Mirdametinib for Histiocytic Disorders

Overseen By Caitlin Cottrell

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital Medical Center, Cincinnati

Must not be taking: Steroids, Glucocorticoids, MEK inhibitors

Disqualifiers: Glaucoma, Retinal pathology, Uncontrolled hypertension, 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

Compensation: Varies

Number of Visits: 4

Duration: 2 years

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new drug, mirdametinib (a MEK inhibitor), for individuals with Langerhans cell histiocytosis (LCH) or similar histiocytic disorders. Researchers seek to determine if mirdametinib is more effective and has fewer side effects than current treatments. Suitable candidates for this trial include those with a histiocytic disorder requiring treatment and measurable disease on a PET scan or brain MRI. The trial seeks participants who have not recently undergone certain treatments, such as chemotherapy or MEK inhibitors, and who have adequate organ function. As a Phase 2 trial, this 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 requires a washout period for certain medications. You must stop taking myelosuppressive chemotherapy 14 days before enrolling, biologic agents 30 days before, investigational drugs 30 days before, and glucocorticoids 14 days before starting mirdametinib. Chronic steroid use is not allowed, but necessary physiologic doses for endocrine deficiencies are permitted.

Is there any evidence suggesting that mirdametinib is likely to be safe for humans?

Research has shown that mirdametinib is already approved in the U.S. for treating neurofibromatosis type 1, a condition that causes tumors to grow on nerves. This approval indicates that its safety for that condition is well understood. Studies have combined data to demonstrate that mirdametinib is generally safe for people. However, like any treatment, it can have side effects. Although specific details for histiocytic disorders are not available, similar drugs, such as trametinib, have been used safely. This suggests that mirdametinib might also be well-tolerated. During the trial, researchers will closely monitor all participants to ensure safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for histiocytic disorders, which typically involve chemotherapy or targeted therapies like BRAF inhibitors, Mirdametinib offers a new approach by targeting the MEK pathway. This pathway is a crucial part of cell signaling that can contribute to the growth of these disorders. Mirdametinib is administered orally, making it a more convenient option compared to some existing treatments that require intravenous administration. Researchers are excited about its potential to provide a more targeted and less invasive treatment option, potentially leading to fewer side effects and improved patient outcomes.

What evidence suggests that mirdametinib might be an effective treatment for histiocytic disorders?

Research has shown that mirdametinib, the investigational treatment in this trial, may help treat histiocytic disorders such as Langerhans cell histiocytosis (LCH). In earlier studies, patients taking mirdametinib experienced significant symptom improvements compared to their initial condition. This medication blocks a pathway that aids certain cells in growing and multiplying. By targeting this pathway, it may slow the growth of abnormal cells associated with these disorders. Although more research is needed specifically for LCH, these early findings suggest mirdametinib could be an effective treatment. ^{1 2 4 6 7}

Who Is on the Research Team?

Ashish Kumar, MD, PhD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Allison Bartlett, MD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Are You a Good Fit for This Trial?

This trial is for individuals aged 2 years or older with a confirmed diagnosis of histiocytic disorders like LCH, JXG, RDD, or others with specific gene mutations. They must have measurable disease and not have received certain myelosuppressive chemotherapy within the last 14 days. Adults unable to consent or those without biopsy material (except in specific CNS cases) cannot participate.

Inclusion Criteria

I haven't taken specific strong chemotherapy drugs in the last 14 days.

My cancer diagnosis was confirmed by a specific hospital's pathologist and involves a certain gene mutation.

My condition affects multiple systems in my body, with or without affecting critical organs.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive mirdametinib dosed by mouth twice a day at a dose of 2 mg/m2 BID with a max of 4 mg BID for up to 2 years

2 years

Visits every 4 weeks for 26 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Mirdametinib

Trial Overview The study tests mirdametinib's effectiveness on patients with various histiocytic disorders compared to current treatments. It aims to determine if this treatment offers better outcomes and fewer side effects than existing options.

How Is the Trial Designed?

Group I: Mirdametinib Experimental Treatment 1 Intervention

Mirdametinib will be dosed by mouth twice a day at a dose of 2 mg/m2 BID with a max of 4 mg BID (8 mg per day max).

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Published Research Related to This Trial

The study identified and characterized various feline histiocytic disorders, including five cases of feline progressive histiocytosis and eight histiocytic sarcomas, using immunohistochemistry to assess the expression of PDGFRβ and KIT.

Treatment with tyrosine kinase inhibitors and lomustine showed partial responses, while radiotherapy provided long-term control in some cases, suggesting that PDGFRβ may be a potential therapeutic target for these disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcome, PDGFRβ and KIT expression in feline histiocytic disorders: a multicentre study. Treggiari, E., Ressel, L., Polton, GA., et al.[2017]

In a clinical trial involving 18 patients with histiocytic neoplasms, the oral MEK inhibitor cobimetinib showed an impressive overall response rate of 89%, with all responses being durable and 94% of patients remaining progression-free after one year.

The study demonstrated that histiocytic neoplasms, regardless of specific genetic mutations, are dependent on MAPK signaling, making MEK inhibition a promising treatment option for all patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of MEK inhibition in patients with histiocytic neoplasms. Diamond, EL., Durham, BH., Ulaner, GA., et al.[2021]

In a review of 10 patients with Erdheim-Chester disease (ECD), it was found that they often require significantly lower doses of BRAF and MEK inhibitors, with a median tolerated dose of only 25% of the FDA-approved amount.

Despite the need for reduced dosing due to common side effects like rash and joint pain, 80% of the patients achieved a partial remission, indicating that lower doses of these targeted therapies can still be effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Toxicity Experience with BRAF/MEK Inhibitors in Patients with Erdheim-Chester Disease. Saunders, IM., Goodman, AM., Kurzrock, R.[2021]

In a study of 26 adult patients with Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD), the MEK inhibitor trametinib showed a high response rate of 71%, demonstrating its efficacy even in patients without the BRAFV600E mutation.

Most patients experienced manageable side effects, primarily rash (27%), and were effectively treated with lower doses of trametinib (0.5-1.0 mg daily), indicating a favorable safety profile and durable treatment effects over a median follow-up of 23 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of non-Langerhans cell histiocytosis with the MEK inhibitor trametinib: a multicenter analysis. Aaroe, A., Kurzrock, R., Goyal, G., et al.[2023]

An 18-year-old male with refractory histiocytic sarcoma showed a significant response to the MEK inhibitor trametinib, indicating its potential effectiveness in treating this aggressive cancer.

Next-generation sequencing revealed a pathogenic variant of MAP2K1, suggesting that targeting the RAS/MEK/ERK pathway could be a promising therapeutic strategy for patients with histiocytic sarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of recurrent histiocytic sarcoma with MAP2K1 pathogenic variant treated with the MEK inhibitor trametinib. Kumamoto, T., Aoki, Y., Sonoda, T., et al.[2020]

BRAF V600E mutations were found in 4 out of 11 cases of Langerhans cell histiocytosis (LCH) and all 4 cases of Erdheim-Chester disease (ECD), indicating a potential target for BRAF and MEK inhibitor therapies.

Significant expression of the PD-L1 immune checkpoint protein was identified in various histiocytic diseases, suggesting that immune checkpoint inhibitors could be a promising treatment option for patients with disseminated or refractory histiocytoses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disseminated histiocytoses biomarkers beyond BRAFV600E: frequent expression of PD-L1. Gatalica, Z., Bilalovic, N., Palazzo, JP., et al.[2020]

In a study of 34 patients with metastatic melanoma treated with dabrafenib and trametinib, high plasma concentrations of dabrafenib showed only a weak association with progression-free survival, indicating that monitoring these levels may not effectively predict treatment response.

No significant relationship was found between plasma concentrations of dabrafenib and trametinib and the occurrence of common adverse events, suggesting that these measurements may not be useful for assessing safety in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600mut melanoma patients. Raynal, M., Alvarez, JC., Saiag, P., et al.[2022]

Rare histiocytoses encompass a variety of disorders involving histiocytes, macrophages, and dendritic cells, with a classification system that includes multiple subgroups, some of which have excellent prognoses while others require intensive treatment.

BRAF inhibitors show promise as a potential treatment for certain non-malignant rare histiocytoses due to identified BRAF mutations, and the establishment of the International Rare Histiocytic Disorders Registry aims to enhance understanding and management of these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Non-Langerhans Cell Histiocytoses (Rare Histiocytoses) - Clinical Aspects and Therapeutic Approaches. Classen, CF., Minkov, M., Lehrnbecher, T.[2017]

Citations

1. withpower.com withpower.com/trial/mirdametinib-for-histiocytic-disorders-b2d6d

Mirdametinib for Histiocytic Disorders Trial Overview The study tests mirdametinib's effectiveness on patients with various histiocytic disorders compared to current treatments. It aims to ...

2. centerwatch.com centerwatch.com/clinical-trials/listings/NCT06153173/mirdametinib-in-histiocytic-disorders

Mirdametinib in Histiocytic Disorders | Clinical Research ... The purpose of this study is to see if treatment with mirdametinib in patients with LCH or other histiocytic disorders will be better than ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03962543

NCT03962543 | MEK Inhibitor Mirdametinib (PD-0325901) ... This study evaluates mirdametinib (PD-0325901) in the treatment of symptomatic inoperable neurofibromatosis type-1 (NF1)-associated plexiform neurofibromas (PNs) ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12234624/

Mirdametinib: First Approval - PMC - PubMed Central Therapy with mirdametinib resulted in significant (p ≤ 0.02) improvements from baseline to cycle 13 in patient-reported outcome (PRO) measures ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06153173?cond=Rosai-Dorfman%20Disease&viewType=Table&rank=3

NCT06153173 | Mirdametinib in Histiocytic Disorders The purpose of this study is to see if treatment with mirdametinib in patients with Langerhans cell histiocytosis (LCH) or other histiocytic disorders will be ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2025/219379Orig1s000,219389Orig1s000MultidisciplineR.pdf

219379Orig1s000 219389Orig1s000 - accessdata.fda.gov The data from these studies were analyzed together as a single pool and are supportive safety data used to assess the safety profile of mirdametinib. This ...

7. medchemexpress.com medchemexpress.com/PD0325901.html?srsltid=AfmBOoqkVU_I3qeAP-jfuqmZN7m4oD0CAnVbsisqJM2hs2bO8HAdymRg

Mirdametinib (PD0325901) | MEK Inhibitor Mirdametinib suppresses the expression of p-ERK1/2 and induces apoptosis. Mirdametinib has anti-cancer activity for a broad spectrum of human tumor xenografts.