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

临床试验：卡培他滨快速崩解片的 I 期试验

• 批准号: 8356676
• 负责人: SUSAN M. BLANEY
• 金额: $ 0.24万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356676
• 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; Diffusion; Disease; Dose-Limiting; Drug Kinetics; Enzymes; Fluorouracil; Funding; Glioblastoma; Glioma; Grant; Human; Image; Investigation; Lesion; Magnetic Resonance Imaging; Malignant Glioma; Maximum Tolerated Dose; Midbrain structure; National Center for Research Resources; New Agents; Newly Diagnosed; Operative Surgical Procedures; Oral; Patients; Perfusion; Phase; Phase I Clinical Trials; Pontine structure; Positron-Emission Tomography; Primary Brain Neoplasms; Principal Investigator; Progression-Free Survivals; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Research; Research Infrastructure; Resources; Role; Source; Tablets; Therapeutic Index; Thymidine Phosphorylase; Toxic effect; United States National Institutes of Health; Xenograft Model; Xenograft procedure; brain tissue; capecitabine; chemotherapy; cost; 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. 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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 假设 口服卡培他滨在新诊断的非弥散性、内源性脑干胶质瘤和非弥散性高级别胶质瘤儿科患者中耐受性良好。 ISPECIFIC AIMS 主要目的： 1. 评估卡培他滨与放疗（RT）同时用于新诊断的非播散性、内源性脑干胶质瘤或新诊断的非播散性高级别胶质瘤儿童的最大耐受剂量（MTD）。 2. 描述卡培他滨与放疗同时给药治疗新诊断的非播散性、内源性脑干胶质瘤或新诊断的非播散性高级别胶质瘤儿童的剂量限制性毒性。 次要目的： 1. 在该儿科患者人群中表征卡培他滨速崩片给药后的卡培他滨药代动力学。 2. 在这项I期研究的背景下，描述卡培他滨和放疗在新诊断的非播散性、内源性脑干胶质瘤或新诊断的非播散性高级别胶质瘤儿童中观察到的抗肿瘤活性。 3. 采用MRI、MRS、灌注和扩散成像以及PET扫描表征接受放疗和卡培他滨治疗的非播散性、新诊断的脑干神经胶质瘤和高级别神经胶质瘤的影像学变化。 三. 背景和意义 脑干胶质瘤是发生在儿童和青少年的脑桥、中脑或髓质的星形细胞肿瘤。儿童期高级别星形细胞瘤是临床上侵袭性、区域性侵袭性肿瘤，儿童原发性脑干恶性胶质瘤的1年和5年无进展生存率（PFS）分别低于25%和10%。除放射治疗外，没有任何治疗对这些患者有益。化疗在治疗这种疾病中的作用尚不清楚。先前的研究表明，与单独的手术和放疗相比，增加化疗的益处充其量是适度的。显然，对于患有高级别神经胶质瘤的儿童，需要新的药物和新的治疗方法。 卡培他滨转化为5-氟尿嘧啶（5-FU），胸苷磷酸化酶（TP）作为肿瘤内活化的最终限速酶。先前的研究已经将卡培他滨的功效与细胞培养和人异种移植模型中的TP表达水平相关联。放射治疗是脑肿瘤治疗的标准组成部分，已显示在胶质母细胞瘤异种移植物中显著诱导TP。此外，卡培他滨已被证明是一种放射增敏剂以及针对转移性脑病变的活性单药。因此，评价卡培他滨联合放疗治疗原发性脑肿瘤有很强的理论依据。也可以实现有利的治疗指数，因为TP似乎在脑肿瘤中的表达量远大于正常脑组织。成人联合治疗的初步经验表明，治疗耐受性良好，未观察到意外或附加毒性。