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

  • End date
    Dec 1, 2026
  • participants needed
  • sponsor
    St. Justine's Hospital
Updated on 28 March 2021
platelet count
biologic agent
serum pregnancy test
colony stimulating factor
neutrophil count
brain tumor


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.

Condition Plexiform Neurofibroma, Low Grade Glioma, Central Nervous System Glioma
Treatment Trametinib
Clinical Study IdentifierNCT03363217
SponsorSt. Justine's Hospital
Last Modified on28 March 2021


Yes No Not Sure

Inclusion Criteria

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
\. Prior therapy timeline Participants having previously received a
Toxicities will be graded as per the National Cancer Institute Common
chemotherapy agent(s) and/or radiation must conform to the timeline described
Terminology Criteria for Adverse Events (CTCAE), version 5.0
below. There is no limitation on the number of previous treatments or cycles
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/L
Absolute neutrophil count (ANC) 1, 000/L
Total bilirubin 1.5 times the ULN within normal institutional limits for age
Hemoglobin > 80 g/l (transfusion independent within last 2 weeks prior to starting trametinib)
Alanine Aminotransferase (ALT) 2.5 upper limit of normal (ULN)
Platelet count 100,000/L (transfusion independent within last 2 weeks prior to starting trametinib)
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 starting trametinib 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 starting trametinib. 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
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

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
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 enrollment
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
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
Previous surgery Patients who had major surgery within 2 weeks prior to starting trametinib
Pregnant or breastfeeding patients Pregnant or breastfeeding female patients are not eligible for this study
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