Rapamycin as an Antineoplastic Agent

描述（由申请人提供）：本申请提出开发雷帕霉素（RAPA）的Ib期试验，雷帕霉素（RAPA）是雷帕霉素（mTOR）抑制剂的哺乳动物靶点，作为抗肿瘤药物并进行药效学（PD）分析。RAPA目前是FDA批准的治疗同种异体肾移植排斥反应的药物。由于mTOR被认为是几种癌症类型的相关靶点，因此正在研究RAPA类似物作为癌症治疗方法。然而，在这种情况下，从来没有任何关于RAPA的研究。针对不同适应症开发FDA批准的药物的过程通常比研究药物的批准要快得多，因此RAPA可以比它的类似物更快地用于癌症患者。美国关于RAPA治疗恶性疾病的专利已经过期，因此对开发该药物没有专有保护，从而抑制了商业利益。RAPA很容易获得，已经在异体移植患者中得到了很好的研究，是第一个被认可的mTOR抑制剂，并在临床前癌症模型中证明了有效性。本研究的目的是寻找最大耐受剂量（MTD），观察到的毒性，剂量限制毒性，并模拟晚期恶性肿瘤患者给予RAPA的PD标记物。RAPA与抑制已知的RAPA/mTOR依赖的p70 S6激酶（S6K）苏氨酸389磷酸化之间存在剂量效应关系。S6K磷酸化抑制与血中RAPA水平的关系也将被确定。RAPA将以每周一次的间歇性计划逐步递增的剂量给予连续的患者队列。计划的选择是为了避免与每日给药RAPA相关的免疫抑制。一旦确定了MTD，在试验的Ib期部分，最大限度地抑制phospho-S6K的剂量将会扩大。在试验结束时，RAPA的毒性和对p-S6K的影响将在一定剂量范围内确定，并在未来开发该药物的研究中使用MTD。

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.