Clinical Trials /

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

NCT03363217

Description:

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.

Related Conditions:
  • Glioma
  • Neurofibromatosis Type 1
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • 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.

Clinical Trial IDs

  • ORG STUDY ID: Trametinib study TRAM-01
  • NCT ID: NCT03363217

Conditions

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

Interventions

DrugSynonymsArms
TrametinibMekinistNeurofibromatosis Type 1 (NF1) with low-grade glioma

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.

Trial Arms

NameTypeDescriptionInterventions
Neurofibromatosis Type 1 (NF1) with low-grade gliomaExperimentalPatients presenting with Neurofibromatosis Type 1 (NF1) and a progressing/refractory low-grade glioma.
  • Trametinib
Neurofibromatosis Type 1 (NF1) with Plexiform NeurofibromaExperimentalPatients presenting with Neurofibromatosis Type 1 (NF1) and a plexiform neurofibroma
  • Trametinib
Progressing/refractory low grade-glioma, KIAA1549-BRAF fusionExperimentalPatients presenting with a progressing/refractory low-grade glioma with a KIAA1549-BRAF fusion.
  • Trametinib
Progressing/Refractory central nervous system (CNS) glioma.ExperimentalPatients 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.
  • Trametinib

Eligibility 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.
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:1 Month
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate
Time Frame:From date of study inclusion until the date of first documented progression, up to 504 treatment days.
Safety Issue:
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.

Secondary Outcome Measures

Measure:Time to Progression (time from registration to progression)
Time Frame:Every 6 months up to 3 years following completion of treatment (504 treatment days).
Safety Issue:
Description: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.
Measure: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).
Safety Issue:
Description: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.
Measure:Overall Survival (time from registration to death)
Time Frame:Every 6 months up to 3 years following completion of treatment (504 treatment days).
Safety Issue:
Description:Time from registration to death due to any cause, or censored at date last known alive. Applicable to group 1-2-3-4.
Measure: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.
Safety Issue:
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.
Measure:Determination of the Serum Level of Trametinib.
Time Frame:At day 22 and at tumor progression up to the end of treatment day 504.
Safety Issue:
Description:Determination of the serum level of trametinib by assessment of the through level. Applicable to group 1-2-3-4.
Measure: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.
Safety Issue:
Description:Evaluation of the quality of life during treatment with the PedsQL cancer/brain tumor modules. Applicable to group 1-2-3-4.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Justine's Hospital

Trial 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

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