CLINICAL TRIAL: NANT 2004-04: PHASE I STUDY OF FENRETINIDE (4-HPR, NSC 374551)

临床试验：NANT 2004-04：芬维A胺 I 期研究（4-HPR，NSC 374551）

• 批准号: 7950616
• 负责人: HEIDI V RUSSELL
• 金额: $ 0.06万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950616
• 关键词: 4 year old; Biological Availability; Cell Line; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Dose; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Fatty acid glycerol esters; Fenretinide; Food; Funding; Grant; In Vitro; Institution; Lipids; Milk; Neuroblastoma; Oral; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase I Clinical Trials; Plasma; Powder dose form; Recurrence; Research; Research Personnel; Resistance; Resources; Retinoids; Schedule; Source; Technology; Testing; Tissues; Toxic effect; United States National Institutes of Health; Weight; base; capsule; cytotoxic; dietary supplements; improved; neoplastic cell; novel; response; soy; tumor; 4 year old; Biological Availability; Cell Line; Clinical Research; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Dose; Drug Combinations; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Fatty acid glycerol esters; Fenretinide; Food; Funding; Grant; In Vitro; Institution; Lipids; Milk; Neuroblastoma; Oral; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase I Clinical Trials; Plasma; Powder dose form; Recurrence; Research; Research Personnel; Resistance; Resources; Retinoids; Schedule; Source; Technology; Testing; Tissues; Toxic effect; United States National Institutes of Health; Weight; base; capsule; cytotoxic; dietary supplements; improved; neoplastic cell; novel; response; soy; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We hypothesize that 4-HPR/LXS oral powder will: 1) allow drug administration to patients intolerant of the current NCI 4-HPR capsule, 2) produce more consistent, and possibly higher, 4-HPR plasma levels resulting in increased drug delivery to tumor cells, and 3) facilitate the testing of fenretinide-based drug combinations. SPECIFIC AIMS 1. To determine the maximun tolerated dose of Fenretinide (4-HPR, NSC 374551) Lym-X-Sorb (LXS) Oral Powder (4-HPR/LXS oral powder) given orally, BID, for seven consecutive days every three weeks, in patients with recurrent and/or resistant neuroblastoma. 2. To define the toxicities of 4-HPR/LXS oral powder given on this schedule. 3. To determine the plasma pharmacokinetics of 4-HPR given on this schedule. Secondary Aims: 1. To determine the response rate to 4-HPR/LXS oral powder in patients with recurrent and/or resistant neuroblastoma within teh confines of a Phase I study. 2. To determine the level of 4-HPR delivered as 4-HPR/LXS oral powder in normal peripheral blood mononuclear cells (PBMC) as a tumor cell surrogate tissue. BACKGROUND AND SIGNIFICANCE Fenretinide (N-(4-hydroxyphenyl)retinamide, 4-HPR), is a cytotoxic retinoid that has activity against neuroblastoma cell lines in vitro in a dose-related manner. Fenretinide has provenclinical tolerability at plasma doses of 1-18 uM when given orally using a 100 mg capsule (NCI, IND#40294). However, the current 4-HPR oral capsule has low bioavailability, produces wide interpatient variability in peak and steady-state plasma levels, and is difficult to deliver in patients <4 years of age. Thus, 4-HPR pharmacokinetics and tumor response may benefit from an improved formulation of delivery. In an attempt to improve the antitumor activity of 4-HPR, a novel oral 4-HPR powder formulation (4-HPR/LXS oral powder, -3% by weight 4-HPR) has beenprepared based on a lipid matrix technology, called Lym-X-Sorb (LXS). 4-HPR/LXS oral powder is suitable for delivery in non-milk fat-containing foods, and especially as a slurry in non-milk fat-containing, or soy-based nutritional supplements, such as Slim-Fast Meal.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 我们假设4-HPR/LXS口服粉末将：1）允许对当前NCI 4-HPR胶囊不耐受的患者进行药物给药，2）产生更一致的，可能更高的，可能更高的4-HPR血浆水平，从而导致药物递送到肿瘤细胞，3）促进基于Fenretinide的药物组合的测试。 具体目标 1。为了确定fenretinide（4-HPR，NSC 374551）的最大耐受剂量，在患有复发性和/或/或/或/或抗药性神经细胞瘤的患者中，每三周连续七个星期连续七个星期，口服七个星期，bid连续七天给出口服的lym-X-sorb（LXS）口服粉末（4-HPR/LXS口服粉末）。 2。定义在此时间表下给出的4-HPR/LXS口服粉末的毒性。 3。确定该时间表中给出的4-HPR的血浆药代动力学。 次要目的： 1。确定在I期研究的TEH范围内复发和/或抗性神经母细胞瘤患者中对4-HPR/LXS口服粉末的反应率。 2。确定在正常外周血单核细胞（PBMC）中作为肿瘤细胞替代组织中的4-HPR/LXS口服粉末的4-HPR水平。 背景和意义 fenretinide（N-（4-羟基苯基）视网膜化酰胺，4-HPR）是一种细胞毒性类视丁素，在剂量相关的方式中具有对神经母细胞瘤细胞系的活性。 使用100 mg胶囊口服时，芬雷丁胺的血浆剂量为1-18 um（NCI，IND＃40294）时具有前伦敦的耐受性。 但是，当前的4-H​​PR口腔胶囊具有较低的生物利用度，在峰值和稳态血浆水平上产生较大的室内变异性，并且在<4岁的患者中很难递送。 因此，4-HPR药代动力学和肿瘤反应可能受益于改善的递送配方。 为了改善4-HPR的抗肿瘤活性，一种新型的口服4-HPR粉末配方（4-HPR/LXS口服粉末，重量为4-HPR）已根据脂质基质技术（称为Lym-X-SORB（LXS））进行了准备。 4-HPR/LXS口腔粉适用于非乳脂脂肪的食物中，尤其是作为非乳脂脂肪或基于大豆的营养补充剂的浆液，例如纤细的餐。