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

描述(由申请人提供)：SB559457(SB)是葛兰素史克(GSK)在开发促血小板生成素受体(c-MPL)激动剂时作为工具化合物使用的非肽、肼类有机小分子。在与葛兰素史克科学家合作确定SB的生物活性的过程中，我的实验室观察到它对原代人类髓系白血病细胞有毒性。ELTROMBOPG是FDA批准的一种口服形式的SB，适用于难治性特发性血小板减少性紫癜(ITP)和丙型肝炎相关性血小板减少症患者，也被证明对髓系白血病细胞有毒性。一种口服可用、耐受性良好的药物，在刺激血小板生成的同时杀死髓系白血病细胞，在临床上可能被证明非常有用，可能特别适合患有急性髓细胞白血病和血小板减少症的老年患者，他们不是传统化疗的候选者，也不希望接受传统化疗。我们建议在“新癌症疗法快速试验”R21探索性拨款计划中测试这一假设，并提出在该奖项的两年任期内将实施的以下具体目标。具体目标#1-确定老年AML患者单用单药埃拉莫的安全性、耐受性和活性。这将在宾夕法尼亚大学医院开设的单中心I/II期临床试验中进行测试。具体目标#2--对接受艾尔莫博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，eltrombopg和血小板生成素启动了不同的信号转导级联反应，导致了不同的转录反应。我们假设，这些差异为eltrombopg对AML细胞的细胞病变效应提供了线索。利用研究中患者的细胞样本，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，还可能有助于阐明新的治疗靶点。 与公共卫生相关：在过去的四分之一个世纪里，急性髓系白血病一直使用大致相同的药物治疗。为了改善大多数患者的预后，需要新的治疗方法。评估一种新型白血病疗法的有效性并了解其作用机制的机会应该是令人信服的，这种疗法具有非常可取的特性，即口服可用，对治疗而不是引起血小板减少症有效。

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.