NCT03962543进行中（未招募）2 期
A Phase 2b Trial of the MEK 1/2 Inhibitor (MEKi) PD-0325901 in Adult and Pediatric Patients With Neurofibromatosis Type 1 (NF1)-Associated Inoperable Plexiform Neurofibromas (PNs) That Are Causing Significant Morbidity
SpringWorks Therapeutics, Inc., a healthcare company of Merck KGaA, Darmstadt, Germany43 个研究点 分布在 1 个国家目标入组 114 人开始时间: 2019年9月29日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 114
- 试验地点
- 43
- 主要终点
- Confirmed Objective Response Rate at the End of the Treatment Phase.
研究概览
简要总结
This study evaluates mirdametinib (PD-0325901) in the treatment of symptomatic inoperable neurofibromatosis type-1 (NF1)-associated plexiform neurofibromas (PNs). All participants will receive mirdametinib (PD-0325901). Eligible participants may continue in a long-term follow-up phase.
详细描述
Neurofibromas are non-malignant peripheral nerve sheath tumors, which are classified as plexiform neurofibromas (PNs) if they extend longitudinally along a nerve and involve multiple fascicles. PNs are a major cause of morbidity and disfigurement in individuals with NF1, and as the tumor growth progresses, can cause a multitude of clinical problems including pain and impaired physical function. PNs have the potential to undergo malignant transformation to Malignant Peripheral Nerve Sheet Tumors (MPNST).
Mirdametinib (PD-0325901) is an orally delivered, highly selective small-molecule inhibitor of the dual specificity kinases, MEK1 and MEK2 (MAPK/ERK Kinase) which prevents the phosphorylation and subsequent activation of mitogen-activated protein kinase (MAPK).
Previous studies of mirdametinib (PD-0325901) demonstrated PN shrinkage and sustained inhibition of pERK. Reduced tumor volume indicated that cell proliferation or cell death may be altered in PNs with administration of mirdametinib (PD-0325901).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant has documented NF1 mutation or a diagnosis of neurofibromatosis type 1 (NF1) using National Institute of Health (NIH) Consensus Conference criteria inclusive of the presence of a plexiform neurofibroma (PN).
- •Participant has a PN that is causing significant morbidity.
- •Participant has a PN that cannot be completely surgically removed.
- •Participant has a target tumor that is amenable to volumetric MRI analysis.
- •Participant is willing to undergo a tumor biopsy pre and post treatment if ≥ 18 years of age.
- •Participant has adequate organ and bone marrow function.
排除标准
- •Participant has abnormal liver function or history of liver disease.
- •Participant has lymphoma, leukemia or any malignancy within the past 5 years (except for resected basal/squamous skin carcinomas without metastases within 3 years).
- •Participant has breast cancer within 10 years.
- •Participant has active optic glioma or other low-grade glioma requiring treatment.
- •Participant has abnormal QT interval corrected or other heart disease within 6 months.
- •Participant has a history of retinal pathology, risk factors for retinal vein occlusion or has a history of glaucoma.
- •Participant has known malabsorption syndrome or gastrointestinal conditions that would impair absorption of mirdametinib (PD-0325901).
- •Participant has received NF1 PN-targeted therapy within 45 days.
- •Participant previously received or is currently receiving therapy with mirdametinib (PD-0325901) or any other MEK1/2 inhibitor.
- •Participant has received radiation therapy within 6 months or has received radiation to the orbit at any time.
- •Participant is unable to undergo or tolerate MRI.
- •Participant has active bacterial, fungal or viral infection.
- •Participant has experienced other severe acute or chronic medical or psychiatric conditions within 1 year.
研究组 & 干预措施
Mirdametinib (PD-0325901)
Experimental
Mirdametinib (PD-0325901) capsule or dispersible tablet 2 mg/m^2 (maximum dose of 4 mg) by mouth twice daily
干预措施: Mirdametinib (PD-0325901) oral capsule or dispersible tablet (Drug)
结局指标
主要结局
Confirmed Objective Response Rate at the End of the Treatment Phase.
时间窗: Up to 24 months
Response will be determined by a blinded centralized review of volumetric MRI. The confirmed objective response rate (complete or partial response) by the end of Treatment Phase (i.e., Cycle 24) is defined as the proportion of participants who have a confirmed ≥ 20% reduction in target tumor volume as compared to baseline as assessed by a BICR, and the response needs to be confirmed by BICR in a consecutive tumor assessment within 2 - 6 months. Partial response is defined as a ≥ 20% reduction in target tumor volume from baseline. Complete response is defined as the complete resolution of the target tumor.
次要结局
- Percentage of Patients With Treatment-Emergent Adverse Events.(All SAEs and AEs were collected from the time of signing ICF until 30 days after the last dose of study treatment, an average of 1 year and 10 months and up to 3 years and 10 months.)
- Duration of Response (DOR) for Participants Who Meet Criteria for Confirmed Objective Response.(Starting on the onset of confirmed objective response in the Treatment Phase and afterwards on the 15th day of every 4 cycles (each cycle is 28 days) until disease progression or death, whichever comes first, assessed up to approximately 3 years)
- Change From Baseline on Quality of Life (QOL) as Measured by the Pediatric Quality of Life Inventory (PedsQL) at Cycle 13, Acute Version.(Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months)
- Change From Baseline in Pain as Measured by the Numeric Rating Scale-11 (NRS-11) at Cycle 13.(Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months)
- Change From Baseline in Pain as Measured by the Pain Interference Index (PII) at Cycle 13.(Baseline and Cycle 13 (1 cycle = 28 days), up to 12 months)
研究者
研究点 (43)
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相关资讯
Mirdametinib Shows Deep Responses in NF1-Associated Plexiform Neurofibromas- Mirdametinib demonstrates deep responses, defined as over 50% reduction in tumor volume, in patients with NF1-associated plexiform neurofibromas (NF1-PN).
- Exploratory analysis found no specific baseline characteristics, such as age or sex, associated with a higher likelihood of achieving a deep response with mirdametinib.
- Longer treatment duration with mirdametinib appeared to correlate with deeper responses, suggesting the importance of extended therapy for optimal outcomes.
- The FDA granted priority review to mirdametinib for NF1-associated plexiform neurofibromas, with a decision expected by February 28, 2025.last yearMirdametinib Demonstrates Significant Tumor Reduction and Improved Quality of Life in NF1-Associated Plexiform Neurofibroma- Mirdametinib shows a confirmed objective response rate of 41% in adults and 52% in pediatric patients with NF1-PN in the ReNeu trial.
- The treatment led to significant reductions in plexiform neurofibroma volume, with median best percentage changes of -41% and -42% in adults and children, respectively.
- Patients reported notable improvements in pain severity, pain interference, and health-related quality of life (HRQOL) following mirdametinib treatment.
- Mirdametinib has a manageable safety profile, suggesting it could be a valuable treatment option for NF1-PN, with FDA review ongoing.last yearMirdametinib's NDA for NF1-PN Granted Priority Review by FDA- The FDA has granted priority review to SpringWorks Therapeutics' NDA for mirdametinib in treating Neurofibromatosis Type 1-associated plexiform neurofibromas (NF1-PN).
- The PDUFA target action date is set for February 28, 2025, with the FDA indicating no current plans for an advisory committee meeting.
- Mirdametinib's MAA for NF1-PN has also been validated by the European Medicines Agency, potentially offering a new treatment option in Europe.
- The NDA and MAA submissions include data from the Phase 2b ReNeu trial, demonstrating significant objective response rates and improved quality of life.2 years agoFDA Grants Priority Review to Mirdametinib for NF1-Associated Plexiform NeurofibromasThe FDA has granted priority review to mirdametinib for treating neurofibromatosis type 1–associated plexiform neurofibromas, based on promising phase 2b trial results.2 years agoSpringWorks Therapeutics Submits NDA for Mirdametinib in NF1-Associated Plexiform Neurofibromas• SpringWorks Therapeutics has completed its NDA submission to the FDA for mirdametinib, targeting pediatric and adult patients with NF1-PN.
• The submission is based on Phase 2b ReNeu trial data, showcasing significant objective response rates and improved quality of life.
• Mirdametinib has received Orphan Drug and Fast Track designations from the FDA, and a MAA filing with the EMA is planned for later in 2024.
• NF1-PN affects approximately 30-50% of individuals with NF1, causing tumors along nerve sheaths, leading to disfigurement and functional impairment.2 years ago