Purpose: Fenretinide (4HPR), a synthetic retinoid, induces apoptosis in neuroblastoma cells. A Phase I study in children with neuroblastoma was designed to determine maximum tolerated dose, toxicity, and pharmacokinetics. Experimental Design: Fifty-four patients received oral 4HPR, once daily, for 28 days, followed by a 7-day interruption, for up to 6 courses. The starting dose was 100 mg/m2/day. At least 3 patients were entered at each escalating 4HPR dose level. Pharmacokinetic sampling was performed on days 1 and 28 of the first course. Results: Fifty-four patients, of whom 53 were evaluable, received doses between 100 and 4000 mg/m2/day for a total of 168 courses. Additional dose escalation was precluded by capsule number intake. A total of 34 of 53 evaluable patients showed manageable, reversible toxicities, which were not dose related. One dose-limiting toxicity (nyctalopia grade 3) occurred after the 1000 mg/m2/day dose. Twelve patients showed grade 2 toxicity: skin xerosis (6 cases); nyctalopia (3 cases); hepatic toxicity (1 case); diarrhea (1 case); and headache (1 case). Stable disease was observed in 41 patients for a median period of 23 months (range 2-35+). After first administration, average 4HPR peak plasma levels ranged from 0.6 to 6 μM (after 100 and 4000 mg/m2/day, respectively) and increased 2-fold (to 1.3 and 12.9 μM, respectively) after the 28-day treatment. 4HPR half-life increased from 17 h after the first administration to 25 h after the 28th administration. Incidence of grade 2-3 toxicity was 0 of 12 (0%), 7 of 22 (31%), and 4 of 8 (50%) with peak 4HPR concentrations 10 μM, respectively. After repeated treatment, retinol levels decreased from 20 to 10% of pretreatment levels after all of the doses. Conclusions: In children, 4HPR administration up to 4000 mg/m2/day over 28 days, followed by a 7-day interruption, results in manageable toxicity and in drug plasma concentrations comparable with those that induce apoptosis in neuroblastoma cell lines.
|Number of pages||8|
|Journal||Clinical Cancer Research|
|Publication status||Published - Jun 1 2003|
ASJC Scopus subject areas
- Cancer Research