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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 当被激活并与适当的功能复合体成员结合时，哺乳动物雷帕霉素靶标(MTOR)在调节蛋白质合成、细胞生长和增殖方面发挥着重要作用。MTOR抑制剂有可能增强传统化疗药物的活性，包括那些经常用于治疗儿童恶性肿瘤的药物。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应用于复发或难治性实体肿瘤患者。伊立替康+替莫唑胺 该方案对包括尤文肉瘤和神经母细胞瘤在内的实体瘤具有活性。 与该方案相关的毒性相对较轻，即使在接受大量预治疗的患者中也是如此。与替西莫司和雷诺替康+替莫唑胺相关的毒性有限的重叠表明，这三种药物方案很可能是耐受性良好的。伊立替康(50 mg/m2)和替莫唑胺(100 mg/m2)每日5次，每3周一次。替西罗莫司将分别在第1天和第8天服用 3周为一周期。替西罗莫司的起始剂量为15 mg/m2，该药的剂量将逐步递增，在第1天和第8天最大剂量为35 mg/m2。 由于这项研究的主要目标是确定与广泛使用的伊立替康和替莫唑胺联合使用的替西罗莫司的最大剂量，因此在试验期间，伊立替康和替莫唑胺的剂量不会增加。如果泰西罗莫司在第1天和第8天与伊立替康和替莫唑胺联合给药时耐受性不佳，则每个周期只给药一次。使用Rolling Six阶段I试验设计，患者将累积到2至6个队列的剂量水平。不会有患者内部剂量的增加。毒性将使用CTCAE版本4.0进行分级，响应将使用RECIST标准进行评估。对mTOR通路信号调制的可选实验室分析将使用含肿瘤的骨骼进行 自愿性患者的骨髓样本。

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.