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Phase I Trial of Oral Fenretinide in Children With High-Risk Solid Tumors: A Report From the Children's Oncology Group (CCG 09709)

Judith G. Villablanca, Mark D. Krailo, Matthew M. Ames, Joel M. Reid, Gregory H. Reaman, C. Patrick Reynolds

From the Children's Hospital Los Angeles and the Department Pediatrics, University of Southern California Keck School of Medicine; Developmental Therapeutics Program, University of Southern California–Children’s Hospital Los Angeles Institute for Pediatric Clinical Research, Los Angeles; Children's Oncology Group, Arcadia, CA; Mayo Clinic, Rochester, MN; and the Children's National Medical Center and Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC

Address reprint requests to Judith G. Villablanca, MD, Division of Hematology-Oncology, 4650 Sunset Blvd, MS #54, Los Angeles, CA 90027; e-mail: jvillablanca{at}chla.usc.edu; CC: pubs{at}childrensoncologygroup.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 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.

Supported by the Neil Bogart Memorial Laboratories of the T.J. Martell Foundation for Leukemia, Cancer, and AIDS Research, the Whitier Foundation via the University of Southern California Norris Comprehensive Cancer Center, and National Cancer Institute Grants No. CA81403, U10 CA13539, U01 CA57746, and U01 CA97452.

Presented at the 38th Annual Meeting of the American Society of Clinical Oncology in Orlando, FL, May 18-21, 2002.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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