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

摘要：这项资助支持Keystone Nano(KN)Ceraxa(C6神经酰胺)的临床研究 纳米脂质体联合长春花碱治疗复发/难治性急性髓系白血病 领先的NCI癌症中心。最近完成的一项由NCI支持的实体肿瘤患者(NCT)1期研究 02834611)没有显示出剂量限制毒性，并且只有轻微的不良反应，Ceraxa的剂量达到 323 mg/m2，是拟议的急性髓细胞白血病试验计划剂量的五倍。提议的独一无二的 Ceraxa加长春花碱的创新组合给药策略是基于一项 最近续签了NIH NCI P01奖金(CA171983-06A1)，授予KN首席技术官兼联合创始人， 马克·凯斯特博士，他的鞘脂代谢障碍被证明参与了脑膜瘤的发病机制 AML。发表的机械数据文件表明长春花碱扰乱自噬导致诱导 Ceraxa介导的自噬细胞死亡和Ceraxa代谢向促凋亡鞘磷脂的分流 代谢物。这笔赠款的目标是：1)为急性髓细胞白血病患者建立一个推荐剂量的Ceraxa 和测试作为单一疗法的初步疗效，2)建立推荐的第二阶段剂量以测试Ceraxa在 与长春花碱联合，以及3)在RP2D处测试Ceraxa与长春花碱的安全性。次要的 赠款的目的是：1)获得疗效评估(CR，PR)，2)评估药物动力学 Ceraxa和VBL的(PK)，3)获得治疗后90天的总生存期(OS)的估计 Ceraxa和VBL的组合，4)验证了推测的基于脂质的预后或治疗生物标记物 患者血浆样本；5)确定需要输注的红细胞(RBC)和血小板数量 支持性护理，以及6)评估参与者在治疗前、治疗中和治疗后的生活质量 Ceraxa和Vbl。KN拥有开放的IND 142902和IRB批准(IRB-HSR 22000)进行单一疗法研究。 这笔赠款整合了重要的转化医学机会-与三所研究型大学、一所 公司、支持PO1团队和私人基金会(弗吉尼亚联邦基金会) 合作开展研究和临床调查，包括探索基因组、蛋白质组和 一项具有SMART临床试验的新AML治疗方法对血脂的影响。所有的学习将在两个月内完成 具体目标：1)将Ceraxa作为临床药物产品生产；2)对AML进行Ceraxa临床试验 领先癌症中心的病人。

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.