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

结合芬维A胺和 safingol 的 I 期试验，旨在解决 di 的过量生产

基本信息

批准号：
8291974
负责人：
CHARLES Patrick REYNOLDS
金额：
$ 31.17万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8291974
关键词：
Address Adult Behavior Biochemical Biochemistry Biological Assay Biological Availability Blood Bolus Infusion Calibration Cancer cell line Canis familiaris Cells Ceramides Cisplatin Clinical Clinical Trials Clinical Trials Design Continuous Infusion Coupled Data Doctor of Philosophy Dose Drug Combinations Drug Exposure Drug Formulations Drug Kinetics Emulsions Erythro Fenretinide Future Grant Hematopoietic Human In Situ In Vitro In complete remission Infusion procedures Intravenous Laboratories Life Lymphoma Malignant Childhood Neoplasm Malignant Neoplasms Mammalian Cell Maximum Tolerated Dose Measurement Measures Modeling Mononuclear Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Plasma Property Reactive Oxygen Species Relapse Retinoids Safingol Schedule Signal Transduction Solid Neoplasm Sphingolipids Surrogate Markers T-Cell Lymphoma Toxic effect Toxicology Variant base burden of illness cancer cell cancer therapy cytotoxic cytotoxicity dihydroceramide improved kinase inhibitor leukemia/lymphoma man neoplastic cell novel oncology phase 1 study pre-clinical programs response sphinganine sphingosine 1-phosphate sphingosine kinase tumor

项目摘要

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.

描述（由申请人提供）：一项结合静脉注射芬维A胺和 safingol 的 I 期试验，旨在靶向恶性细胞中细胞毒性二氢神经酰胺的过量产生。通过活性氧的增加和天然长链 D-赤型二氢神经酰胺的从头增加来抑制癌细胞。 Safingol 是 L-苏型二氢鞘氨醇，是二氢鞘氨醇的人工立体化学变体，二氢鞘氨醇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癌细胞系中证明，safingol 被整合到长寿命的 L-苏型二氢神经酰胺中。我们的临床前数据表明，safingol 通过以肿瘤细胞特异性方式同时增加人工 L-苏型二氢神经酰胺和天然 D-赤型二氢神经酰胺，在体外显着协同芬维A胺细胞毒性。我们假设，如果在患者肿瘤的原位中可以达到足够的药物水平，那么这种新颖的癌症特异性生物化学可能可以在人类癌症中实现。通过 NCI RAID 拨款，我们制备了适合高剂量输送的芬维A胺和 safingol 的新型静脉乳液制剂。我们对静脉注射 4-HPR 进行的 I 期成人试验表明，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，并在实体瘤中产生了额外的活性信号。我们的静脉注射 safingol 制剂的 I 期试验表明，它与顺铂联合使用具有良好的耐受性，safingol 剂量相信足以实现所需的二氢神经酰胺调节。我们以 IND 为导向的犬毒理学研究表明，静脉注射 safingol 和芬维A胺的组合具有良好的耐受性，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 safingol 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safingol与芬维A胺联合使用时的最大耐受剂量（MTD）、两种药物联合用药的药代动力学，通过测量血浆鞘脂和1-磷酸鞘氨醇获得两种药物联合用药的药效学作用的辅助标志物水平，并在 I 期试验的范围内确定这种新型药物组合的活性。该试验是首次在人类中专门针对二氢神经酰胺途径作为细胞毒性癌症治疗方法。如果成功，这种针对恶性细胞的新型生化攻击将构成一种基础广泛、不依赖于 p53 的疗法，在成人和儿童恶性肿瘤中广泛活跃。