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

II 期随机、交叉、双盲、安慰剂对照试验 O

• 批准号: 7605845
• 负责人: SUSAN M. BLANEY
• 金额: $ 0.03万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605845
• 关键词: Ants; Blood specimen; Cells; Cellular biology; Child; Child Behavior; Childhood; Chronic; Clinical; Communities; Computer Retrieval of Information on Scientific Projects Database; Data Analyses; Development; Disease; Disease Progression; Evaluation; Farnesyl Transferase Inhibitor; Funding; GTPase-Activating Proteins; Gene Mutation; Genetic; Genetic Crossing Over; Grant; HRAS gene; Institution; Magnetic Resonance Imaging; Measures; Mutation; NF1 gene; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Nerve Growth Factors; Neurofibromatosis 1; Neurofibromatosis Type 1 Protein; Operative Surgical Procedures; Oral; Pathology; Patients; Peripheral Blood Mononuclear Cell; Peripheral Nervous System; Phase; Placebos; Plexiform Neurofibroma; Proteins; Quality of life; R115777 (Zarnestra); Randomized; Rate; Research; Research Ethics Committees; Research Personnel; Resources; Rest; Risk; Sampling; Schedule; Signal Pathway; Signal Transduction; Source; Specimen; Standards of Weights and Measures; Surrogate Markers; Time; Tissue Banks; Toxic effect; Transferase; Tumor Cell Line; United States National Institutes of Health; abstracting; day; double-blind placebo controlled trial; farnesylation; mutant; neoplastic cell; neurofibroma; neurotoxicity; prelamin A; ras GTPase-Activating Proteins; ras Proteins; response; tool; tumor; tumor growth; two-dimensional; young adult

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.

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