FENRETINIDE (4-HPR, NSC 374551) LYM-X-SORBO(LXS) ORAL POWDER IN NEUROBLASTOMA

这个子项目是许多研究子项目中的一个 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来源获得主要资金， 因此可以在其他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。 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胺已被证明在1 - 18 M的血浆剂量下具有临床耐受性（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型口服4-HPR粉末制剂（4-HPR/LXS口服粉末，约3%重量4-HPR），称为LXS（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。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。在本研究中，仿照目前在复发性/耐药性神经母细胞瘤中进行的COG II期口服4-HPR胶囊研究（ANBL 0321），患者将接受4-HPR/LXS口服粉末，BID x 7天，每三周一次。 主要研究目的是确定4-HPR/LXS口服粉剂的最大耐受剂量（MTD）和毒性特征，以及4-HPR在复发性/难治性神经母细胞瘤儿科患者中以4-HPR/LXS口服粉剂给药时的药代动力学。 次要研究目的是评估4-HPR/LXS口服粉剂中4-HPR在外周血单核细胞中的生物利用度。 在第二个疗程第6天上午给予4-HPR/LXS口服粉剂后6小时，测定外周血单核细胞（PBMC）中4-HPR及其代谢物4-MPR的水平。

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. 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 proven clinical tolerability at plasma doses of 1 - 18 M 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 yrs 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 been prepared 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. 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. In the present study, modeled after the current COG Phase II oral 4-HPR capsule study in recurrent/resistant neuroblastoma (ANBL0321), patients will receive 4-HPR/LXS oral powder, BID x 7 days, every three weeks. PRIMARY STUDY AIMS are to define the maximally tolerated dose (MTD) and toxicity profile of 4-HPR/LXS oral powder, and the pharmacokinetics of 4-HPR when given in 4-HPR/LXS oral powder, in pediatric patients with relapsed/refractory neuroblastoma. SECONDARY STUDY AIMS are to assess the bioavailability of 4-HPR in 4-HPR/LXS oral powder in peripheral blood mononuclear cells. Levels of 4-HPR, and its metabolite, 4-MPR, will be determined in peripheral blood mononuclear cells (PBMC) six hours after the AM dose of 4-HPR/LXS oral powder on Day 6 of the Second Course.