Ceraxa (Ceramide NanoLiposome) and Vinblastine For the Improved Treatment of Relapsed or Refractory Acute Myeloid Leukemia

Ceraxa（神经酰胺纳米脂质体）和长春花碱用于改善复发性或难治性急性髓系白血病的治疗

• 批准号: 10704116
• 负责人: Bernadette McMahon Adair
• 金额: $ 99.96万
• 依托单位: KEYSTONE NANO, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-14 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704116
• 关键词: Acute Myelocytic Leukemia; Adverse effects; Adverse event; Aftercare; Amendment; Apoptotic; Autophagocytosis; Award; Biological Markers; Cancer Center; Cell Death; Ceramides; Chloroquine; Clinical; Clinical Research; Clinical Trials; Data; Disease Progression; Disease remission; Dose; Dose Limiting; Drug Kinetics; Effectiveness; Erythrocytes; Experimental Leukemia; Foundations; Funding; Genomics; Gifts; Grant; Histone Deacetylase; Hydrophobicity; In Vitro; Institutional Review Boards; Legal patent; Lipids; Malignant Neoplasms; Mediating; Medical; Membrane; Memorial Sloan-Kettering Cancer Center; Metabolism; Methods; Microtubules; Modeling; N-caproylsphingosine; NCI-Designated Cancer Center; Orphan Drugs; Participant; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Physiological; Plasma; Platelet Transfusion; Privatization; Prognosis; Prognostic Marker; Proteomics; Protocols documentation; Publishing; Quality of life; Recommendation; Refractory; Regimen; Relapse; Research; Research Personnel; Running; Sampling; Site; Solid Neoplasm; Specialist; Sphingolipids; Sphingosine; Supportive care; Surrogate Markers; Survival Rate; System; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; United States National Institutes of Health; Universities; University of Virginia Cancer Center; Validation; Vinblastine; Virginia; clinical investigation; combinatorial; commercialization; cost; design; disorder control; drug candidate; effective therapy; improved; in vivo; inhibitor; innovation; leukemia treatment; lipidomics; liposomal delivery; manufacture; nano; nanoliposome; novel; novel strategies; novel therapeutics; patient biomarkers; phase 1 study; phase I trial; phase II trial; pre-clinical; predictive marker; prognostic; research clinical testing; safety testing; sphingosine 1-phosphate; success; therapeutic biomarker; trafficking; translational medicine; trial design; virtual

ABSTRACT: This grant supports the clinical study of Keystone Nano’s (KN) Ceraxa (C6 Ceramide NanoLiposome) and Vinblastine (VBL) in patients with relapsed/refractory Acute Myeloid Leukemia (AML) at leading NCI cancer centers. A recently completed NCI-supported Phase 1 study in solid tumor patients (NCT 02834611) has shown no Dose Limiting Toxicities and only modest adverse events with Ceraxa at doses up to 323 mg/m2, a dose five times the planned dose for the proposed AML trial. The rationale for the proposed unique and innovative combinatorial strategy of administration of Ceraxa plus Vinblastine is based upon findings from a recently renewed NIH NCI P01 grant (CA171983-06A1) awarded to KN Chief Technical Officer and co-founder, Dr. Mark Kester, where dysfunctional sphingolipid metabolism was shown to contribute to the pathogenesis of AML. Published mechanistic data document that Vinblastine disrupts autophagy leading to the induction of Ceraxa-mediated autophagic-cell death and shunting Ceraxa metabolism into pro-apoptotic sphingolipid metabolites. The objectives of this grant are to: 1) establish a recommended dose of Ceraxa for AML patients and test preliminary efficacy as a monotherapy, 2) establish a Recommended Phase 2 Dose to test Ceraxa in combination with Vinblastine, and 3) test the safety of Ceraxa plus Vinblastine at the RP2D. Secondary objectives of the grant are to: 1) obtain estimates of effectiveness (CR, PR), 2) assess the pharmacokinetics (PK) of Ceraxa and VBL, 3) obtain estimates of the overall survival (OS) at 90 days after treatment with the combination of Ceraxa and VBL, 4) validate putative lipid-based prognostic or therapeutic biomarkers from patient plasma samples; 5) determine the number of red blood cell (RBC) and platelet transfusions needed for supportive care, and 6) estimate the quality of life of participants prior, during, and following treatment with Ceraxa and VBL. KN has an open IND 142902 and IRB approval (IRB-HSR 22000) for the monotherapy study. This grant integrates important translational medicine opportunities – with three research universities, a company, a supporting PO1 team, and a private foundation (Commonwealth Foundation of Virginia) cooperatively conducting research and clinical investigations including exploring genomic, proteomic, and lipidomic impacts of a new AML treatment with a smart clinical trial. All studies will be completed through two specific aims: 1) Manufacture Ceraxa as a Clinical Drug Product; 2) Conduct Ceraxa clinical trials for AML patients at leading cancer centers.

摘要：该赠款支持Keystone Nano（KN）Ceraxa的临床研究（C6 Ceramide 在患有复发/难治性急性髓样白血病（AML）患者的纳米脂质体）和葡萄蛋白（VBL） 领先的NCI癌症中心。在实体瘤患者中，最近完成的NCI支持的1期研究（NCT） 02834611）没有显示剂量限制毒性，只有适度的广告事件，剂量为剂量 323 mg/m2，剂量是拟议AML试验的计划剂量的五倍。拟议独特的理由 Ceraxa Plus Vinbrastine的给药的创新组合策略是基于来自 最近，授予KN首席技术官兼联合创始人，最近更新了NIH NIH NCI P01 Grant（CA171983-06A1） 马克·凯斯特（Mark Kester）博士，功能失调的鞘脂代谢有助于 AML。已发表的机械数据文档，葡萄碱会破坏自噬，导致诱导 CERAXA介导的自噬细胞死亡和shhunting ceraxa代谢成促凋亡鞘脂 代谢物。这笔赠款的目标是：1）为AML患者建立建议的CERAXA剂量 并测试初步效率作为单一疗法，2）建立建议的2阶段2剂量以测试Ceraxa 与葡萄碱结合使用，3）在RP2D上测试Ceraxa Plus Vinblastine的安全性。次要 赠款的目标是：1）获得有效性的估计值（CR，PR），2）评估药代动力学 （pk）ceraxa和vbl，3）在治疗后90天获得总生存期（OS）的估计值 Ceraxa和VBL的组合，4）验证基于脂质的假定脂质预后或治疗生物标志物 患者血浆样品； 5）确定红细胞的数量（RBC）和血小板输血所需的数量 支持护理和6）估计参与者的生活质量 Ceraxa和VBL。 KN具有开放式IND 142902和IRB批准（IRB-HSR 22000）进行单一疗法研究。 该赠款将重要的转化医学机会整合在一起 - 与三所研究型大学一起 公司，支持PO1团队和私人基金会（弗吉尼亚州联邦基金会） 合作进行研究和临床研究，包括探索基因组，蛋白质组学和 通过智能临床试验，新的AML治疗对脂质组的影响。所有研究将通过两个 具体目的：1）生产Ceraxa作为临床药物； 2）进行AML的Ceraxa临床试验 领先的癌症中心的患者。