Mirdametinib for Brain Tumor

Overseen by Giles Robinson, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: St. Jude Children's Research Hospital

Must not be taking: MEK inhibitors

Disqualifiers: Retinal pathology, Malabsorption, Liver disease, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests mirdametinib, a drug that blocks cancer growth signals, in children and young adults with specific types of brain tumors. It aims to see if the drug is safe and effective in slowing down or stopping tumor growth. Mirdametinib has been tested in studies for neurofibromatosis type 1-related plexiform neurofibromas.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking P-gp and BCRP inhibitors, you must stop them at least a week or 5 half-lives before starting the trial medication. Also, if you are on corticosteroids, your dose must be stable or decreasing for at least a week before enrollment.

What makes the drug Mirdametinib unique for treating brain tumors?

Mirdametinib is a MEK inhibitor, which means it targets a specific part of the cell signaling pathway involved in tumor growth, making it potentially effective for brain tumors with certain genetic mutations. This approach is different from traditional chemotherapy, which targets all rapidly dividing cells, and may offer a more targeted treatment option for patients with specific tumor profiles. ^{1 2 3 4 5}

Research Team

Giles Robinson, MD

Principal Investigator

St. Jude Children's Research Hospital

Anna Vinitsky, MD, MS

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children, adolescents, and young adults up to 25 years old with a specific type of brain tumor called low-grade glioma. They must have relapsed or progressed after previous treatments but can't have had any MEK inhibitors before (except in certain cases). Participants need proper organ function and no history of liver disease or other serious medical conditions that could affect the study.

Inclusion Criteria

Participant and/or guardian can understand and is willing to sign a written informed consent document according to institutional guidelines

I am between 2 and 25 years old at the time of joining the study.

I have recovered from my previous cancer treatments.

Exclusion Criteria

I have a known liver disease or liver-related condition.

I have glaucoma that is not well-managed.

I have a condition that affects how my body absorbs medication.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive mirdametinib to determine safety, tolerability, and maximum tolerated dose. Treatment is administered in cycles of 28 days.

Up to 25 months

Monthly visits for dose adjustments and monitoring

Phase 2 Treatment

Participants receive mirdametinib at the recommended phase 2 dose to evaluate efficacy and safety. Treatment is administered in cycles of 28 days.

Up to 24 months

Monthly visits for efficacy and safety assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Periodic visits for long-term monitoring

Treatment Details

Interventions

• Mirdametinib (MEK inhibitor)

Trial Overview The trial is testing Mirdametinib, a drug designed to penetrate the brain and target tumors by inhibiting a protein called MEK. It's an open-label Phase 1/2 study, meaning both researchers and participants know what treatment is being given, aimed at seeing how well this drug works in pediatric patients with low-grade glioma.

Participant Groups

Group I: Phase I: Recurrent and/or progressive low-grade glioma without prior exposure to MEK inhibitors Experimental Treatment 1 Intervention

Participants will receive mirdametinib at one of the dose levels twice daily days 1-28. For the first cycle of treatment, participants will take mirdametinib tablets dissolved in water. After the first cycle of treatment, participants may receive the medicine the same way (dissolved in water) or may receive capsules. Treatment repeats every 28 days for up to 26 cycles of treatment (24 months) in the absence of disease progression or unacceptable toxicity.

Group II: Phase 2, Cohort 3b: Experimental Treatment 1 Intervention

Participants with recurrent and/or progressive low-grade glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy. Participants will receive the RP2D of mirdametinib. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.

Group III: Phase 2, Cohort 3a: Experimental Treatment 1 Intervention

Participants with recurrent and/or progressive low-grade glioma who previously received ≥ 6 courses MEK inhibitor (including mirdametinib) and did not progress while on active MEKi therapy. Participants will receive the RP2D of mirdametinib. Participants with previous exposure to mirdametinib may receive a starting dose lower than the RP2D, depending on the dose they tolerated during their previous exposure. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.

Group IV: Phase 2, Cohort 2: Recurrent and/or Progressive without prior exposure to MEK inhibitors Experimental Treatment 1 Intervention

Participants will receive the RP2D of mirdametinib. Participants may take mirdametinib tablets dissolved in water, or receive capsules. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.

Group V: Phase 2, Cohort 1: Newly diagnosed and/or previously untreated (except surgery) Experimental Treatment 1 Intervention

Participants will receive the RP2D of mirdametinib. Therapy will be administered in cycles of 28 days and may be continued for up to 24 months (26 cycles) in absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Dr. James R. Downing

St. Jude Children's Research Hospital

Chief Executive Officer since 2014

MD from University of Michigan Medical School

Dr. Ellis J. Neufeld

St. Jude Children's Research Hospital

Chief Medical Officer since 2017

MD, PhD from Harvard Medical School

SpringWorks Therapeutics, Inc.

Industry Sponsor

Trials

14

Recruited

900+

Findings from Research

In a phase I clinical trial involving 10 patients with brain metastases, trametinib combined with whole brain radiation therapy (WBRT) was found to be highly toxic, with a maximum tolerated dose (MTD) of less than 1.5 mg due to significant side effects like thrombocytopenia and diarrhea.

The study indicated that 89% of patients completed the therapy as planned, but the trial was closed early due to a shift in treatment practices towards stereotactic radiosurgery (SRS), highlighting the need for further research on the safety of trametinib in combination with SRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases. Palmer, JD., Prasad, RN., Fabian, D., et al.[2023]

The FDA approved the combination of dabrafenib and trametinib for treating pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation, marking the first systemic therapy approved for this condition.

In a clinical trial with 110 patients, the combination therapy showed a significantly higher overall response rate of 47% compared to 11% for the standard treatment of carboplatin and vincristine, along with longer progression-free survival of 20.1 months versus 7.4 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Dabrafenib in combination with trametinib for BRAF V600E mutation-positive low-grade glioma. Barbato, MI., Nashed, J., Bradford, D., et al.[2023]

BRAF inhibitors have shown promising antineoplastic activity and are generally well-tolerated in treating neuroepithelial brain tumors with BRAF-V600 mutations, suggesting a novel therapeutic option for these challenging cases.

Despite the encouraging results, the current evidence is mostly anecdotal, highlighting the need for further prospective clinical studies to confirm the efficacy and safety of BRAF inhibitors in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BRAF inhibitors in BRAF-V600 mutated primary neuroepithelial brain tumors. Preusser, M., Bienkowski, M., Birner, P.[2016]

In a study involving 25 children with newly diagnosed diffuse intrinsic pontine glioma (DIPG), the combination of vandetanib and dasatinib was found to be well tolerated, with a maximum tolerated dose of 65 mg/m² for each drug, and the most significant side effect being diarrhea.

The treatment showed promising pharmacokinetics, with the plasma levels of dasatinib remaining comparable to those seen in adults, and a decrease in phosphorylated 70S6K in blood cells, indicating effective target inhibition during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma. Broniscer, A., Baker, SD., Wetmore, C., et al.[2022]

BRAF(V600E) mutations were found in 10% of pediatric malignant astrocytomas, indicating a significant subset of these aggressive tumors may be targeted for specific therapies.

The BRAF(V600E)-specific inhibitor PLX4720 showed effective tumor growth reduction and increased survival in preclinical models with BRAF(V600E) mutations, while it was ineffective and potentially harmful in tumors with wild-type BRAF, suggesting a tailored approach to treatment could be beneficial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapy for BRAFV600E malignant astrocytoma. Nicolaides, TP., Li, H., Solomon, DA., et al.[2022]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases. [2023]

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

FDA Approval Summary: Dabrafenib in combination with trametinib for BRAF V600E mutation-positive low-grade glioma. [2023]

3. England pubmed.ncbi.nlm.nih.gov

BRAF inhibitors in BRAF-V600 mutated primary neuroepithelial brain tumors. [2016]

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

Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma. [2022]

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

Targeted therapy for BRAFV600E malignant astrocytoma. [2022]