Real-world Study of Darafenib or Trametinib and Clofarabine for High-risk/Recurrent/Refractory Langerhans Cell Histiocytosis in Children

June 7, 2025 updated by: Ju Gao, West China Second University Hospital

A Real-world Investigation of the Combination of Darafenib or Trametinib and Clofarabine in the Treatment of High-risk, Recurrent, or Refractory Pediatric Patients With Langerhans Cell Histiocytosis.

Langerhans cell histiocytosis (LCH) is the most common histiocytosis in children, with an incidence of 2.6-8.9 per million. It is an inflammatory myeloid tumor with varied symptoms. Mild cases often resolve spontaneously, while severe cases can affect multiple organs and be life-threatening. LCH affecting the liver, spleen, or hematopoietic system has a poor prognosis and is high-risk group. The LCH-III study showed that low-risk children respond well to prednisone and vinblastine, with nearly 100% survival, but high-risk children's survival is about 80%, with a 30% reactivation rate.Long-term studies reveal that about 50% of patients are resistant to prednisone and vinblastine, leading to progression and recurrence.

Except combination of prednisone and vinblastine, cladribine (introduced in 1998) and MAPK inhibitors (introduced in 2014), have lowered the mortality rate of LCH in children. Cladribine, a nucleoside analogue, is used for treating recurrent acute myeloid leukemia in children by disrupting DNA synthesis. In the LCH-98-S regimen, low-risk children with LCH responded well to moderate doses of cladribine, but 44% of high-risk children still faced disease progression. Later studies showed that high-dose cladribine with medium-dose cytarabine increased survival in refractory LCH from 30% to 85%, but also raised chemotherapy toxicity, with some cases experiencing severe hematological toxicity and half of the deaths resulting from chemotherapy complications. Clofarabine, a nucleoside analogue, inhibits ribonucleotide reductase and DNA polymerase, offering stronger anti-tumor effects and fewer side effects than cladribine and fludarabine in treating refractory leukemia. Case reports show that LCH patients unresponsive to cladribine improve with clofarabine treatment at moderate doses (25mg/m2/day). A retrospective study of 58 LCH patients using clofarabine (25mg/m2/day) showed an 87% progression-free survival rate after one year. While the main side effect was grade 3 or higher hematological toxicity, 98.3% of patients tolerated it and completed treatment. Further prospective studies are needed to determine the optimal dose, duration, long-term efficacy, and complications of clofarabine in children with LCH.

Research indicates that childhood LCH is often linked to mutations in MAPK pathway genes, with over half of cases involving BRAFV600E mutations. MAPK inhibitors, like vemurafenib, dabrafenib and trametinib, are effective for relapsed and refractory LCH, but they don't eliminate malignant clones, leading to disease reactivation after stopping treatment. Some BRAF-deficient mutation LCH patients resist vemurafenib and dabrafenib, but trametinib can manage the disease in these cases. Activation of the MAPK pathway increases BCL2L1 expression in LCH cells, and rapamycin fails to induce apoptosis in BRAFV600E+ LCH cells, enhancing resistance to cell death. MAPK inhibitors combined with chemotherapy are theoretically more effective at inducing apoptosis in LCH cells and resetting the immune environment to eliminate malignant clones. Two clinical studies confirm their safety and efficacy in treating refractory recurrent LCH. In a follow-up of 10 LCH cases treated with nucleotide analogues and MAPK inhibitors, only 2 patients relapsed after a short treatment duration. Additionally, 19 children with BRAFV600E mutation LCH were treated with cladribine, cytarabine, and vemurafenib, achieving a 100% response rate. Nearly 80% completed treatment without recurrence, and no increase in side effects was observed.

Since 2020, our center treated nearly 40 LCH patients with MAPK inhibitors, including 14 combined with LCH-III chemotherapy. Follow-ups show no severe toxic side effects, aligning with literature. However, most high-risk patients, especially those who stopped oral MAPK inhibitors, had disease reactivation. Two high-risk patients with liver involvement achieved complete liver lesion regression with cladribine. This clinical study aims to assess the efficacy and safety of dabrafenib or trametinib and clofarabine for high-risk/recurrent/refractory LCH in children.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

20

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

  • China
    • Sichuan
      • Chengdu, Sichuan, China, 610041
        • Recruiting
        • Department of Pediatric Hematology and Oncology, West China Second University Hospital, Sichuan University, Chengdu, China
        • 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 with LCH (CD1a+/CD207+);
  2. Initial LCH diagnosis with hematopoietic, liver, or spleen involvement;
  3. LCH patients with disease progression or reactivation after chemotherapy (e.g., prednisone, vincristine, cytarabine, clarithromycin) or targeted therapy;
  4. Consent to treatment and follow-up;
  5. ECOG score ≥ 2, Lansky score ≥ 50, organ function suitable for chemotherapy.

Exclusion Criteria:

  1. Other underlying diseases (e.g., primary immunodeficiency, heart/kidney failure, hepatitis, HIV, organ transplant);
  2. Secondary tumor;
  3. Recent chemotherapy, radiotherapy, or MAPK inhibitor use with lingering adverse effects;
  4. Ongoing nephrotoxic drug use;
  5. Refusal to consent.

Exit Criteria:

  1. Allergies to dabrafenib or trametinib and clofarabine；
  2. Disease progression after 3 months on dabrafenib or trametinib；
  3. Severe toxic side effects from clofarabine (grade 4 non-infectious non-hematological toxicity, SIRS, capillary leak syndrome)； 4）The doctor recommends halting the current treatment plan for the patient's benefit.

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: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Dabrafenib or Trametinib and Clofarabine
Drug: Dabrafenib or Trametinib and Clofarabine

Drug: Dabrafenib or Trametinib Dabrafenib: 3-5 mg/kg/day; Trametinib: 0.025mg/kg/day

Drug: Clofarabine Consolidation therapy: 25 mg/m2/d, days 1-5 Maintenance therapy: 25 mg/m2/d, days 1-2

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Progression Free Survival
Time Frame: 24 months
24 months

Secondary Outcome Measures

Outcome Measure
Time Frame
Overall Response Rates
Time Frame: 3 months
3 months
Nature and Severity of Adverse Events
Time Frame: 18 months
18 months

Collaborators and Investigators

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

Sponsor

West China Second University Hospital

Investigators

  • Study Chair: Ju Gao, MD, West China Second University Hospital, Sichuan University, Sichuan, China

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 1, 2025

Primary Completion (Estimated)

June 1, 2028

Study Completion (Estimated)

June 1, 2030

Study Registration Dates

First Submitted

June 7, 2025

First Submitted That Met QC Criteria

June 7, 2025

First Posted (Actual)

June 15, 2025

Study Record Updates

Last Update Posted (Actual)

June 15, 2025

Last Update Submitted That Met QC Criteria

June 7, 2025

Last Verified

June 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • WCSH-LCH-2025

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Patient's clinical data, treatment , treatment evaluation response, and follow-up results

IPD Sharing Time Frame

Start date：Experimental completion, data cleaning, and preliminary analysis completed End date：5 years after the completion of the experiment

IPD Sharing Access Criteria

Research team members Ethics Committee/Institutional Review Committee Data and Security Monitoring Committee

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF
  • CSR

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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