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：
8188810
负责人：
CHARLES Patrick REYNOLDS
金额：
$ 32.37万
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 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8188810
关键词：
Address Adult Behavior Biochemical Biochemistry Biological Assay Biological Availability Blood Bolus Infusion Calibration Cancer cell line Canis familiaris Cells Ceramides Childhood 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 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. 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.

描述（由申请人提供）：一项I期试验，将静脉静脉融肾上腺素和SAFINGOL靶向恶性细胞中的细胞毒性二氢可酰胺的产生过量生产PI：Barry J. Maurer，MD Phd Abstract Fenretinide（4-HPR）是p53依赖性的细胞，对天然毒性的细胞增强了p53依赖性的细胞，从而增强了癌症的癌症，从而增强了癌症的癌细胞。 d-erthro-dihydroceramides。 Safingol是l-硫二氢磷酸化合物，这是一种人工立体化学变体，是鞘氨酸的人工立体化学变异，是哺乳动物细胞中二氢可氧酰胺的天然前体。我们已经在人类和犬类癌细胞系中显示了Safingol纳入长寿命的L-Threo-dihydrocamamides中。我们的临床前数据表明，Safingol在体外具有惊人的协同性的芬肠丁素细胞毒性，同时增加了人工L- threo-dihydrocamides和天然的D-内thro-dihydroceramides，以肿瘤细胞特异性方式。我们假设，如果在患者肿瘤的原位可以达到足够的药物水平，那么这种新颖的，癌症特异性的生物化学可能是可以在人类癌症中实现的。通过NCI RAID赠款，我们制备了芬雷丁苷和Safingol的新型静脉乳液制剂，适合于高剂量递送。我们的I期成人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细胞淋巴瘤中产生了持久的完整反应，并具有实体瘤活性的其他信号。我们静脉注射Safingol配方的I期试验表明，在Safingol剂量时与顺铂相结合，认为它足以达到所需的二氢可氧酰胺调制。我们指导的犬类毒理学研究表明，静脉注射Safingol和Fenretinide的结合良好，并且在我们的目标剂量中缺乏造血毒性。现在，我们建议在成年实体瘤和淋巴瘤中对静脉注射SAFINGOL进行I期试验，并结合静脉注射4-HPR。拟议的试验将定义静脉内safingol的最大耐受剂量（MTD）与芬雷丁胺结合使用，两种药物的药代动力学（两种药物的药代动力学）可以从测量等离子鞘脂和鞘氨醇1-磷酸化的阶段和阶段的阶段，并在阶段中，并在中层中的阶段，并在中间的阶段中获得辅助作用的辅助作用。组合。该试验是第一个专门针对二氢可胺途径作为细胞毒性癌症治疗的人。如果成功的话，这种新型的生化攻击对恶性细胞将构成一种基于p53的广泛的，独立于p53的疗法，在成人和小儿恶性肿瘤中广泛活跃。公共卫生相关性：需要对癌细胞的生化攻击以改善临床结果。提出的静脉内Safingol + fenretinide的I期研究是一种一流的药物组合，专门针对二氢可酰胺途径作为细胞毒性癌症治疗。如果成功的话，这种新颖的生物化学可能构成一种基于p53的广泛的，独立于p53的疗法，在成人和小儿恶性肿瘤中都广泛活跃，并满足了主要的未满足需求。