Phase I trial of oral fenretinide in children with high-risk solid tumors: A report from the Children's Oncology Group (CCG 09709)

Purpose To determine the maximal tolerated dosage (MTD) of oral fenretinide given as intact capsules for 7 days, repeated every 21 days, in children with high-risk solid tumors. Methods Children 21 years of age or younger received daily doses from 350 mg/m(2) to 3,300 mg/m(2) (divided into two or three doses), with pharmacokinetics during course one. The MTD was defined as zero to one of six patients with dose-limiting toxicity (DLT), with at least two of three or two of six DLT at next higher dose. Results Fifty-four patients, age 2 years to 20 years (median, 9 years), were treated: neuroblastoma (n = 39), Ewing sarcoma (n = 5), and other (n = 10). Prior therapy included autologous stem cell transplantation (n = 42), 13-cis-RA (n = 35), and 9-cis-RA (n = 1). One of four patients at 1,050 mg/m(2) with prior liver transplant had grade 3 ALT/abdominal pain/nausea/dehydration and grade 4 AST/emesis. At 1,860 mg/m(2), one of seven patients had grade 3 hypoalbuminemia/hypophosphatemia. At 2,475 mg/m(2), one of eight patients had grade 3 alkaline phosphatase, three of five patients had DLT at 3,300 mg/m(2) grade 3 AST/ALT (n = 1), grade 4 bilrubin/grade 3 AST/ALT (n = 1), pseudotumor cerebri (n = 1). Pseudotumor cerebri also occurred at 600 mg/m(2) and 800 mg/m(2). There was one complete response and 13 patients With stable disease (SD) for 8 or more courses in 30 assessable neuroblastoma patients. SD for 8 or more courses was seen in one of five Ewing sarcoma patients and one melanoma patient. Mean N-4-hydroxyphenyl retinamide plasma level (day 7, steady-state concentration) was 9.9 mu mol/L at MTD. Conclusion The pediatric MTD of oral capsular fenretinide was 2,475 mg/m(2) per day, which achieved levels active against neuroblastoma in vitro with minimal toxicity. Response data support a phase II trial in neuroblastoma.