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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
Author(s) -
Maurer Barry J.,
Kang Min H.,
Villablanca Judith G.,
Janeba Jitka,
Groshen Susan,
Matthay Katherine K.,
Sondel Paul M.,
Maris John M.,
Jackson Hollie A.,
Goodarzian Fariba,
Shimada Hiroyuki,
Czarnecki Scarlett,
Hasenauer Beth,
Reynolds C. Patrick,
Marachelian Araz
Publication year - 2013
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.24643
Subject(s) - medicine , fenretinide , neuroblastoma , refractory (planetary science) , gastroenterology , pharmacokinetics , toxicity , alkaline phosphatase , urology , retinoid , retinoic acid , biochemistry , chemistry , genetics , physics , biology , astrobiology , gene , enzyme , cell culture
Background 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. Procedure 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. Results 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. Conclusions 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. Pediatr Blood Cancer 2013;60:1801–1808. © 2013 Wiley Periodicals, Inc.