Clinical Trial of Ceramide nanoLiposomes in AML

神经酰胺纳米脂质体治疗 AML 的临床试验

• 批准号: 10160825
• 负责人: MARK KESTER
• 金额: $ 57.19万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10160825
• 关键词: Acute Myelocytic Leukemia; Animal Model; Apoptotic; BCL2 gene; BIRC4 gene; Biochemistry; Biological; Biological Markers; Biology; Cardiovascular Diseases; Cell Death; Ceramide glucosyltransferase; Ceramides; Clinical; Clinical Trials; Cytarabine; Data; Diagnosis; Dose; Down-Regulation; Drug Kinetics; Enzymes; Exhibits; Funding; Goals; Grant; In Vitro; In complete remission; Licensing; Lipids; Liposomes; MCL1 gene; Maximum Tolerated Dose; Mediating; Memorial Sloan-Kettering Cancer Center; Metabolism; Molecular; N-caproylsphingosine; Outcome; Pathway interactions; Patients; Pharmacology; Phase; Pre-Clinical Model; Prognosis; Prognostic Marker; Progression-Free Survivals; Proteins; Protocols documentation; Publishing; Refractory; Regimen; Relapse; Resources; Review Committee; STAT3 gene; Safety; Sampling; Site; Solid Neoplasm; Sphingolipids; Stable Disease; Survival Rate; Testing; Therapeutic; Treatment Protocols; Universities; Validation; Virginia; acute myeloid leukemia cell; base; cancer biomarkers; chemotherapy; clinical application; cohort; combinatorial; conventional therapy; design; diagnostic biomarker; dihydroceramide desaturase; efficacious treatment; galactosylgalactosylglucosylceramidase; improved; in vivo Model; inhibitor/antagonist; innovation; interest; leukemia; liposomal delivery; nano; nanoliposome; nanoscience; phase I trial; prevent; prognostic; sphingosine kinase; standard of care; synergism; targeted treatment; treatment response; treatment strategy

PROJECT SUMMARY Acute Myeloid Leukemia (AML) is the 2nd most common type of leukemia diagnosed with a 5-year survival rate of only 27%. Though dose-intensive induction and consolidation chemotherapy induces clinical complete remission in the majority of patients suitable for treatment, most relapse whereas others develop refractory AML. Recently, the Bcl-2 inhibitor, venetoclax, demonstrated improved clinical outcomes when combined with the conventional therapeutic, cytarabine (AraC), in relapsed and refractory AML. Based upon efficacy in preclinical models, we hypothesize that liposomal delivery of the pro-apoptotic bioactive lipid C6-ceramide will augment the efficacy of this low dose AraC/venetoclax standard-of-care regimen and have a meaningful clinical impact in treating relapsed/refractory AML. This hypothesis will be examined in three Specific Aims. In Specific Aim 1, a Phase 1b (dose escalation)/2a (dose-expansion) clinical trial for ceramide nanoLiposomes (CNL) in relapsed/refractory AML patients treated in combination with low dose AraC and venetoclax (pre-IND #142902, UVA Protocol Review Committee Approval #5414, CAV trial) will be conducted. The premise of this trial is supported by the fact that CNL has already reached its putative MTD in an FDA (IND 109471, NCT02834611) NCI-supported (U43 CA186118) Phase 1 trial for solid tumors, where CNL has been well- tolerated with multiple patients exhibiting stable disease. In Specific Aim 2, we examine the underlying cooperativity between CNL, AraC, and venetoclax in AML. We show that co-administration of CNL with AraC and/or venetoclax exerts multiple synergistic mechanisms of efficacy. First, we demonstrate that this regimen increases the ratio of pro-apoptotic C16- and C18-ceramides over less apoptotic C24 ceramides. Utilizing molecular strategies in both in vitro and in vivo models, we will test the hypothesis that this is mediated by ceramide synthases and determine how ceramide synthases regulate AML survival. Second, we show that CNL reduces venetoclax-induced elevation of pro-survival proteins. We will test the hypothesis that this effect is STAT3-dependent using molecular approaches in preclinical models. In Specific Aim 3, we show that the ratio of C18 to C24 ceramides predicts progression-free survival in AML patients, which is the first application of this ratio as a biomarker for cancer. We will extend and confirm sphingolipid metabolites or ratios as biomarkers of AML biology and prognosis utilizing large, well-characterized AML samples as a validation cohort. while also investigating clinical samples from Specific Aim 1 to assess biomarkers of CNL efficacy. Published and unpublished observations demonstrate that high-expression of enzymes that decrease ceramide levels (acid ceramidase, sphingosine kinase, glucosylceramide synthase) and reduce pro-apoptotic ceramides (e.g. C16/C18) leads to lower survival in AML patients. Together, the proposed studies will test the clinical application and unravel the mechanistic pathways of CNL cooperativity with AraC/venetoclax, while ascertaining the prognostic impact of dysregulated sphingolipid metabolism in AML.

项目摘要 急性髓样白血病（AML）是诊断为5年生存率的第二种最常见的白血病类型 仅27％。尽管剂量密集型诱导和巩固化疗却诱导临床完整 大多数适合治疗的患者的缓解 AML。最近，Bcl-2抑制剂Venetoclax与与 常规的治疗性细胞滨（ARAC），复发和难治性AML。基于功效 临床前模型，我们假设促凋亡生物活性脂质C6-钙酰胺的脂质体递送将 增强这种低剂量ARAC/Venetoclax护理标准方案的功效，并具有有意义的 治疗复发/难治性AML的临床影响。该假设将以三个特定目的进行研究。在 特定目标1，1B期（剂量升级）/2A（剂量扩张）临床试验 （CNL）在复发/难治性的AML患者中与低剂量ARAC和VENETOCLAX联合治疗的患者（预点 ＃142902，UVA协议审查委员会批准＃5414，CAV审判）。这个前提 CNL已经在FDA中达到了推定的MTD（IND 109471， NCT02834611）NCI支持的（U43 CA186118）实体瘤试验，其中CNL已经很好 可耐受多个表现出稳定疾病的患者。在特定目标2中，我们检查了基础 AML中CNL，ARAC和Venetoclax之间的合作性。我们证明了CNL与ARAC共同给药 和/或Venetoclax具有多种功效的协同机制。首先，我们证明了这种方案 促凋亡的C16-和C18-钙酰胺的比率与降低凋亡C24神经酰胺相比。利用 在体外和体内模型中的分子策略，我们将检验以下假设： 神经酰胺合酶并确定神经酰胺合酶如何调节AML存活。第二，我们证明 CNL降低了维内托克拉克斯诱导的促生存蛋白的升高。我们将测试这种效果的假设 使用临床前模型中使用分子方法的STAT3依赖性。在特定目标3中，我们证明了 C18与C24神经酰胺的比率预测AML患者的无进展生存率，这是第一个应用 该比率是癌症的生物标志物。我们将扩展并确认鞘脂代谢物或比率为 AML生物学和预后的生物标志物利用大型，良好的AML样品作为验证 队列。同时还研究了特定目标1的临床样本，以评估CNL功效的生物标志物。 发表和未发表的观察结果表明，降低的酶的高表达 神经酰胺水平（酸性神经酶，鞘氨醇激酶，葡萄糖基酶合酶）并降低促凋亡 神经酰胺（例如C16/C18）导致AML患者的存活率较低。拟议的研究一起将测试 临床应用和揭示CNL与ARAC/VENETOCLAX合作的机理途径，而 确定AML中鞘脂代谢失调的预后影响。