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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 芬维甲素(N-(4-羟基苯基)维甲酰胺，4-HPR)是一种细胞毒性维甲酸类化合物，在体外对神经母细胞瘤细胞株具有一定的抑制作用，且呈剂量依赖关系。Fenretinide已被证明在口服100 mg胶囊时的血浆剂量为1-18M时的临床耐受性(NCI，IND#40294)。然而，目前的4-HPR口服胶囊生物利用度低，峰值和稳态血药浓度在患者之间产生很大的变异性，并且难以在4岁的患者中使用。因此，4-HPR的药代动力学和肿瘤反应可能受益于改进的给药方案。为了提高4-HPR的抗肿瘤活性，基于LYM-X-Sorb(LXS)脂质骨架技术，制备了一种新的4-HPR口服粉剂(4-HPR/LXS口服粉，4-HPR重量约为3%)。4-HPR/LXS口服粉适用于不含牛奶脂肪的食品，尤其是不含牛奶脂肪或大豆为基础的营养补充剂的浆料，如减肥快餐。我们假设，4-HPR/LXS口服粉将：1)允许对目前的NCI 4-HPR胶囊不耐受的患者给药；2)产生更稳定的、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)促进基于非维甲酸的药物组合的测试。在目前的COG II期口服4-HPR胶囊治疗复发/耐药神经母细胞瘤研究(ANBL0321)的基础上，患者将接受4-HPR/LXS口服粉，每天2次，共7天，每3周进行一次。 初步研究目的是确定4-HPR/LXS口服粉在儿童复发/难治性神经母细胞瘤患者中的最大耐受量(MTD)和毒性分布，以及4-HPR/LXS口服粉中4-HPR的药代动力学。二是评价4-HPR/LXS口服粉中4-HPR在外周血单核细胞中的生物利用度。在第二个疗程的第6天，在AM剂量4-HPR/LXS口服粉6小时后，测定外周血单个核细胞(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.