Mirdametinib for Brain Tumor

Overseen By Tabatha E. Doyle, RN

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: MEK inhibitors

Disqualifiers: Retinal pathology, Malabsorption, Liver disease, others

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

Compensation: Varies

Number of Visits: Unknown

132 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests mirdametinib, a new drug, to determine its effectiveness and safety in treating low-grade gliomas, a type of brain tumor. Participants may receive mirdametinib in different forms, such as tablets or capsules, over 28-day cycles for up to two years. The trial seeks participants with low-grade gliomas that have returned or progressed, especially those who haven't responded to other treatments or have not previously taken MEK inhibitors. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that mirdametinib is being tested as a treatment for low-grade glioma, a type of brain tumor. Earlier studies have examined the safety of mirdametinib in both children and adults, finding it generally well-tolerated. Common side effects include mild rashes, diarrhea, and nausea, while more serious side effects, such as changes in heart rhythm and eye problems, were less common. Researchers are also studying mirdametinib for other conditions to better understand its safety profile. As this trial is in the early stages, it aims to further assess the safety and tolerability of mirdametinib for patients. ^{1 2 3 4 5}

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

Researchers are excited about mirdametinib for brain tumors because it offers a targeted approach that differs from traditional treatments like surgery, radiation, and chemotherapy. Unlike these standard options, mirdametinib specifically targets MEK, a protein involved in the growth of low-grade gliomas. This precision can potentially reduce side effects and improve outcomes compared to broader treatments. Additionally, mirdametinib can be administered orally, which might offer more convenience and flexibility for patients. These features make mirdametinib a promising option for those with recurrent or progressive low-grade gliomas.

What evidence suggests that mirdametinib could be an effective treatment for pediatric low-grade glioma?

Research has shown that mirdametinib, a type of medication, may help treat pediatric low-grade glioma (pLGG), a brain tumor in children. In past cases, children with recurrent or progressive pLGG responded well to mirdametinib, achieving better tumor control. Studies indicate that most patients tolerate the drug well, as it usually doesn't cause serious side effects. Mirdametinib targets specific pathways that aid tumor growth, potentially slowing or stopping tumor progression. This trial will evaluate mirdametinib in various cohorts, including those newly diagnosed and those with recurrent or progressive glioma, to further assess its effectiveness as a treatment for this brain tumor. ^{1 2 6 7 8}

Who Is on the 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

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Mirdametinib

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.

How Is the Trial Designed?

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+

SpringWorks Therapeutics, Inc.

Industry Sponsor

Trials

14

Recruited

900+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9164943/

Phase I/II evaluation of single agent mirdametinib (PD- ... BACKGROUND: MEK inhibitor trials in pediatric low-grade glioma (pLGG) have yielded promising results, but there remains room for improvement since objective ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04923126

NCT04923126 | SJ901: Evaluation of Mirdametinib in ... To evaluate the effects of mirdametinib treatment on memory in children treated for low-grade glioma. This will be assessed using different instruments as ...

3. springworkstx.com springworkstx.com/wp-content/uploads/2024/11/Robinson_SNO2024_SJ901_ph1_pLGG_FINAL.pdf

A Phase 1/2 trial of single-agent mirdametinib (PD Objectives include assessing efficacy, comparing radiographic measurement techniques, and evaluating changes in QOL.

4. stjude.org stjude.org/care-treatment/clinical-trials/sj901-low-grade-glioma.html

SJ901: Study of Mirdametinib as a Treatment for Children ... The main goal of this study is to test the experimental drug mirdametinib in hopes of finding a treatment that may be effective against low-grade glioma brain ...

5. academic.oup.com academic.oup.com/neuro-oncology/article/26/Supplement_8/viii113/7890299

A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD ... Mirdametinib is well-tolerated and has promising clinical activity in patients with recurrent/progressive pLGG. Phase 2 is ongoing to establish ...

6. springworkstx.com springworkstx.com/pipeline/mirdametinib/

Mirdametinib - NF1 Treatment Mirdametinib is an oral small molecule designed to inhibit MEK1 and MEK2, which are proteins that occupy pivotal positions in the MAPK pathway.

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.

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.24.01034

ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults ... Confirmed ORR with mirdametinib was numerically higher in children than it was in adults; however, median tumor volume reduction was very ...