CLINICAL TRIAL: LXS ORAL POWDER IN PATIENTS WITH RECURRENT OR RESISTANT NEUROBLA

临床试验：LXS 口服散剂治疗复发性或耐药性神经胶质细胞瘤患者

• 批准号: 7717905
• 负责人: CLARE J TWIST
• 金额: $ 0.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7717905
• 关键词: Age-Years; Biological Availability; Cell Line; Childhood; Clinical; 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; Hour; In Vitro; Institution; Lipids; Maximum Tolerated Dose; Milk; N-(4-methoxyphenyl)retinamide; Neuroblastoma; Oral; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Plasma; Powder dose form; Recurrence; Refractory; Relapse; Research; Research Personnel; Resistance; Resources; Retinoids; Source; Study models; Technology; Testing; Toxic effect; United States National Institutes of Health; Week; Weight; base; capsule; cytotoxic; day; 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. 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 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 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.

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。 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胺已被证明在血浆剂量为 1 - 18 µM 时具有临床耐受性（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，约 3% 重量的 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。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。在本研究中，以当前针对复发/耐药神经母细胞瘤的 COG II 期口服 4-HPR 胶囊研究 (ANBL0321) 为模型，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 口服粉末的最大耐受剂量 (MTD) 和毒性特征，以及在复发/难治性神经母细胞瘤儿科患者中以 4-HPR/LXS 口服粉末给药时 4-HPR 的药代动力学。 二次研究的目的是评估 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，AM 剂量 4-HPR/LXS 口服粉末后 6 小时，将测定外周血单核细胞 (PBMC) 中的 4-HPR 及其代谢物 4-MPR 的水平。