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

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。 新诊断的非播散性、固有脑干胶质瘤和非播散性高级别胶质瘤的儿童患者对口服卡培他滨的耐受性良好。 具体目标 目的：评估卡培他滨在放射治疗(RT)的同时对儿童新诊断的非播散性固有脑干胶质瘤或新诊断的非播散性高级别胶质瘤的最大耐受量(MTD)。 目的：描述卡培他滨在放射治疗的同时对儿童新诊断的非播散性、固有脑干胶质瘤或新诊断的非播散性高级别胶质瘤的剂量限制性毒性。 研究卡培他滨快速崩解片在儿科患者中的药代动力学特征。 为了在这一阶段研究的背景下描述卡培他滨的抗肿瘤活性，在新诊断的非播散性固有脑干胶质瘤或新诊断的非播散性高级别胶质瘤的儿童中观察到的卡培他滨和放射治疗的抗肿瘤活性。 目的：利用MRI、MRS、灌注和弥散成像及正电子发射计算机断层扫描(PET)研究放射治疗和卡培他滨治疗的非播散性、新诊断的固有脑干胶质瘤和高级别胶质瘤的放射学改变。 脑干胶质瘤是一种发生在儿童和青少年的脑桥、中脑或延髓的星形细胞肿瘤。儿童高级别星形细胞瘤是临床上具有侵袭性的局部侵袭性肿瘤，而患有脑干恶性胶质瘤的儿童1年和5年无进展生存率(PFS)分别小于25%和10%。除了放射治疗，没有任何治疗方法显示对这些患者有好处。化疗在治疗这种疾病中的作用尚不清楚。以前的研究表明，与单纯手术和放射治疗相比，增加化疗的好处充其量也是温和的。显然，需要新的药物和新的治疗方法来治疗患有高级别胶质瘤的儿童。 卡培他滨被转化为5-氟尿嘧啶(5-FU)，胸苷磷酸化酶(TP)是肿瘤内激活的最终限速酶。以前的研究已经将卡培他滨的疗效与细胞培养和人类异种移植模型中TP的表达水平联系起来。放射治疗是脑肿瘤治疗的一个标准组成部分，已被证明在胶质母细胞瘤异种移植中实质上诱导了TP。此外，卡培他滨已被证明是一种放射增敏剂，也是一种有效的单药抗脑转移病变。因此，有一个强有力的理由来评估卡培他滨联合放射治疗原发性脑肿瘤的疗效。由于TP在脑肿瘤中的表达似乎比正常脑组织中的量要大得多，因此也可能实现一个有利的治疗指数。成人联合治疗的初步经验表明，治疗耐受性良好，没有意外或附加毒性。

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.