Clinical Trial of ABC294640 in Patients with Refractory Multiple Myeloma

 描述（由申请人提供）：多发性骨髓瘤（MM）是美国第二常见的血液恶性肿瘤，并且仍然是一种无法治愈的疾病，因为几乎所有MM患者最终都会复发并对目前可用的药物产生耐药性。鞘脂代谢越来越被认为是肿瘤生物学的一个关键途径。特别是，鞘氨醇激酶（SK 1和SK 2）提供了一个潜在的网站操纵神经酰胺/鞘氨醇1-磷酸（S1 P）变阻器，调节肿瘤细胞增殖和凋亡之间的平衡，以及肿瘤对药物和辐射的敏感性。我们最近证明，SK2在MM中过表达，并且通过ABC 294640抑制MM细胞系中的SK2下调c-Myc表达并促进MM细胞的凋亡。重要的是，ABC 294640还有效地抑制骨髓瘤异种移植模型中的体内肿瘤生长。ABC 29460最近在晚期实体瘤患者中完成了I期试验，我们假设这种药物将用于治疗MM患者。在该2期SBIR项目中，我们将进行以下具体目标：1：进行Ib期临床试验，以确定ABC 294640与地塞米松联合治疗复发性/难治性MM患者的安全性、药代动力学和药效学。我们将在多达18名患者中进行Ib期试验，以确定ABC 294640与地塞米松组合在先前用蛋白酶体抑制剂和免疫调节剂两者治疗的复发性和/或难治性MM患者中的安全性、最大耐受剂量（MTD）、药代动力学和药效学;以及2：开展II期临床试验，确定ABC 294640联合地塞米松治疗复发/难治性MM患者的初步疗效。一旦确定MTD，将在MTD水平额外入组最多36例难治性/复发性MM患者，以确认安全性并研究该人群的初步疗效。我们预计这项临床试验将对MM的治疗产生重要影响。我们认为，拟议的研究构成了为MM患者开发新型治疗方法的重点方法，MM是一种临床需求高度未满足的疾病。如果是阳性，这些数据将为更大规模的多中心研究提供依据。 III期研究。

 DESCRIPTION (provided by applicant): Multiple myeloma (MM) is the second most common hematological malignancy in the United States, and remains an incurable disease since nearly all MM patients will eventually relapse and develop resistance to currently available drugs. Sphingolipid metabolism is being increasingly recognized as a key pathway in tumor biology. In particular, sphingosine kinases (SK1 and SK2) provide a potential site for manipulation of the ceramide/ sphingosine 1-phosphate (S1P) rheostat that regulates the balance between tumor cell proliferation and apoptosis, as well as tumor sensitivity to drugs and radiation. We have recently demonstrated that SK2 is overexpressed in MM and that inhibition of SK2 in MM cell lines by ABC294640 down-regulates c-Myc expression and promotes apoptosis in MM cells. Importantly, ABC294640 also effectively inhibits tumor growth in vivo in myeloma xenograft models. ABC29460 has recently completed phase I testing in patients with advanced solid tumors, and we hypothesize that this drug will be useful for the treatment of MM patients. In this phase 2 SBIR project, we will conduct the following Specific Aims: 1: Perform a phase Ib clinical trial to determine the safety, pharmacokinetics and pharmacodynamics of ABC294640 when combined with dexamethasone in relapsed/refractory MM patients. We will perform a phase 1b trial with up to 18 patients to determine the safety, maximal tolerated dose (MTD), pharmacokinetics and pharmacodynamics of ABC294640 combined with dexamethasone in relapsed and/or refractory MM patients who have previously been treated with both a proteasome inhibitor and an immunomodulatory agent; and 2: Perform a phase II clinical trial to determine the preliminary efficacy of ABC294640 combined with dexamethasone in relapsed/refractory MM patients. Once the MTD has been established, up to 36 additional patients with refractory/relapsed MM will be enrolled at the MTD to confirm safety and to investigate preliminary efficacy in this population. We expect that this clinical trial will have important implications in the treatment of MM. We believe that the proposed studies constitute a focused approach for developing a novel treatment for patients with MM, a disease with a high unmet clinical need. If positive, these data will provide justification for a larger, multi- center phase III study.