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，旨在开发雷帕霉素（RAPA），一种哺乳动物雷帕霉素靶点（mTOR）抑制剂，作为抗肿瘤剂并进行药效（PD）分析。 RAPA目前是FDA批准的治疗肾同种异体移植排斥反应的药物。由于 mTOR 被认为是多种癌症类型的相关靶点，因此 RAPA 类似物正在作为癌症疗法进行研究。然而，从未在这种情况下对 RAPA 进行过任何研究。开发 FDA 批准的针对不同适应症的药物的过程通常比批准研究药物的过程要快得多，因此 RAPA 可以比其类似物更快地用于癌症患者。 RAPA 在恶性疾病方面的美国专利已过期，因此开发该药物没有专有保护，从而降低了商业利益。 RAPA 很容易获得，已在同种异体移植患者中进行了充分研究，是第一个公认的 mTOR 抑制剂，并在临床前癌症模型中证明了疗效。本研究的目的是找出最大耐受剂量 (MTD)、观察到的毒性、剂量限制毒性，并对晚期恶性肿瘤患者施用 RAPA 的 PD 标记物进行建模。将定义 RAPA 和对 p70 S6 激酶 (S6K) 苏氨酸 389 处已知的 RAPA/mTOR 依赖性磷酸化的抑制之间的剂量效应关系。还将确定 S6K 磷酸化抑制与 RAPA 血液水平之间的关系。 RAPA 将按照每周一次的间歇性时间表逐步增加剂量，对连续的患者组进行给药。选择该时间表是为了避免与每日 RAPA 给药相关的免疫抑制。一旦确定了 MTD，在试验的 Ib 期部分中，将扩大最大程度地抑制磷酸-S6K 的剂量。试验结束时，将在一定剂量范围内确定 RAPA 的毒性和对 p-S6K 的影响以及 MTD，以用于未来开发该药物的研究。