CLINICAL TRIAL: A PHASE I TRIAL OF CAPECITABINE RAPIDLY DISINTEGRATING TABLETS A

临床试验：卡培他滨快速崩解片 A 的 I 期试验

• 批准号: 7950629
• 负责人: SUSAN M. BLANEY
• 金额: $ 0.36万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950629
• 关键词: Adolescent; Adult; Astrocytoma; Brain; Brain Neoplasms; Brain Stem; Brain Stem Glioma; Cell Culture Techniques; Child; Childhood; Childhood Astrocytic Tumor; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Diffusion; Disease; Dose-Limiting; Drug Kinetics; Enzymes; Fluorouracil; Funding; Glioblastoma; Glioma; Grant; Human; Image; Institution; Investigation; Lesion; Magnetic Resonance Imaging; Malignant Glioma; Maximum Tolerated Dose; Midbrain structure; New Agents; Newly Diagnosed; Operative Surgical Procedures; Oral; Patients; Perfusion; Phase; Phase I Clinical Trials; Pontine structure; Positron-Emission Tomography; Primary Brain Neoplasms; Progression-Free Survivals; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Research; Research Personnel; Resources; Role; Source; Tablets; Therapeutic Index; Thymidine Phosphorylase; Toxic effect; United States National Institutes of Health; Xenograft Model; Xenograft procedure; brain tissue; capecitabine; chemotherapy; experience; novel strategies; patient population; tumor

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. Oral capecitabine will be well tolerated by pediatric patients with newly diagnosed nondisseminated, intrinsic brainstem gliomas and non-disseminated high-grade gliomas. SPECIFIC AIMS To estimate the maximum tolerated dose (MTD) of capecitabine administered concurrently with radiation therapy (RT) to children with newly diagnosed nondisseminated, intrinsic brainstem gliomas or newly diagnosed non-disseminated high-grade gliomas. To describe the dose-limiting toxicity (ies) of capecitabine administered concurrently with radiation therapy to children with newly diagnosed nondisseminated, intrinsic brainstem gliomas or newly diagnosed non-disseminated high-grade gliomas. To characterize the pharmacokinetics of capecitabine as delivered by Capecitabine Rapidly Disintegrating Tablets in this pediatric patient population. To describe in the context of this phase 1 investigation, the anti-tumor activity of capecitabine and radiation that is observed in children with newly diagnosed nondisseminated, intrinsic brainstem gliomas or newly diagnosed non-disseminated high-grade gliomas. To characterize radiographic changes in non-disseminated, newly diagnosed intrinsic brainstem gliomas and high-grade gliomas treated with radiation and capecitabine using MRI, MRS, perfusion and diffusion imaging and PET scans. Brainstem gliomas are astrocytic neoplasms that occur in the pons, midbrain or medulla of children and adolescents. High-grade astrocytomas of childhood are clinically aggressive, regionally invasive tumors, and children with intrinsic brainstem malignant gliomas have a 1- and 5-year progression-free survival (PFS) of less than 25 and 10%, respectively. Other than radiation therapy, no therapy has demonstrated benefit for these patients. The role of chemotherapy in the treatment of this disease is not clear. Previous studies suggest that the benefit from addition of chemotherapy, when compared to surgery and radiotherapy alone, is modest at best. Clearly, new agents and new approaches to therapy are needed for children with high-grade glial tumors. Capecitabine is converted to 5-fluorouracil (5-FU), with thymidine phosphorylase (TP) as the final and rate limiting enzyme for intra-tumoral activation. Previous studies have correlated capecitabine efficacy with the level of TP expression in both cell culture and human xenograft models. Radiation therapy, a standard component of brain tumor management, has been shown to substantially induce TP in glioblastoma xenografts. Additionally, capecitabine has been shown to be a radiosensitizer as well as an active single agent against metastatic brain lesions. Thus there is a strong rationale for evaluating the combination of capecitabine and radiation in the treatment of primary brain tumors. A favorable therapeutic index may also be achieved, since TP appears to be expressed in far greater amounts in brain tumors compared to normal brain tissue. Initial experience with combination treatment in adults indicates that treatment is well tolerated with no unexpected or additive toxicities seen.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 新诊断为非诊断的，内在的脑干神经胶质瘤和未染色的高级神经胶质瘤的儿科患者可以很好地耐受口服卡培他滨。 具体目标 为了估计与新诊断的非诊断为非诊断的，内在的脑干神经胶质瘤或新诊断的未诊断的高级神经胶质瘤的儿童同时给予的代甲滨的最大耐受剂量（MTD）。 描述与新诊断的非诊断为非诊断的，内在的脑干神经胶质瘤或新诊断的未诊断的高级神经胶质瘤的儿童同时施用的卡皮滨的剂量限制毒性（IES）。 为了表征卡皮替滨在该儿科患者人群中迅速分解片剂的代理的药代动力学。 为了在这一阶段1研究的背景下描述，在具有新诊断的非诊断为非诊断的，固有的脑干胶质瘤或新诊断的未诊断的高级胶质瘤的儿童中，观察到卡培他滨和辐射的抗肿瘤活性。 为了表征使用MRI，MRS，灌注和扩散成像和PET扫描，用辐射和卡皮替滨处理的非疾病，新诊断的新诊断的内在脑干神经膜瘤和高级神经胶质瘤的射线照相变化。 脑干神经胶质瘤是发生在儿童和青少年的脑海中，中脑或髓质中的星形胶质细胞肿瘤。儿童时期的高级星形胶质细胞瘤是临床上的侵略性，侵入性肿瘤，内在脑干恶性神经胶质瘤的儿童的1.和5年无进展生存率（PFS）分别小于25％和10％。除了放射治疗外，没有治疗对这些患者有好处。化学疗法在治疗该疾病中的作用尚不清楚。先前的研究表明，与单独的手术和放射疗法相比，化疗的益处充其量是适中的。显然，具有高级神经胶质肿瘤的儿童需要新的药物和新的治疗方法。 卡培他滨将其转化为5-氟尿嘧啶（5-FU），胸苷磷酸化酶（TP）作为肿瘤内激活的最终和速率限制酶。先前的研究已将卡皮他滨的功效与细胞培养和人异种移植模型中TP表达水平相关。辐射疗法是脑肿瘤管理的标准组成部分，已显示出在异种胶质母细胞瘤中大大诱导TP。此外，卡培他滨已被证明是放射敏感剂以及针对转移性脑损伤的活性单剂。因此，有很强的理由来评估卡培他滨和辐射在原发性脑肿瘤治疗中的组合。也可以实现有利的治疗指数，因为与正常的脑组织相比，TP在脑肿瘤中似乎以较大的量表达。成人组合治疗的最初经验表明，治疗耐受性良好，看不到意外或加性毒性。