This is an adaptive platform-basket trial that aims to evaluate the safety and efficacy of multiple novel agents and combination therapies in patients with NF2-related schwannomatosis (NF2-SWN). The study employs a basket design to assess treatment responses across four tumor types commonly associated with NF2-SWN: vestibular schwannomas, non-vestibular schwannomas, meningiomas, and ependymomas.
A shared natural history observational cohort, receiving routine clinical follow-up without investigational treatment, serves as a common control for all substudies. The adaptive platform enables the dynamic addition or closure of substudies based on interim analyses, thereby optimizing trial efficiency.
Eligible patients who meet the master protocol criteria and satisfy substudy-specific safety requirements will be assigned to receive the corresponding intervention. Currently open substudies include:
* Substudy A: Selumetinib * Substudy B: Luvometinib plus Serplulimab
Bilateral vestibular schwannomas (VS)
An identical NF2 pathogenic variant in at least 2 anatomically distinct NF2-related tumors (schwannoma, meningioma, and/or ependymoma). (Note: if the variant allele fraction (VAF) in unaffected tissues such as blood is clearly <50%, the diagnosis is mosaic NF2-related schwannomatosis)
Unilateral VS
First-degree relative other than sibling with NF2-related schwannomatosis
Coexisting other genetic syndromes that may cause multiple intracranial tumors (e.g., SMARCB1/LZTR1-related schwannomatosis, Cowden syndrome);
Expected survival <12 months;
Presence of severe psychiatric disorders or cognitive impairment that precludes cooperation with imaging or hearing assessments;
Extreme social or geographic factors that, in the investigator's judgment, may impede follow-up for more than 12 months;
Parallel
Selumetinib 25mg/m2
DrugOral twice daily per predetermined dosage per protocol.
Luvometinib
DrugOral once daily per predetermined dosage per protocol.
Serplulimab
DrugIntravenous infusion per predetermined dosage per protocol.
Tumor-Type-Specific Response Rate in NF2-SWN Tumors
Vestibular schwannoma: HRR is defined as WRS improvement exceeding the 95% critical difference from baseline; if baseline WRS is \<20%, HRR is defined as a PTA decrease of at least 10 dB. Meningioma or non-vestibular schwannoma: ORR is defined as at least a 20% reduction in target tumor volume from baseline. Ependymoma: ORR is defined as at least a 30% reduction in maximum diameter from baseline according to RECIST v1.1.
Incidence of Adverse Events in Interventional Substudies
Percentage of participants receiving active treatment who experience at least one adverse event. Adverse events will be coded and graded according to NCI CTCAE v5.0.
Maximum Severity Grade of Adverse Events in Interventional Substudies
Maximum NCI CTCAE v5.0 grade of adverse events experienced by each participant during the reporting period.
Incidence of Serious Adverse Events in Interventional Substudies
Percentage of participants receiving active treatment who experience at least one serious adverse event.
Incidence of Dose Modifications Due to Adverse Events
Percentage of participants receiving active treatment who require at least one dose modification due to an adverse event.
Change From Baseline in MRI-Based Total Tumor Burden (TTB)
TTB will be assessed using serial MRI. TTB is calculated as the sum of the volumes of all prespecified measurable NF2-SWN-related tumors included in the tumor-burden assessment. The outcome is the relative percentage change in TTB from baseline to 12 months, based on blinded central radiology review.
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