ActivePhase 2ACTRN12620001229965

TiNT: Trametinib in Neurofibromatosis type 1 associated tumours

A phase II study of trametinib in paediatric, adolescent and young adult patients with neurofibromatosis type 1 associated plexiform neurofibromas or progressive optic pathway gliomas

Sponsor

Australian and New Zealand Children's Haematology/Oncology Group

Enrollment

120 participants

Start Date

Mar 10, 2021

Study Type

Interventional

Conditions

Optic pathway glioma Plexiform neurofibromatosis

Summary

The purpose of this study is to determine if a targeted therapy (a drug called trametinib) has an effect on tumour response in children, teenagers and young adults with neurofibromatosis type 1 (NF1) associated Plexiform Neurofibromas and Optic Pathway Gliomas. Who is it for? You may be eligible for the treatment arm of this study if you are between 3 months and 25 years old and have NF1 associated plexiform neurofibromas or progressive optic pathway gliomas. You may be eligible for the control arm of the substudy if you are between 3 months and 25 years old with NF1. Study details All participants in the main part of this study will receive the targeted therapy (trametinib) and are expected to take this drug daily for two years. The medication will be provided as either an oral tablet or an oral solution. Participants taking trametinib will be expected to complete some assessments at enrolment and attend monthly hospital visits for general health reviews. Additionally, every three months for two years, assessments will include MRI scans, and cardiac and vision testing. These assessments will measure whether trametinib is effectively treating the tumour and will also monitor any side effects. There is also a sub-study occurring within this study to find out if trametinib can improve learning, behaviour and well-being for those with NF1. For this part of the study, an untreated control group will be enrolled to compare to the trametinib-treated group described above. The untreated control group will be children, teenagers and young adults with NF1 who do not have a tumour that requires trametinib treatment. All participants in the trametinib-treated and the control groups will attend four Neuropsychology Clinic Visits over a two-year period. During these visits they will complete a number of questionnaires and tests to measure their cognitive function (thinking skills), behaviour and quality of life. It is hoped this research will help determine if trametinib has an effect on tumours and if there are any additional impacts to cognitive function, behaviour and quality of life.

Eligibility

Sex: Both males and femalesMin Age: 3 MonthssMax Age: 25 Yearss

Inclusion Criteria30

NF1-PN and NF1-OPG Cohorts:
Age of patient: Patient must be between 3 months and 25 years at time of enrolment
Diagnosis of NF1: Patient must meet NIH criteria for NF1 or has a documented germline genetic lesion in NF1 gene predicted to be deleterious
PN (clinically or pathologically diagnosed) with actual or impending functional or major cosmetic deficit and surgery not deemed appropriate
or
OPG (radiologically or pathologically diagnosed) which has progressed after at least 1 line of previous chemotherapy.
Measurable disease:
or
Lansky/Karnofsky performance score greater than or equal to 50 (Use Karnofsky for patients greater than 16 years of age and Lansky for patients less than or equal to 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score)
Life expectancy greater than 3 months
Haematologic function defined as:
i. Haemoglobin greater than or equal to 80 g/L
ii. Absolute Neutrophil Count greater than or equal to 1000/µL
iii. Platelet count greater than or equal to 100,000/µL
Adequate renal function defined as Serum creatinine normal as per institutional parameters for age and sex
Adequate liver function defined as:
i. Total bilirubin less than or equal to 1.5 x upper limit of normal for age
ii. AST and ALT less than or equal to 2.5 x upper limit of normal for age
Adequate cardiac function defined as:
i. Fractional shortening (FS) greater than or equal to 27% by echocardiogram or Ejection fraction = 53% by echocardiogram
ii. Corrected QT interval less than 460ms
Negative pregnancy test for women of child bearing potential (WOCBP)
For those of reproductive potential:
i. Agreement to use effective contraception (methods that result in less than 1% pregnancy rates) for the duration of study and 16 weeks after stopping study treatment AND
ii. Agreement not to breastfeed for the duration of study and 4 weeks after stopping study treatment
Provide a signed and dated informed consent form or has a legally acceptable representative capable of understanding the informed consent document and providing consent on the participant’s behalf.
Neurocognitive/Behavioural/QoL Substudy Control Group:
Age of patient: Patient must be between 3 months and 25 years at time of enrolment
Diagnosis of NF1: Patient must meet NIH criteria for NF1 or has a documented germline genetic lesion in NF1 gene predicted to be deleterious
Provide a signed and dated informed consent form or has a legally acceptable representative capable of understanding the informed consent document and providing consent on the participant’s behalf.

Exclusion Criteria16

NF1-PN and NF1-OPG Cohorts:
Has a known hypersensitivity to trametinib
Has had treatment with any other investigational or anti-neoplastic drug within 4 weeks prior to starting investigational agent
Treatment naïve OPG
OPG which has been biopsied and shown to have histology other than WHO grade 1 or 2 astrocytoma
PN with clinical suspicion of or histologically proven MPNST
Previous treatment with MEK inhibitor
Any concurrent anti-neoplastic therapy
Neurocognitive/Behavioural/QoL Substudy Control Group:
Diagnosed intracranial pathology including diagnosed head injury, CVA or hydrocephalus. OPGs allowed.
Significant visual or hearing problems that invalidate neurocognitive testing
Intellectual disability (FSIQ less than 70)
Insufficient English in patient or at least 1 parent to complete assessment.
Has had treatment with any other investigational or anti-neoplastic drug within 4 weeks
prior to starting investigational agent
Has had previous treatment with a MEK inhibitor.

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Interventions

In the main study, Cohorts 1 and 2 will all receive Trametinib intervention as follows: Cohort 1: Neurofibromatosis Type 1 associated Plexiform Neurofibroma (NF1-PN) Cohort 2: Neurofibromatosis Type

In the main study, Cohorts 1 and 2 will all receive Trametinib intervention as follows: Cohort 1: Neurofibromatosis Type 1 associated Plexiform Neurofibroma (NF1-PN) Cohort 2: Neurofibromatosis Type 1 associated Optic Pathway Glioma (NF1-OPG) Drug: Trametinib Dose: 0.025mg/kg once daily for children 6 years and over, 0.032mg/kg once daily for children under 6. Duration: 24 months Mode of administration: Oral Formulation: 0.5 or 2mg tablets; or Solution (for participants under 6 years old, or those 6 years old and over who are unable to swallow tablets). Compliance to drug administration will be monitored by use of a participant drug diary and measurement of bottle returns. In the sub-study, a suite of neurocognitive, quality of life and behaviour assessments and questionnaires will be evaluated in the treated Cohort 1 (NF1-PN) and Cohort 2 (NF1-OPG) and in a control group of untreated participants with Neurofibromatosis Type 1.