Trametinib for Pediatric Brain Tumor

Recruiting at 6 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

114 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug Trametinib for pediatric brain tumors?

Research shows that Trametinib, often used with another drug called Dabrafenib, has been effective in treating certain pediatric brain tumors, especially those with specific genetic mutations like BRAF V600. In studies, many children with these mutations experienced tumor shrinkage or stable disease, indicating the drug's potential effectiveness. ^{1 2 3 4 5}

How is the drug trametinib unique for treating pediatric brain tumors?

Trametinib is unique because it targets specific genetic mutations (like BRAF mutations) in pediatric brain tumors, offering a more personalized treatment approach compared to traditional chemotherapy or radiation. It is a MEK inhibitor, which means it blocks a specific protein involved in tumor growth, and can be used alone or in combination with other drugs like dabrafenib for enhanced effectiveness. ^{1 4 5 6 7}

Research Team

Sébastien Perreault, MD

Principal Investigator

St. Justine's Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Trametinib-based Treatment of Pediatric CNS Tumors: A Single Institutional Experience. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

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

5. United States pubmed.ncbi.nlm.nih.gov

Neuropsychological impact of trametinib in pediatric low-grade glioma: A case series. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Trametinib for the treatment of recurrent/progressive pediatric low-grade glioma. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors. [2018]