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

艾曲波帕治疗老年急性髓系白血病患者的 I/II 期试验

• 批准号: 8112492
• 负责人: MARTIN CARROLL
• 金额: $ 32.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-16 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112492
• 关键词: Acute Myelocytic Leukemia; Agonist; Award; Biological; Blast Cell; Blood Platelets; Cells; Clinic; Clinical Trials; Collaborations; Development; Disease; Dose; Drug Kinetics; Elderly; FDA approved; Frequencies; Grant; Hematologic Neoplasms; Hepatitis C; Human; Hydrazones; Idiopathic Thrombocytopenic Purpura; Incidence; Individual; Laboratories; Lead; Learning; Morbidity - disease rate; Myeloid Leukemia; Outcome; Patients; Pennsylvania; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I/II Trial; Platelet Count measurement; Platelet Transfusion; Protocols documentation; Refractory; Regimen; Safety; Sampling; Scientist; Signal Transduction; Testing; Thrombocytopenia; Thrombopoiesis; Thrombopoietin; Time; University Hospitals; age group; base; cancer therapy; chemotherapy; human MPL protein; improved; killings; leukemia; mortality; new therapeutic target; novel; older patient; programs; public health relevance; recombinant human thrombopoietin; response; small molecule; tool

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.

描述（由申请人提供）： SB559457 (SB) 是一种非肽基腙类有机小分子，被葛兰素史克 (GSK) 用作开发血小板生成素受体 (c-Mpl) 激动剂的工具化合物。在与 GSK 科学家合作确定 SB 的生物活性过程中，我的实验室观察到它对原代人骨髓性白血病细胞具有毒性。艾曲波帕是 FDA 批准的口服 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，也被证明对骨髓性白血病细胞有毒。一种口服、耐受性良好的药物可以刺激血小板生成，同时杀死髓性白血病细胞，这可能在临床上非常有用，并且可能特别适合不适合或不希望接受传统化疗的患有 AML 和血小板减少症的老年患者。我们建议在“新型癌症疗法快速试验”R21 探索性资助计划中检验这一假设，并提出将在该资助的 2 年任期内实现以下具体目标。具体目标#1-确定单药艾曲波帕在老年 AML 患者中的安全性、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 - 对接受艾曲波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，艾曲波帕和血小板生成素启动不同的信号转导级联，从而产生不同的转录反应。我们假设这些差异为艾曲波帕对 AML 细胞的细胞病变作用提供了线索。我们将使用来自研究患者的细胞样本来研究这些反应，以确定此类药物的作用机制。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。 公共健康相关性：在过去的四分之一个世纪里，急性髓性白血病一直使用几乎相同的药物进行治疗。为了改善大多数患者的治疗结果，需要新的治疗方法。评估一种新型白血病疗法的功效并了解其作用机制的机会应该是令人信服的，该疗法具有口服可用且有效治疗而不是引起血小板减少症的非常理想的品质。