A Phase I trial combining IV fenretinide and IV safingol to target overproduction

项目摘要/摘要 CerRx，Inc.，Lubbock TX，一家临床阶段抗癌药物开发初创公司，要求关键 通过SBIR快速通道I/II期应用程序提供资金，以支持一项非常新颖的成人I期临床试验 静脉注射芬维替尼+萨芬戈，它获得了配方和药物组合的知识产权。这 试验将转包给总部设在德克萨斯州西部的学术组织南平原肿瘤学联盟(SPOC)， 总部设在德克萨斯理工大学健康科学中心(TTUHSC)。芬维替尼(4-HPR)是一种P53- 独立维甲酸通过增加活性氧和De对癌细胞选择性细胞毒作用 天然长链D-红血球二氢神经酰胺的新增加。萨芬戈为L-苏二氢鞘氨醇 神经鞘氨醇的人工立体化学变体，它是哺乳动物细胞中二氢神经酰胺的天然前体。 我们已经在人和狗的癌细胞系中表明，萨芬戈被整合到长寿的L-苏氨酸中。 二氢神经酰胺。我们的临床前数据表明，萨芬戈对芬维甲素的细胞毒性有显著的协同作用 体外同时增加人工L-苏氨酸二氢神经酰胺和天然D-红血球蛋白 二氢神经酰胺以肿瘤细胞特异性的方式。我们假设这部专为癌症而生的小说 如果患者可以达到足够的药物水平，生物化学可能在人类癌症中实现 原位肿瘤。通过NCI Raid赠款，芬维替尼和萨芬戈的新型静脉乳剂配方 适合大剂量给药的药物已研制成功。静脉注射4-HPR的I期成人试验表明 耐受性好，达到高循环血浆4-HPR水平，并产生多个耐久的完全 实体瘤中有额外活性信号的复发性T细胞淋巴瘤的反应。的第一阶段试验 我们的静脉注射萨芬戈制剂表明，它与顺铂联合应用耐受性良好。 预计萨芬戈剂量足以达到所需的二氢神经酰胺调节作用。我们的Ind-Directed，狗 毒理学研究表明，静脉注射萨芬戈+芬维奈德耐受性良好， 在我们的目标剂量范围内缺乏造血毒性。在SBIR第一阶段，初步概念验证临床 将进行联合给药。在SBIR第二阶段，静脉注射4-羟色胺的I期剂量递增试验 成人实体瘤和淋巴瘤采用HPR+萨芬戈尔治疗。第一阶段试验将定义 沙芬戈与非维甲酸合用的最大耐受量(MTD)药代动力学 获得两种药物药效学作用的辅助标记物 通过测量血浆鞘磷脂和鞘氨醇-1-磷酸水平进行组合，并在 第一阶段试验，确定这种新型药物组合的活性。这是人类第一次明确 将二氢神经酰胺途径作为细胞毒性癌症治疗的靶点。如果成功，这种新的生物化学可能会 构成了一种广泛的、不依赖于P53的治疗方法，在成人和儿童恶性肿瘤中广泛活跃。

PROJECT SUMMARY/ABSTRACT CerRx, Inc., Lubbock TX, a clinical stage anticancer drug development start-up company, requests critical funding via this SBIR Fast-Track Phase I/II application to support a highly novel, adult Phase I clinical trial of intravenous fenretinide + safingol, for which it licenses both formulation and drug combination IP rights. This trial will be subcontracted to the academic West Texas-based, South Plains Oncology Consortium (SPOC), based at the Texas Tech University Health Sciences Center (TTUHSC). Fenretinide (4-HPR) is a p53- independent retinoid selectively cytotoxic to cancer cells via increase of reactive oxygen species and the de novo increase of native long chain D-erythro-dihydroceramides. Safingol is L-threo-dihydrosphingosine, an artificial stereochemical variant of sphinganine, the native precursor of dihydroceramides in mammalian cells. We have shown in human and canine cancer cell lines that safingol is incorporated into long-lived, L-threo- dihydroceramides. Our preclinical data demonstrated that safingol strikingly synergized fenretinide cytotoxicity in vitro by simultaneously increasing both artificial L-threo-dihydroceramides and native D-erythro- dihydroceramides in a tumor cell-specific manner. We hypothesized that this novel, cancer-specific biochemistry might be achievable in human cancers should adequate drug levels be achievable in patient tumors in situ. Via an NCI RAID grant, novel intravenous emulsion formulations of both fenretinide and safingol suitable for high-dose delivery were developed. Phase I adult trials of intravenous 4-HPR demonstrated that it is well-tolerated, achieved high circulating plasma 4-HPR levels, and produced multiple durable complete responses in relapsed T-cell lymphomas with additional signals of activity in solid tumors. A Phase I trial of our intravenous safingol formulation demonstrated that it was well-tolerated in combination with cisplatin at safingol doses predicted sufficient to attain the desired dihydroceramide modulation. Our IND-directed, canine toxicology studies showed that the combination of intravenous safingol + fenretinide was well-tolerated and lacked hematopoietic toxicity within our target dosing. Under SBIR Phase I, initial proof-of-concept clinical combination dosing will be conducted. Under SBIR Phase II, a Phase I dose escalation trial of intravenous 4- HPR + safingol in adult solid tumors and lymphomas will be conducted. The Phase I trial will define the maximally tolerated dose (MTD) of intravenous safingol when combined with fenretinide, the pharmacokinetics of both agents in combination, obtain ancillary markers of the pharmacodynamic actions of both agents in combination by measuring plasma sphingolipid and sphingosine-1-phosphate levels, and, within the confines of a phase I trial, determine the activity of this novel drug combination. This trial is the first in man to specifically target the dihydroceramide pathway as a cytotoxic cancer treatment. If successful, this novel biochemistry may constitute a broad-based, p53-independent therapy widely active in both adult and pediatric malignancies.