Phase II Trial of Pirfenidone in Children, Adolescents, and Young Adults With Neurofibromatosis Type 1 and Progressive Plexiform Neurofibromas
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 36
- 试验地点
- 15
- 主要终点
- Median Time to Disease Progression
研究概览
简要总结
Background:
Neurofibromatosis Type 1 (NF1) is an autosomal dominant, progressive genetic disorder characterized by diverse clinical manifestations. Patients with NF1 have an increased risk of developing tumors of the central and peripheral nervous system including plexiform neurofibromas, which are benign nerve sheath tumors that may cause severe morbidity and possible mortality. The histopathology of these tumors suggests that events connected with formation of fibroblasts might constitute a point of molecular vulnerability. Gene profile analysis demonstrates overexpression of fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor in plexiform neurofibromas in patients with NF1. Pirfenidone is a novel antifibrotic agent that inhibits these and other growth factors. Clinical experience in adults has demonstrated that pirfenidone is effective in a variety of fibrosing conditions and pirfenidone is presently under study in a phase II trial for adults with progressive plexiform neurofibromas. A phase I trial of pirfenidone in children and young adults with NF1 and plexiform neurofibromas was completed, and has established the phase II dose (the dose resulting in a mean drug exposure [AUC] not more than 1 standard deviation below the mean drug exposure [AUC] in adults who received pirfenidone at the dose level demonstrating activity in fibrosing conditions). Pirfenidone has been well tolerated.
Objectives:
To determine whether pirfenidone increases the time to disease progression based on volumetric measurements in children and young adults with NF1 and growing plexiform neurofibromas.
To define the objective response rate to pirfenidone in NF1-related plexiform neurofibromas.
To describe and define the toxicities of pirfenidone.
Eligibility:
Individuals (greater than or equal to 3 years to less than or equal to 21 years of age) with a clinical diagnosis of NF1 and inoperable, measurable, and progressive plexiform neurofibromas that have the potential to cause substantial morbidity.
Design:
The phase II dose will be used in a single stage, single arm phase II trial The natural history of the growth of plexiform neurofibromas is unknown. For this reason, time to disease progression on the placebo arm of an ongoing National Cancer Institute (NCI) Pediatric Oncology Branch (POB) placebo-controlled, double-blind, cross-over phase II trial of the farnesyltransferase inhibitor R115777 for children and young adults with NF1 and progressive plexiform neurofibromas.
Funding source - Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD)
详细描述
Background:
Neurofibromatosis Type 1 (NF1) is an autosomal dominant, progressive genetic disorder characterized by diverse clinical manifestations. Patients with NF1 have an increased risk of developing tumors of the central and peripheral nervous system including plexiform neurofibromas, which are benign nerve sheath tumors that may cause severe morbidity and possible mortality. The histopathology of these tumors suggests that events connected with formation of fibroblasts might constitute a point of molecular vulnerability. Gene profile analysis demonstrates overexpression of fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor in plexiform neurofibromas in patients with NF1. Pirfenidone is a novel antifibrotic agent that inhibits these and other growth factors. Clinical experience in adults has demonstrated that pirfenidone is effective in a variety of fibrosing conditions and pirfenidone is presently under study in a phase II trial for adults with progressive plexiform neurofibromas. A phase I trial of pirfenidone in children and young adults with NF1 and plexiform neurofibromas was completed, and has established the phase II dose (the dose resulting in a mean drug exposure [AUC] not more than 1 standard deviation below the mean drug exposure [AUC] in adults who received pirfenidone at the dose level demonstrating activity in fibrosing conditions). Pirfenidone has been well tolerated.
Objectives:
To determine whether pirfenidone increases the time to disease progression based on volumetric measurements in children and young adults with NF1 and growing plexiform neurofibromas.
To define the objective response rate to pirfenidone in NF1-related plexiform neurofibromas.
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
- 3 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Pirfenidone
Pirfenidone orally as capsules three times a day approximately every 8 hours for cycles of 28 days with no rest period between cycles (28 day treatment cycles); 500 mg/m^2 every 8 hours (1500 mg/m2/day).
干预措施: Pirfenidone (Drug)
结局指标
主要结局
Median Time to Disease Progression
时间窗: 5 years
Time to progression is defined as greater than or equal to 20% increase in plexiform neurofibromas (PN) volume on magnetic resonance imaging (MRI).
Number of Participants With Adverse Events
时间窗: 5 years
Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Percentage of Participants Who Had an Objective Response Rate
时间窗: ≥4 weeks
Objective response rate is defined as a complete response (CR) or partial response (PR). Complete response is a complete resolution of all measurable or palpable soft tissue tumors for ≥4 weeks and no appearance of new lesions. Partial response is a ≥50% reduction in the sum of the volume of all index lesions for ≥4 weeks.
次要结局
- Quality of Life (QOL) Using the Impact of Pediatric Illness (IPI) Scale at Baseline(Baseline)
- Longitudinal Total Quality of Life Scores Assessed by the Impact of Pediatric Illness Scale(prior to cycles 1, 4, 7 and 10.)
- Number of Participants With A Response Evaluation Determined by the Comparison of Three-Dimensional (3D) Magnetic Resonance Imaging(Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter, approximately 5 years)
- Number of Participants With A Response Evaluation Determined by the Comparison of One-Dimensional (1D) Magnetic Resonance Imaging(Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter until progression)
- Number of Participants With A Response Evaluation Determined by the Comparison of Two-Dimensional (2D) Magnetic Resonance Imaging(Prior to cycles 1, 4, 7, and 10 and then every 6 cycles thereafter until progression)
- Number of Participants Who Contributed to the Tissue Bank(5 years)
研究者
Brigitte Widemann, M.D.
Dr. Brigitte Widemann, M.D.
National Cancer Institute (NCI)