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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 新诊断的非播散性内源性脑干胶质瘤和非播散性高级胶质瘤的儿科患者对口服卡培他滨有良好的耐受性。 具体目标 旨在估计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与放射治疗 (RT) 同时施用的卡培他滨的最大耐受剂量 (MTD)。 描述卡培他滨与放射治疗同时给予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毒性。 旨在表征卡培他滨快速崩解片在该儿科患者群体中的药代动力学。 描述在这一第一阶段研究的背景下，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卡培他滨和放射的抗肿瘤活性。 使用 MRI、MRS、灌注和扩散成像以及 PET 扫描来表征经放射和卡培他滨治疗的非播散性、新诊断的内在性脑干胶质瘤和高级别胶质瘤的放射学变化。 脑干胶质瘤是发生在儿童和青少年的脑桥、中脑或髓质中的星形细胞肿瘤。儿童高级别星形细胞瘤是临床上具有侵袭性、区域侵袭性的肿瘤，患有内源性脑干恶性胶质瘤的儿童的 1 年和 5 年无进展生存率 (PFS) 分别低于 25% 和 10%。除了放射治疗之外，没有任何治疗方法被证明对这些患者有益。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，联合化疗的益处充其量是有限的。显然，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) 作为肿瘤内激活的最终酶和限速酶。先前的研究已将卡培他滨功效与细胞培养物和人类异种移植模型中的 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，已被证明可在胶质母细胞瘤异种移植物中显着诱导 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，评估卡培他滨和放射治疗联合治疗原发性脑肿瘤的效果是有充分理由的。还可以实现有利的治疗指数，因为与正常脑组织相比，TP在脑肿瘤中的表达量似乎高得多。成人联合治疗的初步经验表明，治疗的耐受性良好，没有观察到意外或附加的毒性。