TY - JOUR
T1 - Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma
AU - Garaventa, Alberto
AU - Luksch, Roberto
AU - Lo Piccolo, Maria Serena
AU - Cavadini, Elena
AU - Montaldo, Paolo G.
AU - Pizzitola, Maria Rosa
AU - Boni, Luca
AU - Ponzoni, Mirco
AU - Decensi, Andrea
AU - De Bernardi, Bruno
AU - Bellani, Franca Fossati
AU - Formelli, Franca
PY - 2003/6/1
Y1 - 2003/6/1
N2 - 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.
AB - 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.
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M3 - Article
C2 - 12796365
AN - SCOPUS:0038176443
VL - 9
SP - 2032
EP - 2039
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 6
ER -