CLINICAL TRIAL: A PHASE 1 STUDY OF TEMSIROLIMUS IN COMBINATION WITH IRINOTECAN

临床试验：替西罗莫司联合伊立替康的 1 期研究

• 批准号: 8356756
• 负责人: PATRICK THOMPSON
• 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: 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/8356756
• 关键词: Bone Marrow; Childhood; Clinical Research; Clinical Trials; Clinical Trials Design; Common Terminology Criteria for Adverse Events; Complex; Consent; Dose; Ewings sarcoma; Funding; Grant; Laboratories; Malignant Neoplasms; National Center for Research Resources; Neuroblastoma; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Principal Investigator; Protein Biosynthesis; Recurrence; Refractory; Regimen; Regulation; Research; Research Infrastructure; Resources; Role; Sampling; Signal Pathway; Solid Neoplasm; Source; Toxic effect; United States National Institutes of Health; cell growth; cohort; cost; inhibitor/antagonist; irinotecan; mTOR protein; member; phase 1 study; response; temozolomide; 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. When activated and associated with appropriate members of a functional complex, the mammalian target of rapamycin (mTOR) plays an important role in regulation of protein synthesis, cell growth, and proliferation. mTOR inhibitors have the potential to augment the activity of conventional chemotherapeutic drugs, including those frequently used in the treatment of pediatric malignancies. In this Phase I study, the mTOR inhibitor temsirolimus will be administered in combination with irinotecan and temozolomide to patients with recurrent or refractory solid tumors. The irinotecan + temozolomide regimen has activity against solid tumors including Ewing sarcoma and neuroblastoma. Toxicity associated with this regimen has been relatively mild even in heavily pretreated patients. The limited overlap in toxicities associated with temsirolimus and with rinotecan + temozolomide suggests that this three drug regimen is likely to be well-tolerated. Irinotecan (50 mg/m2) and temozolomide (100 mg/m2) will be administered daily x 5 every 3 weeks. Temsirolimus will be administered on days 1 and 8 of each 3 week cycle. The starting dose of temsirolimus will be 15 mg/m2, and the dose of this agent will be escalated stepwise to a maximum dose of 35 mg/m2 on Days 1 and 8. Because the primary objective of the study is to determine the maximum dose of temsirolimus that can be administered in combination with widely used doses of irinotecan and temozolomide, doses of the irinotecan and temozolomide will not be escalated during this trial. If the administration of temsirolimus on Days 1 and 8 is not well tolerated when given in combination with irinotecan and temozolomide, then temsirolimus will be administered once per cycle only. Patients will be accrued to dose levels in cohorts of 2 to 6 using the Rolling Six Phase I trial design. There will be no intrapatient dose escalation. Toxicity will be graded using the CTCAE version 4.0 and response will be assessed using RECIST criteria. Optional laboratory analyses of modulation of mTOR pathway signaling will be conducted using tumor-containing bone marrow samples from consenting patients.

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。 当被激活并与功能复合物的适当成员相关联时，雷帕霉素的哺乳动物靶标（mTOR）在调节蛋白质合成、细胞生长和增殖中起重要作用。mTOR抑制剂有可能增强常规化疗药物的活性，包括那些经常用于治疗儿科恶性肿瘤的药物。在这项I期研究中，mTOR抑制剂替西罗莫司将与伊立替康和替莫唑胺联合给药于复发性或难治性实体瘤患者。伊立替康+替莫唑胺 该方案具有抗实体瘤的活性，包括尤文肉瘤和神经母细胞瘤。 与此方案相关的毒性相对较轻，即使在重度预治疗的患者中也是如此。与替西罗莫司和与立替康+替莫唑胺相关的毒性的有限重叠表明这三种药物方案可能耐受良好。伊立替康（50 mg/m2）和替莫唑胺（100 mg/m2）将每日给药，每3周一次，共5次。替西罗莫司将分别在第1天和第8天给药， 3周周期替西罗莫司的起始剂量为15 mg/m2，第1天和第8天，该药物的剂量将逐步递增至最大剂量35 mg/m2。 由于本研究的主要目的是确定替西罗莫司可与广泛使用的伊立替康和替莫唑胺联合给药的最大剂量，因此在本试验期间不会递增伊立替康和替莫唑胺的剂量。如果第1天和第8天坦罗莫司与伊立替康和替莫唑胺联合给药时耐受性不佳，则坦罗莫司将仅每周期给药一次。使用滚动六期I期试验设计，将患者累积至2至6个队列的剂量水平。将不进行患者内剂量递增。将使用CTCAE 4.0版对毒性进行分级，并使用RECIST标准评估缓解。将使用含肿瘤的骨进行mTOR通路信号传导调节的可选实验室分析 患者的骨髓样本