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

描述（由申请方提供）：弥漫性大B细胞淋巴瘤（DLBCL）是非霍奇金淋巴瘤（NHL）最常见的变体之一，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+）患者中大多数此类肿瘤的病原体。尽管接受标准疗法的患者的结局有适度改善，但患有病毒相关DLBCL的患者表现出更广泛的（“结节性”）疾病和更不利的结局。值得注意的是，在病毒相关DLBCL和HIV感染率高的城市、少数民族为主的队列中观察到治疗失败和死亡率增加，这些患者在很大程度上被排除在临床试验之外。Apogee生物技术公司开发了第一种鞘氨醇激酶（SK）的非脂质抑制剂，并在各种癌症和炎性疾病模型中评估了其生物学和治疗活性。该系列中的第一个临床化合物ABC 294640是一种口服可获得的SK-2选择性抑制剂，其减弱信号转导，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。我们已经发现，ABC 294640诱导病毒感染的DLBCL细胞系的凋亡，部分是通过减弱病毒相关的信号转导。最重要的是，ABC 294640显著降低了EBV+和KSHV+ DLBCL的异种移植模型中的病毒相关DLBCL肿瘤负荷。因此，我们假设ABC 294640对许多标准治疗难治的DLBCL，特别是病毒相关DLBCL具有显著的临床活性。为了开始将ABC 294640开发为治疗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民族为主的城市人群中患有难治性/复发性DLBCL的患者，这些患者患有这种疾病的预后不良风险高。在这项开放标签、剂量递增研究中，将向HIV阴性或HIV+患者口服给予ABC 294640，主要目的包括确定这些患者中ABC 294640的最大耐受剂量（MTD）、剂量限制性毒性和药代动力学。次要目的将包括确定ABC 294640对血浆鞘氨醇1-磷酸水平、PBMC和肿瘤相关病毒载量（EBV和KSHV）以及S1 P受体的肿瘤表达的影响，作为鉴定药物抗性的推定生物标志物的第一步。我们还将使用客观的放射学和临床评估来评估ABC 294640的抗肿瘤活性。研究的剂量递增阶段将入组多达21例患者，一旦确定MTD，将使用该剂量入组多达12例DLBCL患者，以获得额外的初步疗效和安全性数据。这项研究将为ABC 294640在DLBCL患者中的后续临床试验奠定基础，从而将该药物的商业市场扩大到包括血液恶性肿瘤，并为DLBCL死亡率特别高的代表性不足的患者提供新的治疗方法。

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.