A Phase I trial combining fenretinide and safingol to target overproduction of di

描述(由申请人提供)：一项联合静脉注射芬维甲素和萨芬戈的I期试验，旨在靶向在恶性肿瘤细胞中过量生产细胞毒性二氢神经酰胺PI：Barry J.Maurer，MD PhD摘要芬维甲素(4-HPR)是一种不依赖于P53的维甲酸类化合物，通过增加活性氧物种和天然长链D-红血球二氢神经酰胺的从头增加而选择性地对癌细胞产生细胞毒性。赛芬戈是一种L二氢鞘氨醇，是神经鞘氨醇的人工立体化学变体，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，萨芬戈被结合到长寿的L苏氨酸二氢神经酰胺中。我们的临床前研究表明，萨芬戈通过同时以肿瘤细胞特异性方式增加人工L-苏氨酸二氢神经酰胺和天然D-红血球二氢神经酰胺，在体外显著增强了芬维甲素的细胞毒性。我们假设，如果在患者原位肿瘤中能够达到足够的药物水平，这种新颖的、癌症特异性的生物化学可能在人类癌症中实现。通过NCI的Raid赠款，我们制备了适用于大剂量给药的芬维替尼和萨芬戈的新型静脉乳剂。我们的静脉注射4-HPR的I期成人试验表明，它耐受性好，循环血浆4-HPR水平高，在T细胞淋巴瘤中产生持久的完全反应，并在实体瘤中产生额外的活动信号。我们的静脉注射萨芬戈制剂的I期试验表明，在萨芬戈剂量下，它与顺铂联合使用耐受性良好，据信足以达到所需的二氢神经酰胺调节。我们的IND指导的犬毒理学研究表明，静脉注射萨芬戈和芬维奈德的联合用药耐受性良好，在我们的目标剂量范围内没有造血毒性。我们现在建议进行静脉注射萨芬戈联合静脉注射4-HPR治疗成人实体瘤和淋巴瘤的I期试验。这项拟议的试验将确定萨芬戈与非维甲酸合用时静脉注射的最大耐受量(MTD)、两种药物组合的药代动力学、通过测量血浆鞘磷脂和1-磷酸鞘氨醇水平来获得两种药物组合药效作用的辅助标记物，并在I期试验范围内确定这种新型药物组合的活性。这项试验是人类首次将二氢神经酰胺途径作为细胞毒性癌症治疗的特定靶点。如果成功，这种针对恶性细胞的新型生化攻击将构成一种广泛的、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。 公共卫生相关性：需要对癌细胞进行新的生化攻击以改善临床结果。拟议的静脉注射萨芬戈+芬维奈德的I期研究是一种一流的药物组合，专门针对二氢神经酰胺途径作为一种细胞毒性癌症治疗。如果成功，这种新的生物化学可能构成一种广泛的、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，并解决一个主要的未得到满足的需求。

DESCRIPTION (provided by applicant): A Phase I trial combining intravenous fenretinide and safingol to target overproduction of cytotoxic dihydroceramides in malignant cells PI: Barry J. Maurer, MD PhD ABSTRACT 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, we prepared novel intravenous emulsion formulations of both fenretinide and safingol suitable for high-dose delivery. Our phase I adult trials of intravenous 4-HPR demonstrated that it is well-tolerated, achieved high circulating plasma 4-HPR levels, and produced durable complete responses in 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 believed sufficient to attain the desired dihydroceramide modulation. Our IND-directed, canine toxicology studies showed that the combination of intravenous safingol and fenretinide was well-tolerated and lacked hematopoietic toxicity within our target dosing. We now propose to conduct a phase I trial of intravenous safingol in combination with intravenous 4-HPR in adult solid tumors and lymphomas. The proposed 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 biochemical attack on malignant cells will constitute a broad-based, p53-independent therapy widely active in both adult and pediatric malignancies. PUBLIC HEALTH RELEVANCE: .Novel biochemical attacks on cancer cells are needed to improve clinical outcomes. The proposed Phase I study of intravenous safingol + fenretinide is a first-in-class drug combination that specifically targets 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 and address a major unmet need.