Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma

Alberto Garaventa, Roberto Luksch, Maria Serena Lo Piccolo, Elena Cavadini, Paolo G. Montaldo, Maria Rosa Pizzitola, Luca Boni, Mirco Ponzoni, Andrea Decensi, Bruno De Bernardi, Franca Fossati Bellani, Franca Formelli

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)2032-2039
Number of pages8
JournalClinical Cancer Research
Issue number6
Publication statusPublished - Jun 1 2003

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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