CLINICAL TRIAL: A PHASE I STUDY OF MK-0752 IN PEDIATRIC PATIENTS WITH RECURREN

临床试验：MK-0752 在复发性儿科患者中的 I 期研究

• 批准号: 8356709
• 负责人: SUSAN M. BLANEY
• 金额: $ 0.28万
• 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/8356709
• 关键词: 12 year old; Adolescent; Central Nervous System Neoplasms; Child; Childhood; Cleaved cell; Clinical; Clinical Research; Clinical Trials; Dose; Drug Kinetics; Enzymes; Evaluable Disease; Funding; Gene Targeting; Genetic Polymorphism; Grant; Incidence; Ligands; Magnetic Resonance Imaging; Malignant Neoplasms; National Center for Research Resources; Neuraxis; Outcome; Pathway interactions; Patients; Pharmacodynamics; Pharmacogenetics; Phase; Principal Investigator; Protocols documentation; Recurrence; Refractory; Research; Research Infrastructure; Resources; Sampling; Scanning; Schedule; Source; Stable Disease; Toxic effect; Treatment Protocols; United States National Institutes of Health; base; cancer stem cell; cost; phase 1 study; receptor; 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: MK-0752 will be administered orally for 3 consecutive days of every 7 days for 28 days to children with recurrent or refractory central nervous system (CNS) malignancies. The starting dose is 200 mg/m2/day and inter-patient dose escalation or reduction will occur in set increments (to an estimated maximum of 400mg/m2/day). At the recommended MTD, we will treat a minimum of 6 evaluable patients who are 12 years of age. Although the dose escalation will be based on toxicities observed during the first course, any grade 3/4 toxicities that occur after the first course will be documented and may warrant a review of the treatment regimen. Therapy may continue for 6 courses. If patients are deriving benefit from the therapy and have at least clinical and radiographic stable disease at the end of course 6, patients may continue therapy for an additional 13 courses (for a total of 19 courses) with the prior approval of the study Chair and representatives from Merck and Co. I. HYPOTHESIS MK-0752 will have anti-tumor activity in children and adolescents with refractory primary CNS tumors. II. SPECIFIC AIMS PRIMARY OBJECTIVES To estimate the MTD and recommend a Phase II dose of MK-0752 administered for 3 consecutive days of every 7 days for 28 days to children with recurrent or refractory central nervous system (CNS) malignancies. SECONDARY OBJECTIVES To characterize the pharmacokinetics of MK-0752 administered on this schedule. To document and describe toxicities associated with MK-0752 administrated on this schedule. To preliminarily define the antitumor activity of MK-0752 within the confines of a Phase I setting. To explore the incidence of NOTCH receptor and ligand expression and pathway activation in recurrent or refractory CNS tumor samples. To estimate the fraction of cancer stem cells and their association with the tumor vasculature in recurrent or refractory CNS tumor samples. To explore changes in correlative magnetic resonance imaging in children receiving MK-0752. Volumetric MR imaging findings may be combined across similar PBTC protocols to increase the power for detecting correlations among scans and associations with outcome. To explore the pharmacogenetic polymorphisms in MK-0752 metabolizing enzymes and relate these polymorphisms to MK-0752 pharmacokinetics. To explore the pharmacodynamic relationships between NOTCH-cleaved forms and NOTCH pathway target genes and MK-0752 pharmacokinetics.

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： MK-0752将在复发性或难治性中枢神经系统（CNS）恶性肿瘤儿童中口服给药，每7天连续3天，持续28天。起始剂量为200 mg/m2/天，患者间剂量递增或降低将以设定的增量进行（估计最大剂量为400 mg/m2/天）。在推荐的MTD下，我们将治疗至少6例12岁的可评价患者。尽管剂量递增将基于第一个疗程期间观察到的毒性，但将记录第一个疗程后发生的任何3/4级毒性，并可能需要对治疗方案进行审查。治疗可持续6个疗程。如果患者从治疗中获益，并且在第6个疗程结束时至少具有临床和放射学稳定的疾病，则在研究主席和默克公司代表的事先批准下，患者可以继续治疗额外的13个疗程（总共19个疗程）。 I. 假设 MK-0752将在患有难治性原发性CNS肿瘤的儿童和青少年中具有抗肿瘤活性。 二. 具体目标 主要目标 估计MTD并推荐MK-0752的II期剂量，每7天连续3天给药，共28天，用于复发性或难治性中枢神经系统（CNS）恶性肿瘤儿童。 次要目的 表征按照该方案给药的MK-0752的药代动力学。 记录并描述与按照该时间表给予MK-0752相关的毒性。 初步确定MK-0752在I期范围内的抗肿瘤活性。 探讨复发性或难治性CNS肿瘤样本中NOTCH受体和配体表达及通路激活的发生率。 估计复发性或难治性CNS肿瘤样本中癌症干细胞的比例及其与肿瘤血管系统的相关性。 探索接受MK-0752治疗的儿童相关磁共振成像的变化。可以在类似的PBTC方案中组合体积MR成像结果，以增加检测扫描之间的相关性以及与结果的关联的能力。 探讨MK-0752代谢酶的药物遗传学多态性及其与MK-0752药代动力学的关系。 探索NOTCH切割形式和NOTCH途径靶基因与MK-0752药代动力学之间的药效学关系。