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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 抽象的： MK-0752 将连续 3 天口服给药，每 7 天一次，持续 28 天，用于患有复发性或难治性中枢神经系统 (CNS) 恶性肿瘤的儿童。起始剂量为 200 mg/m2/天，患者之间的剂量将以设定的增量递增或减少（估计最大剂量为 400mg/m2/天）。按照建议的 MTD，我们将治疗至少 6 名 12 岁的可评估患者。尽管剂量递增将基于第一个疗程期间观察到的毒性，但第一个疗程后发生的任何 3/4 级毒性都将被记录下来，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疾病，则经研究主席和事先批准，患者可以继续治疗另外 13 个疗程（总共 19 个疗程）。默克公司代表 一、假设 MK-0752 对患有难治性原发性中枢神经系统肿瘤的儿童和青少年具有抗肿瘤活性。 二. 具体目标 主要目标 评估 MTD 并推荐对患有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（每 7 天一次）施用 MK-0752 的 II 期剂量，持续 28 天。 次要目标 表征按此方案给药的 MK-0752 的药代动力学。 记录并描述与按此时间表施用的 MK-0752 相关的毒性。 初步确定 MK-0752 在 I 期设置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 受体和配体表达以及通路激活的发生率。 评估复发性或难治性中枢神经系统肿瘤样本中癌症干细胞的比例及其与肿瘤脉管系统的关联。 探讨接受 MK-0752 治疗的儿童相关磁共振成像的变化。体积 MR 成像结果可以与类似的 PBTC 协议相结合，以提高检测扫描之间的相关性以及与结果的关联性的能力。 探索 MK-0752 代谢酶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。 探讨 NOTCH 裂解形式与 NOTCH 通路靶基因和 MK-0752 药代动力学之间的药效关系。