An Early-Phase Clinical Trial Evaluating ABC294640 in Patients with Refractory/Re

描述(申请人提供)：弥漫性大B细胞淋巴瘤(DLBCL)是非霍奇金淋巴瘤(NHL)最常见的变种之一，致癌疱疹病毒(EBV和KSHV)是50岁以上患者或感染人类免疫缺陷病毒(HIV+)患者的大多数肿瘤的病原体。尽管接受标准治疗的患者的预后略有改善，但与病毒相关的DLBCL患者表现出更广泛的(“结外”)疾病和不太有利的结果。值得注意的是，观察到来自城市、少数族裔占主导地位、病毒相关DLBCL和艾滋病毒感染率较高的人群的患者治疗失败和死亡率增加，这些患者基本上被排除在临床试验之外。阿波吉生物技术公司开发了第一种非脂类鞘氨醇激酶(SK)抑制剂，并在癌症和炎症性疾病的各种模型中评估了它们的生物学和治疗活性。该系列的第一个临床化合物ABC294640是一种口服的选择性抑制剂SK-2，它可以减弱信号转导，诱导肿瘤细胞死亡，并在实体瘤形成的背景下抑制宿主血管生成和炎症。我们发现ABC294640诱导病毒感染的DLBCL细胞凋亡，部分是通过减弱病毒相关的信号转导。最重要的是，ABC294640显著降低了EBV+和KSHV+DLBCL异种移植模型中病毒相关的DLBCL肿瘤负担。因此，我们假设ABC294640对许多标准治疗无效的DLBCL，特别是病毒相关性DLBCL具有显著的临床活性。为了开始开发ABC294640作为治疗DLBCL的新药，我们建议对该药物进行I/IIa期临床研究，招募路易斯安那州少数族裔占主导地位的城市人口中患有难治性/复发性DLBCL的患者，这些患者具有这种疾病预后不良的高风险。在这项开放的剂量递增研究中，ABC294640将被口服给HIVneg或HIV+患者，主要目标包括确定ABC294640在这些患者中的最大耐受剂量(MTD)、剂量限制毒性和药代动力学。次要目标将包括确定ABC294640对血浆1-磷酸鞘氨醇水平、PBMC和肿瘤相关病毒载量(EBV和KSHV)以及S1P受体的肿瘤表达的影响，作为识别假定的耐药生物标记物的第一步。我们还将使用客观的放射学和临床评估来评估ABC294640的抗肿瘤活性。多达21名患者将被纳入研究的剂量升级阶段，一旦MTD建立，将再招募多达12名DLBCL患者使用该剂量，以获得更多的初步疗效和安全性数据。这项研究将为ABC294640在DLBCL患者中的后续临床试验奠定基础，从而扩大该药的商业市场，包括血液系统恶性肿瘤，并为DLBCL死亡率特别高的代表性不足的患者提供一种新的治疗方法。

DESCRIPTION (provided by applicant): Diffuse large B-cell lymphoma (DLBCL) represents one of the most common variants of Non-Hodgkin's lymphoma (NHL), and oncogenic herpesviruses (EBV and KSHV) are the etiologic agents for the majority of these tumors in patients over 50 or those infected with the human immunodeficiency virus (HIV+). Despite modest improvements in outcomes for patients receiving standard therapy, patients with virus-associated DLBCLs exhibit more widespread ("extranodal") disease and less favorable outcomes. Notably, increased treatment failure and mortality have been observed for patients from urban, minority-predominant cohorts with high rates of virus-associated DLBCL and HIV infection who have been largely excluded from clinical trials. Apogee Biotechnology Corporation has developed the first non-lipid inhibitors of sphingosine kinase (SK) and has evaluated their biologic and therapeutic activity in a variety of models for cancer and inflammatory diseases. The first clinical compound in this series, ABC294640, is an orally-available selective inhibitor o SK-2 that attenuates signal transduction, induces tumor cell death, and inhibits host angiogenesis and inflammation in the context of solid tumor formation. We have found that ABC294640 induces apoptosis for virus-infected DLBCL lines, in part through attenuation of virus-associated signal transduction. Most importantly, ABC294640 significantly reduces virus-associated DLBCL tumor burden in xenograft models for both EBV+ and KSHV+ DLBCLs. Therefore, we hypothesize that ABC294640 will have significant clinical activity for many DLBCLs refractory to standard therapy, especially virus-associated DLBCLs. To begin development of ABC294640 as a new drug for DLBCL, we propose to conduct a Phase I/IIa clinical study of this agent enrolling patients with refractory/relapsed DLBCL from minority-predominant urban populations in Louisiana at high-risk for poor outcomes with this disease. In this open-label, dose-escalation study, ABC294640 will be given orally to HIVneg or HIV+ patients, with primary objectives including determination of the maximum tolerated dose (MTD), dose- limiting toxicities, and pharmacokinetics for ABC294640 in these patients. Secondary objectives will include determination of the effects of ABC294640 on plasma sphingosine 1-phosphate levels, PBMC- and tumor- associated viral load (EBV and KSHV), and tumor expression of S1P receptors as first steps toward identification of putative biomarkers for drug resistance. We will also evaluate antitumor activity for ABC294640 using objective radiographic and clinical assessments. Up to 21 patients will be enrolled in the dose-escalation phase of the study, and once the MTD has been established, up to 12 additional patients with DLBCL will be enrolled using this dose in order to obtain additional preliminary efficacy and safety data. This study will form the foundation for follow-on clinical trials of ABC294640 in patients with DLBCL, thereby expanding the commercial market for this agent to include hematologic malignancies and offering a new therapeutic approach for underrepresented patients for whom DLBCL incurs especially high mortality.