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，以开发雷帕霉素（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类似物正在被研究作为癌症疗法，因为mTOR被认为是几种癌症类型中的相关靶标。然而，从来没有任何研究RAPA在这种情况下。开发FDA批准的用于不同适应症的药物的过程通常比批准研究药物要快得多，因此RAPA可以比其类似物更快地用于癌症患者。美国关于RAPA在恶性疾病中的专利已经过期，因此没有专利保护来开发这种抑制商业利益的药剂。RAPA是容易获得的，已经在同种异体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疗效。本研究的目的是找到最大耐受剂量（MTD），观察到的毒性，剂量限制性毒性，并建立晚期恶性肿瘤患者使用RAPA的PD标志物模型。将在RAPA和已知的RAPA/mTOR依赖性磷酸化在p70 S6激酶（S6 K）的苏氨酸389处的抑制之间定义剂量-效应关系。还将确定S6 K磷酸化抑制与RAPA血液水平之间的关系。将按照每周一次的间歇性方案，以递增剂量对连续队列的患者进行RAPA给药。选择该方案以避免与每日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，将在最大程度抑制磷酸-S6 K的剂量下进行扩展。在试验结束时，RAPA对p-S6 K的毒性和作用将在一系列剂量以及MTD范围内定义，以用于开发该药物的未来研究。

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.