Trametinib for Pediatric Brain Tumor

Not currently recruiting at 7 trial locations

Overseen By Sébastien Perreault, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Justine's Hospital

Must not be taking: MEK inhibitors, others

Disqualifiers: Other malignancy, Uncontrollable disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 34

Duration: 504 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests trametinib (Mekinist) to evaluate its effectiveness for children and young adults with specific brain and nerve tumors. It targets low-grade gliomas (a type of brain tumor) and plexiform neurofibromas (a type of nerve tumor) in patients who have previously tried other treatments. The study includes groups with a specific gene change (BRAF fusion) or pathway activation (MAPK/ERK) associated with their tumors. Individuals with these conditions who have not responded to other treatments might be suitable candidates. The trial also examines tumor growth and the treatment's impact on patients' quality of life. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, there are specific waiting periods after certain treatments before starting the trial medication, so it's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatment is likely to be safe?

Research shows that trametinib is safe for treating conditions like neurofibromatosis type 1 and low-grade gliomas. Studies have found that children and young adults generally tolerate trametinib well. The most common side effects include skin rash, diarrhea, and fatigue, but these are usually mild and manageable.

The FDA has also approved trametinib for other conditions, indicating well-documented safety. While individual experiences may vary, these findings provide a positive view of trametinib's safety for young patients with brain tumors. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for brain tumors?

Trametinib is unique because it specifically targets the MAPK/ERK pathway, which is often activated in certain brain tumors like low-grade gliomas and those associated with Neurofibromatosis Type 1 (NF1). This is different from standard treatments, such as chemotherapy and radiation, which do not target this specific pathway. By honing in on this pathway, trametinib has the potential to be more effective and cause fewer side effects. Researchers are excited about trametinib because it offers a targeted approach, potentially leading to better outcomes for patients with these specific genetic markers.

What evidence suggests that trametinib might be an effective treatment for pediatric brain tumors?

This trial will evaluate trametinib for various pediatric brain tumor conditions. Research has shown that trametinib can help control tumor growth in patients with Neurofibromatosis Type 1 (NF1) and plexiform neurofibromas (PN), one of the conditions studied in this trial. Another arm of the trial will assess trametinib's potential benefits for those with low-grade gliomas, a type of brain tumor, who have NF1. Trametinib targets a specific pathway involved in tumor growth. In earlier studies, trametinib effectively shrank tumors or halted their growth for many patients. Most patients tolerated the treatment well, allowing them to continue without stopping early due to side effects. Overall, trametinib offers hope for managing these challenging childhood tumors. ^{1 2 5 6 7}

Who Is on the Research Team?

Sébastien Perreault, MD

Principal Investigator

St. Justine's Hospital

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 1 month to 25 years with specific brain tumors or neurofibromatosis who have not responded to at least one prior treatment. Eligible participants must be able to take oral medication, agree to use contraception if applicable, and commit to study requirements like MRI scans.

Inclusion Criteria

I have a specific type of progressing brain tumor or nerve tumor.

I am between 1 month and 25 years old and starting trametinib treatment.

Patients must have a life expectancy of greater than 6 months

Exclusion Criteria

My condition worsened while on a MEK inhibitor treatment.

I had major surgery less than 2 weeks before starting trametinib.

Pregnant or breastfeeding female patients

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral administration of trametinib at a daily dose of 0.025 mg/kg for up to 18 cycles, in 28-day cycles

504 days

Regular visits every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Every 6 months

Neurocognitive Assessment

Neurocognitive assessments are conducted to evaluate cognitive changes in patients with NF1 during treatment

Up to 504 days

At study inclusion and at the end of treatment

What Are the Treatments Tested in This Trial?

Interventions

• Trametinib

Trial Overview

The trial tests Trametinib's effectiveness in treating pediatric patients with glioma or plexiform neurofibroma that involves the MAPK/ERK pathway. It's an open-label phase 2 study where patients receive daily doses of Trametinib over cycles lasting 28 days each.

How Is the Trial Designed?

Group I: Progressing/refractory low grade-glioma, KIAA1549-BRAF fusion Experimental Treatment 1 Intervention

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

Group II: Progressing/Refractory central nervous system (CNS) glioma. Experimental Treatment 1 Intervention

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.

Group III: Neurofibromatosis Type 1 (NF1) with low-grade glioma Experimental Treatment 1 Intervention

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

Group IV: Neurofibromatosis Type 1 (NF1) with Plexiform Neurofibroma Experimental Treatment 1 Intervention

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

Trametinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Mekinist for:

• Melanoma
• Non-small cell lung cancer

Approved in United States as Mekinist for:

• Melanoma
• Non-small cell lung cancer
• Thyroid cancer

Approved in Canada as Mekinist for:

• Melanoma
• Non-small cell lung cancer

Approved in Japan as Mekinist for:

• Melanoma

Who Is Running the Clinical Trial?

St. Justine's Hospital

Lead Sponsor

Trials

205

Recruited

87,300+

Montreal Children's Hospital of the MUHC

Collaborator

Trials

32

Recruited

117,000+

CHU de Quebec-Universite Laval

Collaborator

Trials

177

Recruited

110,000+

Published Research Related to This Trial

In a study of 14 pediatric patients with recurrent low-grade glioma or high-grade CNS tumors, 64% were progression-free while receiving trametinib, indicating promising efficacy for this MEK inhibitor in treating MAP kinase pathway mutations.

While trametinib showed potential benefits, including partial responses and improved clinical symptoms in some patients, adverse events were common, particularly in those receiving combination therapy, highlighting the need for careful monitoring and further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib-based Treatment of Pediatric CNS Tumors: A Single Institutional Experience. Paul, MR., Pehlivan, KC., Milburn, M., et al.[2021]

In a phase I/II study involving 139 pediatric patients with relapsed/refractory malignancies, trametinib was found to have a recommended dose of 0.032 mg/kg for children under 6 years and 0.025 mg/kg for those 6 years and older, with manageable safety profiles and no dose-limiting toxicities when combined with dabrafenib.

Among 49 patients with BRAF V600-mutant low-grade gliomas, the combination therapy of dabrafenib and trametinib showed a higher objective response rate of 25% compared to 15% for trametinib alone, indicating improved efficacy with the combination treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. Bouffet, E., Geoerger, B., Moertel, C., et al.[2023]

In a phase 2 trial involving 110 pediatric patients with low-grade glioma and BRAF V600 mutations, the combination of dabrafenib and trametinib resulted in a significantly higher overall response rate (47%) compared to standard chemotherapy (11%).

Dabrafenib plus trametinib also demonstrated a longer median progression-free survival (20.1 months) and a better safety profile, with fewer severe adverse events (47% vs. 94% for chemotherapy), making it a promising first-line treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations. Bouffet, E., Hansford, JR., Garrè, ML., et al.[2023]

The phase II TADPOLE trial demonstrated that the combination of dabrafenib and trametinib is more effective than traditional chemotherapy for treating pediatric brain tumors with BRAF mutations, particularly in low-grade gliomas.

The trial also showed promising responses in high-grade gliomas, emphasizing the critical role of biomarker testing in tailoring treatment for pediatric glioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Therapy Win in BRAF-Mutant Gliomas. [2023]

The pediatric oral solution of trametinib showed improved bioavailability compared to the tablet formulation, with significant increases in key pharmacokinetic measures such as Cmax and AUC, indicating it may be more effective in delivering the drug to patients.

The safety profile of the trametinib pediatric oral solution was consistent with existing data, with no serious adverse events leading to withdrawal from the study, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. Cox, DS., Allred, A., Zhou, Y., et al.[2018]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9415905/

Efficacy and Safety of Trametinib in Neurofibromatosis Type 1 ...

The results yielded in this systematic review and meta-analysis showed that trametinib significantly controlled the tumor progression of NF1- ...

2.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.2042

A phase 2 study of trametinib for patients with pediatric ...

A total of 59 (69.4%) patients discontinued treatment as planned after 18 cycles and 9 (10.6%) patients had to stop trametinib due to adverse ...

3.

asco.org

asco.org/abstracts-presentations/ABSTRACT369422

A phase 2 study of trametinib for patients with pediatric ...

A total of 59 (69.4%) patients discontinued treatment as planned after 18 cycles and 9 (10.6%) patients had to stop trametinib due to adverse events.

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8178485/

Trametinib therapy for children with neurofibromatosis type ...

Trametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF‐1 and is well tolerated in children.

5.

bmccancer.biomedcentral.com

bmccancer.biomedcentral.com/articles/10.1186/s12885-019-6442-2

A phase 2 study of trametinib for patients with pediatric glioma ...

The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK ...

6.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.22.01000

Efficacy and Safety of Trametinib Monotherapy or in ...

We describe a phase I/II study establishing pediatric dosing and pharmacokinetics of trametinib with or without dabrafenib, as well as efficacy and safety

7.

frontiersin.org

frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1503894/full

The role of MEK inhibition in pediatric low-grade gliomas

This mini-review explores the emerging role of MEK inhibitors in the management of pLGGs, highlighting their potential to transform current treatment paradigms.