Modified LCH-III Regimen With or Without Luvometinib for Multisystem Pediatric Langerhans Cell Histiocytosis

February 20, 2026 updated by: Xia Guo, West China Second University Hospital

Modified LCH-III Regimen Versus Modified LCH-III Regimen Combined With Luvometinib in the Treatment of Multisystem Pediatric Langerhans Cell Histiocytosis: A Multicenter, Open-Label, Randomized Controlled Clinical Trial

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children, caused by excessive proliferation and accumulation of Langerhans cells (a type of immune cell) in various body tissues. The annual incidence is about 2.6-8.9 cases per million children.Clinical presentation varies widely.

Mild (low-risk) cases may resolve spontaneously or cause minimal issues with excellent outcomes. Severe multisystem LCH involves multiple organs, particularly high-risk sites such as liver, spleen, or bone marrow, leading to poorer prognosis and potential life-threatening complications without appropriate treatment.Standard first-line therapy for many children is prednisone (a corticosteroid) plus vinblastine (chemotherapy). Trials like LCH-III show near-100% survival in low-risk disease, but long-term survival drops to ~80% in high-risk cases. Reactivation occurs in ~37% of low-risk patients post-treatment, and ~50% of children eventually develop resistance, resulting in progression or relapse. Treatment failure heightens risks of long-term sequelae, including growth retardation, endocrine dysfunction, and neurological damage, severely impacting quality of life.

More than half of LCH cases harbor the BRAF V600E mutation, activating the MAPK pathway abnormally. This has driven development of targeted MAPK inhibitors (e.g., vemurafenib, dabrafenib, trametinib), which demonstrate strong efficacy and acceptable safety (mainly manageable skin rash) in relapsed/refractory pediatric cases, with no reported secondary malignancies to date. These agents provide rapid symptom relief and durable control, though monotherapy often fails to eradicate abnormal cells in multisystem disease, leading to relapse after discontinuation.

No MAPK inhibitors were previously approved specifically for LCH. In 2025, luvometinib (developed by Fosun Pharma, China; a selective MEK1/2 inhibitor) received approval in China for adult LCH and histiocytic neoplasms. Adult studies showed ~83% objective response rate and ~74% progression-free at ≥12 months, with mostly mild side effects (skin issues, hypertriglyceridemia) and no discontinuations due to serious toxicity.

Laboratory evidence indicates MAPK overactivation confers apoptosis resistance to LCH cells; combining MAPK inhibitors with chemotherapy may enhance cell killing and leverage chemotherapy-induced immune microenvironment changes for better clearance.

Small studies and real-world data in refractory LCH support this: combination regimens yielded low relapse rates (especially with prolonged therapy), 100% responses in some pediatric cohorts with sustained remission and no added severe toxicity, and notably lower relapse (20% vs 75% with inhibitor alone) in our center's early experience with LCH-III backbone plus MAPK inhibitor.

This multicenter randomized trial will enroll children with multisystem LCH, assigning them to modified standard LCH-III chemotherapy alone or the same regimen combined with luvometinib, to evaluate whether adding this targeted agent improves outcomes.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Lab studies show that when the MAPK pathway is overactive, it makes LCH cells harder to kill (more resistant to dying naturally). Combining an MAPK inhibitor with chemotherapy might make the abnormal cells easier to destroy. Chemotherapy also changes the immune environment in the body, which could help clear out the bad cells more completely.

Several small studies and real-world experiences have already tested this idea in children and adults with hard-to-treat LCH:

One study combined MAPK inhibitors with certain chemotherapy drugs and saw very few relapses, especially when treatment lasted longer.

Another study using a similar approach achieved 100% response in a group of children (including some as first treatment), with most staying in remission afterward, and no extra serious side effects from the combination.

A Chinese study using prednisone, another chemo drug, plus an MAPK inhibitor showed good results with low relapse after stopping.

Early data from our own center found that children who got an MAPK inhibitor together with the standard LCH-III treatment had much lower relapse rates (only 20%) compared to those who got the inhibitor alone (75% relapse).

Based on this growing evidence, this study plans to run a large, carefully designed trial at multiple hospitals. It will randomly assign children with multisystem LCH to receive either the improved (modified) version of the standard LCH-III chemotherapy alone, or the same chemotherapy combined with luvometinib. The goal is to compare how well each approach works and to learn more about whether adding this targeted drug to chemotherapy can improve treatment for children with this disease.

Study Type

Interventional

Enrollment (Estimated)

120

Phase

  • Not Applicable

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 Locations

  • China
      • Chengdu, China
        • Recruiting
        • West China Second Hospital, Sichuan University
        • Contact:
      • Guiyang, China
        • Recruiting
        • Affiliated Hospital of Guizhou Medical University
        • Contact:
      • Hefei, China
        • Recruiting
        • The Second Affiliated Hospital of Anhui Medical University
        • Contact:
      • Hefei, China
        • Recruiting
        • Anhui Provincial Children's Hospital
        • Contact:
      • Jiangxi, China
        • Recruiting
        • Jiangxi Provincial Children's Hospital
        • Contact:
      • Kunming, China
        • Recruiting
        • Kunming Children's Hospital
        • Contact:
      • Nanning, China
        • Recruiting
        • The Second Affiliated Hospital of Guangxi Medical University
        • Contact:
          • Hong Ying Wei
          • Phone Number: 86+15977767103
          • Email: whylhr@qq.com
      • Xi'an, China
        • Recruiting
        • Xi'an Children's Hospital
        • Contact:
      • Xi'an, China
        • Recruiting
        • Xi'an Northwest Women's and Children's Hospital
        • Contact:
      • Zunyi, China
        • Recruiting
        • Zunyi Medical University Affiliated Hospital, Guizhou Provincial Children's Hospital
        • Contact:
      • Ürümqi, China
        • Recruiting
        • The first affiliated hospital of Xinjiang medical university
        • 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:

  1. Children aged 0-18 years, of either sex.
  2. Pathologically confirmed diagnosis of Langerhans cell histiocytosis (LCH) with positive staining for CD1a and/or CD207 (Langerin), and no prior treatment specifically directed against LCH.
  3. Multisystem involvement of LCH, as determined by clinical and imaging evaluation.
  4. Provision of written informed consent (by parent/legal guardian and, where appropriate, assent from the child), with willingness to comply with the study treatment regimen and follow-up assessments.

Exclusion Criteria:

  1. Presence of any other significant underlying medical condition, including but not limited to primary immunodeficiency disorders, congestive heart failure, renal insufficiency, chronic viral hepatitis, HIV infection, or status post solid organ transplantation.
  2. History of a second (secondary) malignancy.
  3. QTcF interval > 0.47 seconds on electrocardiogram performed prior to enrollment.
  4. Ophthalmologic screening prior to enrollment revealing retinal vein occlusion, retinal pigment epithelial detachment, or other clinically significant ocular abnormalities that, in the opinion of the investigator, contraindicate participation.
  5. LCH harboring Class 3 MEK pathway mutations, specifically the following alterations: L98_I103del, L98_K104del, P105_A106del, P105_I107delinsL, L101_I103delinsF, E102_I103delinsF, E102_I103del, E102_I103delinsV, E102_I103delinsVN, E102_K104delinsQ, or I103_A106del.
  6. Refusal or inability to provide written informed consent (or assent, as applicable).

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: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Modified LCH-III Chemotherapy + Luvometinib (Experimental Arm)
Participants receive the same modified LCH-III chemotherapy regimen (prednisone, vinblastine, mercaptopurine) combined with oral luvometinib throughout the treatment period
Drug: Prednisone
Corticosteroid administered orally as part of the modified LCH-III regimen
Drug: Vincristine
Intravenous vinca alkaloid chemotherapy agent used in the modified LCH-III regimen
Drug: Mercaptopurine
Oral purine analog antimetabolite used in the maintenance phase of therapy for multisystem LCH
Drug: Luvometinib
Oral selective MEK1/2 inhibitor added to the experimental arm. Administered daily in combination with modified LCH-III chemotherapy for multisystem Langerhans cell histiocytosis.
Active Comparator: Modified LCH-III Chemotherapy Alone (Control Arm)
Participants receive the modified standard LCH-III chemotherapy regimen consisting of prednisone and vincristine.
Drug: Prednisone
Corticosteroid administered orally as part of the modified LCH-III regimen
Drug: Vincristine
Intravenous vinca alkaloid chemotherapy agent used in the modified LCH-III regimen
Drug: Mercaptopurine
Oral purine analog antimetabolite used in the maintenance phase of therapy for multisystem LCH

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Event-Free survival rate
Time Frame: From Day 1 until the date of first event or last follow-up, assessed up to 2 years.
Event-free survival (EFS) is defined as the time from Day 1 to the first occurrence of any event, including disease reactivation , second primary malignancy, or death from any cause. Events will be assessed by clinical examination, imaging, and laboratory tests. The 2-year EFS rate will be estimated using the Kaplan-Meier method, reported as percentage with 95% confidence interval.
From Day 1 until the date of first event or last follow-up, assessed up to 2 years.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective response rate
Time Frame: At 1 month and 3 months post-treatment
Objective response rate (ORR) is defined as the proportion of participants achieving NAD or ADB at the specified time points. Responses will be assessed by clinical evaluation, imaging, and risk organ function (if involved). ORR will be reported separately at 1 month and 3 months as percentage of participants with NAD or ADB (combined), with exact 95% confidence intervals.
At 1 month and 3 months post-treatment
Overall survival rate
Time Frame: From Day1 until date of death from any cause or last follow-up, assessed up to 2 years.
Overall survival (OS) is defined as Day 1 to death from any cause. Participants alive at last follow-up will be censored. The 2-year OS rate will be estimated using the Kaplan-Meier method and reported as percentage with 95% confidence interval.
From Day1 until date of death from any cause or last follow-up, assessed up to 2 years.
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Time Frame: From Day 1 until through study completion, an average of 2 years
Safety and tolerability of the combination regimen (luvometinib added to modified LCH-III chemotherapy: prednisone + Vincristine backbone) will be assessed by the number of participants experiencing treatment-related adverse events (TRAEs), and serious adverse events (SAEs). Events will be graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Data will be summarized as: Incidence of any TRAE (percentage of participants) , Incidence by maximum grade (e.g., Grade 3-5) ,Incidence of specific events of interest (e.g., skin rash, hypertriglyceridemia, cytopenias) and Rate of treatment discontinuation due to toxicity
From Day 1 until through study completion, an average of 2 years

Collaborators and Investigators

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

Sponsor

West China Second University Hospital

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 (Estimated)

February 13, 2026

Primary Completion (Estimated)

December 31, 2030

Study Completion (Estimated)

December 31, 2030

Study Registration Dates

First Submitted

February 13, 2026

First Submitted That Met QC Criteria

February 20, 2026

First Posted (Actual)

February 24, 2026

Study Record Updates

Last Update Posted (Actual)

February 24, 2026

Last Update Submitted That Met QC Criteria

February 20, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • WCSH-NCP-MS-LCH-2026

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

IPD might be shared in the future upon approval by the ethics committee and under a data use agreement.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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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