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

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ClinicalTrials.gov Identifier: NCT03363217
Recruitment Status : Recruiting
First Posted : December 6, 2017
Last Update Posted : November 5, 2018
Sponsor:
Collaborators:
Montreal Children's Hospital of the MUHC
CHU de Quebec-Universite Laval
Information provided by (Responsible Party):
Dr Perreault, St. Justine's Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Low-grade Glioma Plexiform Neurofibroma Central Nervous System Glioma Drug: Trametinib Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention 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.
Primary Purpose: Treatment
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.
Actual Study Start Date : August 16, 2018
Estimated Primary Completion Date : June 1, 2026
Estimated Study Completion Date : December 1, 2026


Arm Intervention/treatment
Experimental: Neurofibromatosis Type 1 (NF1) with low-grade glioma
Patients presenting with Neurofibromatosis Type 1 (NF1) and a progressing/refractory low-grade glioma.
Drug: Trametinib
Daily administration of oral trametinib at a unique dose of 0.025 mg/kg.
Other Name: Mekinist

Experimental: Neurofibromatosis Type 1 (NF1) with Plexiform Neurofibroma
Patients presenting with Neurofibromatosis Type 1 (NF1) and a plexiform neurofibroma
Drug: Trametinib
Daily administration of oral trametinib at a unique dose of 0.025 mg/kg.
Other Name: Mekinist

Experimental: Progressing/refractory low grade-glioma, KIAA1549-BRAF fusion
Patients presenting with a progressing/refractory low-grade glioma with a KIAA1549-BRAF fusion.
Drug: Trametinib
Daily administration of oral trametinib at a unique dose of 0.025 mg/kg.
Other Name: Mekinist

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.
Other Name: Mekinist




Primary Outcome Measures :
  1. Objective Response Rate [ Time Frame: From date of study inclusion until the date of first documented progression, up to 504 treatment days. ]
    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 :
  1. Time to Progression (time from registration to progression) [ Time Frame: Every 6 months up to 3 years following completion of treatment (504 treatment days). ]
    Time from registration to progression, or censored at the date of last disease evaluation for those without progression reported. Applicable to group 1-2-3-4.

  2. Progression Free Survival (time from registration to the earlier of progression or death). [ Time Frame: Every 6 months up to 3 years following completion of treatment (504 treatment days). ]
    Time from registration 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.

  3. Overall Survival (time from registration to death) [ Time Frame: Every 6 months up to 3 years following completion of treatment (504 treatment days). ]
    Time from registration to death due to any cause, or censored at date last known alive. Applicable to group 1-2-3-4.

  4. Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability). [ Time Frame: At treatment week 2, 3, 4, 5, 9, 13, 17, 21, 25, 48, 72; at the end of 504 treatment days and every 6 months for up to 3 years. ]
    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.

  5. Determination of the Serum Level of Trametinib. [ Time Frame: At day 22 and at tumor progression up to the end of treatment day 504. ]
    Determination of the serum level of trametinib by assessment of the through level. Applicable to group 1-2-3-4.

  6. Evaluation of the Quality of Life During Treatment. [ Time Frame: At screening, week 13, week 25, week 37, week 49, week 61 and at the end of treatment day 504. ]
    Evaluation of the quality of life during treatment with the PedsQL cancer/brain tumor modules. Applicable to group 1-2-3-4.


Other Outcome Measures:
  1. Neurocognitive assessment of NF1 patients between 1 and 42 months using the Bayley Scales of Infant and Toddlers Development, Third Edition (Bailey-III). [ Time Frame: At study inclusion and at the end of treatment (up to treatment day 504). ]
    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.

  2. Neurocognitive assessment of NF1 patients between 2 years and 6 years using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV). [ Time Frame: At study inclusion and at the end of treatment (up to treatment day 504). ]
    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.

  3. 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). [ Time Frame: At study inclusion and at the end of treatment (up to treatment day 504). ]
    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.

  4. Neurocognitive assessment of NF1 patients between 16 years 11 months and 25 years using the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV). [ Time Frame: At study inclusion and at the end of treatment (up to treatment day 504). ]
    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.

  5. Response rate of patients with refractory glioma with activation of the MAPK pathway other than BRAF fusion and NF1 [ Time Frame: At study inclusion and at the end of treatment (up to treatment day 504). ]
    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

  6. Comparison of responses with RECIST 1.1 and volumetric measurement for plexiform neurofibroma [ Time Frame: At the achievement of best response to treatment up to treatment day 504. ]
    Comparison of the best response rate using the RECIST 1.1 criteria and volumetric measurement. Applicable to group 2.

  7. Investigation and correlation of biological features to tumor response. [ 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. ]
    Gene expression profiling on fresh frozen tissue and mutational analysis on paraffin-embedded tissue. Circulating tumor DNA (ctDNA) evolution through treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Month to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03363217


Contacts
Contact: Sébastien Perreault, MD 1-(514)-345-4931 ext 6729 s.perreault@umontreal.ca

Locations
Canada, Ontario
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Ruben Machado, MSc    (416) 813-7654 ext 203204    ruben.machado@sickkids.ca   
Principal Investigator: Eric Bouffet, MD         
Sub-Investigator: Uri Tabouri, MD         
Canada, Quebec
CHU Sainte-Justine Recruiting
Montreal, Quebec, Canada, H3T 1C5
Contact: Linda Hershon    1-(514)-345-4931 ext 5899    linda.hershon@recherche-ste-justine.qc.ca   
Principal Investigator: Sébastien Perreault, MD         
Montreal Children's Hospital Not yet recruiting
Montreal, Quebec, Canada, H4A 3J1
Contact: Nada Jabado, MD    1-(514)-934-1934 ext 76163    nada.jabado@mcgill.ca   
Principal Investigator: Genevieve Legault, MD         
Sub-Investigator: Nada Jabado, MD         
CHU de Québec Recruiting
Quebec City, Quebec, Canada, G1V 4G2
Contact: Pana Giannakouros, MSc    1(418) 525-4444 ext 71671    panagiota.giannak@crchudequebec.ulaval.ca   
Contact: Valerie Larouche, MD    1(418) 525-4444    Valerie.Larouche@mail.chudequebec.ca   
Principal Investigator: Valerie Larouche, MD         
Sponsors and Collaborators
St. Justine's Hospital
Montreal Children's Hospital of the MUHC
CHU de Quebec-Universite Laval
Investigators
Principal Investigator: Sébastien Perreault, MD St. Justine's Hospital

Responsible Party: Dr Perreault, Principal Investigator, St. Justine's Hospital
ClinicalTrials.gov Identifier: NCT03363217     History of Changes
Other Study ID Numbers: Trametinib study TRAM-01
First Posted: December 6, 2017    Key Record Dates
Last Update Posted: November 5, 2018
Last Verified: November 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Dr Perreault, St. Justine's Hospital:
Central Nervous System
CNS
Brain Tumor
Glioma
Optic Pathway Glioma
Low grade glioma
MAPK/ERK
Plexiform Neurofibroma
Neurofibromatosis Type 1
LGG
NF1
KIAA1549-BRAF
Mitogen-activated Protein Kinase (MEK) inhibitor
Trametinib

Additional relevant MeSH terms:
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Nerve Sheath Neoplasms
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Neoplastic Syndromes, Hereditary
Glioma
Neurofibroma
Neurofibromatoses
Neurofibroma, Plexiform
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Neurocutaneous Syndromes
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Trametinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action