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

Primary Purpose

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

Status
Active
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Trametinib
Sponsored by
St. Justine's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Low-grade Glioma focused on measuring 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

Eligibility Criteria

1 Month - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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 when starting trametinib.
  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 (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.

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 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

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 prior to starting trametinib)
  • Platelet count ≥ 100,000/µL (transfusion independent within last 2 weeks prior to starting trametinib)
  • 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 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.

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 enrollment.
  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 starting trametinib.
  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.

Sites / Locations

  • Alberta Children's Hospital
  • Children and Women's Health Centre of British Colombia
  • IWK Health Centre
  • The Hospital for Sick Children
  • CHU Sainte-Justine
  • Montreal Children's Hospital
  • CHU de Québec

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Neurofibromatosis Type 1 (NF1) with low-grade glioma

Neurofibromatosis Type 1 (NF1) with Plexiform Neurofibroma

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

Progressing/Refractory central nervous system (CNS) glioma.

Arm Description

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

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

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

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Time to Progression
Time from treatment start, or censored at the date of last disease evaluation for those without progression reported. Applicable to group 1-2-3-4.
Progression Free Survival
Time from treatment start to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at the date of last disease evaluation. Applicable to group 1-2-3-4.
Overall Survival
Time from treatment start to death due to any cause, or censored at date last known alive. Applicable to group 1-2-3-4.
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability).
Determination of the safety and tolerability of trametinib by assessment of toxicity associated with trametinib (Adverse Events (AEs), Serious Adverse Events (SAEs)). Applicable to group 1-2-3-4.
Determination of the Serum Level of Trametinib.
Determination of the serum level of trametinib by assessment of the through level. Applicable to group 1-2-3-4.
Evaluation of the Quality of Life During Treatment.
Evaluation of the quality of life during treatment with the PedsQL cancer/brain tumor modules. Applicable to group 1-2-3-4.

Full Information

First Posted
November 10, 2017
Last Updated
October 25, 2022
Sponsor
St. Justine's Hospital
Collaborators
Montreal Children's Hospital of the MUHC, CHU de Quebec-Universite Laval
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1. Study Identification

Unique Protocol Identification Number
NCT03363217
Brief Title
Trametinib for Pediatric Neuro-oncology Patients With Refractory Tumor and Activation of the MAPK/ERK Pathway.
Official Title
A Phase 2 Study of Trametinib for Patients With Pediatric Glioma or Plexiform Neurofibroma With Refractory Tumor and Activation of the MAPK/ERK Pathway.
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 16, 2018 (Actual)
Primary Completion Date
March 1, 2027 (Anticipated)
Study Completion Date
March 1, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
St. Justine's Hospital
Collaborators
Montreal Children's Hospital of the MUHC, CHU de Quebec-Universite Laval

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
This trial will include 4 parallel groups. Each group will include a particular type of peripheral nerve or central nervous system tumor or mutation.
Masking
None (Open Label)
Masking Description
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.
Allocation
Non-Randomized
Enrollment
114 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Neurofibromatosis Type 1 (NF1) with low-grade glioma
Arm Type
Experimental
Arm Description
Patients presenting with Neurofibromatosis Type 1 (NF1) and a progressing/refractory low-grade glioma.
Arm Title
Neurofibromatosis Type 1 (NF1) with Plexiform Neurofibroma
Arm Type
Experimental
Arm Description
Patients presenting with Neurofibromatosis Type 1 (NF1) and a plexiform neurofibroma
Arm Title
Progressing/refractory low grade-glioma, KIAA1549-BRAF fusion
Arm Type
Experimental
Arm Description
Patients presenting with a progressing/refractory low-grade glioma with a KIAA1549-BRAF fusion.
Arm Title
Progressing/Refractory central nervous system (CNS) glioma.
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Trametinib
Other Intervention Name(s)
Mekinist
Intervention Description
Daily administration of oral trametinib at a unique dose of 0.025 mg/kg.
Primary Outcome Measure Information:
Title
Objective Response Rate
Description
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.
Time Frame
From date of treatment start until the date of first documented progression, up to completion of treatment (504 treatment days).
Secondary Outcome Measure Information:
Title
Time to Progression
Description
Time from treatment start, or censored at the date of last disease evaluation for those without progression reported. Applicable to group 1-2-3-4.
Time Frame
From date of treatment start up to 3 years following completion of treatment (504 treatment days).
Title
Progression Free Survival
Description
Time from treatment start to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at the date of last disease evaluation. Applicable to group 1-2-3-4.
Time Frame
From date of treatment start up to 3 years following completion of treatment (504 treatment days).
Title
Overall Survival
Description
Time from treatment start to death due to any cause, or censored at date last known alive. Applicable to group 1-2-3-4.
Time Frame
From date of treatment start up to 3 years following completion of treatment (504 treatment days).
Title
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability).
Description
Determination of the safety and tolerability of trametinib by assessment of toxicity associated with trametinib (Adverse Events (AEs), Serious Adverse Events (SAEs)). Applicable to group 1-2-3-4.
Time Frame
From treatment start until 30-day follow-up visit.
Title
Determination of the Serum Level of Trametinib.
Description
Determination of the serum level of trametinib by assessment of the through level. Applicable to group 1-2-3-4.
Time Frame
At Cycle 1 day 22 and at tumor progression OR on Day 1 of Cycle 16 (each cycle is 28 days long).
Title
Evaluation of the Quality of Life During Treatment.
Description
Evaluation of the quality of life during treatment with the PedsQL cancer/brain tumor modules. Applicable to group 1-2-3-4.
Time Frame
At screening, week 13, week 25, week 37, week 49, week 61 and at the end of treatment day 504.
Other Pre-specified Outcome Measures:
Title
Neurocognitive assessment of NF1 patients between 1 and 42 months using the Bayley Scales of Infant and Toddlers Development, Third Edition (Bailey-III).
Description
Determine if there are cognitive changes in patients with NF1 during treatment with trametinib. The areas of development assessed to calculate the composite score are: cognition, communication, physical, social/emotional and adaptative. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.
Time Frame
At study inclusion and at the end of treatment (up to treatment day 504).
Title
Neurocognitive assessment of NF1 patients between 2 years and 6 years using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV).
Description
Determine if there are cognitive changes in patients with NF1 during treatment with trametinib.The areas of cognition assessed to calculate the composite score are: verbal comprehension, visual spatial, fluid reasoning, working memory and processing speed. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.
Time Frame
At study inclusion and at the end of treatment (up to treatment day 504).
Title
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).
Description
Determine if there are cognitive changes in patients with NF1 during treatment with trametinib.The areas of cognition assessed to calculate the composite score are: verbal comprehension, visual spatial, fluid reasoning, working memory and processing speed. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.
Time Frame
At study inclusion and at the end of treatment (up to treatment day 504).
Title
Neurocognitive assessment of NF1 patients between 16 years 11 months and 25 years using the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV).
Description
Determine if there are cognitive changes in patients with NF1 during treatment with trametinib.The areas of cognition assessed to calculate the composite score are: verbal comprehension, perceptual reasoning, working memory and processing speed. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.
Time Frame
At study inclusion and at the end of treatment (up to treatment day 504).
Title
Response rate of patients with refractory glioma with activation of the MAPK pathway other than BRAF fusion and NF1
Description
Determination of trametinib usefulness in patients with refractory glioma with activation of the MAPK pathway other than BRAF fusion and NF1. Applicable to group 4
Time Frame
At study inclusion and at the end of treatment (up to treatment day 504).
Title
Comparison of responses with RECIST 1.1 and volumetric measurement for plexiform neurofibroma
Description
Comparison of the best response rate using the RECIST 1.1 criteria and volumetric measurement. Applicable to group 2.
Time Frame
At the achievement of best response to treatment up to treatment day 504.
Title
Investigation and correlation of biological features to tumor response.
Description
Gene expression profiling on fresh frozen tissue and mutational analysis on paraffin-embedded tissue. Circulating tumor DNA (ctDNA) evolution through treatment.
Time Frame
Within 14 days prior to treatment start for investigations of tumor tissue. At screening, week 13, week 25, week 37, week 49, week 61, at the end of treatment day 504 and every 6 months up to 3 years for ctDNA evaluation.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Month
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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. 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 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 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 prior to starting trametinib) Platelet count ≥ 100,000/µL (transfusion independent within last 2 weeks prior to starting trametinib) 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 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. 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: Other investigational agents Patients who are receiving any other investigational agents. 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. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sébastien Perreault, MD
Organizational Affiliation
St. Justine's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Alberta Children's Hospital
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T3B 6A8
Country
Canada
Facility Name
Children and Women's Health Centre of British Colombia
City
Vancouver
State/Province
British Columbia
Country
Canada
Facility Name
IWK Health Centre
City
Halifax
State/Province
Nova Scotia
Country
Canada
Facility Name
The Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
CHU Sainte-Justine
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada
Facility Name
Montreal Children's Hospital
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H4A 3J1
Country
Canada
Facility Name
CHU de Québec
City
Quebec City
State/Province
Quebec
ZIP/Postal Code
G1V 4G2
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
31881853
Citation
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.
Results Reference
derived

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

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