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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 摘要 假设 R115777是一种法尼基转移酶抑制剂，可阻断ras和其他franesylated蛋白的翻译后异戊烯化。 ras蛋白是细胞信号传导途径中不可或缺的一部分，法尼基化对于突变型和非突变型ras蛋白的功能都是必需的。 患有I型神经纤维瘤病（NF 1）的患者具有发生中枢和外周神经系统肿瘤的增加的风险，对于这些肿瘤，除了手术之外，没有标准的治疗选择。 神经纤维蛋白是NF 1基因的产物，含有与ras GTP酶激活蛋白（GAP）具有显著同源性的结构域。 虽然NF 1患者缺乏生殖系ras突变，但神经纤维蛋白水平的降低已被证明与组成性激活的ras-GTP状态相关。 因此，上游抑制ras法尼基化可以抑制NF 1患者的肿瘤生长。 具体目标 主要研究目的： 评估R115777长期口服给药方案（给药21天，然后停药7天）对1型神经纤维瘤病（NF 1）和进行性丛状神经纤维瘤儿童和年轻人疾病进展时间的影响（包括毒性和缓解率）。 确定进行性丛状神经纤维瘤对R115777的客观缓解率。 描述和定义R115777在儿科患者和年轻成人中长期口服给药方案（给药21天，随后停药7天）的毒性。 次要研究顺序： 测定本试验治疗患者的肿瘤标本和外周血单个核细胞中法尼基蛋白转移酶（FPTase）活性水平，并评估FPTase活性作为R115777抗增殖作用替代标志物的价值。 评估治疗期间不同时间点颊粘膜细胞中的前层蛋白A，以评估前层蛋白A测定作为R115777抗增殖作用替代标志物的价值。 评价三维MRI（3D-MRI）和一维MRI（ID-MRI）数据分析在评价丛状神经纤维瘤中的价值，并与常规二维MRI（2D-MRI）数据分析进行比较。 分析接受R115777治疗的NF 1患者的肿瘤标本中N-ras、K-ras和H-ras的表达水平，并将表达水平和ras突变状态与R115777的疗效相关联。 分析本试验治疗患者的肿瘤标本中差距相关结构域的NF 1基因突变，并将这些结果与R115777的抗增殖作用相关联。 从本试验治疗患者的肿瘤标本（丛状神经纤维瘤和离散神经纤维瘤）中建立肿瘤细胞系。 将本试验中获得的肿瘤标本贡献给现有的组织库。 丛状神经纤维瘤的肿瘤样本将接受中心病理学审查，包括详细的形态学、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学、遗传学和细胞生物学的更多信息。 确定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NGF水平与R115777临床神经毒性的发生相关联。 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，并评价这种新评估工具测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.