Rapamycin as an Antineoplastic 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)，一种雷帕霉素(MTOR)抑制剂的哺乳动物靶标，作为一种具有药效学(PD)分析的抗肿瘤药物。RAPA目前是FDA批准的治疗肾移植排斥反应的药物。RAPA类似物正在作为癌症治疗方法进行研究，因为mTOR被认为是几种癌症类型的相关靶点。然而，在这种背景下，从来没有人对拉帕进行过任何研究。开发FDA批准的不同适应症药物的过程通常比批准研究药物快得多，因此RAPA可能比其类似物更快地用于癌症患者。美国治疗恶性疾病的RAPA专利已经到期，因此没有专利保护来开发该制剂，从而抑制了商业利益。RAPA很容易获得，已经在异基因移植患者中进行了充分的研究，是第一个公认的mTOR抑制剂，并在临床前癌症模型中证明了有效性。本研究的目的是找出RAPA的最大耐受量(MTD)、观察的毒性、剂量限制毒性，并建立RAPA用于晚期恶性肿瘤患者的PD标志物。在RAPA和抑制已知的RAPA/mTOR依赖的p70S6激酶(S6K)苏氨酸389处的磷酸化之间存在剂量-效应关系。S6K磷酸化抑制与RAPA血液水平之间的关系也将被确定。RAPA将以每周一次的间歇计划逐步增加剂量，用于连续的患者队列。该计划的选择是为了避免与每日服用RAPA相关的免疫抑制。一旦确定了MTD，在试验的Ib期部分，将有一个最大限度抑制磷酸化S6K的剂量(S)的扩张。在试验结束时，将在一系列剂量和MTD范围内确定RAPA的毒性和对p-S6K的影响，以便在未来开发该制剂的研究中使用。

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.