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

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们假设 4-HPR/LXS 口服粉末将：1）允许对当前 NCI 4-HPR 胶囊不耐受的患者给药，2）产生更一致且可能更高的 4-HPR 血浆水平，从而增加向肿瘤细胞的药物输送，3）促进基于芬维A胺的药物组合的测试。 具体目标 1. 确定复发性和/或耐药性神经母细胞瘤患者每三周连续 7 天口服 BID 芬维A胺 (4-HPR，NSC 374551) Lym-X-Sorb (LXS) 口服粉剂（4-HPR/LXS 口服粉剂）的最大耐受剂量。 2. 确定本表中4-HPR/LXS口服粉剂的毒性。 3. 测定按此方案给药的 4-HPR 的血浆药代动力学。 次要目标： 1. 确定 I 期研究范围内复发性和/或耐药性神经母细胞瘤患者对 4-HPR/LXS 口服粉剂的反应率。 2. 测定作为肿瘤细胞替代组织的正常外周血单核细胞（PBMC）中以 4-HPR/LXS 口服粉末形式递送的 4-HPR 水平。 一、背景及意义 Fenretinide (N-(4-羟苯基)视黄酰胺，4-HPR) 是一种细胞毒性类维生素A，在体外以剂量相关的方式具有对抗神经母细胞瘤细胞系的活性。 当使用 100 mg 胶囊口服给药时，芬维A胺在血浆剂量为 1-18 uM 时具有经过验证的临床耐受性（NCI，IND#40294）。 然而，目前的 4-HPR 口服胶囊生物利用度较低，峰值和稳态血浆水平存在较大的患者间差异，并且难以在 4 岁以下的患者中给药。 因此，4-HPR 药代动力学和肿瘤反应可能受益于改进的递送制剂。 为了提高4-HPR的抗肿瘤活性，基于脂质基质技术制备了一种新型口服4-HPR粉末制剂（4-HPR/LXS口服粉末，-3重量％4-HPR），称为Lym-X-Sorb（LXS）。 4-HPR/LXS口服粉剂适合在不含乳脂的食品中输送，特别是作为不含乳脂或大豆基营养补充剂（例如瘦身快餐）中的浆料。