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, Patrick C. Reynolds

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3423-3430
Number of pages8
JournalJournal of Clinical Oncology
Volume24
Issue number21
DOIs
StatePublished - Jul 20 2006

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Fenretinide
Neoplasms
Neuroblastoma
Pseudotumor Cerebri
Ewing's Sarcoma
Hypophosphatemia
Hypoalbuminemia
Stem Cell Transplantation
Dehydration
Bilirubin
Nausea
Abdominal Pain
Capsules
Vomiting
Alkaline Phosphatase
Melanoma
Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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

In: Journal of Clinical Oncology, Vol. 24, No. 21, 20.07.2006, p. 3423-3430.

Research output: Contribution to journalArticle

Villablanca, Judith G. ; Krailo, Mark D. ; Ames, Matthew M. ; Reid, Joel M ; Reaman, Gregory H. ; Reynolds, Patrick C. / Phase I trial of oral fenretinide in children with high-risk solid tumors : A report from the children's oncology group (CCG 09709). In: Journal of Clinical Oncology. 2006 ; Vol. 24, No. 21. pp. 3423-3430.
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abstract = "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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T2 - A report from the children's oncology group (CCG 09709)

AU - Villablanca, Judith G.

AU - Krailo, Mark D.

AU - Ames, Matthew M.

AU - Reid, Joel M

AU - Reaman, Gregory H.

AU - Reynolds, Patrick C.

PY - 2006/7/20

Y1 - 2006/7/20

N2 - 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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