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

JG Villablanca, MD Krailo, MM Ames… - Journal of clinical …, 2006 - ascopubs.org
JG Villablanca, MD Krailo, MM Ames, JM Reid, GH Reaman, CP Reynolds
Journal of clinical oncology, 2006ascopubs.org
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/m2 to 3,300
mg/m2 (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 …
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/m2 to 3,300 mg/m2 (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/m2 with prior liver transplant had grade 3 ALT/abdominal pain/nausea/dehydration and grade 4 AST/emesis. At 1,860 mg/m2, one of seven patients had grade 3 hypoalbuminemia/hypophosphatemia. At 2,475 mg/m2, one of eight patients had grade 3 alkaline phosphatase; three of five patients had DLT at 3,300 mg/m2: grade 3 AST/ALT (n = 1), grade 4 bilirubin/grade 3 AST/ALT (n = 1), pseudotumor cerebri (n = 1). Pseudotumor cerebri also occurred at 600 mg/m2 and 800 mg/m2. 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 μmol/L at MTD.
Conclusion
The pediatric MTD of oral capsular fenretinide was 2,475 mg/m2 per day, which achieved levels active against neuroblastoma in vitro with minimal toxicity. Response data support a phase II trial in neuroblastoma.
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