-day follow-up visit.

• Determination of the Serum Level of Trametinib.

  At Cycle 1 day 22 and at tumor progression OR on Day 1 of Cycle 16 (each cycle is 28 days long).

Other Outcomes (7)

• Neurocognitive assessment of NF1 patients between 1 and 42 months using the Bayley Scales of Infant and Toddlers Development, Third Edition (Bailey-III).

  At study inclusion and at the end of treatment (up to treatment day 504).

• Neurocognitive assessment of NF1 patients between 2 years and 6 years using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV).

  At study inclusion and at the end of treatment (up to treatment day 504).

• Neurocognitive assessment of NF1 patients between 6 years and 16 years and 11 months using the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V).

  At study inclusion and at the end of treatment (up to treatment day 504).

Study Arms (4)

Neurofibromatosis Type 1 (NF1) with low-grade glioma

EXPERIMENTAL

Patients presenting with Neurofibromatosis Type 1 (NF1) and a progressing/refractory low-grade glioma.

Drug: Trametinib

Neurofibromatosis Type 1 (NF1) with Plexiform Neurofibroma

EXPERIMENTAL

Patients presenting with Neurofibromatosis Type 1 (NF1) and a plexiform neurofibroma

Drug: Trametinib

Progressing/refractory low grade-glioma, KIAA1549-BRAF fusion

EXPERIMENTAL

Patients presenting with a progressing/refractory low-grade glioma with a KIAA1549-BRAF fusion.

Drug: Trametinib

Progressing/Refractory central nervous system (CNS) glioma.

EXPERIMENTAL

Patients presenting with a progressing/refractory central nervous system glioma with an activation of the MAPK/ERK pathway who do not meet criteria for inclusion in other study groups.

Drug: Trametinib

Interventions

Trametinib DRUG

Daily administration of oral trametinib at a unique dose of 0.025 mg/kg.

Also known as: Mekinist

Neurofibromatosis Type 1 (NF1) with Plexiform Neurofibroma; Neurofibromatosis Type 1 (NF1) with low-grade glioma; Progressing/Refractory central nervous system (CNS) glioma.; Progressing/refractory low grade-glioma, KIAA1549-BRAF fusion

Eligibility Criteria

• Age: 1 Month - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Signed written informed consent Prior to study participation, written informed consent from participants, or in the case of minors, written permission (informed consent) from parents, guardians, or legally acceptable representatives must be obtained according to local laws and regulations.
• Assent Assent from minor participants should be obtained per local laws and regulations and should be documented in accordance with local requirements.
• Study activities compliance. Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study, including disease assessment by contrast-enhanced MRI.
• Age Patient must be aged ≥ 1 month (corrected age) to ≤ 25 years when starting trametinib.
• Study group Participants must belong to one of the following groups to be eligible. Group 1: NF1 with progressing/refractory LGG Group 2: NF1 with PN Group 3: Progressing/refractory LGG with KIAA 1549-BRAF fursion Group 4: Progressing/refractory glioma with activation of the MPAK/ERK pathway who do not meet criteria for other study groups
• Tumor Tissue Sample Tumor tissue will be required for all patients (minimally paraffin-embedded tissue block and additionally fresh frozen tissue \[if available\]). Patients with NF1 and LGG or PN can still be enrolled without tissue if no surgery or biopsy was conducted.
• Previous MRI At least two previous MRIS fro Group 1, 3, 4 and one previous MRI for Group 2 must be available for central review.
• \. Prior therapy Participants must have failed at least one line of treatment including chemotherapy and/or radiation therapy except for plexiform neurofibroma (since there is no recognized standard treatment for his tumor).
• \. Prior therapy toxicity Patients must have recovered to grade ≤ 1 from acute toxic effects of all prior chemotherapy, immunotherapy or radiotherapy prior to enrollment except for alopecia and non-treatment related clinically insignificant laboratory abnormalities. prior to starting trametinib. Toxicities will be graded as per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0
• \. Prior therapy timeline Participants having previously received a chemotherapy agent(s) and/or radiation must conform to the timeline described below. There is no limitation on the number of previous treatments or cycles received.
• An interval of at least 28 days after the last dose of a myelosuppressive chemotherapy, and at least 42 days after the last dose of Nitrosoureas is required prior to starting trametinib.
• An interval of at least 28 days after the last dose of any biologic agents including monoclonal antibody treatment, immunotherapy, viral therapy and other investigational agent is required prior to starting trametinib.
• An interval of at least 84 days after the end of the radiation therapy is required prior to starting trametinib.
• An interval of at least 48 hours for short-acting colony stimulating factor agents and 10 days interval for long-acting colony stimulating factor agents are required prior to starting trametinib.
• \. Life expectancy Patients must have a life expectancy of greater than 6 months.

You may not qualify if:

• Other investigational agents Patients who are receiving any other investigational agents.
• Presence of another malignancy Patient has any other malignancy except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
• Previous MEK inhibitor treatment Participants previously treated with a MEK inhibitor who showed less than stable disease during treatment.
• Tumor with BRAF V600E mutation Patients with a tumor presenting a positive BRAF V600E mutation.
• Other uncontrollable medical disease Patient has a severe and uncontrollable medical disease (i.e., uncontrolled diabetes, chronic renal disease or active uncontrolled infection), has a chronic liver disease (i.e., chronic active hepatitis and cirrhosis), uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Known HIV infection Patient has a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C.
• Previous surgery Patients who had major surgery within 2 weeks prior to starting trametinib.
• Allergy History of allergic reactions attributed to compounds of similar chemical or biologic composition to trametinib.
• Previous history of non-compliance Patients with a previous significant history of non-compliance to their treatment or medical regimen.
• Pregnant or breastfeeding patients Pregnant or breastfeeding female patients are not eligible for this study.

Sponsors & Collaborators

• St. Justine's Hospital: lead
• Montreal Children's Hospital of the MUHC: collaborator
• CHU de Quebec-Universite Laval: collaborator

Study Sites (7)

Alberta Children's Hospital

Calgary, Alberta, T3B 6A8, Canada

Location

Children and Women's Health Centre of British Colombia

Vancouver, British Columbia, Canada

Location

IWK Health Centre

Halifax, Nova Scotia, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

CHU Sainte-Justine

Montreal, Quebec, H3T 1C5, Canada

Location

Montreal Children's Hospital

Montreal, Quebec, H4A 3J1, Canada

Location

CHU de Québec

Québec, Quebec, G1V 4G2, Canada

Location

Related Publications (1)

• Perreault S, Larouche V, Tabori U, Hawkin C, Lippe S, Ellezam B, Decarie JC, Theoret Y, Metras ME, Sultan S, Cantin E, Routhier ME, Caru M, Legault G, Bouffet E, Lafay-Cousin L, Hukin J, Erker C, Jabado N. A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01. BMC Cancer. 2019 Dec 27;19(1):1250. doi: 10.1186/s12885-019-6442-2.

  PMID: 31881853 DERIVED

MeSH Terms

Conditions

Neurofibroma, Plexiform; Glioma; Neurofibromatosis 1; Brain Neoplasms

Interventions

trametinib

Condition Hierarchy (Ancestors)

Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Peripheral Nervous System Neoplasms; Nervous System Neoplasms; Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neurofibromatoses; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Central Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases

Study Officials

• Sébastien Perreault, MD

  St. Justine's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: There is no masking as part of this study. Only one study treatment will be given to all treatment groups at age and weight based dose.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This trial will include 4 parallel groups. Each group will include a particular type of peripheral nerve or central nervous system tumor or mutation.

Study Record Dates

• First Submitted: November 10, 2017
• First Posted: December 6, 2017
• Study Start: August 16, 2018
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027
• Last Updated: April 24, 2026

Record last verified: 2026-04

Locations

CA (7)