Response-adapted Luvometinib With or Without Cytarabine in Langerhans Cell Histiocytosis

NCT07728201 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: LUCAS-2026-V4.0
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This single-center, prospective, interventional phase 2 study evaluates a response-adapted treatment strategy for patients aged 10 years and older with histologically confirmed Langerhans cell histiocytosis requiring systemic therapy. All participants receive six 35-day cycles of luvometinib induction. Post-induction treatment follows the cycle 6 PET/CT response: participants with complete metabolic response continue luvometinib maintenance without cytarabine, whereas participants without complete metabolic response who are judged suitable to continue protocol treatment receive luvometinib plus cytarabine followed by luvometinib maintenance; participants with progression or otherwise unsuitable to continue protocol treatment may receive other standard therapy or discontinue study treatment per protocol. The primary endpoint is objective response rate after six cycles by blinded independent central review.

Conditions

Langerhans Cell Histiocytosis

Keywords

Langerhans cell histiocytosis; LCH; luvometinib; cytarabine; MEK inhibitor; response-adapted therapy; PET/CT; cfDNA; ctDNA; MAPK pathway; LUCAS

Outcome Measures

Primary Outcomes (2)

• Objective response rate after six cycles of luvometinib induction by blinded independent central review

  Proportion of full analysis set participants achieving complete metabolic response (CMR) or partial metabolic response (PMR) by PET response criteria at the cycle 6 assessment window (target C7D1 +/- 7 days), as determined by blinded independent central review. No subsequent confirmatory PET/CT is required. The analysis is descriptive and will report the point estimate with an exact two-sided 95% confidence interval; no confirmatory hypothesis test is planned. Mild out-of-window assessments may be included with protocol deviation documentation if no major treatment or disease-status change affects interpretation. Clearly out-of-window, non-evaluable, or unreliable assessments, death, progression, treatment discontinuation due to toxicity, withdrawal from study treatment, or non-evaluable imaging before the cycle 6 assessment are counted as non-responders.

  At completion of six 35-day cycles, approximately week 30 / target C7D1 +/- 7 days

• Incidence of adverse events and serious adverse events

  AEs, TRAEs, grade \>=3 AEs, SAEs, deaths, and clinically significant laboratory abnormalities summarized by NCI-CTCAE v5.0 and MedDRA SOC/PT. All AEs after informed consent will be recorded; treatment-emergent summaries will start at first study treatment and be summarized by actual exposure period, including luvometinib monotherapy, luvometinib plus cytarabine, and post-progression or salvage treatment descriptions as applicable. SAEs, study-related AEs, pregnancy, and important safety information after study treatment discontinuation may be followed during continued follow-up unless follow-up consent is withdrawn.

  Routine AE recording: consent to 30 days after last study treatment; TEAE summaries from first dose; SAEs, study-related AEs, pregnancy, and important safety information followed per protocol

Secondary Outcomes (6)

• Kaplan-Meier estimated progression-free survival rate at 24 months

  24 months after first dose

• Time to response among CMR/PMR responders

  From first dose through the first documented CMR/PMR, up to 24 cycles (each cycle is 35 days)

• Kaplan-Meier estimated overall survival rate at 12 and 24 months

  12 and 24 months after first dose

• Objective response rate at cycles 12, 18, and 24

  At the end of Cycle 12, 18, and 24 (each cycle is 35 days)

• Disease control rate at cycles 12, 18, and 24

  At the end of Cycle12, 18, and 24 (each cycle is 35 days)

Other Outcomes (5)

• Duration of response among CMR/PMR responders

  From first documented CMR/PMR through progression, death, or last evaluable disease assessment, up to 24 cycles (each cycle is 35 days)

• Spearman Correlation Between Changes in MAPK VAF in cfDNA and peripheral blood cell DNA

  Baseline and the end of cycles 6, 12, 18, and 24 as applicable (each cycle is 35 days)

• Spearman Correlation Coefficient for Changes in MAPK VAF in cfDNA/Peripheral Blood Cell DNA and SUVmax change

  Baseline and cycles 6, 12, 18, and 24 as applicable (each cycle is 35 days)

Study Arms (2)

A: CMR response path

EXPERIMENTAL

All participants receive luvometinib induction for six 35-day cycles before response assessment. Participants achieving complete metabolic response after induction continue luvometinib maintenance without cytarabine for 18 additional 35-day cycles unless progression, unacceptable toxicity, death, or withdrawal occurs. If confirmed progression occurs during maintenance, participants may transition to combination treatment, receive other standard salvage therapy, or discontinue study treatment; progression is counted as a PFS event and, if the participant previously achieved CMR or PMR, a DOR event. Follow-up continues unless follow-up consent is withdrawn.

Drug: Luvometinib

B: Non-CMR response path

EXPERIMENTAL

All participants receive luvometinib induction for six 35-day cycles before response assessment. Participants not achieving complete metabolic response and judged suitable to continue protocol treatment receive luvometinib plus cytarabine for 12 35-day cycles, followed by luvometinib maintenance for 6 additional 35-day cycles.

Drug: Luvometinib, Cytarabine.

Interventions

Luvometinib DRUG

Luvometinib is administered orally once daily in 35-day cycles. Adult participants receive 8 mg once daily. Pediatric participants receive body-surface-area-adjusted dosing at 5 mg/m² once daily, rounded according to protocol with a maximum single dose of 8 mg. Luvometinib is used during induction and maintenance according to the assigned response path.

A: CMR response path

Luvometinib, Cytarabine. DRUG

Luvometinib is administered as described for induction and maintenance. In the B response path, cytarabine is administered at 100 mg/m² by subcutaneous injection on days 1-5 of each 35-day cycle for 12 cycles, followed by luvometinib maintenance for 6 additional 35-day cycles.

B: Non-CMR response path

Eligibility Criteria

• Age: 10 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed Langerhans cell histiocytosis (LCH).
• Age 10 years or older.
• Systemic treatment indication and at least one PET response criteria-evaluable lesion.
• Expected survival of at least 12 weeks, as judged by the investigator, and able to undergo protocol-specified treatment, assessments, and follow-up.
• ECOG performance status 0-2 or Lansky score \>=60.
• Adequate organ function as defined in the protocol.
• Written informed consent from adult participants or legal guardians, with participant assent when applicable.

You may not qualify if:

• Hypersensitivity to luvometinib or any excipient.
• Concurrent other malignant tumor.
• Pregnancy or breastfeeding.
• Failure to meet protocol contraception requirements.
• Active bacterial, fungal, or viral infection.
• Significant retinal disease or glaucoma.
• NYHA class \>=3 heart failure or LVEF \<50%.
• Psychiatric disease or other condition preventing protocol compliance.
• Investigator judgment that participation is unsuitable.

Sponsors & Collaborators

• Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University: lead
• Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.: collaborator

Study Sites (1)

Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine

Shanghai, China

Location

MeSH Terms

Conditions

Histiocytosis, Langerhans-Cell

Interventions

Cytarabine

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Central Study Contacts

Qi Zhu

CONTACT

0086-18116215629; zhuqi70@hotmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Open-label treatment. Protocol-defined PET/CT response endpoints are assessed by blinded independent central review (BICR). Post-discontinuation clinically performed imaging or documentation used only for PFS event recording may be investigator-adjudicated, with BICR review or audit when feasible. BICR reviewers are not involved in treatment decisions, safety management, or emergency medical handling.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: All participants receive luvometinib induction for six 35-day cycles. At cycle 6 PET/CT, participants with complete metabolic response enter the A response path and continue luvometinib maintenance for 18 additional cycles. Participants without complete metabolic response who are suitable to continue protocol treatment enter the B response path and receive luvometinib plus cytarabine for 12 cycles followed by luvometinib maintenance for 6 cycles. Participants with confirmed progression or unsuitable status may receive combination treatment when appropriate, other standard therapy, or discontinue study treatment. Progression is counted for PFS and, after CMR/PMR, for DOR. Survival, subsequent anti-LCH therapy, SAEs, study-related AEs, and clinically performed disease assessments may be followed unless follow-up consent is withdrawn.

Study Record Dates

• First Submitted: July 13, 2026
• First Posted: July 27, 2026
• Study Start: June 30, 2026
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): June 30, 2030
• Last Updated: July 27, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)