Pharmacodynamic-guided Dose-finding Study of Rapamycin

描述(申请人提供)：mTOR是一种丝氨酸-苏氨酸激酶，参与磷脂酰肌醇激酶(PI3K)/Akt信号通路，是细胞生长、增殖和存活的关键调节因子。通过mTOR的异常信号是癌症中一种常见的改变，是抗癌药物开发的战略靶点。目前，有几种mTOR抑制剂正在临床开发中用于癌症治疗，结果令人振奋。雷帕霉素是典型的mTOR抑制剂，目前被批准用于预防固体器官移植受者的移植物排斥反应。在临床前模型中，雷帕霉素具有抗肿瘤作用，包括抑制细胞周期进程、诱导细胞凋亡和抑制血管生成，这表明它应该作为一种抗癌药物进行测试。我们研究团队的长期目标是开发雷帕霉素作为抗癌剂。在这项研究应用中，我们建议对晚期癌症患者进行雷帕霉素的I期研究，作为迈向这一目标的第一步。这项拟议的研究是基于这样一个假设，即只有在可耐受的剂量有效抑制雷帕霉素在肿瘤组织中的靶点时，雷帕霉素才会作为抗癌药物有效。在应用中，我们提出了一项药效学指导下的雷帕霉素在晚期实体瘤患者中的剂量发现研究。在特定的目标#1中，我们将评估雷帕霉素在癌症患者中的药效学活性剂量。为此，我们将根据我们以前使用mTOR抑制剂的经验，测量外周血单个核细胞(PBMC)中mTOR功能的下游介体S6激酶的激活情况，作为药效学终点，并将利用适用于药效学终点的改进的连续重新评估方法(MCRM)，在I期剂量发现研究中优化剂量递增和剂量选择。在特定目标#2中，我们将确认在特定目标#1中选择的剂量在抑制成对肿瘤活检中的S6K活性方面是有效的。总体而言，这项研究将确定雷帕霉素在癌症患者中的生物活性剂量，然后可以在疾病导向研究中进行探索。

DESCRIPTION (provided by applicant): mTOR, a serine-threonine kinase involved in the phosphatidyl-inositol kinase (PI3K)/Akt signaling pathway, is a key regulator of cell growth, proliferation, and survival. Aberrant signaling through mTOR is a frequent alteration in cancer and represents a strategic target for anticancer drug development. Currently, there are several mTOR inhibitors in clinical development for cancer treatment with promising results. Rapamycin is the prototypal mTOR inhibitor, which is currently approved for the prevention of graft rejection in recipients of solid organ transplants. In preclinical models, rapamycin exerts antitumor effects including inhibition of cell cycle progression, induction of apoptosis, and inhibition of angiogenesis suggesting that it should be tested as an anticancer drug. The long-term goal of our research team is to develop rapamycin as an anticancer agent. In this research application we propose a phase I study of rapamycin in patients with advanced cancer as the first step towards this goal. The proposed research is based on the hypothesis that rapamycin will only be effective as an anticancer drug if tolerable doses efficiently inhibit its target in tumor tissues. In the application we proposed a pharmacodynamic-guided dose finding study of rapamycin in patients with advanced solid tumors. In Specific Aim # 1 we will estimate a pharmacodynamic active dose of rapamycin in cancer patients. To this end we will measure activation of S6 kinase, a downstream mediator of mTOR function, in peripheral blood mononuclear cells (PBMC) as the pharmacodynamic endpoint based on our prior experience with mTOR inhibitors and will utilize a modified continuous reassessment method (mCRM) adapted for a pharmacodynamic endpoint to optimize dose escalation and dose selection in a phase I dose-finding study. In Specific Aim # 2 we will confirm that the dose selected in Specific Aim # 1 is effective in inhibiting S6K activity in pair tumor biopsies. Overall this study will determine the biologically active dose of rapamycin in cancer patients that can then be explored in disease-oriented studies.