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：这笔资金支持 Keystone Nano (KN) Ceraxa（C6 神经酰胺）的临床研究 纳米脂质体）和长春花碱（VBL）治疗复发/难治性急性髓系白血病（AML）患者 领先的 NCI 癌症中心最近完成了 NCI 支持的针对实体瘤患者的 1 期研究 (NCT) 02834611）显示，Ceraxa 在剂量高达 323 mg/m2，剂量是拟议的 AML 试验计划剂量的五倍。 Ceraxa 加长春花碱的创新组合给药策略基于一项研究的发现 最近更新了 NIH NCI P01 拨款 (CA171983-06A1)，授予 KN 首席技术官和联合创始人， Mark Kester 博士指出，鞘脂代谢功能失调会导致以下疾病的发病机制： 已发表的机制数据文件表明，长春花碱会破坏自噬，从而诱导 Ceraxa 介导的自噬细胞死亡并将 Ceraxa 代谢分流为促凋亡鞘脂 这笔资助的目的是：1) 为 AML 患者确定 Ceraxa 的推荐剂量。 并测试作为单一疗法的初步疗效，2) 建立推荐的 2 期剂量来测试 Ceraxa 与长春花碱组合，3) 在 RP2D 测试 Ceraxa 加长春花碱的安全性。 拨款的目标是：1) 获得有效性估计（CR、PR），2) 评估药代动力学 (PK) Ceraxa 和 VBL，3) 获得使用 Ceraxa 治疗后 90 天的总生存期 (OS) 的估计值 Ceraxa 和 VBL 的组合，4) 验证假定的基于脂质的预后或治疗生物标志物 5) 确定患者血浆样本输注所需的红细胞 (RBC) 和血小板数量 支持性护理，6) 评估参与者在治疗前、治疗期间和治疗后的生活质量 Ceraxa 和 VBL 已获得单一疗法研究的开放 IND 142902 和 IRB 批准（IRB-HSR 22000）。 这笔赠款整合了重要的转化医学机会——与三所研究型大学、 公司、支持 PO1 团队和私人基金会（弗吉尼亚联邦基金会） 合作进行研究和临床调查，包括探索基因组学、蛋白质组学和 一项新的 AML 治疗的脂质组学影响和智能临床试验将通过两项研究完成。 具体目标：1) 生产 Ceraxa 作为临床药品；2) 进行 AML 的 Ceraxa 临床试验 领先癌症中心的患者。