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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要 假设 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。 ISPECIFIC AIMS 主要目标： 1.评估卡培他滨在放射治疗(RT)的同时对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)。 2.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。 次要目标： 1.研究卡培他滨快速崩解片在儿科患者中的药代动力学。 2.在这项第一阶段研究的背景下，描述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的抗肿瘤活性。 3.应用MRI、MRS、灌注弥散成像和正电子发射计算机体层摄影(PET)技术，研究放射治疗和卡培他滨联合治疗的非播散性脑干胶质瘤和高级别脑干胶质瘤的X线表现。 三、背景和意义 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT HYPOTHESIS Oral capecitabine will be well tolerated by pediatric patients with newly diagnosed nondisseminated, intrinsic brainstem gliomas and non-disseminated high-grade gliomas. ISPECIFIC AIMS Primary Objectives: 1. 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. 2. 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. Secondary Objectives: 1. To characterize the pharmacokinetics of capecitabine as delivered by Capecitabine Rapidly Disintegrating Tablets in this pediatric patient population. 2. 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. 3. 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. III. BACKGROUND AND SIGNIFICANCE 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.