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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 抽象的： MK-0752将与复发性或难治性中枢神经系统（CNS）恶性肿瘤的儿童连续3天口服28天，共3天。起始剂量为200 mg/m2/day，患者间剂量升级或减少将以设定的增量（估计最大为400mg/m2/day）。在推荐的MTD上，我们将至少对6岁的6岁可评估患者进行治疗。尽管剂量升级将基于在第一门课程期间观察到的毒性，但将记录第一疗程后发生的任何3/4级毒性，并可能保证对治疗方案进行审查。治疗可能继续进行6门课程。如果患者从治疗中受益，并且在6末期至少患有临床和放射学稳定疾病，则患者可能会在默克公司和公司的代表事先批准下，继续接受另外13个课程（总共19个课程）。 I.假设 MK-0752将在患有难治性原发性中枢神经系统肿瘤的儿童和青少年中具有抗肿瘤活性。 ii。 具体目标 主要目标 为了估算MTD并建议对复发性或难治性中枢神经系统（CNS）恶性肿瘤的儿童连续3天连续3天给予II期MK-0752。 次要目标 为了表征在此时间表中管理的MK-0752的药代动力学。 记录并描述与MK-0752相关的毒性，并在此时间表中管理。 初步定义MK-0752在I期设置的范围内的抗肿瘤活性。 探索在复发或难治性中枢神经系统肿瘤样品中Notch受体和配体表达以及途径激活的发生率。 为了估计癌症干细胞的分数及其与复发性或难治性中枢神经系统样品中肿瘤脉管系统的关联。 探索接收MK-0752的儿童中相关磁共振成像的变化。可以在类似的PBTC方案中合并体积MR成像结果，以增加检测扫描和与结果关联之间相关性的功能。 探索MK-0752代谢酶中的药物遗传学多态性，并将这些多态性与MK-0752药代动力学联系起来。 探索Notch旋转形式与Notch途径靶基因和MK-0752药代动力学之间的药效学关系。