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

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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.