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

摘要：该基金支持Keystone Nano（KN）Ceraxa（C6神经酰胺）的临床研究 纳米脂质体）和长春碱（VBL）治疗复发性/难治性急性髓系白血病（AML）患者 国家癌症研究所的顶尖癌症中心最近完成的一项在实体瘤患者（NCT）中进行的NCI支持的I期研究 02834611）没有显示出剂量限制性毒性，并且在剂量高达 323 mg/m2，是拟定AML试验计划剂量的5倍。提议的唯一性的理由 Ceraxa+长春碱联合给药的创新组合策略是基于一项研究的发现， 最近更新的NIH NCI P01补助金（CA 171983 - 06 A1）授予KN首席技术官和联合创始人， 博士马克·凯斯特（Mark Kester）的研究表明，功能失调的鞘脂代谢有助于 急性髓细胞白血病已发表的机制数据表明，长春碱破坏自噬，导致诱导 Ceraxa介导的自噬细胞死亡和将Ceraxa代谢分流为促凋亡鞘脂 代谢物。该基金的目的是：1）确定AML患者的Ceraxa推荐剂量 并测试作为单药治疗的初步疗效，2）建立推荐的II期剂量，以测试Ceraxa在 与长春碱联合使用，以及3）在RP 2D下测试Ceraxa加长春碱的安全性。二次 补助金的目的是：1）获得有效性（CR，PR）的估计值，2）评估药代动力学 (PK)3）获得Ceraxa和VBL治疗后90天的总生存期（OS）估计值， Ceraxa和VBL的组合，4）验证来自以下的假定的基于脂质的预后或治疗生物标志物： 患者血浆样品; 5）确定患者血液透析所需的红细胞（RBC）和血小板输注的数量， 支持性治疗，和6）估计参与者的生活质量之前，期间和之后的治疗， Ceraxa和VBL。KN已获得单药治疗研究的开放IND 142902和IRB批准（IRB-HSR 22000）。 该补助金整合了重要的转化医学机会-与三所研究型大学， 公司，支持PO 1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，包括探索基因组学，蛋白质组学， 一个新的AML治疗与智能临床试验的脂质组学影响。所有研究将通过两个 具体目标：1）将Ceraxa作为临床药物产品生产; 2）进行Ceraxa治疗AML的临床试验 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.