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

一项评估 ABC294640 在难治性/再发性骨髓瘤患者中的早期临床试验

• 批准号: 9120662
• 负责人: Christopher H Parsons
• 金额: $ 13.31万
• 依托单位: APOGEE BIOTECHNOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-17 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120662
• 关键词: Address; Aggressive course; Anabolism; Apoptosis; Apoptotic; Area; Attenuated; B-Cell Neoplasm; Biological Assay; Biological Markers; Biotechnology; Cancer Model; Cell Death; Cells; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical assessments; Coupled; Critical Pathways; Cytotoxic Chemotherapy; Data; Development; Disease; Disease Outcome; Disease remission; Dose; Dose-Limiting; Drug Combinations; Drug Kinetics; Drug resistance; Enrollment; Exhibits; Extranodal; Foundations; Funding; Future; Gene Expression; Growth; HIV; HIV Infections; Health Sciences; Hematologic Neoplasms; Herpesviridae; High Prevalence; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immunodeficient Mouse; Incidence; Inflammation; Inflammatory; Life; Link; Louisiana; Lytic; Malignant Neoplasms; Marketing; Maximum Tolerated Dose; Medical; Metabolism; Minority; Modeling; Non-Hodgkin' s Lymphoma; Oncogenes; Oncogenic; Oncogenic Viruses; Oral Administration; Outcome; Pathogenesis; Patient-Focused Outcomes; Patients; Performance; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phosphorylation; Plasma; Play; Population; Primary Neoplasm; Process; Prognostic Marker; Protein Isoforms; Protocols documentation; Publishing; Recurrence; Refractory; Refractory Disease; Relapse; Resistance; Risk; Role; Safety; Sampling; Satellite Viruses; Series; Signal Transduction; Small Business Technology Transfer Research; Solid Neoplasm; Sphingolipids; Sphingosine; Sphingosine-1-Phosphate Receptor; Therapeutic; Toxic effect; Treatment Failure; Tumor Burden; Underrepresented Minority; Universities; Urban Population; Variant; Viral Genes; Viral Load result; Virus; Xenograft Model; Xenograft procedure; advanced disease; angiogenesis; attenuation; clinical efficacy; cohort; drug standard; effective therapy; gammaherpesvirus; high risk; in vivo; in vivo Model; inhibitor/antagonist; kinase inhibitor; large cell Diffuse non-Hodgkin' s lymphoma; mortality; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; open label; pre-clinical; preclinical study; programs; public health relevance; receptor expression; research study; small molecule inhibitor; sphingosine 1-phosphate; sphingosine kinase; standard of care; tumor; tumor growth

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.

描述（由申请人提供）：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，致癌性疱疹病毒（EBV 和 KSHV）是大多数此类肿瘤的病原体50 岁以上的患者或感染人类免疫缺陷病毒 (HIV+) 的患者。尽管接受标准治疗的患者的结局略有改善，但病毒相关 DLBCL 患者表现出更广泛的（“结外”）疾病和较差的结局。值得注意的是，对于来自城市、少数民族人群、病毒相关 DLBCL 和 HIV 感染率较高的患者，观察到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。 Apogee Biotechnology Corporation 开发了首个非脂质鞘氨醇激酶 (SK) 抑制剂，并在多种癌症和炎症性疾病模型中评估了其生物活性和治疗活性。该系列中的第一个临床化合物 ABC294640 是一种口服选择性 SK-2 抑制剂，可减弱信号转导，诱导肿瘤细胞死亡，并抑制实体瘤形成过程中的宿主血管生成和炎症。我们发现 ABC294640 部分通过减弱病毒相关信号转导来诱导病毒感染的 DLBCL 系细胞凋亡。最重要的是，ABC294640 显着降低了 EBV+ 和 KSHV+ DLBCL 异种移植模型中病毒相关的 DLBCL 肿瘤负荷。因此，我们假设 ABC294640 对于许多标准治疗难治的 DLBCL，特别是病毒相关的 DLBCL 具有显着的临床活性。为了开始开发 ABC294640 作为 DLBCL 新药，我们建议对该药物进行 I/IIa 期临床研究，招募来自路易斯安那州少数族裔为主的城市人口的难治性/复发性 DLBCL 患者，这些患者预后不良。疾病。在这项开放标签剂量递增研究中，ABC294640将口服给予HIVneg或HIV+患者，主要目标包括确定这些患者中ABC294640的最大耐受剂量（MTD）、剂量限制性毒性和药代动力学。次要目标包括确定 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 受体肿瘤表达的影响，作为识别假定的耐药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 ABC294640 的抗肿瘤活性。最多 21 名患者将被纳入该研究的剂量递增阶段，一旦 MTD 确定，将另外招募最多 12 名 DLBCL 患者使用该剂量，以获得额外的初步疗效和安全性数据。这项研究将为 ABC294640 在 DLBCL 患者中进行后续临床试验奠定基础，从而扩大该药物的商业市场以包括血液恶性肿瘤，并为代表性不足的 DLBCL 死亡率特别高的患者提供一种新的治疗方法。