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.

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