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

摘要：一项I期临床试验，联合静脉注射芬维甲酸和沙芬酚靶向恶性细胞中细胞毒性二氢神经酰胺的过量产生。芬维甲酸（4-HPR）是一种不依赖p53的类维甲酸，通过增加活性氧和从头增加天然长链d -红-二氢神经酰胺，选择性地对癌细胞产生细胞毒性。Safingol是L-threo-二氢鞘氨酸，是鞘氨酸的人造立体化学变体，是哺乳动物细胞中二氢神经酰胺的天然前体。我们已经在人类和犬的癌细胞系中表明，safingol被纳入了长寿命的l -三氢神经酰胺中。我们的临床前数据表明，沙芬酚在体外通过以肿瘤细胞特异性的方式同时增加人工l-三氢神经酰胺和天然d -红-二氢神经酰胺，显著协同芬维甲酸的细胞毒性。我们假设，如果在患者原位肿瘤中可以获得足够的药物水平，这种新颖的癌症特异性生物化学可能在人类癌症中实现。通过NCI RAID拨款，我们制备了适合大剂量静脉注射的芬维甲酸和沙芬ingol的新型静脉乳剂配方。我们的成人I期静脉注射4-HPR试验表明，它具有良好的耐受性，达到了高循环血浆4-HPR水平，并在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性信号。我们静脉注射safingol制剂的一期试验表明，在safingol剂量足以达到所需的二氢神经酰胺调节的情况下，它与顺铂联合使用具有良好的耐受性。我们的ind指导犬毒理学研究表明，静脉注射safingol和fenretinide的组合耐受性良好，并且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沙芬酚联合静脉注射4-HPR治疗成人实体瘤和淋巴瘤的I期试验。拟议的试验将确定静脉注射沙芬酚与芬维甲酸联合使用时的最大耐受剂量（MTD），两种药物联合使用的药代动力学，通过测量血浆鞘脂和鞘氨醇-1-磷酸水平获得两种药物联合使用的药效学作用的辅助标记物，并在I期试验的范围内确定这种新型药物组合的活性。这项试验是第一个专门针对二氢神经酰胺途径作为细胞毒性癌症治疗的人体试验。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p53的治疗方法，广泛活跃于成人和儿童恶性肿瘤。

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.