Trametinib for Histiocytosis

Overseen By Megan Gibbs, BSN, RN

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Cook Children's Health Care System

Must be taking: Trametinib

Disqualifiers: Low-risk lesions, MAP2K1 mutation, jaundice, 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: Unknown

Duration: 104 weeks

75 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests trametinib, a targeted therapy, to determine its safety and effectiveness for children with Langerhans Cell Histiocytosis (LCH), a rare disease that can cause organ damage. Participants will either receive trametinib in 28-day cycles or join a long-term observation if they have been on the treatment since 2020. Children who are newly diagnosed or have LCH that hasn't responded well to treatment, and who have good heart and organ function, might be suitable candidates. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.

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

Research has shown that trametinib is generally safe for treating histiocytoses, including Langerhans Cell Histiocytosis (LCH). In studies with adults, many patients responded well to trametinib, with no reports of serious side effects like nerve damage.

For children, early findings suggest that trametinib can be a safe and effective option. A review of past cases found that children with LCH tolerated trametinib well, experiencing no significant side effects.

Overall, trametinib appears to be a promising treatment for LCH with a good safety record. However, as with any treatment, individual experiences may vary, so discussing potential risks and benefits with a healthcare professional is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Trametinib is unique because it specifically targets a pathway involved in the growth of Langerhans Cell Histiocytosis (LCH) cells, known as the MAPK/ERK pathway. Unlike standard treatments for histiocytosis, which often involve chemotherapy or steroids, trametinib acts as a MEK inhibitor, aiming to halt the abnormal cell growth more directly. Researchers are excited about this approach because it could potentially offer a more targeted treatment with fewer side effects compared to traditional, broader therapies.

What evidence suggests that trametinib might be an effective treatment for Langerhans Cell Histiocytosis?

Research has shown that trametinib effectively treats histiocytic conditions, including Langerhans Cell Histiocytosis (LCH). One study found that 78% of patients responded well to the treatment, with nearly all showing a high survival rate over two years. Another study reported that about 94% of patients experienced positive results, with long-lasting benefits. For children, trametinib has been reported as an effective and well-tolerated treatment option for LCH. These findings suggest that trametinib could be a promising choice for managing LCH in children. In this trial, participants will either receive trametinib as part of the prospective treatment arm or be included in an observational chart review if they have been receiving trametinib since January 1, 2020. ^{1 3 4 5 6}

Who Is on the Research Team?

Anish K. Ray

Principal Investigator

Cook Children's Health Care System

Are You a Good Fit for This Trial?

This trial is for pediatric patients with newly diagnosed or relapsed Langerhans Cell Histiocytosis (LCH). Participants must have confirmed diagnosis, adequate heart function, and be able to follow study procedures. It's not for those with low-risk LCH, jaundice at diagnosis, trametinib allergy, pregnancy/breastfeeding, substance dependence or certain mutations.

Inclusion Criteria

Diagnosis confirmed with biopsy prior to start of treatment

Patient must have adequate cardiac function evident through Echocardiogram (ECHO) and Electrocardiogram (EKG)

I understand and can follow the study's procedures.

Exclusion Criteria

Inability or unwillingness to give written informed consent

I have a low-risk skin condition or a single bone issue that doesn't need treatment.

I had jaundice when my condition was diagnosed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive trametinib in 28-day cycles for a minimum of two years

104 weeks

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Annual visits (in-person)

Open-label extension (optional)

Participants may continue treatment beyond two years if agreed upon with their physician

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Trametinib

Trial Overview The trial tests the safety and effectiveness of Trametinib in treating LCH. This Phase II study focuses on children who are newly diagnosed or have not responded to previous treatments. The goal is to see how well this targeted therapy works against LCH.

How Is the Trial Designed?

Group I: Prospective Treatment Experimental Treatment 1 Intervention

Trametinib will be administered in 28-day cycles, given once daily or adjusted as per clinical judgment of the treating physician, with a maximum dosage of 2mg daily. Patients will be followed for 4 years after receiving treatment for two years. Patients may continue on the same treatment beyond two years if they and their treating physicians agree to do so in the best interest of the patient.

Group II: Observation Only Active Control 1 Intervention

Patients who have been receiving trametinib as a treatment for LCH since January 1, 2020 may be included in an observational chart review to track long-term follow-up.

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?

Cook Children's Health Care System

Lead Sponsor

Trials

11

Recruited

5,001,000+

Published Research Related to This Trial

Systemic Mastocytosis (SM) is characterized by abnormal mast cell proliferation in various organs, often linked to the D816V (KIT) mutation and elevated serum tryptase, which are important for diagnosis.

Treatment for SM primarily focuses on managing symptoms, with bisphosphonates recommended as a first-line therapy for bone-related issues, and denosumab showing potential effectiveness due to its action on bone metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endocrine manifestations of systemic mastocytosis in bone. Greene, LW., Asadipooya, K., Corradi, PF., et al.[2018]

Imatinib mesylate, administered at 400 mg daily for 3 to 6 months, effectively reduced serum tryptase levels and urinary N-methylhistamine excretion in patients with systemic mastocytosis, with 10 out of 14 patients showing significant improvements.

The treatment was well-tolerated and led to symptom reduction in 8 out of 13 patients, demonstrating efficacy particularly in those with the D816V mutation, highlighting its potential as a targeted therapy for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Droogendijk, HJ., Kluin-Nelemans, HJ., van Doormaal, JJ., et al.[2016]

Over 90% of systemic mastocytosis cases are linked to the KIT D816V mutation, but patients with non-advanced forms of the disease generally have a low risk of progression and a life expectancy similar to the general population.

Avapritinib has been approved as the first tyrosine kinase inhibitor for treating indolent systemic mastocytosis, with other TKIs currently being tested in clinical trials for patients experiencing severe symptoms despite existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tyrosine Kinase Inhibitors in Non-advanced Systemic Mastocytosis. Akin, C.[2023]

Myeloproliferative neoplasms often involve the activation of tyrosine kinases, and while some eosinophilic disorders respond well to imatinib, others like chronic eosinophilic leukemia and idiopathic hypereosinophilic syndrome lack known druggable targets.

Midostaurin has shown promising results in treating advanced systemic mastocytosis, and ongoing research into selective KIT D816V inhibitors and other targeted therapies may improve treatment options for patients with eosinophilic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tyrosine Kinase Inhibitors and Therapeutic Antibodies in Advanced Eosinophilic Disorders and Systemic Mastocytosis. Gotlib, J.[2022]

Midostaurin is effective in rapidly reducing the disease burden in patients with systemic mastocytosis, even in cases that are resistant to cladribine treatment.

The management of systemic mastocytosis requires a comprehensive diagnostic approach and tailored treatment strategies, highlighting the complexity of this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of aggressive systemic mastocytosis with bulky lymphadenopathy showing response to midostaurin. Sciumè, M., Serpenti, F., Muratori, S., et al.[2021]

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]

Dabrafenib, either alone or in combination with trametinib, showed significant clinical efficacy in treating pediatric patients with BRAF V600-mutant Langerhans cell histiocytosis (LCH), with response rates of 76.9% for monotherapy and 58.3% for combination therapy, and most responses were ongoing at the end of the studies.

The treatment was generally well-tolerated, with manageable side effects similar to those seen in other pediatric and adult conditions, although some patients discontinued due to adverse events like vomiting and increased blood creatinine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis. Whitlock, JA., Geoerger, B., Dunkel, IJ., 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]

Trametinib, when combined with dabrafenib, significantly prolongs median survival by about 8 months compared to vemurafenib alone in patients with metastatic or inoperable melanoma, based on a study of 704 patients.

While trametinib can enhance treatment efficacy, it also carries serious adverse effects, including life-threatening conditions like heart failure and gastrointestinal perforation, making it essential for patients to weigh the benefits against the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trametinib (MEKINIST°) Metastatic or inoperable BRAF V600-positive melanoma: a few extra months of life. [2019]

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]

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 study of two pediatric patients with Langerhans cell histiocytosis (LCH) and confirmed MAPK pathway mutations, treatment with trametinib led to complete resolution of the disease in both cases.

Trametinib, a MAP2K inhibitor, was well-tolerated with no adverse effects reported, suggesting it may be a safe and effective second-line treatment option for LCH driven by specific genetic mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Success of Trametinib in the Treatment of Langerhans Cell Histiocytosis With Novel MAPK Pathway Mutations. Orr, K., Hustak, S., Beaudoin, R., et al.[2023]

Trametinib, a MEK inhibitor, is effective for treating metastatic melanoma with BRAF V600E and V600K mutations, but it is associated with significant skin-related side effects.

In a case study of a 66-year-old man, the severity of skin reactions increased when trametinib was used alone compared to when it was combined with a BRAF inhibitor, highlighting the need for careful management of these adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Xanthogranulomatous reaction to trametinib for metastatic malignant melanoma. Min, MS., Yao, J., Chee, N., et al.[2019]

In a study of 34 patients with various histiocytoses, including LCH, treatment with BRAF and MEK inhibitors (dabrafenib and trametinib) resulted in sustained favorable responses in 94% of patients with recurrent or refractory disease over a median duration of 4.3 years.

The inhibitors were also effective as first-line treatment for 18 patients, all of whom showed sustained favorable responses over a median duration of 2.5 years, indicating that these targeted therapies can be a safe and effective alternative to traditional chemotherapy for children with histiocytoses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders. Cournoyer, E., Ferrell, J., Sharp, S., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10431469/

EFFICACY AND SAFETY OF TRAMETINIB IN ADULTS ... In 3/8 patients (37,5%) complete response was achieved with non-detectable disease. Other 5/8 (62,5%) had a partial response. Two patients had ...

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/1802/529609/Efficacy-and-Tolerability-of-Trametinib-in-Adults

Efficacy and Tolerability of Trametinib in Adults with Histiocytic ... A clinical response rate of 78% (28/36) and 2-year overall survival of 97% were observed. No clinical response was reported in 1/12 on dual ...

3. hematologyadvisor.com hematologyadvisor.com/reports/pediatric-langerhans-cell-trametinib-effective-option-treatment-risk/

Trametinib May Be an Effective Option for Pediatric ... Results from a retrospective study suggest that trametinib may be an effective and well-tolerated option for pediatric patients with Langerhans cell ...

4. haematologica.org haematologica.org/article/view/haematol.2023.283295

Dabrafenib and trametinib in Langerhans cell histiocytosis ... With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients, aged 0.2-45 years, ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2950328024000232

Real-world experience with targeted therapy in patients ... In a recent study by Cournoyer et al, 0 of 34 patients with histiocytosis treated with dabrafenib and/or trametinib developed neurodegeneration while on therapy ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10985423/

Dabrafenib and trametinib in Langerhans cell histiocytosis ... Our data suggest that children suffering from histiocytoses can be treated safely and effectively with dabrafenib or trametinib. Additional studies are, however ...