Rapamycin as an Antineoplastic Agent

雷帕霉素作为抗肿瘤剂

• 批准号: 7140146
• 负责人: Ezra Cohen
• 金额: $ 29.59万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-06 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140146
• 关键词: analog; antineoplastics; biomarker; clinical research; clinical trials; dosage; drug administration rate /duration; drug adverse effect; drug design /synthesis /production; drug metabolism; drug screening /evaluation; enzyme activity; homologous transplantation; human subject; kidney transplantation; neoplasm /cancer chemotherapy; patient oriented research; pharmacokinetics; phosphorylation; protein kinase; ribosomal proteins; sirolimus; toxicology; transplant rejection

DESCRIPTION (provided by applicant): This application proposes a phase Ib trial to develop rapamycin (RAPA), a mammalian target of rapamycin (mTOR) inhibitor, as an anti-tumor agent with pharmacodynamic (PD) analysis. RAPA is currently an FDA approved drug in the treatment of renal allograft rejection. RAPA analogues are being studied as cancer therapies since mTOR is recognized as a relevant target in several cancer types. Yet there has never been any study of RAPA in this setting. The process of developing an FDA approved drug for a different indication is normally much more rapid than approval of investigational agents and thus RAPA could be available for use in cancer patients sooner than its analogues. The United States patent for RAPA in malignant disease has expired and thus there is no proprietary protection for developing the agent dampening commercial interest. RAPA is readily available, has been well-studied in allo-transplant patients, was the first recognized mTOR inhibitor, and demonstrates efficacy in pre-clinical cancer models. The aims of this study are to find the maximum tolerated dose (MTD), observed toxicities, dose limiting toxicities, and model a PD marker of RAPA administered to patients with advanced malignancies. A dose-effect relationship will be defined between RAPA and inhibition of the known RAPA/mTOR dependent phosphorylation at threonine 389 of p70 S6 kinase (S6K). The relationship between suppression of S6K phosphorylation and RAPA blood levels will also be determined. RAPA will be administered to successive cohorts of patients in escalating doses on a once-weekly intermittent schedule. The schedule was chosen to avoid immunosuppression associated with daily RAPA administration. Once the MTD is determined, there will be an expansion at the dose(s) that maximally inhibit phospho-S6K in the phase Ib portion of the trial. At the conclusion of the trial RAPA toxicity and effect on p-S6K will be defined over a range of doses as well as the MTD for use in future studies that will develop this agent.

描述（由申请人提供）：本申请提出了一项IB期试验，以开发雷帕霉素（RAPA），雷帕霉素（MTOR）抑制剂的哺乳动物靶标，作为药物学（PD）分析的抗肿瘤剂。 RAPA目前是FDA批准的药物，用于治疗肾脏同种异体抑制。由于MTOR被认为是几种癌症类型的相关靶标，因此正在研究Rapa类似物作为癌症疗法。然而，在这种情况下，从未对Rapa进行任何研究。开发FDA批准的用于不同指示的药物的过程通常比批准研究剂要快得多，因此RAPA可以比其类似物更快地用于癌症患者。美国在恶性疾病中的RAPA专利已过期，因此没有专有保护来发展代理商的商业利益。 RAPA容易获得，在同种移植患者中得到了充分研究，是首次公认的MTOR抑制剂，并在临床前癌症模型中证明了功效。这项研究的目的是找到最大耐受剂量（MTD），观察到的毒性，限制毒性的剂量，并建模对晚期恶性肿瘤患者的RAPA的PD标记。在P70 S6激酶（S6K）的苏氨酸389（S6K）的RAPA和抑制rapA和抑制之间，将定义剂量效应关系。还将确定抑制S6K磷酸化与RAPA血液水平之间的关系。 RAPA将以每周一次的间歇时间表的持续剂量进行连续的患者队列。选择时间表是为了避免与每日RAPA管理相关的免疫抑制。一旦确定了MTD，在试验的IB一部分中，将在剂量下最大地抑制磷酸-S6K。在试验结束时，将在一系列剂量和MTD上定义RapA毒性和对P-S6K的影响，以在未来的研究中使用，以开发该药物。