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

Phase 2Not Yet RecruitingNCT07728201

Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University30 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

Conditions

Langerhans Cell Histiocytosis

Interventions

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.

Eligibility

Sex: ALLMin age: 10 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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. Exclusion Criteria: * 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.

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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

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

Kaplan-Meier estimated proportion of participants without PRC-defined PMD, investigator-confirmed clinical progression supported by clinically performed imaging or documentation after study treatment discontinuation, or death from any cause. Clinically performed data may be used to record PFS progression events but are not included in ORR/DCR/CBR endpoint analyses. Such PFS events may be investigator-adjudicated, with BICR review or audit when feasible; if BICR review is not feasible, the source, assessment date, adjudicator, rationale, and reason will be documented. A sensitivity analysis will include only BICR-confirmed progression, protocol-window imaging-confirmed progression meeting PRC/BICR requirements, or death from any cause.

Time frame: 24 months after first dose

Time to response among CMR/PMR responders

Time from first dose to first documented CMR or PMR. TTR will be calculated only for participants who achieve CMR or PMR. SMD is not considered a response for TTR; if SMD precedes later PMR/CMR, TTR is measured from first dose to first documented PMR/CMR. Participants with SMD only are not assigned a TTR value.

Time frame: 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

Kaplan-Meier estimated survival rate from first dose to death from any cause. Participants who transition to combination treatment, receive salvage therapy, or discontinue study treatment remain in survival follow-up unless follow-up consent is withdrawn.

Time frame: 12 and 24 months after first dose

Objective response rate at cycles 12, 18, and 24

Proportion of evaluable participants achieving CMR or PMR by PRC/BICR at the cycle 12, 18, and 24 assessment windows. Later ORR is summarized descriptively using the evaluable response set at each time point; the FAS denominator, number evaluable, and reasons for missing or non-evaluable assessments will also be reported. These later visits evaluate durability and subsequent response patterns and do not confirm the primary ORR endpoint.

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

Disease control rate at cycles 12, 18, and 24

Proportion of evaluable participants achieving CMR, PMR, or stable metabolic disease (SMD) by PRC/BICR at the cycle 12, 18, and 24 assessment windows. DCR is summarized descriptively using the evaluable response set at each time point; the FAS denominator, number evaluable, and missing or non-evaluable reasons will be listed.

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

Clinical benefit rate at cycles 12, 18, and 24

Proportion of evaluable participants who achieve CMR, PMR, or SMD and maintain disease control for at least 24 weeks. The 24-week duration is counted from the first assessment date documenting CMR, PMR, or SMD to first PMD, death, or loss of disease control, whichever occurs first. Node-specific CBR at cycles 12, 18, and 24 will count only participants who have met the at-least-24-week disease control duration requirement by that assessment node. Participants pending confirmation or not yet meeting the duration requirement remain in the denominator and will be listed separately.