Clinical Trial of ABC294640 in Patients with Refractory Multiple Myeloma

 描述(申请人提供)：多发性骨髓瘤(MM)是美国第二常见的血液系统恶性肿瘤，由于几乎所有MM患者最终都会复发并对现有药物产生抗药性，因此仍是一种无法治愈的疾病。鞘磷脂代谢被认为是肿瘤生物学中的一条重要途径。具体地说，鞘氨醇激酶(SK1和SK2)为神经酰胺/鞘氨醇1-磷酸(S1P)变阻器提供了一个潜在的操纵位点，该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。我们最近发现SK2在MM中高表达，ABC294640抑制MM细胞株中SK2的表达可下调c-Myc的表达，促进MM细胞的凋亡。重要的是，ABC294640在骨髓瘤异种移植模型中也有效地抑制了体内肿瘤的生长。ABC29460最近完成了对晚期实体瘤患者的I期测试，我们假设该药物将用于多发性骨髓瘤患者的治疗。在这个二期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ABC294640与地塞米松联合治疗复发/难治性多发性骨髓瘤患者的安全性、药动学和药效学。我们将对18名患者进行1b期试验，以确定ABC294640联合地塞米松治疗复发和/或难治性MM患者的安全性、最大耐受量(MTD)、药代动力学和药效学；2：进行II期临床试验，以确定ABC294640联合地塞米松治疗复发/难治性MM患者的初步疗效。一旦MTD建立，多达36名难治性/复发性多发性骨髓瘤患者将在MTD登记，以确认安全性并调查该人群的初步疗效。我们预计这项临床试验将对MM的治疗产生重要影响。我们相信，拟议的研究构成了一种有针对性的方法，为MM患者开发一种新的治疗方法，MM是一种高度未满足临床需求的疾病。如果是肯定的，这些数据将为更大的多中心提供理由 第三阶段研究。

 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.