Clinical Trial of ABC294640 in Patients with Refractory Multiple Myeloma

ABC294640在难治性多发性骨髓瘤患者中的临床试验

• 批准号: 8980087
• 负责人: Charles D Smith
• 金额: $ 66.67万
• 依托单位: APOGEE BIOTECHNOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8980087
• 关键词: Accounting; Apoptosis; Cancer Biology; Cell Line; Cell Proliferation; Cells; Ceramides; Cessation of life; Clinical; Clinical Trials; Data; Development; Dexamethasone; Disease; Dose; Drug Kinetics; Enrollment; Enzymes; Equilibrium; Goals; Hematologic Neoplasms; Kinetics; Maximum Tolerated Dose; Medical; Metabolism; Multiple Myeloma; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Plasma; Population; Proteasome Inhibitor; RNA Interference; Radiation; Refractory; Relapse; Resistance development; Safety; Site; Small Business Innovation Research Grant; Solid Neoplasm; Sphingolipids; Testing; Therapeutic; Therapeutic Agents; Tumor Biology; United States; Xenograft Model; absorption; c-myc Genes; in vivo; inhibitor/antagonist; neoplastic cell; novel; novel therapeutics; overexpression; phase 3 study; pre-clinical; public health relevance; research clinical testing; sphingosine 1-phosphate; sphingosine kinase; tumor; tumor growth

 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.

 描述（由申请人提供）：多发性骨髓瘤 (MM) 是美国第二大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。特别是，鞘氨醇激酶（SK1 和 SK2）被认为是肿瘤生物学中的关键途径，为操纵神经酰胺/鞘氨醇提供了潜在的位点。 1-磷酸 (S1P) 变阻器可调节肿瘤细胞增殖和凋亡之间的平衡，以及肿瘤对药物和放射的敏感性。我们最近证明 SK2 在 MM 中过度表达，并且 ABC294640 抑制 MM 细胞系中的 SK2。 - 调节 MM 细胞中的 c-Myc 表达并促进细胞凋亡。重要的是，ABC294640 还可有效抑制骨髓瘤异种移植模型中的体内肿瘤生长。 ABC29460最近在晚期实体瘤患者中完成了I期测试，我们追求该药物将有助于治疗MM患者。在这个2期SBIR项目中，我们将进行以下具体目标： 1：执行一个阶段。 Ib 临床试验以确定 ABC294640 与地塞米松联合治疗复发/难治性 MM 患者的安全性、药代动力学和药效学。 18 名患者确定 ABC294640 联合地塞米松治疗既往接受过蛋白酶体抑制剂和免疫调节剂治疗的复发性和/或难治性 MM 患者的安全性、最大耐受剂量 (MTD)、药代动力学和药效学；2：进行II期临床试验确定ABC294640联合地塞米松对复发/难治性MM患者的初步疗效。 MTD 已经建立，将招募多达 36 名难治性/复发性 MM 患者，以确认该人群的安全性并初步研究其疗效，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，拟议的研究构成了为 MM 患者开发新疗法的重点方法，这种疾病的临床需求高度未得到满足。如果结果积极，这些数据将为更大规模的多中心研究提供依据。 III 期研究。