Platform Research for Innovative Medicines in NF2-SWN (PRIME-NF2)
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 200
- 试验地点
- 5
- 主要终点
- Tumor-Type-Specific Response Rate in NF2-SWN Tumors
研究概览
简要总结
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
详细描述
This is an investigator-initiated, prospective, multicenter, adaptive platform-basket clinical trial designed to evaluate the safety and efficacy of multiple therapies in patients with NF2-related schwannomatosis (NF2-SWN). The study includes four tumor baskets: vestibular schwannoma, meningioma, non-vestibular schwannoma, and ependymoma.
MASTER STUDY All patients with a confirmed diagnosis of NF2-SWN who provide written informed consent will be enrolled in the master study and enter the natural history observational cohort. Patients who meet eligibility criteria for one or more active substudies may be assigned to a corresponding treatment arm. When multiple treatment arms are open, allocation will follow a predefined randomization scheme. When only one treatment arm is available, eligible patients may be enrolled directly into that substudy. Patients not eligible for any active intervention will remain in the master study cohort for standardized follow-up.
Patients who experience progression of the target tumor during substudy treatment may be considered for enrollment into another active treatment arm if eligibility criteria are met. Patients who are not eligible for any active substudy will return to the master study observational cohort. Data collected during follow-up may serve as shared control data across the platform.
Patients in the observational cohort will undergo standardized follow-up assessments every 12 months until study completion or voluntary withdrawal. Patients receiving treatment within a substudy will undergo efficacy and safety assessments approximately every 3 months according to the corresponding substudy protocol. The master study plans to enroll at least 200 patients with NF2-SWN, with enrollment continuing over time as eligible patients are identified across participating centers.
SUBSTUDY 1: Selumetinib
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Eligibility Specific For MASTER STUDY
- •Inclusion Criteria:
- •Subjects must satisfy all of the following criteria to be enrolled into the main study natural history observation cohort:
- •(1) Must meet the 2022 International Consensus Criteria for NF2-SWN, defined by having at least one of the following:
- •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)
- •Either 2 major or 1 major and 2 minor criteria as described in the following:
- •Major criteria:
- •Unilateral VS
- •First-degree relative other than sibling with NF2-related schwannomatosis
- •2 or more meningiomas (Note: single meningioma qualifies as minor criteria).
- •NF2 pathogenic variant in an unaffected tissue such as blood (Note: if the VAF is clearly <50%, the diagnosis is mosaic NF2-related schwannomatosis)
- •Minor criteria:
- •Can count >1 of a type (eg, 2 distinct schwannomas would count as 2 minor criteria)
- •Ependymoma, meningioma (Note: multiple meningiomas qualify as a major criteria), schwannoma (Note: if the major criterion is unilateral VS, at least 1 schwannoma must be dermal in location) Can count only once (eg, bilateral cortical cataracts count as a single minor criterion)
- •Juvenile subcapsular or cortical cataract, retinal hamartoma, epiretinal membrane in a person aged <40 years, meningioma
- •(2) Presence of at least one evaluable lesion: Vestibular schwannoma, meningioma, or non-vestibular schwannoma: clearly identifiable lesion on contrast-enhanced T1-weighted MRI; Ependymoma: clearly identifiable lesion on contrast-enhanced T1-weighted or T2/FLAIR sequences; (3) Expected ability to complete at least 12 months of follow-up assessments; (4) Ability to understand and voluntarily sign a written informed consent form, or a legally authorized guardian signs the informed consent form together ; (5) Sub-study-specific criteria (for intervention arms only): If the subject intends to enter an interventional sub-study, in addition to meeting the above main study criteria, the subject must also satisfy the specific inclusion criteria specified in that sub-study protocol (e.g., organ function, prior treatment restrictions, washout periods, etc.), as determined by the drug characteristics.
排除标准
- •Subjects meeting any of the following criteria will not be permitted to enter the main study:
- •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;
- •Sub-study-specific exclusion criteria (for intervention arms only): If the subject intends to enter an interventional sub-study, the subject must also satisfy the specific exclusion criteria specified in that sub-study protocol (e.g., specific organ dysfunction, active infection, pregnancy, etc.).
结局指标
主要结局
Tumor-Type-Specific Response Rate in NF2-SWN Tumors
时间窗: 12 months
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.
次要结局
- Incidence of Adverse Events in Interventional Substudies(From first dose through 30 days after last dose (or as specified by individual substudy protocols))
- Maximum Severity Grade of Adverse Events in Interventional Substudies(12 months)
- Incidence of Serious Adverse Events in Interventional Substudies(From first dose through 30 days after last dose.)
- Incidence of Dose Modifications Due to Adverse Events(From first dose through 30 days after last dose.)
- Incidence of Treatment Interruptions Due to Adverse Events(From first dose through 30 days after last dose.)
- Incidence of Treatment Discontinuations Due to Adverse Events(From first dose through 30 days after last dose.)