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Clinical Trials |
Department of Pediatric Hematology/Oncology [A. G., M. S. L. P., M. R. P., B. D. B.] and Oncology Laboratory [P. G. M., M. P.], G. Gaslini Children’s Hospital, Genova; Department of Experimental Oncology [E. C., F. F.] and Operative Unit of Pediatrics [R. L., F. F. B.], Istituto Nazionale Tumori, Milan; and Epidemiology and Clinical Trials Unit [L. B.], National Institute for Cancer Research, Genova and Division of Cancer Prevention [A. D.], European Institute of Oncology, Milan, Italy
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 <3 µM, 3–10 µM, and >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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