A Phase I/II Trial of Eltrombopag in Elderly Acute Myeloid Leukemia Patients

描述（由申请人提供）：SB 559457（SB）是一种非肽基、腙类有机小分子，被GlaxoSmithKline（GSK）用作血小板生成素受体（c-Mpl）激动剂开发中的工具化合物。在与GSK科学家合作确定SB生物活性的过程中，我的实验室观察到它对原代人类髓系白血病细胞有毒性。艾曲泊帕是一种口服的、FDA批准的SB形式，适用于难治性特发性血小板减少性紫癜（ITP）和丙型肝炎相关血小板减少症患者，也被证明对髓系白血病细胞具有毒性。一种口服的，耐受性良好的药物，刺激血小板生成的同时，它杀死骨髓性白血病细胞可能被证明在临床上非常有用，可能特别适合于老年AML和血小板减少症患者谁不是候选人，或不希望，传统的化疗。我们建议在“新型癌症治疗快速试验”R21探索性资助计划中验证这一假设，并提出以下具体目标，这些目标将在该奖项的2年任期内实施。具体目标1-确定艾曲泊帕单药治疗老年AML患者的安全性、耐受性和活性。这将在宾夕法尼亚大学医院开展的单中心I/II期临床试验中进行测试。具体目标#2-对接受艾曲泊帕治疗的患者进行药代动力学和药效学研究，以确定其作用机制。我们的初步研究表明，艾曲泊帕和血小板生成素启动不同的信号转导级联，导致不同的转录反应。我们假设这些差异为艾曲泊帕对AML细胞的致细胞病变作用提供了线索。使用来自研究患者的细胞样本，我们将研究这些反应，以确定这类药物的作用机制。这些研究不仅有助于提供作用机制，还可能导致新的治疗靶点的阐明。 公共卫生相关性：在过去的四分之世纪里，急性髓性白血病一直用几乎相同的药物治疗。为了改善大多数患者的预后，需要新的治疗方法。一种新的白血病治疗方法，具有非常理想的口服有效性和治疗血小板减少症的有效性，而不是引起血小板减少症，因此有机会评价这种方法的疗效并了解其作用机制是非常有吸引力的。

DESCRIPTION (provided by applicant): SB559457 (SB) is a non-peptidyl, hydrazone class, organic small molecule employed by GlaxoSmithKline (GSK) as a tool compound in the development of thrombopoietin receptor (c-Mpl) agonists. In the course of collaboration with GSK scientists to determine SB's biological activities, my laboratory observed that it was toxic to primary human myeloid leukemia cells. Eltrombopag, an orally available, FDA approved form of SB that is indicated for patients with refractory idiopathic thrombocytopenic purpura (ITP), and Hepatitis C associated thrombocytopenia, also proved toxic to myeloid leukemia cells. An orally available, well tolerated medication that stimulates thrombopoiesis at the same time that it kills myeloid leukemia cells could prove highly useful in the clinic, and might be particularly appropriate for elderly patients with AML and thrombocytopenia who were not candidates, or did not desire, traditional chemotherapy. We propose to test this hypothesis in the "Quick-Trials for Novel Cancer Therapies" R21 Exploratory Grant program and propose the following specific aims that will be carried out during the 2 year tenure of such an award. Specific Aim # 1- Determine the safety, tolerability and activity of single agent eltrombopag in elderly patients with AML. This will be tested in a single center Phase I/II clinical trial to be opened at the Hospital of the University of Pennsylvania. Specific Aim #2- Carry out Pharmacokinetic and Pharmacodynamic Studies on patients treated with Eltrombopag to determine its mechanism of action. Our preliminary studies have demonstrated that eltrombopag and thrombopoietin initiate different signal transduction cascades with resulting differing transcriptional responses. We hypothesize that these differences provide clues to eltrombopag's cytopathic effect on AML cells. Using cell samples derived from patients on study, we will investigate these responses to determine a mechanism of action for this class of drug. These studies will not only help provide a mechanism of action, but may also lead to the elucidation of novel therapeutic targets. PUBLIC HEALTH RELEVANCE: Acute Myelogenous Leukemia has been treated with much the same drugs for the past quarter century. To improve the outcome for most patients, new treatment approaches are needed. The opportunity to evaluate the efficacy, and learn the mechanism of action, of a novel leukemia therapy with the very desirable qualities of being orally available and effective for treating, not causing, thrombocytopenia should be compelling.