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

NCT07431060 | Recruiting DMC

• 1 other identifier: WCSH-NCP-MS-LCH-2026
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 11

Brief Summary

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.

Conditions

Langerhans Cell Histiocytosis (LCH)

Keywords

Langerhans Cell Histiocytosis; Luvometinib

Outcome Measures

Primary Outcomes (1)

• Event-Free survival rate

  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 Outcomes (3)

• Objective response rate

  At 1 month and 3 months post-treatment

• Overall survival rate

  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

  From Day 1 until through study completion, an average of 2 years

Study Arms (2)

Modified LCH-III Chemotherapy + Luvometinib (Experimental Arm)

EXPERIMENTAL

Participants receive the same modified LCH-III chemotherapy regimen (prednisone, vinblastine, mercaptopurine) combined with oral luvometinib throughout the treatment period

Drug: Prednisone; Drug: Vincristine; Drug: Mercaptopurine; Drug: Luvometinib

Modified LCH-III Chemotherapy Alone (Control Arm)

ACTIVE COMPARATOR

Participants receive the modified standard LCH-III chemotherapy regimen consisting of prednisone and vincristine.

Drug: Prednisone; Drug: Vincristine; Drug: Mercaptopurine

Interventions

Prednisone DRUG

Corticosteroid administered orally as part of the modified LCH-III regimen

Modified LCH-III Chemotherapy + Luvometinib (Experimental Arm); Modified LCH-III Chemotherapy Alone (Control Arm)

Vincristine DRUG

Intravenous vinca alkaloid chemotherapy agent used in the modified LCH-III regimen

Modified LCH-III Chemotherapy + Luvometinib (Experimental Arm); Modified LCH-III Chemotherapy Alone (Control Arm)

Mercaptopurine DRUG

Oral purine analog antimetabolite used in the maintenance phase of therapy for multisystem LCH

Modified LCH-III Chemotherapy + Luvometinib (Experimental Arm); Modified LCH-III Chemotherapy Alone (Control Arm)

Luvometinib DRUG

Oral selective MEK1/2 inhibitor added to the experimental arm. Administered daily in combination with modified LCH-III chemotherapy for multisystem Langerhans cell histiocytosis.

Modified LCH-III Chemotherapy + Luvometinib (Experimental Arm)

Eligibility Criteria

• Age: 0 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Children aged 0-18 years, of either sex.
• 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.
• Multisystem involvement of LCH, as determined by clinical and imaging evaluation.
• 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.

You may not qualify if:

• 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.
• History of a second (secondary) malignancy.
• QTcF interval \> 0.47 seconds on electrocardiogram performed prior to enrollment.
• 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.
• 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.
• Refusal or inability to provide written informed consent (or assent, as applicable).

Sponsors & Collaborators

• West China Second University Hospital: lead

Study Sites (11)

West China Second Hospital, Sichuan University

Chengdu, China

RECRUITING

Affiliated Hospital of Guizhou Medical University

Guiyang, China

RECRUITING

Anhui Provincial Children's Hospital

Hefei, China

RECRUITING

The Second Affiliated Hospital of Anhui Medical University

Hefei, China

RECRUITING

Jiangxi Provincial Children's Hospital

Jiangxi, China

RECRUITING

Kunming Children's Hospital

Kunming, China

RECRUITING

The Second Affiliated Hospital of Guangxi Medical University

Nanning, China

RECRUITING

The First Affiliated Hospital of Xinjiang Medical University

Ürümqi, China

RECRUITING

Xi'an Children's Hospital

Xi'an, China

RECRUITING

Xi'an Northwest Women's and Children's Hospital

Xi'an, China

RECRUITING

Zunyi Medical University Affiliated Hospital, Guizhou Provincial Children's Hospital

Zunyi, China

RECRUITING

Related Publications (14)

• Lei J, Wang W, Lin D, Zhu C, Jia W, Weng W, Liu X, Ma Y, Wang Z, Yang L, He X, He Y, Li Y. Vemurafenib combined with chemotherapy achieved sustained remission in pediatric LCH: a multi-center observational study. J Cancer Res Clin Oncol. 2024 Jan 17;150(1):12. doi: 10.1007/s00432-023-05551-y.

  PMID: 38231288 RESULT

• Evseev D, Osipova D, Kalinina I, Raykina E, Ignatova A, Lyudovskikh E, Baidildina D, Popov A, Zhogov V, Semchenkova A, Litvin E, Kotskaya N, Cherniak E, Voronin K, Burtsev E, Bronin G, Vlasova I, Purbueva B, Fink O, Pristanskova E, Dzhukaeva I, Erega E, Novichkova G, Maschan A, Maschan M. Vemurafenib combined with cladribine and cytarabine results in durable remission of pediatric BRAF V600E-positive LCH. Blood Adv. 2023 Sep 26;7(18):5246-5257. doi: 10.1182/bloodadvances.2022009067.

  PMID: 37216396 RESULT

• Karri V, Lin H, Velazquez J, Batajoo A, Parekh D, Stanton W, Abhyankar H, El-Mallawany NK, Agrusa J, Eckstein O, Gulati N, Schwartz J, Woods-Swafford W, Boyd J, Saha A, Allen CE, McClain KL. Clinical, radiological and molecular responses to combination chemotherapy with MAPK pathway inhibition in relapsed and refractory Langerhans cell histiocytosis. Br J Haematol. 2024 May;204(5):1882-1887. doi: 10.1111/bjh.19380. Epub 2024 Mar 19.

  PMID: 38501390 RESULT

• Bigenwald C, Le Berichel J, Wilk CM, Chakraborty R, Chen ST, Tabachnikova A, Mancusi R, Abhyankar H, Casanova-Acebes M, Laface I, Akturk G, Jobson J, Karoulia Z, Martin JC, Grout J, Rafiei A, Lin H, Manz MG, Baccarini A, Poulikakos PI, Brown BD, Gnjatic S, Lujambio A, McClain KL, Picarsic J, Allen CE, Merad M. BRAFV600E-induced senescence drives Langerhans cell histiocytosis pathophysiology. Nat Med. 2021 May;27(5):851-861. doi: 10.1038/s41591-021-01304-x. Epub 2021 May 6.

  PMID: 33958797 RESULT

• Hogstad B, Berres ML, Chakraborty R, Tang J, Bigenwald C, Serasinghe M, Lim KPH, Lin H, Man TK, Remark R, Baxter S, Kana V, Jordan S, Karoulia Z, Kwan WH, Leboeuf M, Brandt E, Salmon H, McClain K, Poulikakos P, Chipuk J, Mulder WJM, Allen CE, Merad M. RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions. J Exp Med. 2018 Jan 2;215(1):319-336. doi: 10.1084/jem.20161881. Epub 2017 Dec 20.

  PMID: 29263218 RESULT

• Cao XX, Zhu Q, Cai Z, Ma J, Zhou H, Chang L, Zhong LP, Wu ZL, Wang X, Han P, Lin HM, Wei Z, Guo JY, Zheng Y, Li J. Luvometinib in patients with Langerhans cell histiocytosis, Erdheim-Chester disease, and other histiocytic neoplasms: a single-arm, multicentre, phase 2 study. EClinicalMedicine. 2025 Sep 17;88:103486. doi: 10.1016/j.eclinm.2025.103486. eCollection 2025 Oct.

  PMID: 41035796 RESULT

• Keam SJ. Luvometinib: First Approval. Drugs. 2025 Sep;85(9):1177-1183. doi: 10.1007/s40265-025-02217-6. Epub 2025 Aug 2.

  PMID: 40751881 RESULT

• Whitlock JA, Geoerger B, Dunkel IJ, Roughton M, Choi J, Osterloh L, Russo M, Hargrave D. Dabrafenib, alone or in combination with trametinib, in BRAF V600-mutated pediatric Langerhans cell histiocytosis. Blood Adv. 2023 Aug 8;7(15):3806-3815. doi: 10.1182/bloodadvances.2022008414.

  PMID: 36884302 RESULT

• Cournoyer E, Ferrell J, Sharp S, Ray A, Jordan M, Dandoy C, Grimley M, Roy S, Lorsbach R, Merrow AC, Nelson A, Bartlett A, Picarsic J, Kumar A. Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders. Haematologica. 2024 Apr 1;109(4):1137-1148. doi: 10.3324/haematol.2023.283295.

  PMID: 37731389 RESULT

• Donadieu J, Larabi IA, Tardieu M, Visser J, Hutter C, Sieni E, Kabbara N, Barkaoui M, Miron J, Chalard F, Milne P, Haroche J, Cohen F, Helias-Rodzewicz Z, Simon N, Jehanne M, Kolenova A, Pagnier A, Aladjidi N, Schneider P, Plat G, Lutun A, Sonntagbauer A, Lehrnbecher T, Ferster A, Efremova V, Ahlmann M, Blanc L, Nicholson J, Lambilliote A, Boudiaf H, Lissat A, Svojgr K, Bernard F, Elitzur S, Golan M, Evseev D, Maschan M, Idbaih A, Slater O, Minkov M, Taly V, Collin M, Alvarez JC, Emile JF, Heritier S. Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study. J Clin Oncol. 2019 Nov 1;37(31):2857-2865. doi: 10.1200/JCO.19.00456. Epub 2019 Sep 12.

  PMID: 31513482 RESULT

• Haupt R, Nanduri V, Calevo MG, Bernstrand C, Braier JL, Broadbent V, Rey G, McClain KL, Janka-Schaub G, Egeler RM. Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effects Study Group. Pediatr Blood Cancer. 2004 May;42(5):438-44. doi: 10.1002/pbc.20021.

  PMID: 15049016 RESULT

• Parekh D, Lin H, Batajoo A, Peckham-Gregory E, Karri V, Stanton W, Scull B, Fleishmann R, El-Mallawany N, Eckstein OS, Prudowsky ZD, Gulati N, Agrusa JE, Ahmed AZ, Chu R, Dietz MS, Goldman SC, Hogarty MD, Imran H, Intzes S, Kim JM, Kopp LM, Levy CF, Neff P, Pillai PM, Sisk BA, Schiff DE, Trobaugh-Lotrario AD, Walkovich K, McClain KL, Allen CE. Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis. Br J Haematol. 2024 May;204(5):1888-1893. doi: 10.1111/bjh.19376. Epub 2024 Mar 19.

  PMID: 38501389 RESULT

• Lin H, Batajoo A, Peckham-Gregory E, Zinn D, Eckstein OS, El-Mallawany NK, Gulati N, Prudowsky ZD, Scull B, Velazquez J, Abhyankar H, Simko SJ, Vakula D, Fleischmann R, Karri V, Hicks MJ, Fisher KE, Curry CV, Roy A, Schiff D, Heym KM, Scheurer ME, Parsons DW, Merad M, Man TK, McClain KL, Picarsic J, Allen CE. BRAF V600E-positive mononuclear cells in blood at diagnosis portend treatment failure and neurodegeneration in pediatric LCH. Blood. 2025 Jul 10;146(2):206-218. doi: 10.1182/blood.2024026671.

  PMID: 40167581 RESULT

• Rodriguez-Galindo C, Allen CE. Langerhans cell histiocytosis. Blood. 2020 Apr 16;135(16):1319-1331. doi: 10.1182/blood.2019000934.

  PMID: 32106306 RESULT

MeSH Terms

Conditions

Histiocytosis, Langerhans-Cell

Interventions

Prednisone; Vincristine; Mercaptopurine

Condition Hierarchy (Ancestors)

Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Sulfhydryl Compounds; Sulfur Compounds; Organic Chemicals; Purines

Central Study Contacts

Xue Tang

CONTACT

86+18280145819; txily0912@126.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Pediatrics

Study Record Dates

• First Submitted: February 13, 2026
• First Posted: February 24, 2026
• Study Start: February 13, 2026
• Primary Completion (Estimated): December 31, 2030
• Study Completion (Estimated): December 31, 2030
• Last Updated: February 24, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

CN (11)