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
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
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
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
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).
1. Other investigational agents Patients who are receiving any other investigational
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
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
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.