A PHASE II RANDOMIZED, CROSS-OVER, DOUBLE-BLINDED, PLACEBO-CONTROLLED TRIAL O

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 摘要 假设 R115777是一种法尼基转移酶抑制剂，可以阻止ras和其他乳糖化蛋白的翻译后异戊烯基化。Ras蛋白是细胞信号通路中不可或缺的一部分，法尼化对突变型和非突变型ras蛋白的功能至关重要。I型神经纤维瘤病(NF1)患者发生中枢和外周神经系统肿瘤的风险增加，除了手术外，没有标准的治疗方案可用于这些肿瘤。神经纤维蛋白是NF1基因的产物，它含有一个与ras GTP酶激活蛋白(GAP)有显著同源性的结构域。尽管NF1患者缺乏胚系ras突变，但神经纤维蛋白水平的降低已被证明与结构性激活的ras-GTP状态有关。因此，上游抑制ras法尼化可能会抑制NF1患者的肿瘤生长。 具体目标 主要研究目标： 目的：评估长期口服R115777(21天后休息7天)对1型神经纤维瘤病(NF1)和进行性丛状神经纤维瘤的儿童和年轻人疾病进展时间的影响(包括毒性和应答率)。 明确进行性丛状神经纤维瘤对R115777的客观有效率。 描述和确定长期口服R115777(21天后休息7天)对儿科患者和年轻人的毒性。 次要研究目标： 目的：检测肿瘤标本和患者外周血单个核细胞中的法尼基蛋白转移酶(FPTase)活性水平，并评价FPTase活性作为R115777抗增殖作用替代标志物的价值。 检测治疗过程中不同时间点口腔黏膜细胞中前层素A的含量，以评价其作为R115777抗增殖作用替代标志物的价值。 评价三维磁共振成像(3D-MRI)和一维磁共振成像(ID-MRI)数据分析在丛状神经纤维瘤诊断中的价值，并与常规二维磁共振成像(2D-MRI)数据分析进行比较。 分析R115777治疗的NF1患者肿瘤标本中N-ras、K-ras和H-ras的表达水平，并将其表达水平和ras突变状态与R115777的疗效进行相关性分析。 分析在这项试验中接受治疗的患者的肿瘤标本，以寻找GAP相关区域中NF1基因突变，并将这些发现与R115777的抗增殖作用相关联。 从肿瘤标本(丛状神经纤维瘤和离散神经纤维瘤)中建立肿瘤细胞系。 将在这项试验中获得的肿瘤标本捐赠给已经存在的组织库。丛状神经纤维瘤的肿瘤样本将接受中心病理学检查，包括详细的形态、超微结构和免疫组织化学分析。在获得IRB批准后，将向科学界提供肿瘤细胞系和肿瘤样本，以收集有关丛状和离散神经纤维瘤的病理、遗传学和细胞生物学的更多信息。 测定R115777/安慰剂治疗期间不同时间点血液样本中神经生长因子的循环水平，并将神经生长因子水平与R115777开始的临床神经毒性的发展相关联。 使用新开发的美国国立卫生研究院(NIH)儿科疾病影响(IPI)量表来评估接受R115777或安慰剂治疗的患者的生活质量，该量表评估疾病和治疗对儿童行为的影响，并评估这一新评估工具衡量儿童生活质量变化的能力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT HYPOTHESIS R115777 is a farnesyltransferase inhibitor that blocks the post-translational isprenylation of ras and other franesylated proteins. The ras proteins are integral in cell signaling pathways, farnesylation is essential for the function of both mutrant and non-mutant ras proteins. patients with neurofibromatosis type I (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, ant there are no standard treatment options, other than surgery, available for these tumors. Neurofibromin, which is the product of the NF1 gene, contains a domain with significant homology to ras GTPase-activating proteins (GAP). Although NF1 patients lack germline ras mutations, the decreased levels of neurofibromin have been shown to be associated with constitutively activated ras-GTP status. Thus, upstream inhibition of ras farnesylation may inhibit growth of tumors in NF1 patients. SPECIFIC AIMS PRIMARY STUDY OBJECTIVE: To assess the effects (including toxicities & response rate) of R115777, administered on a chronic oral schedule (21 days on followed by 7 days rest), on the time to disease progression in children and young adults with neurofibromatosis type 1 (NF1) and progressive plexiform neurofibromas. To define the objective response rate of progressive plexiform neurofibromas to R115777. To describe and define the toxicities of R115777, administered on a chronic oral schedule (21 days on followed by 7 days rest), in pediatric patients and young adults. SECONDARY STUDY OBJECTIVES: To measure the level of farnesylprotein transferase (FPTase) activity intumor specimens and peripheral blood mononuclear cells obtained from patients treated on this trial, and to assess the value of FPTase activity as a surrogate marker for the antiproliferative effect of R115777. To assess prelamin A in buccal mucosal cells at various time points during treatment in order to assess the value of prelamin A determination as a surrogate marker for the antiproliferative effect of R115777. To assess the value of three-dimensional MRI (3D-MRI) and uni-dimensional MRI (ID-MRI) data analysis in the evaluation of plexiform neurofibromas, and to compare both to conventional two-dimensional MRI (2D-MRI) data analysis. To analyze tumor specimens from patients with NF1 treated with R115777 for the level of expression of N-ras, K-ras, and H-ras, and to correlate the level of expression and the ras mutation status with the efficacy of R115777. To analyze tumor specimens from patients treated on this trial, for NF1 gene mutations in the GAP related domain, and to correlate these findings with the antiproliferative effect of R115777. To establish tumor cell lines from tumor specimens (plexiform neurofibromas and discrete neurofibromas obtained from patients treated on this trial. To contribute tumor specimens obtained on this trial to an already existing tissue bank. Tumor samples from plexiform neurofibromas will undergo a central pathology review including a detailed morphologic, ultrastructural and immunohistochemical analysis. Tumor cell lines and tumor samples will be made available to the scientific community, after obtaining IRB approval in order to collect more information on the pathology, genetics, and cell biology of plexiform and discrete neurofibromas. To determine circulating levels of nerve growth factor from blood samples at various time points during treatment with R115777/placebo, and to correlate levels of NGF with the development of clinical neurotoxicity from R115777. To assess the quality of life of patients treated with R115777 or placebo using the newly developed National Institutes of Health (NIH) Impact of Pediatric Illness (IPI) Scale, which assesses the impact of disease and treatment on children's behavior, and to evaluate the ability of this new assessment tool to measure changein a child's quality of life.