Phase I trial of fenretinide delivered orally in a novel organized lipid complex in patients with relapsed/refractory neuroblastoma: a report from the New Approaches to Neuroblastoma Therapy (NANT) consortium.

A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4-HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma.
4-HPR/LXS powder (352-2,210 mg/m(2) /day) was administered on Days 0-6, in 21-day courses, by standard 3 + 3 design.
Thirty-two patients (median age = 8 years, range 3-27 years) enrolled with 30 evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), (125/131) I-MIBG (n = 13), and anti-GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m(2) /day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m(2) /day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1,700 mg/m(2) /day. Of 29 response-evaluable patients, six had stable disease (SD) (4-26 courses); four with marrow- or bone disease-only had complete responses (CR) (10-46 courses). 4-HPR plasma levels were several folds higher (P < 0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1,700 mg/m(2) /day was 21 µM. An MTD was not reached.
4-HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti-tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4-HPR/LXS powder is 1,500 mg/m(2) /day, TID, on Days 0-6, of a 21-day course.
AuthorsBarry J Maurer, Min H Kang, Judith G Villablanca, Jitka Janeba, Susan Groshen, Katherine K Matthay, Paul M Sondel, John M Maris, Hollie A Jackson, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, Beth Hasenauer, C Patrick Reynolds, Araz Marachelian
JournalPediatric blood & cancer (Pediatr Blood Cancer) Vol. 60 Issue 11 Pg. 1801-8 (Nov 2013) ISSN: 1545-5017 [Electronic] United States
PMID23813912 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Wiley Periodicals, Inc.
Chemical References
  • Antineoplastic Agents
  • Fenretinide
  • Adolescent
  • Adult
  • Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
  • Child
  • Child, Preschool
  • Female
  • Fenretinide (administration & dosage, adverse effects, pharmacokinetics)
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Neoplasm Recurrence, Local (drug therapy)
  • Neuroblastoma (drug therapy)
  • Young Adult

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