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

Study Purpose

This is a phase 1/2, 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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.

An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.

Searching Both is inclusive of interventional and observational studies.

Eligible Ages 1 Month - 25 Years
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

1. 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. 2. Assent Assent from minor participants should be obtained per local laws and regulations and should be documented in accordance with local requirements. 3. 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. 4. Age Patient must be aged ≥ 1 month (corrected age) to ≤ 25 years at the time of study enrollment 5. 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 6. Tumor Tissue Sample Tumor tissue will be required for all patients (fresh tissue recommended when available). Patients with NF1 and LGG or PN can still be enrolled without tissue if no surgery or biopsy was conducted. 7 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. 8. 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). 9. Prior therapy toxicity Patients must have recovered to grade ≤ 1 from acute toxic effects of all prior chemotherapy, immunotherapy or radiotherapy prior to enrollment. Toxicities will be graded as per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. 10. 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.
11. Life expectancy Patients must have a life expectancy of greater than 6 months. 12. Performance level Patients must have a performance status corresponding to a Lansky/Karnofsky score ≥50. 13. Organ Function Requirements Participants must have normal organ and marrow function as defined below:
  • - Total leukocytes ≥ 3,000/µL - Absolute neutrophil count (ANC) ≥ 1, 000/µL - Hemoglobin > 80 g/l (transfusion independent within last 2 weeks) - Platelet count ≥ 100,000/µL (transfusion independent within last 2 weeks) - Total bilirubin ≤ 1.5 times the ULN within normal institutional limits for age - Alanine Aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN)* - Creatinine serum within normal institutional limits for age OR creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.
  • - Creatine phosphokinase ≤ 2x ULN - A cardiac function defined as Corrected QT (QTcB) interval < 480 msec and LVEF ≥ lower limit of normal (LLN) by echocardiogram (ECHO).
  • - Blood pressure must be smaller or equal to the 95th percentile for patient's age, height and gender.
  • - For uniformity reasons, the ULN for ALT will be 45 U/L in this study 14.
Reproductive status Children of childbearing and child-fathering potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a female become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males and females treated or enrolled in this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of trametinib administration. Furthermore, females of childbearing potential (older than 10 years old for this study) must have a negative serum pregnancy test within 7 days prior to the start of study drug. A urine pregnancy test will be done according to evaluation calendar at at 30 days and at 6 months following the last does of study medications. 15. Administration of oral medication Patients must be able to ingest and retain enterally (per os, nasogastric tube or gastrostomy) administered medication and be free of any clinically significant gastrointestinal abnormalities limiting the absorption of the medication. Tablets cannot be crushed. If the patient cannot swallow tablets, the liquid form should then be used. SPECIFIC INCLUSION CRITERIA Participants must belong to one of the following groups to be eligible.
  • - Group 1: NF1 with Progressing/Refractory LGG (42 patients).
  • - Group 2: NF1 with Progressing/Refractory PN (46 patients).
  • - Group 3: Progressing/Refractory LGG with KIAA1549-BRAF fusion (42 patients).
  • - Group 4: Progressing/Refractory CNS Glioma with activation of the MAPK/ERK pathway who do not meet criteria of other study groups (20 patients).

Exclusion Criteria:

1. Other investigational agents Patients who are receiving any other investigational agents. 2. Cardiac exclusion criteria Patients who have an ejection fraction inferior to the institution LLN, a QTcB ≥ 480 msec or an absolute resting left ventricular ejection fraction (LVEF) of ≤ 39% are not eligible for enrolment. 3. Presence of another malignancy Patient has any other malignancy except if the other primary malignancy is neither currently clinically significant nor requiring active intervention. 4. Previous MEK inhibitor treatment Participants previously treated with a MEK inhibitor who showed less than stable disease during treatment. 5. Tumor with BRAF V600E mutation Patients with a tumor presenting a positive BRAF V600E mutation. 6. 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. 7. Known HIV infection Patient has a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C. 8. Previous surgery Patients who had major surgery within 2 weeks prior to study entry. 9. Allergy History of allergic reactions attributed to compounds of similar chemical or biologic composition to trametinib. 10. Previous history of non-compliance Patients with a previous significant history of non-compliance to their treatment or medical regimen. 11. Pregnant or breastfeeding patients Pregnant or breastfeeding female patients are not eligible for this study.

Trial Details

Trial ID:

This trial id was obtained from, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.


Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1/Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

St. Justine's Hospital
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Sébastien Perreault, MD
Principal Investigator Affiliation St. Justine's Hospital
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Overall Status Recruiting
Countries Canada

The disease, disorder, syndrome, illness, or injury that is being studied.

Low-grade Glioma, Plexiform Neurofibroma, Central Nervous System Glioma
Arms & Interventions


Experimental: Neurofibromatosis Type 1 (NF1) with low-grade glioma

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

Experimental: Neurofibromatosis Type 1 (NF1) with Plexiform Neurofibroma

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

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

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

Experimental: Progressing/Refractory central nervous system (CNS) glioma.

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

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

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

International Sites

Alberta Children's Hospital, Calgary, Alberta, Canada




Alberta Children's Hospital

Calgary, Alberta, T3B 6A8

Site Contact

Lucie Lafay-Cousin, MD

1 403-955-2554

Vancouver, British Columbia, Canada




Children and Women's Health Centre of British Colombia

Vancouver, British Columbia,

Site Contact

Juliette Hukin, MD


The Hospital for Sick Children, Toronto, Ontario, Canada




The Hospital for Sick Children

Toronto, Ontario, M5G 1X8

Site Contact

Ruben Machado, MSc

(416) 813-7654 #203204

CHU Sainte-Justine, Montreal, Quebec, Canada




CHU Sainte-Justine

Montreal, Quebec, H3T 1C5

Montreal Children's Hospital, Montreal, Quebec, Canada




Montreal Children's Hospital

Montreal, Quebec, H4A 3J1

Site Contact

Genevieve Legault, MD


CHU de Québec, Quebec City, Quebec, Canada




CHU de Québec

Quebec City, Quebec, G1V 4G2

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