Targeted Approach to Langerhans Cell Histiocytosis (LCH) Using MEK Inhibitor, Trametinib

April 1, 2026 updated by: Cook Children's Health Care System
The purpose of this Phase II clinical trial is to establish the safety and effectiveness of trametinib, a targeted therapy, for the treatment of newly or recently diagnosed Langerhans Cell Histiocytosis (LCH) among pediatric patients.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Langerhans cell histiocytosis (LCH) is a rare histiocytic disease derived from the mononuclear phagocytic system, affecting between 2 and 10 cases per one million children under 15 years. Controversy exists as to whether it is a true malignancy or a cancer-like disease, given that the BRAFV600E mutation frequently found in LCH has been found in several cancers as well as in benign nevi. Regardless, among histiocytic disorders, LCH is well-known to result from clonal proliferation of immature cells that can affect a single organ (single system LCH) which may be unifocal or multifocal; or LCH may involve multiple organs which may be limited or widespread. Notably, involvement of specific organs such as the liver, spleen, and bone marrow is typically considered high risk. A biopsy is a critical element for diagnosis as histiocytes with surface expression of CD207 (langerin) and CD1a are a defining characteristic of LCH. In addition to a biopsy of either skin lesion, lymph node, or tumor, standard imaging such as CT, MRI, and PET will be used to assess the extent of disease.

This trial is designed to evaluate treatment of newly diagnosed or relapsed LCH patients with targeted therapy (trametinib). The investigators hypothesize that this will help establish a new treatment for these patients who have historically been treated with cytotoxic chemotherapy that can potentially be associated with serious adverse effects as well as relapse which have typically been noted within two years, therefore justifying the rationale to treat for minimum of two years. This clinical trial will provide an opportunity to assess for adverse events and toxicities associated with trametinib for the treatment of LCH among pediatric patients. Additionally, the investigators will critically analyze the effectiveness of genomic cancer testing through the use of liquid, tumor, and tumor-match next-generation sequencing (NGS) in patients with an LCH diagnosis.

Study Type

Interventional

Enrollment (Estimated)

75

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Texas
      • Fort Worth, Texas, United States, 76104
        • Recruiting
        • Cook Children's Health Care System
        • Principal Investigator:
          • Anish Ray, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Diagnosis/disease status:

    • Patients with newly diagnosed Langerhans cell histiocytosis (LCH) OR
    • Patients with relapsed or refractory disease OR
    • Patients with newly diagnosed or relapsed/refractory disease who are receiving the liquid formula of trametinib OR
    • Patients who have been receiving trametinib as a treatment for LCH since January 1, 2020 may be included in the observational chart review to track long-term follow-up. Eligibility for chart review cohort will include receiving trametinib as treatment.
  • Diagnosis confirmed with biopsy prior to start of treatment

  • Patient must have adequate cardiac function evident through Echocardiogram (ECHO) and Electrocardiogram (EKG) within 30 days of starting treatment.

    • Shortening fraction of ≥ 27% by echocardiogram or
    • Ejection fraction of ≥ 50% by gated radionuclide study
    • QTC < 480 msec
  • Performance status: Patients must have a performance status corresponding to ECOG scores of 0, 1, or 2. Use Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥50% for patients ≤16 years of age.

  • Adequate organ and marrow function as defined below:

    • Absolute Neutrophil count ≥ 1,500/μL
    • Platelets ≥ 100x103/μL
    • Total bilirubin ≤ 1.5X ULN for age
    • AST/ALT ≤ 2.5 X ULN for age
    • Serum creatinine based on age/gender

    • Hemoglobin ≥ 8 g/dL

      • Patients with bone marrow disease must have hemoglobin ≥ 8 g/dL with transfusion support allowed
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after the last dose. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
  • Ability to understand study procedures and to comply with them for the entire length of the study.

Exclusion Criteria:

  • Patients diagnosed with Low-Risk True Skin Only or a Single Bone lesion that does not require treatment and will only be observed will not be eligible, with the exception of CNS-risk lesions/special site disease or functionally critical lesions:

    • CNS-risk/special site includes: Sphenoid, Mastoid, Orbital, zygomatic, ethmoid, maxillary, or temporal bones, the cranial fossa, pituitary gland or neurodegenerative disease, odontoid peg, vertebral lesion with intraspinal soft tissue extension
    • Functionally critical: A single lesion not described above which may cause "functionally critical anatomic abnormality" wherein attempts at local therapy would cause unacceptable morbidity. This can be at the discretion of the Principal Investigator.

  • Patients whose genetic testing reveals a class 3 MAP2K1 mutation:

    • I103_K104del
    • E102_I103del
    • L98_K104delinsQ
    • L98_I103del
    • I99_K104del
  • Patients who present with jaundice at diagnosis.

  • Patients who are pregnant or breastfeeding are not eligible. Women of childbearing potential must receive a negative pregnancy test within 14 days of starting treatment or the patient will not be eligible.

    • Patients who are allergic to trametinib
    • Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
  • Inability or unwillingness of patient or parent/legally authorized representative to give written informed consent.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Prospective Treatment
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.
Drug: Trametinib
Participants will be given trametinib as a single agent once a day dosing, with a maximum dose of 2kg. Participants who are able to swallow pills will be given oral tablets. Participants unable to swallow pills will be dispensed the liquid formula concentrate at 0.05mg/mL with dosing of 0.015mg/kg.
Other Names:
  • Mekinist
No Intervention: Observation Only
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to Progression (TTP)
Time Frame: Up to six years
TTP defined for each participant as the period of time from start of treatment to the manifestation of objective progression, but excluding occurrences of death.
Up to six years
Progression-free Survival (PFS)
Time Frame: Up to six years
PFS defined for each participant as the time from start of treatment to disease progression (recurrence) or death by any cause in the absence of progression.
Up to six years
Overall Survival (OS)
Time Frame: Up to six years
OS defined for each participant as the time from the date of first administration until the date of death from any cause. Participants not having an event at the time of analysis will be censored at the date they were last known to be alive.
Up to six years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response Rate
Time Frame: Up to six years
The response rate will be defined as the percentage of patients with Complete Response (the disappearance of all signs of LCH in response to treatment), Stable Disease (neither increasing nor decreasing in extent or severity), Partial Response (at least a 30% decrease in the signs of LCH), and Progressive Disease (at least a 20 percent growth in the signs of LCH since the beginning of treatment).
Up to six years
Blood HistioTrak Levels in Participants with BRAF V600E Mutations
Time Frame: Up to six years
The HistioTrak test is a highly sensitive droplet digital PCR (ddPCR)-based molecular assay designed to measure MRD in patients with BRAF V600E-driven histiocytic and other neoplasms.
Up to six years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Cook Children's Health Care System

Investigators

  • Principal Investigator: Anish Ray, MD, Cook Children's Health Care System

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 24, 2024

Primary Completion (Estimated)

June 1, 2039

Study Completion (Estimated)

December 1, 2039

Study Registration Dates

First Submitted

August 30, 2024

First Submitted That Met QC Criteria

August 30, 2024

First Posted (Actual)

September 3, 2024

Study Record Updates

Last Update Posted (Actual)

April 7, 2026

Last Update Submitted That Met QC Criteria

April 1, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2023-058

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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