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

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们假设4-HPR/LXS口服粉剂将：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递送，以及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口服芬维A胺（4-HPR，NSC 374551）/LXS-Sorb（LXS）口服粉剂（4-HPR/LXS口服粉剂）的最大耐受剂量，BID，连续7天，每3周一次。 2. 确定按此方案给予4-HPR/LXS口服粉剂的毒性。 3. 确定按此方案给药的4-HPR的血浆药代动力学。 次要目标： 1. 确定在I期研究范围内复发和/或耐药神经母细胞瘤患者对4-HPR/LXS口服粉剂的反应率。 2. 测定4-HPR/LXS口服粉剂在作为肿瘤细胞替代组织的正常外周血单核细胞（PBMC）中的4-HPR水平。 背景和意义 芬维A胺（N-（4-羟基苯基）维A酰胺，4-HPR）是一种细胞毒性类维生素A，在体外以剂量相关方式对神经母细胞瘤细胞系具有活性。 当使用100 mg胶囊口服给药时，芬维A胺在1-18 μ M的血浆剂量下具有经证实的临床耐受性（NCI，IND#40294）。 然而，目前的4-HPR口服胶囊生物利用度低，在峰值和稳态血浆水平上产生广泛的患者间差异，并且难以在<4岁的患者中递送。 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的口服4-HPR粉末制剂（4-HPR/LXS口服粉末，约3wt% 4-HPR），称为LXS-X-Sorb（LXS）。4-HPR/LXS口服粉剂适用于在不含乳脂的食物中递送，特别是作为不含乳脂或基于大豆的营养补充剂（如减肥餐）中的浆液递送。

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.